Utilisation of chimeric lyssaviruses to assess vaccine protection against highly divergent lyssaviruses

Lyssaviruses constitute a diverse range of viruses with the ability to cause fatal encephalitis known as rabies. Existing human rabies vaccines and post exposure prophylaxes (PEP) are based on inactivated preparations of, and neutralising antibody preparations directed against, classical rabies viruses, respectively. Whilst these prophylaxes are highly efficient at neutralising and preventing a productive infection with rabies virus, their ability to neutralise other lyssaviruses is thought to be limited. The remaining 15 virus species within the lyssavirus genus have been divided into at least three phylogroups that generally predict vaccine protection. Existing rabies vaccines afford protection against phylogroup I viruses but offer little to no protection against phylogroup II and III viruses. As such, work involving sharps with phylogroup II and III must be considered of high risk as no PEP is thought to have any effect on the prevention of a productive infection with these lyssaviruses. Whilst rabies virus itself has been characterised in a number of different animal models, data on the remaining lyssaviruses are scarce. As the lyssavirus glycoprotein is considered to be the sole target of neutralising antibodies we generated a vaccine strain of rabies using reverse genetics expressing highly divergent glycoproteins of West Caucasian Bat lyssavirus and Ikoma lyssavirus. Using these recombinants, we propose that recombinant vaccine strain derived lyssaviruses containing heterologous glycoproteins may be a suitable surrogate for wildtype viruses when assessing vaccine protection for the lyssaviruses

Detection of prions in the faeces of sheep naturally infected with classical scrapie

Classical scrapie is a naturally transmitted prion disease of sheep and goats. Contaminated environments may contribute to the spread of disease and evidence from animal models has implicated urine, blood, saliva, placenta and faeces as possible sources of the infection. Here we sought to determine whether sheep naturally infected with classical scrapie shed prions in their faeces. We used serial protein misfolding cyclic amplification (sPMCA) along with two extraction methods to examine faeces from sheep during both the clinical and preclinical phases of the disease and showed amplification of PrPSc in 7 of 15 and 14 of 14 sheep respectively. However PrPSc was not amplified from the faeces of 25 sheep not exposed to scrapie. These data represent the first demonstration of prion shedding in faeces from a naturally infected host and thus a likely source of prion contamination in the environment

Energy-momentum/Cotton tensor duality for AdS4 black holes

We consider the theory of gravitational quasi-normal modes for general linear perturbations of AdS4 black holes. Special emphasis is placed on the effective Schrodinger problems for axial and polar perturbations that realize supersymmetric partner potential barriers on the half-line. Using the holographic renormalization method, we compute the energy-momentum tensor for perturbations satisfying arbitrary boundary conditions at spatial infinity and discuss some aspects of the problem in the hydrodynamic representation. It is also observed in this general framework that the energy-momentum tensor of black hole perturbations and the energy momentum tensor of the gravitational Chern-Simons action (known as Cotton tensor) exhibit an axial-polar duality with respect to appropriately chosen supersymmetric partner boundary conditions on the effective Schrodinger wave-functions. This correspondence applies to perturbations of very large AdS4 black holes with shear viscosity to entropy density ratio equal to 1/4\pi, thus providing a dual graviton description of their hydrodynamic modes. We also entertain the idea that the purely dissipative modes of black hole hydrodynamics may admit Ricci flow description in the non-linear regime.Comment: 38 pages; minor typos corrected, a few extra references and a note adde

Deconstructing holographic liquids

We argue that there exist simple effective field theories describing the long-distance dynamics of holographic liquids. The degrees of freedom responsible for the transport of charge and energy-momentum are Goldstone modes. These modes are coupled to a strongly coupled infrared sector through emergent gauge and gravitational fields. The IR degrees of freedom are described holographically by the near-horizon part of the metric, while the Goldstone bosons are described by a field-theoretical Lagrangian. In the cases where the holographic dual involves a black hole, this picture allows for a direct connection between the holographic prescription where currents live on the boundary, and the membrane paradigm where currents live on the horizon. The zero-temperature sound mode in the D3-D7 system is also re-analyzed and re-interpreted within this formalism.Comment: 21 pages, 2 figure

Epstein-Barr Virus Infection Is Common in Inflamed Gastrointestinal Mucosa

Epstein-Barr virus (EBV) is present in the malignant epithelial cells of 10% of all gastric adenocarcinomas, however localization of the virus in normal gastrointestinal mucosa is largely unexplored. In the current study, we measured EBV DNA and localized viral gene products in gastritis specimens (n=89), normal gastric and colonic mucosa (n=14), Crohn’s disease (n=9), and ulcerative colitis (n=11) tissues

High levels of Epstein–Barr virus DNA in latently infected gastric adenocarcinoma

Gastric adenocarcinoma is the second leading cause of cancer death worldwide. Epstein-Barr virus (EBV) is present in the malignant cells of approximately 10% of cases. It is unclear whether EBV is being missed in some gastric adenocarcinomas due to insensitive test methods or partial EBV genome loss. In the current study, we screened 113 gastric adenocarcinomas from low and high incidence regions (United States and Central America) for the presence of EBV using a battery quantitative real-time PCR (Q-PCR) assays targeting disparate segments of the EBV genome (BamH1W, EBNA1, LMP1, LMP2, BZLF1, EBER1) and histochemical stains targeting EBV-encoded RNA (EBER), the latent proteins LMP1 and LMP2, and the lytic proteins BMRF1 and BZLF1. EBV DNA was detected by Q-PCR in 48/75 United States cancers (64%) and in 38/38 Central American cancers (100%), which was a significant differrence. EBER was localized to malignant epithelial cells in 8/48 (17%) United States and 3/38 (8%) Central American cancers. Viral loads were considerably higher for EBER-positive versus EBER-negative cancers (mean 162,986 versus 62 EBV DNA copies per 100,000 cells). A viral load of 2,000 copies per 100,000 cells is recommended as the threshold distinguishing EBER-positive from EBER-negative tumors. One infected cancer selectively failed to amplify the LMP2 gene because of a point mutation, while another cancer had an atypical pattern of Q-PCR positivity suggesting deletion of large segments of the EBV genome. Three different viral latency profiles were observed in the cancers based on constant expression of EBER and focal or variable expression of LMP1 or LMP2, without lytic protein expression. We conclude that EBV DNA levels generally reflect EBER status, and a panel of at least two Q-PCR assays is recommended for sensitive identification of infected cancers

A Six-Gene Signature Predicts Survival of Patients with Localized Pancreatic Ductal Adenocarcinoma

Jen Jen Yeh and colleagues developed and validated a six-gene signature in patients with pancreatic ductal adenocarcinoma that may be used to better stage the disease in these patients and assist in treatment decisions

Performance of Three-Biomarker Immunohistochemistry for Intrinsic Breast Cancer Subtyping in the AMBER Consortium

Classification of breast cancer into intrinsic subtypes has clinical and epidemiologic importance. To examine accuracy of immunohistochemistry (IHC)-based methods for identifying intrinsic subtypes, a three-biomarker IHC panel was compared to the clinical record and RNA-based intrinsic (PAM50) subtypes

Generalized Modules for Membrane Antigens (GMMA), an outer membrane vesicle-based vaccine platform, for efficient viral antigen delivery.

Vaccine platforms enable fast development, testing, and manufacture of more affordable vaccines. Here, we evaluated Generalized Modules for Membrane Antigens (GMMA), outer membrane vesicles (OMVs) generated by genetically modified Gram-negative bacteria, as a vaccine platform for viral pathogens. Influenza A virus hemagglutinin (HA), either physically mixed with GMMA (HA+STmGMMA mix), or covalently linked to GMMA surface (HA-STmGMMA conjugate), significantly increased antigen-specific humoral and cellular responses, with HA-STmGMMA conjugate inducing further enhancement than HA+STmGMMA mix. HA-STmGMMA conjugate protected mice from lethal challenge. The versatility for this platform was confirmed by conjugation of rabies glycoprotein (RABVG) onto GMMA through the same method. RABVG+STmGMMA mix and RABVG-STmGMMA conjugate exhibited similar humoral and cellular response patterns and protection efficacy as the HA formulations, indicating relatively consistent responses for different vaccines based on the GMMA platform. Comparing to soluble protein, GMMA was more efficiently taken up in vivo and exhibited a B-cell preferential uptake in the draining lymph nodes (LNs). Together, GMMA enhances immunity against viral antigens, and the platform works well with different antigens while retaining similar immunomodulatory patterns. The findings of our study imply the great potential of GMMA-based vaccine platform also against viral infectious diseases

Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer

Breast cancer metastasis remains a clinical challenge, even within a single patient across multiple sites of the disease. Genome-wide comparisons of both the DNA and gene expression of primary tumors and metastases in multiple patients could help elucidate the underlying mechanisms that cause breast cancer metastasis. To address this issue, we performed DNA exome and RNA sequencing of matched primary tumors and multiple metastases from 16 patients, totaling 83 distinct specimens. We identified tumor-specific drivers by integrating known protein-protein network information with RNA expression and somatic DNA alterations and found that genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases