Search

We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13∶03-*03∶01 OR = 3.3, Pc 5.1×10−5, *04∶05-*03∶01 OR = 2.1, Pc 9.7×10−8, *15∶01-*06∶02 OR = 2.0, Pc = 9.1×10−3, *03∶01-*02∶01 OR = 1.7 Pc = 7.9×10−22) and protection (*11, OR = 0.8, Pc = 2.7×10−2, *16∶01-*05∶02 OR = 0.6, Pc = 4.8×10−16, *14∶01-4-*05∶031 = OR = 0.5, Pc = 9.8×10−4 and *15∶02-*06∶01 OR = 0.4, Pc = 5.1×10−4). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14∶01, *04∶05, *13∶03, *08∶01 and *03∶01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85–99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms. [ABSTRACT FROM AUTHOR]

Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism. [ABSTRACT FROM AUTHOR]

We utilized volcanic CO 2 vents at Castello Aragonese off Ischia Island as a natural laboratory to investigate the effect of lowered pH/elevated CO 2 on the bioactivities of extracts from fleshy brown algae Sargassum vulgare C. Agardh. We analysed the carbohydrate levels, antioxidant capacity, antibacterial, antifungal, antiprotozoal, anticancer properties and antimutagenic potential of the algae growing at the acidified site (pH ∼ 6.7) and those of algae growing at the nearby control site Lacco Ameno (pH∼8.1). The results of the present study show that the levels of polysaccharides fucoidan and alginate were higher in the algal population at acidified site. In general, extracts for the algal population from the acidified site showed a higher antioxidant capacity, antilipidperoxidation, antibacterial, antifungal, antiprotozoal, anticancer activities and antimutagenic potential compared to the control population. The increased bioactivity in acidified population could be due to elevated levels of bioactive compounds of algae and/or associated microbial communities. In this snapshot study, we performed bioactivity assays but did not characterize the chemistry and source of presumptive bioactive compounds. Nevertheless, the observed improvement in the medicinal properties of S. vulgare in the acidified oceans provides a promising basis for future marine drug discovery. Image 1 • Bioactivities of S. vulgare from Ischia CO 2 vents and nearby control site were analysed. • Elevated DIC increases polysaccharide content in the algae at CO 2 vents. • Algal extract from acidified population showed higher antimicrobial, and antiprotozoal activity. • Acidified population showed pronounced antimutagenic potential and anticancer activities. Elevated DIC improves bioactivity in fleshy brown macroalgae at natural volcanic CO 2 off Ischia Island, Italy. [ABSTRACT FROM AUTHOR]