Morphological response accompanying size reduction of belemnites during an Early Jurassic hyperthermal event modulated by life history

International audienceOne of the most common responses of marine ectotherms to rapid warming is a reduction in body size, but the underlying reasons are unclear. Body size reductions have been documented alongside rapid warming events in the fossil record, such as across the Pliensbachian-Toarcian boundary (PToB) event (~ 183 Mya). As individuals grow, parallel changes in morphology can indicate details of their ecological response to environmental crises, such as changes in resource acquisition, which may anticipate future climate impacts. Here we show that the morphological growth of a marine predator belemnite species (extinct coleoid cephalopods) changed significantly over the PToB warming event. Increasing robustness at different ontogenetic stages likely results from indirect consequences of warming, like resource scarcity or hypercalcification, pointing toward varying ecological tolerances among species. The results of this study stress the importance of taking life history into account as well as phylogeny when studying impacts of environmental stressors on marine organisms

The impact of the Pliensbachian–Toarcian crisis on belemnite assemblages and size distribution

The second-order Pliensbachian–Toarcian crisis affected major groups of marine organisms. While its impact has been intensively studied for ammonites, the response of belemnites is only currently emerging through quantitative studies. Novel overall and regional diversity analyses suggest that belemnite richness in the NW-Tethys drops at the Pliensbachian–Toarcian boundary, while overall diversity slightly increases in NW-Tethys assemblages during the Toarcian Oceanic Anoxic event (T-OAE), mostly driven by NW European assemblages (e.g., Yorkshire). The T-OAE coincides with marked taxonomic turnover within individual basins, which is associated with an increase in median rostrum size of specimens in taxa at most localities. The changes in median body size across the Pliensbachian–Toarcian boundary are less consistent and driven by changes in body size within individual lineages crossing the boundary. However, our analyses also illustrate differences in sampling across the Pliensbachian–Toarcian crisis, which needs to be considered in further studies. © 2021, The Author(s).Open Access funding enabled and organized by Projekt DEAL. KDB, PN and PR were supported by the DFG (Ba 5148/1-1, Ba 5148/1-2 to KDB). This research benefitted from a Synthesys Grant to Patricia Rita

A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects

Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo. Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography–tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method. Results: CPL500036 inhibited PDE10A at an IC(50) of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC(50) of 9.2 µM. Despite inhibiting hERG tail current at an IC(25) of 3.2 μM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 μM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg. Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate