RESUMO
Pyroglutamate amyloid beta3-42 (pGlu-Abeta3-42), a highly amyloidogenic and neurotoxic form of Abeta, is N-terminally truncated to form a pyroglutamate and has recently been proposed as a key target for immunotherapy. Optimized ACI-24, a vaccine in development for the treatment and prevention of Alzheimer's disease, focuses the antibody response on the first 15 N-terminal amino acids of Abeta (Abeta1-15). Importantly, clinical data with an initial version of ACI-24 incorporating Abeta1-15, established the vaccine's safety and tolerability with evidence of immunogenicity. To explore optimized ACI-24's capacity to generate antibodies to pGlu-Abeta3-42, pre-clinical studies were carried out. Vaccinating mice and non-human primates demonstrated that optimized ACI-24 was well-tolerated and induced an antibody response against Abeta1-42 as expected, as well as high titres of IgG reactive with pyroGlu-Abeta. Epitope mapping of the polyclonal response confirmed these findings revealing broad coverage of epitopes particularly for Abeta peptides mimicking where cleavage occurs to form pGlu-Abeta3-42. These data are in striking contrast to results obtained with other clinically tested Abeta targeting vaccines which generated restricted and limited antibody diversity. Taken together, our findings demonstrate that optimized ACI-24 vaccination represents a breakthrough to provide a safe immune response with a broader Abeta sequence recognition compared to previously tested vaccines, creating binders to pathogenic forms of Abeta important in pathogenesis including pGlu-Abeta3-42.
RESUMO
This study aims to investigate the depth distribution of the Nitrate Reduction Potential (NRP) on a natural and a re-established wetland. The obtained NRP provides a valuable data of the driving factors affecting denitrification, the Dissimilatory Nitrate Reduction to Ammonium (DNRA) process and the performance of a re-established wetland. Intact soil cores were collected and divided in slices for the determination of Organic Matter (OM) through Loss of Ignition (LOI) as well as Dissolved Organic Carbon (DOC) and NRP spiking nitrate in batch tests. The Nitrate Reduction (NR) was fitted as a pseudo-first order rate constant (k) from where NRPs were obtained. NR took place in a narrow superficial zone showing a dropping natural logarithmic trend along depth. The main driving factor of denitrification, besides depth, was OM. Although, DOC and LOI could not express by themselves and absolute correlation with NRP, high amounts of DOC ensured enough quantity and quality of labile OM for NR. Besides, high concentration of LOI but a scarce abundance of DOC failed to drive NR. DNRA was only important in superficial samples with high contents of OM. Lastly, the high NRP of the re-established wetland confirms that wetlands can be restored satisfactorily.
