Hayat, D. | bioRxiv Science

bioRxiv2019

Regulation of the 20S proteasome by a novel family of inhibitory proteins

The protein degradation machinery plays a critical role in the maintenance of cellular homeostasis, preventing the accumulation of damaged or misfolded proteins and controlling the levels of regulatory proteins. The 20S proteasome degradation machinery is able to cleave any protein with a partially unfolded region, however uncontrolled degradation of the myriad of potential substrates is improbable. Thus, there must exist a regulatory mechanism to control 20S proteasome mediated degradation. Here we have discovered a family of 20S proteasome regulators, named Catalytic Core Regulators (CCRs). They coordinate the function of the 20S proteasome and are involved in the oxidative stress response via Nrf2. The CCRs organize into a feed-forward loop regulatory circuit, with some members stabilizing Nrf2, others being induced by Nrf2, and all of them inhibiting the 20S proteasome. This provides a fine-tuned mechanism to carefully modulate the 20S proteasome, ensuring its proper functioning by controlling the degradative flux.

biochemistry↗

bioRxiv2018

Anesthesia-induced loss of consciousness disrupts auditory responses beyond primary cortex

Despite its ubiquitous use in medicine, and extensive knowledge of its molecular and cellular effects, how anesthesia induces loss of consciousness (LOC) and affects sensory processing remains poorly understood. Specifically, it is unclear whether anesthesia primarily disrupts thalamocortical relay or intercortical signaling. Here we recorded intracranial EEG (iEEG), local field potentials (LFPs), and single-unit activity in patients during wakefulness and light anesthesia. Propofol infusion was gradually increased while auditory stimuli were presented and patients responded to a target stimulus until they became unresponsive. We found widespread iEEG responses in association cortices during wakefulness, which were attenuated and restricted to auditory regions upon LOC. Neuronal spiking and LFP responses in primary auditory cortex (PAC) persisted after LOC, while responses in higher-order auditory regions were variable, with neuronal spiking largely attenuated. Gamma power induced by word stimuli increased after LOC while its frequency profile slowed, thus differing from local spiking activity. In summary, anesthesia-induced LOC disrupts auditory processing in association cortices while relatively sparing responses in PAC, opening new avenues for future research into mechanisms of LOC and the design of anesthetic monitoring devices.

neuroscience↗