👤 Paula Amato

BackgroundSubjective cognitive decline (SCD) represents the first early symptomatic stage of Alzheimer's disease (AD).ObjectiveWe aimed to investigate the relationships between features in SCD and to assess the importance of these features in the future development of dementia to inform a targeted management protocol.Methods440 SCD patients underwent neurological and neuropsychological assessments, MRI scans, Show less

G-quadruplexes (G4s) are non-canonical secondary nucleic acid structures with important biological implications in telomere elongation and gene expression. A large number of small molecules have been developed to bind and even covalently target these structures, enhancing the potency and duration of binding. Alternatively, peptide-based ligands have been studied and shown to offer several advantages, including high specificity, a modular design, and ease of synthesis. In this work, we describe a peptide-based methodology for covalent G4-targeting, based on the introduction of two photoactivatable moieties in a peptide derived from the RHAU helicase. Rational insertion of crosslinkers at different positions yielded nine different peptides, which were evaluated for their G4-stabilizing effect and alkylation potential. Moderate to high alkylation yields towards G4s were obtained. The G4 stabilizing potential drastically increased for N-terminal modifications of the RHAU18 peptide. This led to the design of a further series of peptides with varying N-terminal residues to gain insight in the stabilization potential of each single amino acid modification and provided a comprehensive study of the binding behaviour of modified RHAU peptides. Show less

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMT Show less

Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR-Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations. Show less