Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons also express SP receptors. However, the mechanisms of ...peripheral SP signaling are poorly understood. We report a signaling pathway of SP in nociceptive neurons: Acting predominantly through NK1 receptors and G i/o proteins, SP stimulates increased release of reactive oxygen species from the mitochondrial electron transport chain. Reactive oxygen species, functioning as second messengers, induce oxidative modification and augment M-type potassium channels, thereby suppressing excitability. This signaling cascade requires activation of phospholipase C but is largely uncoupled from the inositol 1,4,5-trisphosphate sensitive Ca 2+ stores. In rats SP causes sensitization of TRPV1 and produces thermal hyperalgesia. However, the lack of coupling between SP signaling and inositol 1,4,5-trisphosphate sensitive Ca 2+ stores, together with the augmenting effect on M channels, renders the SP pathway ineffective to excite nociceptors acutely and produce spontaneous pain. Our study describes a mechanism for neurokinin signaling in sensory neurons and provides evidence that spontaneous pain and hyperalgesia can have distinct underlying mechanisms within a single nociceptive neuron.
Fluorescent reporters of cardiac electrophysiology provide valuable information on heart cell and tissue function. However, motion artifacts caused by cardiac muscle contraction interfere with ...accurate measurement of fluorescence signals. Although drugs such as blebbistatin can be applied to stop cardiac tissue from contracting by uncoupling calcium-contraction, their usage prevents the study of excitation-contraction coupling and, as we show, impacts cellular structure. We therefore developed a robust method to remove motion computationally from images of contracting cardiac muscle and to map fluorescent reporters of cardiac electrophysiological activity onto images of undeformed tissue. When validated on cardiomyocytes derived from human induced pluripotent stem cells (iPSCs), in both monolayers and engineered tissues, the method enabled efficient and robust reduction of motion artifact. As with pharmacologic approaches using blebbistatin for motion removal, our algorithm improved the accuracy of optical mapping, as demonstrated by spatial maps of calcium transient decay. However, unlike pharmacologic motion removal, our computational approach allowed direct analysis of calcium-contraction coupling. Results revealed calcium-contraction coupling to be more uniform across cells within engineered tissues than across cells in monolayer culture. The algorithm shows promise as a robust and accurate tool for optical mapping studies of excitation-contraction coupling in heart tissue.
The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) ...and are associated with increased risk of mortality.
The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile.
The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %).
These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.
Present-day lake water phosphorus (P) enrichment and accelerated P cycling are changes superimposed on a dynamic Holocene history of landscape development following glaciation, changes in climate, ...and long-term low-intensity human activity. Knowledge of the history of long-term P dynamics is essential for understanding present-day landscape P export and for managing both terrestrial and aquatic environments. This study is the first attempt to constrain the timing and magnitude of terrestrial changes in Holocene P dynamics across the Northern Hemisphere using lake sediment records.
Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the ...membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.TRPA1 has been reported to contribute lung cancer adenocarcinoma (LUAD), but the mechanisms are unclear. Here the authors propose that TRPA1/FGFR2 interaction is functional in LUAD and show that astrocytes oppose brain metastasis by mediating the downregulation of TRPA1 through exosome-delivered miRNA-142-3p.
Allergic rhinitis (AR; also nasal allergies or "hay fever") is a chronic upper airway inflammatory disease that affects ∼60 million adults and children in the United States. The duration and severity ...of AR symptoms contribute to a substantial burden on patients' quality of life (QoL), sleep, work productivity, and activity. This study was designed to examine symptoms, QoL, productivity, comorbidities, disease management, and pharmacologic treatment of AR in United States and ex-U.S. sufferers. Allergies in America was a comprehensive telephone-based survey of 2500 adults with AR. These data are compared and contrasted with findings from the Pediatric Allergies in America, Allergies in Latin America, and Allergies in Asia-Pacific telephone surveys. The prevalence of physician-diagnosed AR was 14% in U.S. adults, 7% in Latin America adults, and 9% in Asia-Pacific adults. Nasal congestion is the most common and bothersome symptom for adults. Approximately two-thirds of adults rely on medication to relieve intolerable AR symptoms. Incomplete relief, slow onset, <24-hour relief, and reduced efficacy with sustained use were commonly reported with AR medications, including intranasal corticosteroids. One in seven U.S. adults reported achieving little to no relief with AR medications. Bothersome adverse effects of AR medications included drowsiness, a drying feeling, medication dripping down the throat, and bad taste. Perception of inadequate efficacy was the leading cause of medication discontinuation or change and contributed to treatment dissatisfaction. These findings support the assertion that AR burden has been substantially underestimated and identify several important challenges to successful management of AR.
Oxidative stress and damage are well-established components of neurodegenerative diseases, contributing to neuronal death during disease progression. Here, we consider key K(+) channels as target ...proteins that can undergo oxidative modulation, describe what is understood about how this influences disease progression, and consider regulation of these channels by gasotransmitters as a means of cellular protection.
Oxidative regulation of the delayed rectifier Kv2.1 and the Ca(2+)- and voltage-sensitive BK channel are established, but recent studies contest how their redox sensitivity contributes to altered excitability, progression of neurodegenerative diseases, and healthy aging.
Both Kv2.1 and BK channels have recently been established as target proteins for regulation by the gasotransmitters carbon monoxide and hydrogen sulfide. Establishing the molecular basis of such regulation, and exactly how this influences excitability and vulnerability to apoptotic cell death will determine whether such regulation can be exploited for therapeutic benefit.
Developing a more comprehensive picture of the oxidative modulation of K(+) channels (and, indeed, other ion channels) within the central nervous system in health and disease will enable us to better understand processes associated with healthy aging as well as distinct processes underlying progression of neurodegenerative diseases. Advances in the growing understanding of how gasotransmitters can regulate ion channels, including redox-sensitive K(+) channels, are a research priority for this field, and will establish their usefulness in design of future approaches for the treatment of such diseases.
Chemical named entity recognition (NER) has traditionally been dominated by conditional random fields (CRF)-based approaches but given the success of the artificial neural network techniques known as ...“deep learning” we decided to examine them as an alternative to CRFs. We present here several chemical named entity recognition systems. The first system translates the traditional CRF-based idioms into a deep learning framework, using rich per-token features and neural word embeddings, and producing a sequence of tags using bidirectional long short term memory (LSTM) networks—a type of recurrent neural net. The second system eschews the rich feature set—and even tokenisation—in favour of character labelling using neural character embeddings and multiple LSTM layers. The third system is an ensemble that combines the results of the first two systems. Our original BioCreative V.5 competition entry was placed in the top group with the highest F scores, and subsequent using transfer learning have achieved a final F score of 90.33% on the test data (precision 91.47%, recall 89.21%).
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