G-protein-coupled receptors (GPCRs) represent one of the largest gene families in the animal genome. These receptors can be classified into several groups based on the sequence similarity of their ...common heptahelical domain. The family 3 (or C) GPCRs are receptors for the main neurotransmitters glutamate and gamma-aminobutyric acid, for Ca(2+), for sweet and amino acid taste compounds, and for some pheromone molecules, as well as for odorants in fish. Although none of these family 3 receptors have been found in plants, members have been identified in ancient organisms, such as slime molds (Dictyostelium) and sponges. Like any other GPCRs, family 3 receptors possess a transmembrane heptahelical domain responsible for G-protein activation. However, most of these identified receptors also possess a large extracellular domain that is responsible for ligand recognition, is structurally similar to bacterial periplasmic proteins involved in the transport of small molecules, and is called a Venus Flytrap module. The recent resolution of the structure of this binding domain in one of these receptors, the metabotropic glutamate 1 receptor, together with the recent demonstration that these receptors are dimers, revealed a unique mechanism of activation for these GPCRs. Such data open new possibilities in the development of drugs aimed at modulating these receptors, and raise a number of interesting questions on the activation mechanism of the other GPCRs.
18F-FDG PET-CT is routinely performed as part of the initial staging of numerous cancers. Other than having descriptive, predictive and prognostic values for tumors, 18F-FDG PET-CT provides full-body ...data, which could inform on concurrent pathophysiological processes such as malnutrition. To test this hypothesis, we measured the 18F-FDG uptake in several organs and evaluated their association with weight loss in patients at diagnosis of esophageal cancer. Forty-eight patients were included in this retrospective monocentric study. 18F-FDG uptake quantification was performed in the brain, the liver, the spleen, bone marrow, muscle and the esophageal tumor itself and was compared between patients with different amounts of weight loss. We found that Total Lesion Glycolysis (TLG) and peak Standardized Uptake Values (SUVpeak) measured in the brain correlated with the amount of weight loss: TLG was, on average, higher in patients who had lost more than 5% of their usual weight, whereas brain SUVpeak were, on average, lower in patients who had lost more than 10% of their weight. Higher TLG and lower brain SUVpeak were associated with worse OS in the univariate analysis. This study reports a new and significant association between 18F-FDG uptake in the brain and initial weight loss in patients with esophageal cancer.
Endocytosis and recycling of membrane proteins are key processes for nutrient uptake, receptor signaling and synaptic transmission. Different steps in these fission and fusion cycles have been ...proposed to be regulated by physiological changes in plasma membrane (PM) phosphatidylinositol (4,5)-bisphosphate PtdIns(4,5)P₂ concentration. Here, we use a chemical enzyme-translocation strategy to rapidly reduce PM PtdIns(4,5)P₂ levels while monitoring clathrin-mediated endocytosis and recycling. PtdIns(4,5)P₂ hydrolysis blocked transferrin receptor endocytosis and led to a marked increase in the concentration of transferrin receptors in the PM, suggesting that endocytosis is more sensitive to changes in PtdIns(4,5)P₂ than recycling. Reduction of PM PtdIns(4,5)P₂ levels led to a near complete dissociation of Adaptor protein 2 (AP-2) from the PM but had only a small effect on clathrin assembly. This argues that receptor-mediated PtdIns(4,5)P₂ reduction preferentially suppresses AP-2-mediated targeting of cargo to endocytic sites rather than the assembly of clathrin coats or recycling of endocytic vesicles.
Functional genomics screens using multi-parametric assays are powerful approaches for identifying genes involved in particular cellular processes. However, they suffer from problems like noise, and ...often provide little insight into molecular mechanisms. A bottleneck for addressing these issues is the lack of computational methods for the systematic integration of multi-parametric phenotypic datasets with molecular interactions. Here, we present Integrative Multi Profile Analysis of Cellular Traits (IMPACT). The main goal of IMPACT is to identify the most consistent phenotypic profile among interacting genes. This approach utilizes two types of external information: sets of related genes (IMPACT-sets) and network information (IMPACT-modules). Based on the notion that interacting genes are more likely to be involved in similar functions than non-interacting genes, this data is used as a prior to inform the filtering of phenotypic profiles that are similar among interacting genes. IMPACT-sets selects the most frequent profile among a set of related genes. IMPACT-modules identifies sub-networks containing genes with similar phenotype profiles. The statistical significance of these selections is subsequently quantified via permutations of the data. IMPACT (1) handles multiple profiles per gene, (2) rescues genes with weak phenotypes and (3) accounts for multiple biases e.g. caused by the network topology. Application to a genome-wide RNAi screen on endocytosis showed that IMPACT improved the recovery of known endocytosis-related genes, decreased off-target effects, and detected consistent phenotypes. Those findings were confirmed by rescreening 468 genes. Additionally we validated an unexpected influence of the IGF-receptor on EGF-endocytosis. IMPACT facilitates the selection of high-quality phenotypic profiles using different types of independent information, thereby supporting the molecular interpretation of functional screens.
Factitious hypoglycemia is a factitious disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), referring to intentionally covertly induced hypoglycemia, with ...potentially severe consequences. Knowledge of factitious hypoglycemia relies on case reports, and evidence-based information and guidelines are lacking. Diagnosing factitious hypoglycemia in insulin-treated diabetic persons is therefore challenging and often requires a long and costly process. Moreover, the typical metrics proposed to differentiate insulin-induced factitious hypoglycemia from insulinoma (i.e., high insulin and low C-peptide versus high insulin and high C-peptide, respectively) are not always applicable, depending on whether the insulin quantification method can detect the insulin analog. When factitious hypoglycemia is suspected, an emerging trend from recent publications advocates a combination of two insulin quantification methods with different cross-reactivity for insulin analogs, early on in the diagnostic process.
sup.18F-FDG PET-CT is routinely performed as part of the initial staging of numerous cancers. Other than having descriptive, predictive and prognostic values for tumors, sup.18F-FDG PET-CT provides ...full-body data, which could inform on concurrent pathophysiological processes such as malnutrition. To test this hypothesis, we measured the sup.18F-FDG uptake in several organs and evaluated their association with weight loss in patients at diagnosis of esophageal cancer. Forty-eight patients were included in this retrospective monocentric study. sup.18F-FDG uptake quantification was performed in the brain, the liver, the spleen, bone marrow, muscle and the esophageal tumor itself and was compared between patients with different amounts of weight loss. We found that Total Lesion Glycolysis (TLG) and peak Standardized Uptake Values (SUVsub.peak) measured in the brain correlated with the amount of weight loss: TLG was, on average, higher in patients who had lost more than 5% of their usual weight, whereas brain SUVsub.peak were, on average, lower in patients who had lost more than 10% of their weight. Higher TLG and lower brain SUVsub.peak were associated with worse OS in the univariate analysis. This study reports a new and significant association between sup.18F-FDG uptake in the brain and initial weight loss in patients with esophageal cancer.
F-FDG PET-CT is routinely performed as part of the initial staging of numerous cancers. Other than having descriptive, predictive and prognostic values for tumors,
F-FDG PET-CT provides full-body ...data, which could inform on concurrent pathophysiological processes such as malnutrition. To test this hypothesis, we measured the
F-FDG uptake in several organs and evaluated their association with weight loss in patients at diagnosis of esophageal cancer. Forty-eight patients were included in this retrospective monocentric study.
F-FDG uptake quantification was performed in the brain, the liver, the spleen, bone marrow, muscle and the esophageal tumor itself and was compared between patients with different amounts of weight loss. We found that Total Lesion Glycolysis (TLG) and peak Standardized Uptake Values (SUV
) measured in the brain correlated with the amount of weight loss: TLG was, on average, higher in patients who had lost more than 5% of their usual weight, whereas brain SUV
were, on average, lower in patients who had lost more than 10% of their weight. Higher TLG and lower brain SUV
were associated with worse OS in the univariate analysis. This study reports a new and significant association between
F-FDG uptake in the brain and initial weight loss in patients with esophageal cancer.
Recent studies on G‐protein‐coupled receptors revealed that they can dimerize. However, the role of each subunit in the activation process remains unclear. The γ‐amino‐n‐butyric acid type B (GABAB) ...receptor is comprised of two subunits: GB1 and GB2. Both consist of an extracellular domain (ECD) and a heptahelical domain composed of seven transmembrane α‐helices, loops and the C‐terminus (HD). Whereas GB1 ECD plays a critical role in ligand binding, GB2 is required not only to target GB1 subunit to the cell surface but also for receptor activation. Here, by analysing chimeric GB subunits, we show that only GB2 HD contains the determinants required for G‐protein signalling. However, the HD of GB1 improves coupling efficacy. Conversely, although GB1 ECD is sufficient to bind GABAB ligands, the ECD of GB2 increases the agonist affinity on GB1, and is necessary for agonist activation of the receptor. These data indicate that multiple allosteric interactions between the two subunits are required for wild‐type functioning of the GABAB receptor and highlight further the importance of the dimerization process in GPCR activation.
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