A technique to resolve road accident problems

Accidents occur and result In death, Injury, damage. Inconvenience and economic loss; some are reported, the reports are collected and collated; various outputs of information are produced. The outputs are used in many ways, some quite non-productive in affecting the occurrence or severity of the accidents. The collection and processing of accident data must be viewed today in relation to the legal requirements for reporting accidents; the definitions (legal or otherwise) related to roads, intersections and physical features; and the regulations that govern the registration of vehicles, the equipment on/in vehicles and the manner of useage of vehicles on roads. The legal obligations on road users imposed by traffic signs, signals and other controls should also be taken into account. This work examines certain aspects of what data should/could be collected, how it can be classified after collection, how the accidents can be located and assigned an accident-type and then how this transformed data can be used to size-up the particurlar accident problems in a city or country and provide a systematic approach to the reduction of accidents and/or their severity and cost

The Synthesis of Malonganenone Analogues for Antiparasitic Structure-Activity Relationship Analyses

The most lethal causative species of malaria, Plasmodium falciparum, has been reported as developing resistance against current antimalarial drugs in South-East Asia. New antimalarial drugs, especially those with novel modes of action, need to be established before resistance spreads. The marine natural products malonganenones A, B, and C, isolated from the gorgonian Leptogorgia gilchristi, have recently been shown to inhibit P. falciparum parasite growth. Therefore, a library of malonganenone analogues were synthesised for structure activity relationship analysis. A range of purines, purinones, and pyrimidines were alkylated with simple terpenoid chains to generate malonganenone A and B analogues, while malonganenone C analogues were made by acetylation or formylation, then methylation of terpenoid amines. The compounds were moderately active against P. falciparum infected red blood cells, but exhibited significant activity against Trypanosoma brucei, the parasite responsible for African sleeping sickness. Off target activity was assessed by assay against Escherichia coli, Staphylococcus aureus, Steptococcus uberis and HeLa cells. The overall structureactivity relationship analysis resulted in the identification of lead candidate, geranylgeranyl imidazole (146), which had IC50 values of 10.2 μM and 3.4 μM against P. falciparum and T. brucei, respectively. In addition, the minimum inhibitory concentration of 146 against S. uberis and S. aureus was 16 – 32 μM and 128 μM, respectively. Compound 146 was inactive against E. coli and was also non-toxic to HeLa cells. In addition, a geometric mixture of E and Z isomers at the alkene closest to the imidazole head group was more active than just the E isomer as for 146, which suggested the Z isomer was more active than the E isomer. Therefore, the lead compound identified within this project was the 2Z isomer of geranylgeranyl imidazole

Screening for Small Molecule Modulators of Trypanosoma brucei Hsp70 Chaperone Activity Based upon Alcyonarian Coral-Derived Natural Products

The Trypanosoma brucei Hsp70/J-protein machinery plays an essential role in survival, differentiation, and pathogenesis of the protozoan parasite, and is an emerging target against African Trypanosomiasis. This study evaluated a set of small molecules, inspired by the malonganenones and nuttingins, as modulators of the chaperone activity of the cytosolic heat inducible T. brucei Hsp70 and constitutive TbHsp70.4 proteins. The compounds were assessed for cytotoxicity on both the bloodstream form of T. b. brucei parasites and a mammalian cell line. The compounds were then investigated for their modulatory effect on the aggregation suppression and ATPase activities of the TbHsp70 proteins. A structure–activity relationship for the malonganenone-class of alkaloids is proposed based upon these results

Screening for small molecule modulators of Trypanosoma brucei Hsp70 chaperone activity based upon alcyonarian coral-derived natural products

The Trypanosoma brucei Hsp70/J-protein machinery plays an essential role in survival, differentiation, and pathogenesis of the protozoan parasite, and is an emerging target against African Trypanosomiasis. This study evaluated a set of small molecules, inspired by the malonganenones and nuttingins, as modulators of the chaperone activity of the cytosolic heat inducible T. brucei Hsp70 and constitutive TbHsp70.4 proteins. The compounds were assessed for cytotoxicity on both the bloodstream form of T. b. brucei parasites and a mammalian cell line. The compounds were then investigated for their modulatory effect on the aggregation suppression and ATPase activities of the TbHsp70 proteins. A structure–activity relationship for the malonganenone-class of alkaloids is proposed based upon these results

Screening for small molecule modulators of trypanosoma brucei HSP70 chaperone activity based upon alcyonarian coral-derived natural products

The Trypanosoma brucei Hsp70/J-protein machinery plays an essential role in survival, differentiation, and pathogenesis of the protozoan parasite, and is an emerging target against African Trypanosomiasis. This study evaluated a set of small molecules, inspired by the malonganenones and nuttingins, as modulators of the chaperone activity of the cytosolic heat inducible T. brucei Hsp70 and constitutive TbHsp70.4 proteins. The compounds were assessed for cytotoxicity on both the bloodstream form of T. b. brucei parasites and a mammalian cell line. The compounds were then investigated for their modulatory effect on the aggregation suppression and ATPase activities of the TbHsp70 proteins. A structure–activity relationship for the malonganenone-class of alkaloids is proposed based upon these results

Metagenomic Exploration of the Marine Sponge Mycale hentscheli Uncovers Multiple Polyketide-Producing Bacterial Symbionts

Mycale hentscheli is a marine sponge that is rich in bioactive small molecules. Here, we use direct metagenomic sequencing to elucidate highly complete and contiguous genomes for the major symbiotic bacteria of this sponge. We identify complete biosynthetic pathways for the three potent cytotoxic polyketides which have previously been isolated from M. hentscheli. Remarkably, and in contrast to previous studies of marine sponges, we attribute each of these metabolites to a different producing microbe. We also find that the microbiome of M. hentscheli is stably maintained among individuals, even over long periods of time. Collectively, our data suggest a cooperative mode of defensive symbiosis in which multiple symbiotic bacterial species cooperatively contribute to the defensive chemical arsenal of the holobiont.Marine sponges have been a prolific source of unique bioactive compounds that are presumed to act as a deterrent to predation. Many of these compounds have potential therapeutic applications; however, the lack of efficient and sustainable synthetic routes frequently limits clinical development. Here, we describe a metagenomic investigation of Mycale hentscheli, a chemically gifted marine sponge that possesses multiple distinct chemotypes. We applied shotgun metagenomic sequencing, hybrid assembly of short- and long-read data, and metagenomic binning to obtain a comprehensive picture of the microbiome of five specimens, spanning three chemotypes. Our data revealed multiple producing species, each having relatively modest secondary metabolomes, that contribute collectively to the chemical arsenal of the holobiont. We assembled complete genomes for multiple new genera, including two species that produce the cytotoxic polyketides pateamine and mycalamide, as well as a third high-abundance symbiont harboring a proteusin-type biosynthetic pathway that appears to encode a new polytheonamide-like compound. We also identified an additional 188 biosynthetic gene clusters, including a pathway for biosynthesis of peloruside. These results suggest that multiple species cooperatively contribute to defensive symbiosis in M. hentscheli and reveal that the taxonomic diversity of secondary-metabolite-producing sponge symbionts is larger and richer than previously recognized