scholarly journals Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies

2019 ◽  
Vol 37 (1) ◽  
pp. 247-267 ◽  
Author(s):  
Carolina Uggenti ◽  
Alice Lepelley ◽  
Yanick J. Crow
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Evolutionary Strategy ◽  
Type I ◽  
Self Awareness ◽  
Inborn Errors ◽  
Biological Challenge ◽  
Disease States ◽  
Dna And Rna ◽  
Type I Interferonopathies

Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon–mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self–nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self/nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid–driven inflammation.

scholarly journals Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

2016 ◽  
Vol 94 (10) ◽  
pp. 1081-1084 ◽  
Author(s):  
Min Ae Lee-Kirsch ◽  
Claudia Günther ◽  
Axel Roers
Keyword(s):  
Nucleic Acid ◽  
Type I ◽  
Type I Interferonopathies

scholarly journals Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Amanda L. Gavin ◽  
Deli Huang ◽  
Tanya R. Blane ◽  
Therese C. Thinnes ◽  
Yusuke Murakami ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Inflammatory Diseases ◽  
Type I ◽  
Multiple Sensors ◽  
Dna And Rna ◽  
Elevated Type ◽  
Minor Contribution ◽  
Ifn Γ ◽  
A Minor ◽  
Rna And Dna

AbstractPhospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases. Here, we show that PLD3 and PLD4 digest ssRNA in addition to ssDNA as reported previously. Moreover, Pld3−/−Pld4−/− mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ. Pathology is rescued in Unc93b13d/3dPld3−/−Pld4−/− mice, which lack all endosomal TLR signaling; genetic codeficiency or antibody blockade of TLR9 or TLR7 ameliorates disease less effectively, suggesting that both RNA and DNA sensing by TLRs contributes to inflammation. IFN-γ made a minor contribution to pathology. Elevated type I IFN and some other remaining perturbations in Unc93b13d/3dPld3−/−Pld4−/− mice requires STING (Tmem173). Our results show that PLD3 and PLD4 regulate both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways and have implications for the treatment of nucleic acid-driven inflammatory disease.

Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids

2018 ◽  
Vol 72 (1) ◽  
pp. 447-478 ◽  
Author(s):  
Xiaojun Tan ◽  
Lijun Sun ◽  
Jueqi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Defense ◽  
Innate Immune ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Immune Recognition ◽  
Microbial Infection ◽  
Microbial Infections

Microbial infections are recognized by the innate immune system through germline-encoded pattern recognition receptors (PRRs). As most microbial pathogens contain DNA and/or RNA during their life cycle, nucleic acid sensing has evolved as an essential strategy for host innate immune defense. Pathogen-derived nucleic acids with distinct features are recognized by specific host PRRs localized in endolysosomes and the cytosol. Activation of these PRRs triggers signaling cascades that culminate in the production of type I interferons and proinflammatory cytokines, leading to induction of an antimicrobial state, activation of adaptive immunity, and eventual clearance of the infection. Here, we review recent progress in innate immune recognition of nucleic acids upon microbial infection, including pathways involving endosomal Toll-like receptors, cytosolic RNA sensors, and cytosolic DNA sensors. We also discuss the mechanisms by which infectious microbes counteract host nucleic acid sensing to evade immune surveillance.

An Investigation of the Anomalous Staining of Chromatin by the Acid Dyes, Methyl Blue and Aniline Blue

1962 ◽  
Vol s3-103 (64) ◽  
pp. 519-530
Author(s):  
R. B. McKAY
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Methyl Blue ◽  
Aniline Blue ◽  
Acid Dyes ◽  
Dna And Rna ◽  
Basic Dyes ◽  
Blue Stain ◽  
High Degree ◽  
Mechanism Of The Reaction

Methyl blue and aniline blue, though acid dyes, stain the chromatin of the spermatogenetic cells of the mouse (especially of the primary spermatocytes) strongly. Extraction of the basiphil nucleic acid constituents from the chromatin causes loss of this property, while destruction of acidophilia in the protein constituents does not. It has been concluded that the dyes interact with the nucleic acids. Further, they appear to react with both DNA and RNA in the chromatin, although they show no affinity for the cytoplasm of the exocrine cells in sections of pancreas, which is rich in RNA. The mechanism of the reaction has not been fully elucidated, although apparently the dyes do not behave as basic dyes towards the nucleic acids, and the interaction is non-ionic. Methyl blue and aniline blue stain strongly other ‘acidic’ substrates, such as cellulose and nitrocellulose, and attempts have been made to relate the staining of nucleic acids to the staining of these substrates, particularly cellulose; for the staining properties of this substrate have been intensively investigated elsewhere. No satisfactory correlation, however, has been obtained, for nitrocellulose has been found to be less strongly stained at pH 3.0 than at pH 7.1, while the reverse is true for cellulose. Further, only one of 3 direct cotton dyes used appears to have any affinity for the chromatin of the spermatogenetic cells. Direct cotton dyes have large flat molecules with a high degree of conjugation. It is suggested that these characteristics are essential for interaction with nucleic acids, and also that the molecule must be reasonably compact. Finally, it has been shown that methyl blue, aniline blue, and 3 direct cotton dyes of the azo type have no ability to stain the glycogen in liver cells, yet glycogen is very closely related to cellulose.

scholarly journals Oligonucleotide-based systems: DNA, microRNAs, DNA/RNA aptamers

2016 ◽  
Vol 60 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Pawan Jolly ◽  
Pedro Estrela ◽  
Michael Ladomery
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Rna Aptamers ◽  
Locked Nucleic Acid ◽  
Synthetic Analogue ◽  
Dna And Rna ◽  
Naturally Occurring ◽  
Wide Range ◽  
Synthetic Oligonucleotides ◽  
Shed Light

There are an increasing number of applications that have been developed for oligonucleotide-based biosensing systems in genetics and biomedicine. Oligonucleotide-based biosensors are those where the probe to capture the analyte is a strand of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or a synthetic analogue of naturally occurring nucleic acids. This review will shed light on various types of nucleic acids such as DNA and RNA (particularly microRNAs), their role and their application in biosensing. It will also cover DNA/RNA aptamers, which can be used as bioreceptors for a wide range of targets such as proteins, small molecules, bacteria and even cells. It will also highlight how the invention of synthetic oligonucleotides such as peptide nucleic acid (PNA) or locked nucleic acid (LNA) has pushed the limits of molecular biology and biosensor development to new perspectives. These technologies are very promising albeit still in need of development in order to bridge the gap between the laboratory-based status and the reality of biomedical applications.

Highly stable triple helix formation by homopyrimidine (l)-acyclic threoninol nucleic acids with single stranded DNA and RNA

2015 ◽  
Vol 13 (8) ◽  
pp. 2366-2374 ◽  
Author(s):  
Vipin Kumar ◽  
Venkitasamy Kesavan ◽  
Kurt V. Gothelf
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Triple Helix ◽  
Helical Structures ◽  
Single Stranded Dna ◽  
Dna And Rna ◽  
Helix Formation ◽  
Triple Helix Formation

Homopyrimidine acyclic (l)-threoninol nucleic acid (aTNA) was synthesized and found to form highly stable (l)-aTNA–DNA–(l)-aTNA and (l)-aTNA–RNA–(l)-aTNA triple helical structures.

scholarly journals Dissecting and predicting different types of binding sites in nucleic acids based on structural information

2021 ◽  
Author(s):  
Zheng Jiang ◽  
Si-Rui Xiao ◽  
Rong Liu
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Binding Sites ◽  
Structural Information ◽  
Machine Learning Algorithms ◽  
Nucleic Acid Binding ◽  
Integrative Framework ◽  
Dna And Rna ◽  
Feature Spaces ◽  
Critical Binding

Abstract The biological functions of DNA and RNA generally depend on their interactions with other molecules, such as small ligands, proteins and nucleic acids. However, our knowledge of the nucleic acid binding sites for different interaction partners is very limited, and identification of these critical binding regions is not a trivial work. Herein, we performed a comprehensive comparison between binding and nonbinding sites and among different categories of binding sites in these two nucleic acid classes. From the structural perspective, RNA may interact with ligands through forming binding pockets and contact proteins and nucleic acids using protruding surfaces, while DNA may adopt regions closer to the middle of the chain to make contacts with other molecules. Based on structural information, we established a feature-based ensemble learning classifier to identify the binding sites by fully using the interplay among different machine learning algorithms, feature spaces and sample spaces. Meanwhile, we designed a template-based classifier by exploiting structural conservation. The complementarity between the two classifiers motivated us to build an integrative framework for improving prediction performance. Moreover, we utilized a post-processing procedure based on the random walk algorithm to further correct the integrative predictions. Our unified prediction framework yielded promising results for different binding sites and outperformed existing methods.

Introduction to DNA

2018 ◽  
pp. 1-10
Author(s):  
David Bensimon ◽  
Vincent Croquette ◽  
Jean-François Allemand ◽  
Xavier Michalet ◽  
Terence Strick
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Structural Properties ◽  
Helical Structure ◽  
3D Structures ◽  
Double Helical Structure ◽  
Dna And Rna

This chapter provides a quick introduction to the structural properties of nucleic acids (DNA and RNA). It describes the famed double-helical structure of DNA, the more complex 3D structures adopted by RNA, and the random (possibly) twisted coil that nucleic acid can display at large scales.

Thermodynamics of nucleic acids and their interactions with ligands

2000 ◽  
Vol 33 (3) ◽  
pp. 255-306 ◽  
Author(s):  
Andrew N. Lane ◽  
Terence C. Jenkins
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Large Scale ◽  
Wide Spectrum ◽  
Model Systems ◽  
Linear Polymers ◽  
Dna And Rna ◽  
Rna Duplexes ◽  
Scale Properties ◽  
Folded Structures

1. Introduction 2551.1 General thermodynamics 2562. Nucleic acid thermodynamics 2602.1 DNA duplexes 2612.2 RNA duplexes 2632.3 Hybrid DNA–RNA duplexes 2642.4 Hydration 2672.5 Conformational flexibility 2692.6 Thermodynamics 2723. Nucleic acid–ligand interactions 2773.1 Minor groove binders 2783.2 DNA intercalators 2843.3 Triple-helical systems 2883.3.1 Structures 2883.3.2 Hydration 2913.3.3 Thermodynamics 2914. Conclusions 2955. Acknowledgements 2986. References 298In recent years the availability of large quantities of pure synthetic DNA and RNA has revolutionised the study of nucleic acids, such that it is now possible to study their conformations, dynamics and large-scale properties, and their interactions with small ligands, proteins and other nucleic acids in unprecedented detail. This has led to the (re)discovery of higher order structures such as triple helices and quartets, and also the catalytic activity of RNA contingent on three-dimensional folding, and the extraordinary specificity possible with DNA and RNA aptamers.Nucleic acids are quite different from proteins, even though they are both linear polymers formed from a small number of monomeric units. The major difference reflects the nature of the linkage between the monomers. The 5′–3′ phosphodiester linkage in nucleic acids carries a permanent negative charge, and affords a relatively large number of degrees of freedom, whereas the essentially rigid planar peptide linkage in proteins is neutral and provides only two degrees of torsional freedom per backbone residue. These two properties conspire to make nucleic acids relatively flexible and less likely to form extensive folded structures. Even when true 3D folded structures are formed from nucleic acids, the topology remains simple, with the anionic phosphates forming the surface of the molecule. Nevertheless, nucleic acids do occur in a variety of structures that includes single strands and high-order duplex, triplex or tetraplex (‘quadruplex’) forms. The principles of biological recognition and the related problem of understanding the forces that stabilise such folded structures are in some respects more straightforward than for proteins, making them attractive model systems for understanding general biophysical problems. This view is aided by the relatively facile chemical synthesis of pure nucleic acids of any desired size and defined sequence, and the ease of incorporation of a wide spectrum of chemically modified bases, sugars and backbone linkers. Such modifications are considerably more difficult to achieve with oligopeptides or proteins.

scholarly journals Highly specific enrichment of rare nucleic acid fractions using Thermus thermophilus argonaute with applications in cancer diagnostics

2019 ◽  
Vol 48 (4) ◽  
pp. e19-e19 ◽  
Author(s):  
Jinzhao Song ◽  
Jorrit W Hegge ◽  
Michael G Mauk ◽  
Junman Chen ◽  
Jacob E Till ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Elevated Temperatures ◽  
Thermus Thermophilus ◽  
Low Frequency ◽  
Cancer Diagnostics ◽  
Detection Methods ◽  
Dna And Rna ◽  
Novel Approach ◽  
Clinically Significant

Abstract Detection of disease-associated, cell-free nucleic acids in body fluids enables early diagnostics, genotyping and personalized therapy, but is challenged by the low concentrations of clinically significant nucleic acids and their sequence homology with abundant wild-type nucleic acids. We describe a novel approach, dubbed NAVIGATER, for increasing the fractions of Nucleic Acids of clinical interest Via DNA-Guided Argonaute from Thermus thermophilus (TtAgo). TtAgo cleaves specifically guide-complementary DNA and RNA with single nucleotide precision, greatly increasing the fractions of rare alleles and, enhancing the sensitivity of downstream detection methods such as ddPCR, sequencing, and clamped enzymatic amplification. We demonstrated 60-fold enrichment of the cancer biomarker KRAS G12D and ∼100-fold increased sensitivity of Peptide Nucleic Acid (PNA) and Xenonucleic Acid (XNA) clamp PCR, enabling detection of low-frequency (<0.01%) mutant alleles (∼1 copy) in blood samples of pancreatic cancer patients. NAVIGATER surpasses Cas9-based assays (e.g. DASH, Depletion of Abundant Sequences by Hybridization), identifying more mutation-positive samples when combined with XNA-PCR. Moreover, TtAgo does not require targets to contain any specific protospacer-adjacent motifs (PAM); is a multi-turnover enzyme; cleaves ssDNA, dsDNA and RNA targets in a single assay; and operates at elevated temperatures, providing high selectivity and compatibility with polymerases.

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