ABSTRACT
Resumen Actualmente la secuenciación del exoma completo (WES; Whole-exome sequencing) mediante la técnica NGS (Next-generation sequencing) es uno de los estudios genéticos más solicitados dentro del abordaje de pacientes con Discapacidad Intelectual con o sin otras anomalías. Al igual que con otros proce dimientos y estudios clínicos, es conveniente que los médicos prescriptores tengan una comprensión clara de los alcances y limitaciones del uso de WES, del proceso de análisis de las variantes genéticas identificadas, así como de aspectos a evaluar acerca de la calidad y estructura de los informes de los estudios de NGS, con el objetivo de que puedan interpretar mejor los resultados de un estudio y plantear de la mejor manera la correlación de los mismos con la clínica observada.
Abstract Currently, Whole exome sequencing (WES) using NGS (Next-generation sequencing) technology is one of the most requested genetic studies within the approach of patients with intellectual disability with or without other anomalies. As with other procedures and clinical studies, it is convenient for prescribing physicians to have a clear understanding of the scope and limitations of the use of WES, the analysis process of the genetic variants identified, as well as aspects to be evaluated regarding quality and structure of the reports of the NGS studies, with the aim that they can better interpret the results of a study, evaluate its quality, and propose in the best way the correlation of the same with the observed phenotype.
ABSTRACT
Currently, Whole exome sequencing (WES) using NGS (Next-generation sequencing) technology is one of the most requested genetic studies within the approach of patients with intellectual disability with or without other anomalies. As with other procedures and clinical studies, it is convenient for prescribing physicians to have a clear understanding of the scope and limitations of the use of WES, the analysis process of the genetic variants identified, as well as aspects to be evaluated regarding quality and structure of the reports of the NGS studies, with the aim that they can better interpret the results of a study, evaluate its quality, and propose in the best way the correlation of the same with the observed phenotype.
Actualmente la secuenciación del exoma completo (WES; Whole-exome sequencing) mediante la técnica NGS (Next-generation sequencing) es uno de los estudios genéticos más solicitados dentro del abordaje de pacientes con Discapacidad Intelectual con o sin otras anomalías. Al igual que con otros procedimientos y estudios clínicos, es conveniente que los médicos prescriptores tengan una comprensión clara de los alcances y limitaciones del uso de WES, del proceso de análisis de las variantes genéticas identificadas, así como de aspectos a evaluar acerca de la calidad y estructura de los informes de los estudios de NGS, con el objetivo de que puedan interpretar mejor los resultados de un estudio y plantear de la mejor manera la correlación de los mismos con la clínica observada.
Subject(s)
Intellectual Disability , Humans , Intellectual Disability/genetics , Phenotype , Exome Sequencing , High-Throughput Nucleotide Sequencing/methodsABSTRACT
Single nucleotide polymorphisms associated with lipid metabolism and energy balance are implicated in the weight loss response caused by nutritional interventions. Dietinduced weight loss is also associated with differential global DNA methylation. DNA methylation has been proposed as a predictive biomarker for weight loss response. Personalized biomarkers for successful weight loss may inform clinical decisions when deciding between behavioral and surgical weight loss interventions. The aim of the present study was to investigate the association between global DNA methylation, genetic variants associated with energy balance and lipid metabolism, and weight loss following a nonsurgical weight loss regimen. The present study included 105 obese participants that were enrolled in a personalized weight loss program based on their allelic composition of the following five energy balance and lipid metabolismassociated loci: Near insulininduced gene 2 (INSIG2); melanocortin 4 receptor; adrenoceptor ß2; apolipoprotein A5; and Gprotein subunit ß3. The present study investigated the association between a global DNA methylation index (GDMI), the allelic composition of the five energy balance and lipid metabolismassociated loci, and weight loss during a 12 month program, after controlling for age, sex and body mass index (BMI). The results demonstrated a significant association between the GDMI and near INSIG2 locus, after adjusting for BMI and weight loss, and significant trends were observed when stratifying by gender. In conclusion, a combination of genetic and epigenetic biomarkers may be used to design personalized weight loss interventions, enabling adherence and ensuring improved outcomes for obesity treatment programs. Precision weight loss programs designed based on molecular information may enable the creation of personalized interventions for patients, that use genomic biomarkers for treatment design and for treatment adherence monitoring, thus improving response to treatment.
Subject(s)
DNA Methylation , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Obesity/genetics , Weight Loss/genetics , Adolescent , Adult , Aged , Child , Gene Frequency , Genetic Association Studies , Humans , Middle Aged , Obesity/diet therapy , Polymorphism, Single Nucleotide , Treatment Outcome , Weight Reduction Programs , Young AdultABSTRACT
Exploring the principles that regulate rhythmic membrane potential (Vm) oscillations and bursts in hippocampal CA1 pyramidal neurons is essential to understanding the theta rhythm (theta). Recordings were performed in vitro in hippocampal slices from young rats, and a group of the recorded CA1 pyramidal cells were dye-filled with carboxifluorescein and immunolabeled for the R1 subunit of the NMDA receptor. Tetanic stimulation of Schaffer collaterals (SCs) and iontophoresis of glutamate evoked rhythmic Vm oscillations and bursts (approximately 10 mV, approximately 7 Hz, 2-5 spikes per burst) in cells (31%) placed close to the midline ("medial cells"). Rhythmic bursts remained under picrotoxin (10 microM) and Vm oscillations persisted with tetrodotoxin (1.5 microM), but bursts were blocked by AP5 (25 microM) and Mg2+-free solutions. Depolarization and AMPA never induced rhythmic bursts. The rest of the neurons (69%), recorded closer to the CA3 region ("lateral cells"), discharged rhythmically single repetitive spikes under SC stimulation and glutamate in control conditions, but fired rhythmic bursts under similar stimulation, both when NMDA was applied and when non-NMDA receptors were blocked with CNQX (20 microM). Medial cells exhibited a larger NMDA current component and a higher NMDAR1 density at the apical dendritic shafts than lateral cells, suggesting that these differences underlie the dissimilar responses of both cell groups. We conclude that the "theta-like" rhythmic oscillations and bursts induced by glutamate and SC stimulation relied on the activation of NMDA receptors at the apical dendrites of medial cells. These results suggest a role of CA3 pyramidal neurons in the generation of CA1 theta via the activation of NMDA receptors of CA1 pyramidal neurons.
