Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function.

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation

ABI3 ectopic expression reduces in vitro and in vivo cell growth properties while inducing senescence

<p>Abstract</p> <p>Background</p> <p>Mounting evidence has indicated that <it>ABI3 </it>(ABI family member 3) function as a tumor suppressor gene, although the molecular mechanism by which ABI3 acts remains largely unknown.</p> <p>Methods</p> <p>The present study investigated <it>ABI3 </it>expression in a large panel of benign and malignant thyroid tumors and explored a correlation between the expression of ABI3 and its potential partner ABI3-binding protein (ABI3BP). We next explored the biological effects of <it>ABI3 </it>ectopic expression in thyroid and colon carcinoma cell lines, in which its expression was reduced or absent.</p> <p>Results</p> <p>We not only observed that <it>ABI3 </it>expression is reduced or lost in most carcinomas but also that there is a positive correlation between <it>ABI3 </it>and <it>ABI3BP </it>expression. Ectopic expression of <it>ABI3 </it>was sufficient to lead to a lower transforming activity, reduced tumor <it>in vitro </it>growth properties, suppressed <it>in vitro </it>anchorage-independent growth and <it>in vivo </it>tumor formation while, cellular senescence increased. These responses were accompanied by the up-regulation of the cell cycle inhibitor <it>p21 </it>^WAF1and reduced ERK phosphorylation and <it>E2F1 </it>expression.</p> <p>Conclusions</p> <p>Our result links <it>ABI3 </it>to the pathogenesis and progression of some cancers and suggests that ABI3 or its pathway might have interest as therapeutic target. These results also suggest that the pathways through which <it>ABI3 </it>works should be further characterized.</p

Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function.

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation

Direito humano à alimentação adequada: um olhar urbano The human right to adequate food: an urban vision

O direito humano à alimentação adequada é compreendido em duas dimensões: estar livre da fome e da desnutrição e ter acesso a uma alimentação adequada1,2. No contexto urbano, com seu forte apelo ao consumo e em que a aquisição de alimentos se dá prioritariamente a partir de relações mercantis, debater este tema em bairros empobrecidos apresenta-se como grande desafio. Este artigo reúne reflexões realizadas a partir de um estudo qualitativo realizado em São João de Meriti, município localizado na Baixada Fluminense (RJ), reunindo líderes da Pastoral da Criança em sessões de grupo focal. O desemprego e subemprego e a dificuldade de acesso aos serviços públicos de saúde, assistência social e saneamento foram apresentados como principais obstáculos para a efetivação do direito humano à alimentação. Foi possível identificar que, dentre as estratégias de enfrentamento da pobreza e da fome, o estabelecimento de circuitos de ajuda mútua tem grande destaque. Apoio social, dádiva e religiosidade apresentaram-se como categorias relevantes nas reflexões dos líderes. Diante de uma realidade em que a pobreza e a fome ou são naturalizadas ou se revertem em moeda de troca durante as eleições, a questão do clientelismo aparece como grande preocupação e desafio para estes líderes.<br>The human right to adequate food is comprehended in two dimensions: being free of hunger and denutrition and having access to an adequate food. The urban context, in which the possession of food is done primarily through merchandising because of its strong consuming appealing, became a big challenge to debate this topic in poor districts today. Here we combine considerations of a qualitative study carried out in São João de Meriti, Rio de Janeiro State, joining leaders from Pastoral da Criança in focal group sessions. The unemployment, the sub-employment and the difficulty in reaching the public health system, the social assistance and basic sanitation were presented as the major obstacles to bring into effect the human right to food. It was possible to determine that, among the strategies to fight the poverty and hunger, a big highlight is the establishment of mutual help mechanisms. The social support, generosity and religiousness were presented as the most important categories among the thoughts of the leaders. Facing a reality in which poverty and hunger appear as something inherent or become a mechanism of change during elections, the issue of the clienteles appears as a huge concern and challenge for those leaders

Fatores de risco e conduta nas complicações do trato biliar no transplante hepático

A reconstrução biliar é um dos pontos vulneráveis do transplante hepático apresentando incidência de complicações biliares, variando de 10 a 35%, nos diversos estudos da literatura. Esse trabalho tem por objetivo apresentar a experiência do nosso serviço em relação à incidência e ao manejo das complicações biliares no transplante de fígado. Foram incluídos no estudo 147 transplantes hepáticos ortotópicos, com idade média de 37,3 anos, correspondendo a 88 procedimentos em pacientes do sexo masculino e 59 do sexo feminino. Complicações biliares ocorreram em 27 transplantes (18,36%) em 25 pacientes (dois retransplantes). A presença de rejeição celular e de complicações vasculares foi identificada como fator de risco para as complicações biliares. A idade, o sexo, a etiologia da cirrose e a técnica utilizada na reconstrução biliar não foram fatores de risco. No total, foram empregados 52 cursos terapêuticos: tratamento cirúrgico em 23 vezes; tratamento endoscópico em 15 vezes; retransplante em sete vezes; drenagem biliar transparieto-hepática em seis vezes e um paciente está em lista de espera para retransplante. Conclui-se deste estudo que as complicações biliares são freqüentes após o transplante hepático e que as vasculares e a rejeição celular são fatores de risco