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1.
Proc Natl Acad Sci U S A ; 121(23): e2320388121, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38805284

RESUMO

Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22phox are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple ß-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation.


Assuntos
Microscopia Crioeletrônica , NADPH Oxidase 2 , NADPH Oxidases , Fagócitos , Humanos , NADPH Oxidase 2/metabolismo , NADPH Oxidase 2/genética , NADPH Oxidase 2/química , Fagócitos/metabolismo , NADPH Oxidases/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/química , Ligação Proteica , Sítios de Ligação , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/genética , Modelos Moleculares , Espécies Reativas de Oxigênio/metabolismo
2.
Neuroimage ; 298: 120805, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39173692

RESUMO

The study of the neural substrates that serve conscious vision is one of the unsolved questions of cognitive neuroscience. So far, consciousness literature has endeavoured to disentangle which brain areas and in what order are involved in giving rise to visual awareness, but the problem of consciousness still remains unsolved. Availing of two different but complementary sources of data (i.e., Fast Optical Imaging and EEG), we sought to unravel the neural dynamics responsible for the emergence of a conscious visual experience. Our results revealed that conscious vision is characterized by a significant increase of activation in extra-striate visual areas, specifically in the Lateral Occipital Complex (LOC), and that, more interestingly, such activity occurred in the temporal window of the ERP component commonly thought to represent the electrophysiological signature of visual awareness, i.e., the Visual Awareness Negativity (VAN). Furthermore, Granger causality analysis, performed to further investigate the flow of activity occurring in the investigated areas, unveiled that neural processes relating to conscious perception mainly originated in LOC and subsequently spread towards visual and motor areas. In general, the results of the present study seem to advocate for an early contribution of LOC in conscious vision, thus suggesting that it could represent a reliable neural correlate of visual awareness. Conversely, striate visual areas, showing awareness-related activity only in later stages of stimulus processing, could be part of the cascade of neural events following awareness emergence.


Assuntos
Estado de Consciência , Eletroencefalografia , Lobo Occipital , Percepção Visual , Humanos , Estado de Consciência/fisiologia , Percepção Visual/fisiologia , Masculino , Feminino , Adulto , Adulto Jovem , Lobo Occipital/fisiologia , Lobo Occipital/diagnóstico por imagem , Córtex Visual Primário/fisiologia , Córtex Visual Primário/diagnóstico por imagem , Mapeamento Encefálico , Potenciais Evocados Visuais/fisiologia , Córtex Visual/fisiologia , Córtex Visual/diagnóstico por imagem , Conscientização/fisiologia
3.
J Clin Immunol ; 44(7): 149, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38896305

RESUMO

Chronic granulomatous disease (CGD) primarily results from inherited defects in components of the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex. These include gene defects in cytochrome B-245/558 subunit α/ß and neutrophil cytosolic factors 1, 2, and 4. Recently, homozygous loss-of-function variants in cytochrome B-245 chaperone 1 gene (CYBC1) have been discovered to cause CGD (CYBC1-CGD). Data on variant-proven CGD from low-income countries, the most underprivileged regions of the world, remain sparse due to numerous constraints. Herein, we report the first cohort of patients with CGD from Nepal, a low-income country in the Himalayas' challenging terrain. Our report includes a description of a new case of CYBC1 deficiency who was first diagnosed with CGD at our center. Only a dozen cases of CYBC1-CGD have been described in the literature thus far which have been reviewed comprehensively herein. Most of these patients have had significant infections and autoimmune/inflammatory manifestations. Pulmonary and invasive/disseminated bacterial/fungal infections were the most common followed by skin and soft-tissue infections. Inflammatory bowel disease (IBD) was the most common inflammatory manifestation (median age at diagnosis: 9 years) followed by episodes of recurrent/prolonged fever. Other autoimmune/inflammatory manifestations reported in CYBC1-CGD include acute pancreatitis, hemophagocytic lymphohistiocytosis, systemic granulomatosis, interstitial lung disease, arthritis, autoimmune hemolytic anemia, uveitis, nephritis, and eczema. Our analysis shows that patients with CYBC1-CGD are at a significantly higher risk of IBD-like illness as compared to other forms of CGD which merits further confirmatory studies in the future.


Assuntos
Doença Granulomatosa Crônica , Humanos , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/diagnóstico , Nepal/epidemiologia , Masculino , Feminino , Criança , NADPH Oxidases/genética , NADPH Oxidases/deficiência , Pré-Escolar , Adolescente , Mutação/genética
4.
Clin Immunol ; 255: 109761, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37673227

RESUMO

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterised by opportunistic infection and sterile granulomatous inflammation. CGD is caused by a failure of reactive oxygen species (ROS) production by the phagocyte NADPH oxidase. Mutations in the genes encoding phagocyte NADPH oxidase subunits cause CGD. We and others have described a novel form of CGD (CGD5) secondary to lack of EROS (CYBC1), a highly selective chaperone for gp91phox. EROS-deficient cells express minimal levels of gp91phox and its binding partner p22phox, but EROS also controls the expression of other proteins such as P2X7. The full nature of CGD5 is currently unknown. We describe a homozygous frameshift mutation in CYBC1 leading to CGD. Individuals who are heterozygous for this mutation are found in South Asian populations (allele frequency = 0.00006545), thus it is not a private mutation. Therefore, it is likely to be the underlying cause of other cases of CGD.


Assuntos
Doença Granulomatosa Crônica , Humanos , Doença Granulomatosa Crônica/genética , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Fagócitos , Espécies Reativas de Oxigênio/metabolismo , Mutação/genética
5.
Clin Immunol ; 251: 109316, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37055004

RESUMO

Chronic granulomatous disease (CGD) is a human IEI caused by mutations in genes encoding the NADPH oxidase subunits, the enzyme responsible for the respiratory burst. CGD patients have severe life-threatening infections, hyperinflammation and immune dysregulation. Recently, an additional autosomal recessive AR-CGD (type 5) caused by mutations in CYBC1/EROS gene was identified. We report a AR-CGD5 patient with a novel loss of function (LOF) homozygous deletion c.8_7del in the CYBC1 gene including the initiation ATG codon that leads to failure of CYBC1/EROS protein expression and presenting with an unusual clinical manifestation of childhood-onset sarcoidosis-like disease requiring multiple immunosuppressive therapies. We described an abnormal gp91phox protein expression/function in the patient's neutrophils and monocytes (about 50%) and a severely compromised B cell subset (gp91phox < 15%; DHR+ < 4%). Our case-report emphasized the importance of considering a diagnosis of AR-CGD5 deficiency even in absence of typical clinical and laboratory findings.


Assuntos
Doença Granulomatosa Crônica , Humanos , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/diagnóstico , Homozigoto , Deleção de Sequência/genética , NADPH Oxidases/genética , Mutação , Fenótipo
6.
Purinergic Signal ; 18(4): 495-498, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35960424

RESUMO

High concentration of extracellular ATP acts as a danger signal that is sensed by the P2X7 receptor (P2X7R). This ATP-gated ion channel has been shown to induce multiple metabotropic events such as changes in plasma membrane composition and morphology, ectodomain shedding, activation of lipases, kinases, and transcription factors as well as cytokine release. The specific signaling pathways and molecular mechanisms remain largely obscure. Using an unbiased genome-scale CRISPR/Cas9 screening approach in a murine T cell line, Ryoden et al. (2022, 2020) identified three proteins involved in P2X7 regulation and signaling: Essential for Reactive Oxygen Species (EROS) is essential for P2X7 folding and maturation, and Xk and Vsp13a are required for P2X7-mediated phosphatidyl serine exposure and cell lysis. They further provide evidence for an interaction of Xk and Vsp13a at the plasma membrane and confirm the role of Xk in ATP-induced cytolysis in primary CD25+CD4+ T cells from Xk-/- mice.


Assuntos
Transdução de Sinais , Linfócitos T , Camundongos , Animais , Ativação Linfocitária , Trifosfato de Adenosina/farmacologia , Receptores Purinérgicos P2X7
7.
Hum Brain Mapp ; 42(13): 4102-4121, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34160860

RESUMO

The link between spatial (where) and temporal (when) aspects of the neural correlates of most psychological phenomena is not clear. Elucidation of this relation, which is crucial to fully understand human brain function, requires integration across multiple brain imaging modalities and cognitive tasks that reliably modulate the engagement of the brain systems of interest. By overcoming the methodological challenges posed by simultaneous recordings, the present report provides proof-of-concept evidence for a novel approach using three complementary imaging modalities: functional magnetic resonance imaging (fMRI), event-related potentials (ERPs), and event-related optical signals (EROS). Using the emotional oddball task, a paradigm that taps into both cognitive and affective aspects of processing, we show the feasibility of capturing converging and complementary measures of brain function that are not currently attainable using traditional unimodal or other multimodal approaches. This opens up unprecedented possibilities to clarify spatiotemporal integration of brain function.


Assuntos
Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiologia , Eletroencefalografia/métodos , Neuroimagem Funcional/métodos , Raios Infravermelhos , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Adolescente , Adulto , Emoções/fisiologia , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Reconhecimento Visual de Modelos/fisiologia , Estudo de Prova de Conceito , Adulto Jovem
8.
Neuroimage ; 222: 117244, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798674

RESUMO

The mechanisms of visuospatial attention are mediated by two distinct fronto-parietal networks: a bilateral dorsal network (DAN), involved in the voluntary orientation of visuospatial attention, and a ventral network (VAN), lateralized to the right hemisphere, involved in the reorienting of attention to unexpected, but relevant, stimuli. The present study consisted of two aims: 1) to characterize the spatio-temporal dynamics of attention and 2) to examine the predictive interactions between and within the two attention systems along with visual areas, by using fast optical imaging combined with Granger causality. Data were collected from young healthy participants performing a discrimination task in a Posner-like paradigm. Functional analyses revealed bilateral dorsal parietal (i.e. dorsal regions included in the DAN) and visual recruitment during orienting, highlighting a recursive predictive interplay between specific dorsal parietal regions and visual cortex. Moreover, we found that both attention networks are active during reorienting, together with visual cortex, highlighting a mutual interaction among dorsal and visual areas, which, in turn, predicts subsequent ventral activity. For attentional reorienting our findings indicate that dorsal and visual areas encode disengagement of attention from the attended location and trigger reorientation to the unexpected location. Ventral network activity could instead reflect post-perceptual maintenance of the internal model to generate and keep updated task-related expectations.


Assuntos
Atenção/fisiologia , Lateralidade Funcional/fisiologia , Imagem Óptica , Orientação/fisiologia , Percepção Espacial/fisiologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Imagem Óptica/métodos , Orientação Espacial/fisiologia , Estimulação Luminosa/métodos , Adulto Jovem
9.
Hum Brain Mapp ; 41(11): 2883-2897, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32170910

RESUMO

Current theories of automatic or preattentive change detection suggest a regularity or prediction violation mechanism involving functional connectivity between the inferior frontal cortex (IFC) and the superior temporal cortex (STC). By disrupting the IFC function with transcranial magnetic stimulation (TMS) and recording the later STC mismatch response with event-related optical signal (EROS), previous study demonstrated a causal IFC-to-STC functional connection in detecting a pitch or physical change. However, physical change detection can be achieved by memory comparison of the physical features and may not necessarily involve regularity/rule extraction and prediction. The current study investigated the IFC-STC functional connectivity in detecting rule violation (i.e., an abstract change). Frequent standard tone pairs with a constant relative pitch difference, but varying pitches, were presented to establish a pitch interval rule. This abstract rule was violated by deviants with reduced relative pitch intervals. The EROS STC mismatch response to the deviants was abolished by the TMS applied at the IFC 80 ms after deviance onset, but preserved in the spatial (TMS on vertex), auditory (TMS sound), and temporal (200 ms after deviance onset) control conditions. These results demonstrate the IFC-STC connection in preattentive abstract change detection and support the regularity or prediction violation account.


Assuntos
Conectoma , Discriminação Psicológica/fisiologia , Raios Infravermelhos , Rede Nervosa/fisiologia , Fotometria , Percepção da Altura Sonora/fisiologia , Córtex Pré-Frontal/fisiologia , Lobo Temporal/fisiologia , Percepção do Tempo/fisiologia , Estimulação Magnética Transcraniana , Adolescente , Adulto , Feminino , Humanos , Masculino , Rede Nervosa/diagnóstico por imagem , Adulto Jovem
10.
Appl Environ Microbiol ; 86(11)2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32220848

RESUMO

Bacteria regulate the life histories of diverse eukaryotes, but relatively little is known about how eukaryotes interpret and respond to multiple bacterial cues encountered simultaneously. To explore how a eukaryote might respond to a combination of bioactive molecules from multiple bacteria, we treated the choanoflagellate Salpingoeca rosetta with two sets of bacterial cues, one that induces mating and another that induces multicellular development. We found that simultaneous exposure to both sets of cues enhanced multicellular development in S. rosetta, eliciting both larger multicellular colonies and an increase in the number of colonies. Thus, rather than conveying conflicting sets of information, these distinct bacterial cues synergize to augment multicellular development. This study demonstrates how a eukaryote can integrate and modulate its response to cues from diverse bacteria, underscoring the potential impact of complex microbial communities on eukaryotic life histories.IMPORTANCE Eukaryotic biology is profoundly influenced by interactions with diverse environmental and host-associated bacteria. However, it is not well understood how eukaryotes interpret multiple bacterial cues encountered simultaneously. This question has been challenging to address because of the complexity of many eukaryotic model systems and their associated bacterial communities. Here, we studied a close relative of animals, the choanoflagellate Salpingoeca rosetta, to explore how eukaryotes respond to diverse bacterial cues. We found that a bacterial chondroitinase that induces mating on its own can also synergize with bacterial lipids that induce multicellular "rosette" development. When encountered together, these cues enhance rosette development, resulting in both the formation of larger rosettes and an increase in the number of rosettes compared to rosette development in the absence of the chondroitinase. These findings highlight how synergistic interactions among bacterial cues can influence the biology of eukaryotes.


Assuntos
Bacteroidetes/fisiologia , Coanoflagelados/fisiologia , Coanoflagelados/crescimento & desenvolvimento , Sinais (Psicologia)
11.
Exp Brain Res ; 238(11): 2665-2684, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32945889

RESUMO

It remains to be investigated whether syntax-related mismatch activity would be evoked in event-related optical signals by syntactic violations that deviate from our language knowledge and expectations. In the current study, we have employed fast optical neuroimaging with a frequency-domain oximeter to examine whether syntactic violations of English bare infinitives in the non-finite complement clause would trigger syntax-related mismatch effects. Recorded sentences of bare or full infinitive structures (without or with the 'to' infinitival marker) with syntactically correct or incorrect versions and non-syntactic lexical items (verbs) were presented to native speakers of English (n = 8) during silent movie viewing as a passive oddball task. The analysis of source strength (i.e., minimum norm current amplitudes) revealed that the syntactic category violations of bare object infinitives led to significantly more robust optical mismatch effects than the other syntactic violation and non-structural, lexical elements. This mismatch response had a peak latency of 186 ms in the left anterior superior temporal gyrus. In combination with our prior MEG report (Kubota et al. in Neurosci Lett 662:195-204, 2018), the present optical neuroimaging findings show that syntactic marking (unmarked-to-marked) violations of the bare object infinitive against the rule of the mental grammar enhance the signal strength exactly in the same manner seen with MEG scanning, including the peak latency of mismatch activity and the activated area of the brain.


Assuntos
Potenciais Evocados , Neuroimagem , Encéfalo/diagnóstico por imagem , Humanos , Idioma , Semântica , Percepção da Fala , Lobo Temporal
12.
J Environ Sci Health B ; 54(8): 647-654, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31146638

RESUMO

The aim of this study was to investigate the in vitro effect of an antifungal fraction obtained from Jacquinia macrocarpa plant (JmAF) in the generation of reactive oxygen species (ROS) and the activity of the catalase (CAT) and superoxide dismutase (SOD) enzymes from Fusarium verticillioides, as well as their influence in the viability of the fungus spores. The compounds present in the JmAF were determined by gas chromatography/quadrupole time-of-flight mass spectrometry (GC/QTOF-MS). The effect of the exposition to JmAF on the generation of ROS, as well as in the CAT and SOD activities in F. verticillioides, was determined. The main compounds detected were γ-sitosterol, stephamiersine, betulinol and oleic acid. JmAF showed very high ability in inhibiting the spore viability of F. verticillioides, and their capacity to cause oxidative stress by induction of ROS production. JmAF induced the highest ROS concentration and also inhibited CAT and SOD activities. The results obtained in this study indicate that JmAF is worthy of being considered for the fight against phytopathogenic fungi.


Assuntos
Antifúngicos/farmacologia , Catalase/antagonistas & inibidores , Fusarium/efeitos dos fármacos , Primulaceae/química , Superóxido Dismutase/antagonistas & inibidores , Antifúngicos/análise , Antifúngicos/química , Antioxidantes/metabolismo , Catalase/metabolismo , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/metabolismo , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Fusarium/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
13.
Neuroimage ; 179: 403-413, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29929005

RESUMO

Current theories of pre-attentive deviant detection postulate that before the Superior Temporal Cortex (STC) detects a change, the Inferior Frontal Cortex (IFC) engages in stimulus analysis, which is particularly critical for ambiguous deviations (e.g., deviant preceded by a short train of standards). These theories rest on the assumption that IFC and STC are functionally connected, which has only been supported by correlational brain imaging studies. We examined this functional connectivity assumption by applying Transcranial Magnetic Stimulation (TMS) to disrupt IFC function, while measuring the later STC mismatch response with the event-related optical signal (EROS). EROS can localize brain activity in both spatial and temporal dimensions via measurement of optical property changes associated with neuronal activity, and is inert to the electromagnetic interference produced by TMS. Specifically, the STC mismatch response at 120-180 ms elicited by a deviant preceded by a short standard train when IFC TMS was applied at 80 ms was compared with the STC mismatch responses in temporal control (TMS with 200 ms delay), spatial control (sham TMS at vertex), auditory control (TMS pulse noise only), and cognitive control (deviant preceded by a long standard train) conditions. The STC mismatch response to deviants preceded by the short train was abolished by TMS of the IFC at 80 ms, while the STC responses remained intact in all other control conditions. These results confirm the involvement of the IFC in the STC mismatch response and support a functional connection between IFC and STC.


Assuntos
Atenção/fisiologia , Mapeamento Encefálico/métodos , Lobo Frontal/anatomia & histologia , Vias Neurais/anatomia & histologia , Lobo Temporal/anatomia & histologia , Adolescente , Potenciais Evocados/fisiologia , Feminino , Lobo Frontal/fisiologia , Humanos , Masculino , Vias Neurais/fisiologia , Imagem Óptica/métodos , Lobo Temporal/fisiologia , Estimulação Magnética Transcraniana/métodos , Adulto Jovem
14.
Neuroimage ; 85 Pt 1: 592-607, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23664952

RESUMO

Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy- and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function.


Assuntos
Envelhecimento/fisiologia , Vasos Sanguíneos/inervação , Vasos Sanguíneos/fisiologia , Eletroencefalografia/métodos , Potenciais Evocados/fisiologia , Imageamento por Ressonância Magnética/métodos , Tomografia Óptica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Circulação Cerebrovascular/fisiologia , Escolaridade , Feminino , Hemoglobinas/análise , Hemoglobinas/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Consumo de Oxigênio/fisiologia , Estimulação Luminosa , Desempenho Psicomotor/fisiologia , Adulto Jovem
15.
Redox Biol ; 73: 103214, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38805973

RESUMO

The chaperone protein EROS ("Essential for Reactive Oxygen Species") was recently discovered in phagocytes. EROS was shown to regulate the abundance of the ROS-producing enzyme NADPH oxidase isoform 2 (NOX2) and to control ROS-mediated cell killing. Reactive oxygen species are important not only in immune surveillance, but also modulate physiological signaling responses in multiple tissues. The roles of EROS have not been previously explored in the context of oxidant-modulated cell signaling. Here we show that EROS plays a key role in ROS-dependent signal transduction in vascular endothelial cells. We used siRNA-mediated knockdown and developed CRISPR/Cas9 knockout of EROS in human umbilical vein endothelial cells (HUVEC), both of which cause a significant decrease in the abundance of NOX2 protein, associated with a marked decrease in RAC1, a small G protein that activates NOX2. Loss of EROS also attenuates receptor-mediated hydrogen peroxide (H2O2) and Ca2+ signaling, disrupts cytoskeleton organization, decreases cell migration, and promotes cellular senescence. EROS knockdown blocks agonist-modulated eNOS phosphorylation and nitric oxide (NO●) generation. These effects of EROS knockdown are strikingly similar to the alterations in endothelial cell responses that we previously observed following RAC1 knockdown. Proteomic analyses following EROS or RAC1 knockdown in endothelial cells showed that reduced abundance of these two distinct proteins led to largely overlapping effects on endothelial biological processes, including oxidoreductase, protein phosphorylation, and endothelial nitric oxide synthase (eNOS) pathways. These studies demonstrate that EROS plays a central role in oxidant-modulated endothelial cell signaling by modulating NOX2 and RAC1.


Assuntos
Células Endoteliais da Veia Umbilical Humana , NADPH Oxidase 2 , Oxirredução , Espécies Reativas de Oxigênio , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP , Humanos , NADPH Oxidase 2/metabolismo , NADPH Oxidase 2/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Espécies Reativas de Oxigênio/metabolismo , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/metabolismo , Movimento Celular , Fosforilação , Senescência Celular , Técnicas de Silenciamento de Genes
16.
Int J Psychoanal ; 105(1): 40-59, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38470282

RESUMO

This article explores the notion of inhibition at a theoretical and clinical level in psychoanalysis. The first part follows the development of the notion in Freud's work, from the "Project" (1950a [1895]) to Inhibitions, Symptoms and Anxiety (1926d). It identifies the two approaches to inhibition, the first from an energetic point of view, the second from the angle of its relations to anxiety. The second part of the article is devoted to the links between inhibition and Freud's thoughts about death, in particular in Inhibitions, Symptoms and Anxiety and the links to the death drive. It draws on some of Jones' notes and presents a brief clinical illustration. The third part focuses more particularly on general inhibition, especially in depression and melancholia. Based on the treatment of one patient, the author shows how the slow process of overcoming general inhibition is achieved through the gradual use of negation. From an economic point of view, it is suggested that psychoanalytic treatment, through the transference and associative speech, has an effect on the depletion of energy by diverting the "suction" of stimuli, paving the way for the formation of drive representatives, or inhibitions as symptoms, which will need to be dissected.


Assuntos
Transtorno Depressivo , Psicanálise , Humanos , Ansiedade
17.
Neuropsychologia ; 198: 108864, 2024 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-38521150

RESUMO

Early visual cortex (V1-V3) is believed to be critical for normal visual awareness by providing the necessary feedforward input. However, it remains unclear whether visual awareness can occur without further involvement of early visual cortex, such as re-entrant feedback. It has been challenging to determine the importance of feedback activity to these areas because of the difficulties in dissociating this activity from the initial feedforward activity. Here, we applied single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal cortex to elicit phosphenes in the absence of direct visual input to early visual cortex. Immediate neural activity after the TMS pulse was assessed using the event-related optical signal (EROS), which can measure activity under the TMS coil without artifacts. Our results show that: 1) The activity in posterior parietal cortex 50 ms after TMS was related to phosphene awareness, and 2) Activity related to awareness was observed in a small portion of V1 140 ms after TMS, but in contrast (3) Activity in V2 was a more robust correlate of awareness. Together, these results are consistent with interactive models proposing that sustained and recurrent loops of activity between cortical areas are necessary for visual awareness to emerge. In addition, we observed phosphene-related activations of the anteromedial cuneus and lateral occipital cortex, suggesting a functional network subserving awareness comprising these regions, the parietal cortex and early visual cortex.


Assuntos
Conscientização , Fosfenos , Estimulação Magnética Transcraniana , Córtex Visual , Humanos , Masculino , Feminino , Conscientização/fisiologia , Adulto , Córtex Visual/fisiologia , Adulto Jovem , Fosfenos/fisiologia , Percepção Visual/fisiologia , Estimulação Luminosa , Lobo Parietal/fisiologia , Mapeamento Encefálico , Vias Visuais/fisiologia
18.
Bioengineering (Basel) ; 11(8)2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39199739

RESUMO

Event-related optical signals (EROS) measure fast modulations in the brain's optical properties related to neuronal activity. EROS offer a high spatial and temporal resolution and can be used for brain-computer interface (BCI) applications. However, the ability to classify single-trial EROS remains unexplored. This study evaluates the performance of neural network methods for single-trial classification of motor response-related EROS. EROS activity was obtained from a high-density recording montage covering the motor cortex during a two-choice reaction time task involving responses with the left or right hand. This study utilized a convolutional neural network (CNN) approach to extract spatiotemporal features from EROS data and perform classification of left and right motor responses. Subject-specific classifiers trained on EROS phase data outperformed those trained on intensity data, reaching an average single-trial classification accuracy of around 63%. Removing low-frequency noise from intensity data is critical for achieving discriminative classification results with this measure. Our results indicate that deep learning with high-spatial-resolution signals, such as EROS, can be successfully applied to single-trial classifications.

19.
Neurobiol Aging ; 137: 78-93, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38452574

RESUMO

Oddball task-related EEG delta and theta responses are associated with frontal executive functions, which are significantly impaired in patients with dementia due to Parkinson's disease (PDD) and Lewy bodies (DLB). The present study investigated the oddball task-related EEG delta and theta responses in patients with PDD, DLB, and Alzheimer's disease dementia (ADD). During visual and auditory oddball paradigms, EEG activity was recorded in 20 ADD, 17 DLB, 20 PDD, and 20 healthy (HC) older adults. Event-related EEG power spectrum and phase-locking analysis were performed at the delta (1-4 Hz) and theta (4-7 Hz) frequency bands for target and nontarget stimuli. Compared to the HC persons, dementia groups showed lower frontal and central delta and theta power and phase-locking associated with task performance and neuropsychological test scores. Notably, this effect was more significant in the PDD and DLB than in the ADD. In conclusion, oddball task-related frontal and central EEG delta and theta responses may reflect frontal supramodal executive dysfunctions in PDD and DLB patients.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Idoso , Doença por Corpos de Lewy/psicologia , Corpos de Lewy , Eletroencefalografia
20.
J Anal Psychol ; 69(2): 227-245, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38501575

RESUMO

After every school shooting in the United States both a wish and a fear arise: Will this be the one? Will this be the tipping point for change in a nation so deeply divided over the meaning of "the right to bear arms?" Sandy Hook, Connecticut? No. Parkland, Florida? No. So, why might the killing of 19 children and 2 teachers in Uvalde, Texas, prove different? The American epidemic of mass school shootings betrays a country's willingness to let its children disappear, to sacrifice them on the altar of an archetypally violent ethos. While the internal experiences of alienation, resentment and contempt are often at play in the individuals who carry out such violence, the author suggests that the uniquely American glorification of "the lone wolf", the "rugged individual" and the "misunderstood hero" fuels a supportive background for mass shooters in a nation that appears to be enamoured of ancient patriarchal attitudes as it doubles down on its valuing of weaponry. Such patriarchal attitudes, underscored by capitalism and the profits of the gun industry, are implicated in the territorial adhesion to American gun rights and in the high cost paid by the blood of innocents. Drawing on Vestergaard & Odde's (2021) concepts of socio-analysis and sociality, this paper explores the dynamic process of "mass-character" marked by "contagion, imitation, attraction and repulsion" that convolute cultural values of heritage and freedom into the perverse expression of mass violence.


Aux États­Unis, après chaque fusillade dans une école, un souhait et une crainte surgissent à la fois : est­ce que celle­ci fera une différence? Marquera­t­elle le point de basculement d'un changement dans une nation si profondément divisée sur la signification du « droit de porter des armes ¼? Sandy Hook, dans le Connecticut? Non. Santa Fe, au Texas? Non. Alors, pourquoi l'assassinat de 19 enfants et de 2 enseignants à Uvalde, au Texas, pourrait­il s'avérer différent? L'épidémie américaine de fusillades de masse dans les écoles trahit la volonté d'un pays de laisser ses enfants disparaître, de les sacrifier sur l'autel d'une philosophe archétypale de la violence. Alors que les expériences internes d'aliénation, de ressentiment et de mépris sont souvent en jeu chez les individus qui commettent de telles violences, l'auteur suggère que la glorification typiquement américaine du « loup solitaire ¼, de « l'individu robuste ¼ et du « héros incompris ¼ alimente un arrière­plan favorable aux tireurs de masse. Ceci dans une nation qui semble éprise d'anciennes attitudes patriarcales et qui persiste et signe concernant son attachement pour les armes. De telles attitudes patriarcales, soulignées par le capitalisme et les profits de l'industrie des armes à feu, sont impliquées dans l'adhésion territoriale aux droits américains sur les armes à feu et dans le coût élevé payé par le sang d'innocents. S'appuyant sur les concepts de socioanalyse et de socialité de Vestergaard et Odde (2021), cet article explore le processus dynamique du « caractère de masse ¼ marqué par « la contagion, l'imitation, l'attrait et la répulsion ¼ qui tournent les valeurs culturelles liées au patrimoine et à la liberté en une expression perverse de violence de masse.


Después de cada tiroteo en un colegio de Estados Unidos surge un deseo y un temor: ¿será éste? ¿Será éste el punto de inflexión para el cambio en una nación tan profundamente dividida sobre el significado del "derecho a portar armas"? ¿Sandy Hook, Connecticut? No. ¿Santa Fe, Texas? No. Entonces, ¿por qué la matanza de 19 niños y 2 profesores en Uvalde, Texas, podría ser diferente? La epidemia estadounidense de tiroteos masivos en escuelas revela la voluntad de un país de dejar desaparecer a sus niños, de sacrificarlos en el altar de un ethos arquetípicamente violento. Aunque las experiencias internas de alienación, resentimiento y desprecio suelen ponerse en juego en los individuos que llevan a cabo este tipo de violencia, la autora sugiere que la glorificación exclusivamente estadounidense del "lobo solitario", el "individuo rudo" y el "héroe incomprendido" alimenta un trasfondo de sostén para los autores de tiroteos masivos, en una nación que parece estar enamorada de antiguas actitudes patriarcales mientras redobla su valoración del armamento. Dichas actitudes patriarcales, acentuadas por el capitalismo y los beneficios de la industria armamentística, están implicadas en la adhesión territorial al derecho estadounidense a las armas y en el alto costo pagado por la sangre de inocentes. Basándose en los conceptos de socioanálisis y socialidad de Vestergaard y Odde (2021), este artículo explora el proceso dinámico del "carácter de masas", marcado por el "contagio, la imitación, la atracción y la repulsión", que convierte los valores culturales del patrimonio y la libertad en la expresión perversa de la violencia de masas.


Assuntos
Teoria Junguiana , Criança , Humanos , Estados Unidos , Estrutura Familiar
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