Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABAA_{A} Receptors without Affecting Synaptic Plasticity

Neurosteroids and benzodiazepines are modulators of the GABA$_{A}$ receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity

Future-ai:International consensus guideline for trustworthy and deployable artificial intelligence in healthcare

Despite major advances in artificial intelligence (AI) for medicine and healthcare, the deployment and adoption of AI technologies remain limited in real-world clinical practice. In recent years, concerns have been raised about the technical, clinical, ethical and legal risks associated with medical AI. To increase real world adoption, it is essential that medical AI tools are trusted and accepted by patients, clinicians, health organisations and authorities. This work describes the FUTURE-AI guideline as the first international consensus framework for guiding the development and deployment of trustworthy AI tools in healthcare. The FUTURE-AI consortium was founded in 2021 and currently comprises 118 inter-disciplinary experts from 51 countries representing all continents, including AI scientists, clinicians, ethicists, and social scientists. Over a two-year period, the consortium defined guiding principles and best practices for trustworthy AI through an iterative process comprising an in-depth literature review, a modified Delphi survey, and online consensus meetings. The FUTURE-AI framework was established based on 6 guiding principles for trustworthy AI in healthcare, i.e. Fairness, Universality, Traceability, Usability, Robustness and Explainability. Through consensus, a set of 28 best practices were defined, addressing technical, clinical, legal and socio-ethical dimensions. The recommendations cover the entire lifecycle of medical AI, from design, development and validation to regulation, deployment, and monitoring. FUTURE-AI is a risk-informed, assumption-free guideline which provides a structured approach for constructing medical AI tools that will be trusted, deployed and adopted in real-world practice. Researchers are encouraged to take the recommendations into account in proof-of-concept stages to facilitate future translation towards clinical practice of medical AI

FUTURE-AI: International consensus guideline for trustworthy and deployable artificial intelligence in healthcare

Despite major advances in artificial intelligence (AI) for medicine and healthcare, the deployment and adoption of AI technologies remain limited in real-world clinical practice. In recent years, concerns have been raised about the technical, clinical, ethical and legal risks associated with medical AI. To increase real world adoption, it is essential that medical AI tools are trusted and accepted by patients, clinicians, health organisations and authorities. This work describes the FUTURE-AI guideline as the first international consensus framework for guiding the development and deployment of trustworthy AI tools in healthcare. The FUTURE-AI consortium was founded in 2021 and currently comprises 118 inter-disciplinary experts from 51 countries representing all continents, including AI scientists, clinicians, ethicists, and social scientists. Over a two-year period, the consortium defined guiding principles and best practices for trustworthy AI through an iterative process comprising an in-depth literature review, a modified Delphi survey, and online consensus meetings. The FUTURE-AI framework was established based on 6 guiding principles for trustworthy AI in healthcare, i.e. Fairness, Universality, Traceability, Usability, Robustness and Explainability. Through consensus, a set of 28 best practices were defined, addressing technical, clinical, legal and socio-ethical dimensions. The recommendations cover the entire lifecycle of medical AI, from design, development and validation to regulation, deployment, and monitoring. FUTURE-AI is a risk-informed, assumption-free guideline which provides a structured approach for constructing medical AI tools that will be trusted, deployed and adopted in real-world practice. Researchers are encouraged to take the recommendations into account in proof-of-concept stages to facilitate future translation towards clinical practice of medical AI

Midazolam at Low Nanomolar Concentrations Affects Long-term Potentiation and Synaptic Transmission Predominantly via the α1-γ-Aminobutyric Acid Type A Receptor Subunit in Mice

Background: Midazolam amplifies synaptic inhibition via different γ-aminobutyric acid type A (GABAA) receptor subtypes defined by the presence of α1-, α2-, α3-, or α5-subunits in the channel complex. Midazolam blocks long-term potentiation and produces postoperative amnesia. The aims of this study were to identify the GABAA receptor subtypes targeted by midazolam responsible for affecting CA1 long-term potentiation and synaptic inhibition in neocortical neurons. Methods: The effects of midazolam on hippocampal CA1 long-term potentiation were studied in acutely prepared brain slices of male and female mice. Positive allosteric modulation on GABAA receptor-mediated miniature inhibitory postsynaptic currents was investigated in organotypic slice cultures of the mouse neocortex. In both experiments, wild-type mice and GABAA receptor knock-in mouse lines were compared in which α1-, α5-, α1/2/3-, α1/3/5- and α2/3/5-GABAA receptor subtypes had been rendered benzodiazepine-insensitive. Results: Midazolam (10 nM) completely blocked long-term potentiation (mean ± SD, midazolam, 98 ± 11%, n = 14/8 slices/mice vs. control 156 ± 19%, n = 20/12; P < 0.001). Experiments in slices of α1-, α5-, α1/2/3-, α1/3/5-, and α2/3/5-knock-in mice revealed a dominant role for the α1-GABAA receptor subtype in the long-term potentiation suppressing effect. In slices from wild-type mice, midazolam increased (mean ± SD) charge transfer of miniature synaptic events concentration-dependently (50 nM: 172 ± 71% [n = 10/6] vs. 500 nM: 236 ± 54% [n = 6/6]; P = 0.041). In α2/3/5-knock-in mice, charge transfer of miniature synaptic events did not further enhance when applying 500 nM midazolam (50 nM: 171 ± 62% [n = 8/6] vs. 500 nM: 175 ± 62% [n = 6/6]; P = 0.454), indicating two different binding affinities for midazolam to α2/3/5- and α1-subunits. Conclusions: These results demonstrate a predominant role of α1-GABAA receptors in the actions of midazolam at low nanomolar concentrations. At higher concentrations, midazolam also enhances other GABAA receptor subtypes. α1-GABAA receptors may already contribute at sedative doses to the phenomenon of postoperative amnesia that has been reported after midazolam administration

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA A Receptors without Affecting Synaptic Plasticity

Neurosteroids and benzodiazepines are modulators of the GABAA receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity.ISSN:1422-006

Designed peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly

Amyloid self-assembly is linked to numerous devastating cell-degenerative diseases. However, designing inhibitors of this pathogenic process remains a major challenge. Cross-interactions between amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP), key polypeptides of Alzheimer's disease (AD) and type 2 diabetes (T2D), have been suggested to link AD with T2D pathogenesis. Here, we show that constrained peptides designed to mimic the Aβ amyloid core (ACMs) are nanomolar cross-amyloid inhibitors of both IAPP and Aβ42 and effectively suppress reciprocal cross-seeding. Remarkably, ACMs act by co-assembling with IAPP or Aβ42 into amyloid fibril-resembling but non-toxic nanofibers and their highly ordered superstructures. Co-assembled nanofibers exhibit various potentially beneficial features including thermolability, proteolytic degradability, and effective cellular clearance which are reminiscent of labile/reversible functional amyloids. ACMs are thus promising leads for potent anti-amyloid drugs in both T2D and AD while the supramolecular nanofiber co-assemblies should inform the design of novel functional (hetero-)amyloid-based nanomaterials for biomedical/biotechnological applications