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

Track E Implementation Science, Health Systems and Economics

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

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

The impact of agronomic inputs on selected physicochemical features and their relationships with heavy metals levels in surface sediment and water in sugarcane farms in Nzoia, Kenya.

Sugarcane farming is the most important cash crop cultivation activity in the Lake Victoria basin of Kenya practised in an area covering approximately 114,000 Ha in total. For better yields, various agronomic inputs including fertilizers and herbicides have been used intensively in the farms, causing serious concerns about their potential impacts on the aquatic ecosystems within the lake basin. In this study, the physicochemical features of surface sediment and water including pH, total organic carbon contents and heavy metal (Cd, Cu, Zn, Pb and Cr) loads in River Kuywa and in runoff canals in sugarcane farms in Nzoia nucleus estate within the lake basin were determined to assess the effects of agronomic activities including agronomic inputs in the form of nitrogenous fertilizers [urea and diammonium phosphate (DAP)], herbicides and sewage sludge used in farming on their levels. The results indicated significant differences (p a parts per thousand currency sign 0.05) in the heavy metal levels in sediment and water samples taken before and after the farms, respectively, indicating a positive impact on the concentration levels. The canal water and sediment samples' heavy metal levels were also significantly higher than those of the river samples showing that the influent sugarcane farm canal waters transfer these contaminants into River Kuywa. Although the levels of these parameters were significantly higher in the canals than in the controls obtained from outside the sugarcane farms, the heavy metal levels in soil samples from within the farms with similar agronomic activities did not differ significantly among the various plots. The turbidity, electrical conductivity, temperature, water and soil pH and total organic carbon values in samples obtained within the sugarcane farms showed significant seasonal variations and differed significantly from the values in the controls showing a significant negative impact of agronomic inputs on water quality

Levels of toxic metals in multisectoral samples from Winam Gulf of Lake Victoria.

In this study, the distribution and sources of inputs of trace metals including Cd, Cu, Zn and Pb from various sources as well as Fe which is widely used in the construction industry, into Winam Gulf of Lake Victoria were investigated. The sampling sites were located up streams and down streams of four rivers (Sio, Nyamasaria, Nyando and Sondu-Miriu), in four beaches along the lake (Port Victoria, Kisumu Car Wash, Dunga and Hippo point beaches) and in three estates (Nyamasaria, Migosi and Nyawita) in Kisumu city, covering potential agrochemical and industrial sources and drinking water points, respectively. The concentrations (in mu g/L) of trace metals analysed in the lake and river waters ranged from < 1.79 (Cd), < 3.83 (Pb), < 1.53-3.86 (Cu), 4.37-11.6 (Zn), 11.8-2,440 (Fe). The sediment concentrations (in mu g/kg x 10(3)) ranged from 0.19 to 1.91 (Cd), 6.86-138 (Pb), 18-100 (Cu), 36.2-443 (Zn) and 960-73,200 (Fe), with highest concentrations of all metals being recorded at Kisumu Car Wash area. The study confirmed that the concentrations of the metals accumulate downstream in the rivers both in water and sediment and these rivers are major sources of the heavy metal load into Winam Gulf of Lake Victoria

Declining commercial fish catches in Lake Victoria's Winam Gulf: The importance of restructuring Kenya's aquaculture programme.

The total weight of commercial fish (metric tons) caught in the Winam Gulf area of Lake Victoria in Kenya declined from 3300 mt to 760 mt between 1995 and 2009. Associated with this decline, and ranked in descending order, the species richness of the commercial fish catch was limited to seven major groups (Rastrineobola argentea; Lates niloticus; Protopterus aethiopicus; Labeo victorianus; Haplochromis species; Clarias gariaepinus; Bagrus domac). Numerous hypotheses ranging from eutrophication, inadequate control of the exotic water hyacinth and overfishing were advanced to explain this decline. The Kenyan government, working in partnership with international organizations, implemented multiple restoration and management programmes in response, including aquaculture. Unfortunately, success for this implemented programme has been very limited because important socio-economic driving factors were overlooked. To provide a better understanding of the issues, 150 members of the Winam Gulf fishing community, ranging in age from 20 to 40 years, were surveyed. The results of this survey identified poverty and inadequate education as two major issues requiring substantial attention. The survey also suggested that if societal changes are to occur, it will rest upon changing the beliefs of the youth in the Winam Gulf area. Restructuring Kenya's aquaculture programme, with a focus on the youth, provides a pathway for increasing the literacy level of the community, as well as for reducing poverty