GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine s

ABSTRACT GPR139 is an orphan G-protein-coupled receptor expressed in the central nervous system. To identify its physiologic ligand, we measured GPR139 receptor activity from recombinant cells after treatment with amino acids, orphan ligands, serum, and tissue extracts. GPR139 activity was measured using guanosine 59-O-(3-[ Sequence alignment revealed that GPR139 is highly conserved across species, and RNA sequencing studies of rat and human tissues indicated its exclusive expression in the brain and pituitary gland. Immunohistochemical analysis showed specific expression of the receptor in circumventricular regions of the habenula and septum in mice. Together, these findings suggest that L-Trp and L-Phe are candidate physiologic ligands for GPR139, and we hypothesize that this receptor may act as a sensor to detect dynamic changes of L-Trp and L-Phe in the brain

Fifteen compelling open questions in plant cell biology

International audienceAbstract As scientists, we are at least as excited about the open questions—the things we do not know—as the discoveries. Here, we asked 15 experts to describe the most compelling open questions in plant cell biology. These are their questions: How are organelle identity, domains, and boundaries maintained under the continuous flux of vesicle trafficking and membrane remodeling? Is the plant cortical microtubule cytoskeleton a mechanosensory apparatus? How are the cellular pathways of cell wall synthesis, assembly, modification, and integrity sensing linked in plants? Why do plasmodesmata open and close? Is there retrograde signaling from vacuoles to the nucleus? How do root cells accommodate fungal endosymbionts? What is the role of cell edges in plant morphogenesis? How is the cell division site determined? What are the emergent effects of polyploidy on the biology of the cell, and how are any such “rules” conditioned by cell type? Can mechanical forces trigger new cell fates in plants? How does a single differentiated somatic cell reprogram and gain pluripotency? How does polarity develop de-novo in isolated plant cells? What is the spectrum of cellular functions for membraneless organelles and intrinsically disordered proteins? How do plants deal with internal noise? How does order emerge in cells and propagate to organs and organisms from complex dynamical processes? We hope you find the discussions of these questions thought provoking and inspiring

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor

A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure–activity relationship studies identified (<i>S</i>)-3-chloro-<i>N</i>-(2-oxo-2-((1-phenylethyl)­amino)­ethyl)­benzamide <b>7c</b> as a potent and selective agonist of hGPR139 with an EC₅₀ = 16 nM. The compound was found to cross the blood–brain barrier and have good drug-like properties amenable for oral dosing in rat

A definitive prognostication system for patients with thoracic malignancies diagnosed with COVID-19: an update from the TERAVOLT registry

Background: Patients with thoracic malignancies are at increased risk for mortality from Coronavirus disease 2019 (COVID-19) and large number of intertwined prognostic variables have been identified so far. Methods: Capitalizing data from the TERAVOLT registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure and a tree-based model to screen and optimize a broad panel of demographics, clinical COVID-19 and cancer characteristics. Results: As of April 15, 2021, 1491 consecutive evaluable patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened approximately 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection then identified seven major determinants of death ECOG-PS (OR 2.47 1.87-3.26), neutrophil count (OR 2.46 1.76-3.44), serum procalcitonin (OR 2.37 1.64-3.43), development of pneumonia (OR 1.95 1.48-2.58), c-reactive protein (CRP) (OR 1.90 1.43-2.51), tumor stage at COVID-19 diagnosis (OR 1.97 1.46-2.66) and age (OR 1.71 1.29-2.26). The ROC analysis for death of the selected model confirmed its diagnostic ability (AUC 0.78; 95%CI: 0.75 - 0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90% and the tree-based model recognized ECOG-PS, neutrophil count and CRP as the major determinants of prognosis. Conclusion: From 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS demonstrated the strongest association with poor outcome from COVID-19. With our analysis we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19