Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy.

Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.

The Role of Executive Functioning and Technological Anxiety (FOMO) in College Course Performance as Mediated by Technology Usage and Multitasking Habits / El papel del funcionamiento ejecutivo y de la ansiedad tecnológica (FOMO) en el desempeño académico universitario mediatizado por la utilización de la tecnología y los hábitos multi-tarea

This study investigated how technology use impacts academic performance. A proposed model postulated that academic performance could be predicted by a cognitive independent variable-executive functioning problems-and an affective independent variable-technological anxiety or FOMO (fear of missing out)-mediated by how students choose to use technology. An unobtrusive smartphone application called "Instant Quantified Self" monitored daily smartphone s and daily minutes of use. Other mediators d self-reported smartphone use, self-observed studying attention, self-reported multitasking preference, and a classroom digital metacognition tool that assessed the studen's ability to understand the ramifications of technology use in the classroom that is not relevant to the learning process. Two hundred sixteen participants collected an average of 56 days of "Instant" application data, demonstrating that their smartphone was ed more than 60 times a day for three to four minutes each time for a total of 220 daily minutes of use. Results indicated that executive functioning problems predicted academic course performance mediated by studying attention and a single classroom digital metacognition subscale concerning availability of strategies of when to use mobile phones during lectures. FOMO predicted performance directly as well as mediated by a second classroom digital metacognition concerning attitudes toward mobile phone use during lectures. Implications for college students and professors increasing metacognition about technology use in the classroom and taking "tech breaks" to reduce technology anxiety

Este estudio analiza la repercusión del uso de la tecnología en el desempeño académico. Se propuso un modelo que postulaba que el desempeño académico podía predecirse mediante una variable independiente cognitiva (los problemas de funcionamiento ejecutivo) y una variable independiente afectiva (la ansiedad tecnológica o FOMO -el miedo a perderse algo), influido por el modo como los alumnos elegían utilizar la tecnología. Mediante una aplicación para móvil no intrusiva, denominada "Yo cuantificado instantáneo" seguía los desbloqueos diarios del móvil y los minutos de uso. Había otros mediadores, como el uso del móvil según el usuario, la atención en el estudio según la observa el usuario, preferencias de multi-tarea según el usuario y una nueva herramienta de medida digital en el aula para analizar la capacidad del alumno para entender las ramificaciones del uso de la tecnología en el aula que no es relevante para el proceso de aprendizaje. Un total de 216 participantes recogieron datos de la aplicación "instantánea" durante una media de 56 días, mostrando que su teléfono móvil era desbloqueado más de 60 veces al día entre tres y cuatro minutos cada vez durante un total de 220 minutos diarios de uso. Los resultados indicaban que los problemas de funcionamiento ejecutivo predecían el rendimiento académico mediatizado por la atención en el estudio y una única subescala de metacognición digital en el aula relativa a la disponibilidad de estrategias sobre cuándo utilizar el móvil durante las clases. El FOMO predecía el desempeño directamente además de a través de una segunda metacognición digital del aula relativa a las actitudes hacia el teléfono móvil durante las clases. Entre las implicaciones para los alumnos y los profesores está el aumento de la metacognición sobre el uso de la tecnología en el aula y "descansar de la tecnología" para disminuir la ansiedad que produce

The Role of Executive Functioning and Technological Anxiety (FOMO) in College Course Performance as Mediated by Technology Usage and Multitasking Habits.

This study investigated how technology use impacts academic performance. A proposed model postulated that academic performance could be predicted by a cognitive independent variable-executive functioning problems-and an affective independent variable-technological anxiety or FOMO (fear of missing out)-mediated by how students choose to use technology. An unobtrusive smartphone application called "Instant Quantified Self" monitored daily smartphone un-locks and daily minutes of use. Other mediators included self-reported smartphone use, self-observed studying attention, self-reported multitasking preference, and a classroom digital metacognition tool that assessed the student's ability to understand the ramifications of technology use in the classroom that is not relevant to the learning process. Two hundred sixteen participants collected an average of 56 days of "Instant" application data, demonstrating that their smartphone was unlocked more than 60 times a day for three to four minutes each time for a total of 220 daily minutes of use. Results indicated that executive functioning problems predicted academic course performance mediated by studying attention and a single classroom digital metacognition subscale concerning availability of strategies of when to use mobile phones during lectures. FOMO predicted performance directly as well as mediated by a second classroom digital metacognition concerning attitudes toward mobile phone use during lectures. Implications for college students and professors include increasing metacognition about technology use in the classroom and taking "tech breaks" to reduce technology anxiety.

Este estudio analiza la repercusión del uso de la tecnología en el desempeño académico. Se propuso un modelo que postulaba que el desempeño académico podía predecirse mediante una variable independiente cognitiva (los problemas de funcionamiento ejecutivo) y una variable independiente afectiva (la ansiedad tecnológica o FOMO ­el miedo a perderse algo), influido por el modo como los alumnos elegían utilizar la tecnología. Mediante una aplicación para móvil no intrusiva, denominada "Yo cuantificado instantáneo" seguía los desbloqueos diarios del móvil y los minutos de uso. Había otros mediadores, como el uso del móvil según el usuario, la atención en el estudio según la observa el usuario, preferencias de multi-tarea según el usuario y una nueva herramienta de medida digital en el aula para analizar la capacidad del alumno para entender las ramificaciones del uso de la tecnología en el aula que no relevante para el proceso de aprendizaje. Un total de 216 participantes recogieron datos de la aplicación "instantánea" durante una media de 56 días, mostrando que su teléfono móvil era desbloqueado más de 60 veces al día entre tres y cuatro minutos cada vez durante un total de 220 minutos diarios de uso. Los resultados indicaban que los problemas de funcionamiento ejecutivo predecían el rendimiento académico mediatizado por la atención en el estudio y una única subescala de metacognición digital en el aula relativa a la disponibilidad de estrategias sobre cuándo utilizar el móvil durante las clases. El FOMO predecía el desempeño directamente además de a través de una segunda metacognición digital del aula relativa a las actitudes hacia el teléfono móvil durante las clases. Entre las implicaciones para los alumnos y los profesores está el aumento de la metacognición sobre el uso de la tecnología en el aula y "descansar de la tecnología" para disminuir la ansiedad que produce.

Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis.

The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. Site-directed mutagenesis (SDM) and domain exchange (chimera) studies have provided important insight into key features of the OX1 and OX2 binding sites. However, the precise determinants of antagonist binding and selectivity are still not fully known. In this work, we used homology modeling of OX receptors to direct further SDM studies. These SDM studies were followed by molecular dynamics (MD) simulations to rationalize the full scope of the SDM data and to explain the role of each mutated residue in the binding and selectivity of a set of OX antagonists: Almorexant (dual OX1 and OX2 antagonist), SB-674042 (OX1 selective antagonist), EMPA (OX2 selective antagonist), and others. Our primary interest was focused on transmembrane helix 3 (TM3), which is identified as being of great importance for the selectivity of OX antagonists. These studies revealed conformational differences between the TM3 helices of OX1 and OX2, resulting from differences in amino acid sequences of the OX receptors that affect key interhelical interactions formed between TM3 and neighboring TM domains. The MD simulation protocol used here, which was followed by flexible docking studies, went beyond the use of static models and allowed for a more detailed exploration of the OX structures. In this work, we have demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors. The MD simulations allowed refinement of the OX receptor models to a degree that was not possible with static homology modeling alone and provided a deeper rationalization of the SDM data obtained. To validate these findings and to demonstrate that they can be usefully applied to the design of novel, very selective OX antagonists, we show here two examples of antagonists designed in house: EP-109-0092 (OX1 selective) and EP-009-0513 (OX2 selective).

Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists.

A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.

Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists.

A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.

Synthesis and structure-activity relationship of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-5-(2-pyridinyl)-1,3-thiazol-2-amines derivatives as NPY Y5 antagonists.

A novel class of small molecule NPY Y5 antagonists based around an azabicyclo[3.1.0]hexane scaffold was identified through modification of a screening hit. Structure-activity relationships and efforts undertaken to achieve a favourable pharmacokinetic profile in rat are described.

Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.

A convergent approach to huperzine A and analogues.

We describe a concise and convergent synthesis of (rac)-5-methoxy-6-azatricyclco[7.3.1.0(2,7)]trideca-2(7),3,5,11-tetraen-13-ol, which has the basic ring system of huperzine A, a potent inhibitor of acetylcholinesterase. We also describe the synthesis of the novel system 5-methoxy-6-azatricyclo[7.2.2.0(2,7)]trideca-2(7),3,5-trien-10-one and a series of related systems.