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Previous research has found that people choose to reappraise low intensity images more often than high intensity images. However, this research does not account for image ambivalence, which is presence of both positive and negative cues in a stimulus. The purpose of this research was to determine differences in ambivalence in high intensity and low intensity images used in previous research (experiments 1-2), and if ambivalence played a role in emotion regulation choice in addition to intensity (experiments 3-4). Experiments 1 and 2 found that the low intensity images were more ambivalent than the high intensity images. Experiment 2 further found a positive relationship between ambivalence of an image and reappraisal affordances. Experiments 3 and 4 found that people chose to reappraise ambivalent images more often than non-ambivalent images, and they also chose to reappraise low intensity images more often than high intensity images. These experiments support the idea that ambivalence is a factor in emotion regulation choice. Future research should consider the impact ambivalent stimuli have on emotion regulation, including the potential for leveraging ambivalent stimuli to improve one's emotion regulation ability.
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Regulación Emocional , Humanos , Emociones/fisiología , Afecto , Cognición/fisiología , Señales (Psicología)RESUMEN
With the growth in electroencephalography (EEG) based applications the demand for affordable consumer solutions is increasing. Here we describe a compact, low-cost EEG device suitable for daily use. The data are transferred from the device to a personal server using the TCP-IP protocol, allowing for wireless operation and a decent range of motion for the user. The device is compact, having a circular shape with a radius of only 25 mm, which would allow for comfortable daily use during both daytime and nighttime. Our solution is also very cost effective, approximately $350 for 24 electrodes. The built-in noise suppression capability improves the accuracy of recordings with a peak input noise below 0.35 µV. Here, we provide the results of the tests for the developed device. On our GitHub page, we provide detailed specification of the steps involved in building this EEG device which should be helpful to readers designing similar devices for their needs https://github.com/Ildaron/ironbci .
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Interfaces Cerebro-Computador , Encéfalo , Electrodos , Electroencefalografía , Humanos , Procesamiento de Señales Asistido por Computador , Interfaz Usuario-ComputadorRESUMEN
OBJECTIVE: Mass exposure to alkylating agents such as nitrogen mustard (NM), whether accidental or intentional as during warfare, are known to cause systemic toxicity and severe blistering from cutaneous exposure. Thus, establishing the timing and appropriate dose of any potential drug designed to reverse or impede these toxicities is critical for wound repair and survival. Our previous data demonstrates that a single intraperitoneal injection of low-dose 25-hydroxyvitamin D3 (25(OH)D) given as early as 1 h following NM exposure is sufficient to rescue mice from pancytopenia and death. However, the duration of time following exposure where intervention is still effective as a countermeasure is unknown. In this study, we sought to assess the maximal time permissible following NM exposure where 25(OH)D still affords protection against NM-induced cutaneous injury. Additionally, we determined if a higher dose of 25(OH)D would be more efficacious at time interval where low dose 25(OH)D is no longer effective. METHODS: Low (5 ng) and high (50 ng) doses of 25(OH)D were administered intraperitoneally to mice following exposure to topical NM to assess wound resolution and survival. Mice were imaged and weighed daily to measure wound healing and to monitor systemic toxicity. RESULTS: We demonstrated that 5 ng 25(OH)D administered as early as 1 h and as late as 24 h post-NM exposure is able to achieve 100% recovery in mice. In contrast, intervention at and beyond 48 h of NM exposure failed to achieve full recovery and resulted in ≥60% death between days 6 and 12, demonstrating the critical nature of timely intervention with 25(OH)D at each respective dose. In order to circumvent the observed failure at >48 h exposure, we provided two consecutive doses of 5 ng or 50 ng of 25(OH)D at 48 h and 72 h post-NM exposure. Repeat dosing with 25(OH)D at 48 h and beyond led to marked improvement of lesion size with 75% recovery from mortality. CONCLUSIONS: The opportunity to use 25(OH)D as a medical countermeasure for NM-induced toxicity has a finite of window for intervention. However, modifications such as repeat dosing can be an effective strategy to extend the intervention potential of 25(OH)D.
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Calcifediol/administración & dosificación , Sustancias para la Guerra Química/toxicidad , Mecloretamina/toxicidad , Administración Cutánea , Animales , Calcifediol/uso terapéutico , Esquema de Medicación , Femenino , Inyecciones Intraperitoneales , Ratones Endogámicos C57BL , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The present study examined the roles of shame- and guilt-proneness as mediators of associations between general causality orientations and depressive symptoms. We expected autonomy would be associated with less depressive symptoms based on higher guilt-proneness and lower shame-proneness, whereas control would be associated with more depressive symptoms based on lower guilt-proneness and higher shame-proneness. Undergraduates (N = 354) completed assessments of general causality orientations, shame- and guilt-proneness, and depressive symptoms in exchange for extra credit. Results of mediation analyses were generally supportive of the framework indicating that shame- and guilt-proneness mediate associations between self-determination and depressive symptoms. Autonomy was indirectly associated with less depressive symptoms through positive associations with guilt-proneness, in spite of unexpected positive associations with shame-proneness. Control and impersonal orientation were indirectly associated with more depressive symptoms through positive associations with shame-proneness. Results extend previous research relating self-determination to mental health in providing preliminary support suggesting that individual differences in self-determination facilitate differential tendencies in experiencing guilt and shame.
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BACKGROUND: The current study evaluated the roles of drinking motives and shyness in predicting problem alcohol use over 2 years. METHODS: First-year college student drinkers (n = 818) completed assessments of alcohol use and related problems, shyness, and drinking motives every 6 months over a 2-year period. RESULTS: Generalized linear mixed models indicated that shyness was associated with less drinking, but more alcohol-related problems. Further, shyness was associated with coping, conformity, and enhancement drinking motives, but was not associated with social drinking motives. However, when examining coping motives, moderation analyses revealed that social drinking motives were more strongly associated with coping motives among individuals higher in shyness. In addition, coping, conformity, and enhancement motives, but not social motives, mediated associations between shyness and alcohol-related problems over time. Finally, coping motives mediated the association between the interaction of shyness and social motives and alcohol-related problems. CONCLUSIONS: Together, the results suggest that shy individuals may drink to reduce negative affect, increase positive affect, and fit in with others in social situations, which may then contribute to greater risk for subsequent alcohol-related problems.
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Consumo de Bebidas Alcohólicas/psicología , Trastornos Relacionados con Alcohol/psicología , Motivación , Timidez , Estudiantes/psicología , Universidades , Adaptación Psicológica , Adolescente , Consumo de Bebidas Alcohólicas/epidemiología , Trastornos Relacionados con Alcohol/diagnóstico , Trastornos Relacionados con Alcohol/epidemiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Adulto JovenRESUMEN
Rift Valley fever virus (RVFV) is an emerging RNA virus with devastating economic and social consequences. Clinically, RVFV induces a gamut of symptoms ranging from febrile illness to retinitis, hepatic necrosis, hemorrhagic fever, and death. It is known that type I interferon (IFN) responses can be protective against severe pathology; however, it is unknown which innate immune receptor pathways are crucial for mounting this response. Using both in vitro assays and in vivo mucosal mouse challenge, we demonstrate here that RNA helicases are critical for IFN production by immune cells and that signaling through the helicase adaptor molecule MAVS (mitochondrial antiviral signaling) is protective against mortality and more subtle pathology during RVFV infection. In addition, we demonstrate that Toll-like-receptor-mediated signaling is not involved in IFN production, further emphasizing the importance of the RNA cellular helicases in type I IFN responses to RVFV.
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ARN Helicasas DEAD-box/inmunología , Interferón beta/inmunología , Membrana Mucosa/virología , Fiebre del Valle del Rift/enzimología , Fiebre del Valle del Rift/inmunología , Virus de la Fiebre del Valle del Rift/fisiología , Animales , Línea Celular , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , Células Dendríticas/inmunología , Células Dendríticas/virología , Femenino , Humanos , Interferón beta/genética , Macrófagos/inmunología , Macrófagos/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados/genética , Membrana Mucosa/inmunología , Fiebre del Valle del Rift/prevención & control , Fiebre del Valle del Rift/virología , Transducción de Señal , Receptores Toll-Like/genética , Receptores Toll-Like/inmunologíaRESUMEN
In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Edición Génica , Liposomas , Pulmón , Nanopartículas , Células Madre , Animales , Humanos , Ratones , Sistemas CRISPR-Cas , Fibrosis Quística/terapia , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células Epiteliales/metabolismo , Terapia Genética/métodos , Pulmón/metabolismo , Organoides , Células Madre/metabolismoRESUMEN
Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.
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Fibrosis Quística , Humanos , Ratones , Animales , Fibrosis Quística/terapia , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Sistemas CRISPR-Cas/genética , ARN Guía de Sistemas CRISPR-Cas , Pulmón/metabolismo , ARN Mensajero/genética , ARN Mensajero/uso terapéuticoRESUMEN
BACKGROUND: Low-intensity transcranial focused ultrasound (tFUS) has gained considerable attention as a promising noninvasive neuromodulatory technique for human brains. However, the complex morphology of the skull hinders scholars from precisely predicting the acoustic energy transmitted and the region of the brain impacted during the sonication. This is due to the fact that different ultrasound frequencies and skull morphology variations greatly affect wave propagation through the skull. PURPOSE: Although the acoustic properties of human skull have been studied for tFUS applications, such as tumor ablation using a multielement phased array, there is no consensus about how to choose a single-element focused ultrasound (FUS) transducer with a suitable frequency for neuromodulation. There are interests in exploring the magnitude and dimension of tFUS beam through human parietal bone for modulating specific brain lobes. Herein, we aim to investigate the wave propagation of tFUS on human skulls to understand and address the concerns above. METHODS: Both experimental measurements and numerical modeling were conducted to investigate the transmission efficiency and beam pattern of tFUS on five human skulls (C3 and C4 regions) using single-element FUS transducers with six different frequencies (150-1500 kHz). The degassed skull was placed in a water tank, and a calibrated hydrophone was utilized to measure acoustic pressure past it. The cranial computed tomography scan data of each skull were obtained to derive a high-resolution acoustic model (grid point spacing: 0.25 mm) in simulations. Meanwhile, we modified the power-law exponent of acoustic attenuation coefficient to validate numerical modeling and enabled it to be served as a prediction tool, based on the experimental measurements. RESULTS: The transmission efficiency and -6 dB beamwidth were evaluated and compared for various frequencies. An exponential decrease in transmission efficiency and a logarithmic decrease of -6 dB beamwidth with an increase in ultrasound frequency were observed. It is found that a >750 kHz ultrasound leads to a relatively lower tFUS transmission efficiency (<5%), whereas a <350 kHz ultrasound contributes to a relatively broader beamwidth (>5 mm). Based on these observations, we further analyzed the dependence of tFUS wave propagation on FUS transducer aperture size. CONCLUSIONS: We successfully studied tFUS wave propagation through human skulls at different frequencies experimentally and numerically. The findings have important implications to predict tFUS wave propagation for ultrasound neuromodulation in clinical applications, and guide researchers to develop advanced ultrasound transducers as neural interfaces.
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Encéfalo , Cráneo , Humanos , Cráneo/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Ultrasonografía/métodos , Cabeza , Transductores , Ondas UltrasónicasRESUMEN
Both respiratory syncytial virus (RSV) and influenza A virus induce nucleotide/P2Y purinergic receptor-mediated impairment of alveolar fluid clearance (AFC), which contributes to formation of lung edema. Although genetically dissimilar, both viruses generate double-stranded RNA replication intermediates, which act as Toll-like receptor (TLR)-3 ligands. We hypothesized that double-stranded RNA/TLR-3 signaling underlies nucleotide-mediated inhibition of amiloride-sensitive AFC in both infections. We found that addition of the synthetic double-stranded RNA analog poly-inosinic-cytidylic acid [poly(I:C)] (500 ng/ml) to the AFC instillate resulted in nucleotide/P2Y purinergic receptor-mediated inhibition of amiloride-sensitive AFC in BALB/c mice but had no effect on cystic fibrosis transmembrane regulator (CFTR)-mediated Cl(-) transport. Poly(I:C) also induced acute keratinocyte cytokine-mediated AFC insensitivity to stimulation by the ß-adrenergic agonist terbutaline. Inhibitory effects of poly(I:C) on AFC were absent in TLR-3(-/-) mice and were not replicated by addition to the AFC instillate of ligands for other TLRs except TLR-2. Intranasal poly(I:C) administration (250 µg/mouse) similarly induced nucleotide-dependent AFC inhibition 2-3 days later, together with increased lung water content and neutrophilic inflammation. Intranasal treatment of BALB/c mice with poly(I:C) did not induce airway hyperresponsiveness at day 2 but did result in insensitivity to airway bronchodilation by ß-adrenergic agonists. These findings suggest that viral double-stranded RNA replication intermediates induce nucleotide-mediated impairment of amiloride-sensitive AFC in both infections, together with ß-adrenergic agonist insensitivity. Both of these effects also occur in RSV infection. However, double-stranded RNA replication intermediates do not appear to be sufficient to induce either adenosine-mediated, CFTR-dependent Cl(-) secretion in the lung or severe, lethal hypoxemia, both of which are features of influenza infection.
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Pulmón/fisiopatología , Pulmón/virología , ARN Bicatenario/farmacología , Infecciones por Virus Sincitial Respiratorio/fisiopatología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/fisiología , Administración Intranasal , Agonistas Adrenérgicos beta/farmacología , Animales , Líquidos Corporales/efectos de los fármacos , Exposición por Inhalación , Ligandos , Pulmón/efectos de los fármacos , Lesión Pulmonar/complicaciones , Lesión Pulmonar/patología , Lesión Pulmonar/fisiopatología , Ratones , Ratones Endogámicos BALB C , Poli I-C/administración & dosificación , Poli I-C/farmacología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/metabolismo , Receptores Purinérgicos P2Y/metabolismo , Infecciones por Virus Sincitial Respiratorio/complicaciones , Virus Sincitiales Respiratorios/efectos de los fármacos , Factores de Tiempo , Receptor Toll-Like 3/metabolismoRESUMEN
This paper aims to review the current state of brain-to-brain interface (B2BI) technology and its potential. B2BIs function via a brain-computer interface (BCI) to read a sender's brain activity and a computer-brain interface (CBI) to write a pattern to a receiving brain, transmitting information. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to systematically review current literature related to B2BI, resulting in 15 relevant publications. Experimental papers primarily used transcranial magnetic stimulation (tMS) for the CBI portion of their B2BI. Most targeted the visual cortex to produce phosphenes. In terms of study design, 73.3% (11) are unidirectional and 86.7% (13) use only a 1:1 collaboration model (subject to subject). Limitations are apparent, as the CBI method varied greatly between studies indicating no agreed upon neurostimulatory method for transmitting information. Furthermore, only 12.4% (2) studies are more complicated than a 1:1 model and few researchers studied direct bidirectional B2BI. These studies show B2BI can offer advances in human communication and collaboration, but more design and experiments are needed to prove potential. B2BIs may allow rehabilitation therapists to pass information mentally, activating a patient's brain to aid in stroke recovery and adding more complex bidirectionality may allow for increased behavioral synchronization between users. The field is very young, but applications of B2BI technology to neuroergonomics and human factors engineering clearly warrant more research.
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beta-Adrenergic agonists (beta-agonists) are commonly used to treat respiratory syncytial virus (RSV) bronchiolitis but are generally ineffective for unknown reasons. We have previously shown that RSV strain A2 inhibits bronchoalveolar epithelial responses to beta-agonists in a BALB/c mouse model by inducing heterologous keratinocyte cytokine (KC)/CXCR2-mediated desensitization of epithelial beta(2)-adrenergic receptors. The aim of the current study was to determine whether RSV also induces airway insensitivity to beta-agonists. Total lung resistance (R) was measured in anesthetized female BALB/c mice undergoing mechanical ventilation on a flexiVent computer-controlled piston ventilator. Data were analyzed using the single-compartment model. Infection with RSV A2 did not induce airway hyperresponsiveness to increasing doses of the nebulized cholinergic agonist methacholine (MCh) at any time point after RSV infection. Prenebulization with the beta-agonist terbutaline (100 muM) significantly attenuated bronchoconstrictive responses to 20 and 50 mg/ml MCh in uninfected mice and in mice infected with RSV 4-8 days postinfection (d.p.i.). However, in mice infected with replication-competent, but not UV-inactivated, RSV for 2 days, significant terbutaline insensitivity was found. Terbutaline insensitivity at 2 d.p.i. could be reversed by systemic preinfection treatment with neutralizing anti-CXCR2 antibodies, which reduced bronchoalveolar lavage (BAL) neutrophil counts but did not alter viral replication, BAL KC levels, or lung edema. Terbutaline insensitivity was also reversed by postinfection nebulization with neutralizing anti-KC or anti-CXCR2 antibodies and could be replicated in normal, uninfected mice by nebulization with recombinant KC. These data suggest that KC/CXCR2-mediated airway insensitivity to beta-agonists may underlie the modest utility of these drugs as bronchodilators in therapy for acute RSV bronchiolitis.
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Agonistas Adrenérgicos beta/farmacología , Pulmón/inmunología , Pulmón/virología , Virus Sincitiales Respiratorios/fisiología , Aerosoles/farmacología , Animales , Quimiocinas/farmacología , Humanos , Pulmón/efectos de los fármacos , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos BALB C , Nebulizadores y Vaporizadores , Receptores de Interleucina-8B/antagonistas & inhibidores , Pruebas de Función Respiratoria , Mecánica Respiratoria/efectos de los fármacos , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/fisiopatología , Infecciones por Virus Sincitial Respiratorio/virología , Replicación Viral/efectos de los fármacosRESUMEN
In vitro studies show that hsp70 promotes gene expression for multiple viral families, although there are few reports on the in vivo significance of virus-hsp70 interaction. Previously we showed that hsp70-dependent stimulation of Edmonston measles virus (Ed MeV) transcription caused an increased cytopathic effect and mortality in transgenic hsp70-overexpressing C57BL/6 mice (H-2(b)). The response to MeV infection is influenced by the major histocompatibility complex haplotype; H-2(d) mice are resistant to brain infection due to robust antiviral immune responses, whereas H-2(b) mice are susceptible due to deficiencies in this response. We therefore tested the hypothesis that the outcome of MeV-hsp70 interaction may be dependent upon the host H-2 haplotype. The impact of selective neuronal hsp70 overexpression on Ed MeV brain infection was tested with congenic C57BL/10 H-2(d) neonatal mice. In this context, hsp70 overexpression conferred complete protection against virus-induced mortality, compared to >30% mortality in nontransgenic mice. Selective depletion of T-cell populations showed that transgenic mice exhibit a diminished reliance on T cells for protection. Brain transcript analysis indicated enhanced innate immune activation and signaling through Toll-like receptors 2 and 4 at early times postinfection for transgenic infected mice relative to those for nontransgenic infected mice. Collectively, results suggest that hsp70 can enhance innate antiviral immunity through Toll-like receptor signaling, supporting a protective role for physiological responses that enhance tissue levels of hsp70 (e.g., fever), and that the H-2 haplotype determines the effectiveness of this response.
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Encefalopatías/inmunología , Proteínas del Choque Térmico HSP72/inmunología , Proteínas del Choque Térmico HSP72/metabolismo , Complejo Mayor de Histocompatibilidad/inmunología , Virus del Sarampión/inmunología , Virus del Sarampión/patogenicidad , Sarampión/inmunología , Animales , Encefalopatías/genética , Encefalopatías/metabolismo , Encefalopatías/patología , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Proteínas del Choque Térmico HSP72/genética , Haplotipos , Humanos , Inmunidad Innata/inmunología , Masculino , Sarampión/genética , Sarampión/metabolismo , Sarampión/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Tasa de Supervivencia , Subgrupos de Linfocitos T/inmunología , VirulenciaRESUMEN
High tidal volume ventilation is detrimental to alveolar fluid clearance (AFC), but effects of ventilation pressure (P) on AFC are unknown. In anesthetized BALB/c mice ventilated at constant tidal volume (8 ml/kg), mean AFC rate was 12.8% at 6 cmH(2)O P, but increased to 37.3% at 18 cmH(2)O P. AFC rate declined at 22 cmH(2)O P, which also induced lung damage. Increased AFC at 18 cmH(2)O P did not result from elevated plasma catecholamines, hypercapnia, or hypocapnia, but was due to augmented Na(+) and Cl(-) absorption. PKA agonists and beta-agonists stimulated AFC at 10 cmH(2)O P by upregulating amiloride-sensitive Na(+) transport. However, at 18 cmH(2)O P, PKA agonists and beta-agonists reduced AFC. At 15 cmH(2)O P, the AFC rate was intermediate (mean 26.6%), and forskolin and beta-agonists had no effect. Comparable P dependency of AFC and beta-agonist responsiveness was found in C57BL/6 mice. The effect on AFC of increasing P to 18 cmH(2)O was blocked by adenosine deaminase or an A(2b)-adenosine receptor antagonist, and could be mimicked by adenosine in mice ventilated at 10 cmH(2)O P. Modulation of adenosine signaling also resulted in altered responsiveness to beta-agonists. These findings indicate that, in the normal mouse lung, basal AFC rates and responses to beta-agonists are impacted by ventilation pressure in an adenosine-dependent manner.
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Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacología , Pulmón/metabolismo , Depuración Mucociliar , Alveolos Pulmonares/metabolismo , Respiración Artificial , Mucosa Respiratoria/metabolismo , Amilorida/farmacología , Animales , Líquido del Lavado Bronquioalveolar , Colforsina/farmacología , Células Epiteliales/metabolismo , Femenino , Pulmón/citología , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Oxígeno/metabolismo , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , Mucosa Respiratoria/citología , Mucosa Respiratoria/efectos de los fármacosRESUMEN
RATIONALE: Pulmonary infections can impair alveolar fluid clearance (AFC), contributing to formation of lung edema. Effects of influenza A virus (IAV) on AFC are unknown. OBJECTIVES: To determine effects of IAV infection on AFC, and to identify intercellular signaling mechanisms underlying influenza-mediated inhibition of AFC. METHODS: BALB/c mice were infected intranasally with influenza A/WSN/33 (10,000 or 2,500 focus-forming units per mouse). AFC was measured in anesthetized, ventilated mice by instilling 5% bovine serum albumin into the dependent lung. MEASUREMENTS AND MAIN RESULTS: Infection with high-dose IAV resulted in a steady decline in arterial oxygen saturation and increased lung water content. AFC was significantly inhibited starting 1 hour after infection, and remained suppressed through Day 6. AFC inhibition at early time points (1-4 h after infection) did not require viral replication, whereas AFC inhibition later in infection was replication-dependent. Low-dose IAV infection impaired AFC for 10 days, but induced only mild hypoxemia. High-dose IAV infection increased bronchoalveolar lavage fluid ATP and UTP levels. Impaired AFC at Day 2 resulted primarily from reduced amiloride-sensitive AFC, mediated by increased activation of the pyrimidine-P2Y purinergic receptor axis. However, an additional component of AFC impairment was due to activation of A(1) adenosine receptors and stimulation of increased cystic fibrosis transmembrane regulator-mediated anion secretion. Finally, IAV-mediated inhibition of AFC at Day 2 could be reversed by addition of beta-adrenergic agonists to the AFC instillate. CONCLUSIONS: AFC inhibition may be an important feature of early IAV infection. Its blockade may reduce the severity of pulmonary edema and hypoxemia associated with influenza pneumonia.
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Líquido del Lavado Bronquioalveolar/virología , Virus de la Influenza A/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Animales , Transporte Biológico Activo , Peso Corporal , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Oxígeno/sangre , Permeabilidad , Factores de TiempoRESUMEN
Cutaneous inflammation from UV radiation exposure causes epidermal damage, cellular infiltration, and secretion of pro-inflammatory mediators that exacerbate tissue destruction. Recovery is mediated chiefly by anti-inflammatory M2 macrophages that suppress inflammation and augment epidermal regeneration. Vitamin D enables anti-inflammation to promote tissue repair in response to injury. Since vitamin D enhances cellular macroautophagy/autophagy, we investigated the role of autophagy in vitamin D protection of UV-mediated sunburn and inflammation. Using a UV-mediated acute skin injury mouse model, we demonstrate that a single dose of vitamin D resolves injury with sustained inhibition of inflammatory cytokines associated with enhanced autophagy in myeloid anti-inflammatory M2 macs. Increased MAP1LC3B/LC3 expression corroborated with complete autolysosome formation detected by electron microscopy and correlated with degradation of SQSTM1/p62 in the skin following vitamin D treatment. Specifically, pharmacological inhibition of autophagy increased UV-induced apoptosis, suppressed M2 macs recruitment, and prevented vitamin D downregulation of Tnf and Mmp9 in the skin. Furthermore, selective deletion of autophagy in myeloid cells of atg7 cKO mice abrogated vitamin D-mediated protection and recapitulated UV-induced inflammation. Mechanistically, vitamin D signaling activated M2-autophagy regulators Klf4, Pparg, and Arg1. Lastly, analysis of UV-exposed human skin biopsies detected a similar increase in macrophage autophagy following vitamin D intervention, identifying an essential role for autophagy in vitamin D-mediated protection of skin from UV damage. Abbreviations: ARG1: arginase 1; ATG7 cKO: autophagy related 7 conditional knockout; HPF: high powered field; KLF4: Kruppel like factor 4; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; macs: macrophage; 3-MA: 3-methyladenine; MMP9: matrix metallopeptidase 9; NOS2: nitric oxide synthase 2, inducible; PPARG: peroxisome proliferator activated receptor gamma; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; UV: ultraviolet; VD: vitamin D, 25-hydroxy vitamin D3; 1,25-VD: 1, 25-dihydroxy vitamin D3.
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Autofagia/efectos de los fármacos , Macrófagos/efectos de los fármacos , Quemadura Solar/tratamiento farmacológico , Vitamina D/farmacología , Vitamina D/uso terapéutico , Animales , Autofagia/genética , Estudios de Casos y Controles , Femenino , Humanos , Factor 4 Similar a Kruppel , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Piel/efectos de los fármacos , Piel/inmunología , Piel/metabolismo , Piel/patología , Quemadura Solar/genética , Quemadura Solar/inmunología , Quemadura Solar/patología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Heat shock proteins (HSPs) play an important role in the maintenance of cellular homeostasis, particularly in response to stressful conditions that adversely affect normal cellular structure and function, such as hyperthermia. A remarkable intrinsic resistance of brain to hyperthermia reflects protection mediated by constitutive and induced expression of HSPs in both neurons and glia. Induced expression underlies the phenomenon of hyperthermic pre-reconditioning, where transient, low-intensity heating induces HSPs that protect brain from subsequent insult, reflecting the prolonged half-life of HSPs. The expression and activity of HSPs that is characteristic of nervous tissue plays a role not just in the maintenance and defense of cellular viability, but also in the preservation of neuron-specific luxury functions, particularly those that support synaptic activity. In response to hyperthermia, HSPs mediate preservation or rapid recovery of synaptic function up to the point where damage in other organ systems becomes evident and life threatening. Given the ability of HSPs to enhance gene expression by neurotropic viruses, the constitutive and inducible HSP expression profiles would seem to place nervous tissues at risk. However, we present evidence that the virus-HSP relationship can promote viral clearance in animals capable of mounting effective virus-specific cell-mediated immune responses, potentially reflecting HSP-dependent increases in viral antigenic burden, immune adjuvant effects and cross-presentation of viral antigen. Thus, the protective functions of HSPs span the well-characterized intracellular roles as chaperones to those that may directly or indirectly promote immune function.
Asunto(s)
Encéfalo/metabolismo , Proteínas de Choque Térmico/metabolismo , Respuesta al Choque Térmico/fisiología , Animales , Fiebre/fisiopatología , Fiebre/prevención & control , Regulación de la Expresión Génica/fisiología , HumanosRESUMEN
The diverse immunomodulatory effects of vitamin D are increasingly being recognized. However, the ability of oral vitamin D to modulate acute inflammation in vivo has not been established in humans. In a double-blinded, placebo-controlled interventional trial, 20 healthy adults were randomized to receive either placebo or a high dose of vitamin D3 (cholecalciferol) one hour after experimental sunburn induced by an erythemogenic dose of UVR. Compared with placebo, participants receiving vitamin D3 (200,000 international units) demonstrated reduced expression of proinflammatory mediators tumor necrosis factor-α (P = 0.04) and inducible nitric oxide synthase (P = 0.02) in skin biopsy specimens 48 hours after experimental sunburn. A blinded, unsupervised hierarchical clustering of participants based on global gene expression profiles revealed that participants with significantly higher serum vitamin D3 levels after treatment (P = 0.007) demonstrated increased skin expression of the anti-inflammatory mediator arginase-1 (P = 0.005), and a sustained reduction in skin redness (P = 0.02), correlating with significant expression of genes related to skin barrier repair. In contrast, participants with lower serum vitamin D3 levels had significant expression of proinflammatory genes. Together the data may have broad implications for the immunotherapeutic properties of vitamin D in skin homeostasis, and implicate arginase-1 upregulation as a previously unreported mechanism by which vitamin D exerts anti-inflammatory effects in humans.
Asunto(s)
Colecalciferol/administración & dosificación , Inflamación/tratamiento farmacológico , Quemadura Solar/tratamiento farmacológico , Administración Oral , Adulto , Colecalciferol/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Masculino , Persona de Mediana Edad , Piel/patología , Piel/efectos de la radiación , Quemadura Solar/sangre , Quemadura Solar/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Vitaminas/administración & dosificación , Vitaminas/farmacocinética , Adulto JovenRESUMEN
The use of sulfur mustard (SM) as a chemical weapon for warfare has once again assumed center stage, endangering civilian and the military safety. SM causes rapid local skin vesication and late-onset systemic toxicity. Most studies on SM rely on obtaining tissue and blood for characterizing burn pathogenesis and assessment of systemic pathology, respectively. However the present study focuses on developing a non-invasive method to predict mortality from high dose skin SM exposure. We demonstrate that exposure to SM leads to a dose dependent increase in wound area size on the dorsal surface of mice that is accompanied by a progressive loss in body weight loss, blood cytopenia, bone marrow destruction, and death. Thus our model utilizes local skin destruction and systemic outcome measures as variables to predict mortality in a novel skin-based model of tissue injury. Based on our recent work using vitamin D (25(OH)D) as an intervention to treat toxicity from SM-related compounds, we explored the use of 25(OH)D in mitigating the toxic effects of SM. Here we show that 25(OH)D offers protection against SM and is the first known demonstration of an intervention that prevents SM-induced mortality. Furthermore, 25(OH)D represents a safe, novel, and readily translatable potential countermeasure following mass toxic exposure.
Asunto(s)
Calcifediol/uso terapéutico , Sustancias para la Guerra Química/toxicidad , Gas Mostaza/toxicidad , Enfermedades de la Piel/prevención & control , Administración Cutánea , Animales , Recuento de Células Sanguíneas , Calcifediol/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Estimación de Kaplan-Meier , Ratones Endogámicos C57BL , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/patología , Análisis de Supervivencia , Cicatrización de Heridas/efectos de los fármacosRESUMEN
BACKGROUND: Mosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock and humans. To determine the exposure factors and range of symptoms associated with human RVF, we performed a population-based cross-sectional survey in six villages across a 40 km transect in northeastern Kenya. METHODOLOGY/PRINCIPAL FINDINGS: A systematic survey of the total populations of six Northeastern Kenyan villages was performed. Among 1082 residents tested via anti-RVFV IgG ELISA, seroprevalence was 15% (CI95%, 13-17%). Prevalence did not vary significantly among villages. Subject age was a significant factor, with 31% (154/498) of adults seropositive vs. only 2% of children ≤15 years (12/583). Seroprevalence was higher among men (18%) than women (13%). Factors associated with seropositivity included a history of animal exposure, non-focal fever symptoms, symptoms related to meningoencephalitis, and eye symptoms. Using cluster analysis in RVFV positive participants, a more severe symptom phenotype was empirically defined as having somatic symptoms of acute fever plus eye symptoms, and possibly one or more meningoencephalitic or hemorrhagic symptoms. Associated with this more severe disease phenotype were older age, village, recent illness, and loss of a family member during the last outbreak. In multivariate analysis, sheltering livestock (aOR = 3.5 CI95% 0.93-13.61, P = 0.065), disposing of livestock abortus (aOR = 4.11, CI95% 0.63-26.79, P = 0.14), and village location (P = 0.009) were independently associated with the severe disease phenotype. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that a significant proportion of the population in northeastern Kenya has been infected with RVFV. Village and certain animal husbandry activities were associated with more severe disease. Older age, male gender, herder occupation, killing and butchering livestock, and poor visual acuity were useful markers for increased RVFV infection. Formal vision testing may therefore prove to be a helpful, low-technology tool for RVF screening during epidemics in high-risk rural settings.