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Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice. The mechanism of CGRP-evoked peripheral pain is unclear. Here, the authors show that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.

Nanoparticle-mediated drug delivery is especially useful for targets within endosomes because of the endosomal transport mechanisms of many nanomedicines within cells. Here, we report the design of a pH-responsive, soft polymeric nanoparticle for the targeting of acidified endosomes to precisely inhibit endosomal signalling events leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK1R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK1R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK1R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK1R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. Treatment with the nanoparticles leads to complete and persistent relief from nociceptive, inflammatory and neuropathic nociception and offers a much-needed non-opioid treatment option for chronic pain.

Peripheral and central neurons in the pain pathway are well equipped to detect and respond to extracellular stimuli such as pro-inflammatory mediators and neurotransmitters through the cell surface expression of receptors that can mediate rapid intracellular signaling. Following injury or infection, activation of cell surface G protein-coupled receptors (GPCRs) initiates cell signaling processes that lead to the generation of action potentials in neurons or inflammatory responses such as cytokine secretion by immune cells. However, it is now appreciated that cell surface events alone may not be sufficient for all receptors to generate their complete signaling repertoire. Following an initial wave of signaling at the cell surface, active GPCRs can engage with endocytic proteins such as the adaptor protein -arrestin (Arr) to promote clathrin-mediated internalization. Classically, Arr-mediated internalization of GPCRs was hypothesized to terminate signaling, yet for multiple GPCRs known to contribute to pain, it has been demonstrated that endocytosis can also promote a unique ‘second wave’ of signaling from intracellular membranes, including those of endosomes and the Golgi, that is spatiotemporally distinct from initial cell surface events. In the context of pain, understanding the cellular and molecular mechanisms that drive spatiotemporal signaling of GPCRs is invaluable for understanding how pain occurs and persists, and how current analgesics achieve efficacy or promote side-effects. This review discusses the importance of receptor localization for signaling outcomes of pro- and anti-nociceptive GPCRs, and new analgesic opportunities emerging through development of “location-biased” ligands that favor binding with intracellular GPCR populations.

Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT2A receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca2+ in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca2+ signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT2A to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca2+ signaling through a PLA2 and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT2A-induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release. Serotonin (5-HT) is an important mediator of tissue edema and inflammation. The authors used mouse models and cell-based signaling assays to provide greater understanding of the mechanisms involved. They demonstrate that effects of 5-HT are mediated through the 5-HT2A receptor and involve activation of the mechanosensitive ion channel TRPV4 and neuropeptide release.

Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca signaling through a PLA and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT -induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release. Serotonin (5-HT) is an important mediator of tissue edema and inflammation. The authors used mouse models and cell-based signaling assays to provide greater understanding of the mechanisms involved. They demonstrate that effects of 5-HT are mediated through the 5-HT receptor and involve activation of the mechanosensitive ion channel TRPV4 and neuropeptide release.

This work presents the performance projection of a metal-insulator-graphene diode as the building block of a radiofrequency power detector, highlighting its rectifying figures of merit. The analysis was performed by means of a computer-aided design tool validated with experimental measurements of fabricated devices. Transient simulations were used to accurately determine the detector output voltage, while particular consideration was given to suitable convergence of the non-linear circuit response. The diode was analyzed in both ideal and non-ideal cases, with the latter accounting for its parasitic effects. In the non-ideal case, the diode exhibited a tangential responsivity of 26.9 V/W at 2.45 GHz and 31.9 V/W at 1.225 GHz. However, when parasitic elements were neglected in the ideal case, the responsivity significantly increased to 47.3 V/W at 2.45 GHz and 38.7 V/W at 1.225 GHz. Additionally, the diode demonstrated a non-linearity of 6.64 at 0.7 V and an asymmetry of 806.6 in a bias window of ±1 V, which resulted in a competitive value compared to other state-of-the-art rectifying technologies. Tangential responsivities (βv) of graphene diodes at less-studied frequencies in the gigahertz band are presented, showing a high βv value of 63.7 V/W at 1 GHz.

Objective Evidence from low- and middle-income countries regarding the effect of smoking in people with diabetes is lacking. Here, we report the association of smoking with mortality in a large cohort of Mexican adults with diabetes. Methods Participants with diabetes mellitus (self-reported diagnosis, use of antidiabetic medications or HbA1c ≥ 6.5%) aged 35–74 years when recruited into the Mexico City Prospective Study were included. Cox regression confounder-adjusted mortality rate ratios (RRs) associated with baseline smoking status were estimated. Results Among 15,975 women and 8225 men aged 35–74 years with diabetes but no other comorbidities at recruitment, 2498 (16%) women and 2875 (35%) men reported former smoking and 2753 (17%) women, and 3796 (46%) men reported current smoking. During a median of 17 years of follow-up there were 5087 deaths at ages 35–74 years. Compared with never smoking, all-cause mortality RR was 1.08 (95%CI 1.01–1.17) for former smoking, 1.11 (95%CI 1.03–1.20) for current smoking, 1.09 (95%CI 0.99–1.20) for non-daily smoking, 1.06 (95%CI 0.96–1.16) for smoking < 10 cigarettes/day (median during follow-up 4 cigarettes/day), and 1.28 (95% CI 1.14–1.43) for smoking ≥ 10 cigarettes/day (median during follow-up 15 cigarettes/day). Mortality risk among daily smokers was greatest for COPD, lung cancer, cardiovascular diseases, and acute diabetic complications. Conclusion In this cohort of Mexican adults with diabetes, low-intensity daily smoking was associated with increased mortality, despite observing smoking patterns which are different from other populations, and over 5% of total deaths were associated with smoking.

Accelerator Mass Spectrometry is a technique commonly used to approach low concentrations of certain long half-life radioisotopes. The most important contribution of the technique is the accurate measure of organic sample ages, by separating masses 12,13 and 14 in the case of carbon allocated in such samples. However, the reach of AMS could cover many other scientific scopes, since it can give us a precise measure of a very small concentration of a radioisotope. On this direction, AMS can be used to approach reactions of interest for astrophysics, if we spot an specific radioisotope which concentration can be measure with AMS. Starting with this, we have selected specific reactions involving 14 C, 10 Be and 26 Al, produced with slow neutrons from a reactor and positive ions at an accelerator. The main idea is to produce a particular reaction and later to measure the radioisotopic concentration using AMS. In this study our first results for 14 C and 10 Be nuclei produced with neutrons, and the preliminary results for 26 Al nuclei produced with deuterium are shown.

Abstract Aging occurs across different domains at the individual level, encompassing distinct physiological systems which can be captured using biological age (BA) metrics. Second generation BA metrics are aimed at proxying BA using 10-year mortality risk and include PhenoAge and AnthropoAge. Here, we explored the complementary application of AnthropoAge and an NMR-Metabolomics derived BA measure to explore aging in body composition and metabolic domains in a subsample of 35,541 participants of the Mexico City Prospective Study. Using LASSO Cox regression, we identified 17 metabolites associated with all-cause mortality, in men and 75 in women. We then fitted age-adjusted Gompertz regression models and identified 7 unique metabolites for men and 15 for women. We transformed the results from these regressions to define MetaboAge. Both AnthropoAge (AUC 0.784, 95%CI 0.778-0.790) and MetaboAge (AUC 0.808, 95%CI 0.802-0.814) showed superior performance for prediction of all-cause mortality compared to chronological age (AUC 0.779, 95%CI 0.773-0.786). By regressing AnthropoAge and MetaboAge onto chronological age we obtained acceleration metrics (≥0 defined accelerated aging). By combining acceleration metrics from anthropometry and NMR-metabolomics we identified distinct trajectories of all-cause mortality. Notably, cases with acceleration only in AnthropoAge (HR 1.43, 95%CI 1.33-1.54) and those with acceleration only in MetaboAge (HR 1.86, 95%CI 1.73-2.01) had higher risk of all-cause mortality compared to non-accelerated cases but lower compared to cases with acceleration in both metrics (HR 2.28, 95%CI 2.12-2.45). Multidimensional evaluation of BA may prove useful to capture heterogeneity of aging in diverse populations by capturing aging at distinct physiological domains.