ß-Hairpin mimics containing a piperidine-pyrrolidine scaffold modulate the ß-amyloid aggregation process preserving the monomer species

Alzheimer’s disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of Aβ1-42-amyloid related β-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid β-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of Aβ1-42. According to these peptide sequences, a stable β-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of Aβ1-42 aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. Furthermore, compounds protect against toxic effects of Aβ on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small β-hairpin mimics possessing such a highly efficient anti-aggregation activity. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. The structural elements made in this study provide valuable insights in the understanding of the aggregation process and insights to explore the design of novel acyclic β-hairpin targeting other types of amyloid-forming proteins

The first myriapod genome sequence reveals conservative arthropod gene content and genome organisation in the centipede Strigamia maritima.

Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.This work was supported by the following grants: NHGRIU54HG003273 to R.A.G; EU Marie Curie ITN #215781 “Evonet” to M.A.; a Wellcome Trust Value in People (VIP) award to C.B. and Wellcome Trust graduate studentship WT089615MA to J.E.G; Marine rhythms of Life” of the University of Vienna, an FWF (http://www.fwf.ac.at/) START award (#AY0041321) and HFSP (http://www.hfsp.org/) research grant (#RGY0082/2010) to KT-­‐R; MFPL Vienna International PostDoctoral Program for Molecular Life Sciences (funded by Austrian Ministry of Science and Research and City of Vienna, Cultural Department -­‐Science and Research to T.K; Direct Grant (4053034) of the Chinese University of Hong Kong to J.H.L.H.; NHGRI HG004164 to G.M.; Danish Research Agency (FNU), Carlsberg Foundation, and Lundbeck Foundation to C.J.P.G.; U.S. National Institutes of Health R01AI55624 to J.H.W.; Royal Society University Research fellowship to F.M.J.; P.D.E. was supported by the BBSRC via the Babraham Institute;This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pbio.100200

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd

Association of Substance Use and Gender Based Violence among Students in a Tertiary Institution in Kakamega County, Kenya

Background: Substance use among college and university students remains an important area of research due to the implications of early substance dependence on the future of the youth. Prior studies from various settings indicate relatively high rates of substance use among students in tertiary educational institutions. However most of these studies were based on tertiary institutions in urban settings, and few have examined substance use and its association with Gender based violence. Objective: Study aim was to establish the prevalence and factors associated with substance abuse among students, and their relationship with Gender Based Violence in a tertiary institution in a relatively rural setting. Methods: The study was conducted in November 2018 after obtaining the relevant approval from KEMRI and from the university administration. Quantitative and qualitative methods were used to collect the data. Quantitative data was collected using self-reported questionnaires across all the faculties among first to fourth year students. Focus group discussions were held with a group of students and Key informant interviews were also held with the institutional administrators and student leaders. Results: A total of 412 university students completed the questionnaires. Majority were males at 57.9% and average age was 21 years. The overall prevalence of substance use was 21.1% and the most commonly used substance was alcohol at 25%. The study found out that 90% of the participants had their first time use of substances between ages of 12-20 years with median age of 18 years

Contextualizing and pilot testing the Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) to primary healthcare workers in Kilifi, Kenya

Background: Little data exists about the methodology of contextualizing version two of the Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) in resource-poor settings. This paper describes the contextualisation and pilot testing of the guide in Kilifi, Kenya. Methods: Contextualisation was conducted as a collaboration between the KEMRI-Wellcome Trust Research Programme (KWTRP) and Kilifi County Government's Department of Health (KCGH) between 2016 and 2018. It adapted a mixed-method design and involved a situational analysis, stakeholder engagement, local adaptation and pilot testing of the adapted guide. Qualitative data were analysed using content analysis to identify key facilitators and barriers to the implementation process. Pre- and post-training scores of the adapted guide were compared using the Wilcoxon signed-rank test. Results: Human resource for mental health in Kilifi is strained with limited infrastructure and outdated legislation. Barriers to implementation included few specialists for referral, unreliable drug supply, difficulty in translating the guide to Kiswahili language, lack of clarity of the roles of KWTRP and KCGH in the implementation process and the unwillingness of the biomedical practitioners to collaborate with traditional health practitioners to enhance referrals to hospital. In the adaptation process, stakeholders recommended the exclusion of child and adolescent mental and behavioural problems, as well as dementia modules from the final version of the guide. Pilot testing of the adapted guide showed a significant improvement in the post-training scores: 66.3% (95% CI 62.4-70.8) v. 76.6% (95% CI 71.6-79.2) (p < 0.001). Conclusion: The adapted mhGAP-IG version two can be used across coastal Kenya to train primary healthcare providers. However, successful implementation in Kilifi will require a review of new evidence on the burden of disease, improvements in the mental health system and sustained dialogue among stakeholders