Whole-transcriptome sequencing analysis of placental differential miRNA expression profile in Down syndrome / 南方医科大学学报

OBJECTIVE@#To identify new biomarkers and molecular pathogenesis of Down syndrome (DS) by analyzing differentially expressed miRNAs in the placentas and their biological pathways.@*METHODS@#Whole transcriptome sequencing was used to identify the differentially expressed miRNAs in DS (n=3) and normal placental samples (n=3) diagnosed by prenatal diagnosis. The target genes were predicted using miRWalk, Targetscan and miRDB, and GO and KEGG pathway analyses were performed for gene enrichment studies.@*RESULTS@#We identified a total of 82 differentially expressed miRNAs in the placental tissues of DS, including 29 up-regulated miRNAs (fold change ≥2, P < 0.05) and 15 down-regulated miRNAs (fold change ≥2, P < 0.05), among which 10 miRNAs with relatively high expression abundance were selected for further analysis, including 4 up-regulated and 6 down-regulated miRNAs. These selected miRNAs shared the common target genes BTBD3 and AUTS2, both of which were associated with neurodevelopment. GO analysis showed that the target genes of the selected miRNAs were mainly enriched in protein binding, hydrolytic enzymes, metal ion binding protein combining, transferase activity, nucleotide, cytoplasmic constituents, nucleus composition, transcriptional regulation, RNA metabolism regulation, DNA-dependent RNA polymerase Ⅱ promoter transcriptional regulation, eye development, and sensory organ development. KEGG enrichment analysis showed that the target genes of these differentially expressed miRNAs were involved in the signaling pathways including tumor-related signaling pathway, PI3K-Akt signaling pathway, Ras signaling pathway, Rap1 signaling pathway, cytoskeletal regulatory signaling pathway, purine metabolization-related signaling pathway and P53 signaling pathway.@*CONCLUSION@#The differentially expressed miRNAs may play important roles in placental damage and pregnancy pathology in DS and provide clues for the prevention and treatment of mental retardation-related diseases.

Hippocampal overexpression of Down syndrome cell adhesion molecule in amyloid precursor protein transgenic mice

Down syndrome cell adhesion molecule (DSCAM) is located within the Down syndrome critical region of chromosome 21. DSCAM is a broadly expressed neurodevelopmental protein involved in synaptogenesis, neurite outgrowth, and axon guidance. We previously demonstrated DSCAM overexpression in the cortex of amyloid precursor protein (APP) transgenic mice, suggesting possible regulatory interactions between APP and DSCAM. APP mice exhibit deficits in hippocampus-dependent learning and memory. In this preliminary study, we examined age-related changes in DSCAM expression within the hippocampus in 16 APP transgenic mice (1, 3, 6 and 12 months old). Hippocampus-dependent spatial memory was assessed in APP mice and age-matched wild type littermates (WTs) using the Morris water maze (MWM). The cellular distribution of hippocampal DSCAM and total expression at both mRNA and protein levels were measured by immunohistochemistry, qRT-PCR, and western blotting, respectively. APP mice exhibited spatial memory deficits in the MWM. Intense DSCAM immunoreactivity was observed in the dentate gyrus granule cell layer and hippocampal stratum pyramidale. Total hippocampal DSCAM mRNA and protein expression levels were substantially higher in APP mice than WTs at 1 and 3 months of age. Expression decreased with age in both groups but remained higher in APP mice. DSCAM is overexpressed in the hippocampus over the first 12 months of life in APP mice, but especially during maturation to adulthood. In conclusion, these results suggest an association between DSCAM and APP mice, which is characterized by neuropathology and behavioral deficits. These results provide some clues for future studies on the role of DSCAM overexpression in the precocious cognitive decline observed in APP transgenic mice.

Análise da postura e apoio plantar de crianças portadoras de Síndrome de Down consideradas obesas / Analysis of posture and foot support of children with Down syndrome considered obese

Objetivo - Os indivíduos portadores de Síndrome de Down apresentam algumas características próprias da síndrome, hiperextensão dos joelhos com pronação e eversão dos pés, e o aumento do apetite que poderá levar alguns indivíduos a um quadro de obesidade, podendo modificar assim sua postura e o apoio plantar. O objetivo foi analisar o comportamento biomecânico estático da postura e do apoio plantar de crianças portadoras de Síndrome de Down consideradas obesas pelo índice de massa corporal. Método - Foram avaliados 20 indivíduos,subdivididos em dois grupos: G1 crianças portadoras de Síndrome de Down consideradas obesas e G2 (grupo controle) crianças portadoras de Síndrome de Down consideradas não obesas. Para avaliação da postura os indivíduos foram fotografados nas vistas anterior, lateral direita,lateral esquerda e posterior; para avaliação da impressão plantar, foi realizada uma fotocópia colorida da face plantar de cada indivíduo.Resultados - As crianças portadoras de Síndrome de Down consideradas obesas apresentaram maiores alterações posturais e do apoio plantar quando comparadas com as eutróficas. Conclusão - O aumento de peso pode influenciar no comportamento biomecânico dessas crianças.

Objective - Individuals with Down syndrome have some characteristics of the syndrome, hyperextension of the knee with pronation and eversion of the feet, and increased appetite that may lead some individuals to a framework for obesity and may thereby modify its stance and foot support. The objective was to assess the biomechanical behavior of the static posture and foot support of children with Down syndrome considered obese by body mass index. Method - We studied 20 subjects, divided into two groups: G1 children with Down syndrome as obese and G2 (control group) children with Down syndrome not considered obese. To assess the posture individuals were photographed in the sights before, right side, left side, and later, for assessing it was done a color photocopy of the plantar surface of each individual.Results - Children with Down syndrome considered obese had greater postural changes and foot support when compared with norma lweight. Conclusion - Weight gain may influence the biomechanical behavior of these children.

Impacto de 12 semanas de treinamento de força sobre a composição corporal de portadores de síndrome de Down / Impact of an twelve-week weight training program on the body composition for people with Down syndrome

Introdução: O objetivo do presente estudo foi verificar o impacto de 12 semanas de treinamento de força na composição corporal de portadores da síndrome de Down. Material e métodos: Participaram 12 portadores da síndrome de Down com idades entre 15 e 35 anos, divididos em dois grupos: experimental (G1=08), submetidos a um programa de treinamento de musculação, e controle (G2=04), sem intervenção. A composição corporal foi estimada através da equação de sete dobras cutâneas. As avaliações foram realizadas em pré e pós-teste, com frequência semanal de três vezes em dias alternados e duração de 60 minutos. O protocolo experimental foi elaborado com nove exercícios sob a forma de circuito, sendo realizados em três séries de 8 a 12 repetições, com intervalos de descanso entre 30-60 segundos. Resultados: Foi observado no G1 uma diminuição significativa no percentual de gordura (­2,0%; p=0,036). Os controles apresentaram um aumento desfavorável (+1,0%; p=0,043). Em relação à massa magra (MM), observou-se um ganho significativo no G1 (+1,2kg; p=0,008), tendo o G2 apresentado uma redução de MM (­2,0kg; p=0,003). Sobre o efeito adverso nos níveis de gordura, o programa de musculação para o G1 mostrou uma eficácia de 75% em relação aos controles. Conclusão: O programa de treinamento apresentou efeito favorável, promovendo redução na gordura corporal e aumento na massa muscular, podendo ser sugerido para indivíduos com características similares aos aqui investigados (AU)

Introduction: The aim of this study was to investigate the impact of a twelve-week weight training program on body composition among people with Down syndrome. Material and methods: The participants were 12 people with Down syndrome aged between 15 and 35 years, divided in two groups: experimental group (G1=08), submitted to a weight training program, and a control group (G2=04), without any intervention. Body composition was estimated through the equation of seven skin folds. Pre­ and post-test evaluations were performed three times every other day and duration of 60 minutes. The experimental protocol consisted in nine rounds of exercise, performed in three series of 8-12 repetitions and rests of 30-60 seconds in-between. Results: A significant decrease of fat percentage was found in G1 (­2.0%; p=0.036). The controls presented a unfavorable increase in fat (+1.0%; p=0.043). As regards lean mass (LM), a significant increase was observed in G1 (+1.2kg; p=0.008) and a decrease in G2 (­2,0kg; p=0.003). Regarding the adverse effect in fat levels, the weight training program for G1 showed an efficacy of 75% as compared to controls. Conclusion: The weight training program had a favorable effect, promoting body fat reduction and muscle mass increase, suggesting that this program should be indicated for individuals with similar characteristics (AU)

Down syndrome critical region 1 enhances the proteolytic cleavage of calcineurin

Down syndrome critical region 1 (DSCR1), an oxidative stress-response gene, interacts with calcineurin and represses its phosphatase activity. Recently it was shown that hydrogen peroxide inactivates calcineurin by proteolytic cleavage. Based on these facts, we investigated whether oxidative stress affects DSCR1-mediated inactivation of calcineurin. We determined that overexpression of DSCR1 leads to increased proteolytic cleavage of calcineurin. Convertsely, knockdown of DSCR1 abolished calcineurin cleavage upon treatment with hydrogen peroxide. The PXIIXT motif in the COOH-terminus of DSCR1 is responsible for both binding and cleavage of calcineurin. The knockdown of overexpressed DSCR1 in DS fibroblast cells also abrogated calcineurin proteolysis by hydrogen peroxide. These results suggest that DSCR1 has the ability to inactivate calcineurin by inducing proteolytic cleavage of calcineurin upon oxidative stress.

Small-molecule aggregation inhibitors reduce excess amyloid in a trisomy 16 mouse cortical cell line

We have previously characterized a number of small molecule organic compounds that prevent the aggregation of the β-amyloid peptide and its neurotoxicity in hippocampal neuronal cultures. We have now evaluated the effects of such compounds on amyloid precursor protein (APP) accumulation in the CTb immortalized cell line derived from the cerebral cortex of a trisomy 16 mouse, an animal model of Down's syndrome. Compared to a non-trisomic cortical cell line (CNh), CTb cells overexpress APP and exhibit slightly elevated resting intracellular Ca2+ levéis ([Ca2+]¡). Here, we show that the compounds 2,4-dinitrophenol, 3-nitrophenol and 4-anisidine decreased intracellular accumulation of APP in CTb cells. Those compounds were non-toxic to the cells, and slightly increased the basal [Ca2+]¡. Results indícate that the compounds tested can be leads for the development of drugs to decrease intracellular vesicular accumulation of APP in trisomic cells.

Bone mineral density of children with physical disabilities in the United Arab Emirates: a feasibility study

To investigate the feasibility of measuring the bone mineral density [BMD] of Emirati children with physical disabilities. Ten boys and 7 girls, 4 years 2 months to 18 years 4 months [Mean: 10 years], 12 with cerebral palsy and 5 with Down syndrome were studied A Child Information Profile was developed. Dual-energy x-ray absorptiometry [DXA] was used to measure the BMD of the lumbar spine and hips. Peripheral quantitative ultrasound [pQUS] was used to obtain the estimated BMD of the subjects'non-dominant heel Methods varied in effectiveness. Recruitment and nutritional data return were limited. Not all subjects could be measured through sonography because of technical issues. Dynamometry could not be performed on subjects with low cognitive abilities. Anthropometric and DXA measurements were well tolerated by all subjects. The subjects had lower BMD than the values reported in Western studies. The results indicated that it would not be particularly feasible to conduct a large-scale study under these conditions. Recommendations are provided

Aspectos metabólicos e funcionais do zinco na síndrome de Down / Metabolic and functional aspects of zinc in Down syndrome

Este estudo relata os aspectos funcionais do zinco, bem como a participação desse mineral nas alterações metabólicas presentes em indivíduos portadores de Síndrome de Down. A maioria dos trabalhos realizados observou que o estado nutricional relativo ao zinco nesses pacientes está inadequado, com alterações no sistema antioxidante, imunológico e no metabolismo dos hormônios da tireóide. Estudos in vitro apontam que o zinco participa como cofator da enzima deiodinase tipo II na conversão periférica de Tiroxina em Triiodotironina, e que essa reação está diminuída em indivíduos portadores de Síndrome de Down, o que contribui para a manifestação de distúrbios, como o hipotireoidismo subclínico. As alterações na compartimentalização do zinco no organismo desses indivíduos também favorecem a expressão excessiva da enzima cobre/zinco (Cu/Zn) superóxido dismutase, com aumento do estresse oxidativo, e ainda alterações no sistema imune. Na Síndrome de Down, tem sido demonstrada melhora no metabolismo dos hormônios tireoidianos e na função imune, após a suplementação com zinco. Portanto, o papel metabólico do zinco na Síndrome de Down deve ser mais pesquisado, tendo em vista que esse mineral pode contribuir no controle das alterações metabólicas comumente presentes em indivíduos portadores dessa síndrome.

This study reports the functional aspects of zinc as well as its participation in the metabolic changes present in individuals with Down syndrome. Most of the studies performed observed that the nutritional status related to zinc in these patients is inadequate, with changes in the antioxidant and immunological systems and in the metabolism of thyroid hormones. In vitro studies show that zinc participates as a cofactor of the enzyme deiodinase type II in the peripheral conversion of thyroxin into triiodothyronine, and that this reaction is decreased in individuals with Down syndrome, contributing to the manifestation of disorders such as subclinical hypothyroidism. Changes in zinc compartmentation in the body of these individuals also favor an excessive expression of the copper/zinc enzyme (Cu/Zn) superoxide dismutase, with increased oxidative stress, and also changes in the immune system. In Down syndrome, zinc supplementation has been shown to improve thyroid hormone metabolism and immune function. Therefore, the metabolic role of zinc in Down syndrome should be further researched, knowing that this mineral can.

A calcineurin inhibitory protein overexpressed in Down's syndrome interacts with the product of a ubiquitously expressed transcript

The Down's syndrome candidate region 1 (DSCR1) protein, encoded by a gene located in the human chromosome 21, interacts with calcineurin and is overexpressed in Down's syndrome patients. As an approach to clarifying a putative function for this protein, in the present study we used the yeast two-hybrid system to identify DSCR1 partners. The two-hybrid system is a method that allows the identification of protein-protein interactions through reconstitution of the activity of the yeast GAL 4 transcriptional activator. The gene DSCR1 fused to the GAL 4 binding domain (BD) was used to screen a human fetal brain cDNA library cloned in fusion with the GAL 4 activation domain (AD). Three positive clones were found and sequence analysis revealed that all the plasmids coded for the ubiquitously expressed transcript (UXT). UXT, which is encoded in human Xp11, is a 157-amino acid protein present in both cytosol and nucleus of the cells. This positive interaction of DSCR1 and UXT was confirmed in vivo by mating the yeast strain AH109 (MATa)expressing AD-UXT with the strain Y187 (MATalfa) expressing BD-DSCR1, and in vitro by co-immunoprecipitation experiments. These results may help elucidate a new function for DSCR1 and its participation in Down's syndrome pathogenesis.

Curvas padrão pôndero-estatural de portadores de Síndrome de Down procedentes da região urbana da cidade de São Paulo / Pattern curves weight-statural with of Downïs syndrome proceeding from São Paulo urban area

De fato, por não existir um levantamento antropométrico de crianças portadoras da SD no Brasil, foi realizado em São Paulo um estudo biométrico prospectivo que permitiu a elaboração de curvas antropométricas avaliando taxas de peso, estatura e perímetro cefálico elaboradas por tabelas e gráficos com valores lapidados de 4 percentis de dois grupos etários de ambos os sexos divididos de 0-24 meses e de 2-8 anos respectivamente. O estudo considerou e excluiu, quando pertinente, fatores ambientais ou genéticos paralelos que eventualmente pudessem interferir nas variáveis avaliadas...