RESUMO
Recent studies provide evidence for changes in audiovisual perception as well as for adaptive cross-modal auditory cortex plasticity in older individuals with high-frequency hearing impairments (presbycusis). We here investigated whether these changes facilitate the use of visual information, leading to an increased audiovisual benefit of hearing-impaired individuals when listening to speech in noise. We used a naturalistic design in which older participants with a varying degree of high-frequency hearing loss attended to running auditory or audiovisual speech in noise and detected rare target words. Passages containing only visual speech served as a control condition. Simultaneously acquired scalp electroencephalography (EEG) data were used to study cortical speech tracking. Target word detection accuracy was significantly increased in the audiovisual as compared to the auditory listening condition. The degree of this audiovisual enhancement was positively related to individual high-frequency hearing loss and subjectively reported listening effort in challenging daily life situations, which served as a subjective marker of hearing problems. On the neural level, the early cortical tracking of the speech envelope was enhanced in the audiovisual condition. Similar to the behavioral findings, individual differences in the magnitude of the enhancement were positively associated with listening effort ratings. Our results therefore suggest that hearing-impaired older individuals make increased use of congruent visual information to compensate for the degraded auditory input.
Assuntos
Córtex Cerebral/fisiopatologia , Ruído , Presbiacusia/fisiopatologia , Percepção da Fala/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Idoso , Limiar Auditivo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pessoas com Deficiência Auditiva , Estimulação LuminosaRESUMO
Listening selectively to one out of several competing speakers in a "cocktail party" situation is a highly demanding task. It relies on a widespread cortical network, including auditory sensory, but also frontal and parietal brain regions involved in controlling auditory attention. Previous work has shown that, during selective listening, ongoing neural activity in auditory sensory areas is dominated by the attended speech stream, whereas competing input is suppressed. The relationship between these attentional modulations in the sensory tracking of the attended speech stream and frontoparietal activity during selective listening is, however, not understood. We studied this question in young, healthy human participants (both sexes) using concurrent EEG-fMRI and a sustained selective listening task, in which one out of two competing speech streams had to be attended selectively. An EEG-based speech envelope reconstruction method was applied to assess the strength of the cortical tracking of the to-be-attended and the to-be-ignored stream during selective listening. Our results show that individual speech envelope reconstruction accuracies obtained for the to-be-attended speech stream were positively correlated with the amplitude of sustained BOLD responses in the right temporoparietal junction, a core region of the ventral attention network. This brain region further showed task-related functional connectivity to secondary auditory cortex and regions of the frontoparietal attention network, including the intraparietal sulcus and the inferior frontal gyrus. This suggests that the right temporoparietal junction is involved in controlling attention during selective listening, allowing for a better cortical tracking of the attended speech stream.SIGNIFICANCE STATEMENT Listening selectively to one out of several simultaneously talking speakers in a "cocktail party" situation is a highly demanding task. It activates a widespread network of auditory sensory and hierarchically higher frontoparietal brain regions. However, how these different processing levels interact during selective listening is not understood. Here, we investigated this question using fMRI and concurrently acquired scalp EEG. We found that activation levels in the right temporoparietal junction correlate with the sensory representation of a selectively attended speech stream. In addition, this region showed significant functional connectivity to both auditory sensory and other frontoparietal brain areas during selective listening. This suggests that the right temporoparietal junction contributes to controlling selective auditory attention in "cocktail party" situations.
Assuntos
Discriminação Psicológica , Lobo Parietal/fisiologia , Percepção da Fala , Lobo Temporal/fisiologia , Adulto , Atenção , Cognição , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Lobo Parietal/diagnóstico por imagem , Lobo Temporal/diagnóstico por imagemRESUMO
Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69â years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a ≥5% prevalence across centres.Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher total anaerobe/total aerobe CFU ratio was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared with a Pseudomonas-dominated group with similar proportions of subjects that were homozygous for F508del.In summary, anaerobic bacteria occurred at an early age. In sputum-producing subjects anaerobic bacteria were associated with milder disease, suggesting that targeted eradication of anaerobes may not be warranted in sputum-producing CF subjects.
Assuntos
Bactérias Anaeróbias/classificação , Bactérias Anaeróbias/isolamento & purificação , Infecções Bacterianas/diagnóstico , Fibrose Cística/microbiologia , Sistema Respiratório/microbiologia , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Criança , Pré-Escolar , Fibrose Cística/fisiopatologia , Feminino , Humanos , Lactente , Internacionalidade , Modelos Logísticos , Masculino , Microbiota , Pessoa de Meia-Idade , Análise Multivariada , Escarro/microbiologia , Adulto JovemRESUMO
The acoustic envelope of human speech correlates with the syllabic rate (4-8 Hz) and carries important information for intelligibility, which is typically compromised in multi-talker, noisy environments. In order to better understand the dynamics of selective auditory attention to low frequency modulated sound sources, we conducted a two-stream auditory steady-state response (ASSR) selective attention electroencephalogram (EEG) study. The two streams consisted of 4 and 7 Hz amplitude and frequency modulated sounds presented from the left and right side. One of two streams had to be attended while the other had to be ignored. The attended stream always contained a target, allowing for the behavioral confirmation of the attention manipulation. EEG ASSR power analysis revealed a significant increase in 7 Hz power for the attend compared to the ignore conditions. There was no significant difference in 4 Hz power when the 4 Hz stream had to be attended compared to when it had to be ignored. This lack of 4 Hz attention modulation could be explained by a distracting effect of a third frequency at 3 Hz (beat frequency) perceivable when the 4 and 7 Hz streams are presented simultaneously. Taken together our results show that low frequency modulations at syllabic rate are modulated by selective spatial attention. Whether attention effects act as enhancement of the attended stream or suppression of to be ignored stream may depend on how well auditory streams can be segregated.
Assuntos
Estimulação Acústica , Atenção/fisiologia , Eletroencefalografia , Adulto , Córtex Auditivo/fisiologia , Percepção Auditiva , Sinais (Psicologia) , Feminino , Lateralidade Funcional/fisiologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Percepção Espacial/fisiologia , Adulto JovemRESUMO
BACKGROUND: Chitinases have recently gained attention in the field of pulmonary diseases, particularly in asthma and chronic obstructive pulmonary disease, but their potential role in patients with cystic fibrosis (CF)-associated lung disease remains unclear. OBJECTIVE: The aim of this study was to assess chitinase activity systemically and in the airways of patients with CF and asthma compared with healthy subjects. Additionally, we assessed factors that regulate chitinase activity within the lungs of patients with CF. METHODS: Chitinase activities were quantified in serum and bronchoalveolar lavage fluid from patients with CF, asthmatic patients, and healthy control subjects. Mechanistically, the role of CF airway proteases and genetic chitinase deficiency was assessed. RESULTS: Chitinase activity was systemically increased in patients with CF compared with that in healthy control subjects and asthmatic patients. Further stratification showed that chitinase activity was enhanced in patients with CF colonized with Candida albicans compared with that in noncolonized patients. CF proteases degraded chitinases in the airway microenvironment of patients with CF. Genetic chitinase deficiency was associated with C albicans colonization in patients with CF. CONCLUSION: Patients with CF have enhanced chitinase activation associated with C albicans colonization. Therefore chitinases might represent a novel biomarker and therapeutic target for CF-associated fungal disease.
Assuntos
Candidíase/complicações , Quitinases/metabolismo , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Adolescente , Adulto , Asma/complicações , Candida albicans/isolamento & purificação , Candida albicans/metabolismo , Candidíase/enzimologia , Quitinases/sangue , Quitinases/deficiência , Quitinases/genética , Feminino , Humanos , Masculino , Regulação para Cima , Adulto JovemRESUMO
BACKGROUND: Colonization by Aspergillus fumigatus in patients with cystic fibrosis (CF) can cause A fumigatus sensitization and/or allergic bronchopulmonary aspergillosis (ABPA), which affects pulmonary function and clinical outcomes. Recent studies show that specific allergens upregulate the surface-expressed basophil marker CD203c in sensitized subjects, a response that can be readily measured by using flow cytometry. OBJECTIVE: We sought to identify A fumigatus sensitization in patients with CF by using the basophil activation test (BAT). METHODS: Patients with CF attending Beaumont Hospital were screened for study inclusion. BAT was used to identify A fumigatus sensitization. Serologic (total and A fumigatus-specific IgE), pulmonary function, and body mass index measurements were performed. RESULTS: The BAT discriminates A fumigatus-sensitized from nonsensitized patients with CF. Persistent isolation of A fumigatus in sputum is a significant risk factor for A fumigatus sensitization. Levels of the A fumigatus-stimulated basophil activation marker CD203c inversely correlated with pulmonary function and body mass index in A fumigatus-sensitized but not nonsensitized patients with CF. Total and A fumigatus-specific IgE, but not IgG, levels are increased in A fumigatus-sensitized patients with CF and ABPA when compared with those in A fumigatus-sensitized and nonsensitized patients with CF without ABPA. Itraconazole treatment did not affect A fumigatus sensitization. CONCLUSION: Combining the BAT with routine serologic testing allows classification of patients with CF into 3 groups: nonsensitized, A fumigatus-sensitized, and ABPA. Accurate and prompt identification of A fumigatus-associated clinical status might allow early and targeted therapeutic intervention, potentially improving clinical outcomes.
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Aspergilose/etiologia , Aspergilose/metabolismo , Aspergillus/imunologia , Basófilos/metabolismo , Fibrose Cística/complicações , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Especificidade de Anticorpos/imunologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Antígenos de Fungos/imunologia , Antígenos de Superfície/metabolismo , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Basófilos/imunologia , Biomarcadores , Índice de Massa Corporal , Fibrose Cística/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunofenotipagem , Contagem de Leucócitos , Masculino , Estudos Prospectivos , Escarro/imunologia , Escarro/microbiologiaRESUMO
The diagnosis of cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA) is clinically challenging, due to the absence of an objective biological test. Since blood basophils play a major role in allergic responses, we hypothesised that changes in their surface activation pattern discriminate between CF patients with and without ABPA.We conducted a prospective longitudinal study (Stanford cohort) comparing basophil activation test CD203c levels by flow cytometry before and after activation with Aspergillus fumigatus allergen extract or recombinant Asp f1 in 20 CF patients with ABPA (CF-ABPA) and in two comparison groups: CF patients with A. fumigatus colonisation (AC) but without ABPA (CF-AC; n=13) and CF patients without either AC or ABPA (CF; n=12). Patients were tested every 6â months and when ill with pulmonary exacerbation. We also conducted cross-sectional validation in a separate patient set (Dublin cohort).Basophil CD203c surface expression reliably discriminated CF-ABPA from CF-AC and CF over time. Ex vivo stimulation with A. fumigatus extract or recombinant Asp f1 produced similar results within the Stanford (p<0.0001) and the Dublin cohorts. CF-ABPA patients were likelier to have elevated specific IgE to A. fumigatus and were less frequently co-infected with Staphylococcus aureus.Basophil CD203c upregulation is a suitable diagnostic and stable monitoring biomarker of ABPA in CF.
Assuntos
Aspergilose Broncopulmonar Alérgica/metabolismo , Basófilos/metabolismo , Portador Sadio/metabolismo , Fibrose Cística/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Aspergilose Pulmonar/metabolismo , Pirofosfatases/metabolismo , Adolescente , Adulto , Alérgenos/farmacologia , Aspergilose Broncopulmonar Alérgica/complicações , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergillus fumigatus/imunologia , Basófilos/efeitos dos fármacos , Biomarcadores/metabolismo , Portador Sadio/diagnóstico , Estudos de Casos e Controles , Criança , Estudos de Coortes , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Feminino , Citometria de Fluxo , Humanos , Masculino , Estudos Prospectivos , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/diagnóstico , Adulto JovemRESUMO
Cathepsin B is a lysosomal cysteine protease that is implicated in a number of physiological processes, including protein turnover in lysosomes. Changes in its expression are associated with a variety of pathological processes, including cancer. Due to the structural feature, termed the occluding loop, cathepsin B differs from other cysteine proteases in possessing both, endopeptidase and exopeptidase activity. Here we investigated the impact of both cathepsin B activities on intracellular and extracellular collagen IV degradation and tumour cell invasion using new selective synthetic inhibitors, 2-{[(8-hydroxy-5-nitroquinoline-7-yl)methyl]amino}-acetonitrile (1), 8-(4-methylpiperidin-1-yl)-5-nitroquinoline (2) and 7-[(4-methylpiperidin-1yl)methyl]-5-nitroquinolin-8-ol (3). All three compounds (5 µM) reduced extracellular degradation of collagen IV by MCF-10A neoT cells by 45-70% as determined by spectrofluorimetry and they (50 µM) attenuated intracellular collagen IV degradation by 40-60% as measured with flow cytometry. Furthermore, all three compounds (5 µM) impaired MCF-10A neoT cell invasion by 40-80% as assessed by measuring electrical impedance in real time. Compounds 1 and 3 (5 µM), but not compound 2, significantly reduced the growth of MMTV-PyMT multicellular tumour spheroids. Collectively, these data suggest that the efficient strategy to impair harmful cathepsin B activity in tumour progression may include simultaneous and potent inhibition of cathepsin B endopeptidase and exopeptidase activities.
Assuntos
Aminoacetonitrila/análogos & derivados , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Catepsina B/antagonistas & inibidores , Catepsina B/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Invasividade Neoplásica/prevenção & controle , Nitroquinolinas/farmacologia , Piperidinas/farmacologia , Inibidores de Proteases/farmacologia , Aminoacetonitrila/síntese química , Aminoacetonitrila/química , Aminoacetonitrila/farmacologia , Neoplasias da Mama/enzimologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Estrutura Molecular , Nitroquinolinas/síntese química , Nitroquinolinas/química , Piperidinas/síntese química , Piperidinas/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
RATIONALE: Anaerobic bacteria are present in large numbers in the airways of people with cystic fibrosis (PWCF). In the gut, anaerobes produce short-chain fatty acids (SCFAs) that modulate immune and inflammatory processes. OBJECTIVES: To investigate the capacity of anaerobes to contribute to cystic fibrosis (CF) airway pathogenesis via SCFAs. METHODS: Samples of 109 PWCF were processed using anaerobic microbiological culture with bacteria present identified by 16S RNA sequencing. SCFA levels in anaerobic supernatants and bronchoalveolar lavage (BAL) were determined by gas chromatography. The mRNA and/or protein expression of two SCFA receptors, GPR41 and GPR43, in CF and non-CF bronchial brushings and 16HBE14o(-) and CFBE41o(-) cells were evaluated using reverse transcription polymerase chain reaction, Western blot analysis, laser scanning cytometry, and confocal microscopy. SCFA-induced IL-8 secretion was monitored by ELISA. MEASUREMENTS AND MAIN RESULTS: Fifty-seven (52.3%) of 109 PWCF were anaerobe positive. Prevalence increased with age, from 33.3% to 57.7% in PWCF younger (n = 24) and older (n = 85) than 6 years of age. All evaluated anaerobes produced millimolar concentrations of SCFAs, including acetic, propionic, and butyric acids. SCFA levels were higher in BAL samples of adults than in those of children. GPR41 levels were elevated in CFBE41o(-) versus 16HBE14o(-) cells; CF versus non-CF bronchial brushings; and 16HBE14o(-) cells after treatment with cystic fibrosis transmembrane conductance regulator inhibitor CFTR(inh)-172, CF BAL, or inducers of endoplasmic reticulum stress. SCFAs induced a dose-dependent and pertussis toxin-sensitive IL-8 response in bronchial epithelial cells, with a higher production of IL-8 in CFBE41o(-) than in 16HBE14o(-) cells. CONCLUSIONS: This study illustrates that SCFAs contribute to excessive production of IL-8 in CF airways colonized with anaerobes via up-regulated GPR41.
Assuntos
Bactérias Anaeróbias , Fibrose Cística/microbiologia , Ácidos Graxos/biossíntese , Adolescente , Adulto , Fatores Etários , Western Blotting , Líquido da Lavagem Broncoalveolar/microbiologia , Criança , Pré-Escolar , Cromatografia Gasosa , Regulador de Condutância Transmembrana em Fibrose Cística/análise , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/microbiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Mucosa Respiratória/microbiologia , Regulação para Cima , Adulto JovemRESUMO
Molecular dynamics (MD) and molecular docking are commonly used to study molecular interactions in drug discovery. Most docking approaches consider proteins as rigid, which can decrease the accuracy of predicted docked poses. Therefore MD simulations can be used prior to docking to add flexibility to proteins. We evaluated the contribution of using MD together with docking in a docking study on human cathepsin B, a well-studied protein involved in numerous pathological processes. Using CHARMM biomolecular simulation program and AutoDock Vina molecular docking program, we found, that short MD simulations significantly improved molecular docking. Our results, expressed with the area under the receiver operating characteristic curves, show an increase in discriminatory power i.e. the ability to discriminate active from inactive compounds of molecular docking, when docking is performed to selected snapshots from MD simulations.
Assuntos
Catepsina B/química , Avaliação Pré-Clínica de Medicamentos/métodos , Simulação de Dinâmica Molecular , Bibliotecas de Moléculas Pequenas/farmacologia , Catepsina B/metabolismo , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Curva ROC , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Individuals with structural lung disease or defective immunity are predisposed to Aspergillus-associated disease. Manifestations range from allergic to cavitary or angio-invasive syndromes. Despite daily spore inhalation, immunocompetence facilitates clearance through initiation of innate and adaptive host responses. These include mechanical barriers, phagocyte activation, antimicrobial peptide release and pattern recognition receptor activation. Adaptive responses include Th1 and Th2 approaches. Understanding Aspergillus virulence mechanisms remains critical to the development of effective research and treatment strategies to counteract the fungi. Major virulence factors relate to fungal structure, protease release and allergens; however, mechanisms utilized to evade immune recognition continue to be important in establishing infection. These include the fungal rodlet layer, dihydroxynaphthalene-melanin, detoxifying systems for reactive oxygen species and toxin release. One major immunoevasive toxin, gliotoxin, plays a key role in mediating Aspergillus-associated colonization in the context of cystic fibrosis. Here, it down-regulates vitamin D receptor expression which following itraconazole therapy is rescued concurrent with decreased Th2 cytokine (IL-5 and IL-13) concentrations in the CF airway. This review focuses on the interaction between Aspergillus pathogenic mechanisms, host immune responses and the immunoevasive strategies employed by the organism during disease states such as that observed in cystic fibrosis.
Assuntos
Aspergilose/imunologia , Aspergilose/microbiologia , Aspergillus/crescimento & desenvolvimento , Aspergillus/imunologia , Evasão da Resposta Imune , Fatores de Virulência/metabolismo , HumanosRESUMO
Podosomes, specialized actin-rich structures in macrophages (Mfs), degrade the extra-cellular matrix (ECM) and are involved in cell migration. On two-dimensional (2D) surfaces Mfs form spot-like podosomes at the ventral cell surface that develop into protrusive structures in a three-dimensional (3D) environment resembling the ECM. We have shown that the tips of these protrusive podosomes are characterized by increased accumulation of cysteine cathepsins (Cts) B, X, S, H, and L, both in human blood Mfs and in human monocytic cell line U-937. Monocyte-to-Mf differentiation induces an increase in cysteine cathepsin expression and activity, promoting their translocation to the cell surface, where they interact with ECM. This group of proteases is crucial for the extracellular as well as intracellular degradation of ECM, as demonstrated by quantitative monitoring of collagen IV degradation. Furthermore, inhibiting CtsB, X, and S significantly impairs Mf invasion through the 3D matrix. Time-lapse live-cell imaging of CtsB activity revealed that the extracellular and the intracellular ECM degradation are associated with extensive endocytosis at the tip of protrusive podosomes. The targeting of cysteine cathepsins, as the major mediators of human Mf 3D invasion, could be an approach to the treatment of inflammatory and cancerous diseases.
Assuntos
Catepsinas/imunologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Matriz Extracelular/imunologia , Macrófagos/imunologia , Citoesqueleto de Actina/imunologia , Citoesqueleto de Actina/metabolismo , Catepsinas/metabolismo , Matriz Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica/imunologia , Humanos , Macrófagos/citologia , Macrófagos/enzimologia , Monócitos/citologia , Monócitos/enzimologia , Monócitos/imunologia , Células U937RESUMO
Auditory attention is an important cognitive function used to separate relevant from irrelevant auditory information. However, most findings on attentional selection have been obtained in highly controlled laboratory settings using bulky recording setups and unnaturalistic stimuli. Recent advances in electroencephalography (EEG) facilitate the measurement of brain activity outside the laboratory, and around-the-ear sensors such as the cEEGrid promise unobtrusive acquisition. In parallel, methods such as speech envelope tracking, intersubject correlations and spectral entropy measures emerged which allow us to study attentional effects in the neural processing of natural, continuous auditory scenes. In the current study, we investigated whether these three attentional measures can be reliably obtained when using around-the-ear EEG. To this end, we analyzed the cEEGrid data of 36 participants who attended to one of two simultaneously presented speech streams. Speech envelope tracking results confirmed a reliable identification of the attended speaker from cEEGrid data. The accuracies in identifying the attended speaker increased when fitting the classification model to the individual. Artifact correction of the cEEGrid data with artifact subspace reconstruction did not increase the classification accuracy. Intersubject correlations were higher for those participants attending to the same speech stream than for those attending to different speech streams, replicating previously obtained results with high-density cap-EEG. We also found that spectral entropy decreased over time, possibly reflecting the decrease in the listener's level of attention. Overall, these results support the idea of using ear-EEG measurements to unobtrusively monitor auditory attention to continuous speech. This knowledge may help to develop assistive devices that support listeners separating relevant from irrelevant information in complex auditory environments.
RESUMO
Difficulties in selectively attending to one among several speakers have mainly been associated with the distraction caused by ignored speech. Thus, in the current study, we investigated the neural processing of ignored speech in a two-competing-speaker paradigm. For this, we recorded the participant's brain activity using electroencephalography (EEG) to track the neural representation of the attended and ignored speech envelope. To provoke distraction, we occasionally embedded the participant's first name in the ignored speech stream. Retrospective reports as well as the presence of a P3 component in response to the name indicate that participants noticed the occurrence of their name. As predicted, the neural representation of the ignored speech envelope increased after the name was presented therein, suggesting that the name had attracted the participant's attention. Interestingly, in contrast to our hypothesis, the neural tracking of the attended speech envelope also increased after the name occurrence. On this account, we conclude that the name might not have primarily distracted the participants, at most for a brief duration, but that it alerted them to focus to their actual task. These observations remained robust even when the sound intensity of the ignored speech stream, and thus the sound intensity of the name, was attenuated.
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BACKGROUND & AIMS: Short chain fatty acid (SCFAs) are bacterially derived metabolites suggested to have protective roles against colorectal cancer (CRC) development. However, there is sparse evidence from epidemiological studies in this context. Here, we assessed whether circulating SCFA concentrations varied in patients with colorectal adenomas (CRA) and CRC. METHODS: Levels of seven SCFAs were extracted from plasma samples and determined by gas chromatography for 213 individuals from Ireland and the Czech Republic (CRC, n = 84; CRA, n = 66; controls, n = 63). RESULTS: In the Irish CRA/CRC cohort, only levels of 2-MethylButyric acid were significantly higher in cancers compared to the adenoma and control groups (p-values = 0.016 and 0.043). Using regression analysis, we observed that levels of Acetic and Propionic acid were associated with an increased CRC risk in the Czech cohort (Odd Ratio (OR): 1.02; 95% Confidence interval (CI): 1.00-1.03; OR: 1.29; 95% CI: 1.05-1.59, respectively), while i-Valeric and Valeric acid levels were associated with a decreased cancer risk (OR: 0.92; 95% CI: 0.86-0.99; OR: 0.67; 95% CI: 0.44-1.00). In the Irish cohort, levels of SCFAs were not associated with CRC risk. CONCLUSIONS: The association with colorectal neoplasia varied between the studied SCFAs. Future studies need to confirm these findings and address the mechanism of how these acids may promote or prevent colorectal carcinogenesis.
Assuntos
Adenoma , Neoplasias Colorretais , Microbioma Gastrointestinal , Adenoma/epidemiologia , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Ácidos Graxos Voláteis , HumanosRESUMO
Arsenic trioxide (arsenite) was the first chemotherapeutic drug to be described and is now being rediscovered in cancer treatment, including glioblastoma multiforme. Arsenite toxicity triggers autophagy in cancer cells, although final stages of the process involve executive caspases, suggesting an interplay between autophagic and apoptotic pathways that awaits to be explained at a molecular level. We evaluated the contribution of the lysosomal cathepsins (Cat) L and B, which are upregulated in glioblastomas, in the mechanism of arsenite toxicity in human glioblastoma cells. Arsenite treatment induced autophagosome formation and permeabilization of mitochondria, followed by caspase 3/7-mediated apoptosis. The autophagy inhibitor 3-methyladenine protected from arsenite toxicity, whereas bafilomycin A1 did not. Furthermore, arsenite significantly decreased CatB levels and selectively inhibited its cellular and recombinant protein activity, while not affecting CatL. However, downregulation of CatL greatly enhanced apoptosis by arsenite. Our results show that arsenite toxicity involves a complex interplay between autophagy and apoptosis in human glioblastoma cells and is associated with inhibition of CatB, and that this toxicity is highly exacerbated by simultaneous CatL inhibition. The latter points to a synergy that could be used in clinical treatment to lower the therapeutic dose, thus avoiding the toxic side effects of arsenite in glioblastoma management.
Assuntos
Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Autofagia , Catepsina B/fisiologia , Catepsina L/fisiologia , Glioblastoma/tratamento farmacológico , Óxidos/uso terapêutico , Adenina/análogos & derivados , Adenina/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/efeitos adversos , Autofagia/efeitos dos fármacos , Caspases/metabolismo , Catepsina B/antagonistas & inibidores , Catepsina L/antagonistas & inibidores , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Regulação para Baixo , Compostos de Epóxi/farmacologia , Glioblastoma/metabolismo , Humanos , Macrolídeos/farmacologia , Óxidos/efeitos adversos , Piridinas/farmacologiaRESUMO
Listeners differ in their ability to attend to a speech stream in the presence of a competing sound. Differences in speech intelligibility in noise cannot be fully explained by the hearing ability which suggests the involvement of additional cognitive factors. A better understanding of the temporal fluctuations in the ability to pay selective auditory attention to a desired speech stream may help in explaining these variabilities. In order to better understand the temporal dynamics of selective auditory attention, we developed an online auditory attention decoding (AAD) processing pipeline based on speech envelope tracking in the electroencephalogram (EEG). Participants had to attend to one audiobook story while a second one had to be ignored. Online AAD was applied to track the attention toward the target speech signal. Individual temporal attention profiles were computed by combining an established AAD method with an adaptive staircase procedure. The individual decoding performance over time was analyzed and linked to behavioral performance as well as subjective ratings of listening effort, motivation, and fatigue. The grand average attended speaker decoding profile derived in the online experiment indicated performance above chance level. Parameters describing the individual AAD performance in each testing block indicated significant differences in decoding performance over time to be closely related to the behavioral performance in the selective listening task. Further, an exploratory analysis indicated that subjects with poor decoding performance reported higher listening effort and fatigue compared to good performers. Taken together our results show that online EEG based AAD in a complex listening situation is feasible. Adaptive attended speaker decoding profiles over time could be used as an objective measure of behavioral performance and listening effort. The developed online processing pipeline could also serve as a basis for future EEG based near real-time auditory neurofeedback systems.
RESUMO
Previous results showed that it is possible to decode an attended speech source from EEG data via the reconstruction of the speech envelope in normal hearing (NH) listeners. However, so far it is unknown that how the performance of such a decoder is affected by the decrease in spectral resolution and the electrical artifacts introduced by a cochlear implant (CI) in users of these prostheses. NH listeners and bilateral CI users participated in the present study. Speeches from two audio books, one uttered by a male voice and one by a female voice, were presented to NH listeners and CI users. Participants were instructed to attend to one of the two speech streams presented dichotically while a 96-channel EEG was recorded. Speech envelope reconstruction from the EEG data was obtained by training decoders using a regularized least square estimation method. Decoding accuracy was defined as the percentage of accurately reconstructed trials for each subject. For NH listeners, the experiment was repeated using a vocoder to reduce spectral resolution and simulate speech perception with a CI in NH listeners. The results showed a decoding accuracy of 80.9 % using the original sound files in NH listeners. The performance dropped to 73.2 % in the vocoder condition and to 71.5 % in the group of CI users. In sum, although the accuracy drops when the spectral resolution becomes worse, the results show the feasibility to decode the attended sound source in NH listeners with a vocoder simulation, and even in CI users, albeit more training data are needed.
Assuntos
Atenção/fisiologia , Implantes Cocleares , Eletroencefalografia/métodos , Processamento de Sinais Assistido por Computador , Percepção da Fala/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Identifying the target speaker in hearing aid applications is an essential ingredient to improve speech intelligibility. Recently, a least-squares-based method has been proposed to identify the attended speaker from single-trial EEG recordings for an acoustic scenario with two competing speakers. This least-squares-based auditory attention decoding (AAD) method aims at decoding auditory attention by reconstructing the attended speech envelope from the EEG recordings using a trained spatio-temporal filter. While the performance of this AAD method has been mainly studied for noiseless and anechoic acoustic conditions, it is important to fully understand its performance in realistic noisy and reverberant acoustic conditions. In this paper, we investigate AAD using EEG recordings for different acoustic conditions (anechoic, reverberant, noisy, and reverberant-noisy). In particular, we investigate the impact of different acoustic conditions for AAD filter training and for decoding. In addition, we investigate the influence on the decoding performance of the different acoustic components (i.e., reverberation, background noise, and interfering speaker) in the reference signals used for decoding and the training signals used for computing the filters. First, we found that for all considered acoustic conditions it is possible to decode auditory attention with a considerably large decoding performance. In particular, even when the acoustic conditions for AAD filter training and for decoding are different, the decoding performance is still comparably large. Second, when using speech signals affected by either reverberation and/or background noise there is no significant difference in decoding performance ( ) compared to when using clean speech signals as reference signals. In contrast, when using reference signals affected by the interfering speaker, the decoding performance significantly decreases. Third, the experimental results indicate that it is even feasible to use training signals affected by reverberation, background noise and/or the interfering speaker for computing the filters.