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1.
Int. j. morphol ; 38(2): 356-362, abr. 2020. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1056447

RESUMO

El suicidio es un problema de salud a nivel mundial, siendo la conducta suicida uno de los predictores de mortalidad por suicidio; sin embargo, su valoración aún sigue siendo compleja. Aunque la cantidad de literatura que ha abordado distintas perspectivas de la conducta suicida es abundante, se requiere ahondar en nuevos métodos que permitan una valoración rápida y objetiva de ésta, proporcionando a los clínicos y pacientes, un sistema de evaluación que registre los cambios de estados emocionales de manera dinámica. El objetivo de este manuscrito fue proporcionar una visión general de la morfología de los potenciales evocados auditivos de latencia tardía p300 y su rol en la evaluación de la conducta suicida.


Suicide is a global health problem, with suicidal behavior being one of the predictors of suicide mortality; however, its assessment is still complex. Although the amount of literature that has addressed different perspectives of suicidal behavior is abundant, it is necessary to deepen new methods that allow a rapid and objective assessment of it, providing clinicians and patients with an evaluation system that allows changes in emotional state to be recorded dynamically. The aim of this manuscript was to provide an overview of morphological patterns of auditory evoked potential P300 latency late in the assessment of suicidal behavior.


Assuntos
Comportamento do Adolescente/fisiologia , Potencial Evocado P300/fisiologia , Ideação Suicida , Valores de Referência , Eletrofisiologia , Potenciais Evocados Auditivos/fisiologia
2.
Nat Rev Neurosci ; 21(3): 121-138, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32042146

RESUMO

Astrocytes are a type of glial cell that tile the CNS. They interact with multiple cell types, including neurons, glial cells and blood vessels, and are involved or implicated in brain disorders. Progress has been made in understanding astrocytes, but the field lacks detailed information concerning how they perform their multifarious functions, and how and when they influence the operations of the neural circuits with which they interact. One recognized bottleneck to progress has been the paucity of reliable tools with which to explore astrocytes within the adult vertebrate CNS in vivo. However, improved tools for molecular, genetic, morphological and physiological assessments have been developed recently or have been adapted from their original purposes to study neurons and are now being used to systematically document and interrogate astrocyte biology in vivo. These tools, their uses and limitations, and the insights that they afford are summarized in this Review.


Assuntos
Astrócitos/citologia , Astrócitos/fisiologia , Neurociências/métodos , Animais , Sinalização do Cálcio , Eletrofisiologia/métodos , Perfilação da Expressão Gênica/métodos , Marcação de Genes/métodos , Humanos , Proteômica/métodos
3.
PLoS Comput Biol ; 16(2): e1007678, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32097431

RESUMO

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that paired-like homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na+ channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.


Assuntos
Fibrilação Atrial/metabolismo , Simulação por Computador , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Potenciais de Ação , Animais , Antiarrítmicos/farmacologia , Fibrilação Atrial/genética , Remodelamento Atrial , Cálcio/metabolismo , Eletrofisiologia , Retículo Endoplasmático/metabolismo , Fibrose , Flecainida/farmacologia , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Átrios do Coração/fisiopatologia , Proteínas de Homeodomínio/genética , Humanos , Cinética , Camundongos , Camundongos Knockout , Fenótipo , Canal de Liberação de Cálcio do Receptor de Rianodina/farmacologia , Retículo Sarcoplasmático/metabolismo , Sódio/metabolismo , Fatores de Transcrição/genética
4.
Doc Ophthalmol ; 140(1): 5-12, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31902035

RESUMO

The International Society for the Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum set of tests, but encourages the use of additional protocols for clinical ERG testing. This extended protocol describes recording methods and derivations that will allow analysis of rod-driven components of the dark-adapted (DA) strong flash ERG a-wave, more closely related to rod phototransduction than ISCEV standard DA ERGs. The method involves recording ERGs to a flash strength equivalent to 30 cd s m2 under conditions of dark adaptation and additionally to the same stimulus following light adaptation (LA) and in the presence of a standard photopic background luminance of 30 cd m-2. The isolated rod-driven ERG a-wave is derived by subtracting the LA response from the DA ERG. The method is likely to be of value in the characterization of retinal disorders which affect rod quantal catch, diseases that affect the dynamics of any component of the activation phase of rod phototransduction, or those affecting total numbers of rod photoreceptors.


Assuntos
Protocolos Clínicos/normas , Eletrorretinografia , Estimulação Luminosa , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Sociedades Médicas/normas , Visão Ocular/fisiologia , Adaptação à Escuridão/fisiologia , Eletrofisiologia/normas , Humanos , Internacionalidade , Luz
5.
Nat Commun ; 11(1): 324, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949136

RESUMO

Neural adaptation enables sensory information to be represented optimally in the brain despite large fluctuations over time in the statistics of the environment. Auditory contrast gain control represents an important example, which is thought to arise primarily from cortical processing. Here we show that neurons in the auditory thalamus and midbrain of mice show robust contrast gain control, and that this is implemented independently of cortical activity. Although neurons at each level exhibit contrast gain control to similar degrees, adaptation time constants become longer at later stages of the processing hierarchy, resulting in progressively more stable representations. We also show that auditory discrimination thresholds in human listeners compensate for changes in contrast, and that the strength of this perceptual adaptation can be predicted from physiological measurements. Contrast adaptation is therefore a robust property of both the subcortical and cortical auditory system and accounts for the short-term adaptability of perceptual judgments.


Assuntos
Córtex Auditivo/fisiologia , Vias Auditivas/fisiologia , Percepção Auditiva/fisiologia , Mesencéfalo/fisiologia , Neurônios/fisiologia , Tálamo/fisiologia , Adaptação Fisiológica/fisiologia , Animais , Limiar Auditivo/fisiologia , Discriminação Psicológica , Eletrofisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Modelos Neurológicos , Ruído , Optogenética , Espectrografia do Som
6.
Endocrinology ; 161(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31875912

RESUMO

Changes in gonadotropin-releasing hormone (GnRH) release frequency from the brain help drive reproductive cycles. In polycystic ovary syndrome (PCOS), persistent high GnRH/luteinizing hormone (LH) frequency disrupts cycles and exacerbates hyperandrogenemia. Adult prenatally-androgenized (PNA) mice exhibit increased GnRH neuron firing rate, elevated ovarian androgens, and disrupted cycles, but before puberty, GnRH neuron activity is reduced in PNA mice compared with controls. We hypothesized that ovarian feedback mediates the age-dependent change in GnRH neuron firing rate in PNA vs control mice. Extracellular recordings of green fluorescent protein (GFP)-identified GnRH neurons were made 5 to 7 days after sham-surgery, ovariectomy (OVX), or, in adults, after OVX plus replacement of sub-male androgen levels with dihydrotestosterone implants (OVX + DHT). In 3-week-old mice, OVX did not affect GnRH neuron firing rate in either group. In adult controls, OVX increased GnRH neuron firing rate, which was further enhanced by DHT. In adult PNA mice, however, OVX decreased GnRH neuron firing rate, and DHT restored firing rate to sham-operated levels. In contrast to the differential effects of ovarian feedback on GnRH neuron firing rate, serum LH increased after OVX in both control and PNA mice and was not altered by DHT. Pituitary gene expression largely reflected changes expected with OVX, although in PNA but not control mice, DHT treatment increased Lhb expression. These results suggest prenatal androgen exposure programs marked changes in GnRH neuron regulation by homeostatic steroid feedback. PNA lowers GnRH neuron activity in low-steroid states (before puberty, OVX), and renders activity in adulthood dependent upon ongoing exposure to elevated ovarian androgens.


Assuntos
Androgênios/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Neurônios/fisiologia , Ovário/metabolismo , Animais , Di-Hidrotestosterona/farmacologia , Eletrofisiologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ovariectomia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Maturidade Sexual/fisiologia
7.
Methods Mol Biol ; 2041: 243-259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646494

RESUMO

Xenopus oocytes serve as a standard heterologous expression system for the study of various ligand-gated ion channels including ATP P2X receptors. Here we describe the whole-cell two-electrode voltage clamp and biotinylation/Western blotting techniques to investigate the functional properties and surface trafficking from P2X-expressing oocytes.


Assuntos
Trifosfato de Adenosina/metabolismo , Biotinilação/métodos , Membrana Celular/metabolismo , Eletrofisiologia/métodos , Oócitos/fisiologia , Receptores Purinérgicos P2X/fisiologia , Xenopus laevis/fisiologia , Animais , Western Blotting , Movimento Celular , Ativação do Canal Iônico , Oócitos/citologia , Técnicas de Patch-Clamp/métodos
8.
Methods Mol Biol ; 2041: 261-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646495

RESUMO

P2X receptors (P2XRs) are ligand-gated ion channels gated by extracellular adenosine 5'-triphosphate (ATP) and play a critical role in mediating ATP-induced purinergic signaling in physiological and pathological processes. Heterologous expression of P2XR in human embryonic kidney 293 (HEK293) cells and measurement of P2XR-mediated currents using patch-clamp recording technique have been widely used to study the biophysical and pharmacological properties of these receptors. Combination of electrophysiology with site-directed mutagenesis and structural information has shed light on the molecular basis for receptor activation and mechanisms of actions by receptor antagonists and modulators. It is anticipated that such methodologies will continue helping us to provide more mechanistic understanding of P2XRs and to test novel receptor antagonists and allosteric modulators for therapeutical purposes. In this chapter, we describe protocols of transiently or stably expressing the P2XR in HEK293 cells and measuring P2XR-mediated currents by using whole-cell recording.


Assuntos
Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Membrana Celular/metabolismo , Eletrofisiologia/métodos , Ativação do Canal Iônico/fisiologia , Técnicas de Patch-Clamp/métodos , Receptores Purinérgicos P2X/metabolismo , Animais , Células HEK293 , Humanos , Potenciais da Membrana , Receptores Purinérgicos P2X/genética , Transdução de Sinais
9.
Methods Mol Biol ; 2041: 301-309, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646498

RESUMO

This chapter details methods to express and modify ATP-gated P2X receptor channels so that they can be controlled using light. Following expression in cells, a photoswitchable tool compound can be used to covalently modify mutant P2X receptors, as previously demonstrated for homomeric P2X2 and P2X3 receptors, and heteromeric P2X2/3 receptors. Engineered P2X receptors can be rapidly and reversibly opened and closed by different wavelengths of light. Light-activated P2X receptors can be mutated further to impart ATP-insensitivity if required. This method offers control of specific P2X receptor channels with high spatiotemporal precision to study their roles in physiology and pathophysiology.


Assuntos
Trifosfato de Adenosina/metabolismo , Engenharia Genética/métodos , Ativação do Canal Iônico/fisiologia , Luz , Optogenética/métodos , Receptores Purinérgicos P2X2/fisiologia , Receptores Purinérgicos P2X3/fisiologia , Eletrofisiologia , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos da radiação , Mutação , Receptores Purinérgicos P2X2/química , Receptores Purinérgicos P2X2/efeitos da radiação , Receptores Purinérgicos P2X3/química , Receptores Purinérgicos P2X3/efeitos da radiação
11.
Oxid Med Cell Longev ; 2019: 5820839, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871552

RESUMO

Altered redox state modulates the expression levels of endothelial KCa2.3 and KCa3.1 (KCas) in normal pregnancy (NP) and preeclampsia (PE), thereby regulating vascular contractility. The mechanisms underlying KCas endocytosis and transportation remain unknown. We investigated the regulation of KCas expression in plasma membrane (PM) during NP and PE. Cultured human uterine artery endothelial cells were incubated in serum from normal nonpregnant women and women with NP or PE, or in oxidized LDL-, or lysophosphatidylcholine- (LPC-) containing a medium for 24 hours. NP serum elevated PM levels of KCas and reduced caveolin-1 and clathrin levels. PE serum, oxidized LDL, or LPC reduced PM levels of KCas and elevated caveolin-1, clathrin, Rab5c, and early endosome antigen-1 (EEA1) levels. Reduced KCas levels by PE serum or LPC were reversed by inhibition of caveolin-1, clathrin, or EEA1. Catalase and glutathione peroxidase 1 (GPX1) knockdown elevated PM-localized KCas levels and reduced caveolin-1 and clathrin levels. Elevated KCa2.3 levels upon catalase and GPX1 knockdown were reversed by PEG-catalase treatment. An H2O2 donor reduced clathrin and Rab5c. In contrast, elevated clathrin, caveolin-1, or colocalization of caveolin-1 with KCa3.1 by PE serum or LPC was reversed by NADPH oxidase inhibitors or antioxidants. A superoxide donor xanthine+xanthine oxidase elevated caveolin-1 or Rab5c levels. We concluded that KCas are endocytosed in a caveola- or a clathrin-dependent manner and transported in a Rab5c- and EEA1-dependent manner during pregnancy. The endocytosis and transportation processes may slow down via H2O2-mediated pathways in NP and may be accelerated via superoxide-mediated pathways in PE.


Assuntos
Células Endoteliais/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Pré-Eclâmpsia/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Animais , Biotinilação , Catalase/genética , Catalase/metabolismo , Eletrofisiologia , Feminino , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Immunoblotting , Imunoprecipitação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez
12.
Rev. neurol. (Ed. impr.) ; 69(11): 435-441, 1 dic., 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-187111

RESUMO

Introducción: Las ganglionopatías o neuronopatías sensoriales son enfermedades subagudas adquiridas del ganglio raquídeo dorsal, frecuentemente asociadas con trastornos disinmunes y paraneoplásicos, y agentes tóxicos. Los pacientes presentan alteración sensorial de distribución asimétrica y ataxia temprana. La identificación temprana es esencial, ya que pueden anunciar una neoplasia subyacente o una enfermedad autoinmune. Objetivo. Estudiar las asimetrías del potencial de acción nervioso sensitivo (SNAP) de pares de nervios y la relación de amplitud del potencial de acción sensitivomotor del nervio cubital (USMAR) con estudios electroneurofisiológicos seriados para el diagnóstico precoz de las ganglionopatías sensoriales. Pacientes y métodos: Se estudió retrospectivamente a siete pacientes con ganglionopatías sensoriales con estudios electroneurofisiológicos: cuatro casos paraneoplásicos con positividad para anticuerpos onconeuronales, uno asociado al síndrome de Sjögren y dos idiopáticos. Resultados: Los estudios electroneurofisiológicos mostraron afectación sensorial axonal en todos los casos, con asimetría mayor del 50% en la amplitud de SNAP en dos pares de nervios en cuatro casos y motor normal con USMAR < 0,71 en cinco casos. Los estudios electroneurofisiológicos seriados fueron esenciales en el diagnóstico de dos casos en el inicio de la enfermedad con síntomas sensoriales leves. Conclusiones: Este trabajo evidencia la importancia del estudio de asimetrías en la amplitud del SNAP de pares de nervios, la USMAR y los estudios electroneurofisiológicos seriados en el diagnóstico temprano de ganglionopatías sensoriales, para la consiguiente identificación de los anticuerpos disinmunes y onconeuronales con afectación del sistema nervioso periférico y la búsqueda de neoplasia oculta


Introduction: Sensory ganglionopathies or sensory neuronopathies are subacute acquired diseases of the dorsal root ganglion, frequently associated with disinmune, paraneoplastic and toxic agents. Patients present sensory alteration of asymmetric distribution and early ataxia. Early identification is essential, as they may announce an underlying neoplasia or autoimmune disease. Aim: To study asymmetries of the sensory nervous action potential (SNAP) of nerve pairs and the relationship amplitude of ulnar sensory/ulnar motor potential (USMAR) with serial electroneurophysiological studies for the early diagnosis of sensory ganglionopathies. Patients and methods: Six patients with sensory ganglionopathies were retrospectively studied with electroneurophysiological studies: four paraneoplastic cases with positivity for onconeuronal antibodies, one associated with Sjögren’s syndrome and two idiopathic. Results: Electroneurophysiological studies showed axonal sensory involvement in all cases, with asymmetry > 50% in SNAP amplitude in two pairs of nerves in four cases and normal motor with USMAR < 0.71 in five cases. Serial electroneurophysiological studies were essential in the diagnosis of two cases in the beginning of the disease with mild sensory symptoms. Conclusions: This work evidences the importance of the study of asymmetries in the amplitude of the SNAP of nerve pairs, the USMAR and the serial electroneurophysiological studies in the early diagnosis of sensory ganglionopathies, to further identification of the disinmune and onconeuronal associated antibodies with the nervous system affection to search for hidden neoplasia


Assuntos
Humanos , Polineuropatia Paraneoplásica/diagnóstico , Diagnóstico Precoce , Doenças do Sistema Nervoso/patologia , Polineuropatia Paraneoplásica/fisiopatologia , Estudos Retrospectivos , Eletrofisiologia/métodos , Diagnóstico Diferencial , Eletromiografia/instrumentação
13.
Nat Methods ; 16(11): 1076, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31673157
14.
Rev Esp Cardiol (Engl Ed) ; 72(12): 1054-1064, 2019 Dec.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31727564

RESUMO

INTRODUCTION AND OBJECTIVES: This article presents the data corresponding to automated implantable cardioverter-defibrillator (ICD) implants in Spain reported to the Spanish Registry in 2018. METHODS: The data in this registry include both primary implants and generator replacements and were gathered from a data collection sheet voluntarily completed by implantation centers. RESULTS: In 2018, 6421 implant sheets were received compared with 7077 reported by Eucomed (European Confederation of Medical Suppliers Associations). This represents data on 90.7% of the devices implanted in Spain. Compliance ranged between 99.6% for the field "name of the implanting hospital" and 12.4% for "population of residence". A total of 173 hospitals reported their data to the registry, representing a slight decrease compared with hospitals participating in 2017 (n=181). CONCLUSIONS: After the reduction in ICD implants in 2017, the number of implants increased in 2018, with the highest number of ICDs implanted in Spain. The total number of implants remains much lower than the European Union average, with substantial differences between autonomous communities.


Assuntos
Arritmias Cardíacas/terapia , Cardiologia , Desfibriladores Implantáveis/estatística & dados numéricos , Eletrofisiologia/estatística & dados numéricos , Sistema de Registros , Sociedades Médicas , Coleta de Dados , Feminino , Humanos , Masculino , Estudos Retrospectivos , Espanha
15.
Nat Commun ; 10(1): 4785, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690797

RESUMO

The human brain undergoes significant functional and structural changes in the first decades of life, as the foundations for human cognition are laid down. However, non-invasive imaging techniques to investigate brain function throughout neurodevelopment are limited due to growth in head-size with age and substantial head movement in young participants. Experimental designs to probe brain function are also limited by the unnatural environment typical brain imaging systems impose. However, developments in quantum technology allowed fabrication of a new generation of wearable magnetoencephalography (MEG) technology with the potential to revolutionise electrophysiological measures of brain activity. Here we demonstrate a lifespan-compliant MEG system, showing recordings of high fidelity data in toddlers, young children, teenagers and adults. We show how this system can support new types of experimental paradigm involving naturalistic learning. This work reveals a new approach to functional imaging, providing a robust platform for investigation of neurodevelopment in health and disease.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Magnetoencefalografia/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Cognição/fisiologia , Eletrofisiologia , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
16.
Nat Commun ; 10(1): 4671, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604922

RESUMO

Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX.  Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.


Assuntos
Cardiolipinas/metabolismo , Ácidos Graxos/metabolismo , Subunidade alfa da Proteína Mitocondrial Trifuncional/fisiologia , Miócitos Cardíacos/metabolismo , Cálcio/metabolismo , Linhagem Celular , Eletrofisiologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/fisiologia , Células-Tronco Embrionárias Humanas , Humanos , MicroRNAs/fisiologia , Mitocôndrias/fisiologia , Proteína Mitocondrial Trifuncional/deficiência , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Oxirredução , Técnicas de Patch-Clamp , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/fisiologia
17.
PLoS Biol ; 17(10): e3000449, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31574079

RESUMO

Humans and other animals effortlessly identify natural sounds and categorize them into behaviorally relevant categories. Yet, the acoustic features and neural transformations that enable sound recognition and the formation of perceptual categories are largely unknown. Here, using multichannel neural recordings in the auditory midbrain of unanesthetized female rabbits, we first demonstrate that neural ensemble activity in the auditory midbrain displays highly structured correlations that vary with distinct natural sound stimuli. These stimulus-driven correlations can be used to accurately identify individual sounds using single-response trials, even when the sounds do not differ in their spectral content. Combining neural recordings and an auditory model, we then show how correlations between frequency-organized auditory channels can contribute to discrimination of not just individual sounds but sound categories. For both the model and neural data, spectral and temporal correlations achieved similar categorization performance and appear to contribute equally. Moreover, both the neural and model classifiers achieve their best task performance when they accumulate evidence over a time frame of approximately 1-2 seconds, mirroring human perceptual trends. These results together suggest that time-frequency correlations in sounds may be reflected in the correlations between auditory midbrain ensembles and that these correlations may play an important role in the identification and categorization of natural sounds.


Assuntos
Potenciais de Ação/fisiologia , Mesencéfalo/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Estimulação Acústica/métodos , Animais , Eletrodos Implantados , Eletrofisiologia , Feminino , Mesencéfalo/anatomia & histologia , Rede Nervosa/anatomia & histologia , Neurônios/citologia , Coelhos , Som , Técnicas Estereotáxicas
18.
Parasit Vectors ; 12(1): 486, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619276

RESUMO

BACKGROUND: In the animal production sector, enteritis is responsible for serious economic losses, and intestinal parasitism is a major stress factor leading to malnutrition and lowered performance and animal production efficiency. The effect of enteric parasites on the gut function of teleost fish, which represent the most ancient bony vertebrates, is far from being understood. The intestinal myxozoan parasite Enteromyxum leei dwells between gut epithelial cells and causes severe enteritis in gilthead sea bream (Sparus aurata), anorexia, cachexia, growth impairment, reduced marketability and increased mortality. METHODS: This study aimed to outline the gut failure in this fish-parasite model using a multifaceted approach and to find and validate non-lethal serum markers of gut barrier dysfunction. Intestinal integrity was studied in parasitized and non-parasitized fish by immunohistochemistry with specific markers for cellular adhesion (E-cadherin) and tight junctions (Tjp1 and Cldn3) and by functional studies of permeability (oral administration of FITC-dextran) and electrophysiology (Ussing chambers). Serum samples from parasitized and non-parasitized fish were analyzed using non-targeted metabolomics and some significantly altered metabolites were selected to be validated using commercial kits. RESULTS: The immunodetection of Tjp1 and Cldn3 was significantly lower in the intestine of parasitized fish, while no strong differences were found in E-cadherin. Parasitized fish showed a significant increase in paracellular uptake measured by FITC-dextran detection in serum. Electrophysiology showed a decrease in transepithelial resistance in infected animals, which showed a diarrheic profile. Serum metabolomics revealed 3702 ions, from which the differential expression of 20 identified compounds significantly separated control from infected groups in multivariate analyses. Of these compounds, serum inosine (decreased) and creatine (increased) were identified as relevant and validated with commercial kits. CONCLUSIONS: The results demonstrate the disruption of tight junctions and the loss of gut barrier function, a metabolomic profile of absorption dysfunction and anorexia, which further outline the pathophysiological effects of E. leei.


Assuntos
Enterite/veterinária , Doenças dos Peixes/parasitologia , Metabolômica , Myxozoa/patogenicidade , Doenças Parasitárias em Animais/parasitologia , Dourada/parasitologia , Animais , Caderinas/metabolismo , Claudina-3/metabolismo , Creatina/sangue , Dextranos/metabolismo , Modelos Animais de Doenças , Eletrofisiologia , Enterite/parasitologia , Ensaio de Imunoadsorção Enzimática , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Imuno-Histoquímica , Inosina/sangue , Mucosa Intestinal/metabolismo , Intestinos/parasitologia , Intestinos/patologia , Doenças Parasitárias em Animais/patologia , Permeabilidade , Proteína da Zônula de Oclusão-1/metabolismo
20.
Cell Physiol Biochem ; 53(3): 508-517, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502429

RESUMO

BACKGROUND/AIMS: Glucose transporter 9 (GLUT9/SLC2A9) is the major regulator of uric acid homeostasis in humans. Hyperuricemia due to impaired regulation by GLUT9 in pregnancy is closely associated with preeclampsia. While GLUT9 is expressed in two alternative splice variants, GLUT9a and GLUT9b, with different subcellular localizations, no functional differences of the two splice variants are known to date. The aim of this study was to investigate the function of both GLUT9 isoforms. METHODS: To characterize the different pharmacological properties of GLUT9a and GLUT9b electrophysiological studies of these isoforms and their modified variants, i.e. NmodGLUT9a and NmodGLUT9b, were performed using a Xenopus laevis oocytes model. Currents were measured by an electrode voltage clamp system. RESULTS: Functional experiments unveiled that uric acid transport mediated by GLUT9a but not GLUT9b is chloride-dependent: Replacing chloride by different anions resulted in a 3.43±0.63-fold increase of GLUT9a- but not GLUT9b-mediated currents. However, replacement by iodide resulted in a loss of current for GLUT9a but not GLUT9b. Iodide inhibits GLUT9a with an IC50 of 35.1±6.7µM. Modification of the N-terminal domain leads to a shift of the iodide IC50 to 1200±228µM. Using molecular docking studies, we identified two positively charged residues H23 and R31 in the N-terminal domain of hGLUT9a which can explain the observed functional differences. CONCLUSION: To the best of our knowledge, this is the first study showing that the N-terminal domain of hGLUT9a has a unique regulatory function and the potential to interact with small negatively charged ions like iodide. These findings may have significant implications in our understanding of hyperuricemia-associated diseases, specifically during pregnancy.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Pré-Eclâmpsia/sangue , Processamento Alternativo , Eletrofisiologia , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/metabolismo , Iodetos/metabolismo , Simulação de Acoplamento Molecular , Gravidez , Ácido Úrico/sangue
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