Replicon particles based on Venezuelan equine encephalitis virus (VEE) contain a self‐replicating RNA encoding the VEE replicase proteins and expressing a gene of interest in place of the viral ...structural protein genes. Structural proteins for packaging of replicon RNA into VEE replicon particles (VRPs) are expressed from separate helper RNAs. Aspects of the biology of VEE that are exploited in VRP vaccines include 1) expression of very high levels of immunogen, 2) expression of immunizing proteins in cells in the draining lymph node, and 3) the ability to induce mucosal immunity from a parental inoculation. Results of experiments with VRPs expressing green fluorescent protein or influenza virus hemagglutinin (HA) demonstrated that specific mutations in the VRP envelope glycoproteins affect both targeting in the draining lymph node and efficiency of the immune response in mice. VRPs expressing either the matrix‐capsid portion of Gag, the full‐length envelope gp160, or the secreted gp140 of cloned SIVsm H‐4i were mixed in a cocktail and used to immunize macaques at 0, 1, and 4 months. Neutralizing antibodies against SIVsm H‐4 were induced in 6 of 6 vaccinates and CTL in 4 of 6. An intrarectal challenge with the highly pathogenic SIVsm E660 was given at 5 months. A vaccine effect was seen in reduced peak virus loads, reduced virus loads both at set point and at 41 weeks postchallenge, and preserved or increased CD4 counts compared to controls. A candidate VRP HIV vaccine expressing Clade C Gag contains a sequence that is very close to the South African Clade C consensus and was selected from a recent seroconverter in the Durban cohort to represent currently circulating genotypes in South Africa. A GMP lot of this vaccine has been manufactured and tested for a phase I trial in the first months of 2002.
The path to an RSV vaccine Shaw, Christine A; Ciarlet, Max; Cooper, Brian W ...
Current opinion in virology,
06/2013, Letnik:
3, Številka:
3
Journal Article
Recenzirano
•Maternal immunization provides a path to early infant protection against RSV.•Structure-based engineering overcomes the biochemical challenges of the RSV F antigen.•Improved animal models for RSV ...vaccine-mediated disease enhancement are needed.•A self-amplifying RNA vaccine platform has been designed for safe infant immunization.•Infant RSV vaccines aim for high neutralizing titers and a non-Th2-biased response.
Respiratory syncytial virus (RSV) is the greatest remaining unmet infant vaccine need in developed countries and an important unmet infant vaccine need worldwide. More than 40 years of effort have yet to result in a licensed RSV vaccine for humans. Key challenges to RSV vaccine development include a peak of severe disease at 2–3 months of age, problematic biochemical behavior of key vaccine antigens, a history of vaccine-mediated disease enhancement, and reliance on animal models that may not accurately reflect human disease processes. Potential paths to overcome these challenges include maternal immunization, structure-based engineering of vaccine antigens, the design of a novel platform for safe infant immunization, and the development of improved animal models for vaccine-enhanced disease.
Homes outside of high-risk flood areas file more than 20% of all National Flood Insurance Program (NFIP) claims and typically receive one-third of federal disaster assistance for flooding. Get a ...flood-zone determination "Every time agents quote a property policy, whether it's personal or commercial lines, they should consider running a flood-zone determination," said Julie Duncan, client relations director at Aon National Flood Services.
Zearalane, a resorcyclic acid lactone (RAL) derivative, activates murine macrophages (M phi) in vivo and in vitro. Mouse M phi incubated in vitro with different concentrations of zearalane released ...superoxide anion (O2-) on stimulation with either opsonized zymosan (Op-zym), phorbol myristate acetate (PMA), or Salmonella typhimurium. The levels of O2- released were similar to those released from M phi incubated in vitro with supernatants enriched in macrophage-activating factors from concanavalin A-stimulated mouse spleen cells. In contrast, 17 beta-estradiol (E2) or diethylstilbestrol (DES) induced little or no enhancement of O2- release. Zearalane, dideoxyzearalane, DES and E2 were tested for induction of host resistance to S. typhimurium infection in mice. Treatment of mice with zearalane (9 mg/kg) resulted in at least 65% survival 4 days post-infection, compared to 10% survival of mice with vehicle alone, DES, or E2. Peritoneal and alveolar M phi from the zearalane-treated mice released up to six times as much O2- on stimulation with Op-zym as M phi from the other treatment groups. M phi activation was observed for up to 7 days after intraperitoneal or subcutaneous administration of zearalane in either aqueous or organic vehicles. These results suggest that zearalane may enhance resistance to infection by increasing bactericidal activity due to increased release of toxic oxygen radicals by M phi and mononuclear phagocytes. These effects differ from the immunosuppressive effects reported for DES and E2.
ABSTRACT
We exploit the Mg/Mn-Al/Fe chemical abundance plane to help identify nearby halo stars in the 14th data release from the APOGEE survey that have been accreted on to the Milky Way. Applying a ...Gaussian Mixture Model, we find a ‘blob’ of 856 likely accreted stars, with a low disc contamination rate of ∼7 per cent. Cross-matching the sample with the second data release from Gaia gives us access to parallaxes and apparent magnitudes, which place constraints on distances and intrinsic luminosities. Using a Bayesian isochrone pipeline, this enables us to estimate new ages for the accreted stars, with typical uncertainties of ∼20 per cent. This does not account for systematic uncertainties. Our new catalogue is further supplemented with estimates of orbital parameters. The blob stars span Fe/H between −2.5 to −0.5, and Mg/Fe between −0.1 to 0.5. They constitute ∼30 per cent of the metal-poor (Fe/H < −0.8) halo at Fe/H ∼ −1.4. Our new ages mainly range between 8 to 13 Gyr, with the oldest stars the metal-poorest, and with the highest Mg/Fe abundance. If the blob stars are assumed to belong to a single progenitor, the ages imply that star formation lasted 5 Gyr after which the system merged with our Milky Way around 8 Gyr ago. Dynamical arguments suggest that such a single progenitor would have had a total mass of $\sim 10^{11}\, \mathrm{M}_{\odot }$, similar to that found by other authors using chemical evolution models and simulations.
The detection of rare circulating tumor cells (CTCs) in the blood of cancer patients has the potential to be a powerful and noninvasive method for examining metastasis, evaluating prognosis, ...assessing tumor sensitivity to drugs, and monitoring therapeutic outcomes. In this study, we have developed an efficient strategy to isolate CTCs from the blood of breast cancer patients using a microfluidic immune-affinity approach. Additionally, to gain further access to these rare cells for downstream characterization, our strategy allows for easy detachment of the captured CTCs from the substrate without compromising cell viability or the ability to employ next generation RNA sequencing for the identification of specific breast cancer genes. To achieve this, a chemical ligand-exchange reaction was engineered to release cells attached to a gold nanoparticle coating bound to the surface of a herringbone microfluidic chip (NP-HBCTC-Chip). Compared to the use of the unmodified HBCTC-Chip, our approach provides several advantages, including enhanced capture efficiency and recovery of isolated CTCs.
MicroRNAs (miRNAs) can regulate nearly all biological processes and their dysregulation is implicated in various complex diseases and pathological conditions. Recent years have seen a growing number ...of functional studies of miRNAs using high-throughput experimental technologies, which have produced a large amount of high-quality data regarding miRNA target genes and their interactions with small molecules, long non-coding RNAs, epigenetic modifiers, disease associations, etc These rich sets of information have enabled the creation of comprehensive networks linking miRNAs with various biologically important entities to shed light on their collective functions and regulatory mechanisms. Here, we introduce miRNet, an easy-to-use web-based tool that offers statistical, visual and network-based approaches to help researchers understand miRNAs functions and regulatory mechanisms. The key features of miRNet include: (i) a comprehensive knowledge base integrating high-quality miRNA-target interaction data from 11 databases; (ii) support for differential expression analysis of data from microarray, RNA-seq and quantitative PCR; (iii) implementation of a flexible interface for data filtering, refinement and customization during network creation; (iv) a powerful fully featured network visualization system coupled with enrichment analysis. miRNet offers a comprehensive tool suite to enable statistical analysis and functional interpretation of various data generated from current miRNA studies. miRNet is freely available at http://www.mirnet.ca.
Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in ...epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms.
ABSTRACT
Understanding the assembly of our Galaxy requires us to also characterize the systems that helped build it. In this work, we accomplish this by exploring the chemistry of accreted halo stars ...from Gaia-Enceladus/Gaia-Sausage (GES) selected in the infrared from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) Data Release 16. We use high resolution optical spectra for 62 GES stars to measure abundances in 20 elements spanning the α, Fe-peak, light, odd-Z, and notably, the neutron-capture groups of elements to understand their trends in the context of and in contrast to the Milky Way and other stellar populations. Using these derived abundances we find that the optical and the infrared abundances agree to within 0.15 dex except for O, Co, Na, Cu, and Ce. These stars have enhanced neutron-capture abundance trends compared to the Milky Way, and their Eu/Mg and neutron-capture abundance ratios (e.g. Y/Eu, Ba/Eu, Zr/Ba, La/Ba, and Nd/Ba) point to r-process enhancement and a delay in s-process enrichment. Their α/Fe trend is lower than the Milky Way trend for Fe/H > −1.5 dex, similar to previous studies of GES stars and consistent with the picture that these stars formed in a system with a lower rate of star formation. This is further supported by their depleted abundances in Ni, Na, and Cu abundances, again, similar to previous studies of low-α stars with accreted origins.
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