Brown-York Energy and Radial Geodesics

We compare the Brown-York (BY) and the standard Misner-Sharp (MS) quasilocal energies for round spheres in spherically symmetric space-times from the point of view of radial geodesics. In particular, we show that the relation between the BY and MS energies is precisely analogous to that between the (relativistic) energy E of a geodesic and the effective (Newtonian) energy E_{eff} appearing in the geodesic equation, thus shedding some light on the relation between the two. Moreover, for Schwarzschild-like metrics we establish a general relationship between the BY energy and the geodesic effective potential which explains and generalises the recently observed connection between negative BY energy and the repulsive behaviour of geodesics in the Reissner-Nordstrom metric. We also comment on the extension of this connection between geodesics and the quasilocal BY energy to regions inside a horizon.Comment: v3: 7 pages, shortened and revised version to appear in CQ

T- and B-cell responses to multivalent prime-boost DNA and viral vectored vaccine combinations against hepatitis C virus in non-human primates.

Immune responses against multiple epitopes are required for the prevention of hepatitis C virus (HCV) infection, and the progression to phase I trials of candidates may be guided by comparative immunogenicity studies in non-human primates. Four vectors, DNA, SFV, human serotype 5 adenovirus (HuAd5) and Modified Vaccinia Ankara (MVA) poxvirus, all expressing hepatitis C virus Core, E1, E2 and NS3, were combined in three prime-boost regimen, and their ability to elicit immune responses against HCV antigens in rhesus macaques was explored and compared. All combinations induced specific T-cell immune responses, including high IFN-γ production. The group immunized with the SFV+MVA regimen elicited higher E2-specific responses as compared with the two other modalities, while animals receiving HuAd5 injections elicited lower IL-4 responses as compared with those receiving MVA. The IFN-γ responses to NS3 were remarkably similar between groups. Only the adenovirus induced envelope-specific antibody responses, but these failed to show neutralizing activity. Therefore, the two novel regimens failed to induce superior responses as compared with already existing HCV vaccine candidates. Differences were found in response to envelope proteins, but the relevance of these remain uncertain given the surprisingly poor correlation with immunogenicity data in chimpanzees, underlining the difficulty to predict efficacy from immunology studies.This work was supported by European Union contract QLK2-CT-1999- 00356, by the Biomedical Primate Research Centre, The Netherlands, and by the Swedish Research Council. We are grateful to Alexander van den Berg for technical assistance with the ICS, to our colleagues from Animal Science Department for technical assistance and expert care of the macaques, to the participants of the European HCVacc Cluster who provided help and support, and to Thomas Darton (Oxford Vaccine Group, UK) for input and advice on the manuscript. Christine Rollier is an Oxford Martin fellow and a Jenner Insitute Investigator.This is the author accepted manuscript. The final version is available from Nature Publishing Group at https://doi.org/10.1038/gt.2016.55

Clearance of Genotype 1b Hepatitis C Virus in Chimpanzees in the Presence of Vaccine-Induced E1-Neutralizing Antibodies

Accumulating evidence indicates that neutralizing antibodies play an important role in protection from chronic hepatitis C virus (HCV) infection. Efforts to elicit such responses by immunization with intact heterodimeric E1E2 envelope proteins have met with limited success. To determine whether antigenic sites, which are not exposed by the combined E1E2 heterodimer structure, are capable of eliciting neutralizing antibody responses, we expressed and purified each as separate recombinant proteins E1 and E2, from which the immunodominant hypervariable region (HVR-1) was deleted. Immunization of chimpanzees with either E1 or E2 alone induced antigen-specific T-helper cytokines of similar magnitude. Unexpectedly, the capacity to neutralize HCV was observed in E1 but not in animals immunized with E2 devoid of HVR-1. Furthermore, in vivo only E1-vaccinated animals exposed to the heterologous HCV-1b inoculum cleared HCV infection

Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection

Indoleamine 2,3-dioxygenase (IDO) is induced by proinflammatory cytokines and by CTLA-4-expressing T cells and constitutes an important mediator of peripheral immune tolerance. In chronic hepatitis C, we found upregulation of IDO expression in the liver and an increased serum kynurenine/tryptophan ratio (a reflection of IDO activity). Huh7 cells supporting hepatitis C virus (HCV) replication expressed higher levels of IDO mRNA than noninfected cells when stimulated with gamma interferon or when cocultured with activated T cells. In infected chimpanzees, hepatic IDO expression decreased in animals that cured the infection, while it remained high in those that progressed to chronicity. For both patients and chimpanzees, hepatic expression of IDO and CTLA-4 correlated directly. Induction of IDO may dampen T-cell reactivity to viral antigens in chronic HCV infectio

Geometry of Schroedinger Space-Times, Global Coordinates, and Harmonic Trapping

We study various geometrical aspects of Schroedinger space-times with dynamical exponent z>1 and compare them with the properties of AdS (z=1). The Schroedinger metrics are singular for 1<z<2 while the usual Poincare coordinates are incomplete for z \geq 2. For z=2 we obtain a global coordinate system and we explain the relations among its geodesic completeness, the choice of global time, and the harmonic trapping of non-relativistic CFTs. For z>2, we show that the Schroedinger space-times admit no global timelike Killing vectors.Comment: 15 pages, v2: some comments and references adde

Modulation of vaccine-induced immune responses to hepatitis C virus in rhesus macaques by altering priming before adenovirus boosting

BACKGROUND: Preventive and therapeutic vaccine strategies aimed at controlling hepatitis C virus (HCV) infection should mimic the immune responses observed in patients who control or clear HCV, specifically T helper (Th) type 1 and CD8+ cell responses to multiple antigens, including nonstructural protein (NS) 3. Given the experience with human immunodeficiency virus, the best candidates for this are based on DNA prime, pox, or adenovirus boost regimens. METHODS: In rhesus macaques, we compared NS3-expressing DNA prime and adenovirus boost strategy with 2 alternative priming approaches aimed at modifying Th1 and CD8+ responses: DNA adjuvanted with interleukin (IL)-2- and -12-encoding plasmids or Semliki Forest virus (SFV). RESULTS: All prime-boost regimens elicited NS3-specific B and T cell responses in rhesus macaques, including CD8+ responses. SFV priming induced higher lymphoproliferation and longer Th1 memory responses. The use of IL-2- and IL-12-expressing vectors resulted in reduced Th2 and antibody responses, which led to increased Th1 skewing but not to an increase in the magnitude of the IFN- gamma and CD8+ responses. CONCLUSIONS: All strategies induced Th1 cellular responses to HCV NS3, with fine modulations depending on the different priming approaches. When they are developed for more HCV antigens, these strategies could be beneficial in therapeutic vaccine approaches

Schr\"odinger Manifolds

This article propounds, in the wake of influential work of Fefferman and Graham about Poincar\'e extensions of conformal structures, a definition of a (Poincar\'e-)Schr\"odinger manifold whose boundary is endowed with a conformal Bargmann structure above a non-relativistic Newton-Cartan spacetime. Examples of such manifolds are worked out in terms of homogeneous spaces of the Schr\"odinger group in any spatial dimension, and their global topology is carefully analyzed. These archetypes of Schr\"odinger manifolds carry a Lorentz structure together with a preferred null Killing vector field; they are shown to admit the Schr\"odinger group as their maximal group of isometries. The relationship to similar objects arising in the non-relativisitc AdS/CFT correspondence is discussed and clarified.Comment: 42 pages, 1 figure, published version: J. Phys. A: Math. Theor. 45 (2012) 395203 (24pp