Edited by Luke O'NeillItaconic acid is an important metabolite produced by macrophages after stimulation with LPS. the cell culture medium leads to elevated intracellular levels of unlabeled succinate, with no evidence of intracellular uptake. The goal of this study is to encourage the development of effective pro-drug strategies to increase the intracellular levels of itaconate, which will enable more conclusive analysis of its action on macrophages and other cell and tissue types.Itaconic acid is a dicarboxylic acid polar metabolite originally characterized in Aspergillus terreus, but is also produced in mammalian cells (1). After LPS stimulation, itaconic acid is secreted by macrophages, where it can inhibit bacterial cell growth (1). In macrophages, itaconate synthesis is catalyzed by the immune-responsive gene 1 (IRG1) protein, which mediates the decarboxylation of cis-aconitate to itaconate (2). Metabolomic and fluxomic analysis of LPS-stimulated macrophages demonstrated reduced Isocitrate dehydrogenase-1 (IDH1) expression and increased IRG1 expression, resulting in a diversion of citrate from the TCA cycle 2 toward itaconate production (3). This metabolic remodeling results in glutamate serving as the anaplerotic substrate to maintain or elevate succinate levels (3). Moreover, elevated succinate acts as an inflammatory signal that induces secretion of IL-1 and stabilization of HIF-1␣ (4). Based on the similarity between itaconate (methylene succinic acid) and succinate, recent investigations have focused on the link between itaconate synthesis and succinate accumulation. Two complementary studies reported that itaconate inhibits succinate dehydrogenase and drives succinate accumulation (5, 6). Studying the role of itaconate requires either lowering its intracellular concentration by using IRG1 knock-out mouse models (5, 6) or increasing its intracellular concentration by using either itaconate (5) or a "cell-permeable" analog, dimethyl itaconate (DMI) (6). However, there is no direct evidence that itaconate or DMI can cross cell membranes and increase intracellular itaconate. Without direct evidence of intracellular delivery, it remains unclear whether itaconate-mediated metabolic and inflammatory effects are induced by increasing intracellular itaconate or by an extracellular mechanism.Here we synthesized isotopically labeled [ 13 C]itaconate and dimethyl [13 C]itaconate ([ 13 C]DMI) to directly profile itaconate metabolism and uptake (Fig. 1). This analysis suggests that exogenous itaconate is not taken up into cells and [13 C]DMI is not metabolized into [13 C]itaconate in bone marrow-derived macrophages. We also report that [13 C]itaconate in the cell culture medium leads to elevated intracellular levels of unlabeled succinate, yet there is no evidence of intracellular uptake. Overall, this study highlights current limitations in intracellular itaconate delivery, and emphasizes the development of effective pro-drug strategies to conclusively define its action on macrophages and other cell and tissue t...
Ultraviolet-visible (UV-Vis) absorption spectra are routinely collected as part of highperformance liquid chromatography (HPLC) analysis systems and can be used to identify chemical reaction products by comparison to reference spectra. Here, we present UV-adVISor as a new computational tool for predicting UV-Vis spectra from a molecule's structure alone. UV-Vis prediction was approached as a sequence-to-sequence problem.We utilized Long-Short Term Memory and attention-based neural networks with Extended Connectivity Fingerprint diameter 6 or molecule SMILES to generate predictive models for UV-spectra. We have produced two spectrum datasets (Dataset I, N = 949 and Dataset II, N = 2222) using different compound collections and spectrum acquisition methods to train, validate, and test our models. We evaluated the prediction accuracy of the complete spectra by the correspondence of wavelengths of absorbance maxima and with a series of statistical measures (the best test set median model parameters are in parentheses for Model II), including RMSE (0.064), R 2 (0.71), and dynamic time warping (DTW, 0.194) of the entire spectrum curve. Scrambling molecule structures with experimental spectra during training resulted in a degraded R 2 , confirming the utility of the approaches for prediction. UV-adVISor is able to provide fast and accurate predictions for libraries of compounds.
Tourette syndrome is a neuropsychiatric condition characterized by multiple motor tics and at least one vocal tic that persist for more than 1 year. On September 28, 2005, a symposium was held to (1) describe current diagnostic strategies, (2) discuss recent thoughts on pathogenesis, (3) review current therapies and clinical trials, and (4) define future research directions in Tourette syndrome. In her opening remarks, Dr Story Landis, director of the National Institute of Neurological Disorders and Stroke, emphasized the influence that this conference series has not only on the advancement of research but also on the education of practicing clinicians. Dr Landis also discussed the role of the Institute and the crucial function of volunteer research organizations in funding research to further improve the management of this condition. This article summarizes the presentations and includes the verbatim edited transcript of question and answer sessions
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