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Readable research linked to original sources
Browse normalized, publication-ready research with direct links to its evidence and source.
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Readable research linked to original sources
Browse normalized, publication-ready research with direct links to its evidence and source.
71 articles
Newest firstPeripheral cannabinoid CB1 receptor antagonists that lack central nervous system effects are emerging as promising therapies for metabolic disease, yet the role of endothelial CB1 signaling in atherosclerosis remains unclear. Here, we show that endothelial CB1 is expressed in human atherosclerotic plaques, is induced by oscillatory shear stress in atheroprone flow regions, and promotes vascular inflammation, perme…
Open article record in new tab ↗Substance use runs in families. Beyond genetic transmission, parental genetics can indirectly influence offspring substance use through the rearing environment, known as genetic nurture. This study utilizes transmitted and non-transmitted polygenic scores to investigate genetic nurture on tobacco, alcohol, and cannabis use in up to 15,863 adults with at least one genotyped parent from Lifelines, a population-based…
Open article record in new tab ↗Adaptive emotion regulation is essential for mental health. Reappraisal and acceptance are effective yet cognitively distinct emotion regulation strategies. A key unanswered question is whether their neural implementations are supported by common overarching or distinct neurofunctional processes, especially under dynamic, naturalistic conditions that mirror real-life scenarios. Here, we combined naturalistic fMRI…
Open article record in new tab ↗The limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD) underscore the need for deeper mechanistic insight and new treatment strategies. Here, we identify the orphan G protein-coupled receptor GPR146 as a regulator of hepatic steatosis through adipose-liver crosstalk. Human genetic analyses link the GPR146 locus to circulating markers of liver injury and inflammation. I…
Open article record in new tab ↗In contrast to ynamides, whose chemistry has been extensively explored, ynimines remain underutilized in organic synthesis despite their rich functionalities. Here we report a general strategy to access 2-imido-1,3-dienes, synthetically challenging building blocks, through the reaction of ynimines with carboxylic acids. Leveraging this transformation, we develop a three-component reaction of ynimines, carboxylic a…
Open article record in new tab ↗Unprotected β-fluoroamines are important motifs in synthetic chemistry, offering versatility for the development of β-fluorinated nitrogen-containing compounds. Existing methods to these motifs require tedious operations and suffer from low efficiencies, which has prevented their use in biologically active molecules, such as drug discovery and positron emission tomography (PET) radiotracer development. Herein, an…
GPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, and metabolic diseases. The endogenous activation of lipid GPCRs can be solely mediated by membrane components and different lipids have been proposed as endogenous activators of GPR55, such as cannabinoids and lysophosphatidylinositols. Here, we determine high-resolution cryo-electron microscopy s…
Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for the cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones for de novo synthesis and testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 µM) lea…
About one third of vascular plants develop glandular trichomes, which produce defensive compounds that repel herbivores and act as a natural biofactory for important pharmaceuticals such as artemisinin and cannabinoids. However, only a few regulators of glandular structures have been characterized so far. Here we have identified two closely-related MYB-like genes that redundantly inhibit the formation of glandular…
Sensory perception depends on interactions between external inputs transduced by peripheral sensory organs and internal network dynamics generated by central neuronal circuits. In the sensory cortex, desynchronized network states associate with high signal-to-noise ratio stimulus-evoked responses and heightened perception. Cannabinoid-type-1-receptors (CB1Rs) - which influence network coordination in the hippocamp…
Open article record in new tab ↗The cannabinoid receptor 1 (CB1R) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CB1R antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted…
G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are important drug targets. The discovery of drugs targeting these receptors and their G protein signaling properties are based on assays mainly performed with modified receptors expressed in heterologous cells. However, GPCR responses may differ in their native environment. Here, by using highly sensitive Gi/o sensors, we r…
While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel this engulfment. Here we report that the reverse signaling using CD47 as a receptor additionally enhances a pro-survival function of prostate cancer cells under phagocytic attack. Although low CD47-expressing cancer cells still allow phagocytosis, t…
Brain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing en…
Chronic pain is highly prevalent and is linked to a broad range of comorbidities, including sleep disorders. Epidemiological and clinical evidence suggests that chronic sleep disruption (CSD) leads to heightened pain sensitivity, referred to as CSD-induced hyperalgesia. However, the underlying mechanisms are unclear. The thalamic reticular nucleus (TRN) has unique integrative functions in sensory processing, atten…
Open article record in new tab ↗The limited benefits of immunotherapy against glioblastoma (GBM) is closely related to the paucity of T cells in brain tumor bed. Both systemic and local immunosuppression contribute to the deficiency of tumor-infiltrating T cells. However, the current studies focus heavily on the local immunosuppressive tumor microenvironment but not on the co-existence of systemic immunosuppression. Here, we develop a nanostruct…
Open article record in new tab ↗Nitrogen has five valence electrons and can form a maximum of three shared electron-pair bonds to complete its octet, which suggests that its maximum bond order is three. With a joint anion photoelectron spectroscopy and quantum chemistry investigation, we report herein that nitrogen presents a quadruple bonding interaction with thorium in ThN. The quadruple Th≣N bond consists of two electron-sharing Th-N π bonds…
Open article record in new tab ↗Cannabinoid CB2 receptor (CB2R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB2R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We ide…
The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic ana…
The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid…
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