MicroRNA Biomarkers for Infectious Diseases: From Basic Research to Biosensing

In the pursuit of improved diagnostic tests for infectious diseases, several classes of molecules have been scrutinized as prospective biomarkers. Small (18–22 nucleotide), non-coding RNA transcripts called microRNAs (miRNAs) have emerged as promising candidates with extensive diagnostic potential, due to their role in numerous diseases, previously established methods for quantitation and their stability within biofluids. Despite efforts to identify, characterize and apply miRNA signatures as diagnostic markers in a range of non-infectious diseases, their application in infectious disease has advanced relatively slowly. Here, we outline the benefits that miRNA biomarkers offer to the diagnosis, management, and treatment of infectious diseases. Investigation of these novel biomarkers could advance the use of personalized medicine in infectious disease treatment, which raises important considerations for validating their use as diagnostic or prognostic markers. Finally, we discuss new and emerging miRNA detection platforms, with a focus on rapid, point-of-care testing, to evaluate the benefits and obstacles of miRNA biomarkers for infectious disease

New invasive Nemertean species (Cephalothrix Simula) in England with high levels of tetrodotoxin and a microbiome linked to toxin metabolism

The marine nemertean Cephalothrix simula originates from the Pacific Ocean but in recent years has been discovered in northern Europe. The species has been associated with high levels of the marine neurotoxin Tetrodotoxin, traditionally associated with Pufferfish Poisoning. This study reports the first discovery of two organisms of C. simula in the UK, showing the geographical extent of this species is wider than originally described. Species identification was initially conducted morphologically, with confirmation by Cox 1 DNA sequencing. 16S gene sequencing enabled the taxonomic assignment of the microbiome, showing the prevalence of a large number of bacterial genera previously associated with TTX production including Alteromonas, Vibrio and Pseudomonas. LC-MS/MS analysis of the nemertean tissue revealed the presence of multiple analogues of TTX, dominated by the parent TTX, with a total toxin concentration quantified at 54 µg TTX per g of tissue. Pseudomonas luteola isolated from C. simula, together with Vibrio alginolyticus from the native nemertean Tubulanus annulatus, were cultured at low temperature and both found to contain TTX. Overall, this paper confirms the high toxicity of a newly discovered invasive nemertean species with links to toxin-producing marine bacteria and the potential risk to human safety. Further work is required to assess the geographical extent and toxicity range of C. simula along the UK coast in order to properly gauge the potential impacts on the environment and human safety

Stochastic Inflation Revisited: Non-Slow Roll Statistics and DBI Inflation

Stochastic inflation describes the global structure of the inflationary universe by modeling the super-Hubble dynamics as a system of matter fields coupled to gravity where the sub-Hubble field fluctuations induce a stochastic force into the equations of motion. The super-Hubble dynamics are ultralocal, allowing us to neglect spatial derivatives and treat each Hubble patch as a separate universe. This provides a natural framework in which to discuss probabilities on the space of solutions and initial conditions. In this article we derive an evolution equation for this probability for an arbitrary class of matter systems, including DBI and k-inflationary models, and discover equilibrium solutions that satisfy detailed balance. Our results are more general than those derived assuming slow roll or a quasi-de Sitter geometry, and so are directly applicable to models that do not satisfy the usual slow roll conditions. We discuss in general terms the conditions for eternal inflation to set in, and we give explicit numerical solutions of highly stochastic, quasi-stationary trajectories in the relativistic DBI regime. Finally, we show that the probability for stochastic/thermal tunneling can be significantly enhanced relative to the Hawking-Moss instanton result due to relativistic DBI effects.Comment: 38 pages, 2 figures. v3: minor revisions; version accepted into JCA

Cosmological expansion on a dilatonic brane-world

In this paper we study brane-world scenarios with a bulk scalar field, using a covariant formalism to obtain a 4D Einstein equation via projection onto the brane. We discuss, in detail, the effects of the bulk on the brane and how the scalar field contribute to the gravitational effects. We also discuss choice of conformal frame and show that the frame selected by the induced metric provides a natural choice. We demonstrate our formalism by applying it to cosmological scenarios of Randall-Sundrum and Horava-Witten type models. Finally we consider the cosmology of models where the scalar field couples non-minimally to the matter on the brane. This gives rise to a novel scenario where the universe expands from a finite scale factor with an initial period of accelerated expansion, thus avoiding the singularity and flatness problem of the standard big bang model.Comment: 20 pages - Version to appear in Classical and Quantum Gravity. New section added on conformal rescaling of the metric. Some other minor changes made and references adde

ADAMTS5 is a critical regulator of virus-specific T cell immunity

The extracellular matrix (ECM) provides physical scaffolding for cellular constituents and initiates biochemical and biomechanical cues that are required for physiological activity of living tissues. The ECM enzyme ADAMTS5, a member of the ADAMTS (A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs) protein family, cleaves large proteoglycans such as aggrecan, leading to the destruction of cartilage and osteoarthritis. However, its contribution to viral pathogenesis and immunity is currently undefined. Here, we use a combination of in vitro and in vivo models to show that ADAMTS5 enzymatic activity plays a key role in the development of influenza-specific immunity. Influenza virus infection of Adamts5-/- mice resulted in delayed virus clearance, compromised T cell migration and immunity and accumulation of versican, an ADAMTS5 proteoglycan substrate. Our research emphasises the importance of ADAMTS5 expression in the control of influenza virus infection and highlights the potential for development of ADAMTS5-based therapeutic strategies to reduce morbidity and mortality

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age-associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow-up

The Drivers of Pathology in Zoonotic Avian Influenza: The Interplay Between Host and Pathogen

The emergence of zoonotic strains of avian influenza (AI) that cause high rates of mortality in people has caused significant global concern, with a looming threat that one of these strains may develop sustained human-to-human transmission and cause a pandemic outbreak. Most notable of these viral strains are the H5N1 highly pathogenic AI and the H7N9 low pathogenicity AI viruses, both of which have mortality rates above 30%. Understanding of their mechanisms of infection and pathobiology is key to our preparation for these and future viral strains of high consequence. AI viruses typically circulate in wild bird populations, commonly infecting waterfowl and also regularly entering commercial poultry flocks. Live poultry markets provide an ideal environment for the spread AI and potentially the selection of mutants with a greater propensity for infecting humans because of the potential for spill over from birds to humans. Pathology from these AI virus infections is associated with a dysregulated immune response, which is characterized by systemic spread of the virus, lymphopenia, and hypercytokinemia. It has been well documented that host/pathogen interactions, particularly molecules of the immune system, play a significant role in both disease susceptibility as well as disease outcome. Here, we review the immune/virus interactions in both avian and mammalian species, and provide an overview or our understanding of how immune dysregulation is driven. Understanding these susceptibility factors is critical for the development of new vaccines and therapeutics to combat the next pandemic influenza

Qatar-2: A K dwarf orbited by a transiting hot Jupiter and a more massive companion in an outer orbit

We report the discovery and initial characterization of Qatar-2b, a hot Jupiter transiting a V = 13.3 mag K dwarf in a circular orbit with a short period, P_ b = 1.34 days. The mass and radius of Qatar-2b are M_p = 2.49 M_j and R_p = 1.14 R_j, respectively. Radial-velocity monitoring of Qatar-2 over a span of 153 days revealed the presence of a second companion in an outer orbit. The Systemic Console yielded plausible orbits for the outer companion, with periods on the order of a year and a companion mass of at least several M_j. Thus Qatar-2 joins the short but growing list of systems with a transiting hot Jupiter and an outer companion with a much longer period. This system architecture is in sharp contrast to that found by Kepler for multi-transiting systems, which are dominated by objects smaller than Neptune, usually with tightly spaced orbits that must be nearly coplanar