From Vampire to Apollo: William Blake's Ghosts of the Flea (c. 1819-20)

Varley’s Zodiacal Physiognomy and Blake’s Visionary Heads are the two mainstays of a project which involved séance-like meetings at Varley’s house. While the lights were still on, Varley’s guests would have listened to the stories about the flea. With The Ghost of a Flea in front of them, the recitals of the flea’s pompous speeches, combined with the fact that it was just a ghost who leered after human blood, Varley’s guests may have laughed very heartily, if not in front of him then behind his back. Each evening followed the same protocol. When the lights were off, Varley would call out a name and Blake would look around, suddenly exclaiming ‘There he is!’ and start drawing. The flea is the most striking of the Visionary Heads, though it is not the only head which exists in different versions. If appearance is elemental to any kind of judgement of one human being of another, then Blake deliberately confused Varley. By working up the sketch, he played on Varley’s expectations; he presented him with an extraordinary and very puzzling painting, The Ghost of a Flea. But why, if Blake could have chosen any monster, did he settle on the ghost of a flea

Applying spatial reasoning to topographical data with a grounded geographical ontology

Grounding an ontology upon geographical data has been pro- posed as a method of handling the vagueness in the domain more effectively. In order to do this, we require methods of reasoning about the spatial relations between the regions within the data. This stage can be computationally expensive, as we require information on the location of points in relation to each other. This paper illustrates how using knowledge about regions allows us to reduce the computation required in an efficient and easy to understand manner. Further, we show how this system can be implemented in co-ordination with segmented data to reason abou

Phylogenomic exploration of the relationships between strains of Mycobacterium avium subspecies paratuberculosis.

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (Map) is an infectious enteric pathogen that causes Johne's disease in livestock. Determining genetic diversity is prerequisite to understanding the epidemiology and biology of Map. We performed the first whole genome sequencing (WGS) of 141 global Map isolates that encompass the main molecular strain types currently reported. We investigated the phylogeny of the Map strains, the diversity of the genome and the limitations of commonly used genotyping methods. RESULTS: Single nucleotide polymorphism (SNP) and phylogenetic analyses confirmed two major lineages concordant with the former Type S and Type C designations. The Type I and Type III strain groups are subtypes of Type S, and Type B strains are a subtype of Type C and not restricted to Bison species. We found that the genome-wide SNPs detected provided greater resolution between isolates than currently employed genotyping methods. Furthermore, the SNP used for IS1311 typing is not informative, as it is likely to have occurred after Type S and C strains diverged and does not assign all strains to the correct lineage. Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) differentiates Type S from Type C but provides limited resolution between isolates within these lineages and the polymorphisms detected do not necessarily accurately reflect the phylogenetic relationships between strains. WGS of passaged strains and coalescent analysis of the collection revealed a very high level of genetic stability, with the substitution rate estimated to be less than 0.5 SNPs per genome per year. CONCLUSIONS: This study clarifies the phylogenetic relationships between the previously described Map strain groups, and highlights the limitations of current genotyping techniques. Map isolates exhibit restricted genetic diversity and a substitution rate consistent with a monomorphic pathogen. WGS provides the ultimate level of resolution for differentiation between strains. However, WGS alone will not be sufficient for tracing and tracking Map infections, yet importantly it can provide a phylogenetic context for affirming epidemiological connections

Ability of SP12 mutant of S. typhi to effectively induce antibody responses to the mucosal antigen enterotoxigenic E. coli heat labile toxin B subunit after oral delivery to humans

We have evaluated an oral vaccine based on an Salmonella enteric serovar typhi (S. typhi) Ty2 derivative TSB7 harboring deletion mutations in ssaV (SPI-2) and aroC together with a chromosomally integrated copy of eltB encoding the B subunit of enterotoxigenic Escherichia coli heat labile toxin (LT-B) in volunteers. Two oral doses of 108 or 109 CFU were administered to two groups of volunteers and both doses were well tolerated, with no vaccinemia, and only transient stool shedding. Immune responses to LT-B and S. typhi lipopolysaccharide were demonstrated in 67 and 97% of subjects, respectively, without evidence of anti-carrier immunity preventing boosting of LT-B responses in many cases. Further development of this salmonella-based (spi-VEC) system for oral delivery of heterologous antigens appears warranted

BIO-WELL: The development and validation of a human wellbeing scale that measures responses to biodiversity

The evidence linking nature and human wellbeing is compelling. Yet, there is a lack of understanding regarding which aspects of nature contribute to wellbeing and the role biodiversity plays specifically. This knowledge gap hampers our ability to understand and manage natural environments from an ecological perspective to improve human wellbeing. To investigate the impact of biodiversity on wellbeing in a range of contexts, there is a need for a psychometric scale. Here, we present BIO-WELL, a novel, reliable and validated self-reported wellbeing scale designed to investigate the biodiversity-health/wellbeing relationship. We describe the conceptual foundation, empirical development and psychometric evaluation of BIO-WELL. We detail five studies, involving 2962 participants, describing the steps taken in the scale's development: (1) a series of deliberative workshops to identify how people conceptualise biodiversity metrics and attributes, and the impact these have on wellbeing; (2) an in-depth qualitative analysis of biodiversity-focused stem questions and wellbeing response items, assessed through an expert panel, focus groups and cognitive interviewing techniques; (3) combined methods associated with classical test theory (e.g. factor analysis) and more modern measurement approaches drawn from item response theory to develop the scale; (4) a confirmatory factor analysis alongside classical test and item response theories to evaluate the scale; and (5) scale validation including discriminant/convergent, concurrent and predictive. The studies demonstrate that BIO-WELL is a valid and reliable scale with strong psychometric properties. We discuss ways it could be applied in research, policy and practice to further develop our conceptual and empirical understanding of the biodiversity-health relationship and assess the effectiveness of related interventions

Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation

Significance The Fe(II)- and 2-oxoglutarate (2OG)-dependent hypoxia-inducible transcription factor prolyl-hydroxylases play a central role in human oxygen sensing and are related to other prolyl-hydroxylases involved in eukaryotic collagen biosynthesis and ribosomal modification. The finding that a PHD-related prolyl-hydroxylase in Pseudomonas spp. regulates pyocyanin biosynthesis supports prokaryotic origins for the eukaryotic prolyl-hydroxylases. The identification of the switch I loop of elongation factor Tu (EF-Tu) as a Pseudomonas prolyl-hydroxylase domain containing protein (PPHD) substrate provides evidence of roles for 2OG oxygenases in both translational and transcriptional regulation. A structure of the PPHD:EF-Tu complex, the first to the authors' knowledge of a 2OG oxygenase with its intact protein substrate, reveals that major conformational changes occur in both PPHD and EF-Tu and will be useful in the design of new prolyl-hydroxylase inhibitors. </jats:p

Occurence and Bioactivities of Funicone-Related Compounds

Studies on production of secondary metabolites by fungi have received a substantial boost lately, particularly with reference to applications of their biological properties in human medicine. Funicones represent a series of related compounds for which there is accumulating evidence supporting their possible use as pharmaceuticals. This paper provides a review on the current status of knowledge on these fungal extrolites, with special reference to aspects concerning their molecular structures and biological activities

Histone Deacetylases Regulate Gonadotropin-Releasing Hormone I Gene Expression via Modulating Otx2-Driven Transcriptional Activity

BACKGROUND: Precise coordination of the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. As a central regulator, the appropriate synthesis and secretion of gonadotropin-releasing hormone I (GnRH-I) from the hypothalamus is essential for the coordination. Recently, emerging evidence indicates that histone deacetylases (HDACs) play an important role in maintaining normal reproductive function. In this study, we identify the potential effects of HDACs on Gnrh1 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Inhibition of HDACs activities by trichostatin A (TSA) and valproic acid (VPA) promptly and dramatically repressed transcription of Gnrh1 gene in the mouse immortalized mature GnRH neuronal cells GT1-7. The suppression was connected with a specific region of Gnrh1 gene promoter, which contains two consensus Otx2 binding sites. Otx2 has been known to activate the basal and also enhancer-driven transcription of Gnrh1 gene. The transcriptional activity of Otx2 is negatively modulated by Grg4, a member of the Groucho-related-gene (Grg) family. In the present study, the expression of Otx2 was downregulated by TSA and VPA in GT1-7 cells, accompanied with the opposite changes of Grg4 expression. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the DNA-binding activity of Otx2 to Gnrh1 gene was suppressed by TSA and VPA. Overexpression of Otx2 partly abolished the TSA- and VPA-induced downregulation of Gnrh1 gene expression. CONCLUSIONS/SIGNIFICANCE: Our data indicate that HDAC inhibitors downregulate Gnrh1 gene expression via repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases

Carotenoid-Based Colours Reflect the Stress Response in the Common Lizard

Under chronic stress, carotenoid-based colouration has often been shown to fade. However, the ecological and physiological mechanisms that govern colouration still remain largely unknown. Colour changes may be directly induced by the stressor (for example through reduced carotenoid intake) or due to the activation of the physiological stress response (PSR, e.g. due to increased blood corticosterone concentrations). Here, we tested whether blood corticosterone concentration affected carotenoid-based colouration, and whether a trade-off between colouration and PSR existed. Using the common lizard (Lacerta vivipara), we correlatively and experimentally showed that elevated blood corticosterone levels are associated with increased redness of the lizard's belly. In this study, the effects of corticosterone did not depend on carotenoid ingestion, indicating the absence of a trade-off between colouration and PSR for carotenoids. While carotenoid ingestion increased blood carotenoid concentration, colouration was not modified. This suggests that carotenoid-based colouration of common lizards is not severely limited by dietary carotenoid intake. Together with earlier studies, these findings suggest that the common lizard's carotenoid-based colouration may be a composite trait, consisting of fixed (e.g. genetic) and environmentally elements, the latter reflecting the lizard's PSR

The Characterization of Twenty Sequenced Human Genomes

We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten “case” genomes from individuals with severe hemophilia A and ten “control” genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways