Human viruses: discovery and emergence

There are 219 virus species that are known to be able to infect humans. The first of these to be discovered was yellow fever virus in 1901, and three to four new species are still being found every year. Extrapolation of the discovery curve suggests that there is still a substantial pool of undiscovered human virus species, although an apparent slow-down in the rate of discovery of species from different families may indicate bounds to the potential range of diversity. More than two-thirds of human viruses can also infect non-human hosts, mainly mammals, and sometimes birds. Many specialist human viruses also have mammalian or avian origins. Indeed, a substantial proportion of mammalian viruses may be capable of crossing the species barrier into humans, although only around half of these are capable of being transmitted by humans and around half again of transmitting well enough to cause major outbreaks. A few possible predictors of species jumps can be identified, including the use of phylogenetically conserved cell receptors. It seems almost inevitable that new human viruses will continue to emerge, mainly from other mammals and birds, for the foreseeable future. For this reason, an effective global surveillance system for novel viruses is needed.     

Rarity and genetic diversity in Indo-Pacific Acropora corals

Among various potential consequences of rarity is genetic erosion. Neutral genetic theory predicts that rare species will have lower genetic diversity than common species. To examine the association between genetic diversity and rarity, variation at eight DNA microsatellite markers was documented for 14 Acropora species that display different patterns of distribution and abundance in the Indo-Pacific Ocean. Our results show that the relationship between rarity and genetic diversity is not a positive linear association because, contrary to expectations, some rare species are genetically diverse and some populations of common species are genetically depleted. Our data suggest that inbreeding is the most likely mechanism of genetic depletion in both rare and common corals, and that hybridization is the most likely explanation for higher than expected levels of genetic diversity in rare species. A significant hypothesis generated from our study with direct conservation implications is that as a group, Acropora corals have lower genetic diversity at neutral microsatellite loci than may be expected from their taxonomic diversity, and this may suggest a heightened susceptibility to environmental change. This hypothesis requires validation based on genetic diversity estimates derived from a large portion of the genome.     

Phylogenetic analysis of four nuclear protein-encoding genes largely corroborates the traditional classification of Bivalvia (Mollusca)

Revived interest in molluscan phylogeny has resulted in a torrent of molecular sequence data from phylogenetic, mitogenomic, and phylogenomic studies. Despite recent progress, basal relationships of the class Bivalvia remain contentious, owing to conflicting morphological and molecular hypotheses. Marked incongruity of phylogenetic signal in datasets heavily represented by nuclear ribosomal genes versus mitochondrial genes has also impeded consensus on the type of molecular data best suited for investigating bivalve relationships. To arbitrate conflicting phylogenetic hypotheses, we evaluated the utility of four nuclear protein-encoding genes-ATP synthase β, elongation factor-1α, myosin heavy chain type II, and RNA polymerase II-for resolving the basal relationships of Bivalvia. We sampled all five major lineages of bivalves (Archiheterodonta, Euheterodonta [including Anomalodesmata], Palaeoheterodonta, Protobranchia, and Pteriomorphia) and inferred relationships using maximum likelihood and Bayesian approaches. To investigate the robustness of the phylogenetic signal embedded in the data, we implemented additional datasets wherein length variability and/or third codon positions were eliminated. Results obtained include (a) the clade (Nuculanida+Opponobranchia), i.e., the traditionally defined Protobranchia; (b) the monophyly of Pteriomorphia; (c) the clade (Archiheterodonta+Palaeoheterodonta); (d) the monophyly of the traditionally defined Euheterodonta (including Anomalodesmata); and (e) the monophyly of Heteroconchia, i.e., (Palaeoheterodonta+Archiheterodonta+Euheterodonta). The stability of the basal tree topology to dataset manipulation is indicative of signal robustness in these four genes. The inferred tree topology corresponds closely to those obtained by datasets dominated by nuclear ribosomal genes (18S rRNA and 28S rRNA), controverting recent taxonomic actions based solely upon mitochondrial gene phylogenies.     

"There are too many, but never enough": qualitative case study investigating routine coding of clinical information in depression

Background

We sought to understand how clinical information relating to the management of depression is routinely coded in different clinical settings and the perspectives of and implications for different stakeholders with a view to understanding how these may be aligned.

Materials and Methods

Qualitative investigation exploring the views of a purposefully selected range of healthcare professionals, managers, and clinical coders spanning primary and secondary care.

Results

Our dataset comprised 28 semi-structured interviews, a focus group, documents relating to clinical coding standards and participant observation of clinical coding activities. We identified a range of approaches to coding clinical information including templates and order entry systems. The challenges inherent in clearly establishing a diagnosis, identifying appropriate clinical codes and possible implications of diagnoses for patients were particularly prominent in primary care. Although a range of managerial and research benefits were identified, there were no direct benefits from coded clinical data for patients or professionals. Secondary care staff emphasized the role of clinical coders in ensuring data quality, which was at odds with the policy drive to increase real-time clinical coding.

Conclusions

There was overall no evidence of clear-cut direct patient care benefits to inform immediate care decisions, even in primary care where data on patients with depression were more extensively coded. A number of important secondary uses were recognized by healthcare staff, but the coding of clinical data to serve these ends was often poorly aligned with clinical practice and patient-centered considerations. The current international drive to encourage clinical coding by healthcare professionals during the clinical encounter may need to be critically examined.     

Household factors influencing participation in bird feeding activity: a national scale analysis

Ameliorating pressures on the ecological condition of the wider landscape outside of protected areas is a key focus of conservation initiatives in the developed world. In highly urbanized nations, domestic gardens can play a significant role in maintaining biodiversity and facilitating human-wildlife interactions, which benefit personal and societal health and well-being. The extent to which sociodemographic and socioeconomic factors are associated with engagement in wildlife gardening activities remain largely unresolved. Using two household-level survey datasets gathered from across Britain, we determine whether and how the socioeconomic background of a household influences participation in food provision for wild birds, the most popular and widespread form of human-wildlife interaction. A majority of households feed birds (64% across rural and urban areas in England, and 53% within five British study cities). House type, household size and the age of the head of the household were all important predictors of bird feeding, whereas gross annual household income, the occupation of the head of the household, and whether the house is owned or rented were not. In both surveys, the prevalence of bird feeding rose as house type became more detached and as the age of the head of the household increased. A clear, consistent pattern between households of varying size was less evident. When regularity of food provision was examined in the study cities, just 29% of households provided food at least once a week. The proportion of households regularly feeding birds was positively related to the age of the head of the household, but declined with gross annual income. As concerns grow about the lack of engagement between people and the natural environment, such findings are important if conservation organizations are successfully to promote public participation in wildlife gardening specifically and environmentally beneficial behaviour in society more generally.     

Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model

Background

Repeated adaptive radiations are evident when phenotypic divergence occurs within lineages, but this divergence into different forms is convergent when compared across lineages. Classic examples of such repeated adaptive divergence occur in island (for example, Caribbean Anolis lizards) and lake systems (for example, African cichlids). Host-parasite systems in many respects are analogous to island systems, where host species represent isolated islands for parasites whose life cycle is highly tied to that of their hosts. Thus, host-parasite systems might exhibit interesting cases of repeated adaptive divergence as seen in island and lake systems. The feather lice of birds spend their entire life cycle on the body of the host and occupy distinct microhabitats on the host: head, wing, body and generalist. These microhabitat specialists show pronounced morphological differences corresponding to how they escape from host preening. We tested whether these different microhabitat specialists were a case of repeated adaptive divergence by constructing both morphological and molecular phylogenies for a diversity of avian feather lice, including many examples of head, wing, body and generalist forms.

Results

Morphological and molecular based phylogenies were highly incongruent, which could be explained by rampant convergence in morphology related to microhabitat specialization on the host. In many cases lice from different microhabitat specializations, but from the same group of birds, were sister taxa.

Conclusions

This pattern indicates a process of repeated adaptive divergence of these parasites within host group, but convergence when comparing parasites across host groups. These results suggest that host-parasite systems might be another case in which repeated adaptive radiations could be relatively common, but potentially overlooked, because morphological convergence can obscure evolutionary relationships.     

Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4⁺ T cells but not in cynomolgus T lymphocytes. The sustained Ca⁺⁺-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells.     

Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema

Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model of retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema.     

A novel streptococcal integrative conjugative element involved in iron acquisition

In this study, we determined the function of a novel non-ribosomal peptide synthetase (NRPS) system carried by a streptococcal integrative conjugative element (ICE), ICESe2. The NRPS shares similarity with the yersiniabactin system found in the high-pathogenicity island of Yersinia sp. and is the first of its kind to be identified in streptococci. We named the NRPS product 'equibactin' and genes of this locus eqbA-N. ICESe2, although absolutely conserved in Streptococcus equi, the causative agent of equine strangles, was absent from all strains of the closely related opportunistic pathogen Streptococcus zooepidemicus. Binding of EqbA, a DtxR-like regulator, to the eqbB promoter was increased in the presence of cations. Deletion of eqbA resulted in a small-colony phenotype. Further deletion of the irp2 homologue eqbE, or the genes eqbH, eqbI and eqbJ encoding a putative ABC transporter, or addition of the iron chelator nitrilotriacetate, reversed this phenotype, implicating iron toxicity. Quantification of (55)Fe accumulation and sensitivity to streptonigrin suggested that equibactin is secreted by S. equi and that the eqbH, eqbI and eqbJ genes are required for its associated iron import. In agreement with a structure-based model of equibactin synthesis, supplementation of chemically defined media with salicylate was required for equibactin production.