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

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

Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis

Purpose Purpose Regulatory T cells (Tregs) have been implicated in the pathogenesis of several autoimmune disorders and used in adoptive cell transfer therapies. Neither have been explored in patients with autoimmune encephalitis where treated patient outcomes remain suboptimal with frequent relapses. Here, to identify new treatment strategies for autoimmune encephalitis, we sought to evaluate the proportion of circulating Tregs and Treg subpopulations in peripheral blood of patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis (NMDAR-Ab-E) and compared this with healthy controls. Methods We compared the phenotype of peripheral blood Tregs in four adult NMDAR-Ab-E patients and four age- and sex-matched healthy controls using an 11-color flow cytometry assay panel for characterization of Tregs (CD4+ CD25+ FoxP3+) cells into naïve (chemokine receptor [CCR] 7+ CD45RA+), central memory (CCR7+ CD45RA–), and effector memory (CCR7– CD45RA–) cells. We also examined and compared the expression of the CCR6 by circulating Tregs and the respective Treg subpopulations between the study groups. Results The proportion of circulating Tregs was similar between patients with NMDAR-Ab-E and healthy controls but the proportion of naïve Tregs was lower in NMDAR-Ab-E patients (p = 0.0026). Additionally, the frequency of circulating effector memory Tregs was higher, and the proportion of circulating effector memory Tregs expressing CCR6 was lower, in NMDAR-Ab-E patients compared with healthy controls (p = 0.0026). Conclusion Altered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings

MRI Based Localisation and Quantification of Abscesses following Experimental S. aureus Intravenous Challenge: Application to Vaccine Evaluation.

PURPOSE: To develop and validate a sensitive and specific method of abscess enumeration and quantification in a preclinical model of Staphylococcus aureus infection. METHODS: S. aureus infected murine kidneys were fixed in paraformaldehyde, impregnated with gadolinium, and embedded in agar blocks, which were subjected to 3D magnetic resonance microscopy on a 9.4T MRI scanner. Image analysis techniques were developed, which could identify and quantify abscesses. The result of this imaging was compared with histological examination. The impact of a S. aureus Sortase A vaccination regime was assessed using the technique. RESULTS: Up to 32 murine kidneys could be imaged in a single MRI run, yielding images with voxels of about 25 μm3. S. aureus abscesses could be readily identified in blinded analyses of the kidneys after 3 days of infection, with low inter-observer variability. Comparison with histological sections shows a striking correlation between the two techniques: all presumptive abscesses identified by MRI were confirmed histologically, and histology identified no abscesses not evident on MRI. In view of this, simulations were performed assuming that both MRI reconstruction, and histology examining all sections of the tissue, were fully sensitive and specific at abscess detection. This simulation showed that MRI provided more sensitive and precise estimates of abscess numbers and volume than histology, unless at least 5 histological sections are taken through the long axis of the kidney. We used the MRI technique described to investigate the impact of a S. aureus Sortase A vaccine. CONCLUSION: Post mortem MRI scanning of large batches of fixed organs has application in the preclinical assessment of S. aureus vaccines

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

Pre-Clinical Evaluation of a Replication-Competent Recombinant Adenovirus Serotype 4 Vaccine Expressing Influenza H5 Hemagglutinin

Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4) vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA) gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn). Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis.The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus.Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine

Boundary stress-energy tensor and Newton-Cartan geometry in Lifshitz holography

For a specific action supporting z = 2 Lifshitz geometries we identify the Lifshitz UV completion by solving for the most general solution near the Lifshitz boundary. We identify all the sources as leading components of bulk fields which requires a vielbein formalism. This includes two linear combinations of the bulk gauge field and timelike vielbein where one asymptotes to the boundary timelike vielbein and the other to the boundary gauge field. The geometry induced from the bulk onto the boundary is a novel extension of Newton-Cartan geometry that we call torsional Newton-Cartan (TNC) geometry. There is a constraint on the sources but its pairing with a Ward identity allows one to reduce the variation of the on-shell action to unconstrained sources. We compute all the vevs along with their Ward identities and derive conditions for the boundary theory to admit conserved currents obtained by contracting the boundary stress-energy tensor with a TNC analogue of a conformal Killing vector. We also obtain the anisotropic Weyl anomaly that takes the form of a Hořava-Lifshitz action defined on a TNC geometry. The Fefferman-Graham expansion contains a free function that does not appear in the variation of the on-shell action. We show that this is related to an irrelevant deformation that selects between two different UV completions