Neurocognitive profile and cognitive intervention in Alzheimer's disease

Tese de Doutoramento em Psicologia (Especialidade de Psicologia Clínica)

Type 2 diabetes-related variants influence the risk of developing multiple myeloma: results from the IMMEnSE consortium

Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case–control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)=1.32–2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76–0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)=0.645 vs AUC=0.629; P=4.05×10-06). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (Pinteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.

Structural and enzymatic characterization of ABgp46, a novel phage endolysin with broad anti-Gram-negative bacterial activity

The present study demonstrates the antibacterial potential of a phage endolysin against Gram-negative pathogens, particularly against multidrug resistant strains of Acinetobacter baumannii. We have cloned, heterologously expressed and characterized a novel endolysin (ABgp46) from Acinetobacter phage vb_AbaP_CEB1 and tested its antibacterial activity against several multidrug-resistant A. baumannii strains. LC-MS revealed that ABgp46 is an N-acetylmuramidase, that is also active over a broad pH range (4.0-10.0) and temperatures up to 50°C. Interestingly, ABgp46 has intrinsic and specific anti-A. baumannii activity, reducing multidrug resistant strains by up to 2 logs within 2 hours. By combining ABgp46 with several organic acids that act as outer membrane permeabilizing agents, it is possible to increase and broaden antibacterial activity to include other Gram-negative bacterial pathogens. In the presence of citric and malic acid, ABgp46 reduces A. baumannii below the detection limit (> 5 log) and more than 4 logs P. aeruginosa and Salmonella Typhimurium strains. Overall, this globular endolysin exhibits a broad and high activity against Gram-negative pathogens, that can be enhanced in presence of citric and malic acid, and be used in human and veterinary medicine.

Synthetic biology approaches to shape bacteriophages towards Pseudomonas aeruginosa biofilm control

Dissertation for Ph.D. degree in Biomedical Engineering.