Biology subjects

South, A.

Publications and source records attributed to South, A..

6 recordsLinked to original sources

bioRxiv2025

Mathematical Modeling of Cancer Cell Invasion of Tissue: Development of an in silico Organotypic Assay

BackgroundOrganotypic assays are three-dimensional in vitro models widely used in cancer research to mimic the in vivo extracellular matrix (ECM) and to study cancer cell invasion by allowing investigation of critical interactions between tumor cells and their microenvironment. During invasion, cancer cells undergo genetic and epigenetic changes that disrupt cell-cell adhesion, enabling detachment from the primary tumor. Subsequently, invasive cells must (i) breach the basement membrane, a dense protein meshwork that restricts cell movement, and (ii) migrate through the surrounding ECM. This process relies on proteolytic enzyme secretion to degrade structural barriers, followed by cell-matrix adhesion-mediated migration. MethodsWe present an in silico model of cancer cell invasion in organotypic assays. The model is formulated as a system of partial differential equations capturing spatiotemporal dynamics, with nonlocal terms representing preferential adhesion-driven movement. Key variables in the model are cancer cells, proteolytic enzymes, and the ECM. ResultsComputational simulations demonstrate that modulation of cell-cell and cell-matrix adhesion parameters significantly influences tumor invasiveness. This result is consistent with experimental observations, demonstrating the models ability to accurately reflect in vitro behavior.

biophysics↗

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

Evaluating rotations as a strategy to delay the evolution of insecticide resistance in vectors of human diseases.

IntroductionInsecticide resistance threatens the control of important human vector-borne diseases such as malaria and dengue. The current de facto strategy is to target the insect vectors using a sequential deployment of insecticides i.e. use one insecticide (usually the cheapest available) until resistance has made it ineffective and then replace it with the next insecticide in the repertoire. Rotations of insecticides are often advocated as a potentially superior method of using the insecticide repertoire to delay the evolution of resistance. Testing this hypothesis in the field is logistically demanding and an in silico approach offers a much faster, flexible and transparent method of evaluating rotations. MethodsWe develop an in silico approach to evaluate rotations using sequential deployment as the baseline. We explored a wide range of deployment scenarios, underlying genetics of resistance, and incorporated costs of resistance and gene flow to/from untreated refugia. ResultsWe found that, under most circumstances, resistance to all the insecticides in the repertoire were reached at very similar times for rotations and sequences. Any advantages of one strategy over the other tended to be small (typically <10%) and unpredictable. ConclusionsOperational factors, such as cost or supply-chain security, may therefore largely determine the optimal choice of insecticide deployment strategies.

evolutionary biology↗

bioRxiv2021

Cuticular hydrocarbons are associated with mating success and insecticide resistance in malaria vectors

Anopheles coluzzii females, important malaria vectors in Africa, mate only once in their lifetime. Mating occurs in aerial swarms with a high male-to-female ratio, where the traits underlying male mating success are largely unknown. Here, we investigated whether cuticular hydrocarbons (CHCs) influence mating success in natural mating swarms in Burkina Faso. As insecticides are widely used in this area for malaria control, we also determined whether CHCs affect insecticide resistance levels. We find that mated males have higher CHC abundance than unmated controls, suggesting CHCs could be a determinant of mating success. Additionally, mated males have higher insecticide resistance under pyrethroid challenge, and we show a link between resistance intensity and CHC abundance. Taken together, our results reveal overlapping roles played by CHCs in mate choice and insecticide resistance, and point to sexual selection for insecticide resistance traits that limit the efficacy of our best malaria control tools.

ecology↗

bioRxiv2020

A mating-induced reproductive gene promotes Anopheles tolerance to Plasmodium falciparum infection

Anopheles mosquitoes have transmitted Plasmodium parasites for millions of years, yet it remains unclear whether they suffer fitness costs to infection. Here we report that the fecundity of virgin and mated females of two important vectors--Anopheles gambiae and Anopheles stephensi--is not affected by infection with Plasmodium falciparum, demonstrating that these human malaria parasites do not inflict reproductive costs to their natural mosquito hosts. Additionally, parasite development is not impacted by mating status. However, in field studies using different P. falciparum isolates in Anopheles coluzzii, we find that Mating-Induced Stimulator of Oogenesis (MISO), a female reproductive gene strongly induced after mating by the sexual transfer of the steroid hormone 20-hydroxyecdysone (20E), protects females from incurring fecundity costs to infection. MISO-silenced females produce fewer eggs as they become increasingly infected with P. falciparum, while parasite development is not impacted by this gene silencing. Interestingly, previous work had shown that sexual transfer of 20E has specifically evolved in Cellia species of the Anopheles genus, driving the co-adaptation of MISO. Our data therefore suggest that evolution of male-female sexual interactions may have promoted Anopheles tolerance to P. falciparum infection in the Cellia subgenus, which comprises the most important malaria vectors. Author summaryPlasmodium falciparum, the deadliest form of human malaria, is transmitted when female Anopheles mosquitoes bite people and take a blood meal in order to develop eggs. To date, it is still poorly understood whether Anopheles mosquitoes that get infected with P. falciparum suffer fitness costs. Here, we find that the number of eggs produced by Anopheles gambiae and Anopheles stephensi females is not affected by P. falciparum infection, and that the mating status of the mosquitoes does not impact the parasite. However, in field experiments infecting a related species, Anopheles coluzzii, with P. falciparum using blood from donors in Burkina Faso, we find that interfering with the expression of a gene normally triggered by the sexual transfer of the steroid hormone 20-hydroxyecdysone induces increasing costs to egg development as females become more infected with P. falciparum, with no impacts on the parasite. The results of our study suggest that pathways triggered by mating may help Anopheles prevent reproductive costs associated with P. falciparum infection, providing new insights into evolutionary strategies adopted by anophelines in the face of a longstanding association with Plasmodium parasites.

microbiology↗

bioRxiv2020

JNK signaling regulates oviposition in the malaria vector Anopheles gambiae

The reproductive fitness of the Anopheles gambiae mosquito represents a promising target to prevent malaria transmission. The ecdysteroid hormone 20-hydroxyecdysone (20E), transferred from male to female during copulation, is key to An. gambiae reproductive success as it licenses females to oviposit eggs developed after blood feeding. Here we show that 20E-triggered oviposition in these mosquitoes is regulated by the stress- and immune-responsive c-Jun N-terminal kinase (JNK). The heads of mated females exhibit a transcriptional signature reminiscent of a JNK-dependent wounding response while mating -- or injection of virgins with exogenous 20E -- selectively activates JNK in the same tissue. RNAi-mediated depletion of JNK pathway components inhibits oviposition in mated females, whereas JNK activation by silencing the JNK phosphatase puckered induces egg laying in virgins. Together, these data identify JNK as a potential conduit linking stress responses and reproductive success in the most important vector of malaria.

animal behavior and cognition↗