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Paoli, E.

Publications and source records attributed to Paoli, E..

2 recordsLinked to original sources

The Preoptic Area and Dorsal Habenula Jointly Support Homeostatic Navigation in Larval Zebrafish

Animals must maintain physiological processes within an optimal temperature range despite changes in their environment. While the preoptic area of the hypothalamus (PoA) acts as a thermostat in mammals through autonomic and behavioral adaptations, its role in temperature regulation of animals lacking internal homeostatic mechanisms is not known. Through novel behavioral assays, wholebrain functional imaging and neural ablations, we show that larval zebrafish achieve thermoregulation through movement and a neural network connecting the PoA to brain areas enabling spatial navigation. PoA drives reorientation when thermal conditions are worsening and conveys this information for instructing future motor actions to the navigation-controlling habenula (Hb) - interpeduncular nucleus (IPN) circuit. These results suggest a conserved function of the PoA in thermoregulation acting through species- specific neural networks. We propose that homeostatic navigation arose from an ancient chemotaxis navigation circuit that was subsequently extended to serve in other sensory modalities.

neuroscience↗

Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity against Hepatitis B Virus

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify replication inhibitors. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) an ester prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as an increased H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS-5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious from the in vitro model. Here we discuss potential reasons for the disconnect between in vitro and in vivo efficacy, which highlight the translational difficulties of epigenetic targets for viral diseases.

pharmacology and toxicology↗