The three currently recognized T3 binding thyroid hormone receptor (TR) isoforms, TR alpha 1, TR beta 1, and TR beta 2, arise from two distinct genes (alpha and beta), whereas two closely related non-T3-binding receptor variants, collectively designated TR alpha 2, arise from alternate splicing of the alpha gene transcript. Using a panel of specific antisera to these isoforms we have assessed the presence or absence of TRs in oligodendrocytes and astrocytes of rat cerebrum and cerebellum. Inferences as to colocalization of the receptor isoforms and cell-specific marker proteins were based on immunohistochemical analysis of the differential emissions of paired immunofluorescent probes. Antisera against myelin basic protein (MBP) identified oligodendroglia, and glial fibrillary acidic protein identified astrocytes. MBP-positive oligodendrocytes displayed positive fluorescent signals with each of the three TR isoform-specific antisera and the antiserum to the receptor variants. These findings are consistent with the concept that the MBP gene is a direct target for thyroid hormone action. TR immunoreactivity appeared to localize primarily to the nuclei of these cells. In contrast, we observed no immunofluorescent signals for any of the TR isoforms in glial fibrillary acidic protein-positive astrocytes. These findings raise the possibility that any effect of thyroid hormone on astrocyte function and structure is mediated indirectly as a result of interaction of thyroid hormone with receptors situated in nonastrocyte cells or as a result of nonnuclear mechanisms.

Central pain disorders, such as central post-stroke pain, remain clinically challenging to treat, despite many decades of pharmacological advances and the evolution of neuromodulation. For treatment refractory cases, previous studies have highlighted some benefits of cortical stimulation. Recent advances in new targets for pain and the optimization of neuromodulation encouraged our group to develop a dual cortical target approach paired with Bayesian optimization to provide a personalized treatment. Here, we present a case report of a woman who developed left-sided facial pain after multiple thalamic strokes. All previous pharmacologic and interventional treatments failed to mitigate the pain, leaving her incapacitated due to pain and medication side effects. She subsequently underwent a single burr hole for placement of motor cortex (M1) and dorsolateral prefrontal cortex (dlPFC) paddles for stimulation with externalization. By using Bayesian optimization to find optimal stimulation parameters and stimulation sites, we were able to reduce pain from an 8.5/10 to a 0/10 during a 5-day inpatient stay, with pain staying at or below a 2/10 one-month post-procedure. We found optimal treatment to be simultaneous stimulation of M1 and dlPFC without any evidence of seizure induction. In addition, we found no worsening in cognitive performance during a working memory task with dlPFC stimulation. This personalized approach using Bayesian optimization may provide a new foundation for treating central pain and other functional disorders through systematic evaluation of stimulation parameters.

The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells requires binding of the viral spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor, which triggers subsequent conformational changes to facilitate viral and cellular fusion at the plasma membrane or following endocytosis. Here, we experimentally identified selective and broad inhibitors of SARS-CoV-2 entry that share a tricyclic ring (or similar) structure. The inhibitory effect was restricted to early steps during infection and the entry inhibitors interacted with the receptor binding domain of the SARS-CoV-2 spike but did not significantly interfere with receptor (ACE2) binding. Instead, some of these compounds induced conformational changes or affected spike assembly and blocked SARS-CoV-2 spike cell–cell fusion activity. The broad inhibitors define a highly conserved binding pocket that is present on the spikes of SARS-CoV-1, SARS-CoV-2, and all circulating SARS-CoV-2 variants tested and block SARS-CoV spike activity required for mediating viral entry. These compounds provide new insights into the SARS-CoV-2 spike topography, as well as into critical steps on the entry pathway, and can serve as lead candidates for the development of broad-range entry inhibitors against SARS-CoVs.

IntroductionCortical spreading depolarisation (CSD) is characterised by a near-complete loss of the ionic membrane potential of cortical neurons and glia propagating across the cerebral cortex, which generates a transient suppression of spontaneous neuronal activity. CSDs have become a recognised phenomenon that imparts ongoing secondary insults after brain injury. Studies delineating CSD generation and propagation in humans after traumatic brain injury (TBI) are lacking. Therefore, this study aims to determine the feasibility of using a multistrip electrode array to identify CSDs and characterise their propagation in space and time after TBI.Methods and analysisThis pilot, prospective observational study will enrol patients with TBI requiring therapeutic craniotomy or craniectomy. Subdural electrodes will be placed for continuous electrocorticography monitoring for seizures and CSDs as a research procedure, with surrogate informed consent obtained preoperatively. The propagation of CSDs relative to structural brain pathology will be mapped using reconstructed CT and electrophysiological cross-correlations. The novel use of multiple subdural strip electrodes in conjunction with brain morphometric segmentation is hypothesised to provide sufficient spatial information to characterise CSD propagation across the cerebral cortex and identify cortical foci giving rise to CSDs.Ethics and disseminationEthical approval for the study was obtained from the Hennepin Healthcare Research Institute’s ethics committee, HSR 17-4400, 25 October 2017 to present. Study findings will be submitted for publication in peer-reviewed journals and presented at scientific conferences.Trial registration numberNCT03321370.