Development of a New Vaccine for the Prevention of Lassa Fever

BACKGROUND: Recent importation of Lassa fever into Germany, the Netherlands, the United Kingdom, and the United States by travelers on commercial airlines from Africa underscores the public health challenge of emerging viruses. Currently, there are no licensed vaccines for Lassa fever, and no experimental vaccine has completely protected nonhuman primates against a lethal challenge. METHODS AND FINDINGS: We developed a replication-competent vaccine against Lassa virus based on attenuated recombinant vesicular stomatitis virus vectors expressing the Lassa viral glycoprotein. A single intramuscular vaccination of the Lassa vaccine elicited a protective immune response in nonhuman primates against a lethal Lassa virus challenge. Vaccine shedding was not detected in the monkeys, and none of the animals developed fever or other symptoms of illness associated with vaccination. The Lassa vaccine induced strong humoral and cellular immune responses in the four vaccinated and challenged monkeys. Despite a transient Lassa viremia in vaccinated animals 7 d after challenge, the vaccinated animals showed no evidence of clinical disease. In contrast, the two control animals developed severe symptoms including rashes, facial edema, and elevated liver enzymes, and ultimately succumbed to the Lassa infection. CONCLUSION: Our data suggest that the Lassa vaccine candidate based on recombinant vesicular stomatitis virus is safe and highly efficacious in a relevant animal model that faithfully reproduces human disease

The expanding functional roles and signaling mechanisms of adhesion G protein–coupled receptors

The adhesion class of G protein–coupled receptors (GPCRs) is the second largest family of GPCRs (33 members in humans). Adhesion GPCRs (aGPCRs) are defined by a large extracellular N‐terminal region that is linked to a C‐terminal seven transmembrane (7TM) domain via a GPCR‐autoproteolysis inducing (GAIN) domain containing a GPCR proteolytic site (GPS). Most aGPCRs undergo autoproteolysis at the GPS motif, but the cleaved fragments stay closely associated, with the N‐terminal fragment (NTF) bound to the 7TM of the C‐terminal fragment (CTF). The NTFs of most aGPCRs contain domains known to be involved in cell–cell adhesion, while the CTFs are involved in classical G protein signaling, as well as other intracellular signaling. In this workshop report, we review the most recent findings on the biology, signaling mechanisms, and physiological functions of aGPCRs

A stable (Li, O) and radiogenic (Sr, Nd) isotope perspective on metasomatic processes in a subducting slab

Two distinct types of eclogites from the Raspas Complex (Ecuador), which can be distinguished based on petrography and trace element geochemistry, were analyzed for their stable (Li, O) and radiogenic (Sr, Nd) isotope signature to constrain metasomatic changes due to fluid-overprinting in metabasaltic rocks at high-pressure conditions and to identify fluid sources. MORB-type eclogites are characterized by a relative LREE depletion similar to MORB. High-pressure (HP) minerals from this type of eclogite have highly variable oxygen isotope compositions (garnet: + 4.1 to + 9.8 ‰; omphacite: + 6.1 to + 11.0 ‰; phengite: 8.7 to 10.4 ‰; amphibole: 6.2 to 10.1 ‰) and generally show equilibrium oxygen isotope fractionation. Initial 87Sr/86Sr isotope ratios are also variable (0.7037-0.7063), whereas εNd130Ma values (+ 8.3 to + 11.0) are relatively similar. Sr and O isotopic compositional differences among rocks on outcrop scale, the preservation of O isotopic compositions of low-temperature altered oceanic crust, and Sr-Nd isotopic trends typical for seafloor alteration suggest inheritance from variably altered oceanic crust. However, decreasing δ7Li values (-0.5 to -12.9 ‰) with increasing Li concentrations (11-94 ppm) indicate Li isotope fractionation by diffusion related to fluid-rock interaction. Li isotopes prove to be a very sensitive tracer of metasomatism, although the small effects on the Sr-Nd-O isotope systems suggest that the fluid-induced metasomatic event in the MORB-type eclogites was small-scale at low-water/rock ratios. This metasomatic fluid is thought to predominantly derive from in situ dehydration of MORB-type rocks. Zoisite eclogites, the second eclogite type from the Raspas Complex, are characterized by the presence of zoisite and enrichment in many incompatible trace elements compared to the MORB-type eclogites. The zoisite eclogites have a homogenous Sr-Nd isotopic signature (Initial 87Sr/86Sr = 0.7075-0.7081, εNd130Ma = -6.7 to -8.7), interpreted to reflect a metasomatic overprint. The isotopic signature can be attributed to the metasomatic formation of zoisite because associated zoisite veins are isotopically similar. Relatively homogenous O isotope values for garnet (10.9-12.3 ‰) omphacite (9.4 to 10.8 ‰), amphibole (10.0-10.1 ‰) and zoisite (10.5-11.9 ‰) and inter-mineral O isotopic disequilibria are consistent with a metasomatic overprint via open-system fluid input. Li concentrations (46-76 ppm) and δ7Li values of the zoisite eclogites overlap the range of the MORB-type eclogites. The large amount of fluid required for isotopic homogenization, combined with the results from fluid inclusion studies, suggests that deserpentinization played a major role in generating the metasomatic fluid that altered the zoisite eclogites. However, influence of a (meta)sedimentary source is required based on Sr-Nd isotope data and trace element enrichments. The significant geochemical variation in the various eclogites generated by interaction with metasomatic fluids has to be considered in attempts to constrain recycling at convergent margins

Continuing Methadone for Pain in Palliative Care

BACKGROUND: Methadone is one of the most important medications used for the treatment of refractory pain in the palliative care setting, and is usually initially prescribed by one of a limited number of physicians who have acquired authorization for its use. A lack of authorized physicians able to take over prescribing when the patient is stable is a barrier to accessing methadone for analgesia

Properties of Replication-Competent Vesicular Stomatitis Virus Vectors Expressing Glycoproteins of Filoviruses and Arenaviruses

Replication-competent recombinant vesicular stomatitis viruses (rVSVs) expressing the type I transmembrane glycoproteins and selected soluble glycoproteins of several viral hemorrhagic fever agents (Marburg virus, Ebola virus, and Lassa virus) were generated and characterized. All recombinant viruses exhibited rhabdovirus morphology and replicated cytolytically in tissue culture. Unlike the rVSVs with an additional transcription unit expressing the soluble glycoproteins, the viruses carrying the foreign transmembrane glycoproteins in replacement of the VSV glycoprotein were slightly attenuated in growth. Biosynthesis and processing of the foreign glycoproteins were authentic, and the cell tropism was defined by the transmembrane glycoprotein. None of the rVSVs displayed pathogenic potential in animals. The rVSV expressing the Zaire Ebola virus transmembrane glycoprotein mediated protection in mice against a lethal Zaire Ebola virus challenge. Our data suggest that the recombinant VSV can be used to study the role of the viral glycoproteins in virus replication, immune response, and pathogenesis

Seasonal freeze resistance of rainbow smelt (Osmerus mordax) is generated by differential expression of glycerol-3 phospahte dehydrogenase, phosoenol pyruvate carboxykinase and antifreeze protein genes

In winter, rainbow smelt (Osmerus mordax) accumulate glycerol and produce an antifreeze protein (AFP), which both contribute to freeze resistance. The role of differential gene expression in the seasonal pattern of these adaptations was investigated. First, cDNAs encoding smelt and Atlantic salmon (Salmo salar) phosphoenolpyruvate carboxykinase (PEPCK) and smelt glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were cloned so that all sequences required for expression analysis would be available. Using quantitative PCR, expression of beta actin in rainbow smelt liver was compared with that of GAPDH in order to determine its validity as a reference gene. Then, levels of glycerol-3-phosphate dehydrogenase (GPDH), PEPCK, and AFP relative to beta actin were measured in smelt liver over a fall-winter-spring interval. Levels of GPDH mRNA increased in the fall just before plasma glycerol accumulation, implying a driving role in glycerol synthesis. GPDH mRNA levels then declined during winter, well in advance of serum glycerol, suggesting the possibility of GPDH enzyme or glycerol conservation in smelt during the winter months. PEPCK mRNA levels rose in parallel with serum glycerol in the fall, consistent with an increasing requirement for amino acids as metabolic precursors, remained elevated for much of the winter, and then declined in advance of the decline in plasma glycerol. AFP mRNA was elevated at the onset of fall sampling in October and remained elevated until April, implying separate regulation from GPDH and PEPCK. Thus, winter freezing point depression in smelt appears to result from a seasonal cycle of GPDH gene expression, with an ensuing increase in the expression of PEPCK, and a similar but independent cycle of AFP gene expression.Peer reviewed: YesNRC publication: Ye

Composition of hydrothermal fluids and mineralogy of associated chimney material on the East Scotia Ridge back-arc spreading centre

The East Scotia Ridge is an active back-arc spreading centre located to the west of the South Sandwich island arc in the Southern Ocean. Initial exploration of the ridge by deep-tow surveys provided the first evidence for hydrothermal activity in a back-arc setting outside of the western Pacific, and we returned in 2010 with a remotely operated vehicle to precisely locate and sample hydrothermal sites along ridge segments E2 and E9. Here we report the chemical and isotopic composition of high- and low-temperature vent fluids, and the mineralogy of associated high-temperature chimney material, for two sites at E2 (Dog’s Head and Sepia), and four sites at E9 (Black & White, Ivory Tower, Pagoda and Launch Pad). The chemistry of the fluids is highly variable between the ridge segments. Fluid temperatures were ∼350 °C at all vent sites except Black & White, which was significantly hotter (383 °C). End-member chloride concentrations in E2 fluids (532 - 536 mM) were close to background seawater (540 mM), whereas Cl in E9 fluids was much lower (98 - 220 mM) indicating that these fluids are affected by phase separation. Concentrations of the alkali elements (Na, Li, K and Cs) and the alkaline earth elements (Ca, Sr and Ba) co-vary with Cl, due to charge balance constraints. Similarly, concentrations of Mn and Zn are highest in the high Cl fluids but, by contrast, Fe/Cl ratios are higher in E9 fluids (3.8 – 8.1 × 10−3) than they are in E2 fluids (1.5 - 2.4 × 10−3) and fluids with lowest Cl have highest Cu. Although both ridge segments are magmatically inflated, there is no compelling evidence for input of magmatic gases to the vent fluids. Fluid δD values range from 0.2 to 1.5 ‰, pH values (3.02 - 3.42) are not especially low, and F concentrations (34.6 - 54.4 μM) are lower than bottom seawater (62.8 μM). The uppermost sections of conjugate chimney material from E2, and from Ivory Tower and Pagoda at E9, typically exhibit inner zones of massive chalcopyrite enclosed within an outer zone of disseminated sulphide, principally sphalerite and pyrite, in an anhydrite matrix. By contrast, the innermost part of the chimneys that currently vent fluids with lowest Cl (Black & White and Launch Pad), is dominated by anhydrite. By defining and assessing the controls on the chemical composition of these vent fluids, and associated mineralisation, this study provides new information for evaluating the significance of hydrothermal processes at back-arc basins for ocean chemistry and the formation of seafloor mineral deposits