Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, and Servicio de Farmacología Clínica e Instituto Universitario de Investigación Gerontológica y Metabólica, Hospital ...Universitario de la Princesa, Facultad de Medicina, Universidad Autónoma de Madrid; Unidad de Farmacología, Facultad de Medicina, Universidad de la Laguna; and Instituto de Biología y Genética Molecular, Universidad de Valladolid y CSIC, Departamento de Fisiología, Facultad de Medicina, Valladolid, Spain
At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca 2+ concentration (Ca 2+ c ) depends on at least four efficient regulatory systems: 1 ) plasmalemmal calcium channels, 2 ) endoplasmic reticulum, 3 ) mitochondria, and 4 ) chromaffin vesicles. Different mammalian species express different levels of the L, N, P/Q, and R subtypes of high-voltage-activated calcium channels; in bovine and humans, P/Q channels predominate, whereas in felines and murine species, L-type channels predominate. The calcium channels in chromaffin cells are regulated by G proteins coupled to purinergic and opiate receptors, as well as by voltage and the local changes of Ca 2+ c . Chromaffin cells have been particularly useful in studying calcium channel current autoregulation by materials coreleased with catecholamines, such as ATP and opiates. Depending on the preparation (cultured cells, adrenal slices) and the stimulation pattern (action potentials, depolarizing pulses, high K + , acetylcholine), the role of each calcium channel in controlling catecholamine release can change drastically. Targeted aequorin and confocal microscopy shows that Ca 2+ entry through calcium channels can refill the endoplasmic reticulum (ER) to nearly millimolar concentrations, and causes the release of Ca 2+ (CICR). Depending on its degree of filling, the ER may act as a sink or source of Ca 2+ that modulates catecholamine release. Targeted aequorins with different Ca 2+ affinities show that mitochondria undergo surprisingly rapid millimolar Ca 2+ transients, upon stimulation of chromaffin cells with ACh, high K + , or caffeine. Physiological stimuli generate Ca 2+ c microdomains in which the local subplasmalemmal Ca 2+ c rises abruptly from 0.1 to 50 µM, triggering CICR, mitochondrial Ca 2+ uptake, and exocytosis at nearby secretory active sites. The fact that protonophores abolish mitochondrial Ca 2+ uptake, and increase catecholamine release three- to fivefold, support the earlier observation. This increase is probably due to acceleration of vesicle transport from a reserve pool to a ready-release vesicle pool; this transport might be controlled by Ca 2+ redistribution to the cytoskeleton, through CICR, and/or mitochondrial Ca 2+ release. We propose that chromaffin cells have developed functional triads that are formed by calcium channels, the ER, and the mitochondria and locally control the Ca 2+ c that regulate the early and late steps of exocytosis.
Sleep apnea is a sleep related disorder that significantly affects the population. Polysomnography, the gold standard, is expensive, inaccessible, uncomfortable and an expert technician is needed to ...score. Numerous researchers have proposed and implemented automatic scoring processes to address these issues, based on fewer sensors and automatic classification algorithms. Deep learning is gaining higher interest due to database availability, newly developed techniques, the possibility of producing machine created features and higher computing power that allows the algorithms to achieve better performance than the shallow classifiers. Therefore, the sleep apnea research has currently gained significant interest in deep learning. The goal of this work is to analyze the published research in the last decade, providing an answer to the research questions such as how to implement the different deep networks, what kind of pre-processing or feature extraction is needed, and the advantages and disadvantages of different kinds of networks. The employed signals, sensors, databases and implementation challenges were also considered. A systematic search was conducted on five indexing services from 2008-2018. A total of 255 papers were found and 21 were selected by considering the inclusion and exclusion criteria, using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) approach.
The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached ...clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in
oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound
(2-(6-chloro-9
-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound
can be considered as a first non-nucleotide purine hit for future drug optimizations.
This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential ...therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson’s disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness.
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•Eye diseases leading to retinal degeneration have pathogenic pathways common with neurodegenerative diseases.•Common pathogenic pathways in neurodegeneration are excitotoxicity, oxidative stress and inflammation.•Combined drug triads acting on different targets may afford more effective neuroprotection.
Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical ...trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.
•A method to determinate proximate analysis data in biomass by TG is proposed.•Coal developed methods are compared and improved for biomass use.•Satisfactory results are obtained, main on moisture ...and volatile matter values.
This work proposes a 25min-last thermogravimetric method as a tool to determine biomass sample’s proximate analysis data (moisture, ash, volatile matter and fixed carbon contents) just by direct measure of weight changes on each sample’s TG chart. Compared with international standards commonly used to that aim, TG is a faster and easier to develop technique. Obtained results were satisfactory, with AEE under 6% for moisture and volatile matter, close to 10% for fixed carbon determination and AAD of 1.6 points for ash content.
Characterization of Spanish biomass wastes for energy use García, Roberto; Pizarro, Consuelo; Lavín, Antonio G. ...
Bioresource technology,
January 2012, 2012, 2012-Jan, 2012-01-00, 20120101, Letnik:
103, Številka:
1
Journal Article
Recenzirano
► Proximate, ultimate analysis and HHV database was developed. ► Used data was specific for Spanish biomass fuels. ► Ash content reach values over 30%, higher than expected in bibliography. ► ...Nitrogen and sulphur quantities appear in acceptable values.
Energy plays an important role in the world’s present and future. The best way to absorb the huge increase in energy demands is through diversification. In this context biomass appears as an attractive source for a number of environmental, economical, political and social reasons. There are several techniques used to obtain energy from biomass. Among these techniques, the most commonly used throughout the world is a thermo–chemical process to obtain heat. To optimize the combustion process in adequate reactors, a comprehensive study of the characterization of biomass fuel properties is needed, which includes proximate analysis (determination of moisture, ash, volatile and fixed carbon content), ultimate analysis (C, H, N, S and O composition) and calorimetry, focusing on biomass fuels obtained in Spain.
A Review of Obstructive Sleep Apnea Detection Approaches Mendonca, Fabio; Mostafa, Sheikh Shanawaz; Ravelo-Garcia, Antonio G. ...
IEEE journal of biomedical and health informatics,
2019-March, 2019-03-00, 2019-3-00, 20190301, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Sleep disorders are a common health condition that can affect numerous aspects of life. Obstructive sleep apnea is one of the most common disorders and is characterized by a reduction or cessation of ...airflow during sleep. In many countries, this disorder is usually diagnosed in sleep laboratories, by polysomnography, which is an expensive procedure involving much effort for the patient. Multiple systems have been proposed to address this situation, including performing the examination and analysis in the patient's home, using sensors to detect physiological signals that are automatically analyzed by algorithms. However, the precision of these devices is usually not enough to provide clinical diagnosis. Therefore, the objective of this review is to analyze already existing algorithms that have not been implemented on hardware but have had their performance verified by at least one experiment that aims to detect obstructive sleep apnea to predict trends. The performance of different algorithms and methods for apnea detection through the use of different sensors (pulse oximetry, electrocardiogram, respiration, sound, and combined approaches) has been evaluated. 84 original research articles published from 2003 to 2017 with the potential to be promising diagnostic tools have been selected to cover multiple solutions. This paper could provide valuable information for those researchers who want to carry out a hardware implementation of potential signal processing algorithms.
Synaptic disruption and altered neurotransmitter release occurs in the brains of patients and in murine models of neurodegenerative diseases (NDDs). During the last few years, evidence has ...accumulated suggesting that the sympathoadrenal axis is also affected as disease progresses. Here, we review a few studies done in adrenal medullary chromaffin cells (CCs), that are considered as the amplifying arm of the sympathetic nervous system; the sudden fast exocytotic release of their catecholamines-stored in noradrenergic and adrenergic cells-plays a fundamental role in the stress fight-or-flight response. Bulk exocytosis and the fine kinetics of single-vesicle exocytotic events have been studied in mouse models carrying a mutation linked to NDDs. For instance, in R6/1 mouse models of Huntington's disease (HD), mutated huntingtin is overexpressed in CCs; this causes decreased quantal secretion, smaller quantal size and faster kinetics of the exocytotic fusion pore, pore expansion, and closure. This was accompanied by decreased sodium current, decreased acetylcholine-evoked action potentials, and attenuated Ca
c transients with faster Ca
clearance. In the SOD1
mouse model of amyotrophic lateral sclerosis (ALS), CCs exhibited secretory single-vesicle spikes with a slower release rate but higher exocytosis. Finally, in the APP/PS1 mouse model of Alzheimer's disease (AD), the stabilization, expansion, and closure of the fusion pore was faster, but the secretion was attenuated. Additionally, α-synuclein that is associated with Parkinson's disease (PD) decreases exocytosis and promotes fusion pore dilation in adrenal CCs. Furthermore, Huntington-associated protein 1 (HAP1) interacts with the huntingtin that, when mutated, causes Huntington's disease (HD); HAP1 reduces full fusion exocytosis by affecting vesicle docking and controlling fusion pore stabilization. The alterations described here are consistent with the hypothesis that central alterations undergone in various NDDs are also manifested at the peripheral sympathoadrenal axis to impair the stress fight-or-flight response in patients suffering from those diseases. Such alterations may occur: (i) primarily by the expression of mutated disease proteins in CCs; (ii) secondarily to stress adaptation imposed by disease progression and the limitations of patient autonomy.
Our contribution focuses on the characterization of sleep apnea from a cardiac rate point of view, using Recurrence Quantification Analysis (RQA), based on a Heart Rate Variability (HRV) feature ...selection process. Three parameters are crucial in RQA: those related to the embedding process (dimension and delay) and the threshold distance. There are no overall accepted parameters for the study of HRV using RQA in sleep apnea. We focus on finding an overall acceptable combination, sweeping a range of values for each of them simultaneously. Together with the commonly used RQA measures, we include features related to recurrence times, and features originating in the complex network theory. To the best of our knowledge, no author has used them all for sleep apnea previously. The best performing feature subset is entered into a Linear Discriminant classifier. The best results in the "Apnea-ECG Physionet database" and the "HuGCDN2014 database" are, according to the area under the receiver operating characteristic curve, 0.93 (Accuracy: 86.33%) and 0.86 (Accuracy: 84.18%), respectively. Our system outperforms, using a relatively small set of features, previously existing studies in the context of sleep apnea. We conclude that working with dimensions around 7-8 and delays about 4-5, and using for the threshold distance the Fixed Amount of Nearest Neighbours (FAN) method with 5% of neighbours, yield the best results. Therefore, we would recommend these reference values for future work when applying RQA to the analysis of HRV in sleep apnea. We also conclude that, together with the commonly used vertical and diagonal RQA measures, there are newly used features that contribute valuable information for apnea minutes discrimination. Therefore, they are especially interesting for characterization purposes. Using two different databases supports that the conclusions reached are potentially generalizable, and are not limited by database variability.
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