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1.
J Cogn Psychother ; 38(3): 211-226, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38991742

RESUMEN

Acceptance and commitment therapy (ACT) for obsessive-compulsive disorder (OCD) has been found efficacious in randomized clinical trials (RCTs), but the two widely known RCTs were conducted within the United States with predominantly White samples. Research that evaluates treatments like ACT for OCD outside the typical Western cultures is needed. The current scoping review summarizes the key characteristics and findings from 18 RCTs that evaluated ACT for OCD in Iran. These RCTs are largely unknown in the broader scientific literature despite representing the vast majority of ACT for OCD trials, in part because the majority are published in Persian. The preponderance of RCTs treated participants in groups, and most protocols did not include exposure exercises. Of 18 trials, 5 were single sex. Use of selective serotonin reuptake inhibitors (SSRIs) was common with all participants on stable doses at pretreatment in many of the trials. Methodological quality was low to medium. ACT was inconsistent against nontraditional comparison conditions, slightly favorable to empirically validated treatments, and favorable compared with the waitlist and SSRIs. The process of change data indicated that ACT increased the psychological flexibility more than cognitive behavior therapy or SSRIs. These results highlight that findings on ACT for OCD from Western populations replicate and generalize to individuals in Iran. These findings also offer insights gained from studying ACT in Iran and significantly expand the literature based on ACT for OCD that can be integrated into scholarship by all researchers.


Asunto(s)
Terapia de Aceptación y Compromiso , Trastorno Obsesivo Compulsivo , Trastorno Obsesivo Compulsivo/terapia , Humanos , Irán , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico
2.
Eat Disord ; 32(4): 369-386, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38389388

RESUMEN

Eating disorders are serious mental health conditions that are accompanied by negative health outcomes, high mortality rates, impaired functioning, and comorbid mental health conditions. Despite many empirically supported interventions for eating disorders, it remains one of the most challenging mental disorders to treat, as individuals often struggle to maintain treatment gains. One method of improving our understanding of effective eating disorder treatment is to identify important processes of change to target during therapy. The aim of the current study was to test two candidate mediators of disordered eating symptom change during residential treatment: self-compassion and body image inflexibility. In the present study, women and adolescent girls (N = 132) completed a battery of measures, including eating disorder severity, self-compassion, and body image inflexibility, at admission to and discharge from a residential eating disorder facility. Our results indicated that changes in body image inflexibility and self-compassion, specifically self-judgment, were both mediators between ED symptom severity from pre- to post-treatment. These results have potential treatment implications, pointing to the possible importance of targeting body image inflexibility, self-judgment, and self-compassion while treating eating disorders.


Asunto(s)
Imagen Corporal , Empatía , Trastornos de Alimentación y de la Ingestión de Alimentos , Tratamiento Domiciliario , Autoimagen , Humanos , Femenino , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Imagen Corporal/psicología , Adolescente , Adulto , Adulto Joven , Resultado del Tratamiento
4.
Materials (Basel) ; 16(18)2023 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-37763611

RESUMEN

Methods for the remote detection of warfare agents and explosives have been in high demand in recent times. Among the several detection methods, fluorescence methods appear to be more convenient due to their low cost, simple operation, fast response time, and naked-eye-visible sensory response. For fluorescence methods, a large variety of fluorescent materials, such as small-molecule-based fluorophores, aggregation-induced emission fluorophores/materials, and supramolecular systems, have been reported in the literature. Among them, fluorescent (bio)polymers/(bio)polymer-based materials have gained wide attention due to their excellent mechanical properties and sensory performance, their ability to recognize explosives via different sensing mechanisms and their combinations, and, finally, the so-called amplification of the sensory response. This review provides the most up-to-date data on the utilization of polymers and polymer-based materials for the detection of nitroaromatic compounds (NACs)/nitro-explosives (NEs) in the last decade. The literature data have been arranged depending on the polymer type and/or sensory mechanism.

5.
Molecules ; 28(13)2023 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-37446917

RESUMEN

Two new azaheterocycle-based bolas, such as (1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-bisfunctionalized PEGs, were prepared via Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-(aryl)-oxadiazole-1,3,4 and terminal ethynyls derived from PEG-3 and PEG-4. Due to the presence of two heteroaromatic cores and a PEG linker, these bola molecules are considered as promising fluorescent chemosensors for electron-deficient species. As a result of a well-pronounced "turn-off" fluorescence response towards common nitro-explosive components, such as 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), hard-to-detect pentaerythritol tetranitrate (PETN), as well as Hg2+ cation was observed.


Asunto(s)
Sustancias Explosivas , Trinitrotolueno
6.
Int J Mol Sci ; 24(12)2023 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-37373234

RESUMEN

1,4-Bis(5-phenyl-2-oxazolyl)benzene (POPOP) is a common scintillation fluorescent laser dye. In this manuscript, the synthesis of 2-Ar-5-(4-(4-Ar'-1H-1,2,3-triazol-1-yl)phenyl)-1,3,4-oxadiazoles (Ar, Ar' = Ph, naphtalenyl-2, pyrenyl-1, triphenilenyl-2), as PAH-based aza-analogues of POPOP, by means of Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-Ar-1,3,4-oxadiazole and terminal ethynyl-substituted PAHs is reported. An investigation of the photophysical properties of the obtained products was carried out, and their sensory response to nitroanalytes was evaluated. In the case of pyrenyl-1-substituted aza-POPOP, dramatic fluorescence quenching by nitroanalytes was observed.


Asunto(s)
Hidrocarburos , Fluorescencia
7.
Compr Psychiatry ; 123: 152384, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36913904

RESUMEN

BACKGROUND: Direct to consumer pharmaceutical advertising (DTCPA) may have significant impacts on public perception of diseases and treatments. Our objective was to examine whether DTCPA for antidepressants disproportionately portray and hence target women in the United States. METHODS: DTCPA for branded medications for depression, psoriasis and diabetes were analyzed to determine the gender of the main "patient" portrayed, as well as the content of the disease depiction. RESULTS: DTCPA for antidepressants included only women in 82% of ads, only men in 10.1% of ads, and both genders in 7.8% of ads. There were significantly higher representations of women versus men in DTCPA for antidepressants (82%) compared to either psoriasis (50.4%) or diabetes (37.6%) medications. These differences remained statistically significant even after adjusting for gender disparities in disease prevalence. CONCLUSIONS: Antidepressant DTCPA in the United States disproportionately target women. There are potential adverse consequences for both women and men resulting from unequal representations in DTCPA for antidepressant medications.


Asunto(s)
Publicidad , Sexismo , Femenino , Humanos , Masculino , Estados Unidos/epidemiología , Publicidad/métodos , Antidepresivos/uso terapéutico , Preparaciones Farmacéuticas
8.
Int J Dermatol ; 62(2): 169-176, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35020194

RESUMEN

Given the precipitous rise in its incidence in recent decades, skin cancer has been recognized as a growing epidemic. We explore the sociological underpinnings of this epidemic, including: (1) aging of the demographic; (2) human ecologic factors (residing in areas with high ambient ultraviolet levels and a depleted ozone layer); (3) large-scale European migration to more equatorial latitudes; (4) social structures that for centuries minimized miscegenation and maximized segregation; (5) gender-based differences in sunbathing, tanning, sunscreen use, and clothing choice; (6) occupational ultraviolet exposure; (7) the complex interplay of socioeconomic status, race, and urbanization on skin cancer incidence and mortality; (8) the effects of war on skin cancer incidence; (9) cultural shifts in clothing, travel, outdoor sports, recreation, and attitudes towards being tan; and (10) the indirect effects of religion. We show that without these sociological factors, the most common type of cancer would not be nearly as common.


Asunto(s)
Neoplasias Cutáneas , Baño de Sol , Humanos , Rayos Ultravioleta/efectos adversos , Protectores Solares/uso terapéutico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/tratamiento farmacológico , Factores Sexuales
10.
RSC Adv ; 11(42): 25850-25857, 2021 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-35479431

RESUMEN

Computer vision (CV) algorithms are widely utilized in imaging processing for medical and personal electronics applications. In sensorics CV can provide a great potential to quantitate chemosensors' signals. Here we wish to describe a method for the CV-assisted spectrofluorometer-free detection of common nitro-explosive components, e.g. 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), by using polyaromatic hydrocarbon (PAH, PAH = 1-pyrenyl or 9-anthracenyl) - based bola-type chemosensors. The PAH components of these chemical bolas are able to form stable, bright emissive in a visual wavelength region excimers, which allows their use as extended matrices of the RGB colors after imaging and digital processing. In non-polar solvents, the excimers have poor chemosensing properties, while in aqueous solutions, due to the possible micellar formation, these excimers provide "turn-off" fluorescence detection of DNT and TNT in the sub-nanomolar concentrations. A combination of these PAH-based fluorescent chemosensors with the proposed CV-assisted algorithm offers a fast and convenient approach for on-site, real-time, multi-thread analyte detection without the use of fluorometers. Although we focus on the analysis of nitro-explosives, the presented method is a conceptual work describing a general use of CV for quantitative fluorescence detection of various analytes as a simpler alternative to spectrofluorometer-assisted methods.

12.
Hepatology ; 72(6): 2182-2196, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32654263

RESUMEN

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.


Asunto(s)
Enfermedad Hepática en Estado Terminal/virología , Hepatitis Alcohólica/virología , Mucosa Intestinal/virología , Cirrosis Hepática/virología , Viroma/genética , Adulto , Anciano , Animales , Bacteriófagos/genética , Bacteriófagos/aislamiento & purificación , Estudios de Casos y Controles , ADN Viral/aislamiento & purificación , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/mortalidad , Enfermedad Hepática en Estado Terminal/terapia , Heces/virología , Femenino , Hepatitis Alcohólica/diagnóstico , Hepatitis Alcohólica/mortalidad , Hepatitis Alcohólica/terapia , Herpesviridae/genética , Herpesviridae/aislamiento & purificación , Humanos , Hígado/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/terapia , Masculino , Metagenómica , Persona de Mediana Edad , Parvoviridae/genética , Parvoviridae/aislamiento & purificación , ARN Viral/aislamiento & purificación , Índice de Severidad de la Enfermedad , Tasa de Supervivencia
13.
Microbiome ; 8(1): 86, 2020 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-32513256

RESUMEN

BACKGROUND: Inanimate surfaces within a hospital serve as a reservoir of microbial life that may colonize patients and ultimately result in healthcare associated infections (HAIs). Critically ill patients in intensive care units (ICUs) are particularly vulnerable to HAIs. Little is known about how the microbiome of the ICU is established or what factors influence its evolution over time. A unique opportunity to bridge the knowledge gap into how the ICU microbiome evolves emerged in our health system, where we were able to characterize microbial communities in an established hospital ICU prior to closing for renovations, during renovations, and then after re-opening. RESULTS: We collected swab specimens from ICU bedrails, computer keyboards, and sinks longitudinally at each renovation stage, and analyzed the bacterial compositions on these surfaces by 16S rRNA gene sequencing. Specimens collected before ICU closure had the greatest alpha diversity, while specimens collected after the ICU had been closed for over 300 days had the least. We sampled the ICU during the 45 days after re-opening; however, within that time frame, the alpha diversity never reached pre-closure levels. There were clear and significant differences in microbiota compositions at each renovation stage, which was driven by environmental bacteria after closure and human-associated bacteria after re-opening and before closure. CONCLUSIONS: Overall, we identified significant differences in microbiota diversity and community composition at each renovation stage. These data help to decipher the evolution of the microbiome in the most critical part of the hospital and demonstrate the significant impacts that microbiota from patients and staff have on the evolution of ICU surfaces. Video Abstract.


Asunto(s)
Biodiversidad , Microbiología Ambiental , Arquitectura y Construcción de Hospitales , Unidades de Cuidados Intensivos , Microbiota , Bacterias/genética , Arquitectura y Construcción de Hospitales/estadística & datos numéricos , Microbiota/genética , ARN Ribosómico 16S/genética , Factores de Tiempo
14.
RNA ; 26(4): 512-528, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31980578

RESUMEN

Programmed -1 ribosomal frameshifts (-1 PRFs) are commonly used by viruses to regulate their enzymatic and structural protein levels. Human T-cell leukemia virus type 1 (HTLV-1) is a carcinogenic retrovirus that uses two independent -1 PRFs to express viral enzymes critical to establishing new HTLV-1 infections. How the cis-acting RNA elements in this viral transcript function to induce frameshifting is unknown. The objective of this work was to conclusively define the 3' boundary of and the RNA elements within the HTLV-1 pro-pol frameshift site. We hypothesized that the frameshift site structure was a pseudoknot and that its 3' boundary would be defined by the pseudoknot's 3' end. To test these hypotheses, the in vitro frameshift efficiencies of three HTLV-1 pro-pol frameshift sites with different 3' boundaries were quantified. The results indicated that nucleotides included in the longest construct were essential to highly efficient frameshift stimulation. Interestingly, only this construct could form the putative frameshift site pseudoknot. Next, the secondary structure of this frameshift site was determined. The dominant structure was an H-type pseudoknot which, together with the slippery sequence, stimulated frameshifting to 19.4(±0.3)%. The pseudoknot's critical role in frameshift stimulation was directly revealed by examining the impact of structural changes on HTLV-1 pro-pol -1 PRF. As predicted, mutations that occluded pseudoknot formation drastically reduced the frameshift efficiency. These results are significant because they demonstrate that a pseudoknot is important to HTLV-1 pro-pol -1 PRF and define the frameshift site's 3' boundary.


Asunto(s)
Sistema de Lectura Ribosómico , Virus Linfotrópico T Tipo 1 Humano/genética , ARN Mensajero/genética , Regulación Viral de la Expresión Génica , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Motivos de Nucleótidos , ARN Mensajero/química , Ribosomas/metabolismo
15.
Sci Rep ; 9(1): 13409, 2019 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-31527753

RESUMEN

Standardized conditions for collection, preservation and storage of urine for microbiome research have not been established. We aimed to identify the effects of the use of preservative AssayAssure® (AA), and the effects of storage time and temperatures on reproducibility of urine microbiome results. We sequenced the V3-4 segment of the 16S rRNA gene to characterize the bacterial community in the urine of a cohort of women. Each woman provided a single voided urine sample, which was divided into aliquots and stored with and without AA, at three different temperatures (room temperature [RT], 4 °C, or -20 °C), and for various time periods up to 4 days. There were significant microbiome differences in urine specimens stored with and without AA at all temperatures, but the most significant differences were observed in alpha diversity (estimated number of taxa) at RT. Specimens preserved at 4 °C and -20 °C for up to 4 days with or without AA had no significant alpha diversity differences. However, significant alpha diversity differences were observed in samples stored without AA at RT. Generally, there was greater microbiome preservation with AA than without AA at all time points and temperatures, although not all results were statistically significant. Addition of AA preservative, shorter storage times, and colder temperatures are most favorable for urinary microbiome reproducibility.


Asunto(s)
Bacterias/aislamiento & purificación , Benchmarking , Microbiota , Preservación Biológica/métodos , ARN Ribosómico 16S/orina , Manejo de Especímenes/métodos , Bacterias/clasificación , Bacterias/genética , Femenino , Humanos , ARN Ribosómico 16S/genética , Reproducibilidad de los Resultados , Temperatura
16.
Front Microbiol ; 10: 2061, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31555247

RESUMEN

Traditionally, medicine has held that some human body sites are sterile and that the introduction of microbes to these sites results in infections. This paradigm shifted significantly with the discovery of the human microbiome and acceptance of these commensal microbes living across the body. However, the central nervous system (CNS) is still believed by many to be sterile in healthy people. Using culture-independent methods, we examined the virome of cerebrospinal fluid (CSF) from a cohort of mostly healthy human subjects. We identified a community of DNA viruses, most of which were identified as bacteriophages. Compared to other human specimen types, CSF viromes were not ecologically distinct. There was a high alpha diversity cluster that included feces, saliva, and urine, and a low alpha diversity cluster that included CSF, body fluids, plasma, and breast milk. The high diversity cluster included specimens known to have many bacteria, while other specimens traditionally assumed to be sterile formed the low diversity cluster. There was an abundance of viruses shared among CSF, breast milk, plasma, and body fluids, while each generally shared less with urine, feces, and saliva. These shared viruses ranged across different virus families, indicating that similarities between these viromes represent more than just a single shared virus family. By identifying a virome in the CSF of mostly healthy individuals, it is now less likely that any human body site is devoid of microbes, which further highlights the need to decipher the role that viral communities may play in human health.

17.
Philos Trans R Soc Lond B Biol Sci ; 374(1781): 20190373, 2019 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-31352895

RESUMEN

There is growing recognition that variation in animal personality traits can influence survival and reproduction rates, and consequently may be important for wildlife population dynamics. Despite this, the integration of personality research into conservation has remained uncommon. Alongside the establishment of personality as an important source of individual variation has come an increasing interest in factors affecting the development of personality. Recent work indicates the early environment, including natal nutrition, may play a stronger role in the development of personality than previously thought. In this study, we investigated the importance of three personality metrics (activity, boldness and acclimation time) for estimating survival of a threatened species, the hihi (Notiomystis cincta), and evaluated the influence of early natal nutrition on those metrics. Our results showed that boldness (as measured from a one-off cage test) had a positive effect on the probability of juvenile hihi surviving to adulthood. There was also a tendency for juveniles that received carotenoid supplementation in the nest to be bolder than those that did not, suggesting that the early environment had some influence on the expression of boldness in juvenile hihi. Linking the development of personality traits with ultimate effects on vital rates may benefit conservation management, as it could enable developmentally targeted management interventions. To our knowledge, this study is the first to identify potential linkages between early natal nutrition, personality and fitness in a wild-living population. This article is part of the theme issue 'Linking behaviour to dynamics of populations and communities: application of novel approaches in behavioural ecology to conservation'.


Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales , Longevidad , Personalidad , Pájaros Cantores/fisiología , Animales , Especies en Peligro de Extinción , Conducta Exploratoria , Femenino , Masculino , Movimiento
18.
J Fr Ophtalmol ; 42(5): 464-470, 2019 May.
Artículo en Francés | MEDLINE | ID: mdl-30928241

RESUMEN

PURPOSE: To assess the impact of glaucoma treatment and ocular surface disease (OSD) on the vision-specific quality-of-life (VS-QoL) of glaucoma patients attending Farhat Hached university hospital Sousse-Tunisia. METHODS: This was a cross-sectional study enrolling one-hundred-twenty patients followed for primary open angle glaucoma. All patients successfully responded to the Arabic version of the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ 25). QoL was quantified in terms of scores (0-100) and correlated with the characteristics of glaucoma treatment and status of the ocular surface. RESULTS: One hundred and twenty patients were studied. The mean number of medications and instilled drops was 1.95 (1-4) and 2.69 (1-7) respectively. A total of 66.7% patients reported side effects of treatment. On examination, moderate or severe dry eye syndrome was identified in 90% of cases. A total of 16.7% of patients had superficial punctate keratopathy. The number of instilled drops per day, the use of brimonidine or oral carbonic anhydrase inhibitors, and the presence of OSD had a negative impact on the NEI-VFQ 25 scores. CONCLUSIONS: Glaucoma treatment and OSD are 2 factors potentially reducing the QoL of glaucoma patients, on which the ophthalmologist can act by optimizing treatment and regularly examining the ocular surface of glaucoma patients.


Asunto(s)
Antihipertensivos/efectos adversos , Síndromes de Ojo Seco/epidemiología , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Glaucoma de Ángulo Abierto/epidemiología , Queratitis/epidemiología , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Antihipertensivos/administración & dosificación , Estudios Transversales , Síndromes de Ojo Seco/inducido químicamente , Ojo/efectos de los fármacos , Ojo/patología , Femenino , Glaucoma de Ángulo Abierto/patología , Humanos , Presión Intraocular/efectos de los fármacos , Queratitis/inducido químicamente , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas/administración & dosificación , Soluciones Oftálmicas/efectos adversos , Propiedades de Superficie/efectos de los fármacos , Encuestas y Cuestionarios , Resultado del Tratamiento , Túnez/epidemiología , Trastornos de la Visión/epidemiología , Trastornos de la Visión/etiología , Campos Visuales/efectos de los fármacos
19.
J Neurosci ; 39(1): 28-43, 2019 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-30389838

RESUMEN

Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (K+)-channel dysfunction in hyperexcitability of CA3 pyramidal neurons in Fmr1 knock-out (KO) mice. We observed a reduction of voltage-independent small conductance calcium (Ca2+)-activated K+ (SK) currents in both male and female mice, leading to decreased action potential (AP) threshold and reduced medium afterhyperpolarization. These SK-channel-dependent deficits led to markedly increased AP firing and abnormal input-output signal transmission of CA3 pyramidal neurons. The SK-current defect was mediated, at least in part, by loss of FMRP interaction with the SK channels (specifically the SK2 isoform), without changes in channel expression. Intracellular application of selective SK-channel openers or a genetic reintroduction of an N-terminal FMRP fragment lacking the ability to associate with polyribosomes normalized all observed excitability defects in CA3 pyramidal neurons of Fmr1 KO mice. These results suggest that dysfunction of voltage-independent SK channels is the primary cause of CA3 neuronal hyperexcitability in Fmr1 KO mice and support the critical translation-independent role for the fragile X mental retardation protein as a regulator of neural excitability. Our findings may thus provide a new avenue to ameliorate hippocampal excitability defects in FXS.SIGNIFICANCE STATEMENT Despite two decades of research, no effective treatment is currently available for fragile X syndrome (FXS). Neuronal hyperexcitability is widely considered one of the hallmarks of FXS. Excitability research in the FXS field has thus far focused primarily on voltage-gated ion channels, while contributions from voltage-independent channels have been largely overlooked. Here we report that voltage-independent small conductance calcium-activated potassium (SK)-channel dysfunction causes hippocampal neuron hyperexcitability in the FXS mouse model. Our results support the idea that translation-independent function of fragile X mental retardation protein has a major role in regulating ion-channel activity, specifically the SK channels, in hyperexcitability defects in FXS. Our findings may thus open a new direction to ameliorate hippocampal excitability defects in FXS.


Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/fisiología , Hipocampo/fisiología , Neuronas/fisiología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Potenciales de Acción/fisiología , Animales , Región CA3 Hipocampal/citología , Región CA3 Hipocampal/fisiología , Femenino , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fibras Musgosas del Hipocampo/fisiología , Células Piramidales/fisiología , Receptores de Ácido Kaínico/genética , Receptores de Ácido Kaínico/fisiología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/agonistas , Transmisión Sináptica/fisiología
20.
Mol Genet Metab ; 116(4): 289-97, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26547561

RESUMEN

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive movement disorder that is due to mutations in PANK2. Pathologically, it is a member of a class of diseases known as neurodegeneration with brain iron accumulation (NBIA) and features increased tissue iron and ubiquitinated proteinaceous aggregates in the globus pallidus. We have previously determined that these aggregates represent condensed residue derived from degenerated pallidal neurons. However, the protein content, other than ubiquitin, of these aggregates remains unknown. In the present study, we performed biochemical and immunohistochemical studies to characterize these aggregates and found them to be enriched in apolipoprotein E that is poorly soluble in detergent solutions. However, we did not determine a significant association between APOE genotype and the clinical phenotype of disease in our database of 81 cases. Rather, we frequently identified similar ubiquitin- and apolipoprotein E-enriched lesions in these neurons in non-PKAN patients in the penumbrae of remote infarcts that involve the globus pallidus, and occasionally in other brain sites that contain large γ-aminobutyric acid (GABA)ergic neurons. Our findings, taken together, suggest that tissue or cellular hypoxic/ischemic injury within the globus pallidus may underlie the pathogenesis of PKAN.


Asunto(s)
Apolipoproteínas E/química , Isquemia Encefálica/genética , Neuronas GABAérgicas/química , Neurodegeneración Asociada a Pantotenato Quinasa/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Agregación Patológica de Proteínas/genética , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Isquemia Encefálica/complicaciones , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Estudios de Casos y Controles , Niño , Femenino , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/patología , Expresión Génica , Globo Pálido/metabolismo , Globo Pálido/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neurodegeneración Asociada a Pantotenato Quinasa/complicaciones , Neurodegeneración Asociada a Pantotenato Quinasa/metabolismo , Neurodegeneración Asociada a Pantotenato Quinasa/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Agregación Patológica de Proteínas/complicaciones , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Ubiquitina/química , Ubiquitina/genética , Ubiquitina/metabolismo
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