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1.
Phys Rev Lett ; 132(15): 151001, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38682982

RESUMEN

We report on a measurement of astrophysical tau neutrinos with 9.7 yr of IceCube data. Using convolutional neural networks trained on images derived from simulated events, seven candidate ν_{τ} events were found with visible energies ranging from roughly 20 TeV to 1 PeV and a median expected parent ν_{τ} energy of about 200 TeV. Considering backgrounds from astrophysical and atmospheric neutrinos, and muons from π^{±}/K^{±} decays in atmospheric air showers, we obtain a total estimated background of about 0.5 events, dominated by non-ν_{τ} astrophysical neutrinos. Thus, we rule out the absence of astrophysical ν_{τ} at the 5σ level. The measured astrophysical ν_{τ} flux is consistent with expectations based on previously published IceCube astrophysical neutrino flux measurements and neutrino oscillations.

2.
Phys Rev Lett ; 128(5): 051101, 2022 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-35179913

RESUMEN

We present an all-sky 90% confidence level upper limit on the cosmic flux of relativistic magnetic monopoles using 2886 days of IceCube data. The analysis was optimized for monopole speeds between 0.750c and 0.995c, without any explicit restriction on the monopole mass. We constrain the flux of relativistic cosmic magnetic monopoles to a level below 2.0×10^{-19} cm^{-2} s^{-1} sr^{-1} over the majority of the targeted speed range. This result constitutes the most strict upper limit to date for magnetic monopoles with ß≳0.8 and up to ß∼0.995 and fills the gap between existing limits on the cosmic flux of nonrelativistic and ultrarelativistic magnetic monopoles.

3.
Phys Rev Lett ; 129(15): 151801, 2022 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-36269964

RESUMEN

We present a search for an unstable sterile neutrino by looking for a resonant signal in eight years of atmospheric ν_{µ} data collected from 2011 to 2019 at the IceCube Neutrino Observatory. Both the (stable) three-neutrino and the 3+1 sterile neutrino models are disfavored relative to the unstable sterile neutrino model, though with p values of 2.8% and 0.81%, respectively, we do not observe evidence for 3+1 neutrinos with neutrino decay. The best-fit parameters for the sterile neutrino with decay model from this study are Δm_{41}^{2}=6.7_{-2.5}^{+3.9} eV^{2}, sin^{2}2θ_{24}=0.33_{-0.17}^{+0.20}, and g^{2}=2.5π±1.5π, where g is the decay-mediating coupling. The preferred regions of the 3+1+decay model from short-baseline oscillation searches are excluded at 90% C.L.

4.
Phys Rev Lett ; 129(1): 011804, 2022 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-35841552

RESUMEN

We report a search for nonstandard neutrino interactions (NSI) using eight years of TeV-scale atmospheric muon neutrino data from the IceCube Neutrino Observatory. By reconstructing incident energies and zenith angles for atmospheric neutrino events, this analysis presents unified confidence intervals for the NSI parameter ε_{µτ}. The best-fit value is consistent with no NSI at a p value of 25.2%. With a 90% confidence interval of -0.0041≤ε_{µτ}≤0.0031 along the real axis and similar strength in the complex plane, this result is the strongest constraint on any NSI parameter from any oscillation channel to date.

5.
Phys Rev Lett ; 125(14): 141801, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33064514

RESUMEN

The results of a 3+1 sterile neutrino search using eight years of data from the IceCube Neutrino Observatory are presented. A total of 305 735 muon neutrino events are analyzed in reconstructed energy-zenith space to test for signatures of a matter-enhanced oscillation that would occur given a sterile neutrino state with a mass-squared differences between 0.01 and 100 eV^{2}. The best-fit point is found to be at sin^{2}(2θ_{24})=0.10 and Δm_{41}^{2}=4.5 eV^{2}, which is consistent with the no sterile neutrino hypothesis with a p value of 8.0%.

6.
Phys Rev Lett ; 125(12): 121104, 2020 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-33016752

RESUMEN

We report on the first measurement of the astrophysical neutrino flux using particle showers (cascades) in IceCube data from 2010-2015. Assuming standard oscillations, the astrophysical neutrinos in this dedicated cascade sample are dominated (∼90%) by electron and tau flavors. The flux, observed in the sensitive energy range from 16 TeV to 2.6 PeV, is consistent with a single power-law model as expected from Fermi-type acceleration of high energy particles at astrophysical sources. We find the flux spectral index to be γ=2.53±0.07 and a flux normalization for each neutrino flavor of ϕ_{astro}=1.66_{-0.27}^{+0.25} at E_{0}=100 TeV, in agreement with IceCube's complementary muon neutrino results and with all-neutrino flavor fit results. In the measured energy range we reject spectral indices γ≤2.28 at ≥3σ significance level. Because of high neutrino energy resolution and low atmospheric neutrino backgrounds, this analysis provides the most detailed characterization of the neutrino flux at energies below ∼100 TeV compared to previous IceCube results. Results from fits assuming more complex neutrino flux models suggest a flux softening at high energies and a flux hardening at low energies (p value ≥0.06). The sizable and smooth flux measured below ∼100 TeV remains a puzzle. In order to not violate the isotropic diffuse gamma-ray background as measured by the Fermi Large Area Telescope, it suggests the existence of astrophysical neutrino sources characterized by dense environments which are opaque to gamma rays.

7.
Phys Rev Lett ; 124(5): 051103, 2020 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-32083934

RESUMEN

This Letter presents the results from pointlike neutrino source searches using ten years of IceCube data collected between April 6, 2008 and July 10, 2018. We evaluate the significance of an astrophysical signal from a pointlike source looking for an excess of clustered neutrino events with energies typically above ∼1 TeV among the background of atmospheric muons and neutrinos. We perform a full-sky scan, a search within a selected source catalog, a catalog population study, and three stacked Galactic catalog searches. The most significant point in the northern hemisphere from scanning the sky is coincident with the Seyfert II galaxy NGC 1068, which was included in the source catalog search. The excess at the coordinates of NGC 1068 is inconsistent with background expectations at the level of 2.9σ after accounting for statistical trials from the entire catalog. The combination of this result along with excesses observed at the coordinates of three other sources, including TXS 0506+056, suggests that, collectively, correlations with sources in the northern catalog are inconsistent with background at 3.3σ significance. The southern catalog is consistent with background. These results, all based on searches for a cumulative neutrino signal integrated over the 10 years of available data, motivate further study of these and similar sources, including time-dependent analyses, multimessenger correlations, and the possibility of stronger evidence with coming upgrades to the detector.

8.
Phys Rev Lett ; 122(5): 051102, 2019 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-30822017

RESUMEN

High-energy neutrino emission has been predicted for several short-lived astrophysical transients including gamma-ray bursts (GRBs), core-collapse supernovae with choked jets, and neutron star mergers. IceCube's optical and x-ray follow-up program searches for such transient sources by looking for two or more muon neutrino candidates in directional coincidence and arriving within 100 s. The measured rate of neutrino alerts is consistent with the expected rate of chance coincidences of atmospheric background events and no likely electromagnetic counterparts have been identified in Swift follow-up observations. Here, we calculate generic bounds on the neutrino flux of short-lived transient sources. Assuming an E^{-2.5} neutrino spectrum, we find that the neutrino flux of rare sources, like long gamma-ray bursts, is constrained to <5% of the detected astrophysical flux and the energy released in neutrinos (100 GeV to 10 PeV) by a median bright GRB-like source is <10^{52.5} erg. For a harder E^{-2.13} neutrino spectrum up to 30% of the flux could be produced by GRBs and the allowed median source energy is <10^{52} erg. A hypothetical population of transient sources has to be more common than 10^{-5} Mpc^{-3} yr^{-1} (5×10^{-8} Mpc^{-3} yr^{-1} for the E^{-2.13} spectrum) to account for the complete astrophysical neutrino flux.

9.
Phys Rev Lett ; 120(7): 071801, 2018 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-29542976

RESUMEN

We present a measurement of the atmospheric neutrino oscillation parameters using three years of data from the IceCube Neutrino Observatory. The DeepCore infill array in the center of IceCube enables the detection and reconstruction of neutrinos produced by the interaction of cosmic rays in Earth's atmosphere at energies as low as ∼5 GeV. That energy threshold permits measurements of muon neutrino disappearance, over a range of baselines up to the diameter of the Earth, probing the same range of L/E_{ν} as long-baseline experiments but with substantially higher-energy neutrinos. This analysis uses neutrinos from the full sky with reconstructed energies from 5.6 to 56 GeV. We measure Δm_{32}^{2}=2.31_{-0.13}^{+0.11}×10^{-3} eV^{2} and sin^{2}θ_{23}=0.51_{-0.09}^{+0.07}, assuming normal neutrino mass ordering. These results are consistent with, and of similar precision to, those from accelerator- and reactor-based experiments.

10.
Med Mycol ; 56(6): 668-678, 2018 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-29228380

RESUMEN

Data regarding the epidemiology and diagnosis of invasive aspergillosis in the critically ill population are limited, with data regarding elderly patients (≥75 years old) even scarcer. We aimed to further compare the epidemiology, characteristics and outcome of elderly versus nonelderly critically ill patients with invasive aspergillosis (IA) Prospective, international, multicenter observational study (AspICU) including adult intensive care unit (ICU) patients, with a culture and/or direct examination and/or histopathological sample positive for Aspergillus spp. at any site. We compared clinical characteristics and outcome of IA in ICU patients using two different diagnostic algorithms. Elderly and nonelderly ICU patients with IA differed in a number of characteristics, including comorbidities, clinical features of the disease, mycology testing, and radiological findings. No difference regarding mortality was found. According to the clinical algorithm, elderly patients were more likely to be diagnosed with putative IA. Elderly patients had less diagnostic radiological findings and when these findings were present they were detected late in the disease course. The comparison between elderly survivors and nonsurvivors demonstrated differences in clinical characteristics of the disease, affected sites and supportive therapy needed. All patients who were diagnosed with proven IA died. Increased vigilance combined with active search for mycological laboratory evidence and radiological confirmation are necessary for the timely diagnosis of IA in the elderly patient subset. Although elderly state per se is not a particular risk factor for mortality, a high SOFA score and the decision not to administer antifungal therapy may have an impact on survival of elderly patients.


Asunto(s)
Aspergilosis/diagnóstico , Unidades de Cuidados Intensivos/estadística & datos numéricos , Infecciones Fúngicas Invasoras/diagnóstico , Anciano , Antifúngicos/uso terapéutico , Aspergilosis/diagnóstico por imagen , Aspergilosis/tratamiento farmacológico , Aspergilosis/mortalidad , Causas de Muerte , Estudios de Cohortes , Enfermedad Crítica/mortalidad , Enfermedad Crítica/terapia , Europa (Continente) , Análisis Factorial , Femenino , Humanos , Unidades de Cuidados Intensivos/normas , Infecciones Fúngicas Invasoras/diagnóstico por imagen , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Resultado del Tratamiento
11.
Phys Rev Lett ; 119(4): 041801, 2017 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-29341770

RESUMEN

We report the results of a first experimental search for lepton number violation by four units in the neutrinoless quadruple-ß decay of ^{150}Nd using a total exposure of 0.19 kg yr recorded with the NEMO-3 detector at the Modane Underground Laboratory. We find no evidence of this decay and set lower limits on the half-life in the range T_{1/2}>(1.1-3.2)×10^{21} yr at the 90% C.L., depending on the model used for the kinematic distributions of the emitted electrons.

12.
Eur J Clin Microbiol Infect Dis ; 36(4): 649-655, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27858242

RESUMEN

The primary aim of this study was to collect national epidemiological data on candidaemia and to determine the reporting time of species identification and antifungal susceptibility in clinical practice. During a 1-year period (March 2013 until February 2014), every first Candida isolate from each episode of candidaemia was included prospectively from 30 Belgian hospitals. Identification and susceptibility testing were performed according to local procedures and isolates were sent to the National Reference Center for Mycosis. Species identification was checked by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS) sequencing in case no reliable identification was obtained by MALDI-TOF MS. Antifungal susceptibility testing was performed according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. A total of 355 isolates were retrieved from 338 patients. The mean incidence rate of candidaemia was 0.44 (range: 0.07 to 1.43) per 1000 admissions or 0.65 (range: 0.11 to 2.00) per 10,000 patient days. Candida albicans was most frequently found (50.4 %), followed by C. glabrata (27.3 %) and C. parapsilosis sensu lato (9.8 %). The overall resistance to fluconazole was 7.6 %, ranging from 3.9 % in C. albicans to 20.0 % in C. tropicalis. Only one C. glabrata isolate was resistant to the echinocandins. Four days after blood culture positivity, 99.7 % of the identifications and 90.3 % of the antifungal profiles were reported to the treating clinician. Candidaemia incidence rates differed up to 20-fold among Belgian hospitals; no clear factors explaining this difference were identified. The overall antifungal resistance rates were low but high azole resistance rates were recorded in C. tropicalis.


Asunto(s)
Candida/aislamiento & purificación , Candidemia/diagnóstico , Candidemia/epidemiología , Farmacorresistencia Fúngica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bélgica/epidemiología , Candida/clasificación , Candida/genética , Niño , Preescolar , ADN de Hongos/química , ADN de Hongos/genética , ADN Espaciador Ribosómico/química , ADN Espaciador Ribosómico/genética , Pruebas Diagnósticas de Rutina , Femenino , Hospitales , Humanos , Incidencia , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Secuencia de ADN , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Factores de Tiempo , Adulto Joven
13.
Phys Rev Lett ; 117(24): 241101, 2016 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-28009216

RESUMEN

We report constraints on the sources of ultrahigh-energy cosmic rays (UHECRs) above 10^{9} GeV, based on an analysis of seven years of IceCube data. This analysis efficiently selects very high- energy neutrino-induced events which have deposited energies from 5×10^{5} GeV to above 10^{11} GeV. Two neutrino-induced events with an estimated deposited energy of (2.6±0.3)×10^{6} GeV, the highest neutrino energy observed so far, and (7.7±2.0)×10^{5} GeV were detected. The atmospheric background-only hypothesis of detecting these events is rejected at 3.6σ. The hypothesis that the observed events are of cosmogenic origin is also rejected at >99% CL because of the limited deposited energy and the nonobservation of events at higher energy, while their observation is consistent with an astrophysical origin. Our limits on cosmogenic neutrino fluxes disfavor the UHECR sources having a cosmological evolution stronger than the star formation rate, e.g., active galactic nuclei and γ-ray bursts, assuming proton-dominated UHECRs. Constraints on UHECR sources including mixed and heavy UHECR compositions are obtained for models of neutrino production within UHECR sources. Our limit disfavors a significant part of parameter space for active galactic nuclei and new-born pulsar models. These limits on the ultrahigh-energy neutrino flux models are the most stringent to date.

14.
Phys Rev Lett ; 117(7): 071801, 2016 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-27563950

RESUMEN

The IceCube neutrino telescope at the South Pole has measured the atmospheric muon neutrino spectrum as a function of zenith angle and energy in the approximate 320 GeV to 20 TeV range, to search for the oscillation signatures of light sterile neutrinos. No evidence for anomalous ν_{µ} or ν[over ¯]_{µ} disappearance is observed in either of two independently developed analyses, each using one year of atmospheric neutrino data. New exclusion limits are placed on the parameter space of the 3+1 model, in which muon antineutrinos experience a strong Mikheyev-Smirnov-Wolfenstein-resonant oscillation. The exclusion limits extend to sin^{2}2θ_{24}≤0.02 at Δm^{2}∼0.3 eV^{2} at the 90% confidence level. The allowed region from global analysis of appearance experiments, including LSND and MiniBooNE, is excluded at approximately the 99% confidence level for the global best-fit value of |U_{e4}|^{2}.

15.
Eur J Clin Microbiol Infect Dis ; 34(12): 2403-11, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26407622

RESUMEN

Data on the occurrence and outcome of patients with chronic obstructive pulmonary disease (COPD) and ventilator-associated pneumonia (VAP) are quite limited. The aim of this study was to determine if COPD intensive care unit (ICU) patients have a higher rate of VAP development, different microbiological aetiology or have worse outcomes than other patients without VAP. A secondary analysis of a large prospective, observational study conducted in 27 European ICUs was carried out. Trauma patients were excluded. Of 2082 intubated patients included in the study, 397 (19.1%) had COPD; 79 (19.9%) patients with COPD and 332 (19.7%) patients without COPD developed VAP. ICU mortality increased by 17% (p < 0.05) when COPD patients developed VAP, remaining an independent predictor of mortality [odds ratio (OR) 2.28; 95% confidence interval (CI) 1.35-3.87]. The development of VAP in COPD patients was associated with a median increase of 12 days in the duration of mechanical ventilation and >13 days in ICU stay (p < 0.05). Pseudomonas aeruginosa was more common in VAP when COPD was present (29.1% vs. 18.7%, p = 0.04) and was the most frequent isolate in COPD patients with early-onset VAP, with a frequency 2.5 times higher than in patients without early-onset VAP (33.3% vs. 13.3%, p = 0.03). COPD patients are not more predisposed to VAP than other ICU patients, but if COPD patients develop VAP, they have a worse outcome. Antibiotic coverage for non-fermenters needs to be included in the empiric therapy of all COPD patients, even in early-onset VAP.


Asunto(s)
Neumonía Asociada al Ventilador/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Europa (Continente)/epidemiología , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Neumonía Asociada al Ventilador/tratamiento farmacológico , Neumonía Asociada al Ventilador/microbiología , Neumonía Asociada al Ventilador/mortalidad , Estudios Prospectivos , Pseudomonas aeruginosa/aislamiento & purificación , Análisis de Supervivencia , Resultado del Tratamiento
16.
Science ; 380(6652): 1338-1343, 2023 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-37384687

RESUMEN

The origin of high-energy cosmic rays, atomic nuclei that continuously impact Earth's atmosphere, is unknown. Because of deflection by interstellar magnetic fields, cosmic rays produced within the Milky Way arrive at Earth from random directions. However, cosmic rays interact with matter near their sources and during propagation, which produces high-energy neutrinos. We searched for neutrino emission using machine learning techniques applied to 10 years of data from the IceCube Neutrino Observatory. By comparing diffuse emission models to a background-only hypothesis, we identified neutrino emission from the Galactic plane at the 4.5σ level of significance. The signal is consistent with diffuse emission of neutrinos from the Milky Way but could also arise from a population of unresolved point sources.

17.
Science ; 378(6619): 538-543, 2022 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-36378962

RESUMEN

A supermassive black hole, obscured by cosmic dust, powers the nearby active galaxy NGC 1068. Neutrinos, which rarely interact with matter, could provide information on the galaxy's active core. We searched for neutrino emission from astrophysical objects using data recorded with the IceCube neutrino detector between 2011 and 2020. The positions of 110 known gamma-ray sources were individually searched for neutrino detections above atmospheric and cosmic backgrounds. We found that NGC 1068 has an excess of [Formula: see text] neutrinos at tera-electron volt energies, with a global significance of 4.2σ, which we interpret as associated with the active galaxy. The flux of high-energy neutrinos that we measured from NGC 1068 is more than an order of magnitude higher than the upper limit on emissions of tera-electron volt gamma rays from this source.

18.
Vet Comp Orthop Traumatol ; 24(1): 50-6, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21103651

RESUMEN

OBJECTIVES: To investigate the feasibility of a minimally invasive video-assisted (MIVA) cervical ventral slot (VS) in dogs without the use of fluoroscopy, and to report our initial clinical experiences in dogs. METHODS: Two surgical approaches to an intervertebral disk space (IVDS) were performed in eight intact canine cadavers to determine the feasibility of MIVA-VS using the Destandau Endospine™ Devicea (DED) without fluoroscopic guidance. In a subsequent clinical study, 10 client-owned dogs admitted for a Hansen type 1 disk extrusion underwent a MIVA-VS. Recorded data in both studies included: incision lengths, correct targeting of the IVDS, technical problems encountered during the procedure, and potential damage to major anatomical structures. In the 10 clinical cases, duration of the procedure and clinical outcome at five and 12 days, and after a minimum of three months were also recorded. RESULTS: Correct exposure of the targeted IVDS was achieved in all cases. There was no major iatrogenic damage. Mean skin incision length was 39 mm and mean surgery time was 52 minutes. The technique provided increased illumination and magnification of the surgical field. Recovery was uneventful in all cases. CLINICAL RELEVANCE: The present study provided evidence that MIVA-VS using the DED was feasible and a relatively fast and safe procedure for the treatment of cervical disk herniation. Advantages of the technique seemed to include shorter incisions, less dissection and improved visibility.


Asunto(s)
Vértebras Cervicales/patología , Enfermedades de los Perros/cirugía , Desplazamiento del Disco Intervertebral/veterinaria , Procedimientos Ortopédicos/veterinaria , Cirugía Asistida por Video/veterinaria , Animales , Cadáver , Perros , Desplazamiento del Disco Intervertebral/cirugía , Procedimientos Ortopédicos/instrumentación , Procedimientos Ortopédicos/métodos
19.
Med Intensiva ; 35(1): 6-12, 2011.
Artículo en Español | MEDLINE | ID: mdl-21122950

RESUMEN

OBJECTIVES: To assess Southern European intensive care unit nurses' knowledge about evidence-based guidelines for the prevention of ventilator-associated pneumonia and to compare these findings with a pan-European perspective. DESIGN: A sub-analysis from an observational study performed using a 9-questions, multiple-choice questionnaire performed during the period October 2006 - March 2007. SETTING: Six Southern European countries, selected from 22 participant European countries. PARTICIPANTS: Volunteer nurses from intensive care units. RESULTS: 3329 questionnaires were obtained, 1182 of them belonging to Southern European countries with a 75.8% response rate. Global average score was 45.1%, being it significantly better in the South of Europe (46.6%, P<.001). A linear multiple regression analysis showed that years of working experience (per class of increase) (B=0.154 ± (SD) 0.045) (95% CI (0.066-0.242))(p=0.001) and working in a smaller intensive care unit (B=-0.210 ± (SD) 0.059)((95% CI) -0.326-0.094)(P<.001) was independently associated with better test scores. CONCLUSIONS: Southern European critical care nurses' knowledge about ventilator-associated pneumonia prevention is poor, but significantly better than in the pan-European countries.


Asunto(s)
Cuidados Críticos , Enfermería Basada en la Evidencia , Enfermería , Neumonía Asociada al Ventilador/prevención & control , Guías de Práctica Clínica como Asunto , Europa (Continente) , Femenino , Humanos , Masculino , Encuestas y Cuestionarios
20.
Sci Rep ; 10(1): 9139, 2020 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-32499563

RESUMEN

Duchenne Muscular Dystrophy (DMD) is a lethal muscle disorder, caused by mutations in the DMD gene and affects approximately 1:5000-6000 male births. In this report, we identified dysregulation of members of the Dlk1-Dio3 miRNA cluster in muscle biopsies of the GRMD dog model. Of these, we selected miR-379 for a detailed investigation because its expression is high in the muscle, and is known to be responsive to glucocorticoid, a class of anti-inflammatory drugs commonly used in DMD patients. Bioinformatics analysis predicts that miR-379 targets EIF4G2, a translational factor, which is involved in the control of mitochondrial metabolic maturation. We confirmed in myoblasts that EIF4G2 is a direct target of miR-379, and identified the DAPIT mitochondrial protein as a translational target of EIF4G2. Knocking down DAPIT in skeletal myotubes resulted in reduced ATP synthesis and myogenic differentiation. We also demonstrated that this pathway is GC-responsive since treating mice with dexamethasone resulted in reduced muscle expression of miR-379 and increased expression of EIF4G2 and DAPIT. Furthermore, miR-379 seric level, which is also elevated in the plasma of DMD patients in comparison with age-matched controls, is reduced by GC treatment. Thus, this newly identified pathway may link GC treatment to a mitochondrial response in DMD.


Asunto(s)
Glucocorticoides/uso terapéutico , MicroARNs/metabolismo , Mitocondrias/metabolismo , Distrofia Muscular de Duchenne/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Animales , Sitios de Unión , Dexametasona/farmacología , Modelos Animales de Enfermedad , Perros , Factor 4G Eucariótico de Iniciación/química , Factor 4G Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , MicroARNs/química , ATPasas de Translocación de Protón Mitocondriales/antagonistas & inhibidores , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Mioblastos Esqueléticos/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo
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