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1.
Cell ; 186(22): 4898-4919.e25, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37827155

RESUMEN

Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA's suppression of disease-associated repeat expansions, which may extend to other DNA processes.


Asunto(s)
Proteína de Replicación A , Expansión de Repetición de Trinucleótido , Animales , Humanos , Ratones , ADN/genética , Reparación de la Incompatibilidad de ADN , Enfermedad de Huntington/genética , Proteínas/genética , Ataxias Espinocerebelosas/genética , Proteína de Replicación A/metabolismo
2.
Proc Natl Acad Sci U S A ; 121(40): e2318098121, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39331414

RESUMEN

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.


Asunto(s)
Proteína Huntingtina , Enfermedad de Huntington , Poli Adenosina Difosfato Ribosa , Transducción de Señal , Humanos , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Proteína Huntingtina/metabolismo , Proteína Huntingtina/genética , Poli Adenosina Difosfato Ribosa/metabolismo , Daño del ADN , Neuronas/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Fibroblastos/metabolismo , Reparación del ADN
3.
Genes Dev ; 32(5-6): 341-346, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29563185

RESUMEN

The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (HOXA) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10OM-LZ and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L-AF10 complex and may be involved in the regulation of the HOXA gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against MLL-rearranged leukemia.


Asunto(s)
Transformación Celular Neoplásica/patología , Metiltransferasas , Modelos Moleculares , Proteína de la Leucemia Mieloide-Linfoide , Factores de Transcripción , Cristalización , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina , Proteínas de Homeodominio/genética , Humanos , Metiltransferasas/química , Metiltransferasas/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/química , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Unión Proteica , Dominios Proteicos , Estructura Cuaternaria de Proteína , Relación Estructura-Actividad , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Zinc/química
4.
J Biol Chem ; 300(10): 107727, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39214302

RESUMEN

Ubiquitin-specific proteases (USPs) are a family of multi-domain deubiquitinases (DUBs) with variable architectures, some containing regulatory auxiliary domains. Among the USP family, all occurrences of intramolecular regulation presently known are autoactivating. USP8 remains the sole exception as its putative WW-like domain, conserved only in vertebrate orthologs, is autoinhibitory. Here, we present a comprehensive structure-function analysis describing the autoinhibition of USP8 and provide evidence of the physical interaction between the WW-like and catalytic domains. The solution structure of full-length USP8 reveals an extended, monomeric conformation. Coupled with DUB assays, the WW-like domain is confirmed to be the minimal autoinhibitory unit. Strikingly, autoinhibition is only observed with the WW-like domain in cis and depends on the length of the linker tethering it to the catalytic domain. Modeling of the WW:CD complex structure and mutagenesis of interface residues suggests a novel binding site in the S1 pocket. To investigate the interplay between phosphorylation and USP8 autoinhibition, we identify AMP-activated protein kinase as a highly selective modifier of S718 in the 14-3-3 binding motif. We show that 14-3-3γ binding to phosphorylated USP8 potentiates autoinhibition in a WW-like domain-dependent manner by stabilizing an autoinhibited conformation. These findings provide mechanistic details on the autoregulation of USP8 and shed light on its evolutionary significance.

5.
PLoS Comput Biol ; 19(7): e1011230, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37498959

RESUMEN

The Canadian Open Neuroscience Platform (CONP) takes a multifaceted approach to enabling open neuroscience, aiming to make research, data, and tools accessible to everyone, with the ultimate objective of accelerating discovery. Its core infrastructure is the CONP Portal, a repository with a decentralized design, where datasets and analysis tools across disparate platforms can be browsed, searched, accessed, and shared in accordance with FAIR principles. Another key piece of CONP infrastructure is NeuroLibre, a preprint server capable of creating and hosting executable and fully reproducible scientific publications that embed text, figures, and code. As part of its holistic approach, the CONP has also constructed frameworks and guidance for ethics and data governance, provided support and developed resources to help train the next generation of neuroscientists, and has fostered and grown an engaged community through outreach and communications. In this manuscript, we provide a high-level overview of this multipronged platform and its vision of lowering the barriers to the practice of open neuroscience and yielding the associated benefits for both individual researchers and the wider community.


Asunto(s)
Neurociencias , Canadá , Publicaciones , Comunicación
6.
J Chem Inf Model ; 64(13): 5344-5355, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38916159

RESUMEN

We herewith applied a priori a generic hit identification method (POEM) for difficult targets of known three-dimensional structure, relying on the simple knowledge of physicochemical and topological properties of a user-selected cavity. Searching for local similarity to a set of fragment-bound protein microenvironments of known structure, a point cloud registration algorithm is first applied to align known subpockets to the target cavity. The resulting alignment then permits us to directly pose the corresponding seed fragments in a target cavity space not typically amenable to classical docking approaches. Last, linking potentially connectable atoms by a deep generative linker enables full ligand enumeration. When applied to the WD40 repeat (WDR) central cavity of leucine-rich repeat kinase 2 (LRRK2), an unprecedented binding site, POEM was able to quickly propose 94 potential hits, five of which were subsequently confirmed to bind in vitro to LRRK2-WDR.


Asunto(s)
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Simulación del Acoplamiento Molecular , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/química , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Sitios de Unión , Dominios Proteicos , Humanos , Ligandos , Unión Proteica , Repeticiones WD40 , Algoritmos
7.
Cell Mol Life Sci ; 80(2): 45, 2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36651994

RESUMEN

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder resulting from a CAG expansion in the huntingtin (HTT) gene, which leads to the production and accumulation of mutant huntingtin (mHTT). While primarily considered a disorder of the central nervous system, multiple changes have been described to occur throughout the body, including activation of the immune system. In other neurodegenerative disorders, activation of the immune system has been shown to include the production of antibodies against disease-associated pathological proteins. However, the existence of mHTT-targeted antibodies has never been reported. In this study, we assessed the presence and titer of antibodies recognizing HTT/mHTT in patients with HD (n = 66) and age- and gender-matched healthy controls (n = 66) using a combination of Western blotting and ELISA. Together, these analyses revealed that antibodies capable of recognizing HTT/mHTT were detectable in the plasma samples of all participants, including healthy controls. When antibody levels were monitored at different disease stages, it was observed that antibodies against full-length mHTT were highest in patients with severe disease while antibodies against HTTExon1 were elevated in patients with mild disease. Combined, these results suggest that antibodies detecting different forms of mHTT peak at different disease stages.


Asunto(s)
Enfermedad de Huntington , Enfermedades Neurodegenerativas , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/metabolismo , Anticuerpos
8.
PLoS Biol ; 17(1): e3000120, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30689629

RESUMEN

Transparency lies at the heart of the open lab notebook movement. Open notebook scientists publish laboratory experiments and findings in the public domain in real time, without restrictions or omissions. Research on rare diseases is especially amenable to the open notebook model because it can both increase scientific impact and serve as a mechanism to engage patient groups in the scientific process. Here, I outline and describe my own success with my open notebook project, LabScribbles, as well as other efforts included in the openlabnotebooks.org initiative.


Asunto(s)
Difusión de la Información/ética , Difusión de la Información/métodos , Acceso a la Información/ética , Humanos , Laboratorios , Publicación de Acceso Abierto/ética , Publicación de Acceso Abierto/tendencias , Enfermedades Raras , Programas Informáticos
10.
Eur Arch Otorhinolaryngol ; 278(5): 1595-1604, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-32740720

RESUMEN

PURPOSE: COVID-19 patients requiring mechanical ventilation can overwhelm existing bed capacity. We aimed to better understand the factors that influence the trajectory of tracheostomy care in this population to facilitate capacity planning and improve outcomes. METHODS: We conducted an observational cohort study of patients in a high-volume centre in the worst-affected region of the UK including all patients that underwent tracheostomy for COVID-19 pneumonitis ventilatory wean from 1st March 2020 to 10th May 2020. The primary outcome was time from insertion to decannulation. The analysis utilised Cox regression to account for patients that are still progressing through their tracheostomy pathway. RESULTS: At the point of analysis, a median 21 days (IQR 15-28) post-tracheostomy and 39 days (IQR 32-45) post-intubation, 35/69 (57.4%) patients had been decannulated a median of 17 days (IQR 12-20.5) post-insertion. The overall median age was 55 (IQR 48-61) with a male-to-female ratio of 2:1. In Cox regression analysis, FiO2 at tracheostomy ≥ 0.4 (HR 1.80; 95% CI 0.89-3.60; p = 0.048) and last pre-tracheostomy peak cough flow (HR 2.27; 95% CI 1.78-4.45; p = 0.001) were independent variables associated with prolonged time to decannulation. CONCLUSION: Higher FiO2 at tracheostomy and higher pre-tracheostomy peak cough flow are associated with increased delay in COVID-19 tracheostomy patient decannulation. These finding comprise the most comprehensive report of COVID-19 tracheostomy decannulation to date and will assist service planning for future peaks of this pandemic.


Asunto(s)
COVID-19 , Traqueostomía , Remoción de Dispositivos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Respiración Artificial , SARS-CoV-2
11.
J Biol Chem ; 294(17): 6986-7001, 2019 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-30842263

RESUMEN

The gene mutated in individuals with Huntington's disease (HD) encodes the 348-kDa huntingtin (HTT) protein. Pathogenic HD CAG-expansion mutations create a polyglutamine (polyQ) tract at the N terminus of HTT that expands above a critical threshold of ∼35 glutamine residues. The effect of these HD mutations on HTT is not well understood, in part because it is difficult to carry out biochemical, biophysical, and structural studies of this large protein. To facilitate such studies, here we have generated expression constructs for the scalable production of HTT in multiple eukaryotic expression systems. Our set of HTT expression clones comprised both N- and C-terminally FLAG-tagged HTT constructs with polyQ lengths representative of the general population, HD patients, and juvenile HD patients, as well as the more extreme polyQ expansions used in some HD tissue and animal models. Our expression system yielded milligram quantities of pure recombinant HTT protein, including many of the previously mapped post-translational modifications. We characterized both apo and HTT-HTT-associated protein 40 (HAP40) complex samples produced with this HD resource, demonstrating that this toolkit can be used to generate physiologically meaningful HTT complexes. We further demonstrate that these resources can produce sufficient material for protein-intensive experiments, such as small-angle X-ray scattering, providing biochemical insight into full-length HTT protein structure. The work outlined and the tools generated here lay a foundation for further biochemical and structural work on the HTT protein and for studying its functional interactions with other biomolecules.


Asunto(s)
Expresión Génica , Proteína Huntingtina/genética , Mutación , Animales , Clonación Molecular , Humanos , Proteína Huntingtina/metabolismo , Fosforilación , Procesamiento Proteico-Postraduccional , Spodoptera
12.
Thorax ; 73(1): 62-69, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28971973

RESUMEN

BACKGROUND: Respiratory management of obesity hypoventilation syndrome (OHS) focusses on the control of sleep-disordered breathing rather than the treatment of obesity. Currently, there are no data from randomised trials of weight loss targeted rehabilitation programmes for patients with OHS. INTERVENTION: A 3-month multimodal hybrid inpatient-outpatient motivation, exercise and nutrition rehabilitation programme, in addition to non invasive ventilation (NIV), would result in greater per cent weight loss compared with standard care. METHODS: A single-centre pilot randomised controlled trial allocated patients to either standard care or standard care plus rehabilitation. Primary outcome was per cent weight loss at 12 months with secondary exploratory outcomes of weight loss, exercise capacity and health-related quality of life (HRQOL) at the end of the rehabilitation programme to assess the intervention effect. RESULTS: Thirty-seven patients (11 male, 59.8±12.7 years) with a body mass index of 51.1±7.7 kg/m2 were randomised. At 12 months, there was no between-group difference in per cent weight loss (mean difference -5.9% (95% CI -14.4% to 2.7%; p=0.17)). At 3 months, there was a greater per cent weight loss (mean difference -5% (95% CI -8.3% to -1.4%; p=0.007)), increased exercise capacity (6 min walk test 60 m (95% CI 29.5 to 214.5) vs 20 m (95% CI 11.5 to 81.3); p=0.036) and HRQL (mean difference SF-36 general health score (10 (95% CI 5 to 21.3) vs 0 (95% CI -5 to 10); p=0.02)) in the rehabilitation group. CONCLUSION: In patients with OHS, a 3-month comprehensive rehabilitation programme, in addition to NIV, resulted in improved weight loss, exercise capacity and QOL at the end of the rehabilitation period, but these effects were not demonstrated at 12 months, in part, due to the limited retention of patients at 12 months. TRIAL REGISTRATION NUMBER: Pre-results; NCT01483716.


Asunto(s)
Terapia por Ejercicio , Terapia Nutricional , Síndrome de Hipoventilación por Obesidad/rehabilitación , Anciano , Tolerancia al Ejercicio , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Calidad de Vida , Resultado del Tratamiento , Pérdida de Peso
13.
Acta Pharmacol Sin ; 39(5): 754-769, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29620053

RESUMEN

Many neurodegenerative diseases are characterized by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons. Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular, the ubiquitin-proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides new insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.


Asunto(s)
Proteína Huntingtina/metabolismo , Enfermedad de Huntington/tratamiento farmacológico , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Proteostasis/efectos de los fármacos , Animales , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/fisiología , Enfermedad de Huntington/fisiopatología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Expansión de Repetición de Trinucleótido
14.
J Biol Chem ; 291(33): 17283-92, 2016 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-27255711

RESUMEN

Ubiquitin-specific proteases (USPs) USP15 and USP4 belong to a subset of USPs featuring an N-terminal tandem domain in USP (DUSP) and ubiquitin-like (UBL) domain. Squamous cell carcinoma antigen recognized by T-cell 3 (SART3), a spliceosome recycling factor, binds to the DUSP-UBL domain of USP15 and USP4, recruiting them to the nucleus from the cytosol to control deubiquitination of histone H2B and spliceosomal proteins, respectively. To provide structural insight, we solved crystal structures of SART3 in the apo-form and in complex with the DUSP-UBL domain of USP15 at 2.0 and 3.0 Å, respectively. Structural analysis reveals SART3 contains 12 half-a-tetratricopeptide (HAT) repeats, organized into two subdomains, HAT-N and HAT-C. SART3 dimerizes through the concave surface of HAT-C, whereas the HAT-C convex surface binds USP15 in a novel bipartite mode. Isothermal titration calorimetry measurements and mutagenesis analysis confirmed key residues of USP15 involved in the interaction and indicated USP15 binds 20-fold stronger than USP4.


Asunto(s)
Antígenos de Neoplasias/química , Proteínas de Unión al ARN/química , Proteasas Ubiquitina-Específicas/química , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Cristalografía por Rayos X , Humanos , Unión Proteica , Estructura Cuaternaria de Proteína , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Secuencias Repetitivas de Aminoácido , Relación Estructura-Actividad , Ubiquitina Tiolesterasa/química , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo
15.
Biochim Biophys Acta Gen Subj ; 1861(1 Pt A): 3095-3105, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27776223

RESUMEN

BACKGROUND: Seven in absentia homologs (SIAHs) comprise a family of highly conserved E3 ubiquitin ligases that play an important role in regulating signalling pathways in tumorigenesis, including the DNA damage repair and hypoxia response pathways. SIAH1 and SIAH2 have been found to function as a tumour repressor and a proto-oncogene, respectively, despite the high sequence identity of their substrate binding domains (SBDs). Ubiquitin-specific protease USP19 is a deubiquitinase that forms a complex with SIAHs and counteracts the ligase function. Much effort has been made to find selective inhibitors of the SIAHs E3 ligases. Menadione was reported to inhibit SIAH2 specifically. METHODS: We used X-ray crystallography, peptide array, bioinformatic analysis, and biophysical techniques to characterize the structure and interaction of SIAHs with deubiquitinases and literature reported compounds. RESULTS: We solved the crystal structures of SIAH1 in complex with a USP19 peptide and of the apo form SIAH2. Phylogenetic analysis revealed the SIAH/USP19 complex is conserved in evolution. We demonstrated that menadione destabilizes both SIAH1 and SIAH2 non-specifically through covalent modification. CONCLUSIONS: The SBDs of SIAH E3 ligases are structurally similar with a subtle stability difference. USP19 is the only deubiquitinase that directly binds to SIAHs through the substrate binding pocket. Menadione is not a specific inhibitor for SIAH2. GENERAL SIGNIFICANCE: The crystallographic models provide structural insights into the substrate binding of the SIAH family E3 ubiquitin ligases that are critically involved in regulating cancer-related pathways. Our results suggest caution should be taken when using menadione as a specific SIAH2 inhibitor.


Asunto(s)
Proteínas Nucleares/química , Ubiquitina-Proteína Ligasas/química , Secuencia de Aminoácidos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Cristalografía por Rayos X , Endopeptidasas/metabolismo , Evolución Molecular , Humanos , Modelos Moleculares , Proteínas Nucleares/antagonistas & inhibidores , Filogenia , Unión Proteica , Dominios Proteicos , Estabilidad Proteica/efectos de los fármacos , Estructura Secundaria de Proteína , Proto-Oncogenes Mas , Especificidad por Sustrato/efectos de los fármacos , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Vitamina K 3/farmacología
16.
Neuroimage ; 125: 13-24, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26455899

RESUMEN

Recognising one's self, vs. others, is a key component of self-awareness, crucial for social interactions. Here we investigated whether processing self-face and self-body images can be explained by the brain's prediction of sensory events, based on regularities in the given context. We measured evoked cortical responses while participants observed alternating sequences of self-face or other-face images (experiment 1) and self-body or other-body images (experiment 2), which were embedded in an identity-irrelevant task. In experiment 1, the expected sequences were violated by deviant morphed images, which contained 33%, 66% or 100% of the self-face when the other's face was expected (and vice versa). In experiment 2, the anticipated sequences were violated by deviant images of the self when the other's image was expected (and vice versa), or by two deviant images composed of pictures of the self-face attached to the other's body, or the other's face attached to the self-body. This manipulation allowed control of the prediction error associated with the self or the other's image. Deviant self-images (but not deviant images of the other) elicited a visual mismatch response (vMMR)--a cortical index of violations of regularity. This was source localised to face and body related visual, sensorimotor and limbic areas and had amplitude proportional to the amount of deviance from the self-image. We provide novel evidence that self-processing can be described by the brain's prediction error system, which accounts for self-bias in visual processing. These findings are discussed in the light of recent predictive coding models of self-processing.


Asunto(s)
Encéfalo/fisiología , Reconocimiento en Psicología/fisiología , Autoimagen , Adulto , Electroencefalografía , Femenino , Humanos , Masculino , Procesamiento de Señales Asistido por Computador , Adulto Joven
17.
Mol Cell Biochem ; 412(1-2): 181-95, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26715133

RESUMEN

Myogenic satellite cells are stem cells responsible for muscle growth and regeneration. MicroRNAs (miRNAs) play significant roles in regulating numerous cellular processes. Two genes essential to satellite cell function are syndecan-4 and glypican-1. To determine if miRNAs influence myogenic satellite cell function, one miRNA predicted to bind syndecan-4 (miR-128) and two predicted to bind glypican-1 (miR-24 and miR-16) were inhibited in vitro by transfection of inhibitors targeting each miRNA. Inhibition of these miRNAs differentially affected the expression of syndecan-4, glypican-1, and myogenic regulatory factors myoD and myogenin. Inhibition of miR-16 reduced proliferation of satellite cells at 72 h. Inhibition of miR-128 and miR-24 did not affect proliferation. Inhibition of miRNAs reduced differentiation of satellite cells into myotubes at 48 and 72 h except for miR-16, which only affected differentiation at 72 h. Inhibition of all three miRNAs decreased myotube width at 24 h of differentiation and increased myotube width at 48 h of differentiation. Inhibiting these miRNAs also increased the number of nuclei per myotube at 72 h of differentiation. These data demonstrate individual miRNAs regulate genes essential for myogenic satellite cell proliferation and differentiation.


Asunto(s)
Diferenciación Celular/fisiología , Proliferación Celular/fisiología , MicroARNs/fisiología , Células Satélite del Músculo Esquelético/citología , Animales , Células Cultivadas , Glipicanos/genética , Proteína MioD/genética , Miogenina/genética , Células Satélite del Músculo Esquelético/metabolismo , Sindecano-4/genética , Pavos
18.
Dev Biol ; 392(2): 393-403, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-24858486

RESUMEN

Damage of the zebrafish retina triggers a spontaneous regeneration response that is initiated by Müller Glia (MG) dedifferentiation and asymmetric cell division to produce multipotent progenitor cells. Subsequent expansion of the progenitor pool by proliferation is critical for retina regeneration. Pax6b expression in the progenitor cells is necessary for their proliferation, but exact regulation of its expression is unclear. Here, we show that miR-203 is downregulated during regeneration in proliferating progenitor cells. Elevated miR-203 levels inhibit progenitor cell expansion without affecting MG dedifferentiation or progenitor cell generation. Using GFP-reporter assays and gain and loss of function experiments in the retina, we show that miR-203 expression must be suppressed to allow pax6b expression and subsequent progenitor cell proliferation.


Asunto(s)
Proliferación Celular , Regulación de la Expresión Génica/genética , MicroARNs/metabolismo , Regeneración/fisiología , Retina/fisiología , Células Madre/fisiología , Pez Cebra/fisiología , Animales , Western Blotting , Clonación Molecular , Electroporación , Citometría de Flujo , Inmunohistoquímica , MicroARNs/genética , Microinyecciones , Morfolinos/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no Paramétricas , Pez Cebra/genética
19.
Thorax ; 70(12): 1123-30, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26194996

RESUMEN

RATIONALE: Hospitalised patients with acute exacerbation of COPD may deteriorate despite treatment, with early readmission being common. OBJECTIVES: To investigate whether neural respiratory drive, measured using second intercostal space parasternal muscle electromyography (EMGpara), would identify worsening dyspnoea and physician-defined inpatient clinical deterioration, and predict early readmission. METHODS: Patients admitted to a single-site university hospital with exacerbation of COPD were enrolled. Spirometry, inspiratory capacity (IC), EMGpara, routine physiological parameters, modified early warning score (MEWS), modified Borg scale for dyspnoea and physician-defined episodes of deterioration were recorded daily until discharge. Readmissions at 14 and 28 days post discharge were recorded. MEASUREMENTS AND MAIN RESULTS: 120 patients were recruited (age 70 ± 9 years, forced expiratory volume in 1 s (FEV1) of 30.5 ± 11.2%). Worsening dyspnoea, defined as at least one-point increase in Borg scale, was associated with increases in EMGpara%max and MEWS, whereas an increase in EMGpara%max alone was associated with physician-defined inpatient clinical deterioration. Admission-to-discharge change (Δ) in the normalised value of EMGpara (ΔEMGpara%max) was inversely correlated with ΔFEV1 (r = -0.38, p < 0.001) and ΔIC (r = -0.44, p < 0.001). ΔEMGpara%max predicted 14-day readmission (OR 1.13, 95% 1.03 to 1.23) in the whole cohort and 28-day readmission in patients under 85 years (OR 1.09, 95% CI 1.01 to 1.18). Age (OR 1.08, 95% CI 1.03 to 1.14) and 12-month admission frequency (OR 1.29, 1.01 to 1.66), also predicted 28-day readmission in the whole cohort. CONCLUSIONS: Measurement of neural respiratory drive by EMGpara represents a novel physiological biomarker that may be helpful in detecting inpatient clinical deterioration and identifying the risk of early readmission among patients with exacerbations of COPD. TRIAL REGISTRATION: NCT01361451.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Anciano , Progresión de la Enfermedad , Electromiografía , Femenino , Volumen Espiratorio Forzado , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Curva ROC , Espirometría
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