Biology subjects

Clark, J. S.

Publications and source records attributed to Clark, J. S..

5 recordsLinked to original sources

bioRxiv2026

Preclinical evaluation of Brincidofovir in glioblastoma demonstrates improved long term-survival and cytomegalovirus-dependent and independent effects

Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM) progression. Ongoing clinical trials are assessing therapeutic approaches targeting CMV in GBM but to date no new therapy has been approved outside the standard of care. Previous preclinical studies have highlighted the potential of the antiviral drug Cidofovir (CDV) in GBM; however, its clinical use is limited by dose-dependent nephrotoxicity and poor cellular uptake, necessitating high intravenous doses to achieve therapeutic activity. Brincidofovir (BCV), a lipid conjugate of CDV has been developed, which does not induce nephrotoxicity and has significantly greater cellular bioavailability. Here we examined the effects of BCV in a newly established CMV-driven GBM model (SB28) and in patient-derived tumor neurospheres. We show that BCV prolongs survival in vivo and exerts both CMV-dependent and independent antitumor effects. Mechanistically, BCV induces DNA damage and cell cycle dysregulation in GBM cells and inhibits proliferation of patient-derived neurospheres in a dose-dependent manner. These data identify BCV as a dual-action therapeutic that suppresses viral oncomodulation while directly targeting tumor cell viability.

cancer biology↗

bioRxiv2022

Beyond variance: simple random distributions are not a good proxy for intraspecific variability in systems with environmental structure

The role of intraspecific variability (IV) in shaping community dynamics and species coexistence has been intensively discussed over the past decade and modelling studies have played an important role in that respect. However, these studies often implicitly assume that IV can be represented by independent random draws around speciesspecific mean parameters. This major assumption has largely remained undiscussed, although a great part of observed IV is structured in space or time, in particular when environmental dimensions that influence individual performance are imperfectly characterised or unobserved in the field. To test the impact of this strong assumption on the outcome of community dynamics models, we designed a simulation experiment where we varied the level of knowledge of the environment in virtual communities, resulting in different relative importance of explained vs unexplained spatial individual variation in performance. We used a community dynamics simulator to generate communities where the unexplained individual variation is, or is not, added as an unstructured random noise. Communities simulated with unstructured IV never reached the community diversity and composition of those where all the variation was explained and structured (perfect knowledge model). This highlights that incorporating unstructured IV (i.e. a random noise) to account for unexplained (but structured) variation can lead to incorrect simulations of community dynamics. In addition, the effects of unstructured IV on community diversity and composition depended on the relative importance of structured vs unstructured IV, i.e. on the level of knowledge of the environment, which may partly explain the contrasting results of previous studies on the effect of IV on species coexistence. In particular, the effect of unstructured IV on community diversity was positive when the proportion of structured IV vs unstructured IV in the model was low, but negative when this proportion was high. This is because unstructured random noise can either limit the competitive exclusion of inferior competitors in low dimensions or destabilise tight niche partitioning in high dimension. Our study suggests that it is crucial to account for the sources and structure of observed IV in real communities to better understand its effect on community assembly and properly include it in community dynamics models.

ecology↗

bioRxiv2022

Rethinking the role of intraspecific variability in species coexistence

ContextIntraspecific variability (IV) has been proposed to explain species coexistence in diverse communities. Assuming, sometimes implicitly, that conspecific individuals can perform differently in the same environment and that IV blurs species differences, previous studies have found contrasting results regarding the effect of IV on species coexistence. ObjectiveWe aim at showing that the large IV observed in data does not mean that conspecific individuals are necessarily different in their response to the environment and that the role of high-dimensional environmental variation in determining IV has been largely underestimated in forest plant communities. Methods and ResultsWe first used a simulation experiment where an individual attribute is derived from a high-dimensional model, representing "perfect knowledge" of individual response to the environment, to illustrate how a large observed IV can result from "imperfect knowledge" of the environment. Second, using growth data from clonal Eucalyptus plantations in Brazil, we estimated a major contribution of the environment in determining individual growth. Third, using tree growth data from long-term tropical forest inventories in French Guiana, Panama and India, we showed that tree growth in tropical forests is structured spatially and that despite a large observed IV at the population level, conspecific individuals perform more similarly locally than compared with heterospecific individuals. SynthesisAs the number of environmental dimensions that are typically quantified is generally much lower than the actual number of environmental dimensions influencing individual attributes, a great part of observed IV might be misinterpreted as random variation across individuals when in fact it is environmentally-driven. This mis-representation has important consequences for inference about community dynamics. We emphasize that observed IV does not necessarily impact species coexistence per se but can reveal species response to high-dimensional environment, which is consistent with niche theory and the observation of the many differences between species in nature.

ecology↗

bioRxiv2019

Disturbance Sensitivity Shapes Patterns of Tree Species Distribution in Afrotropical Lowland Rainforests More Than Climate or Soil

Understanding how tropical forests respond to changes in the abiotic environment and human disturbance is critical for preserving biodiversity, mitigating climate change, and maintaining ecosystem services in the coming century. To evaluate the relative roles of the abiotic environment and disturbance on Afrotropical forest community composition we employ tree inventory data, remotely sensed historic climatic data, and soil nutrient data collected from 30 1-ha plots distributed across a large-scale observational experiment in previously logged, hunted, and pristine forests in northern Republic of Congo (Brazzaville). We show that Afrotropical plant communities are more sensitive to human disturbance than to climate, with particular sensitivities to hunting and distance to village (a proxy for other human activities, including tree-cutting, gathering, etc.). This study serves as an important counterpoint to work done in the Neotropics by providing contrasting predictions for Afrotropical forests with substantially different ecological, evolutionary, and anthropogenic histories.

ecology↗

bioRxiv2019

Afrotropical Tree Communities May Have Distinct Responses to Forecasted Climate Change

More refined knowledge of how tropical forests respond to changes in the abiotic environment and human disturbance is necessary to mitigating climate change, maintain biodiversity, and preserve ecosystem services. To evaluate the unique response of Afrotropical forests to changes in the abiotic environment and disturbance, we employ species inventories, remotely sensed historic climatic data, and future climate predictions collected from 104 1-ha plots in the central African country of Gabon. We forecast a 3 - 8% decrease in Afrotropical forest species richness by the end of the century, in contrast to the 30-50% loss of plant diversity predicted to occur with equivalent warming in the Neotropics. This work reveals that community forecasts are not generalizable across regions, and more representative studies are needed in understudied biomes like the Afrotropics. This study serves as an important counterpoint to work done in the Neotropics by providing contrasting predictions for Afrotropical forests with substantially different ecological, evolutionary, and anthropogenic histories.

ecology↗