Novel dimers as inhibitors of alpha-synuclein aggregation

Mitacs GlobalinkNon-Peer ReviewedParkinson’s Disease is characterized by the death of dopaminergic neurons in the substantia nigra as a result of the aggregation of alpha synuclein (AS) Nicotine from smoking and 1 aminoindan (a metabolite of Rasagiline) seem to be neuroprotective compounds and both have been associated with the reduction of the risk to develop Parkinson’s disease These compounds bind to AS at both the N and C terminus, forcing the protein to adopt a loop conformation, which appear to contribute to the neuroprotective activity of the drugs Dimer molecules linked with two neuroprotective compounds should increase the binding constants to AS and increase the efficacy to prevent AS aggregation Phase 1 metabolic studies using hepatic microsomes in vitro are needed to determine the susceptibility of the compounds to biotransformatio

The Effect of Diphenylethane Side-chain Substituents on Dibenzocyclohexadiene Formation and their Inhibition of α-Synuclein Aggregation in vitro

NSERCPeer ReviewedThe naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular cyclization at pH 7.4 to form dibenzocyclooctadienes. Both NDGA and these dibenzocyclooctadienes have been shown to prevent in vitro aggregation of α-synuclein, an intrinsically disordered protein associated with Parkinson's disease. NDGA possesses two vicinal methyl groups on the butyl linker and the presence of these methyl groups attenuates the rate of intramolecular cyclization versus the unsubstituted analog, in opposition to the anticipated Thorpe-Ingold effect, likely due to steric repulsions during cyclization. Numerous 1,2-bis-ethane di-catechols are known to inhibit α-synuclein aggregation in vitro and we hypothesize that these compounds undergo a similar intramolecular cyclization and the cyclized products may be responsible for the activity. To test this hypothesis we prepared a series of 1,2-bis-ethane di-catechols with 0, 2 and 4 methyl substituents on the linker. We have confirmed that these compounds undergo intramolecular cyclization to form dibenzocyclohexadienes and that steric interactions between the methyl substituents leads to an increase in the rate of intramolecular cyclization, which is in contrast to what was observed for lignan di-catechols. The rate of cyclization to form six-membered rings is 10-30 times more rapid than formation of eight membered rings and the dibenzocyclohexadienes also prevent in vitro aggregation of α-synuclein

"`They brought in the horrible key ring thing!" Analysing the Usability of Two-Factor Authentication in UK Online Banking

To prevent password breaches and guessing attacks, banks increasingly turn to two-factor authentication (2FA), requiring users to present at least one more factor, such as a one-time password generated by a hardware token or received via SMS, besides a password. We can expect some solutions -- especially those adding a token -- to create extra work for users, but little research has investigated usability, user acceptance, and perceived security of deployed 2FA. This paper presents an in-depth study of 2FA usability with 21 UK online banking customers, 16 of whom had accounts with more than one bank. We collected a rich set of qualitative and quantitative data through two rounds of semi-structured interviews, and an authentication diary over an average of 11 days. Our participants reported a wide range of usability issues, especially with the use of hardware tokens, showing that the mental and physical workload involved shapes how they use online banking. Key targets for improvements are (i) the reduction in the number of authentication steps, and (ii) removing features that do not add any security but negatively affect the user experience

Mortality and Life Expectancy in Homeless Men and Women in Rotterdam: 2001-2010

Background:Data on mortality among homeless people are limited. Therefore, this study aimed to describe mortality patterns within a cohort of homeless adults in Rotterdam (the Netherlands) and to assess excess mortality as compared to the general population in that city.Methods:Based on 10-year follow-up of homeless adults aged ≥ 20 years who visited services for homeless people in Rotterdam in 2001, and on vital statistics, we assessed the association of mortality with age, sex and type of service used (e.g. only day care, convalescence care, other) within the homeless cohort, and also compared mortality between the homeless and general population using Poisson regression. Life tables and decomposition methods were used to examine difference

Mass Spectrometric Detection and Characterization of Metabolites of Gemini Surfactants Used as Gene Delivery Vectors

NSERCPeer ReviewedGemini surfactants are a class of lipid molecules that have been successfully used in vitro and in vivo as non-viral gene delivery vectors. However, the biological fate of gemini surfactants has not been well investigated. In particular, the metabolism of gemini surfactants after they enter cells as gene delivery vehicles is unknown. In this work, we used a high-resolution quadrupole-Orbitrap mass spectrometry (Q-Exactive®) instrument to detect the metabolites of three model gemini surfactants, namely a) unsubstituted (16-3-16), b) with pyridinium head groups (16(Py)-S-2-S-16(Py)), and c) substituted with a glycyl-lysine di-peptide (16-7N(GK)-16). The metabolites were characterized, and structures proposed, based on accurate masses and characteristic product ions. The metabolism of the three gemini surfactants was very different as 16-3-16 was not metabolized in PAM212 cells, whereas 16(Py)-S-2-S-16(Py) was metabolized primarily via phase I reactions, including oxidation and de-alkylation, producing metabolites that could be linked to its observed high toxicity. The third gemini surfactant 16-7N(GK)-16 was metabolized mainly via phase II reactions, including methylation, acetylation, glucose conjugation, palmityl conjugation, and stearyl conjugation. The metabolism of gemini surfactants provides insight for future directions in the design and development of more effective gemini surfactants with lower toxicity. The reported approach can also be applied to study the metabolism of other structurally related gemini surfactants

Methane budget estimates in Finland from the CarbonTracker Europe-CH4 data assimilation system

We estimated the CH4 budget in Finland for 2004?2014 using the CTE-CH4 data assimilation system with an extended atmospheric CH4 observation network of seven sites from Finland to surrounding regions (Hyytiälä, Kj?lnes, Kumpula, Pallas, Puijo, Sodankylä, and Utö). The estimated average annual total emission for Finland is 0.6?±?0.5 Tg CH4 yr?1. Sensitivity experiments show that the posterior biospheric emission estimates for Finland are between 0.3 and 0.9 Tg CH4 yr?1, which lies between the LPX-Bern-DYPTOP (0.2 Tg CH4 yr?1) and LPJG-WHyMe (2.2 Tg CH4 yr?1) process-based model estimates. For anthropogenic emissions, we found that the EDGAR v4.2 FT2010 inventory (0.4 Tg CH4 yr?1) is likely to overestimate emissions in southernmost Finland, but the extent of overestimation and possible relocation of emissions are difficult to derive from the current observation network. The posterior emission estimates were especially reliant on prior information in central Finland. However, based on analysis of posterior atmospheric CH4, we found that the anthropogenic emission distribution based on a national inventory is more reliable than the one based on EDGAR v4.2 FT2010. The contribution of total emissions in Finland to global total emissions is only about 0.13%, and the derived total emissions in Finland showed no trend during 2004?2014. The model using optimized emissions was able to reproduce observed atmospheric CH4 at the sites in Finland and surrounding regions fairly well (correlation > 0.75, biasPeer reviewe