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

Global methane emission estimates for 2000–2012 from CarbonTracker Europe-CH4 v1.0

We present a global distribution of surface methane (CH4) emission estimates for 2000–2012 derived using the CarbonTracker Europe-CH4 (CTE-CH4) data assimilation system. In CTE-CH4, anthropogenic and biospheric CH4 emissions are simultaneously estimated based on constraints of global atmospheric in situ CH4 observations. The system was configured to either estimate only anthropogenic or biospheric sources per region, or to estimate both categories simultaneously. The latter increased the number of optimizable parameters from 62 to 78. In addition, the differences between two numerical schemes available to perform turbulent vertical mixing in the atmospheric transport model TM5 were examined. Together, the system configurations encompass important axes of uncertainty in inversions and allow us to examine the robustness of the flux estimates. The posterior emission estimates are further evaluated by comparing simulated atmospheric CH4 to surface in situ observations, vertical profiles of CH4 made by aircraft, remotely sensed dry-air total column-averaged mole fraction (XCH4) from the Total Carbon Column Observing Network (TCCON), and XCH4 from the Greenhouse gases Observing Satellite (GOSAT). The evaluation with non-assimilated observations shows that posterior XCH4 is better matched with the retrievals when the vertical mixing scheme with faster interhemispheric exchange is used. Estimated posterior mean total global emissions during 2000–2012 are 516 ± 51 Tg CH4 yr−1 , with an increase of 18 Tg CH4 yr−1 from 2000–2006 to 2007–2012. The increase is mainly driven by an increase in emissions from South American temperate, Asian temperate and Asian tropical TransCom regions. In addition, the increase is hardly sensitive to different model configurations (< 2 Tg CH4 yr−1 difference), and much smaller than suggested by EDGAR v4.2 FT2010 inventory (33 Tg CH4 yr−1 ), which was used for prior anthropogenic emission estimates. The result is in good agreement with other published estimates from inverse modelling studies (16–20 Tg CH4 yr−1 ). However, this study could not conclusively separate a small trend in biospheric emissions (−5 to +6.9 Tg CH4 yr−1 ) from the much larger trend in anthropogenic emissions (15–27 Tg CH4 yr−1 ). Finally, we find that the global and North American CH4 balance could be closed over this time period without the previously suggested need to strongly increase anthropogenic CH4 emissions in the United States. With further developments, especially on the treatment of the atmospheric CH4 sink, we expect the data assimilation system presented here will be able to contribute to the ongoing interpretation of changes in this important greenhouse gas budget.peer-reviewe