No abstract

Sleep and body temperature are tightly interconnected in mammals: warming up our body helps to fall asleep and the body temperature in turn drops while falling asleep. The preoptic area of the hypothalamus (POA) serves as an essential brain region to coordinate sleep and body temperature. Understanding how these two behaviors are controlled within the POA requires the molecular identification of the involved circuits and mapping their local and brain-wide connectivity. Here, we review our current understanding of how sleep and body temperature are regulated with a focus on recently discovered sleep- and thermo-regulatory POA neurons. We further discuss unresolved key questions including the anatomical and functional overlap of sleep- and thermo-regulatory neurons, their pathways and the role of various signaling molecules. We suggest that analysis of genetically defined circuits will provide novel insights into the mechanisms underlying the coordinated regulation of sleep and body temperature in health and disease.

Protein–protein interactions (PPIs), many of which are dominated by α‐helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl‐2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl‐2 pro‐life proteins, such as Mcl‐1, and pro‐death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor‐suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl‐1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl‐1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl‐1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α‐helical domains of their partner proteins.