The Duty of the State Is to Act at Once to Eliminate by Positive Means All Vestiges of the Dual School Structure and to Compensate for the Abiding Scars of Past Discrimination.

Abstract Forthcoming

Educating for peace

Includes bibliographies.Mode of access: Internet

Real-time optical control of CB1 receptor signaling in vitro with tethered photoswitchable THC derivatives

Understanding the intricacies of the endocannabinoid system is hindered by the lack of tools to target specific pools of CB1 receptors (CB1Rs) across diverse neural circuits associated with mood, motor function, cognition, and other physiological processes. Herein we introduce the first photoswitchable, orthogonal remotely tethered cannabinoid ligand, PORTL-THC24, designed to achieve cell-specific and reversible control of CB1R signaling with high spatial and temporal resolution, thereby overcoming the limitations of conventional freely diffusible ligands. PORTL-THC24 was selectively tethered to membrane-anchored SNAP-tags expressed in live cells, providing reversible optical control of CB1R signaling when photoswitched by UV-A irradiation. We validated the functionality of PORTL-THC24 in live Neuro-2a cells using a novel real-time cAMP imaging assay, demonstrating light-dependent and reversible modulation of endogenously expressed CB1R activity. Additionally, we demonstrate that SNAP-tethered PORTL-THC24 does not induce CB1R internalization, distinguishing it from conventional, freely diffusible agonists. Our results establish PORTL-THC24 as a powerful tool for optical control of CB1R in a spatially-restricted manner, setting the stage for dissecting CB1R function in complex settings and advancing the study of cannabinoid signaling across various physiological and pathological contexts

Real-time optical control of CB1 receptor signaling In vitro with tethered photoswitchable (−)-trans-delta-9-detrahydrocannabinol derivatives

Understanding the intricacies of the endocannabinoid system is hindered by the lack of tools to target specific pools of CB1 receptors (CB1Rs) across diverse neural circuits associated with mood, motor function, cognition, and other physiological processes. Herein, we introduce the first photoswitchable, orthogonal remotely tethered cannabinoid ligand, PORTL-THC24, designed to achieve cell-specific and reversible control of CB1R signaling with high spatial and temporal resolution, thereby overcoming the limitations of conventional freely diffusible ligands. PORTL-THC24 was selectively tethered to membrane-anchored SNAP-tags expressed in live cells, and provided reversible optical control of CB1R signaling when photoswitched by UV-A irradiation. We validated the functionality of PORTL-THC24 in live Neuro2a cells using a novel real-time cAMP imaging assay, demonstrating light-dependent and reversible modulation of endogenously expressed CB1R activity. Additionally, we demonstrated that SNAP-tethered PORTL-THC24 does not induce CB1R internalization, distinguishing it from conventional, freely diffusible agonists. Our results establish PORTL-THC24 as a powerful tool for optical control of CB1R in a spatially restricted manner, setting the stage for dissecting CB1R function in complex settings and advancing the study of cannabinoid signaling across various physiological and pathological contexts

An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells.

Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial resolution necessary to interrogate specific protein networks. We provide a solution to this problem by combining quantitative proteomics with a system of spatial references. As proof of principle, we apply this approach to interrogate proteins engaged by G-protein-coupled receptors as they dynamically signal and traffic in response to ligand-induced activation. The method resolves known binding partners, as well as previously unidentified network components. Validating its utility as a discovery pipeline, we establish that two of these proteins promote ubiquitin-linked receptor downregulation after prolonged activation

The Enigma of Samuel Parsons Scott

Samuel Parsons Scott 18461929 singlehandedly translated into English the Corpus Juris Civilis the Visigothic Code and the Siete Partidas The latter was very well received and not long ago was reprinted in a new edition the first mentioned was criticized strongly but often has been used because until recently it contained the only published English translation of Justinian\u27s Code However almost nothing has been known about Scott as he was an independent scholar who lived and worked in the small American town of Hillsboro Ohio This article uses information obtained from Hillsboro newspapers local histories probate court records and the catalog of Scott\u27s personal library to describe his life and the details of his work It proposes an explanation for why he went from being a successful smalltown business man who wrote about history and his travels as an avocation to a being a recluse who devoted his last years to translating ancient laws The article\u27s analysis of Scott and his library also suggests some possible explanations for the flaws in his translation of the Justinianic Corpu