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The first comprehensive structural and extraction study of a 2,2'-bipyridine-6,6'-dicarboxamide (L diamide) extractant for U, Np, Pu, Th, Am, and Eu ions showed great potential for actinide separation due to steric hindrance of the amidic side phenyl ring of the given compound. The study of the complexes of An(VI) and Th(IV) with 2,2'-bipyridyldicarboxamide-type extractants demonstrated the structure of the extraction species for the first time. Investigation of the extraction properties with the radiometric and millimolar quantities of actinides showed similar extraction trends. For the first time, a metal-ion-induced phenyl-ring rotation restriction was found for the U, Th, and Eu complexes by employing temperature-dependent dynamic NMR. A study of the solution behavior of the complexes accompanied by density functional theory modeling studies elucidated the mechanism of the unusual C-N bond rotation restriction induced by metal coordination.
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Current serological tests for the emerging tick-borne pathogen Borrelia miyamotoi lack diagnostic accuracy. To improve serodiagnosis, we investigated a protein array simultaneously screening for IgM and IgG reactivity against multiple recombinant B. miyamotoi antigens. The array included six B. miyamotoi antigens: glycerophosphodiester phosphodiesterase (GlpQ), multiple variable major proteins (Vmps), and flagellin. Sera included samples from cases of PCR-proven Borrelia miyamotoi disease (BMD), multiple potentially cross-reactive control groups (including patients with culture-proven Lyme borreliosis, confirmed Epstein-Barr virus, cytomegalovirus, or other spirochetal infections), and several healthy control groups from regions where Ixodes is endemic and regions where it is nonendemic. Based on receiver operating characteristic (ROC) analyses, the cutoff for reactivity per antigen was set at 5 µg/mL for IgM and IgG. The individual antigens demonstrated high sensitivity but relatively low specificity for both IgM and IgG. The best-performing single antigen (GlpQ) showed a sensitivity of 88.0% (95% confidence interval [CI], 78.9 to 93.5) and a specificity of 94.2% (95% CI, 92.7 to 95.6) for IgM/IgG. Applying the previous published diagnostic algorithm-defining seroreactivity as reactivity against GlpQ and any Vmp-revealed a significantly higher specificity of 98.5% (95% CI, 97.6 to 99.2) but a significantly lower sensitivity of 79.5% (95% CI, 69.3 to 87.0) for IgM/IgG compared to GlpQ alone. Therefore, we propose to define seroreactivity as reactivity against GlpQ and any Vmp or flagellin which resulted in a comparable sensitivity of 84.3% (95% CI, 74.7 to 90.8) and a significantly higher specificity of 97.9% (95% CI, 96.9 to 98.7) for IgM/IgG compared to GlpQ alone. In conclusion, we have developed and validated a novel serological tool to diagnose BMD that could be implemented in clinical practice and epidemiological studies. IMPORTANCE This paper describes the protein array as a novel serological test for the diagnosis of Borrelia miyamotoi disease (BMD), by reporting the methodology, the development of a diagnostic algorithm, and its extensive validation. With rising numbers of ticks and tick bites, tick-borne diseases, such as BMD, urgently deserve further societal and medical attention. B. miyamotoi is prevalent in Ixodes ticks across the northern hemisphere. Humans are exposed to, and infected by, B. miyamotoi and develop BMD in Asia, in North America, and to a lesser extent in Europe. However, the burden of infection and disease remains largely unknown, due to the noncharacteristic clinical presentation, together with the lack of awareness and availability of diagnostic tools. With this paper, we offer a novel diagnostic tool which will assist in assessing the burden of disease and could be implemented in clinical care.
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Anticuerpos Antibacterianos , Infecciones por Borrelia , Borrelia , Ixodes , Animales , Humanos , Flagelina , Inmunoglobulina G , Inmunoglobulina M , Ixodes/microbiología , Análisis por Matrices de Proteínas , Infecciones por Borrelia/inmunología , Anticuerpos Antibacterianos/análisisRESUMEN
Bacterial and mitochondrial DNA, sharing an evolutionary origin, act as danger-associated molecular patterns in infectious and sterile inflammation. They both contain immunomodulatory CpG motifs. Interactions between CpG motifs and the complement system are sparsely described, and mechanisms of complement activation by CpG remain unclear. Lepirudin-anticoagulated human whole blood and plasma were incubated with increasing concentrations of three classes of synthetic CpGs: CpG-A, -B, and -C oligodeoxynucleotides and their GpC sequence controls. Complement activation products were analyzed by immunoassays. Cytokine levels were determined via 27-plex beads-based immunoassay, and CpG interactions with individual complement proteins were evaluated using magnetic beads coated with CpG-B. In whole blood and plasma, CpG-B and CpG-C (p < 0.05 for both), but not CpG-A (p > 0.8 for all), led to time- and dose-dependent increase of soluble C5b-9, the alternative complement convertase C3bBbP, and the C3 cleavage product C3bc. GpC-A, -B, and -C changed soluble fluid-phase C5b-9, C3bBbP, and C3bc to the same extent as CpG-A, -B, and -C, indicating a DNA backbone-dependent effect. Dose-dependent CpG-B binding was found to C1q (r = 0.83; p = 0.006) and factor H (r = 0.93; p < 0.001). The stimulatory complement effect was partly preserved in C2-deficient plasma and completely preserved in MASP-2-deficient serum. CpG-B increased levels of IL-1ß, IL-2, IL-6, IL-8, MCP-1, and TNF in whole blood, which were completely abolished by inhibition of C5 and C5aR1 (p < 0.05 for all). In conclusion, synthetic analogs of bacterial and mitochondrial DNA activate the complement system via the DNA backbone. We suggest that CpG-B interacts directly with classical and alternative pathway components, resulting in complement-C5aR1-dependent cytokine release.
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Citocinas , Oligodesoxirribonucleótidos , Humanos , Activación de Complemento , Complemento C1q , Factor H de Complemento , Complejo de Ataque a Membrana del Sistema Complemento/farmacología , Proteínas del Sistema Complemento/metabolismo , Citocinas/metabolismo , ADN Mitocondrial , Interleucina-2/farmacología , Interleucina-6/farmacología , Interleucina-8 , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Oligodesoxirribonucleótidos/farmacología , Islas de CpGRESUMEN
Oxidative stress may cause extended tyrosine posttranslational modifications of peptides and proteins. The 3-nitro-L-tyrosine (Nit), which is typically formed, affects protein behavior during neurodegenerative processes, such as Alzheimer's and Parkinson's diseases. Such metabolic products may be conveniently detected at very low concentrations by surface enhanced Raman spectroscopy (SERS). Previously, we have explored the SERS detection of the Nit NO2 bending vibrational bands in a presence of hydrogen chloride (Niederhafner et al., Amino Acids 53:517-532, 2021, ibid). In this article, we describe performance of a new SERS substrate, "pink silver", synthesized photochemically. It provides SERS even without the HCl induction, and the acid further decreases the detection limit about 9 times. Strong SERS bands were observed in the asymmetric (1550-1475 cm-1) and symmetric (1360-1290 cm-1) NO stretching in the NO2 group. The bending vibration was relatively weak, but appeared stronger when HCl was added. The band assignments were supported by density functional theory modeling.
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Plata , Espectrometría Raman , Dióxido de Nitrógeno , Péptidos , Proteínas , Plata/química , Espectrometría Raman/métodosRESUMEN
MOTIVATION: There is a plethora of measures to evaluate functional similarity (FS) of genes based on their co-expression, protein-protein interactions and sequence similarity. These measures are typically derived from hand-engineered and application-specific metrics to quantify the degree of shared information between two genes using their Gene Ontology (GO) annotations. RESULTS: We introduce deepSimDEF, a deep learning method to automatically learn FS estimation of gene pairs given a set of genes and their GO annotations. deepSimDEF's key novelty is its ability to learn low-dimensional embedding vector representations of GO terms and gene products and then calculate FS using these learned vectors. We show that deepSimDEF can predict the FS of new genes using their annotations: it outperformed all other FS measures by >5-10% on yeast and human reference datasets on protein-protein interactions, gene co-expression and sequence homology tasks. Thus, deepSimDEF offers a powerful and adaptable deep neural architecture that can benefit a wide range of problems in genomics and proteomics, and its architecture is flexible enough to support its extension to any organism. AVAILABILITY AND IMPLEMENTATION: Source code and data are available at https://github.com/ahmadpgh/deepSimDEF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Biología Computacional , Proteínas , Humanos , Ontología de Genes , Biología Computacional/métodos , Anotación de Secuencia Molecular , Programas Informáticos , Saccharomyces cerevisiae , ARNRESUMEN
The pathogenesis of cardiovascular disease (CVD) is complex and multifactorial, and inflammation plays a central role. Inflammasomes are multimeric protein complexes that are activated in a 2-step manner in response to infection or tissue damage. Upon activation the proinflammatory cytokines, interleukins-1ß and -18 are released. In the last decade, the evidence that inflammasome activation plays an important role in CVD development became stronger. We discuss the role of different inflammasomes in the pathogenesis of CVD, focusing on atherosclerosis and heart failure. This review also provides an overview of existing experimental studies and clinical trials on inflammasome inhibition as a therapeutic target in these disorders.
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ABSTRACT: Vitamin C combined with hydrocortisone is increasingly being used to treat septic patients, even though this treatment regimen is based on questionable evidence. When used, a marked effect on key players of innate immunity would be expected, as sepsis is featured by a dysregulated immune response.Here, we explored the effect of vitamin C and hydrocortisone alone and combined, in an ex vivo human whole-blood model of Escherichia coli- or Staphylococcus aureus-induced inflammation. Inflammatory markers for activation of complement (terminal C5b-9 complement complex [TCC]), granulocytes (myeloperoxidase), platelets (ß-thromboglobulin), cytokines (tumor necrosis factor [TNF], IL-1ß, IL6, and IL-8), and leukocytes (CD11b and oxidative burst) were quantified, by enzyme-linked immunosorbent assay, multiplex technology, and flow cytometry.In E. coli- and S. aureus-stimulated whole blood, a broad dose-titration of vitamin C and hydrocortisone alone did not lead to dose-response effects for the central innate immune mediators TCC and IL-6. Hence, the clinically relevant doses were used further. Compared to the untreated control sample, two of the nine biomarkers induced by E. coli were reduced by hydrocortisone and/or vitamin C. TNF was reduced by hydrocortisone alone (19%, Pâ=â0.01) and by the combination (31%, Pâ=â0.01). The oxidative burst of monocytes and granulocytes was reduced for both drugs alone and their combination, (ranging 8-19%, Pâ<â0.05). Using S. aureus, neither of the drugs, alone nor in combination, had any effects on the nine biomarkers.In conclusion, despite the limitation of the ex vivo model, the effect of vitamin C and hydrocortisone on bacteria-induced inflammatory response in human whole blood is limited and following the clinical data.
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Ácido Ascórbico/farmacología , Escherichia coli/inmunología , Hidrocortisona/farmacología , Staphylococcus aureus/inmunología , Biomarcadores , Antígeno CD11b/sangre , Complejo de Ataque a Membrana del Sistema Complemento/análisis , Citocinas/sangre , Humanos , Peroxidasa/sangre , Estallido Respiratorio , beta-Tromboglobulina/análisisRESUMEN
Uranyl compounds with tetrahedral oxoanions demonstrate a significant structural and topological diversity. Complexes of transuranium elements with such anions are not equally well-represented in the literature. To answer the question about the structural similarity in a series of An6+ complexes with XO42- anions, we synthesized and studied 10 new U, Np, and Pu chromates with outer-sphere organic cations. The structural analysis and comparison with the literature data shows that the Np and Pu complexes are generally based on the same structural blocks as the uranyl compounds. Moreover, the chromate anion does not show any unique structural role as compared to the sulfate and selenate ions. As a result, the neptunium and plutonium chromates contain 1D and 2D structural units similar to those found in the uranyl sulfates and selenates. The templating role of the outer-sphere cations in the actinyl complexes with tetrahedral oxoanions is also not evident, and there is no clear correlation between the nature of the outer-sphere cations and the topology of the structural units.
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Synthesis, FTIR spectral study, and X-ray diffraction analysis of single crystals of (CH3)4N[UO2(mba)3] (I), (CH3)4N[NpO2(mba)2(NO3)] (II), (CH3)4N[PuO2(mba)2(NO3)] (III), and (CH3)4N[NpO2(mba)(NO3)2] (IV), where mba is a monobromoacetate ion (CH2BrCOO-), were conducted. The main structural units of crystals I-IV are mononuclear anionic complexes of the [AnO2(mba)3]-, [AnO2(mba)2(NO3)]-, or [AnO2(mba)(NO3)2]- composition. All these complex units are characterized with the same crystal-chemical formula AB 01 3 (A = AnO2 2+ and B 01 = CH2BrCOO- or NO3 -). Using the method of molecular Voronoi-Dirichlet polyhedra, the contributions of various types of noncovalent interactions into the formation of supramolecular structures of the obtained complexes were characterized. The analysis of coordination modes of all monobromoacetate-containing compounds from the Cambridge Structural Database was accomplished. Actinide contraction in the studied compounds is discussed.
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Analyze performance of unsupervised embedding algorithms in sentiment analysis of knowledge-rich data sets. We apply state-of-the-art embedding algorithms Word2Vec and Doc2Vec as the learning techniques. The algorithms build word and document embeddings in an unsupervised manner. To assess the algorithms' performance, we define sentiment metrics and use a semantic lexicon SentiWordNet (SWN) to establish the benchmark measures. Our empirical results are obtained on the Obesity data set from i2b2 clinical discharge summaries and the Reuters Science dataset. We use the Welch's test to analyze the obtained sentiment evaluation. On the Obesity data, the Welch's test found significant difference between the SWN evaluation of the most positive and most negative texts. On the same data, the Word2Vec results support the SWN results, whereas the Doc2Vec results partially correspond to the Word2Vec and the SWN results. On the Reuters data, the Welch's test did not find significant difference between the SWN evaluation of the most positive and most negative texts. On the same data, Word2Vec and Doc2Vec results only in part correspond to the SWN results. In unsupervised sentiment analysis of medical and scientific texts, the Word2Vec sentiment analysis has been more consistent with the SentiWordNet sentiment assessment than the Doc2Vec sentiment analysis. The Welch's test of the SentiWordNet results has been a strong indicator of future correspondence between Word2Vec and SentiWordNet results.
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Cybersecurity in Russia is not a standalone concept but an integral part of national information security, which influences its legal status and applicable regulation, and determines its development trends. The purpose of this article is to outline the Russian approach to cybersecurity, describe the related legal framework, representative business cases and trends in legal development.
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Obesity-related diseases (e.g. type 2 diabetes mellitus and cardiovascular disorders) represent an increasing health problem worldwide. NLRP3 inflammasome activation may underlie obesity-induced inflammation and insulin resistance, and NLRP3 deficient mice exposed to high fat diet (HFD) appear to be protected from left ventricle (LV) concentric remodeling. Herein, we investigated if these beneficial effects were associated with alterations in plasma metabolites, using metabolomic and lipidomic analysis, and gut microbiota composition, using 16S rRNA sequencing of cecum content, comparing NLRP3 deficient and wild type (WT) mice on HFD and control diet. Obese NLRP3 deficient mice had lower systemic ceramide levels, potentially resulting attenuating inflammation, altered hepatic expression of fatty acids (FA) with lower mono-saturated FA and higher polyunsaturated FA levels, potentially counteracting development of liver steatosis, downregulated myocardial energy metabolism as assessed by proteomic analyses of LV heart tissue, and different levels of bile acids as compared with WT mice. These changes were accompanied by an altered composition of gut microbiota associated with decreased systemic levels of tri-methylamine-N-oxide and lipopolysaccharide, potentially inducing attenuating systemic inflammation and beneficial effects on lipid metabolism. Our findings support a role of NLRP3 inflammasome in the interface between metabolic and inflammatory stress, involving an altered gut microbiota composition.
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Dieta Alta en Grasa/efectos adversos , Microbioma Gastrointestinal , Metaboloma , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Ceramidas/sangre , Metabolismo Energético , Ácidos Grasos/sangre , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos , Lipopolisacáridos/sangre , Hígado/metabolismo , Masculino , Metilaminas/sangre , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.
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Betacoronavirus/inmunología , Activación de Complemento , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Insuficiencia Respiratoria/inmunología , Anciano , Biomarcadores/sangre , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/complicaciones , Femenino , Interacciones Huésped-Patógeno/inmunología , Humanos , Masculino , Lectina de Unión a Manosa/sangre , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Neumonía Viral/complicaciones , Insuficiencia Respiratoria/virología , SARS-CoV-2 , Carga ViralRESUMEN
A series of new dimethyl-sulfoxide-containing pertechnetates and perrhenates of tetravalent U, Np, and Pu were synthesized and structurally characterized by the X-ray diffractometry. In all the synthesized compounds, the actinide atoms were coordinated by eight DMSO molecules with or without an extra XO4- anion in the coordination sphere. This resulted in the square antiprismatic or capped square antiprismatic coordination of An atoms. Three or four XO4- anions play the role of outer-sphere anions. The electron and IR spectra of the compounds correlated with their crystal structure.
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Composites made of a biodegradable polymer, e.g., polylactic acid (PLA) and hydroxyapatite nanoparticles (HAP NPs) are promising orthopedic materials. There is a particular need for biodegradable hybrid nanocomposites with strong mechanical properties. However, obtaining such composites is challenging, since nanoparticles tend to agglomerate, and it is difficult to achieve good bonding between the hydrophilic ceramic and the hydrophobic polymer. This paper describes a two-step technology for obtaining a ceramic matrix composite. The first step is the preparation of composite granules. The granules are obtained by infiltration of porous granules of HAP NPs with PLA through high-pressure infiltration. The homogeneous ceramic-polymer granules are 80 µm in diameter, and the composite granules are 80 wt% HAP NPs. The second step is consolidation of the granules using high pressure. This is performed in three variants: Uniaxial pressing with the pressure of up to 1000 MPa at room temperature, warm isostatic compaction (75 MPa at 155 °C), and a combination of the two methods. The combined methods result in the highest densification (99%) and strongest mechanical properties; the compressive strength is 374 MPa. The structure of the ceramic matrix composite is homogeneous. Good adhesion between the inorganic and the organic component is observable using scanning electron microscopy.
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Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems are evolutionarily conserved throughout species. As a result, the immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interaction between metabolic disturbances and the immune system has been most extensively studied in disorders related to obesity such as insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease. Metabolically induced inflammation seems also to play a role in the development and progression of atherosclerosis including its complications such as myocardial infarction (MI) and post-MI remodeling. There are several lines of evidence suggesting that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a sensor of metabolic stress linking metabolic disturbances to inflammation. Here, we will discuss the role of the NLRP3 inflammasome in the pathogenesis of obesity and diabetes, 2 important risk factors for atherosclerosis and MI. We will also discuss the role of NLRP3 inflammasome in the interaction between metabolic disturbances and myocardial inflammation during MI and during metabolically induced myocardial remodeling.
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Aterosclerosis/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamasomas/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Obesidad/metabolismo , Animales , Aterosclerosis/epidemiología , Aterosclerosis/inmunología , Aterosclerosis/patología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/patología , Metabolismo Energético , Microbioma Gastrointestinal , Humanos , Inflamasomas/inmunología , Inflamación/epidemiología , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/inmunología , Resistencia a la Insulina , Infarto del Miocardio/epidemiología , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Miocardio/inmunología , Miocardio/patología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Obesidad/epidemiología , Obesidad/inmunología , Obesidad/patología , Factores de Riesgo , Transducción de SeñalRESUMEN
Background: Obesity is an increasingly prevalent metabolic disorder in the modern world and is associated with structural and functional changes in the heart. The NLRP3 inflammasome is an innate immune sensor that can be activated in response to endogenous danger signals and triggers activation of interleukin (IL)-1ß and IL-18. Increasing evidence points to the involvement of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, and we hypothesized that it also could play a role in the development of obesity induced cardiac alterations. Methods and Results: WT, Nlrp3-/-, and ASC-/- (Pycard-/-) male mice were exposed to high fat diet (HFD; 60 cal% fat) or control diet for 52 weeks. Cardiac structure and function were evaluated by echocardiography and magnetic resonance imaging, respectively. Whereas, NLRP3 and ASC deficiency did not affect the cardiac hypertrophic response to obesity, it was preventive against left ventricle concentric remodeling and impairment of diastolic function. Furthermore, whereas NLRP3 and ASC deficiency attenuated systemic inflammation in HFD fed mice; long-term HFD did not induce significant cardiac fibrosis or inflammation, suggesting that the beneficial effects of NLRP3 inflammasome deficiency on myocardial remodeling at least partly reflect systemic mechanisms. Nlrp3 and ASC (Pycard) deficient mice were also protected against obesity-induced systemic metabolic dysregulation, as well as lipid accumulation and impaired insulin signaling in hepatic and cardiac tissues. Conclusions: Our data indicate that the NLRP3 inflammasome modulates cardiac concentric remodeling in obesity through effects on systemic inflammation and metabolic disturbances, with effect on insulin signaling as a potential mediator within the myocardium.
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Inflamasomas/metabolismo , Miocardio/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Obesidad/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Inflamación/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVE: In biomedicine, there is a wealth of information hidden in unstructured narratives such as research articles and clinical reports. To exploit these data properly, a word sense disambiguation (WSD) algorithm prevents downstream difficulties in the natural language processing applications pipeline. Supervised WSD algorithms largely outperform un- or semisupervised and knowledge-based methods; however, they train 1 separate classifier for each ambiguous term, necessitating a large number of expert-labeled training data, an unattainable goal in medical informatics. To alleviate this need, a single model that shares statistical strength across all instances and scales well with the vocabulary size is desirable. MATERIALS AND METHODS: Built on recent advances in deep learning, our deepBioWSD model leverages 1 single bidirectional long short-term memory network that makes sense prediction for any ambiguous term. In the model, first, the Unified Medical Language System sense embeddings will be computed using their text definitions; and then, after initializing the network with these embeddings, it will be trained on all (available) training data collectively. This method also considers a novel technique for automatic collection of training data from PubMed to (pre)train the network in an unsupervised manner. RESULTS: We use the MSH WSD dataset to compare WSD algorithms, with macro and micro accuracies employed as evaluation metrics. deepBioWSD outperforms existing models in biomedical text WSD by achieving the state-of-the-art performance of 96.82% for macro accuracy. CONCLUSIONS: Apart from the disambiguation improvement and unsupervised training, deepBioWSD depends on considerably less number of expert-labeled data as it learns the target and the context terms jointly. These merit deepBioWSD to be conveniently deployable in real-time biomedical applications.
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Minería de Datos/métodos , Aprendizaje Profundo , Procesamiento de Lenguaje Natural , Redes Neurales de la Computación , Vocabulario Controlado , Algoritmos , Ontologías Biológicas , Conjuntos de Datos como Asunto , Medical Subject Headings , Systematized Nomenclature of Medicine , Unified Medical Language SystemRESUMEN
Inflammasomes are multiprotein inflammatory platforms that induce caspase-1 activation and subsequently interleukin (IL)-1ß and IL-18 processing. The NLRP3 inflammasome is activated by different forms of oxidative stress, and, based on the central role of IL-1ß in the destruction of pancreatic islets, it could be related to the development of diabetes. We therefore investigated responses in wild-type C57Bl/6 (WT) mice, NLRP3-/- mice, and mice deficient in apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) after exposing islets to short-term hypoxia or alloxan-induced islet damage. NLRP3-deficient islets compared with WT islets had preserved function ex vivo and were protected against hypoxia-induced cell death. Furthermore, NLRP3 and ASC-deficient mice were protected against oxidative stress-induced diabetes caused by repetitive low-dose alloxan administration, and this was associated with reduced ß-cell death and reduced macrophage infiltration. This suggests that the beneficial effect of NLRP3 inflammasome deficiency on oxidative stress-mediated ß-cell damage could involve reduced macrophage infiltration and activation. To support the role of macrophage activation in alloxan-induced diabetes, we injected WT mice with liposomal clodronate, which causes macrophage depletion before induction of a diabetic phenotype by alloxan treatment, resulting in improved glucose homeostasis in WT mice. We show here that the NLRP3 inflammasome acts as a mediator of hypoxia and oxidative stress in insulin-producing cells, suggesting that inhibition of the NLRP3 inflammasome could have beneficial effects on ß-cell preservation.
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Diabetes Mellitus Experimental/metabolismo , Inflamasomas/metabolismo , Islotes Pancreáticos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/fisiología , Animales , Apoptosis/fisiología , Células Secretoras de Insulina/metabolismo , Interleucina-1beta/metabolismo , Activación de Macrófagos/fisiología , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
Due to a distortion in the body image, the people who suffer from muscle dysmorphia have the self-perception of being less muscular than they currently are. With the aim of increasing their muscular development, they resort to the use of AAS. The purpose of the present study is to know the prevalence of the use of AAS in a Spanish sample affected by muscle dysmorphia. 562 male and 172 female bodybuilders and weightlifters were provided with different questionnaires in order to know, firstly, if they suffered from this disorder and, secondly, the percentage of the participants affected who use these substances. Decision trees and regression was applied to create explanatory models for muscle dysmorphia (R = 0.78 and R2 = 0.62). The results show that almost 50% of the participants, male and female, affected by this disorder use this kind of drugs.
Las personas que padecen Dismorfia Muscular (DM) debido a una distorsión en la imagen corporal, se perciben menos musculosas de lo que son en realidad. Para paliar este problema y con el fin de aumentar su musculatura, algunas de estas personas hacen uso de hormonas ilegales, como son los esteroides anabolizantes androgénicos (EAA), cuya función principal es aumentar la musculatura. El objetivo de este estudio es conocer la prevalencia del uso de EAA en personas afectadas por Dismorfia Muscular. La muestra de este estudio estaba compuesta de 562 hombres y 172 mujeres fisicoculturistas y levantadores de pesas, a los que se le administraron medidas antropométricas, la ecuación Fat-Free Mass Index, el cuestionario Escala de Satisfacción Muscular y el test informatizado Somatomorphic Matrix. Como resultado se crearon diferentes modelos de regresión de la DM, empleando las técnicas estadísticas de árboles de decisión (R = .78 y R2 = .62) de minería de datos. La principal conclusión es que el 50% de participantes afectados por este trastorno usa EAA.