ORCID Profile
0000-0002-6677-2797
Current Organisations
University of Queensland
,
University of Manchester
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Publisher: Springer Science and Business Media LLC
Date: 12-11-2022
DOI: 10.1038/S41467-022-34735-2
Abstract: Therapeutic hypothermia at 32-34 °C during or after cerebral ischaemia is neuroprotective. However, peripheral cold sensor-triggered hypothermia is ineffective and evokes vigorous counteractive shivering thermogenesis and complications that are difficult to tolerate in awake patients. Here, we show in mice that deep brain stimulation (DBS) of warm-sensitive neurones (WSNs) in the medial preoptic nucleus (MPN) produces tolerable hypothermia. In contrast to surface cooling-evoked hypothermia, DBS mice exhibit a torpor-like state without counteractive shivering. Like hypothermia evoked by chemogenetic activation of WSNs, DBS in free-moving mice elicits a rapid lowering of the core body temperature to 32-34 °C, which confers significant brain protection and motor function reservation. Mechanistically, activation of WSNs contributes to DBS-evoked hypothermia. Inhibition of WSNs prevents DBS-evoked hypothermia. Maintaining the core body temperature at normothermia during DBS abolishes DBS-mediated brain protection. Thus, the MPN is a DBS target to evoke tolerable therapeutic hypothermia for stroke treatment.
Publisher: Research Square Platform LLC
Date: 28-09-2023
Publisher: Research Square Platform LLC
Date: 29-05-2023
DOI: 10.21203/RS.3.RS-2922796/V1
Abstract: Directed evolution of computationally designed enzymes has provided new insights into the emergence of sophisticated catalytic sites in proteins. In this regard, we have recently shown that a histidine nucleophile and a flexible arginine can work in synergy to accelerate the Morita-Baylis-Hillman (MBH) reaction with unrivalled efficiency. Here, we show that replacing the catalytic histidine with a non-canonical N δ -methylhistidine (MeHis23) nucleophile leads to a substantially altered evolutionary outcome in which the catalytic Arg124 has been abandoned. Instead, a Glu26 has emerged, which mediates a rate-limiting proton transfer step to deliver an enzyme (BH MeHis 1.8) that is an order of magnitude more active than our earlier MBHase. Interestingly, the MeHis nucleophile of BH MeHis 1.8 can be replaced by a canonical histidine with only a modest, 4-fold reduction in k cat . However, analysis of the BH MeHis 1.8 evolutionary trajectory reveals that the non-canonical nucleophile was crucial in the early stages of engineering to unlock the new mechanistic pathway. This study demonstrates how even subtle perturbations to key catalytic elements of designed enzymes can lead to vastly different evolutionary outcomes, resulting in new mechanistic solutions to complex chemical transformations.
Publisher: Frontiers Media SA
Date: 13-12-2021
DOI: 10.3389/FNINS.2021.777183
Abstract: Previous studies showed that entrainment of light flicker at low gamma frequencies provided neuroprotection in mouse models of Alzheimer’s disease (AD) and stroke. The current study was set to explore the feasibility of using 40 Hz light flicker for human brain stimulation for future development as a tool for brain disease treatment. The effect of 40 Hz low gamma frequency light on a cohort of healthy human brains was examined using 64 channel electroencephalography (EEG), followed by microstate analyses. A random frequency light flicker was used as a negative control treatment. Light flicker at 40 Hz significantly increased the corresponding band power in the O1, Oz, and O3 electrodes covering the occipital areas of both sides of the brain, indicating potent entrainment with 40 Hz light flicker in the visual cortex area. Importantly, the 40 Hz light flicker significantly altered microstate coverage, transition duration, and the Lempel-Ziv complexity (LZC) compared to the rest state. Microstate metrics are known to change in the brains of Alzheimer’s disease, schizophrenia, and stroke patients. The current study laid the foundation for the future development of 40 Hz light flicker as therapeutics for brain diseases.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Tom Lister.