Статті в журналах: "Endogenous nucleic acids"

1

Kontaki, Elena, and Dimitrios T. Boumpas. "Innate immunity in systemic lupus erythematosus: Sensing endogenous nucleic acids." Journal of Autoimmunity 35, no. 3 (November 2010): 206–11. http://dx.doi.org/10.1016/j.jaut.2010.06.009.

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2

Roers, Axel, Björn Hiller, and Veit Hornung. "Recognition of Endogenous Nucleic Acids by the Innate Immune System." Immunity 44, no. 4 (April 2016): 739–54. http://dx.doi.org/10.1016/j.immuni.2016.04.002.

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3

Traykovska, Martina, Sjoerd Miedema, and Robert Penchovsky. "Clinical Trials of Functional Nucleic Acids." International Journal of Biomedical and Clinical Engineering 7, no. 2 (July 2018): 46–60. http://dx.doi.org/10.4018/ijbce.2018070104.

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This chapter describes how functional nucleic acids, such as aptamers, antisense oligonucleotides (ASOs), small interfering (si) RNAs, and ribozymes are considered by some researchers as valuable tools to develop therapeutic agents. They have not been particularly fast in reaching the market as medicines, due to endogenous barriers to extracellular trafficking and cellular uptake of nucleic acids and their inherent instability when applied in vivo. However, research carried out by the nucleic acid engineering community and pharmaceutical companies to circumvent these obstacles has led to the approval of a few aptamers and ASOs as drugs. Nucleic acid therapeutics are usually administered locally to diseased tissue. The drug candidates currently in clinical trials commonly use the same administration methods as previously licensed nucleic acid therapeutics. These administration techniques carry their own safety risks and advantages. In this article, the present state is discussed and prospective options for the use ASOs and aptamers as drugs are listed.

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4

Thakkar, H., A. N. Butt, J. Powrie, R. Holt, and R. Swaminathan. "Circulating Nucleic Acids in the Assessment of Endogenous Growth Hormone Production." Annals of the New York Academy of Sciences 1137, no. 1 (August 2008): 58–65. http://dx.doi.org/10.1196/annals.1448.003.

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5

Paramasivam, Prasath, Martin Stöter, Eloina Corradi, Irene Dalla Costa, Andreas Höijer, Stefano Bartesaghi, Alan Sabirsh, et al. "Quantitative intracellular retention of delivered RNAs through optimized cell fixation and immunostaining." RNA 28, no. 3 (December 23, 2021): 433–46. http://dx.doi.org/10.1261/rna.078895.121.

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Detection of nucleic acids within subcellular compartments is key to understanding their function. Determining the intracellular distribution of nucleic acids requires quantitative retention and estimation of their association with different organelles by immunofluorescence microscopy. This is particularly important for the delivery of nucleic acid therapeutics, which depends on endocytic uptake and endosomal escape. However, the current protocols fail to preserve the majority of exogenously delivered nucleic acids in the cytoplasm. To solve this problem, by monitoring Cy5-labeled mRNA delivered to primary human adipocytes via lipid nanoparticles (LNP), we optimized cell fixation, permeabilization, and immunostaining of a number of organelle markers, achieving quantitative retention of mRNA and allowing visualization of levels that escape detection using conventional procedures. The optimized protocol proved effective on exogenously delivered siRNA, miRNA, as well as endogenous miRNA. Our protocol is compatible with RNA probes of single molecule fluorescence in situ hybridization (smFISH) and molecular beacon, thus demonstrating that it is broadly applicable to study a variety of nucleic acids in cultured cells.

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6

Basak, Ranjan, Naveen Kumar Nair, and Indraneel Mittra. "Evidence for cell-free nucleic acids as continuously arising endogenous DNA mutagens." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 793-794 (November 2016): 15–21. http://dx.doi.org/10.1016/j.mrfmmm.2016.10.002.

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7

Scholtissek, Benedikt, Sabine Zahn, Judith Maier, Sophie Klaeschen, Christine Braegelmann, Michael Hoelzel, Thomas Bieber, Winfried Barchet, and Joerg Wenzel. "Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus." Journal of Investigative Dermatology 137, no. 7 (July 2017): 1484–92. http://dx.doi.org/10.1016/j.jid.2017.03.018.

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8

Mahajan, Akanksha, Lisa Hurley, Serena Tommasini-Ghelfi, Corey Dussold, Alexander Stegh, and Chad Mirkin. "IMMU-53. STING-ING GLIOBLASTOMA WITH SPHERICAL NUCLEIC ACIDS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi104—vi105. http://dx.doi.org/10.1093/neuonc/noab196.412.

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Abstract The Stimulator of Interferon Genes (STING) pathway represents a major innate immune sensing mechanism for tumor-derived DNA. Modified cyclic dinucleotides (CDNs) that mimic the endogenous STING ligand cGAMP are currently being explored in patients with solid tumors that are amenable to intratumoral delivery. Inadequate bioavailability and insufficient lipophilicity are limiting factors for clinical CDN development, in particular when consideration is given to systemic administration approaches. We have shown that the formulation of oligonucleotides into Spherical Nucleic Acid (SNA) nanostructures, i.e.,the presentation of oligonucleotides at high density on the surface of nanoparticle cores, lead to biochemical and biological properties that are radically different from those of linear oligonucleotides. First-generation brain-penetrant siRNA-based SNAs (NCT03020017, recurrent GBM) have recently completed early clinical trials. Here, we report the development of a STING-agonistic immunotherapy by targeting cGAS, the sensor of cytosolic dsDNA upstream of STING, with SNAs presenting dsDNA at high surface density. The strategy of using SNAs exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs. SNA nanostructures carrying a 45bp IFN-simulating dsDNA oligonucleotide, the most commonly used and widely characterized cGAS activator, potently activated the cGAS-STING pathway in vitro and in vivo. In a poorly immunogenic and highly aggressive syngeneic mouse glioma model, in which tumours were well-established, only one dose of intranasal treatment with STING-SNAs decelerated tumour growth, improved survival and importantly, was well-tolerated. Our use of SNAs addresses the challenges of nucleic acid delivery to intracranial tumor sites via intranasal route, exploits the binding of dsDNA molecules on the SNA surface to enhance the formation of a dimeric cGAS:DNA complex and establishes cGAS-agonistic SNAs as a novel class of immune-stimulatory modalities for triggering innate immune responses against tumor.

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9

Victoria, Joseph G., Chunlin Wang, Morris S. Jones, Crystal Jaing, Kevin McLoughlin, Shea Gardner, and Eric L. Delwart. "Viral Nucleic Acids in Live-Attenuated Vaccines: Detection of Minority Variants and an Adventitious Virus." Journal of Virology 84, no. 12 (April 7, 2010): 6033–40. http://dx.doi.org/10.1128/jvi.02690-09.

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ABSTRACT Metagenomics and a panmicrobial microarray were used to examine eight live-attenuated viral vaccines. Viral nucleic acids in trivalent oral poliovirus (OPV), rubella, measles, yellow fever, varicella-zoster, multivalent measles/mumps/rubella, and two rotavirus live vaccines were partially purified, randomly amplified, and pyrosequenced. Over half a million sequence reads were generated covering from 20 to 99% of the attenuated viral genomes at depths reaching up to 8,000 reads per nucleotides. Mutations and minority variants, relative to vaccine strains, not known to affect attenuation were detected in OPV, mumps virus, and varicella-zoster virus. The anticipated detection of endogenous retroviral sequences from the producer avian and primate cells was confirmed. Avian leukosis virus (ALV), previously shown to be noninfectious for humans, was present as RNA in viral particles, while simian retrovirus (SRV) was present as genetically defective DNA. Rotarix, an orally administered rotavirus vaccine, contained porcine circovirus-1 (PCV1), a highly prevalent nonpathogenic pig virus, which has not been shown to be infectious in humans. Hybridization of vaccine nucleic acids to a panmicrobial microarray confirmed the presence of endogenous retroviral and PCV1 nucleic acids. Deep sequencing and microarrays can therefore detect attenuated virus sequence changes, minority variants, and adventitious viruses and help maintain the current safety record of live-attenuated viral vaccines.

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10

Burrill, Julia, Rachel Hotta, Barbara Daniel, and Nunzianda Frascione. "Accumulation of endogenous and exogenous nucleic acids in “Touch DNA” components on hands." ELECTROPHORESIS 42, no. 16 (June 10, 2021): 1594–604. http://dx.doi.org/10.1002/elps.202000371.

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11

Bonnard, Elisabeth, Honoré Mazarguil, and Jean-Marie Zajac. "Peptide nucleic acids targeted to the mouse proNPFFA reveal an endogenous opioid tonus." Peptides 23, no. 6 (June 2002): 1107–13. http://dx.doi.org/10.1016/s0196-9781(02)00034-7.

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12

Economos, Nicholas G., Stanley Oyaghire, Elias Quijano, Adele S. Ricciardi, W. Mark Saltzman, and Peter M. Glazer. "Peptide Nucleic Acids and Gene Editing: Perspectives on Structure and Repair." Molecules 25, no. 3 (February 8, 2020): 735. http://dx.doi.org/10.3390/molecules25030735.

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Unusual nucleic acid structures are salient triggers of endogenous repair and can occur in sequence-specific contexts. Peptide nucleic acids (PNAs) rely on these principles to achieve non-enzymatic gene editing. By forming high-affinity heterotriplex structures within the genome, PNAs have been used to correct multiple human disease-relevant mutations with low off-target effects. Advances in molecular design, chemical modification, and delivery have enabled systemic in vivo application of PNAs resulting in detectable editing in preclinical mouse models. In a model of β-thalassemia, treated animals demonstrated clinically relevant protein restoration and disease phenotype amelioration, suggesting a potential for curative therapeutic application of PNAs to monogenic disorders. This review discusses the rationale and advances of PNA technologies and their application to gene editing with an emphasis on structural biochemistry and repair.

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13

Kitagishi, Yasuko, Naoko Okumura, Hitomi Yoshida, Chika Tateishi, Yuri Nishimura, and Satoru Matsuda. "Dicer Functions in Aquatic Species." Journal of Amino Acids 2011 (June 9, 2011): 1–5. http://dx.doi.org/10.4061/2011/782187.

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Dicer is an RNase III enzyme with two catalytic subunits, which catalyzes the cleavage of double-stranded RNA to small interfering RNAs and micro-RNAs, which are mainly involved in invasive nucleic acid defense and endogenous genes regulation. Dicer is abundantly expressed in embryos, indicating the importance of the protein in early embryonic development. In addition, Dicer is thought to be involved in defense mechanism against foreign nucleic acids such as viruses. This paper will mainly focus on the recent progress of Dicer-related research and discuss potential RNA interference pathways in aquatic species.

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14

JIANG, LIXU, LIN NING, CHUNCHAO PU, ZIXIN WANG, BIFANG HE, and JIAN HUANG. "Characterization of endogenous nucleic acids that bind to NgAgo in Natronobacterium gregoryi sp2 cells." BIOCELL 46, no. 2 (2022): 547–57. http://dx.doi.org/10.32604/biocell.2022.016500.

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15

JIANG, LIXU, LIN NING, CHUNCHAO PU, ZIXIN WANG, BIFANG HE, and JIAN HUANG. "Characterization of endogenous nucleic acids that bind to NgAgo in Natronobacterium gregoryi sp2 cells." BIOCELL 46, no. 2 (2022): 547–57. http://dx.doi.org/10.32604/biocell.2021.016500.

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16

Di Domizio, Jeremy, Ran Zhang, Ming Zhuo, Loren Stagg, John Ladbury, Michel Gilliet, and Wei Cao. "A novel class of host-derived etiological agent for autoimmunity: oligomers of endogenous proteins bind to self-nucleic acids and trigger type I IFN production by plasmacytoid dendritic cells (44.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 44.2. http://dx.doi.org/10.4049/jimmunol.186.supp.44.2.

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Abstract Under certain conditions, some soluble endogenous proteins can form ordered oligomeric structures leading to the assembly of stable insoluble amyloids, a process that increases with age. The presence of such structures is associated with cellular toxicity and diseases development, e.g. Alzheimer disease, type II diabetes. Recent studies clearly show that the primary toxic species in such pathologies is the soluble oligomers of proteins, precursors of amyloids. Yet, it is unknown if such aberrant forms of proteins would elicit any immune reaction. Here we obtained oligomers derived from several human endogenous proteins and characterized their biochemical and immunological functions. The oligomeric proteins preferentially bind to both DNA and RNA and can be effectively internalized by cells. Surprisingly, the soluble protein oligomers enable prominent IFNα production by PBMCs to self-DNA, self-RNA and necrotic cell debris in a pDC-dependent manner. Consistently, peptides from amyloid β and prion protein, two known etiological agents associated with amyloid diseases, display similar innate immune functions by complexing with nucleic acids and inducing IFN production by pDCs. Therefore, oligomers of endogenous proteins formed during the aging process may strongly promote the host’s type I IFN response to self-nucleic acids, a reaction likely favoring the development of autoimmunity, such as SLE where strong type I IFN presence correlates with disease pathology.

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17

Kondkar, Altaf A., Wei Hong, Wolfgang Bergmeier, Jay H. Herman, Ying Jin, Srikanth Nagalla, and Paul F. Bray. "Transfection of Human Platelets Down-Regulates Endogenous mRNA." Blood 114, no. 22 (November 20, 2009): 4026. http://dx.doi.org/10.1182/blood.v114.22.4026.4026.

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Abstract Abstract 4026 Poster Board III-962 Platelets are anucleate and, as such, lack the capacity for transcribing and expressing exogenously introduced genes or cDNAs. However, platelets contain megakaryocyte-transcribed mRNAs and respond to physiological stimuli by translating mRNA into protein. Compared to the megakaryocyte, the relative contribution of platelet translation to the platelet proteome is unknown. However, it is noteworthy that platelets in Blood Bank storage conditions increase their levels of integrin β3 over time and that the half-life of some mRNA is longer in platelets than in nucleated cells (Thon et al, Transfusion 2009). Considering the potential clinical and research utility of manipulating platelet gene expression, we tested the feasibility of transfecting platelets in-vitro with a fluorescently (FAM)-labeled siRNA for GAPDH as assessed by flow cytometry. We tested both electroporation and Lipofectamine with both washed platelets and platelet-rich plasma (PRP) using a variety of conditions. Our studies demonstrated optimal transfection efficiency at 24 hours using 2 × 108/mL washed platelets, 6 μL Lipofectamine and 400 pmoles siRNA. These initial studies demonstrated that 8.4% of platelets were transfected with the FAM-labeled siRNA compared to control platelets without Lipofectamine. Transfected platelets were then isolated by cell sorting. Changes in GAPDH mRNA levels were determined by TaqMan gene expression assays using18S RNA as an endogenous control. Two independent experiments demonstrated a 40% reduction in GAPDH mRNA in platelets transfected with GAPDH siRNA as compared to a FAM-labeled scrambled siRNA. These results offer proof-of-concept that nucleic acids can be introduced into platelets by non-viral methods and that these nucleic acids can modify gene expression. Future studies to increase platelet transfection efficiency may be valuable for manipulating platelet qualities in stored platelet products or to use platelets as vehicles for delivering products to the sites of vascular damage. Disclosures: No relevant conflicts of interest to declare.

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18

Herr, A. J. "Silence is green." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 946–51. http://dx.doi.org/10.1042/bst0320946.

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Small RNAs serve as the specificity determinant for a collection of regulatory mechanisms known as RNA silencing. Plants use these mechanisms to control the expression of endogenous genes and to suppress unwanted foreign nucleic acids. Several gene families implicated in silencing have undergone expansion and evidence exists for multiple RNA silencing pathways. Recent progress in defining the components of a number of these pathways is examined here.

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Engalycheva, Maria G., Maria A. Fomina, Dmitry S. Petrov, Daria I. Miroshnikova, and Natalia V. Korotkova. "Assessment of the severity of endogenous intoxication in Alzheimer's disease." Butlerov Communications 63, no. 7 (July 31, 2020): 119–25. http://dx.doi.org/10.37952/roi-jbc-01/20-63-7-119.

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The development of neurodegenerative pathologies, among which the leading positions worldwide belong to Alzheimer's disease, is accompanied by the activation of free radical processes in the tissues of the brain and in the patient's body as a whole, which leads to the accumulation of products of oxidative modification of proteins, lipids, nucleic acids, and the formation of a syndrome of endogenous intoxication. An integral indicator reflecting the severity of this syndrome is the level of substances of low and medium molecular weight in various biological media. It is known that changes at the molecular level in Alzheimer's disease occur 5-10 years before the clinical manifestation of pathology. The development of polymodal panels for biochemical screening, diagnostics, monitoring of the course of pathology is underway. The aim of this study was to determine the severity of endogenous intoxication in patients with Alzheimer's disease and vascular dementia. The object of the study was the blood plasma of patients, as well as fractionated leukocytes - mononuclear and polymorphonuclear. The choice of biological material for the study is dictated by the need to search for a prognostic marker of the disease available for diagnosis, as well as by the accumulated theoretical material on various metabolic changes in peripheral blood cells in neurodegenerative diseases. According to the results of the study, it was found that in patients with Alzheimer's disease in mononuclear leukocytes of peripheral blood, the level of substances of low and medium molecular weight is higher than in patients with vascular dementia and patients without signs of neurodegeneration. In addition, in this fraction of leukocytes, the concentration of hypoxanthine, inosine, xanthosine and their derivatives is high, which may be a consequence of the oxidative modification of nucleic acids in the cells under study.

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20

Orefice, Nicola Salvatore. "Development of New Strategies Using Extracellular Vesicles Loaded with Exogenous Nucleic Acid." Pharmaceutics 12, no. 8 (July 26, 2020): 705. http://dx.doi.org/10.3390/pharmaceutics12080705.

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Gene therapy is a therapeutic strategy of delivering foreign genetic material (encoding for an important protein) into a patient’s target cell to replace a defective gene. Nucleic acids are embedded within the adeno-associated virus (AAVs) vectors; however, preexisting immunity to AAVs remains a significant concern that impairs their clinical application. Extracellular vesicles (EVs) hold great potential for therapeutic applications as vectors of nucleic acids due to their endogenous intercellular communication functions through their cargo delivery, including lipids and proteins. So far, small RNAs (siRNA and micro (mi)RNA) have been mainly loaded into EVs to treat several diseases, but the potential use of EVs to load and deliver exogenous plasmid DNA has not been thoroughly described. This review provides a comprehensive overview of the principal methodologies currently employed to load foreign genetic material into EVs, highlighting the need to find the most effective strategies for their successful clinical translation.

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21

Martemucci, Giovanni, Ciro Costagliola, Michele Mariano, Luca D’andrea, Pasquale Napolitano, and Angela Gabriella D’Alessandro. "Free Radical Properties, Source and Targets, Antioxidant Consumption and Health." Oxygen 2, no. 2 (April 12, 2022): 48–78. http://dx.doi.org/10.3390/oxygen2020006.

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Free radicals have acquired growing importance in the fields of biology and medicine. They are produced during many different endogenous and exogenous processes. Mitochondria are the main source of endogenous reactive oxygen species (ROS) produced at cell level. The overproduction of free radicals can damage macromolecules such as nucleic acids, proteins and lipids. This leads to tissue damage in various chronic and degenerative diseases. Antioxidants play a crucial role in the body’s defense against free radicals. This review concerns the main properties of free radicals, their sources and deleterious effects. It highlights the potential role of the dietary supplementation of antioxidants and discusses unsolved problems regarding antioxidant supplements in the prevention and therapy of diseases.

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22

Van Bruggen, Craig, David Punihaole, Allison R. Keith, Andrew J. Schmitz, Jakub Tolar, Renee R. Frontiera, and Theresa M. Reineke. "Quinine copolymer reporters promote efficient intracellular DNA delivery and illuminate a protein-induced unpackaging mechanism." Proceedings of the National Academy of Sciences 117, no. 52 (December 14, 2020): 32919–28. http://dx.doi.org/10.1073/pnas.2016860117.

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Polymeric vehicles that efficiently package and controllably release nucleic acids enable the development of safer and more efficacious strategies in genetic and polynucleotide therapies. Developing delivery platforms that endogenously monitor the molecular interactions, which facilitate binding and release of nucleic acids in cells, would aid in the rational design of more effective vectors for clinical applications. Here, we report the facile synthesis of a copolymer containing quinine and 2-hydroxyethyl acrylate that effectively compacts plasmid DNA (pDNA) through electrostatic binding and intercalation. This polymer system poly(quinine-co-HEA) packages pDNA and shows exceptional cellular internalization, transgene expression, and low cytotoxicity compared to commercial controls for several human cell lines, including HeLa, HEK 293T, K562, and keratinocytes (N/TERTs). Using quinine as an endogenous reporter for pDNA intercalation, Raman imaging revealed that proteins inside cells facilitate the unpackaging of polymer–DNA complexes (polyplexes) and the release of their cargo. Our work showcases the ability of this quinine copolymer reporter to not only facilitate effective gene delivery but also enable diagnostic monitoring of polymer–pDNA binding interactions on the molecular scale via Raman imaging. The use of Raman chemical imaging in the field of gene delivery yields unprecedented insight into the unpackaging behavior of polyplexes in cells and provides a methodology to assess and design more efficient delivery vehicles for gene-based therapies.

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Lin, Yun, Terry Means, Edwin P. Alyea, Christine M. Canning, Robert J. Soiffer, Jerome Ritz, and Catherine J. Wu. "Effective Graft-Versus-Leukemia Responses Are Associated with the Presence of Nucleic Acid-Immunoglobulin Complexes That Stimulate TLR8 and TLR9." Blood 108, no. 11 (November 16, 2006): 188. http://dx.doi.org/10.1182/blood.v108.11.188.188.

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Abstract To elucidate the basis of the potent graft versus leukemia (GvL) immune response that is initiated with donor lymphocyte infusion (DLI), we hypothesized the existence of an endogenous adjuvant that enhances antigen-specific immunity. In patients with chronic myeloid leukemia (CML) who achieved molecular remission after DLI, we previously identified a panel of CML-associated antigens that are targets of antibodies present in post-DLI sera and are predicted to bind nucleic acids. Recent studies in SLE have identified immunostimulatory nucleic-acid antibody complexes in patient sera, which can stimulate Toll-like receptors (TLRs) in plasmacytoid dendritic cells (pDCs). To identify immunostimulatory factors associated with GvL, we studied 6 patients that responded to DLI without clinically significant GvHD. Consistent with our prediction that sera from DLI responders contain an immunostimulatory activity, we measured a 3 to 50-fold increase in the expression of MIP-1α, TNF-α, IP-10 and IFN-α transcripts in normal peripheral blood mononuclear cells (PBMC) induced by exposure to 5 of 6 post-DLI sera. No increase in cytokine/chemokine expression was observed upon exposure to sera from pre DLI sera from the same patients, from 3 of 3 DLI non-responders, nor from 3 of 3 CML patients who achieved molecular remission after imatinib treatment. To identify the cell type that responds to the immunostimulatory activity in post-DLI sera, we isolated B, T, NK cells, monocytes, myeloid DCs and pDCs, and cultured them with pre- or post-DLI responder sera. In contrast to published findings that SLE sera stimulate pDCs, we found that post DLI sera induced normal monocytes to express high levels of MIP-1α, IP-10, MCP, TNF-α, IFN-α, IL-6, IL-8 and IL-12. Pretreatment of post-DLI sera with DNase, RNase, papain or pepsin resulted in marked decrease in IL-8 induction, demonstrating that this endogenous immunostimulatory factor requires both nucleic acid and protein for its adjuvant activity. Four active post-DLI sera were then used to stimulate stable HEK transfectants expressing TLR2, 3, 4, 8 or 9. IL-8 expression increased only in the TLR8 and TLR9-expressing cells lines that are known to be responsive to RNA and DNA respectively. IL-8 expression was further induced by post-DLI sera in TLR9-expressing cell lines co-transfected with CD32, suggesting that internalization by FcR may enhance delivery of nucleic acids to endosomal TLR8/9. None of the TLR transfectants could be activated by pre-DLI sera from the same responder patients, nor by post-DLI sera from non-responders. Finally, sera from responders collected between 2 weeks to several months after DLI consistently activated TLR8 and TLR9 suggesting that endogenous TLR8/9 activation may contribute to the early immunologic events that lead to an effective DLI response. Ongoing studies are focused on precisely identifying the TLR8/TLR9 agonists in DLI responders, studying the immunologic effects of this endogenous adjuvant and determining the association of our previously identified CML antigens with nucleic acids that activate TLR8 and TLR9. In summary, we demonstrate for the first time that effective tumor immunity is correlated with the presence of endogenous adjuvant-immunoglobulin complexes in patient sera, and propose that these observations form the basis for novel tumor vaccine strategies.

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Preissner, Klaus T., and Heiko Herwald. "Extracellular nucleic acids in immunity and cardiovascular responses: between alert and disease." Thrombosis and Haemostasis 117, no. 07 (2017): 1272–82. http://dx.doi.org/10.1160/th-16-11-0858.

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SummarySevere inflammatory complications are a potential consequence in patients with predetermined conditions of infections, pulmonary diseases, or cardiovascular disorders. Notably, the amplitude of the inflammatory response towards these complications can dictate the disease progression and outcome. During the recent years, evidence from basic research as well as from clinical studies has identified self-extracellular nucleic acids as important players in the crosstalk between immunity and cardiovascular diseases. These stress- or injury-induced endogenous polymeric macromolecules not only serve as “alarmins” or “Danger-associated molecular patterns” (DAMPs), but their functional repertoire goes far beyond such activities in innate immunity. In fact, (patho-) physiological functions of self-extracellular DNA and RNA are associated and in many cases causally related to arterial and venous thrombosis, atherosclerosis, ischemia-reperfusion injury or tumour progression. Yet, the underlying molecular mechanisms are far from being completely understood. Interestingly enough, however, novel antagonistic approaches in vitro and in vivo, particularly using natural endonucleases or synthetic nucleic acid binding polymers, appear to be promising and safe therapeutic options for future studies. The aim of this review article is to provide an overview of the current state of (patho-) physiological functions of self-extracellular nucleic acids with special emphasis on their role as beneficial / alerting or adverse / damaging factors in connection with immune responses, inflammation, thrombosis, and cardiovascular diseases.

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Shin, Min Sun, Youna Kang, Naeun Lee, Ki Soo Kang, Rossitza Lazova, and Insoo Kang. "U1-snRNP activates the NLRP3 inflammasome in human monocytes (171.7)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 171.7. http://dx.doi.org/10.4049/jimmunol.188.supp.171.7.

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Abstract The NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome is a caspase-1-containing cytosolic protein complex that is essential for processing and secretion of IL-1β. The U1-small nuclear ribonucleoprotein (U1-snRNP) which includes U1-small nuclear RNA (U1-snRNA) is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Antibodies against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus (SLE), suggesting a potential role of U1-snRNP in autoimmunity. Although endogenous DNA and microbial nucleic acids are known to activate the inflammasomes, it is unknown whether endogenous RNA-containing U1-snRNP could activate this molecular complex. Here we show that U1-snRNP activates the NLRP3 inflammasome in CD14+ human monocytes dependently of anti-U1-snRNP antibodies, leading to IL-1β production. Reactive oxygen species (ROS) and K+ efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR 7/8 pathway decreased IL-1β production from monocytes treated with U1-snRNP in the presence of anti-U1-snRNP antibodies. Plus, the expression of caspase-1 and IL-1β by CD14+ cells was found in cutaneous lupus tissue. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like SLE where anti-U1-snRNP antibodies are present.

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Pawlak, K., C. Lawi-Berger, and W. Sadée. "Incorporation of nucleotide tracers into nucleic acids in permeabilized cells and cellular homogenates." Biochemical Journal 238, no. 1 (August 15, 1986): 13–21. http://dx.doi.org/10.1042/bj2380013.

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The validity of permeabilized cells as a model of DNA and RNA synthesis was studied with the use of mouse S-49 lymphoblastoma cells rendered permeable by exposure to L-alpha-lysophosphatidylcholine. The permeabilized cells readily incorporated exogenously supplied cytosine and uracil nucleotides into HClO4-insoluble macromolecular material. However, the incorporation of these tracers did not require the three other complementary nucleotides, and adenine, guanine or thymine nucleotide tracers were incorporated at much lower rates. These results, which were also obtained with permeabilized Abelsohn-leukaemia-virus-transformed mouse macrophages, mouse neuroblastoma cells and S-49 lymphoblastoma homogenates, are inconsistent with semi-conservative DNA replication or RNA transcription; rather, they suggest the involvement of terminal nucleotidyltransferase(s) that mediate the incorporation of uracil and cytosine nucleotides. DNA synthesis was restored when permeabilized cells or cellular homogenates were supplemented with denatured salmon testes DNA. These results suggest that endogenous cellular DNA is impaired in its function as a template for DNA replication and transcription in vitro. Metabolic channelling or compartmentation of nucleic-acid-precursor pathways could not be demonstrated in the permeabilized cells.

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27

Nermut, Milan V., and Ariberto Fassati. "Structural Analyses of Purified Human Immunodeficiency Virus Type 1 Intracellular Reverse Transcription Complexes." Journal of Virology 77, no. 15 (August 1, 2003): 8196–206. http://dx.doi.org/10.1128/jvi.77.15.8196-8206.2003.

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ABSTRACT Retroviruses copy their RNA genome into a DNA molecule, but little is known of the structure of the complex mediating reverse transcription in vivo. We used confocal and electron microscopy to study the structure of human immunodeficiency virus type 1 (HIV-1) intracellular reverse transcription complexes (RTCs). Cytoplasmic extracts were prepared 3, 4, and 16 h after acute infection by Dounce homogenization in hypotonic buffer. RTCs were purified by velocity sedimentation, followed by density fractionation in linear sucrose gradients and dialysis in a large pore cellulose membrane. RTCs had a sedimentation velocity of approximately 350 S and a density of 1.34 g/ml and were active in an endogenous reverse transcription assay. Double labeling of nucleic acids and viral proteins allowed specific visualization of RTCs by confocal microscopy. Electron microscopy revealed that RTCs are large nucleoprotein structures of variable shape consisting of packed filaments ca. 6 nm thick. Integrase and Vpr are associated with discrete regions of the 6-nm filaments. The nucleic acids within the RTC are coated by small proteins distinct from nucleocapsid and are partially protected from nuclease digestion.

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28

Chen, Taiping, François-Michel Boisvert, David P. Bazett-Jones, and Stéphane Richard. "A Role for the GSG Domain in Localizing Sam68 to Novel Nuclear Structures in Cancer Cell Lines." Molecular Biology of the Cell 10, no. 9 (September 1999): 3015–33. http://dx.doi.org/10.1091/mbc.10.9.3015.

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The GSG (GRP33, Sam68, GLD-1) domain is a protein module found in an expanding family of RNA-binding proteins. The numerous missense mutations identified genetically in the GSG domain support its physiological role. Although the exact function of the GSG domain is not known, it has been shown to be required for RNA binding and oligomerization. Here it is shown that the Sam68 GSG domain plays a role in protein localization. We show that Sam68 concentrates into novel nuclear structures that are predominantly found in transformed cells. These Sam68 nuclear bodies (SNBs) are distinct from coiled bodies, gems, and promyelocytic nuclear bodies. Electron microscopic studies show that SNBs are distinct structures that are enriched in phosphorus and nitrogen, indicating the presence of nucleic acids. A GFP-Sam68 fusion protein had a similar localization as endogenous Sam68 in HeLa cells, diffusely nuclear with two to five SNBs. Two other GSG proteins, the Sam68-like mammalian proteins SLM-1 and SLM-2, colocalized with endogenous Sam68 in SNBs. Different GSG domain missense mutations were investigated for Sam68 protein localization. Six separate classes of cellular patterns were obtained, including exclusive SNB localization and association with microtubules. These findings demonstrate that the GSG domain is involved in protein localization and define a new compartment for Sam68, SLM-1, and SLM-2 in cancer cell lines.

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29

Lee, Wai-Leng, Jing-Ying Huang, and Lie-Fen Shyur. "Phytoagents for Cancer Management: Regulation of Nucleic Acid Oxidation, ROS, and Related Mechanisms." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–22. http://dx.doi.org/10.1155/2013/925804.

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Accumulation of oxidized nucleic acids causes genomic instability leading to senescence, apoptosis, and tumorigenesis. Phytoagents are known to reduce the risk of cancer development; whether such effects are through regulating the extent of nucleic acid oxidation remains unclear. Here, we outlined the role of reactive oxygen species in nucleic acid oxidation as a driving force in cancer progression. The consequential relationship between genome instability and cancer progression highlights the importance of modulation of cellular redox level in cancer management. Current epidemiological and experimental evidence demonstrate the effects and modes of action of phytoagents in nucleic acid oxidation and provide rationales for the use of phytoagents as chemopreventive or therapeutic agents. Vitamins and various phytoagents antagonize carcinogen-triggered oxidative stress by scavenging free radicals and/or activating endogenous defence systems such as Nrf2-regulated antioxidant genes or pathways. Moreover, metal ion chelation by phytoagents helps to attenuate oxidative DNA damage caused by transition metal ions. Besides, the prooxidant effects of some phytoagents pose selective cytotoxicity on cancer cells and shed light on a new strategy of cancer therapy. The “double-edged sword” role of phytoagents as redox regulators in nucleic acid oxidation and their possible roles in cancer prevention or therapy are discussed in this review.

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30

Souza, Amancio José de, Beatriz Madalena Januzzi Mendes, and Francisco de Assis Alves Mourão Filho. "Gene silencing: concepts, applications, and perspectives in woody plants." Scientia Agricola 64, no. 6 (December 2007): 645–56. http://dx.doi.org/10.1590/s0103-90162007000600014.

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RNA interference, transcriptional gene silencing, virus induced gene silencing, and micro RNAs comprise a series of mechanisms capable of suppressing gene expression in plants. These mechanisms reveal similar biochemical pathways and appear to be related in several levels. The ability to manipulate gene silencing has produced transgenic plants able to switch off endogenous genes and invading nucleic acids. This powerful biotechnological tool has provided plant breeders and researchers with great opportunity to accelerate breeding programs and developmental studies in woody plants. This research work reports on gene silencing in woody plants, and discuss applications and future perspectives.

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31

Kabza, Adam M., and Jonathan T. Sczepanski. "l-DNA-Based Catalytic Hairpin Assembly Circuit." Molecules 25, no. 4 (February 20, 2020): 947. http://dx.doi.org/10.3390/molecules25040947.

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Isothermal, enzyme-free amplification methods based on DNA strand-displacement reactions show great promise for applications in biosensing and disease diagnostics but operating such systems within biological environments remains extremely challenging due to the susceptibility of DNA to nuclease degradation. Here, we report a catalytic hairpin assembly (CHA) circuit constructed from nuclease-resistant l-DNA that is capable of unimpeded signal amplification in the presence of 10% fetal bovine serum (FBS). The superior biostability of the l-DNA CHA circuit relative to its native d-DNA counterpart was clearly demonstrated through a direct comparison of the two systems (d versus l) under various conditions. Importantly, we show that the l-CHA circuit can be sequence-specifically interfaced with an endogenous d-nucleic acid biomarker via an achiral peptide nucleic acid (PNA) intermediary, enabling catalytic detection of the target in FBS. Overall, this work establishes a blueprint for the detection of low-abundance nucleic acids in harsh biological environments and provides further impetus for the construction of DNA nanotechnology using l-oligonucleotides.

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32

Denis, Kathleen A., Scott Provost, Owen N. Witte, Ralph L. Brinster, and Ursula Storb. "Delay of Early B-Lymphocyte Development by Gamma 2b Immunoglobulin Transgene: Effect on Differentiation-Specific Molecules." Developmental Immunology 1, no. 2 (1990): 105–12. http://dx.doi.org/10.1155/1990/71584.

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Mice transgenic forγ2b Ig heavy chain were examined for alterations in B-cell differentiation and endogenous Ig gene rearrangement and expression. Fresh bone marrow from these mice was markedly reduced in BP-1+cells and there were small reductions in B220+and sIg+cells. A-MuLV (Abelson murine leukemia virus) transformants from these bone marrow cells showed little alteration in Ig gene rearrangement and expression when compared to controls, however. Isolation of the B-lymphoid compartment from these mice in vitro using LBMC (lymphoid bone marrow cultures) enabled more detailed characterization of the effects of the transgene. LBMC derived fromγ2b transgenic mice had similar growth kinetics, but a 4-5-week delay in the expression of endogenous mu Ig in comparison to control cultures. Nucleic acids derived from these early cultures prior to endogenous mu Ig expression showed reduced Ig JHrearrangements, some sterile mu transcription, low levels of BP-1 expression, and virtually undetectable TdT (terminal deoxynucleotidyl transferase) expression. Thus, thisγ2b transgene appears able to affect early B-lymphocyte development.

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33

Martellucci, Stefano, Nicola Salvatore Orefice, Adriano Angelucci, Amalia Luce, Michele Caraglia, and Silvia Zappavigna. "Extracellular Vesicles: New Endogenous Shuttles for miRNAs in Cancer Diagnosis and Therapy?" International Journal of Molecular Sciences 21, no. 18 (September 4, 2020): 6486. http://dx.doi.org/10.3390/ijms21186486.

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Extracellular Vesicles (EVs) represent a heterogeneous population of membranous cell-derived structures, including cargo-oriented exosomes and microvesicles. EVs are functionally associated with intercellular communication and play an essential role in multiple physiopathological conditions. Shedding of EVs is frequently increased in malignancies and their content, including proteins and nucleic acids, altered during carcinogenesis and cancer progression. EVs-mediated intercellular communication between tumor cells and between tumor and stromal cells can modulate, through cargo miRNA, the survival, progression, and drug resistance in cancer conditions. These consolidated suggestions and EVs’ stability in bodily fluids have led to extensive investigations on the potential employment of circulating EVs-derived miRNAs as tumor biomarkers and potential therapeutic vehicles. In this review, we highlight the current knowledge about circulating EVs-miRNAs in human cancer and the application limits of these tools, discussing their clinical utility and challenges in functions such as in biomarkers and instruments for diagnosis, prognosis, and therapy.

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34

Saccomanno, L., and B. L. Bass. "The cytoplasm of Xenopus oocytes contains a factor that protects double-stranded RNA from adenosine-to-inosine modification." Molecular and Cellular Biology 14, no. 8 (August 1994): 5425–32. http://dx.doi.org/10.1128/mcb.14.8.5425-5432.1994.

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Here we describe studies of double-stranded RNA (dsRNA) adenosine deaminase in Xenopus laevis, in particular during meiotic maturation, the period during which a stage VI oocyte matures to an egg. We show that dsRNA adenosine deaminase is in the nuclei of stage VI oocytes. Most importantly, we demonstrate that the cytoplasm of stage VI oocytes contains a factor that protects microinjected dsRNA from deamination when dsRNA adenosine deaminase is released from the nucleus during meiotic maturation. Our data suggest that the protection factor is a cytoplasmic dsRNA-binding protein or proteins that bind to dsRNA in a sequence-independent manner to occlude dsRNA from binding to dsRNA adenosine deaminase. The cytoplasmic double-stranded RNA-binding protein(s) does not bind to other nucleic acids and can be titrated at high concentrations of dsRNA. These studies raise the question of whether all dsRNA-binding proteins share endogenous substrates and also suggest potential means of regulating dsRNA adenosine deaminase in vivo.

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35

Saccomanno, L., and B. L. Bass. "The cytoplasm of Xenopus oocytes contains a factor that protects double-stranded RNA from adenosine-to-inosine modification." Molecular and Cellular Biology 14, no. 8 (August 1994): 5425–32. http://dx.doi.org/10.1128/mcb.14.8.5425.

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Анотація:

Here we describe studies of double-stranded RNA (dsRNA) adenosine deaminase in Xenopus laevis, in particular during meiotic maturation, the period during which a stage VI oocyte matures to an egg. We show that dsRNA adenosine deaminase is in the nuclei of stage VI oocytes. Most importantly, we demonstrate that the cytoplasm of stage VI oocytes contains a factor that protects microinjected dsRNA from deamination when dsRNA adenosine deaminase is released from the nucleus during meiotic maturation. Our data suggest that the protection factor is a cytoplasmic dsRNA-binding protein or proteins that bind to dsRNA in a sequence-independent manner to occlude dsRNA from binding to dsRNA adenosine deaminase. The cytoplasmic double-stranded RNA-binding protein(s) does not bind to other nucleic acids and can be titrated at high concentrations of dsRNA. These studies raise the question of whether all dsRNA-binding proteins share endogenous substrates and also suggest potential means of regulating dsRNA adenosine deaminase in vivo.

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36

Fukui, Ryutaro, Shin-ichiroh Saitoh, Fumi Matsumoto, Hiroko Kozuka-Hata, Masaaki Oyama, Koichi Tabeta, Bruce Beutler, and Kensuke Miyake. "Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing." Journal of Experimental Medicine 206, no. 6 (May 18, 2009): 1339–50. http://dx.doi.org/10.1084/jem.20082316.

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Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1.

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37

Patel, Sarju J., Olga Protchenko, Minoo Shakoury-Elizeh, Ethan Baratz, Shyamalagauri Jadhav, and Caroline C. Philpott. "The iron chaperone and nucleic acid–binding activities of poly(rC)-binding protein 1 are separable and independently essential." Proceedings of the National Academy of Sciences 118, no. 25 (June 14, 2021): e2104666118. http://dx.doi.org/10.1073/pnas.2104666118.

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Poly(rC)-binding protein (PCBP1) is a multifunctional adaptor protein that can coordinate single-stranded nucleic acids and iron–glutathione complexes, altering the processing and transfer of these ligands through interactions with other proteins. Multiple phenotypes are ascribed to cells lacking PCBP1, but the relative contribution of RNA, DNA, or iron chaperone activity is not consistently clear. Here, we report the identification of amino acid residues required for iron coordination on each structural domain of PCBP1 and confirm the requirement of iron coordination for binding target proteins BolA2 and ferritin. We further construct PCBP1 variants that lack either nucleic acid– or iron-binding activity and examine their functions in human cells and mouse tissues depleted of endogenous PCBP1. We find that these activities are separable and independently confer essential functions. While iron chaperone activity controls cell cycle progression and suppression of DNA damage, RNA/DNA-binding activity maintains cell viability in both cultured cell and mouse models. The coevolution of RNA/DNA binding and iron chaperone activities on a single protein may prove advantageous for nucleic acid processing that depends on enzymes with iron cofactors.

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38

Seillet, Cyril, Sophie Laffont, Florence Trémollières, Nelly Rouquié, Claude Ribot, Jean-François Arnal, Victorine Douin-Echinard, Pierre Gourdy та Jean-Charles Guéry. "The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling". Blood 119, № 2 (12 січня 2012): 454–64. http://dx.doi.org/10.1182/blood-2011-08-371831.

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Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-α/β) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7 and TLR-9). Enhanced TLR-7–mediated IFN-α production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7–mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17β-estradiol markedly enhances TLR-7– and TLR-9–dependent production of IFN-α by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) α. Genetic ablation of ERα gene in the DC lineage abrogated the enhancing effect of 17β-estradiol on their TLR-mediated production of IFN-α, showing that estrogens directly target pDCs in vivo. Our results uncover a previously unappreciated role for estrogens in regulating the innate functions of pDCs, which may account for sex-based differences in autoimmune and infectious diseases.

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39

Karras, James G., Martin A. Maier, Tao Lu, Andrew Watt та Muthiah Manoharan. "Peptide Nucleic Acids Are Potent Modulators of Endogenous Pre-mRNA Splicing of the Murine Interleukin-5 Receptor-α Chain". Biochemistry 40, № 26 (липень 2001): 7853–59. http://dx.doi.org/10.1021/bi010263l.

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40

Jia, Feng, Li Zhang, Gui Ling Li, and Lei Zeng. "The Mechanism of Leaf Senescence in Tobacco." Advanced Materials Research 524-527 (May 2012): 2211–17. http://dx.doi.org/10.4028/www.scientific.net/amr.524-527.2211.

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Leaf senescence is the final stage of plant development. Senescence also is a complex and highly regulated process that involves a decline in photosynthesis, dismantling of chloroplasts, and degradation of macromolecules such as proteins, nucleic acids, and lipids. This review mainly introduces the process of leaf senescence through leaf senescence pathway in three parts: initiation, degeneration, and terminal. To sort out the tobacco-related genes change that show increased or decreased expression during the leaf senescence. Moreover, endogenous hormones, such as cytokinins, ethylene, and abscisic acid, play the vital role during the leaf senescence. At the same time, many protein degradation, chlorophyll breakdown, and nigtrogen remobilization in the regulation of senescence are discussed.

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41

Price, Aryn A., Timothy R. Sampson, Hannah K. Ratner, Arash Grakoui, and David S. Weiss. "Cas9-mediated targeting of viral RNA in eukaryotic cells." Proceedings of the National Academy of Sciences 112, no. 19 (April 27, 2015): 6164–69. http://dx.doi.org/10.1073/pnas.1422340112.

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Clustered, regularly interspaced, short palindromic repeats–CRISPR associated (CRISPR-Cas) systems are prokaryotic RNA-directed endonuclease machineries that act as an adaptive immune system against foreign genetic elements. Using small CRISPR RNAs that provide specificity, Cas proteins recognize and degrade nucleic acids. Our previous work demonstrated that the Cas9 endonuclease from Francisella novicida (FnCas9) is capable of targeting endogenous bacterial RNA. Here, we show that FnCas9 can be directed by an engineered RNA-targeting guide RNA to target and inhibit a human +ssRNA virus, hepatitis C virus, within eukaryotic cells. This work reveals a versatile and portable RNA-targeting system that can effectively function in eukaryotic cells and be programmed as an antiviral defense.

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42

Chen, Raymond, Charles A. Ishak, and Daniel D. De Carvalho. "Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis." Cancer Discovery 11, no. 11 (October 14, 2021): 2707–25. http://dx.doi.org/10.1158/2159-8290.cd-21-0506.

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Abstract Features of the cancer epigenome distinguish cancers from their respective cell of origin and establish therapeutic vulnerabilities that can be exploited through pharmacologic inhibition of DNA- or histone-modifying enzymes. Epigenetic therapies converge with cancer immunotherapies through “viral mimicry,” a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons. This review describes the initial characterization and expansion of viral mimicry–inducing approaches as well as features that “prime” cancers for viral mimicry induction. Increased understanding of viral mimicry in therapeutic contexts suggests potential physiologic roles in cellular homeostasis. Significance: Recent literature establishes elevated cytosolic double strand RNA (dsRNA) levels as a cancer-specific therapeutic vulnerability that can be elevated by viral mimicry–inducing therapies beyond tolerable thresholds to induce antiviral signaling and increase dependence on dsRNA stress responses mediated by ADAR1. Improved understanding of viral mimicry signaling and tolerance mechanisms reveals synergistic treatment combinations with epigenetic therapies that include inhibition of BCL2, ADAR1, and immune checkpoint blockade. Further characterization of viral mimicry tolerance may identify contexts that maximize efficacy of conventional cancer therapies.

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43

Chen, Raymond, Charles A. Ishak, and Daniel D. De Carvalho. "Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis." Cancer Discovery 11, no. 11 (October 14, 2021): 2707–25. http://dx.doi.org/10.1158/2159-8290.cd-21-0506.

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Анотація:

Abstract Features of the cancer epigenome distinguish cancers from their respective cell of origin and establish therapeutic vulnerabilities that can be exploited through pharmacologic inhibition of DNA- or histone-modifying enzymes. Epigenetic therapies converge with cancer immunotherapies through “viral mimicry,” a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons. This review describes the initial characterization and expansion of viral mimicry–inducing approaches as well as features that “prime” cancers for viral mimicry induction. Increased understanding of viral mimicry in therapeutic contexts suggests potential physiologic roles in cellular homeostasis. Significance: Recent literature establishes elevated cytosolic double strand RNA (dsRNA) levels as a cancer-specific therapeutic vulnerability that can be elevated by viral mimicry–inducing therapies beyond tolerable thresholds to induce antiviral signaling and increase dependence on dsRNA stress responses mediated by ADAR1. Improved understanding of viral mimicry signaling and tolerance mechanisms reveals synergistic treatment combinations with epigenetic therapies that include inhibition of BCL2, ADAR1, and immune checkpoint blockade. Further characterization of viral mimicry tolerance may identify contexts that maximize efficacy of conventional cancer therapies.

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44

Sampson, Timothy R., and David S. Weiss. "Cas9-dependent endogenous gene regulation is required for bacterial virulence." Biochemical Society Transactions 41, no. 6 (November 20, 2013): 1407–11. http://dx.doi.org/10.1042/bst20130163.

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Анотація:

CRISPR (clustered regularly interspaced short palindromic repeats)–Cas (CRISPR-associated) systems are known to mediate bacterial defence against foreign nucleic acids. We recently demonstrated a non-canonical role for a CRISPR–Cas system in controlling endogenous gene expression, which had not previously been appreciated. In the present article, we describe the studies that led to this discovery, beginning with an unbiased genome-wide screen to identify virulence genes in the intracellular pathogen Francisella novicida. A gene annotated as encoding a hypothetical protein, but which we now know encodes the Cas protein Cas9, was identified as one of the most critical to the ability of F. novicida to replicate and survive during murine infection. Subsequent studies revealed a role for this protein in evasion of the host innate immune response. Specifically, Cas9 represses the expression of a BLP (bacterial lipoprotein) that could otherwise be recognized by TLR2 (Toll-like receptor 2), a host protein involved in initiating an antibacterial pro-inflammatory response. By repressing BLP levels, Cas9 mediates evasion of TLR2, promoting bacterial virulence. Finally, we described the molecular mechanism by which Cas9 functions in complex with two small RNAs to target the mRNA encoding the BLP for degradation. This work greatly broadened the paradigm for CRISPR–Cas function, highlighting a role in gene regulation that could be conserved in numerous bacteria, and elucidating its integral contribution to bacterial pathogenesis.

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45

Chen, X. B., F. D. DeB Hovell, E. R. Ørskov, and D. S. Brown. "Excretion of purine derivatives by ruminants: effect of exogenous nucleic acid supply on purine derivative excretion by sheep." British Journal of Nutrition 63, no. 1 (January 1990): 131–42. http://dx.doi.org/10.1079/bjn19900098.

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The present study examined the relationship between the supply of exogenous nucleic acid (NA) purines and their recovery as the derivatives hypoxanthine, xanthine, uric acid and allantoin in urine. Six lambs, totally nourished by intragastric infusions of volatile fatty acids (VFA) and casein (i.e. no rumen fermentation), were given by abomasal infusion a microbial NA concentrate at six levels (from zero to 24·5 mmol purines/d). The true digestibility between the abomasum and terminal ileum of the NA purines was measured in a separate experiment using three lambs. The relative proportion of urinary allantoin increased, and that of other derivatives decreased, as the amount of NA infused was increased. The relationship between total excretion of purine derivatives (Y; mmol/d) and exogenous purines absorbed (X; mmol/d) was Y = 0·84 X + 0.150W0·75e-0.25X, where W is body-weight (kg). This implies that the endogenous contribution to the total excretion of derivative decreased as the supply of exogenous purines increased, with an associated progressive replacement of de novo synthesis by exogenous purines. The model also implies that 0·16 of the purines were eliminated through routes other than derivative excretion in urine. Once excretion exceeded 0·6 mmol/kg W0·75 per d, endogenous excretion was effectively zero and thus Y = 0·84 X. In normally fed sheep, derivative excretion should therefore relate to the microbial purines and, hence, microbial protein absorbed according to these models. The changing proportions of allantoin and other derivatives in urine were probably due to changes in the relative importance of endogenous and exogenous purines as precursors.

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46

Kundu, Nandini, Brian E. Young, and Jonathan T. Sczepanski. "Kinetics of heterochiral strand displacement from PNA–DNA heteroduplexes." Nucleic Acids Research 49, no. 11 (June 14, 2021): 6114–27. http://dx.doi.org/10.1093/nar/gkab499.

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Abstract Dynamic DNA nanodevices represent powerful tools for the interrogation and manipulation of biological systems. Yet, implementation remains challenging due to nuclease degradation and other cellular factors. Use of l-DNA, the nuclease resistant enantiomer of native d-DNA, provides a promising solution. On this basis, we recently developed a strand displacement methodology, referred to as ‘heterochiral’ strand displacement, that enables robust l-DNA nanodevices to be sequence-specifically interfaced with endogenous d-nucleic acids. However, the underlying reaction – strand displacement from PNA–DNA heteroduplexes – remains poorly characterized, limiting design capabilities. Herein, we characterize the kinetics of strand displacement from PNA–DNA heteroduplexes and show that reaction rates can be predictably tuned based on several common design parameters, including toehold length and mismatches. Moreover, we investigate the impact of nucleic acid stereochemistry on reaction kinetics and thermodynamics, revealing important insights into the biophysical mechanisms of heterochiral strand displacement. Importantly, we show that strand displacement from PNA–DNA heteroduplexes is compatible with RNA inputs, the most common nucleic acid target for intracellular applications. Overall, this work greatly improves the understanding of heterochiral strand displacement reactions and will be useful in the rational design and optimization of l-DNA nanodevices that operate at the interface with biology.

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47

Stenvang, Jan, Morten Lindow, and Sakari Kauppinen. "Targeting of microRNAs for therapeutics." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1197–200. http://dx.doi.org/10.1042/bst0361197.

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Анотація:

miRNAs (microRNAs) comprise a class of small endogenous non-coding RNAs that post-transcriptionally repress gene expression by base-pairing with their target mRNAs. Recent evidence has shown that miRNAs play important roles in a wide variety of human diseases, such as viral infections, cancer and cardiovascular diseases, and thus miRNAs have rapidly emerged as potential targets for therapeutics. LNAs (locked nucleic acids) comprise a class of bicyclic conformational analogues of RNA, which exhibit high binding affinity to complementary RNA molecules and high stability in blood and tissues in vivo. Recent reports on LNA-mediated miRNA silencing in rodents and primates support the potential of LNA-modified oligonucleotides in studying miRNA functions in vivo and in the future development of miRNA-based therapeutics.

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48

Barrat, Franck J., Thea Meeker, Josh Gregorio, Jean H. Chan, Satoshi Uematsu, Shizuo Akira, Bonnie Chang, Omar Duramad, and Robert L. Coffman. "Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus." Journal of Experimental Medicine 202, no. 8 (October 17, 2005): 1131–39. http://dx.doi.org/10.1084/jem.20050914.

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Raised serum levels of interferon (IFN)-α have been observed in systemic lupus erythematosus (SLE) patients, and these levels are correlated with both disease activity and severity. The origin of this IFN-α is still unclear, but increasing evidence suggests the critical involvement of activated plasmacytoid predendritic cells (PDCs). In SLE patients, DNA and RNA viruses, as well as immune complexes (ICs), that consist of autoantibodies specific to self-DNA and RNA protein particles can stimulate production of IFN-α. We have developed three series of oligonucleotide (ODN)-based inhibitors of Toll-like receptor (TLR) signaling. These ODNs include inhibitors of TLR9, inhibitors of TLR7 but not TLR9, and sequences that inhibit both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN-α production by PDCs in response to DNA or RNA viruses. We show that mammalian DNA and RNA, in the form of ICs, are potent self-antigens for TLR9 and TLR7, respectively, and induce IFN-α production by PDCs. This work suggests that TLRs may have a critical role in the promotion of lupus through the induction of IFN-α by PDCs. These inhibitors of TLR signaling thus represent novel therapeutic agents with potential for the treatment of lupus.

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Brennan, T., L. Lin, J. Brandstadter, V. Rendell, K. Dredge, X. Huang, and Y. Yang. "The Heparan Sulfate Mimetic, PG545, Induces a Potent Anti-Lymphoma Effect By Enhancing Innate Immune Activation By Endogenous Nucleic Acids." Transplantation 98 (July 2014): 297. http://dx.doi.org/10.1097/00007890-201407151-00933.

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Guiducci, Cristiana, Claudio Tripodo, Mei Gong, Sabina Sangaletti, Mario P. Colombo, Robert L. Coffman, and Franck J. Barrat. "Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9." Journal of Experimental Medicine 207, no. 13 (November 29, 2010): 2931–42. http://dx.doi.org/10.1084/jem.20101048.

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Recognition of endogenous DNA and RNA by cells expressing TLR7 and TLR9 is an important contributor to the pathogenesis of systemic lupus erythematosus and has been suggested to contribute to cutaneous lupus and to a group of related inflammatory skin diseases termed interface dermatitis. We have developed a mouse model of TLR7- and TLR9-dependent skin inflammation using tape stripping. In normal mice, this resulted in a rapid but transient inflammatory cell infiltration accompanied by induction of type I IFN production by plasmacytoid dendritic cells (PDCs) and release of extracellular traps and proinflammatory cytokines by neutrophils. These responses were strongly reduced in MyD88-deficient mice and in mice treated with a bifunctional inhibitor of TLR7 and TLR9. In contrast, in lupus-prone (NZBxNZW)F1 mice, tape stripping induced the development of chronic lesions characterized by a persistent type I IFN gene signature and many clinical and histological features of cutaneous lupus. Depletion of PDCs before injury prevented the development of skin lesions, whereas treatment with a bifunctional TLR7/9 inhibitor before tape stripping or after the initial lesion was established led to a significant reduction of the disease. These data suggest that inhibitors of TLR7 and TLR9 signaling have potential therapeutic application for the treatment of interface dermatitis.

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