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Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections

In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer \u3e1x106) and provided 80–100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P.falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine

Bacterial Antigen Expression Is an Important Component in Inducing an Immune Response to Orally Administered Salmonella-Delivered DNA Vaccines

BACKGROUND: The use of Salmonella to deliver heterologous antigens from DNA vaccines is a well-accepted extension of the success of oral Salmonella vaccines in animal models. Attenuated S. typhimurium and S. typhi strains are safe and efficacious, and their use to deliver DNA vaccines combines the advantages of both vaccine approaches, while complementing the limitations of each technology. An important aspect of the basic biology of the Salmonella/DNA vaccine platform is the relative contributions of prokaryotic and eukaryotic expression in production of the vaccine antigen. Gene expression in DNA vaccines is commonly under the control of the eukaryotic cytomegalovirus (CMV) promoter. The aim of this study was to identify and disable putative bacterial promoters within the CMV promoter and evaluate the immunogenicity of the resulting DNA vaccine delivered orally by S. typhimurium. METHODOLOGY/PRINCIPAL FINDINGS: The results reported here clearly demonstrate the presence of bacterial promoters within the CMV promoter. These promoters have homology to the bacterial consensus sequence and functional activity. To disable prokaryotic expression from the CMV promoter a series of genetic manipulations were performed to remove the two major bacterial promoters and add a bacteria transcription terminator downstream of the CMV promoter. S. typhimurium was used to immunise BALB/c mice orally with a DNA vaccine encoding the C-fragment of tetanus toxin (TT) under control of the original or the modified CMV promoter. Although both promoters functioned equally well in eukaryotic cells, as indicated by equivalent immune responses following intramuscular delivery, only the original CMV promoter was able to induce an anti-TT specific response following oral delivery by S. typhimurium. CONCLUSIONS: These findings suggest that prokaryotic expression of the antigen and co-delivery of this protein by Salmonella are at least partially responsible for the successful oral delivery of C-fragment DNA vaccines containing the CMV promoter by S. typhimurium

Improved representation of particle size and solubility in model simulations of atmospheric dispersion and wet-deposition from Fukushima

Radionuclides released into the atmosphere following the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident were detected by ground-based monitoring stations worldwide. The inter-continental dispersion of radionuclides provides a unique opportunity to evaluate the ability of atmospheric dispersion models to represent the processes controlling their transport and deposition in the atmosphere. Co-located measurements of radioxenon (133Xe) and caesium (137Cs) concentrations enable individual physical processes (dispersion, dry and wet deposition) to be isolated. In this paper we focus on errors in the prediction of 137Cs attributed to the representation of particle size and solubility, in the process of modelling wet deposition. Simulations of 133Xe and 137Cs concentrations using the UK Met Office NAME (Numerical Atmospheric-dispersion Modelling Environment) model are compared with CTBTO (Comprehensive Nuclear-Test-Ban Treaty Organisation) surface station measurements. NAME predictions of 137Cs using a bulk wet deposition parameterisation (which does not account for particle size dependent scavenging or solubility) significantly underestimate observed 137Cs. When a binned wet deposition parameterisation is implemented (which accounts for particle size dependent scavenging) the correlations between modelled and observed air concentrations improve at all 9 of the Northern Hemisphere sites studied and the respective RMSLE (root-mean-square-log-error) decreases by a factor of 7 due to a decrease in the wet-deposition of Aitken and Accumulation mode particles. Finally, NAME simulations were performed in which insoluble submicron particles are represented. Representing insoluble particles in the NAME simulations improves the RMSLE at all sites further by a factor of 7. Thus NAME is able to predict 137Cs with good accuracy (within a factor of 10 of observed 137Cs values) at distances greater than 10,000 km from FDNPP only if insoluble submicron particles are considered in the description of the source. This result provides further evidence of the presence of insoluble Cs-rich microparticles in the release following the accident at FDNPP and suggests that these small particles travelled across the Pacific Ocean to the US and further across the North Atlantic Ocean towards Europe

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56

This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from diferent ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), fve of which are novel including a deletion spanning the 5′ untranslated region and the frst coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identifed in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the frst MFRP genomic rearrangement, ofering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO

Serosurvey of West Nile virus (WNV) in free-ranging raptors from Brazil

Fil: Morel, Ana Paula. Instituto de Pesquisas Veterinárias Desidério Finamor (IPVDF). Centro de Pesquisa em Saúde Animal, Eldorado do Sul, Río Grande del Sur; Brasil.Fil: Webster, Anelise. Instituto de Pesquisas Veterinárias Desidério Finamor (IPVDF). Centro de Pesquisa em Saúde Animal, Eldorado do Sul, Río Grande del Sur; Brasil.Fil: Zitelli, Larissa Calo. Instituto de Pesquisas Veterinárias Desidério Finamor (IPVDF). Centro de Pesquisa em Saúde Animal, Eldorado do Sul, Río Grande del Sur; Brasil.Fil: Umeno, Karen. Instituto de Pesquisas Veterinárias Desidério Finamor (IPVDF). Centro de Pesquisa em Saúde Animal, Eldorado do Sul, Río Grande del Sur; Brasil.Fil: Souza, Ugo Araújo. Instituto de Pesquisas Veterinárias Desidério Finamor (IPVDF). Centro de Pesquisa em Saúde Animal, Eldorado do Sul, Río Grande del Sur; Brasil.Fil: Prusch, Fabiane. Clinica Veterinária Toca dos Bichos, Porto Alegre, Río Grande del Sur; Brasil.Fil: Anicet, Marina. Clinica Veterinária Toca dos Bichos, Porto Alegre, Río Grande del Sur; Brasil.Fil: Marsicano, Gleide. Clinica Veterinária Toca dos Bichos, Porto Alegre, Río Grande del Sur; Brasil.Fil: Bandarra, Paulo. Nucleo de Reabilitação da Fauna Silvestre-UFPel, Pelotas, Río Grande del Sur; Brasil.Fil: Trainini, Gustavo. Hayabusa Consultoria Ambiental, São Francisco de Paula, Río Grande del Sur; Brasil.Fil: Stocker, Julian. Hayabusa Consultoria Ambiental, São Francisco de Paula, Río Grande del Sur; Brasil.Fil: Giani, Denise. Hayabusa Consultoria Ambiental, São Francisco de Paula, Río Grande del Sur; Brasil.Fil: Fortes, Flávia Borges. Secretaria da Agricultura Pecuária e Desenvolvimento Rural (SEAPDR). Programa Estadual de Sanidade Avícola (PESA), Porto Alegre, Río Grande del Sur; Brasil.Fil: Goenaga, Silvina. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Reck, José. Instituto de Pesquisas Veterinárias Desidério Finamor (IPVDF). Centro de Pesquisa em Saúde Animal, Eldorado do Sul, Río Grande del Sur; Brasil.West Nile virus (WNV) is a mosquito-borne Flavivirus that can affect birds, horses, and humans, and is the only zoonotic Flavivirus that has been identified in six continents. In Brazil, until 2010, there was no evidence of WNV circulation. Recently, the virus was isolated from a horse with encephalitis, and the first human cases were registered in Brazil. Despite that, there is still no information on the enzootic cycle of this virus in birds or wildlife. This study aimed to investigate whether there is evidence of WNV circulation among wild birds from Southern Brazil. For this, we used free-living wild raptors (live-trapped or rescued) as potential sentinels to investigate the presence of WNV antibodies using ELISA and plaque reduction neutralization test (PRNT) assay. In addition, the presence of nucleic acids from Flavivirus family members was investigated. None of the birds sampled presented clinical findings compatible with WNV. Of the 200 serum samples from birds of prey belonging to 21 species, ten (5%) were positive for the presence of WNV antibodies on ELISA testing. The PRNT test did not confirm the ELISA results, but indicated that three birds had possibly been exposed to Saint Louis encephalitis virus (SLEV). All samples were negative for Flavivirus RNA. The results presented here evince the need for permanent surveillance for emerging flaviviruses in Brazil, as well as for a contingency policy in the case of human/animal outbreaks, particularly in high-risk areas