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

Holographic Renormalization for z=2 Lifshitz Space-Times from AdS

Lifshitz space-times with critical exponent z=2 can be obtained by dimensional reduction of Schroedinger space-times with critical exponent z=0. The latter space-times are asymptotically AdS solutions of AdS gravity coupled to an axion-dilaton system and can be uplifted to solutions of type IIB supergravity. This basic observation is used to perform holographic renormalization for 4-dimensional asymptotically z=2 locally Lifshitz space-times by Scherk-Schwarz dimensional reduction of the corresponding problem of holographic renormalization for 5-dimensional asymptotically locally AdS space-times coupled to an axion-dilaton system. We can thus define and characterize a 4-dimensional asymptotically locally z=2 Lifshitz space-time in terms of 5-dimensional AdS boundary data. In this setup the 4-dimensional structure of the Fefferman-Graham expansion and the structure of the counterterm action, including the scale anomaly, will be discussed. We find that for asymptotically locally z=2 Lifshitz space-times obtained in this way there are two anomalies each with their own associated nonzero central charge. Both anomalies follow from the Scherk--Schwarz dimensional reduction of the 5-dimensional conformal anomaly of AdS gravity coupled to an axion-dilaton system. Together they make up an action that is of the Horava-Lifshitz type with nonzero potential term for z=2 conformal gravity.Comment: 32 pages, v2: modified discussion of the central charge

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

Geometry of Schroedinger Space-Times II: Particle and Field Probes of the Causal Structure

We continue our study of the global properties of the z=2 Schroedinger space-time. In particular, we provide a codimension 2 isometric embedding which naturally gives rise to the previously introduced global coordinates. Furthermore, we study the causal structure by probing the space-time with point particles as well as with scalar fields. We show that, even though there is no global time function in the technical sense (Schroedinger space-time being non-distinguishing), the time coordinate of the global Schroedinger coordinate system is, in a precise way, the closest one can get to having such a time function. In spite of this and the corresponding strongly Galilean and almost pathological causal structure of this space-time, it is nevertheless possible to define a Hilbert space of normalisable scalar modes with a well-defined time-evolution. We also discuss how the Galilean causal structure is reflected and encoded in the scalar Wightman functions and the bulk-to-bulk propagator.Comment: 32 page

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

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

Heterologous Replacement of the Supposed Host Determining Region of Avihepadnaviruses: High In Vivo Infectivity Despite Low Infectivity for Hepatocytes

Hepadnaviruses, including hepatitis B virus (HBV), a highly relevant human pathogen, are small enveloped DNA viruses that replicate via reverse transcription. All hepadnaviruses display a narrow tissue and host tropism. For HBV, this restricts efficient experimental in vivo infection to chimpanzees. While the cellular factors mediating infection are largely unknown, the large viral envelope protein (L) plays a pivotal role for infectivity. Furthermore, certain segments of the PreS domain of L from duck HBV (DHBV) enhanced infectivity for cultured duck hepatocytes of pseudotyped heron HBV (HHBV), a virus unable to infect ducks in vivo. This implied a crucial role for the PreS sequence from amino acid 22 to 90 in the duck tropism of DHBV. Reasoning that reciprocal replacements would reduce infectivity for ducks, we generated spreading-competent chimeric DHBVs with L proteins in which segments 22–90 (Du-He4) or its subsegments 22–37 and 37–90 (Du-He2, Du-He3) are derived from HHBV. Infectivity for duck hepatocytes of Du-He4 and Du-He3, though not Du-He2, was indeed clearly reduced compared to wild-type DHBV. Surprisingly, however, in ducks even Du-He4 caused high-titered, persistent, horizontally and vertically transmissable infections, with kinetics of viral spread similar to those of DHBV when inoculated at doses of 108 viral genome equivalents (vge) per animal. Low-dose infections down to 300 vge per duck did not reveal a significant reduction in specific infectivity of the chimera. Hence, sequence alterations in PreS that limited infectivity in vitro did not do so in vivo. These data reveal a much more complex correlation between PreS sequence and host specificity than might have been anticipated; more generally, they question the value of cultured hepatocytes for reliably predicting in vivo infectivity of avian and, by inference, mammalian hepadnaviruses, with potential implications for the risk assessment of vaccine and drug resistant HBV variants