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

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

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

<b>Objective</b> <i>ABCB1</i> encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).<p></p> <b>Methods</b> The best candidates from fine-mapping analysis of 21 <i>ABCB1</i> SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either ‘standard’ first-line paclitaxel–carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.<p></p> <b>Result</b> Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77–1.01; p = 0.07). In contrast, <i>ABCB1</i> expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.<p></p> <b>Conclusion</b> Our study represents the largest analysis of <i>ABCB1</i> SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.<p></p&gt

CMBPol Mission Concept Study: Probing Inflation with CMB Polarization

We summarize the utility of precise cosmic microwave background (CMB) polarization measurements as probes of the physics of inflation. We focus on the prospects for using CMB measurements to differentiate various inflationary mechanisms. In particular, a detection of primordial B-mode polarization would demonstrate that inflation occurred at a very high energy scale, and that the inflaton traversed a super-Planckian distance in field space. We explain how such a detection or constraint would illuminate aspects of physics at the Planck scale. Moreover, CMB measurements can constrain the scale-dependence and non-Gaussianity of the primordial fluctuations and limit the possibility of a significant isocurvature contribution. Each such limit provides crucial information on the underlying inflationary dynamics. Finally, we quantify these considerations by presenting forecasts for the sensitivities of a future satellite experiment to the inflationary parameters.Comment: 107 pages, 14 figures, 17 tables; Inflation Working Group contribution to the CMBPol Mission Concept Study; v2: typos fixed and references adde

Immunostimulatory Motifs Enhance Antiviral siRNAs Targeting Highly Pathogenic Avian Influenza H5N1

Highly pathogenic avian influenza (HPAI) H5N1 virus is endemic in many regions around the world and remains a significant pandemic threat. To date H5N1 has claimed almost 300 human lives worldwide, with a mortality rate of 60% and has caused the death or culling of hundreds of millions of poultry since its initial outbreak in 1997. We have designed multi-functional RNA interference (RNAi)-based therapeutics targeting H5N1 that degrade viral mRNA via the RNAi pathway while at the same time augmenting the host antiviral response by inducing host type I interferon (IFN) production. Moreover, we have identified two factors critical for maximising the immunostimulatory properties of short interfering (si)RNAs in chicken cells (i) mode of synthesis and (ii) nucleoside sequence to augment the response to virus. The 5-bp nucleoside sequence 5′-UGUGU-3′ is a key determinant in inducing high levels of expression of IFN -α, -β, -λ and interleukin 1- β in chicken cells. Positioning of this 5′-UGUGU-3′ motif at the 5′- end of the sense strand of siRNAs, but not the 3′- end, resulted in a rapid and enhanced induction of type I IFN. An anti-H5N1 avian influenza siRNA directed against the PB1 gene (PB1-2257) tagged with 5′-UGUGU-3′ induced type I IFN earlier and to a greater extent compared to a non-tagged PB1-2257. Tested against H5N1 in vitro, the tagged PB1-2257 was more effective than non-tagged PB1-2257. These data demonstrate the ability of an immunostimulatory motif to improve the performance of an RNAi-based antiviral, a finding that may influence the design of future RNAi-based anti-influenza therapeutics

Fostering appropriate behaviour in rehabilitant orangutans (Pongo pygmaeus)

Rehabilitation centres in Indonesia and Malaysia accommodate displaced orangutans (Pongo pygmaeus and P. abelii) and aim to facilitate their release into the wild by developing in them the skills that are necessary for survival. Regular forest excursions are provided but their efficacy in improving learning of appropriate behaviours is unknown. We observed forty rehabilitating orangutans from the Orangutan Care and Quarantine Centre during three forest excursions each to determine whether their behaviour fostered the development of survival skills. In total 38% of their time was spent in locomotion, particularly quadrupedal arboreal travel (13%), walking (8%), climbing (7%) and vine-swinging (4%). 26.5% of their time was spent 5 m or more from the ground, at heights up to 25 m. Arboreal activities were more 2 common early in the excursions and interaction with c are-givers more common later (hour 1: 0.3% of time; hour 5: 0.9% of time). Animals of lower body weight were significantly more likely to engage in arboreal movement, locomotion in general, eating of bark and leaves, and social play, and less likely to eat insects. Those that had been at the Centre the longest were less likely to perform arboreal activities and significantly more likely to be found standing and at ground level, than those that were there for a shorter time. During this study, many forest food items were consumed, particularly leaves and fruit, but also invertebrates and bark. Little time was spent in sexual behaviour, tool use, nest building or socially-mediated learning, but social play occupied almost 6% of their time. We conclude that regular excursions into the forest are likely to assist in the development of locomotion and feeding skills for survival in rehabilitating orangutans, but special attention is needed to encourage nest building, social activities and arboreal activity. Animals least likely to benefit are heavy animals and those that have been captive for a long time