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1.
Cell ; 180(3): 568-584.e23, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-31981491

RESUMEN

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.


Asunto(s)
Trastorno Autístico/genética , Corteza Cerebral/crecimiento & desarrollo , Secuenciación del Exoma/métodos , Regulación del Desarrollo de la Expresión Génica , Neurobiología/métodos , Estudios de Casos y Controles , Linaje de la Célula , Estudios de Cohortes , Exoma , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mutación Missense , Neuronas/metabolismo , Fenotipo , Factores Sexuales , Análisis de la Célula Individual/métodos
2.
Am J Hum Genet ; 111(8): 1544-1558, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39079538

RESUMEN

Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.


Asunto(s)
Trastorno Autístico , Encéfalo , Cromosomas Humanos Par 15 , Variaciones en el Número de Copia de ADN , Humanos , Cromosomas Humanos Par 15/genética , Encéfalo/metabolismo , Encéfalo/patología , Masculino , Trastorno Autístico/genética , Femenino , Trastorno del Espectro Autista/genética , Duplicación Cromosómica/genética , Cromatina/genética , Cromatina/metabolismo , Trisomía/genética , Niño , Neuronas/metabolismo , Neuronas/patología , Aberraciones Cromosómicas , Discapacidad Intelectual
3.
Proc Natl Acad Sci U S A ; 120(23): e2300052120, 2023 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-37252957

RESUMEN

Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type-specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type-specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition.


Asunto(s)
Síndrome del Cromosoma X Frágil , Humanos , Síndrome del Cromosoma X Frágil/patología , Temblor/genética , Expansión de Repetición de Trinucleótido , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Ataxia/genética , Ataxia/patología , Encéfalo/metabolismo , Astrocitos/metabolismo
4.
Annu Rev Genomics Hum Genet ; 21: 289-304, 2020 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-32396753

RESUMEN

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants-causing loss-of-function or missense changes-have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants-both inherited and de novo-have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.


Asunto(s)
Trastorno Autístico/genética , Trastorno Autístico/patología , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Humanos
5.
Am J Hum Genet ; 105(5): 1048-1056, 2019 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-31668703

RESUMEN

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.


Asunto(s)
Proteínas Ligadas a GPI/genética , Mutación Missense/genética , Netrinas/genética , Trastornos del Neurodesarrollo/genética , Adolescente , Adulto , Niño , Preescolar , Exoma/genética , Femenino , Homocigoto , Humanos , Discapacidad Intelectual/genética , Masculino , Linaje , Secuenciación del Exoma/métodos , Adulto Joven
6.
J Aging Phys Act ; 30(6): 1118-1132, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-35500909

RESUMEN

The purpose of this study was to summarize the evidence from randomized clinical trials on the effects of dance on fall risk in older adults through a systematic review with meta-analysis. Fall risk was assessed through timed up and go, Berg Balance Scale, or one-leg stand tests. Data are presented as mean differences for timed up and go test and standardized mean differences for Berg Balance Scale and one-leg stand tests between treatments with 95% confidence intervals, and calculations were performed using random effects models. Significance was accepted when p < .05. A significant difference was found between dance interventions and the control groups in the general analysis of fall risk assessed by timed up and go (mean differences: -1.446 s; 95% confidence interval [-1.586, -1.306]; p < .001) and Berg Balance Scale and one-leg stand tests (standardized mean differences: 0.737; 95% confidence interval [0.508, 0.966]; p < .001) in favor of the intervention group. Different dance interventions decreased the fall risk in older practitioners.


Asunto(s)
Modalidades de Fisioterapia , Equilibrio Postural , Humanos , Anciano , Estudios de Tiempo y Movimiento , Ensayos Clínicos Controlados Aleatorios como Asunto
7.
Am J Med Genet A ; 185(8): 2384-2390, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34003604

RESUMEN

TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants' pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Proteína 2 Similar al Factor de Transcripción 7/genética , Adolescente , Alelos , Niño , Preescolar , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Mutación Missense , Sistemas de Lectura Abierta , Fenotipo , Síndrome
8.
J Stroke Cerebrovasc Dis ; 30(6): 105774, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33848906

RESUMEN

This blind randomized clinical trial evaluated the effect of CIMT on the functionality and quality of life (QOL) of chronic hemiparetics. Thirty volunteers were divided into two groups: Control (CG) and CIMT (CIMTG); evaluated before and after 12 and 24 intervention sessions. The scales used were: adapted Fugl-Meyer Motor Assessment (FMA), Modified Ashworth, Stroke Specific Quality Of Life (SS-QOL) and the Functional Reach Test (FRT). The scores for all FMA variables in the CIMTG increased until the 24th session, differing from the pre-treatment. In the CG, the scores increased for pain, coordination/ speed and sensitivity. In the FRT there was an increase in the scores in both groups; after the 12th and 24th sessions, the result of the CIMTG was superior to the CG. For the SS-QOL in the CIMTG, the general score and most of the variables increased, as well as in the CG. Muscle tone in CIMTG was lower compared to CG after 24 sessions. Both protocols used in the study were effective, the CIMT protocol showed benefits in recovering the functionality of the paretic upper limb, in the functional range and in reducing muscle tone, with a consequent improvement in quality of life.


Asunto(s)
Terapia por Ejercicio , Actividad Motora , Paresia/rehabilitación , Calidad de Vida , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular/terapia , Extremidad Superior/inervación , Anciano , Brasil , Femenino , Estado Funcional , Humanos , Masculino , Persona de Mediana Edad , Paresia/diagnóstico , Paresia/fisiopatología , Cooperación del Paciente , Estudios Prospectivos , Recuperación de la Función , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/fisiopatología , Factores de Tiempo , Resultado del Tratamiento
9.
Nature ; 516(7529): 51-5, 2014 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-25383518

RESUMEN

ß-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice ß-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide ß-catenin enrichment mapping, we identify Dicer1-important in small RNA (for example, microRNA) biogenesis--as a ß-catenin target gene that mediates resilience. Small RNA profiling after excising ß-catenin from nucleus accumbens in the context of chronic stress reveals ß-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish ß-catenin as a critical regulator in the development of behavioural resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.


Asunto(s)
ARN Helicasas DEAD-box/genética , Regulación de la Expresión Génica , MicroARNs/genética , Resiliencia Psicológica , Ribonucleasa III/genética , Estrés Fisiológico/genética , beta Catenina/metabolismo , Adaptación Fisiológica/genética , Animales , ARN Helicasas DEAD-box/metabolismo , Depresión/fisiopatología , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Neuronas/metabolismo , Ribonucleasa III/metabolismo , Transducción de Señal , beta Catenina/genética
10.
Dev Med Child Neurol ; 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-39279299
11.
Aging Clin Exp Res ; 31(11): 1573-1581, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30656562

RESUMEN

Aging is associated with a progressive decline in physical and neurophysiological functions, and some studies suggest that cerebral serotonin is decreased in older adults. These factors contribute to reduced ability to perform daily activities, influencing quality of life (QoL). Regular physical activity has demonstrated important benefits in reversing ageing effects; however, little is known whether different training protocols might induce differential effects on QoL. The aim of this study was to verify the effects of different types of training on QoL and its relation with plasma serotonin in healthy older women. Forty-eight older women were randomly assigned in four groups: Strength Training (ST), Endurance Training (ET), Combined Training (CT), and Control Group (CG) which was instructed not to engage in any physical exercise during the study time. Participants underwent 12 weeks of training twice a week. Plasma serotonin and a scoring system questionnaire SF-36 for evaluation of QoL were assessed at baseline and after the completion of training protocols. When comparing pre- and post-training periods all trained groups showed improvement in QoL, but the CT improved more domains. Plasma serotonin was significantly lower in the ST and in the CT groups in comparison with controls after the 12-week training. Significant correlations of plasma serotonin with physical functioning, role-physical, general health, vitality, and mental health were observed. CT resulted in higher amelioration in QoL, in comparison with ET or ST only. All training protocols induced significant reductions in peripheral serotonin levels, which were negatively correlated with improvements in QoL.


Asunto(s)
Envejecimiento , Entrenamiento Aeróbico/métodos , Calidad de Vida , Entrenamiento de Fuerza/métodos , Serotonina/sangre , Anciano , Envejecimiento/fisiología , Envejecimiento/psicología , Estudios de Casos y Controles , Femenino , Humanos , Distribución Aleatoria , Encuestas y Cuestionarios
12.
Proc Natl Acad Sci U S A ; 113(34): 9623-8, 2016 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-27506785

RESUMEN

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.


Asunto(s)
Proteínas Portadoras/genética , Trastornos Relacionados con Cocaína/metabolismo , Cocaína/administración & dosificación , Histonas/metabolismo , Núcleo Accumbens/metabolismo , Procesamiento Proteico-Postraduccional , Acetilación , Animales , Proteínas Portadoras/metabolismo , Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/patología , Histonas/genética , Humanos , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Núcleo Accumbens/patología , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo
13.
J Aging Phys Act ; 27(4): 823-830, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31034302

RESUMEN

Eccentric-focused training promotes greater gains in muscle strength compared to other types of training in adults. However, for older people, these findings are still not well understood. A systematic review and meta-analysis were performed using manuscripts that performed eccentric-focused (ET) and conventional resistance training (CT) at least four weeks and evaluated maximum muscle strength through tests of maximum repetitions in weight machine exercises (knee extension and leg press exercises). Five studies were included (n=138). Increases in muscle strength were found in both resistance training groups, without difference between them through meta-analysis. However, a large effect size has been observed only in ET. The findings suggest that resistance training protocols are similar to improve maximal strength in older people, despite larger effect sizes for eccentric-focused training.


Asunto(s)
Envejecimiento/fisiología , Extremidad Inferior , Fuerza Muscular/fisiología , Entrenamiento de Fuerza/métodos , Anciano , Humanos
14.
J Neurosci ; 36(14): 3954-61, 2016 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-27053203

RESUMEN

ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins. SIGNIFICANCE STATEMENT: We show that BAZ1B, a component of chromatin remodeling complexes, in the nucleus accumbens regulates reward-related behaviors in response to chronic exposure to both rewarding and aversive stimuli by regulating largely distinct subsets of genes.


Asunto(s)
Conducta Animal/fisiología , Emociones/fisiología , Núcleo Accumbens/fisiología , Recompensa , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Adenosina Trifosfatasas/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Cromatina/genética , Proteínas Cromosómicas no Histona/metabolismo , Cocaína/farmacología , Epigénesis Genética/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Autoadministración , Medio Social , Estrés Psicológico
15.
Proc Natl Acad Sci U S A ; 111(5): 2005-10, 2014 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-24449909

RESUMEN

Many of the long-term effects of cocaine on the brain's reward circuitry have been shown to be mediated by alterations in gene expression. Several chromatin modifications, including histone acetylation and methylation, have been implicated in this regulation, but the effect of other histone modifications remains poorly understood. Poly(ADP-ribose) polymerase-1 (PARP-1), a ubiquitous and abundant nuclear protein, catalyzes the synthesis of a negatively charged polymer called poly(ADP-ribose) or PAR on histones and other substrate proteins and forms transcriptional regulatory complexes with several other chromatin proteins. Here, we identify an essential role for PARP-1 in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of PARP-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using PARP-1 inhibitors and viral-mediated gene transfer, we established that PARP-1 induction in NAc mediates enhanced behavioral responses to cocaine, including increased self-administration of the drug. Using chromatin immunoprecipitation sequencing, we demonstrated a global, genome-wide enrichment of PARP-1 in NAc of cocaine-exposed mice and identified several PARP-1 target genes that could contribute to the lasting effects of cocaine. Specifically, we identified sidekick-1--important for synaptic connections during development--as a critical PARP-1 target gene involved in cocaine's behavioral effects as well as in its ability to induce dendritic spines on NAc neurons. These findings establish the involvement of PARP-1 and PARylation in the long-term actions of cocaine.


Asunto(s)
Cocaína/farmacología , Poli Adenosina Difosfato Ribosa/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Inmunoprecipitación de Cromatina , Cocaína/administración & dosificación , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Genoma/genética , Inmunoglobulina G/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/enzimología , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Unión Proteica/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Especificidad por Sustrato/efectos de los fármacos , Transcripción Genética/efectos de los fármacos
16.
Proc Natl Acad Sci U S A ; 110(20): 8254-9, 2013 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-23630294

RESUMEN

Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4, including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.


Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Proteínas de Unión al GTP/metabolismo , Regulación de la Expresión Génica , Neuralgia/tratamiento farmacológico , Proteínas RGS/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Conducta Animal , Encéfalo/patología , Desipramina/farmacología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Trastornos del Humor/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Adulto Joven
17.
Int J Orthod Milwaukee ; 27(4): 15-18, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-29847712

RESUMEN

Tooth impaction is an eruption disorder frequently observed in orthodontic clinical practice. A 9-year-old female patient presented with impacted permanent maxillary central incisors and two supernumerary teeth in the region. The early diagnosis and multidisciplinary treatment approach adopted in our case allowed to successfully restore esthetic appearance and occlusion.


Asunto(s)
Incisivo , Diente Impactado/terapia , Niño , Femenino , Humanos , Maxilar , Grupo de Atención al Paciente , Diente Impactado/complicaciones , Diente Supernumerario/complicaciones
18.
bioRxiv ; 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38826276

RESUMEN

Recurrent copy number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder (ASD). Duplication of 15q11.2-13.1 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of ASD by over 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex we conducted single-nucleus RNA-sequencing and multi-omic sequencing on dup15q cases (n=6) as well as non-dup15q ASD (n=7) and neurotypical controls (n=7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene expression changes. Neuronal subtypes, showed greater upregulation of gene expression across a critical region within the duplication as compared to other cell types. Genes within the duplicated region that had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and ASD had largely distinct signatures of chromatin accessibility, but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding factor motifs implicated in each condition implicated distinct biological mechanisms; neuronal JUN/FOS networks in ASD vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain and finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects CNVs more broadly in neurodevelopmental disorders.

19.
J Bodyw Mov Ther ; 37: 46-50, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38432840

RESUMEN

INTRODUCTION: Due to the rapid advance of coronavírus SARS-CoV-2 (COVID-19) pandemic in 2020, social distancing was the main way to reduce the transmission of the virus. Although this measure was efficient and necessary, the social distancing had severe consequences for physical function, mainly in older individuals. Thus, the aim of this study was to investigate the effects of social distancing in the functional and cognitive capacity of community-dwelling oldest-old adults. METHODS: The present study is part of a larger prospective cohort study. Fifteen participants aged 90 years old or older were assessed in the 8-foot-timed-up-and-go test (8-footTUG), sit-to-stand-up test (STS), handgrip strength test (HGS), Mini Mental State Examination (MMSE), Katz Index and Lawton Scale before and after one year of social distancing. RESULTS: A significant worsening in the 8-footTUG and MMSE score was observed, while there were no significant changes in the other variables. When analyzing the decreases in relation to previous functional capacity, it was observed that individuals categorized as dependent by STS cut-off points had the worst decreases in functional capacity. CONCLUSION: The social distancing provoked by COVID-19 pandemic negatively affected the 8-footTUG and cognition. Moreover, individuals dependents showed greater decline in their functional capacity.


Asunto(s)
COVID-19 , Adulto , Anciano de 80 o más Años , Humanos , Anciano , COVID-19/epidemiología , Centenarios , Nonagenarios , Pandemias , SARS-CoV-2 , Fuerza de la Mano , Distanciamiento Físico , Equilibrio Postural , Estudios Prospectivos , Estudios de Tiempo y Movimiento , Cognición
20.
J Appl Gerontol ; : 7334648241290083, 2024 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-39460474

RESUMEN

The purpose of the present study was to examine the acute effect of a single aerobic or strength training session on memory of cognitively preserved older adults. In this randomized controlled clinical trial, in the first visit the participants (52.2% men, aged 68.65 ± 2.81 years-old, BMI 26.94 ± 4.09), were randomly allocated in one of three groups: AG (aerobic exercise group), SG (strength exercise group, submitted to five exercises with 15 repetitions each), and CG (control group). Participants had a short-term memory assessment (word list memory test) followed by a single exercise session, and were retested immediately after. 24 h later, participants were submitted to a long-term memory assessment about the story that was presented in the previous day. Results showed that the SG group had a significant improvement in the word list test, when comparing pre- and post-intervention scores, suggesting that a single strength training session significantly enhances short-term memory in this population.

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