Biology subjects

Ashcroft, F.

Publications and source records attributed to Ashcroft, F..

3 recordsLinked to original sources

bioRxiv2021

Adipogenic activity of chemicals used in plastic consumer products

Bisphenols and phthalates, chemicals frequently used in plastic products, promote obesity in cell and animal models. However, these well-known metabolism disrupting chemicals (MDCs) represent only a minute fraction of all compounds found in plastics. To gain a comprehensive understanding of plastics as a source of exposure to MDCs, we characterized all chemicals present in 34 everyday products using nontarget high-resolution mass spectrometry and analyzed their joint adipogenic activities by high-content imaging. We detected 55,300 chemical features and tentatively identified 629 unique compounds, including 11 known MDCs. Importantly, chemicals that induced proliferation, growth, and triglyceride accumulation in 3T3-L1 adipocytes were found in one third of the products. Since the majority did not target peroxisome proliferator-activated receptor {gamma}, the effects are likely to be caused by unknown MDCs. Our study demonstrates that daily-use plastics contain potent mixtures of MDCs and can, therefore, be a relevant yet underestimated environmental factor contributing to obesity. TeaserPlastics contain a potent mixture of chemicals promoting adipogenesis, a key process in developing obesity.

pharmacology and toxicology↗

bioRxiv2021

Logical and experimental modeling of cytokine and eicosanoid signaling in psoriatic keratinocytes

Psoriasis is characterized by chronic inflammation, perpetuated by a Th17-dependent signaling loop between the immune system and keratinocytes that could involve phospholipase A2 (PLA2)-dependent eicosanoid release. A prior knowledge network supported by experimental observations was used to encode the regulatory network of psoriatic keratinocytes in a computational model for studying the mode of action of a cytosolic (c) PLA2 inhibitor. A combination of evidence derived from the computational model and experimental data suggests that Th17 cytokines stimulate pro-inflammatory cytokine expression in psoriatic keratinocytes via activation of cPLA2-PGE2-EP4 signaling, which could be suppressed using the anti-psoriatic calcipotriol. cPLA2 inhibition and calcipotriol showed overlapping and distinct modes of action. Model analyses revealed the immunomodulatory role of Th1 cytokines, the modulation of the physiological states of keratinocytes by Th17 cytokines, and how Th1 and Th17 cells together promote the development of psoriasis. Model simulations additionally suggest novel drug targets, including EP4 and PRKACA, for treatment that may restore a normal phenotype. Our work illustrates how the study of complex diseases can benefit from an integrated systems approach.

systems biology↗

bioRxiv2020

Dissection-independent production of a protective whole-sporozoite malaria vaccine

Complete protection against human malaria challenge has been achieved using infected mosquitoes as the delivery route for immunization with Plasmodium parasites. Strategies seeking to replicate this efficacy with either a manufactured whole-parasite or subunit vaccine, however, have shown only limited success. A major roadblock to whole parasite vaccine progress and understanding of the human infective sporozoite form in general, is reliance on manual dissection for parasite isolation from infected mosquitoes. We report here the development of a four-step process based on whole mosquito homogenization, slurry and density-gradient filtration, combined with free-flow electrophoresis that is able to rapidly produce a pure, aseptic sporozoite inoculum from hundreds of mosquitoes. Murine P. berghei or human-infective P. falciparum sporozoites produced in this way are 2-3-fold more infective with in vitro hepatocytes and can confer sterile protection when immunized intravenously with subsequent challenge using a mouse malaria model. Critically, we can also demonstrate for the first time 60-70% protection when the same parasites are administered via intramuscular (i.m.) route. In developing a process amenable to industrialisation and demonstrating efficacy by i.m. route these data represent a major advancement in capacity to produce a whole parasite malaria vaccine at scale. One-Sentence SummaryA four-step process for isolating pure infective malaria parasite sporozoites at scale from homogenized whole mosquitoes, independent of manual dissection, is able to produce a whole parasite vaccine inoculum that confers sterilizing protection.

microbiology↗