Biology subjects

Nimmo, D.

Publications and source records attributed to Nimmo, D..

3 recordsLinked to original sources

bioRxiv2023

Specific cPRC1 complexes are co-opted to mediate oncogenic gene repression in diffuse midline glioma

Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 by inhibiting PRC2 enzymatic activity. Paradoxically, PRC2 is essential in DMG tumour cells where residual complex activity is required for oncogenic gene repression, although the molecular mechanisms acting downstream of PRC2 in this context are poorly understood. Here, weve discovered this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4 and PCGF4 drive oncogenic gene repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 modification landscape characteristic of these tumours rewires the distribution of cPRC1 complexes on chromatin. CBX4 and PCGF4 containing cPRC1 accumulate at sites of H3K27me3 while other cPRC1 formations are displaced. Despite accounting for <5% of cPRC1 complexes in DMG, CBX4/PCGF4-containing complexes predominate as gene repressors. Our findings link the altered distribution of H3K27me3 with imbalanced cPRC1 function, promoting oncogenic gene repression in DMG cells, revealing new disease mechanisms and highlighting potential therapeutic opportunities in this incurable childhood brain tumour.

cancer biology↗

bioRxiv2023

How best to co-deploy insecticides to minimise selection for resistance.

Insecticides are widely used to control the insects that spread human infectious diseases, in particular falciparum malaria. This widespread use has driven insecticide resistance (IR) to high levels that may threaten the effectiveness of future control programmes. There is interest in identifying deployment methods that alleviate the pressures driving IR and we investigate three. Mixtures are, as already known, highly effective in slowing IR providing their effectiveness (ability to kill fully sensitive insects) remain close to 100%. Mixtures may be expensive and/or operationally difficult so two alternatives to mixtures were investigated. Panels, where different insecticides are physically closely adjacent, for examples, different panels on the same bednet; mosquitoes may therefore encounter both insecticides in the same foraging cycle. Micro-mosaics where different insecticides are deployed in slightly wider geographic proximity, for example in adjacent dwellings. The mosquitoes are unlikely to encountered both insecticides in the same foraging cycle but may encounter different insecticides in subsequent foraging. It is hoped that panels and/or micro-mosaics may, by allowing individual mosquitoes to potentially encounter both insecticides, be effective, lower-cost alternatives to mixtures. Our results suggest this is unlikely to be the case. When insecticides are fully effective then mixtures remain clearly the best strategy. As effectiveness falls then all three strategies are roughly equal. The operational decision of what deployment methods to use depends on how confident we are that insecticides will have high effectiveness that will be maintained in realistic field conditions post-deployment.

genetics↗

bioRxiv2022

VECTRON™ T500, a new broflanilide insecticide for indoor residual spraying, provides prolonged control of pyrethroid-resistant malaria vectors

BackgroundBroflanilide is a newly discovered insecticide with a novel mode of action targeting insect {gamma}-aminobutyric acid receptors. The efficacy of VECTRON T500, a wettable powder formulation of broflanilide, was assessed for IRS against wild pyrethroid-resistant malaria vectors in experimental huts in Benin. MethodsVECTRON T500 was evaluated at 100 mg/m{superscript 2} in mud and cement-walled experimental huts against wild pyrethroid-resistant Anopheles gambiae sensu lato (s.l.) in Cove, southern Benin, over 18 months. A direct comparison was made with Actellic(R) 300CS, a WHO-recommended micro-encapsulated formulation of pirimiphos-methyl, applied at 1000 mg/m{superscript 2}. The vector population at Cove was investigated for susceptibility to broflanilide and other classes of insecticides used for vector control. Monthly wall cone bioassays were performed to assess the residual efficacy of VECTRON T500 using insecticide susceptible An. gambiae Kisumu and pyrethroid-resistant An. gambiae s.l. Cove strains. The study complied with OECD principles of good laboratory practice. ResultsThe vector population at Cove was resistant to pyrethroids and organochlorines but susceptible to broflanilide and pirimiphos-methyl. A total of 23,171 free-flying wild pyrethroid-resistant female An. gambiae s.l. were collected in the experimental huts over 12 months. VECTRON T500 induced 56%-60% mortality in wild vector mosquitoes in both cement and mud-walled huts. Mortality with VECTRON T500 was 62%-73% in the first three months and remained >50% for 9 months on both substrate-types. By comparison, mortality with Actellic(R) 300CS was very high in the first three months (72%-95%) but declined sharply to <40% after 4 months. Using a non-inferiority margin defined by the World Health Organization, overall mortality achieved with VECTRON T500 was non-inferior to that observed in huts treated with Actellic(R) 300CS with both cement and mud wall substrates. Monthly in situ wall cone bioassay mortality with VECTRON T500 also remained over 80 % for 18 months but dropped below 80% with Actellic(R) 300CS at 6-7 months post spraying. ConclusionVECTRON T500 shows potential to provide substantial and prolonged control of malaria transmitted by pyrethroid-resistant mosquito vectors when applied for IRS. Its addition to the current list of WHO-approved IRS insecticides will provide a suitable option to facilitate rotation of IRS products with different modes of action.

zoology↗