scholarly journals Uridine Prevents Negative Effects of OXPHOS Xenobiotics on Dopaminergic Neuronal Differentiation

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1407
Author(s):  
Eldris Iglesias ◽  
M. Pilar Bayona-Bafaluy ◽  
Alba Pesini ◽  
Nuria Garrido-Pérez ◽  
Patricia Meade ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Oxidative Phosphorylation ◽  
Neuronal Differentiation ◽  
Fetal Brain ◽  
Global Dna Methylation ◽  
Protective Agent ◽  
Negative Consequences ◽  
Negative Effects ◽  
Negative Effect

Neuronal differentiation appears to be dependent on oxidative phosphorylation capacity. Several drugs inhibit oxidative phosphorylation and might be detrimental for neuronal differentiation. Some pregnant women take these medications during their first weeks of gestation when fetal nervous system is being developed. These treatments might have later negative consequences on the offspring’s health. To analyze a potential negative effect of three widely used medications, we studied in vitro dopaminergic neuronal differentiation of cells exposed to pharmacologic concentrations of azidothymidine for acquired immune deficiency syndrome; linezolid for multidrug-resistant tuberculosis; and atovaquone for malaria. We also analyzed the dopaminergic neuronal differentiation in brains of fetuses from pregnant mice exposed to linezolid. The drugs reduced the in vitro oxidative phosphorylation capacity and dopaminergic neuronal differentiation. This differentiation process does not appear to be affected in the prenatally exposed fetus brain. Nevertheless, the global DNA methylation in fetal brain was significantly altered, perhaps linking an early exposure to a negative effect in older life. Uridine was able to prevent the negative effects on in vitro dopaminergic neuronal differentiation and on in vivo global DNA methylation. Uridine could be used as a protective agent against oxidative phosphorylation-inhibiting pharmaceuticals provided during pregnancy when dopaminergic neuronal differentiation is taking place.

scholarly journals Dominant Negative Mutants Implicate STAT5 in Myeloid Cell Proliferation and Neutrophil Differentiation

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4154-4166 ◽  
Author(s):  
Robert L. Ilaria ◽  
Robert G. Hawley ◽  
Richard A. Van Etten
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Cytokine Signaling ◽  
Transactivation Domain ◽  
Negative Effects ◽  
Murine Bone Marrow ◽  
Negative Effect

Abstract STAT5 is a member of the signal transducers and activation of transcription (STAT) family of latent transcription factors activated in a variety of cytokine signaling pathways. We introduced alanine substitution mutations in highly conserved regions of murine STAT5A and studied the mutants for dimerization, DNA binding, transactivation, and dominant negative effects on erythropoietin-induced STAT5-dependent transcriptional activation. The mutations included two near the amino-terminus (W255KR→AAA and R290QQ→AAA), two in the DNA-binding domain (E437E→AA and V466VV→AAA), and a carboxy-terminal truncation of STAT5A (STAT5A/▵53C) analogous to a naturally occurring isoform of rat STAT5B. All of the STAT mutant proteins were tyrosine phosphorylated by JAK2 and heterodimerized with STAT5B except for the WKR mutant, suggesting an important role for this region in STAT5 for stabilizing dimerization. The WKR, EE, and VVV mutants had no detectable DNA-binding activity, and the WKR and VVV mutants, but not EE, were defective in transcriptional induction. The VVV mutant had a moderate dominant negative effect on erythropoietin-induced STAT5 transcriptional activation, which was likely due to the formation of heterodimers that are defective in DNA binding. Interestingly, the WKR mutant had a potent dominant negative effect, comparable to the transactivation domain deletion mutant, ▵53C. Stable expression of either the WKR or ▵53C STAT5 mutants in the murine myeloid cytokine-dependent cell line 32D inhibited both interleukin-3–dependent proliferation and granulocyte colony-stimulating factor (G-CSF)–dependent differentiation, without induction of apoptosis. Expression of these mutants in primary murine bone marrow inhibited G-CSF–dependent granulocyte colony formation in vitro. These results demonstrate that mutations in distinct regions of STAT5 exert dominant negative effects on cytokine signaling, likely through different mechanisms, and suggest a role for STAT5 in proliferation and differentiation of myeloid cells.

Impact of the Global Financial Crisis on IT Sector. The Case of Greece

2022 ◽  
Vol 9 (1) ◽  
pp. 0-0
Keyword(s):  
Global Financial Crisis ◽  
Extended Period ◽  
Early Years ◽  
Negative Consequences ◽  
Negative Effects ◽  
Innovation Development ◽  
Negative Effect ◽  
Greek Economy ◽  
The Global Financial Crisis ◽  
The Impact

The impact of the Information and Technology (IT) sector on the countries’ innovation development has been recognized as crucial in prior and recent research studies. Moreover, firms’ innovativeness affects positively countries’ economies. Nevertheless, the global economic crisis of the last decade constituted a significant barrier to the development of country economies and had a negative effect on firms’ performance. Specifically, the negative consequences of the global crisis became harder for Southern Europe Countries. More specifically the Greek economy was suffered by an extended period of crisis with harder consequences than those of other European countries. The main purpose of this study was to examine the financial performance of Greek IT firms in the early years of crisis. Our findings have been relevant to those of previous studies which observed negative effects of the financial recession on firms profitability.

scholarly journals Lead Exposure Disrupts Global DNA Methylation in Human Embryonic Stem Cells and Alters Their Neuronal Differentiation

2014 ◽  
Vol 139 (1) ◽  
pp. 142-161 ◽  
Author(s):  
Marie-Claude Senut ◽  
Arko Sen ◽  
Pablo Cingolani ◽  
Asra Shaik ◽  
Susan J. Land ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Neuronal Differentiation ◽  
Human Embryonic Stem Cells ◽  
Lead Exposure ◽  
Embryonic Stem ◽  
Global Dna Methylation

scholarly journals Global DNA methylation: role, status and genome-wide approaches to study epigenetic mark in cloned embryos

2020 ◽  
pp. 41-59
Author(s):  
Shivani Malpotra ◽  
Ahmad Hussain
Keyword(s):  
Dna Methylation ◽  
Developmental Stages ◽  
Gene Expression Pattern ◽  
Methylation Profile ◽  
Global Dna Methylation ◽  
Epigenetic Mark ◽  
Dna Methylation Profile ◽  
Low Efficiency

Somatic cell nuclear transfer (SCNT) technique has been proving its worth for more than two decades now as over 20 different species have been successfully cloned. SCNT protocol for cloning is well established but efficiency in terms of live birth rate is still low. Epigenetic abnormality following nuclear reprogramming is considered as the main culprit behind its low efficiency. DNA methylation is one of the most important epigenetic modifications that directly or indirectly regulate gene expression pattern, development and genome stability. Embryos produced through SCNT are found to express abnormal DNA methylation profile in comparison with in vivo or in vitro produced embryos. In order to improve DNA methylation profile in cloned embryos, a complete database of whole genome is required to find out specific faulty targets. Many techniques including low throughput and high throughput approach has been used to profile DNA methylation pattern in bovine embryos throughout the developmental stages. In the present review, we have compiled the overall status of global DNA methylation, the effect of aberrant DNA methylation on development and evolution in methodologies used for profiling global DNA methylome in cloned embryos.

scholarly journals Dominant Negative Mutants Implicate STAT5 in Myeloid Cell Proliferation and Neutrophil Differentiation

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4154-4166 ◽  
Author(s):  
Robert L. Ilaria ◽  
Robert G. Hawley ◽  
Richard A. Van Etten
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Cytokine Signaling ◽  
Transactivation Domain ◽  
Negative Effects ◽  
Murine Bone Marrow ◽  
Negative Effect

STAT5 is a member of the signal transducers and activation of transcription (STAT) family of latent transcription factors activated in a variety of cytokine signaling pathways. We introduced alanine substitution mutations in highly conserved regions of murine STAT5A and studied the mutants for dimerization, DNA binding, transactivation, and dominant negative effects on erythropoietin-induced STAT5-dependent transcriptional activation. The mutations included two near the amino-terminus (W255KR→AAA and R290QQ→AAA), two in the DNA-binding domain (E437E→AA and V466VV→AAA), and a carboxy-terminal truncation of STAT5A (STAT5A/▵53C) analogous to a naturally occurring isoform of rat STAT5B. All of the STAT mutant proteins were tyrosine phosphorylated by JAK2 and heterodimerized with STAT5B except for the WKR mutant, suggesting an important role for this region in STAT5 for stabilizing dimerization. The WKR, EE, and VVV mutants had no detectable DNA-binding activity, and the WKR and VVV mutants, but not EE, were defective in transcriptional induction. The VVV mutant had a moderate dominant negative effect on erythropoietin-induced STAT5 transcriptional activation, which was likely due to the formation of heterodimers that are defective in DNA binding. Interestingly, the WKR mutant had a potent dominant negative effect, comparable to the transactivation domain deletion mutant, ▵53C. Stable expression of either the WKR or ▵53C STAT5 mutants in the murine myeloid cytokine-dependent cell line 32D inhibited both interleukin-3–dependent proliferation and granulocyte colony-stimulating factor (G-CSF)–dependent differentiation, without induction of apoptosis. Expression of these mutants in primary murine bone marrow inhibited G-CSF–dependent granulocyte colony formation in vitro. These results demonstrate that mutations in distinct regions of STAT5 exert dominant negative effects on cytokine signaling, likely through different mechanisms, and suggest a role for STAT5 in proliferation and differentiation of myeloid cells.

scholarly journals Sleep deprivation and diet affect human GH gene expression in transgenic mice in vivo

2020 ◽  
Vol 9 (12) ◽  
pp. 1135-1147
Author(s):  
Jessica S Jarmasz ◽  
Yan Jin ◽  
Hana Vakili ◽  
Peter A Cattini
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Sleep Deprivation ◽  
Chow Diet ◽  
Negative Effects ◽  
Production Studies ◽  
First Time ◽  
Rna Levels

Human (h) growth hormone (GH) production studies are largely limited to effects on secretion. How pituitary hGH gene (hGH-N/GH1) expression is regulated is important in our understanding of the role hGH plays in physiology and disease. Here we assess for the first time the effect of sleep deprivation (SD) and high-fat diet (HFD) on hGH-N expression in vivo using partially humanized 171hGH/CS transgenic (TG) mice, and attempted to elucidate a role for DNA methylation. Activation of hGH-N expression requires interactions between promoter and upstream locus control region (LCR) sequences including pituitary-specific hypersensitive site (HS) I/II. Both SD and diet affect hGH secretion, but the effect of SD on hGH-N expression is unknown. Mice fed a HFD or regular chow diet for 3 days underwent SD (or no SD) for 6 h at Zeitgeber time (ZT) 3. Serum and pituitaries were assessed over 24 h at 6-h intervals beginning at ZT 14. SD and HFD caused significant changes in serum corticosterone and insulin, as well as hGH and circadian clock-related gene RNA levels. No clear association between DNA methylation and the negative effects of SD or diet on hGH RNA levels was observed. However, a correlation with increased methylation at a CpG (cytosine paired with a guanine) in a putative E-box within the hGH LCR HS II was suggested in situ. Methylation at this site also increased BMAL1/CLOCK-related nuclear protein binding in vitro. These observations support an effect of SD on hGH synthesis at the level of gene expression.

scholarly journals O6D.2 Evidence of dna methylation changes by carbon nanotubes in a translational study design

2019 ◽  
Vol 76 (Suppl 1) ◽  
pp. A57.2-A57
Author(s):  
Manosij Ghosh ◽  
Deniz Öner ◽  
Lode Godderis ◽  
Peter Hoet
Keyword(s):  
Dna Methylation ◽  
Cross Sectional Study ◽  
Methylation Pattern ◽  
Global Dna Methylation ◽  
Limited Information ◽  
Cross Sectional ◽  
Translational Study ◽  
Exposed Workers

IntroductionWhile studies have addressed genotoxic effects of CNT, only limited information are available on epigenetic effects. We designed a study to investigate DNA methylation alterations in vitro, in vivo and in occupationally exposed workers.Material and methodsIn vitro studies were performed in 16-HBE and THP-1 cells. For the in vivo study, BALB/c mice were administered intratracheally with single-wall CNT (SWCNTs) and multi-wall (MWCNTs) at high (2.5 mg/kg) and low (0.25 mg/kg) doses. For the cross sectional study, 24 workers exposed to aggregates of MWCNT of 500 nm–100 µm with concentrations of 4.6–42.6 µg/m3 and 43 unexposed referents were recruited. Global DNA methylation and demethylation patterns were analysed by LC-MS/MS. Methylation of specific genes was measured by Pyromark 24® (Qiagen). Genome-wide assessment of DNA methylation was performed with Infinium HumanMethylation450 BeadChip Array.ResultsIn general, we did not find global DNA methylation alteration for both CNTs. In 16-HBE cells, differentially methylated and expressed genes (MWCNTs>SWCNTs) from p53 signalling, DNA damage repair and cell cycle pathways were observed. In THP-1 cells, CNTs induced promoter-specific methylation of genes involved in several signaling cascade, vascular endothelial growth factor and platelet activation pathways. In lungs of BALB/c mice CNTs affected methylation of ATM gene. Finally, analysis of gene-specific DNA methylation in exposed workers revealed significant changes for DNMT1, ATM, SKI, and HDAC4 promoter CpGs.ConclusionsEpigenetic changes seem to occur at sub cyto-genotoxic concentrations in vitro. Alteration in DNA methylation pattern could be a natural reaction of cells but could also silence critical genes and reprogram cellular functions.

scholarly journals Industrial Robotic Systems & International Human Rights

2018 ◽  
Vol 11 (1) ◽  
pp. 53
Author(s):  
Abbas Basiri ◽  
Reza Mousazadeh
Keyword(s):  
Human Rights ◽  
Health And Safety ◽  
Industrial Robots ◽  
Robotic Systems ◽  
Employment Rate ◽  
Negative Consequences ◽  
Negative Effects ◽  
International Human Rights ◽  
Negative Effect ◽  
International Human

The development and growth of industrial robots started in 1947. The velocity of this process has increased as a result of development technology. Now, industrial robots have broad applications. They can be substituted for human force in different industries. The ever increasing growth and development of robotic technology in the field of industry was always challenging. One of these important challenges emphasizes on the negative effect of robotics on employment rate. As a result of cost reduction and production improvement, industrial countries have been motivated to employ robots and substitute them for workers in production lines. However, the broad use of robotic systems in the field of industry can have negative consequences in different societies. One of the common and negative effects of these systems is the reduction of employment opportunities which increases unemployment for those who look for jobs and for employed individuals. It can lead to employment insecurity and threat the health and safety of workers. These matters violate the human rights regarding the security and health of individuals, equality of opportunity, and particularly the employment rate. It also violates the employment standards supported by the international human rights instruments. 

scholarly journals Hypo-methylation mediates chromosomal instability in pancreatic NET

2017 ◽  
Vol 24 (3) ◽  
pp. 137-146 ◽  
Author(s):  
I Marinoni ◽  
A Wiederkeher ◽  
T Wiedmer ◽  
S Pantasis ◽  
A Di Domenico ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chromosomal Instability ◽  
Global Dna Methylation ◽  
Epigenetic Changes ◽  
Knock Down ◽  
Alternative Lengthening ◽  
Increased Risk ◽  
Pancreatic Net ◽  
G0 Phase

DAXX and or ATRX loss occur in 40% of pancreatic neuroendocrine tumors (PanNETs). PanNETs negative for DAXX or ATRX show an increased risk of relapse. The tumor-associated pathways activated upon DAXX or ATRX loss and how this event may induce chromosomal instability (CIN) and alternative lengthening telomeres (ALT) are still unknown. Both DAXX and ATRX are involved in DNA methylation regulation. DNA methylation of heterochromatin and of non-coding sequences is extremely important for the maintenance of genomic stability. We analyzed the association of DAXX and/or ATRX loss and CIN with global DNA methylation in human PanNET samples and the effect of DAXX knock-down on methylation and cell proliferation. We assessedLINE1as well as global DNA methylation in 167 PanNETs, and we found that DAXX and or ATRX-negative tumors and tumors with CIN were hypomethylated. DAXX knock-down in PanNET cell lines blocked cells in G1/G0 phase and seemed to increase CIN in QGP-1 cells. However, no direct changes in DNA methylation were observed after DAXX knock-downin vitro. In conclusion, our data indicate that epigenetic changes are crucial steps in the progression of PanNETs loss and suggest that DNA methylation is the mechanism via which CIN is induced, allowing clonal expansion and selection.

DNA methylation profile of liver of mice conceived by in vitro fertilization

2021 ◽  
pp. 1-9
Author(s):  
Saúl Lira-Albarrán ◽  
Xiaowei Liu ◽  
Seok Hee Lee ◽  
Paolo Rinaudo
Keyword(s):  
Dna Methylation ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Global Dna Methylation ◽  
Analysis Tool ◽  
Gene Promoters ◽  
Vitro Fertilization ◽  
Natural Mating

Abstract Offspring generated by in vitro fertilization (IVF) are believed to be healthy but display a possible predisposition to chronic diseases, like hypertension and glucose intolerance. Since epigenetic changes are believed to underlie such phenotype, this study aimed at describing global DNA methylation changes in the liver of adult mice generated by natural mating (FB group) or by IVF. Embryos were generated by IVF or natural mating. At 30 weeks of age, mice were sacrificed. The liver was removed, and global DNA methylation was assessed using whole-genome bisulfite sequencing (WGBS). Genomic Regions for Enrichment Analysis Tool (GREAT) and G:Profilerβ were used to identify differentially methylated regions (DMRs) and for functional enrichment analysis. Overrepresented gene ontology terms were summarized with REVIGO, while canonical pathways (CPs) were identified with Ingenuity® Pathway Analysis. Overall, 2692 DMRs (4.91%) were different between the groups. The majority of DMRs (84.92%) were hypomethylated in the IVF group. Surprisingly, only 0.16% of CpG islands were differentially methylated and only a few DMRs were located on known gene promoters (n = 283) or enhancers (n = 190). Notably, the long-interspersed element (LINE), short-interspersed element (SINE), and long terminal repeat (LTR1) transposable elements showed reduced methylation (P < 0.05) in IVF livers. Cellular metabolic process, hepatic fibrosis, and insulin receptor signaling were some of the principal biological processes and CPs modified by IVF. In summary, IVF modifies the DNA methylation signature in the adult liver, resulting in hypomethylation of genes involved in metabolism and gene transcription regulation. These findings may shed light on the mechanisms underlying the developmental origin of health and disease.

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