scholarly journals ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts

2021 ◽  
Vol 118 (9) ◽  
pp. e2025512118
Author(s):  
Qin Li ◽  
Torsten B. Meissner ◽  
Fang Wang ◽  
Ziming Du ◽  
Sai Ma ◽  
...  
Keyword(s):  
Feedback Loop ◽  
First Trimester ◽  
Dual Function ◽  
Small Interfering Rnas ◽  
Closed Expression ◽  
Model Cell ◽  
A Cell ◽  
High Level ◽  
Accessible Chromatin ◽  
Extravillous Trophoblasts

HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal–fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3’s coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence.

scholarly journals Order and stochasticity in the folding of individual Drosophila genomes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sergey V. Ulianov ◽  
Vlada V. Zakharova ◽  
Aleksandra A. Galitsyna ◽  
Pavel I. Kos ◽  
Kirill E. Polovnikov ◽  
...  
Keyword(s):  
Random Walk ◽  
High Resolution ◽  
3D Genome ◽  
Topologically Associating Domains ◽  
Chromatin Folding ◽  
A Cell ◽  
Single Nucleus ◽  
High Level ◽  
Cell To Cell Variability

AbstractMammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome.

Oscillatory Behaviors of Delayed p53 Regulatory Network with microRNA 192 in DNA Damage Response

2021 ◽  
Vol 31 (02) ◽  
pp. 2150020
Author(s):  
Chunyan Gao ◽  
Fangqi Chen
Keyword(s):  
Dna Damage ◽  
Time Delay ◽  
Dna Damage Response ◽  
Positive Feedback ◽  
Regulatory Network ◽  
Feedback Loop ◽  
Research Work ◽  
Positive Feedback Loop ◽  
Damage Response ◽  
High Level

This study develops a general model of delayed p53 regulatory network in the DNA damage response by introducing microRNA 192-mediated positive feedback loop based on the existing research work. Through theoretical analysis and numerical simulation, we find that the delay as a bifurcation parameter can drive the p53-Mdm2 module to undergo a supercritical Hopf bifurcation, thereby producing oscillation behavior. Moreover, we demonstrate how the positive feedback loop formed by p53* and microRNA 192 (miR-192) with the feature of double-negative regulation produces oscillations. Further, a comparison is given to demonstrate that microRNA 192-mediated positive feedback loop affects the robustness of system oscillations. In addition, we show that ataxia telangiectasia mutated kinase (ATM), once activated by DNA damage, makes p53* undergo two Hopf bifurcations. These results reveal that both time delay and miR-192 play tumor suppressing roles by promoting p53 oscillation or high level expression, which will provide a perspective for promoting the development of anti-cancer drugs by targeting miR-192 and time delay.

Introns excised from immunoglobulin pre-mRNAs exist as discrete species

1984 ◽  
Vol 4 (10) ◽  
pp. 2017-2022
Author(s):  
C Coleclough ◽  
D Wood
Keyword(s):  
Cell Lines ◽  
Resolving Power ◽  
Linear Molecule ◽  
Immunoglobulin Kappa ◽  
Polyadenylic Acid ◽  
Nonionic Detergent ◽  
A Cell ◽  
Active Locus ◽  
B Lineage ◽  
High Level

We have discovered a new class of transcripts of immunoglobulin kappa genes in RNA from B-lineage cells. These transcripts have the properties predicted of free introns excised from kappa mRNA precursors. RNA extracted from populations of normal mouse spleen cells polyclonally activated with B-cell mitogens contains four such transcripts; their electrophoretic mobilities correspond to the distances between the intron-exon boundary of the C kappa region and the four useable J kappa elements, and their relative abundance reflects the relative usage of those J segments. Analysis of RNA from monoclonal kappa-expressing cell lines reveals that one active locus produces one free intron, its size determined by which J element is used in that locus. Apart from their distinctive size, free introns are identified by their lack of polyadenylic acid and their ability to hybridize to cloned probes containing intron sequences, but not to the adjacent V or C exonic sequences. They have a characteristic subcellular distribution, being extractable from nuclei by treatment with nonionic detergent; nuclei thus treated retain most of the primary mRNA precursors, but few of the free introns. A high level of kappa gene expression is not a prerequisite of a cell containing detectable free kappa introns; the lymphoma 38c has only 5% or less of the amount of kappa mRNA that the plasmacytoma MCP-11 contains, yet the ratio of free intron to mRNA precursor is about the same in both cell lines. When analyzed by electrophoretic separation of sufficient resolving power, the free introns due to a single kappa locus resolve into two discrete species. We consider that this most likely reflects the existence of two conformers of the intron, one presumably a covalently intact circle and the other linear molecule.

scholarly journals Management of Acute Severe Ulcerative Colitis in a Pregnant Woman With COVID-19 Infection: A Case Report and Review of the Literature

2020 ◽  
Vol 26 (7) ◽  
pp. 971-973 ◽  
Author(s):  
Melissa H Rosen ◽  
Jordan Axelrad ◽  
David Hudesman ◽  
David T Rubin ◽  
Shannon Chang
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
First Trimester ◽  
Review Of The Literature ◽  
Severe Ulcerative Colitis ◽  
Immune Mediated ◽  
First Trimester Of Pregnancy ◽  
Inflammatory Bowel ◽  
High Level

Abstract First detected in Wuhan, China, the novel 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped RNA beta-coronavirus responsible for an unprecedented, worldwide pandemic caused by COVID-19. Optimal management of immunosuppression in inflammatory bowel disease (IBD) patients with COVID-19 infection currently is based on expert opinion, given the novelty of the infection and the corresponding lack of high-level evidence in patients with immune-mediated conditions. There are limited data regarding IBD patients with COVID-19 and no data regarding early pregnancy in the era of COVID-19. This article describes a patient with acute severe ulcerative colitis (UC) during her first trimester of pregnancy who also has COVID-19. The case presentation is followed by a review of the literature to date on COVID-19 in regard to inflammatory bowel disease and pregnancy, respectively.

scholarly journals Chromatin regulates expression of small RNAs to help maintain transposon methylome homeostasis in Arabidopsis

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ranjith K. Papareddy ◽  
Katalin Páldi ◽  
Subramanian Paulraj ◽  
Ping Kao ◽  
Stefan Lutzmayer ◽  
...  
Keyword(s):  
Growth And Development ◽  
Germ Line ◽  
Small Interfering Rnas ◽  
Chromatin States ◽  
Heterochromatin Formation ◽  
Cellular Processes ◽  
A Cell ◽  
Decondensed Chromatin ◽  
And Function ◽  
New Generation

Abstract Background Eukaryotic genomes are partitioned into euchromatic and heterochromatic domains to regulate gene expression and other fundamental cellular processes. However, chromatin is dynamic during growth and development and must be properly re-established after its decondensation. Small interfering RNAs (siRNAs) promote heterochromatin formation, but little is known about how chromatin regulates siRNA expression. Results We demonstrate that thousands of transposable elements (TEs) produce exceptionally high levels of siRNAs in Arabidopsis thaliana embryos. TEs generate siRNAs throughout embryogenesis according to two distinct patterns depending on whether they are located in euchromatic or heterochromatic regions of the genome. siRNA precursors are transcribed in embryos, and siRNAs are required to direct the re-establishment of DNA methylation on TEs from which they are derived in the new generation. Decondensed chromatin also permits the production of 24-nt siRNAs from heterochromatic TEs during post-embryogenesis, and siRNA production from bipartite-classified TEs is controlled by their chromatin states. Conclusions Decondensation of heterochromatin in response to developmental, and perhaps environmental, cues promotes the transcription and function of siRNAs in plants. Our results indicate that chromatin-mediated siRNA transcription provides a cell-autonomous homeostatic control mechanism to help reconstitute pre-existing chromatin states during growth and development including those that ensure silencing of TEs in the future germ line.

scholarly journals Podophyllotoxin and Quercetin in Silico Derivatives Docking Analysis with Cyclooxygenase-2 and Aminopeptidase-N

2021 ◽  
Author(s):  
A.E. Manukyan ◽  
A.A. Hovhannisyan
Keyword(s):  
In Silico ◽  
Biological Activities ◽  
Three Dimensional ◽  
Aminopeptidase N ◽  
Docking Analysis ◽  
Quercetin Derivatives ◽  
Pubchem Database ◽  
A Cell ◽  
Cox 2 ◽  
High Level

ABSTRACTThe cyclooxygenase (COX) enzymes are tumor markers, the inhibition of which can be used in the prevention and therapy of carcinogenesis. It was found that COX-2 IS considered as targets for tumor inhibition. Aminopeptidase N (APN) is a type II membrane-bound metalloprotease associated with cancer, being identified as a cell marker on the surface of malignant myeloid cells and reached a high level of expression in progressive tumors. In anticancer therapy, plant compounds are considered that can inhibit their activity. Modeling of the COX-2 and APN enzymes was carried out on the basis of molecular models of three-dimensional structures from the PDB database [PDB ID: 5f19, 4fyq] RCSB. For docking analysis, 3D ligand models were created using MarvinSketch based on the PubChem database [CID: 5280343, 5281654]. In silico experiments, for the first time, revealed the possible interaction and inhibition of COX-2 and APN by quercetin and quercetin derivatives. Aspirin and Marimastat were taken to compare the results. Possible biological activities and possible side effects of the ligands have been identified.

scholarly journals Trends in maternal use of snus and smoking tobacco in pregnancy. A register study in Southern Norway

2019 ◽  
Author(s):  
Ellen Rygh ◽  
Frode Gallefoss ◽  
Liv Grøtvedt
Keyword(s):  
Tobacco Use ◽  
First Trimester ◽  
Third Trimester ◽  
Smoking During Pregnancy ◽  
Adverse Health Outcomes ◽  
Time Period ◽  
Moist Snuff ◽  
Southern Norway ◽  
High Level ◽  
In Pregnancy

Abstract Background The use of tobacco products including Swedish snus (moist snuff) in pregnancy may cause adverse health outcomes. While smoking prevalence has decreased among fertile women in Norway, snus use has increased during the last years. We investigated whether these trends were reflected also during pregnancy in a population of women in Southern Norway. Methods Data on smoking tobacco and snus use at three time points before and during pregnancy for 20 844 women were retrieved from the electronic birth record for the years 2012-2017. The results for the three-year period 2015-2017 were compared with a previously studied period 2012-2014. Prevalence and quit rates of tobacco use within groups of age, parity and education were reported. Within the same groups adjusted quit rates were analyzed using logistic regression. Mean birthweight and Apgar score of offspring were calculated for tobacco-users and non-users. Results There was an increase of snus use before pregnancy from the period 2012-2014 to the period 2015-2017 from 5.1% (CI; 4.6 to 5.5) to 8.4% (CI; 7.8 to 8.9). Despite this, the use of snus during pregnancy did not increase from the first to the second period, but stabilized at 2.8% (CI; 2.5 to 3.2) in first trimester and 2.0% (CI; 1.7 to 2.2) in third trimester. Cigarette smoking decreased significantly both before and during pregnancy. Snus use and smoking during pregnancy were associated with a reduction in average birthweight, but no significant effects on Apgar scores. Odds ratios for quitting both snus and smoking tobacco during pregnancy were higher for women aged 25-34 years, for the primiparas and for those with a high level of education. Pregnant women were more likely to have quit tobacco use in the last time period compared to the first. Conclusions While smoking during pregnancy was decreasing, the use of snus remained constant, levelling off to around 3% in first trimester and 2% in third trimester. Approximately 25% of those that used snus, and 40% that smoked before pregnancy, continued use to the third trimester. This calls for a continuous watch on the use of snus and other nicotine products during pregnancy.

Spalt modifies EGFR-mediated induction of chordotonal precursors in the embryonic PNS of Drosophila promoting the development of oenocytes

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 711-722 ◽  
Author(s):  
T.E. Rusten ◽  
R. Cantera ◽  
J. Urban ◽  
G. Technau ◽  
F.C. Kafatos ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Fate ◽  
System Development ◽  
Cell Types ◽  
Nervous System Development ◽  
Dual Function ◽  
Evolutionarily Conserved ◽  
A Cell ◽  
And Migration

Genes of the spalt family encode nuclear zinc finger proteins. In Drosophila melanogaster, they are necessary for the establishment of head/trunk identity, correct tracheal migration and patterning of the wing imaginal disc. Spalt proteins display a predominant pattern of expression in the nervous system, not only in Drosophila but also in species of fish, mouse, frog and human, suggesting an evolutionarily conserved role for these proteins in nervous system development. Here we show that Spalt works as a cell fate switch between two EGFR-induced cell types, the oenocytes and the precursors of the pentascolopodial organ in the embryonic peripheral nervous system. We show that removal of spalt increases the number of scolopodia, as a result of extra secondary recruitment of precursor cells at the expense of the oenocytes. In addition, the absence of spalt causes defects in the normal migration of the pentascolopodial organ. The dual function of spalt in the development of this organ, recruitment of precursors and migration, is reminiscent of its role in tracheal formation and of the role of a spalt homologue, sem-4, in the Caenorhabditis elegans nervous system.

Knowledge Disclosed in Patent Documents as Source of Information to Address Emergencies: A Strategy to Achieve Technological Developments Addressing COVID-19

2021 ◽  
Vol 15 ◽  
Author(s):  
Tatiana Duque Martins ◽  
Diéricon Sousa Cordeiro
Keyword(s):  
Emergency Situation ◽  
Daily Basis ◽  
Accurate Information ◽  
Technological Information ◽  
The World ◽  
Technological Developments ◽  
A Cell ◽  
Patent Documents ◽  
High Level ◽  
Source Of Information

Background: Face COVID-19 pandemic, a need for accurate information on SARS-CoV-2 virus is urgent and scientific reports have been published on daily basis to enable effective technologies to fight the disease progression. However, at the first moments of Pandemic, no information on the matter was known and technologies to fight the Pandemic were not readily available. However, searches in patent databases, if strategically designed, can offer quick responses to new pandemics. Objective: Aiming to provide existing information in patent documents useful to develop technologies addressing COVID-19, considering the emergency situation the world was facing and the knowledge of COVID-19 available until April, 2020, this work presents an analysis of the main characteristics of the technological information in patent documents worldwide, related to coronaviruses and the severe acute respiratory syndrome (SARS). Method: Regions of concentration of such technologies, the number of available documents and their technological fields are disclosed in three approaches: 1) a wide search, retrieving technologies on SARS or coronaviruses; 2) a targeted search, retrieving documents additionally referring to Angiotensin converting enzyme (ACE2), which is used by SARS-CoV-2 to enter a cell and 3) a punctual search, which retrieved patents disclosing aspects related to SARS-CoV-2 available at that time. Results and Conclusion: Results evidence the high-level technology involved in these developments and a monopoly tendency of such technologies, evidencing that it is possible to find answers to new problems in patent documents.

scholarly journals Decreased Equilibrative Nucleoside Transporter 1 (ENT1) Activity Contributes to the High Extracellular Adenosine Levels in Mesenchymal Glioblastoma Stem-Like Cells

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1914 ◽  
Author(s):  
Sebastián Alarcón ◽  
María de los Ángeles Toro ◽  
Carolina Villarreal ◽  
Rómulo Melo ◽  
Rodrigo Fernández ◽  
...  
Keyword(s):  
Adenosine Monophosphate ◽  
Prostatic Acid Phosphatase ◽  
Cell Subpopulation ◽  
Migration And Invasion ◽  
Nucleoside Transporter ◽  
Extracellular Adenosine ◽  
Adenosine Uptake ◽  
A Cell ◽  
High Level ◽  
Lower Expression

Glioblastoma multiforme is one of the most malignant types of cancer. This is mainly due to a cell subpopulation with an extremely aggressive potential, called glioblastoma stem-like cells (GSCs). These cells produce high levels of extracellular adenosine which has been associated with increased chemoresistance, migration, and invasion in glioblastoma. In this study, we attempted to elucidate the mechanisms that control extracellular adenosine levels in GSC subtypes. By using primary and U87MG-derived GSCs, we associated increased extracellular adenosine with the mesenchymal phenotype. [3H]-adenosine uptake occurred mainly through the equilibrative nucleoside transporters (ENTs) in GSCs, but mesenchymal GSCs have lower expression and ENT1-mediated uptake activity than proneural GSCs. By analyzing expression and enzymatic activity, we determined that ecto-5′-nucleotidase (CD73) is predominantly expressed in proneural GSCs, driving AMPase activity. While in mesenchymal GSCs, both CD73 and Prostatic Acid Phosphatase (PAP) contribute to the AMP (adenosine monophosphate) hydrolysis. We did not observe significant differences between the expression of proteins involved in the metabolization of adenosine among the GCSs subtypes. In conclusion, the lower expression and activity of the ENT1 transporter in mesenchymal GSCs contributes to the high level of extracellular adenosine that these GSCs present.

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