Biology subjects

Leemans, M.

Publications and source records attributed to Leemans, M..

4 recordsLinked to original sources

bioRxiv2023

A computationally informed comparison between the strategies of humans and rodents in visual object recognition

Many species are able to recognize objects, but it has been proven difficult to pinpoint and compare how different species solve this task. Recent research suggested to combine computational and animal modelling in order to obtain a more systematic understanding of task complexity and compare strategies between species. In the present study, we created a large multidimensional stimulus set and designed a visual discrimination task partially based upon modelling with a convolutional deep neural network (CNN). Experiments included rats (N = 11; 1115 daily sessions in total for all rats together) and humans (N = 45). Each species was able to master the task and generalize to a variety of new images. Nevertheless, rats and humans showed very little convergence in terms of which object pairs were associated with high and low performance, suggesting the use of different strategies. There was an interaction between species and whether stimulus pairs favoured early or late processing in a CNN. A direct comparison with CNN representations and visual feature analyses revealed that rat performance was best captured by late convolutional layers and partially by visual features such as brightness and pixel-level similarity, while human performance related more to the higher-up fully connected layers. These findings highlight the additional value of using a computational approach for the design of object recognition tasks. Overall, this computationally informed investigation of object recognition behaviour reveals a strong discrepancy in strategies between rodent and human vision.

neuroscience↗

bioRxiv2020

ZIKA virus effects on neuroprogenitors are exacerbated by the main pyriproxyfen metabolite via thyroid hormone signaling disruption

North-Eastern Brazil saw intensive application of the insecticide pyriproxyfen (PPF) during the microcephaly outbreak caused by Zika virus (ZIKV). ZIKV requires the neural RNA-binding protein Musashi-1 to replicate. TH represses MSI1. Being a suspected TH disruptor, we hypothesized that co-exposure to the main metabolite of PPF, 4-OH-PPF, would exacerbate ZIKV effects through increased MSI1 expression. This was tested using in vitro mouse neurospheres and an in vivo TH signaling reporter model, Xenopus laevis. TH signaling was decreased by 4-OH-PPF in both models. In mouse-derived neurospheres the metabolite reduced neuroprogenitor proliferation as well as markers of neuronal differentiation. The results demonstrated that 4-OH-PPF significantly induced MSI1 at both the mRNA and protein level, as well as Fasn mRNA. Other TH target genes were also significantly modified. Importantly, several key genes implicated in neuroprogenitor fate and commitment were not dysregulated by 4-OH-PPF alone, but were in combination with ZIKV infection. These included the neuroprogenitor markers Nestin, Egfr, Gfap, Dlx2 and Dcx. Unexpectedly, 4-OH-PPF decreased ZIKV replication, although only at the fourth and last day of incubation, and RNA copy numbers stayed within the same order of magnitude. However, intracellular RNA content of neuroprogenitors was significantly decreased in the combined presence of the PPF metabolite and ZIKV. We conclude that 4-OH-PPF interferes with TH action in vivo and in vitro, inhibiting neuroprogenitor proliferation. In the presence of ZIKV, TH signaling pathways crucial for cortical development are significantly impacted. This provides another example of viral effects that are exacerbated by drug or pesticide use. Significance statementIn 2015, an increase in children born with unusually small heads (microcephaly) in North-Eastern Brazil was linked to infection with the ZIKA virus. An insecticide with thyroid hormone disruptive properties was used in the same areas. We investigated whether simultaneous exposure to the insecticide could increase viral susceptibility. The main metabolite 4-OH-PPF dysregulated thyroid hormone signaling pathways crucial for brain development in both models used. Neural stem cells proliferated less and contained more Musashi-1, a protein the virus needs to replicate. Infecting stem cells pre-exposed to the endocrine disruptor did not amplify viral replication, but aggravated expression of genes implicated in brain development. Our results suggest the insecticide is particularly deleterious to brain development in areas with ZIKA virus prevalence.

neuroscience↗

bioRxiv2018

The pyriproxyfen metabolite 4’OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors

Epidemiological and experimental studies have raised questions as to whether the insecticide pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) disrupting chemical. We investigated whether environmentally relevant amounts of its main metabolite, 4-OH-pyriproxyfen (4-OH-PPF), modified TH signaling and early neuronal development. First, an in silico study revealed strong affinity of 4-OH-PPF to fit the ligand binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4OH-PPF (> 3 mg/L) to act as a TR antagonist. Next, using a transgenic Xenopus TH-sensitive reporter system, Tg(thibz:GFP) tadpoles showed that 4OH-PPF (> 10-7 mg/L) displayed TH-disruptive activity and reduced tadpole mobility (> 10-1 mg/L). Exposure to 4OH-PPF significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily intake of PPF (3x 10-1 mg/L). Most strikingly, in both the Xenopus system in vivo and in mouse neurosphere cultures, environmentally relevant concentrations of 4OH-PPF increased expression of the gene encoding an RNA-binding protein that enables ZIKA replication: Musashi-1 (msi1) in neurogenic brain areas. We conclude that first, the PPF metabolite, 4OH-PPF, disrupts thyroid signaling, neuronal development and behavior in Xenopus embryos, and second, that it increases Musashi-1 levels in neurogenic zones of both mouse and Xenopus, creating the potential to enhance viral replication. As PPF is used in areas with high microcephaly incidence and is readily broken down to 4OH-PPF, these findings provide a plausible mechanism whereby PPF could, through modulating expression of Musashi-1, exacerbate the effects of ZIKA virus infection.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC=\"FIGDIR/small/352088_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (23K):\norg.highwire.dtl.DTLVardef@12f397borg.highwire.dtl.DTLVardef@166bbdforg.highwire.dtl.DTLVardef@1b83665org.highwire.dtl.DTLVardef@fb5a30_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2017

From Cohorts to Molecules: Adverse Impacts of Endocrine Disrupting Mixtures

Convergent evidence associates endocrine disrupting chemicals (EDCs) with major, increasingly-prevalent human disorders. Regulation requires elucidation of EDC-triggered molecular events causally linked to adverse health outcomes, but two factors limit their identification. First, experiments frequently use individual chemicals, whereas real life entails simultaneous exposure to multiple EDCs. Second, population-based and experimental studies are seldom integrated. This drawback was exacerbated until recently by lack of physiopathologically meaningful human experimental systems that link epidemiological data with results from model organisms.\n\nWe developed a novel approach, integrating epidemiological with experimental evidence. Starting from 1,874 mother-child pairs we identified mixtures of chemicals, measured during early pregnancy, associated with language delay or low-birth weight in offspring. These mixtures were then tested on multiple complementary in vitro and in vivo models. We demonstrate that each EDC mixture, at levels found in pregnant women, disrupts hormone-regulated and disease-relevant gene regulatory networks at both the cellular and organismal scale.

molecular biology↗