Labor market impacts of employment quotas for the disabled in Brazil

A inserção ocupacional das pessoas com deficiências e com limitações funcionais menos severas são analisados antes e após a implementação da Lei das Cotas. Os diferenciais são decompostos em (i) fatores produtivos ou socioeconômicos; e (ii) fatores não observáveis, como discriminação e dificuldades sociais. Os fatores não observáveis, que desempenham um papel importante na determinação das diferenças nas taxas de emprego, reduziram substancialmente, especialmente para aqueles com limitações mais severas. Entretanto, enquanto esses trabalhadores continuam obtendo empregos de baixa remuneração, os ocupados com limitações menos severas e mais qualificados atingiram as melhores posições ocupacionais e salários mais elevados.The occupational achievements of people with disabilities and those with less severe functional limitations are analyzed before and after the implementation of employment quotas. The differentials are decomposed into (i) productive or socioeconomic factors; and (ii) unobservable factors such as discrimination and other social constraints. The unobservable difficulties, which play an important role in determining differences in employment rates, reduced substantially, especially for people with more severe limitations. However, while these workers continue to obtain low paid jobs, those most qualified with less severe limitations attained better occupational positions, and hence, higher wages

Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells

Understanding the transcriptional regulation of pluripotent cells is of fundamental interest and will greatly inform efforts aimed at directing differentiation of embryonic stem (ES) cells or reprogramming somatic cells. We first analyzed the transcriptional profiles of mouse ES cells and primordial germ cells and identified genes upregulated in pluripotent cells both in vitro and in vivo. These genes are enriched for roles in transcription, chromatin remodeling, cell cycle, and DNA repair. We developed a novel computational algorithm, CompMoby, which combines analyses of sequences both aligned and non-aligned between different genomes with a probabilistic segmentation model to systematically predict short DNA motifs that regulate gene expression. CompMoby was used to identify conserved overrepresented motifs in genes upregulated in pluripotent cells. We show that the motifs are preferentially active in undifferentiated mouse ES and embryonic germ cells in a sequence-specific manner, and that they can act as enhancers in the context of an endogenous promoter. Importantly, the activity of the motifs is conserved in human ES cells. We further show that the transcription factor NF-Y specifically binds to one of the motifs, is differentially expressed during ES cell differentiation, and is required for ES cell proliferation. This study provides novel insights into the transcriptional regulatory networks of pluripotent cells. Our results suggest that this systematic approach can be broadly applied to understanding transcriptional networks in mammalian species

Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia

Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions

Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia

High-Efficiency Stem Cell Fusion-Mediated Assay Reveals Sall4 as an Enhancer of Reprogramming

Several methods allow reprogramming of differentiated somatic cells to embryonic stem cell-like cells. However, the process of reprogramming remains inefficient and the underlying molecular mechanisms are poorly understood. Here, we report the optimization of somatic cell fusion with embryonic stem cells in order to provide an efficient, quantitative assay to screen for factors that facilitate reprogramming. Following optimization, we achieved a reprogramming efficiency 15–590 fold higher than previous protocols. This allowed observation of cellular events during the reprogramming process. Moreover, we demonstrate that overexpression of the Spalt transcription factor, Sall4, which was previously identified as a regulator of embryonic stem cell pluripotency and early mouse development, can enhance reprogramming. The reprogramming activity of Sall4 is independent of an N-terminal domain implicated in recruiting the nucleosome remodeling and deacetylase corepressor complex, a global transcriptional repressor. These results indicate that improvements in reprogramming assays, including fusion assays, may allow the systematic identification and molecular characterization of enhancers of somatic cell reprogramming

Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL).We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Relacionando cromatina aberta com pluripotência em células estaminais embrionárias : o papel do remodelador da cromatina Chd1

Tese de doutoramento em Bioquímica (Biologia Molecular) apresentada à Fac. de Ciências e Tecnologia da Univ. de CoimbraEmbryonic Stem (ES) cells are the prototypical pluripotent stem cells that can self-renew indefinitely and give rise to all cell types of the body. Through a transcriptional profile using microarrays, we have discovered that the mouse embryonic germ line have high transcriptional similarities to pluripotent stem cells, including mouse ES cells. A group of about 220 genes are up-regulated in pluripotent stem cells when compared to differentiated cells. From this cluster (that we called the pluricluster) we decided to test the effect of down-regulation in ES cells self-renewal and pluripotency. We developed a lentiviral RNA-interference screen to test the role of 41 candidate genes (chosen amongst the pluricluster with a bias towards transcription factors, chromatin remodelers, DNA/RNA binding proteins, oncogenes and unknown genes). Our screen identified 18 genes with RNAi phenotype including Chd1, NFYa, NFYb and Sall4. The last three genes allowed me to follow further characterization of their role in ES cells and reprogramming, as a collaboration project. However, Chd1 was the only novel regulator that had both self-renewal defects and loss of Oct4 activity in this screen. Chd1 is a chromatin remodeler that has been shown to recognize H3K4me3 and is associated with transcriptional activation and splicing. Our work shows clear evidence that Chd1 correlates with H3K4me3 enrichment, which overlaps with RNA polymerase II localization. Downregulation of Chd1 using RNAi in mouse ES cells, leads to increased heterochromatin foci marked by H3K9me3 and HP1. Moreover, in the absence of Chd1, ES cells have self-renewal and pluripotency defects. Chd1-deficient cells are not able to form a typical endodermal layer upon embryoid body differentiation, and have high propensity for neural differentiation. Chd1 also plays a role in the generation of iPS cells by over-expression of the four factors Oct4, Sox2, N-Myc and Klf4. Down-regulation of Chd1 decreases the efficiency of the process, suggesting that Chd1 may be necessary for the chromatin reorganization during reprogramming to pluripotency. The role of Chd1 in ES cells suggests that pluripotent stem cells exist in a dynamic state of opposing influences between euchromatin and heterochromatin. In this thesis, I also suggest that indeed open chromatin may be necessary for ES cells to differentiate into all three germ layers, linking open chromatin to pluripotency.As células estaminais embrionárias são a população típica de células pluripotentes, que têm uma capacidade infinita de auto-renovação e podem dar origem a todas as células do corpo. Através da análise global de expressão genética usando microarrays, descobrimos que células da linha germinal de ratinho são em grande parte semelhantes a células pluripotentes, incluindo células estaminais embrionárias de ratinho. Um conjunto de cerca de 220 genes estão sobre-expressos em células pluripotentes quando comparados com células diferenciadas. Neste conjunto de genes (a que chamámos pluricluster) decidimos testar o efeito da supressão de expressão na capacidade de auto-renovação e pluripotência das células estaminais. Desenvolvemos um ensaio de crivagem de supressão de 41 genes candidatos (em que foram escolhidos preferencialmente factores de transcrição, remodeladores da cromatina, oncogenes, moléculas de ligação a DNA e RNA, e genes com função desconhecida), usando RNA de intereferência através de uma infecção lentiviral. Desse ensaio identificámos 18 genes com fenótipo após a supressão de expressão, entre os quais os genes Chd1, NFYa, NFYb e Sall4. A função em células estaminais embrionárias e em reprogramação dos últimos três genes mencionados foi consequentemente caracterizada em projectos de colaboração. No entanto, o único novo regulador de células estaminais embrionárias que cujo fenótipo apresentava defeitos de auto-renovação e supressão de expressão do marcador Oct4 foi o gene Chd1. Chd1 é um remodelador da cromatina que reconhece a tri-metilação da lisina 4 da histona 3 (H3K4me3) e está associada a activação da transcrição e splicing. Aqui mostramos que Chd1 se liga a regiões do genoma enriquecidas ma marca H3K4me3 e também a RNA polimerase II. Supressão de Chd1 através de RNA de interferência em células estaminais embrionárias induz a formação de focus de heterocromatina marcados por H3K9me3 e HP1. Para além disso, as células perdem a capacidade de pluripotência e mostram defeitos na auto-renovação. Células Chd1-deficientes, após indução de diferenciação em corpos embrioides, não são capazes de formar a típica camada de endoderme, e têm uma alta propensão para neuro diferenciação. Chd1 tem também uma função na reprogramação de células diferenciadas em células pluripotentes induzidas (iPS) através dos factores Oct4, Sox2, Klf4 e N-Myc. Supressão da expressão de Chd1 reduz a eficiência do processo de reprogramação, o que sugere que Chd1 possa ser necessário para a reorganização da cromatina durante o processo de reprogramação. O papel de Chd1 em células estaminais embrionárias sugere que em células pluripotentes existe um estado dinâmico entre eucromatina e heterocromatina. Nesta tese, eu sugiro que de facto, uma cromatina aberta será necessária em células estaminais embrionárias para se diferenciarem em células de todas a linhas germinais, relacionando directamente uma cromatina aberta com pluripotência

Características da participação das pessoas com deficiência e/ou limitação funcional no mercado de trabalho brasileiro

Este trabalho analisa a inserção no mercado de trabalho brasileiro das pessoas com deficiência, com base nos resultados do Censo Demográfico 2010. O estudo apresenta uma classificação para o contingente de pessoas com deficiência (PcD) e pessoas com limitações funcionais (PcLF), no sentido de apurar com mais precisão a dinâmica populacional e de inserção no trabalho de um contingente de pessoas com níveis maiores de limitação física, sensorial ou cognitiva (PcD), separando-o do conjunto de indivíduos com impedimentos "mais leves" (PcLF). Outros objetivos específicos deste trabalho são: comparar os diferenciais de renda e de inserção ocupacional dessas populações; e decompor os determinantes das diferenças de rendimentos em uma parcela devida às características socioeconômica e de inserção ocupacional e em outra devida a fatores não observáveis. Os resultados destacam como as PcD - ao enfrentarem condições mais adversas em termos de formação escolar e acesso ao trabalho, decorrentes, muitas vezes, das barreiras e obstáculos ainda existentes na sociedade - apresentam desvantagens em termos da dinâmica socioeconômica e de inserção ocupacional em relação tanto à população sem qualquer tipo de deficiência ou limitação funcional, como ao segmento populacional com limitações mais leves (PcLF). Ao final, discutem-se políticas e ações que poderiam incrementar e aprimorar as condições de participação das pessoas com deficiência no mercado de trabalho brasileiro

Characteristics of participation of people with disabilities and/or functional limitations in the Brazilian labor market

sem informaçãoEste trabalho analisa a inserção no mercado de trabalho brasileiro das pessoas com deficiência, com base nos resultados do Censo Demográfico 2010. O estudo apresenta uma classificação para o contingente de pessoas com deficiência (PcD) e pessoas com limit312395418sem informaçãosem informaçãosem informaçã