Biology subjects

Walker, F.

Publications and source records attributed to Walker, F..

4 recordsLinked to original sources

bioRxiv2025

Synergistic Enhancement of Acetamiprid Toxicity by Herbicide and Fungicide: Triple Mixture Outperforms Binary Combination

Pesticides are considered a major driver of insect decline, and non-target organisms in agricultural landscapes are frequently exposed to complex mixtures of agrochemicals. However, despite extensive research on mixture toxicity, most studies have predominantly focused on binary combinations, well-known synergistic interactions, and insecticide-fungicide mixtures, while other pesticide classes such as herbicides and higher-order mixtures remain underrepresented. In this study, we investigated the effects of binary and ternary combinations of representative active substances from three major pesticide classes: acetamiprid (insecticide), fluopyram (fungicide), and terbuthylazine (herbicide). We conducted acute contact dose-response assays on the non-target insect Oncopeltus fasciatus. While only acetamiprid showed acute toxicity when applied individually, its combination with terbuthylazine significantly increased toxicity, reducing the median effective dose (ED50) by a factor of 2.7. A similar, although not statistically significant, trend was observed for the combination with fluopyram. The mixture of all three compounds resulted in a marked increase in toxicity, exceeding the effects observed in any binary or single-substance treatment. These mixture effects deviate from classical additivity assumptions and can be interpreted as a potentiation of acetamiprid toxicity. While potential causes are discussed, the underlying mechanisms remain unclear. Our findings add to the growing body of evidence suggesting that non-additive effects beyond well-established pesticide combinations may occur more frequently than previously assumed. The pronounced response in the ternary mixture further indicates that higher-order mixtures may pose particular challenges for environmental risk assessment. Although this study follows a conceptual approach, the selected substances and concentrations are aligned with agricultural use patterns. Overall, our results highlight the potential for unexpected mixture effects across pesticide classes and emphasize the need to account for such interactions in environmental risk assessment.

ecology↗

bioRxiv2024

The neonicotinoid acetamiprid is highly toxic to wild non-target insects

Although pesticides are seen as one of the main drivers of insect decline, there are still only few studies that assess their effects on non-target species under field conditions. Here we investigated the effects of the neonicotinoid insecticide Mospilan(R)SG (active ingredient acetamiprid) on plant bugs (Heteroptera: Miridae), a dominant group of European grassland insect communities. Abundance of three focal mirid species was reduced by up to 78% two days after field exposure at concentrations expected at field margins, with mortality varying considerably among species. Follow-up feeding assays with insecticide-treated host plants in the greenhouse and controlled dose-response assays in the laboratory confirmed the strong negative effects on non-target species. Strikingly, the neonicotinoid was nearly 10,000 times more toxic to plant bugs than to honeybees. In addition, male bugs were 20 times more sensitive than females in two of the three tested species. Thus, continuous exposure to neonicotinoids in the field may reduce the plant bug populations and promote a shift towards more insecticide-tolerant species, altering community composition. We suggest that sex-specific sensitivity should be considered in risk assessment and conclude that the real risk to non-target insects is currently greatly underestimated.

ecology↗

bioRxiv2021

Dual Drug Targeting to Kill Colon Cancer Cells

Colorectal cancer (CRC) is driven by a small set of oncogenic and tumor suppressor mutations. However, different combinations of mutations often lead to poor tumor responses to individual anti-cancer drugs. We have investigated the anti-proliferative and in vitro cytotoxic activity of pair-wise combinations of inhibitors which target specific signalling pathways. Colon cancer cells in non-adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro-apoptotic Bcl-2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumors. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumor cell apoptosis and reduced the rate of SW620 tumor growth. Combinations of Wnt signaling inhibitors and specific inhibitor of pro-survival proteins should be considered for the treatment of precancerous colon adenomas and advanced colorectal cancers with APC mutations.

cancer biology↗

bioRxiv2020

Super elongation complex as a targetable dependency in diffuse midline glioma

Mutations in the histone 3 gene (H3K27M) are the eponymous drivers in diffuse intrinsic pontine gliomas (DIPGs) and other diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. The salient molecular consequence of these recurrent oncohistones is a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify specific, therapeutically targetable epigenetic dependencies within this disease context, we performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived DMG cultures. This approach identified AFF4, the scaffold protein of the super elongation complex (SEC), as a previously-undescribed dependency in DMG. Interrogation of SEC function demonstrated a key role for maintaining DMG cell viability and clonogenic potential while promoting self-renewal of DMG tumor stem cells. Small-molecule inhibition of the SEC with the highly-specific, clinically relevant CDK9 inhibitors atuveciclib and AZD4573 restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a biologic rationale for translational exploration of CDK9 inhibition as a promising therapeutic approach in a disease which currently has no effective medical therapies.

cancer biology↗