Prenatal Tobacco Exposure Shortens Telomere Length in Children

Introduction: Preliminary evidence suggests a possible association between prenatal tobacco exposure and telomere length in children. This study was conducted to investigate whether maternal smoking during pregnancy was associated with telomere shortening in their children and whether prenatal and childhood exposure to environmental tobacco had any impact on this association. Methods: This is a population-representative study on the association between prenatal tobacco exposure and telomere length in children. Ninety-eight Hong Kong Chinese children aged under 15 years with prenatal tobacco exposure and 98 age- and gender-matched controls were recruited from a population health study with stratified random sampling. Results: Telomere length in children with prenatal tobacco exposure was significantly shorter than in those with no exposure (mean T/S ratio = 24.9 [SD = 8.58] in exposed vs. 28.97 [14.15] in control groups; P = 0.02). A negative dose-response relationship was observed between the T/S ratio and tobacco exposure duration: the longer the duration of maternal smoking in pregnancy, the shorter the child's telomere length. The association between the child's telomere length and prenatal tobacco exposure remained significant after considering the influence of family socioeconomic status and exposure to environmental tobacco smoke during pregnancy and childhood. Conclusions: Prenatal tobacco exposure was associated with telomere shortening in children. As this may impose significant health impacts through fetal genetic programming, more efforts should be made to reduce fetal tobacco exposure by educating pregnant women to not smoke and motivating smokers to quit in early pregnancy. Implications: As reflected by telomere shortening, prenatal tobacco exposure in children can cause premature aging and increased health risks, which we suggest is entirely preventable. Not smoking during pregnancy or quitting smoking is critical to improving the health outcome of our future generations as prenatal tobacco exposure may affect children's biological programming. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.postprin

Rede +Brasil : mecanismos de governança digital na redução de irregularidades em instrumentos de transferência voluntária do governo federal

Trabalho de Conclusão de Curso (graduação)—Universidade de Brasília, Faculdade de Economia, Administração, Contabilidade e Gestão de Políticas Públicas, Departamento de Gestão de Políticas Públicas, 2019.Aspectos de inovação em serviços públicos têm sido estudados no âmbito da administração pública brasileira, em termos de processos ou serviços; sendo a governança um fator chave nos contextos de organizações ou em tecnologia da informação. Realça-se a necessidade da legalidade, efetividade, eficiência, eficácia e economicidade no uso de recursos governamentais para o atingimento dos objetivos das políticas públicas. Estas requerem instrumentos adequados de acompanhamento na execução, em especial daquelas advindas das transferências voluntárias da União. No entanto, análises de governança de redes têm sido pouco utilizadas para compreender os mecanismos que atuam em uma rede de capacitação, aprimoramento de gestão e disseminação de informações, cujo objetivo central é possibilitar a boa e correta execução dos recursos transferidos pelo governo federal, a fim de alcançar os resultados desejados. Este trabalho busca compreender como os mecanismos de governança da ‘Rede +Brasil’, que atuam na disseminação dos conhecimentos para a execução de transferências voluntárias da União, por meio da ‘Plataforma +Brasil’, influenciaram na redução de inconformidades e irregularidades apuradas na aplicação dessas transferências, tendo por base processos de tomadas de contas especiais (TCEs) e estudos de órgãos de controle, tais como o Tribunal de Contas da União (TCU) e o Ministério da Transparência e Controladoria da União (CGU). Para tanto, utilizam-se de métodos mistos, iniciando-se com pesquisa qualitativa, no intuito de perceber os aspectos de governança sob a ótica dos diversos atores: gestores do sistema, órgãos de controle, concedentes, convenentes e demais gestores. Para análise dos resultados desta primeira parte, foi utilizada a técnica de análise de conteúdo, tendo como plataforma de suporte alguns softwares: NVivo 12, Google Stream, Word Cloud Generator e editores de áudio. Por meio da análise qualitativa da pesquisa, foram verificados os aspectos funcionais de governança de redes e suas dimensões, na percepção de diversos atores envolvidos. Outras informações obtidas nas entrevistas contribuíram a enriquecer a compreensão em diversos aspectos do Sistema e da própria Rede. No TCU, além dos quantitativos de processos de TCEs, as irregularidades foram mapeadas e classificadas, especialmente em termos de maiores ocorrências nos montantes apurados; e, para pesquisas quantitativas, utilizou-se ferramenta de inteligência de negócios, o QlikView, para obtenção de painéis gerenciais, tanto no Sistema eTCE, como no próprio módulo Siconv e no portal Siga Brasil. As informações quantitativas obtidas possibilitaram análises em termos de evolução temporal dos recursos, tanto em termos de transferências voluntárias de instrumentos celebrados, bem como dos montantes de recursos assinalados com irregularidades. Os quantitativos de processos ou instrumentos deram uma visão da evolução desses instrumentos antes da conformação da Rede e após sua implementação. Dados do Sistema do Ministério da Economia possibilitaram averiguar a redução dos tempos nos ciclos e fases de vida desses instrumentos, com decréscimos substanciais, tanto em fase de execução como, principalmente, nas prestações de contas. Aspectos de governança em termos de institucionalização, normatização, disseminação de capacitações e informações, fluxo de documentos entre sistemas informatizados governamentais, conjuntamente à gestão da Rede trouxeram benefícios para melhor execução dos recursos.Innovation aspects in public services have been studied within the Brazilian public administration, in terms of processes or services; Governance being an important factor in organizational contexts or in information technology. The need for legality, effectiveness, efficiency, effectiveness and economy in the use of government resources to achieve public policy objectives is highlighted. These require appropriate monitoring tools for implementation, in particular those arising from voluntary Union transfers. However, network governance analyzes have been little used to understand the mechanisms that act in a Training, Management Improvement and Information Dissemination Network, whose main objective is to enable the proper and correct execution of the resources transferred by the federal government, in order to achieve the desired results. This paper seeks to understand how the governance mechanisms of ‘Rede +Brasil’ (+Brazil Network), that act in the dissemination of the knowledge for the execution of voluntary Union transfers, through the ‘Plataforma +Brasil’ (+Brazil Platform), influenced the reduction of nonconformities and irregularities found in the application of these transfers, based on special accounting processes (TCEs) and studies of control bodies, such as the Federal Court of Audit (TCU) and the Ministry of Transparency and Comptroller of the Union (CGU). Therefore, mixed methods were used, starting with qualitative research, in order to understand the governance aspects from the perspective of the various interviewees: system managers, control bodies, grantors, conveners and other managers. To analyze the results of this first part, the content analysis technique, having as support platform some software: NVivo 12, Google Stream, Word Cloud Generator and audio editors were used. Through the analysis of the qualitative of the research, the functional aspects of governance of networks and their dimensions were verified, from the perspective of several actors involved. Other information obtained from the interviews contribute to enrich understanding in various aspects of the System and the Network itself. In TCU, in addition to the number of TCE processes, irregularities were mapped and classified, especially in terms of higher occurrences in the amounts determined; and for quantitative research, were used business intelligence tool, QlikView, to obtain management panels, both in the eTCE System, in the Siconv module itself and in the ‘Siga Brasil’ portal. The quantitative information obtained made it possible to analyze the evolution of resources over time, both in terms of voluntary transfers of concluded instruments, as well as the amounts of resources marked with irregularities. Quantitative processes or instruments gave insight into the evolution of these instruments before the Network was formed and after its implementation. Data from the Ministry of Economy System made it possible to verify the reduction of the times in the cycles and life stages of these instruments, with substantial decreases, both in the execution phase and, mainly, in the rendering of accounts. Governance aspects in terms of institutionalization, standardization, dissemination of skills and information, document flow between government computerized systems, together with the management of the Network have brought benefits for the best execution of resources

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells

Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in an concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog

Ribozyme-based insulator parts buffer synthetic circuits from genetic context

Synthetic genetic programs are built from circuits that integrate sensors and implement temporal control of gene expression. Transcriptional circuits are layered by using promoters to carry the signal between circuits. In other words, the output promoter of one circuit serves as the input promoter to the next. Thus, connecting circuits requires physically connecting a promoter to the next circuit. We show that the sequence at the junction between the input promoter and circuit can affect the input-output response (transfer function) of the circuit. A library of putative sequences that might reduce (or buffer) such context effects, which we refer to as 'insulator parts', is screened in Escherichia coli. We find that ribozymes that cleave the 5′ untranslated region (5′-UTR) of the mRNA are effective insulators. They generate quantitatively identical transfer functions, irrespective of the identity of the input promoter. When these insulators are used to join synthetic gene circuits, the behavior of layered circuits can be predicted using a mathematical model. The inclusion of insulators will be critical in reliably permuting circuits to build different programs.Life Technologies, Inc.United States. Defense Advanced Research Projects Agency (DARPA CLIO N66001-12-C-4018)United States. Office of Naval Research (N00014-10-1-0245)National Science Foundation (U.S.) (CCF-0943385)National Institutes of Health (U.S.) (AI067699)National Science Foundation (U.S.). Synthetic Biology Engineering Research Center (SynBERC, SA5284-11210

Low-Level Laser Therapy Activates NF-kB via Generation of Reactive Oxygen Species in Mouse Embryonic Fibroblasts

Background Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear. Methodology/Principal Findings In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm2 and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration. Conclusion We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT.National Institutes of Health (U.S.) (grant R01AI050875)Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006)United States. Dept. of Defense (CDMRP Program in TBI, W81XWH-09-1-0514)United States. Air Force Office of Scientific Research (FA9950-04-1-0079

Virus-free induction of pluripotency and subsequent excision of reprogramming factors

Reprogramming of somatic cells to pluripotency, thereby creating induced pluripotent stem (iPS) cells, promises to transform regenerative medicine. Most instances of direct reprogramming have been achieved by forced expression of defined factors using multiple viral vectors1-7. However, such iPS cells contain a large number of viral vector integrations1,8, any one of which could cause unpredictable genetic dysfunction. While c-Myc is dispensable for reprogramming9,10, complete elimination of the other exogenous factors is also desired since ectopic expression of either Oct4 or Klf4 can induce dysplasia11,12. Two transient transfection reprogramming methods have been published to address this issue13,14. However, the efficiency of either approach is extremely low, and neither has thus far been applied successfully to human cells. Here we show that non-viral transfection of a single multiprotein expression vector, which comprises the coding sequences of c-Myc​,​ Klf4​,​ Oct4 and Sox2 linked with 2A peptides, can reprogram both mouse and human fibroblasts. Moreover, the transgene can be removed once reprogramming has been achieved. iPS cells produced with this non-viral vector show robust expression of pluripotency markers, indicating a reprogrammed state confirmed functionally by in vitro differentiation assays and formation of adult chimeric mice. When the single vector reprogramming system was combined with a piggyBac transposon15,16 we succeeded in establishing reprogrammed human cell lines from embryonic fibroblasts with robust expression of pluripotency markers. This system minimizes genome modification in iPS cells and enables complete elimination of exogenous reprogramming factors, efficiently providing iPS cells that are applicable to regenerative medicine, drug screening and the establishment of disease models

THE EARLY-MIDDLE PALEOZOIC VOLCANISM AND GEODYNAMIC EVOLUTION OF THE HERLEN MASSIF, CENTRAL PART OF THE CAOB: CONSTRAINS FROM GEOCHEMISTRY, U-PB GEOCHRONOLOGY, LU-HF AND RB-SR ISOTOPES OF VOLCANIC ROCKS

Mongolia lies in the central part of the Central Asian Orogenic Belt [Mossakovsky et al., 1994; Zorin, 1999; Jahn, 2004; Khain et al., 2003; Badarch et al., 2002; Windley et al., 2007; Zhang et al, 2008], or Altaids [Şengör et al., 1993; Şengör, Natal’in, 1996; Wilhem et al., 2012], which is fringed by the Siberian craton in the north and by the Tarim and Sino-Korean Cratons in the south. According to the recent tectonic subdivision, the territory of Mongolia is subdivided into Northern and Southern domains which are separated by the so called Mid Mongolian Tectonic Line [Tomurtogoo, 2012]. The Herlen Massif is one of the important tectonic units of the South Mongolian domain in the Argun-Idermeg super terrane extending through the territories of Russia and China [Parfenov et al., 2009; Tomurtogoo, 2014b]. The Herlen massif, also known as Herlen superterrane [Tomurtogoo, 2012] or Idermeg terrane [Tomurtogoo, 2014a] is composed of Ereendavaa, Undur-Khaan, Idermeg and Gobian Altay-Baruun Urt terranes converged at the end of the Cambrianbeginning of the Ordovician [Badarch et al., 2002; Tomurtogoo, 2014b].Mongolia lies in the central part of the Central Asian Orogenic Belt [Mossakovsky et al., 1994; Zorin, 1999; Jahn, 2004; Khain et al., 2003; Badarch et al., 2002; Windley et al., 2007; Zhang et al, 2008], or Altaids [Şengör et al., 1993; Şengör, Natal’in, 1996; Wilhem et al., 2012], which is fringed by the Siberian craton in the north and by the Tarim and Sino-Korean Cratons in the south. According to the recent tectonic subdivision, the territory of Mongolia is subdivided into Northern and Southern domains which are separated by the so called Mid Mongolian Tectonic Line [Tomurtogoo, 2012]. The Herlen Massif is one of the important tectonic units of the South Mongolian domain in the Argun-Idermeg super terrane extending through the territories of Russia and China [Parfenov et al., 2009; Tomurtogoo, 2014b]. The Herlen massif, also known as Herlen superterrane [Tomurtogoo, 2012] or Idermeg terrane [Tomurtogoo, 2014a] is composed of Ereendavaa, Undur-Khaan, Idermeg and Gobian Altay-Baruun Urt terranes converged at the end of the Cambrianbeginning of the Ordovician [Badarch et al., 2002; Tomurtogoo, 2014b]

SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State

SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors

A mRNA landscape of bovine embryos after standard and MAPK-inhibited culture conditions: a comparative analysis.

BACKGROUND: Genes and signalling pathways involved in pluripotency have been studied extensively in mouse and human pre-implantation embryos and embryonic stem (ES) cells. The unsuccessful attempts to generate ES cell lines from other species including cattle suggests that other genes and pathways are involved in maintaining pluripotency in these species. To investigate which genes are involved in bovine pluripotency, expression profiles were generated from morula, blastocyst, trophectoderm and inner cell mass (ICM) samples using microarray analysis. As MAPK inhibition can increase the NANOG/GATA6 ratio in the inner cell mass, additionally blastocysts were cultured in the presence of a MAPK inhibitor and changes in gene expression in the inner cell mass were analysed. RESULTS: Between morula and blastocyst 3,774 genes were differentially expressed and the largest differences were found in blastocyst up-regulated genes. Gene ontology (GO) analysis shows lipid metabolic process as the term most enriched with genes expressed at higher levels in blastocysts. Genes with higher expression levels in morulae were enriched in the RNA processing GO term. Of the 497 differentially expressed genes comparing ICM and TE, the expression of NANOG, SOX2 and POU5F1 was increased in the ICM confirming their evolutionary preserved role in pluripotency. Several genes implicated to be involved in differentiation or fate determination were also expressed at higher levels in the ICM. Genes expressed at higher levels in the ICM were enriched in the RNA splicing and regulation of gene expression GO term. Although NANOG expression was elevated upon MAPK inhibition, SOX2 and POU5F1 expression showed little increase. Expression of other genes in the MAPK pathway including DUSP4 and SPRY4, or influenced by MAPK inhibition such as IFNT, was down-regulated. CONCLUSION: The data obtained from the microarray studies provide further insight in gene expression during bovine embryonic development. They show an expression profile in pluripotent cells that indicates a pluripotent, epiblast-like state. The inability to culture ICM cells as stem cells in the presence of an inhibitor of MAPK activity together with the reported data indicates that MAPK inhibition alone is not sufficient to maintain a pluripotent character in bovine cells