scholarly journals Convolutional models of RNA energetics

2018 ◽  
Author(s):  
Michelle J. Wu
Keyword(s):  
Nucleic Acid ◽  
Network Architecture ◽  
Nearest Neighbor ◽  
Current Model ◽  
Mrna Translation ◽  
Large Space ◽  
Dna And Rna ◽  
Nucleic Acid Interactions

AbstractNucleic acid molecular biology and synthetic biology are undergoing rapid advances with the emergence of designer riboswitches controlling living cells, CRISPR/Cas9-based genome editing, high-throughput RNA-based silencing, and reengineering of mRNA translation. Many of these efforts require the design of nucleic acid interactions, which relies on accurate models for DNA and RNA energetics. Existing models utilize nearest neighbor rules, which were parameterized through careful optical melting measurements. However, these relatively simple rules often fail to quantitatively account for the biophysical behavior of molecules even in vitro, let alone in vivo. This is due to the limited experimental throughput of optical melting experiments and the infinitely large space of possible motifs that can be formed. Here, we present a convolutional neural network architecture to model the energies of nucleic acid motifs, allowing for learning of representations of physical interactions that generalize to arbitrary unmeasured motifs. First, we used existing parameterizations of motif energies to train the model and demonstrate that our model is expressive enough to recapitulate the current model. Then, through training on optical melting datasets from the literature, we have shown that the model can accurately predict the thermodynamics of hairpins containing unmeasured motifs. This work demonstrates the utility of convolutional models for capturing the thermodynamic parameters that underlie nucleic acid interactions.

scholarly journals Nucleic Acid Computing and its Potential to Transform Silicon-Based Technology

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Seth G. Abels ◽  
Emil F. Khisamutdinov
Keyword(s):  
Nucleic Acid ◽  
Logic Gates ◽  
Rna Nanotechnology ◽  
Dna And Rna ◽  
Cellular Machinery ◽  
Living Organisms ◽  
Silicon Based ◽  
Molecular Computers

AbstractMolecular computers have existed on our planet for more than 3.5 billion years. Molecular computing devices, composed of biological substances such as nucleic acids, are responsible for the logical processing of a variety of inputs, creating viable outputs that are key components of the cellular machinery of all living organisms. We have begun to adopt some of the structural and functional knowledge of the cellular apparatus in order to fabricate nucleic-acid-based molecular computers in vitro and in vivo. Nucleic acid computing is directly dependent on advances in DNA and RNA nanotechnology. The field is still emerging and a number of challenges persist. Perhaps the most salient among these is how to translate a variety of nucleic-acid-based logic gates, developed by numerous research laboratories, into the realm of silicon-based computing. This mini-review provides some basic information on the advances in nucleic-acid-based computing and its potential to serve as an alternative that can revolutionize silicon-based technology.

scholarly journals Abnormal Nucleic Acid Metabolism of Lymphocytes in Plasma Cell Myeloma and Macroglobulinemia

Blood ◽  
1969 ◽  
Vol 33 (2) ◽  
pp. 300-312 ◽  
Author(s):  
SYDNEY E. SALMON ◽  
H. HUGH FUDENBERG
Keyword(s):  
Nucleic Acid ◽  
Dna Synthesis ◽  
Past History ◽  
Acid Synthesis ◽  
Nucleic Acid Metabolism ◽  
Lymphocyte Function ◽  
Dna And Rna ◽  
Lymphocyte Dna Synthesis

Abstract Twenty-six patients with multiple myeloma and macroglobulinemia of Waldenström were studied clinically and immunologically with characterization of their paraproteins and normal immunoglobulins, as well as by in vitro culture of their peripheral lymphocytes for evaluation of DNA and RNA synthesis after phytohemagglutinin stimulation. The lymphocytes of the patients were found to be significantly deficient in response to PHA as compared to normals and patients with benign hypergammaglobulinemia. Levels of normal immunoglobulins were reduced in almost all of the paraproteinemic patients, but there was not a direct correlation between lymphocyte unresponsiveness and immunoglobulin deficiency. The defect in lymphocyte function appeared to be cellular inasmuch as normal lymphocytes had normal DNA synthesis when cultured in myeloma plasma. The decrease in lymphocyte nucleic acid synthesis appeared to be unrelated to immunoglobulin class, quantitative levels or antigenic characteristics of the patients’ paraproteins. Untreated myeloma patients with a past history of infection had lower levels of lymphocyte DNA synthesis than those patients who lacked such a history, suggesting a relationship between the in vitro lymphocyte response to PHA and the in vivo response to the antigenic challenge of bacterial infection.

scholarly journals Transcriptional induction of nucleic acid sensors during coronavirus infection.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Dna And Rna ◽  
Coronavirus Infection ◽  
Molecular Patterns ◽  
Microarray Datasets ◽  
Transcriptional Induction ◽  
Acid Sensors

While adaptive immune responses involve antigen-specific responses, rapid innate immune responses involve detection of pathogen-associated molecular patterns such as the nucleic acids DNA and RNA (1). We mined five independent microarray datasets (2-6) to discover in an unbiased and systematic fashion pattern recognition receptors associated with coronavirus infection across a series of coronaviruses capable of infecting humans. We describe here the transcriptional induction of four nucleic acid and PAMP sensors following coronavirus infection in vitro and in vivo: Z-DNA-binding protein ZBP1, the DExH-box helicase DHX58 (LGP2), PYHIN1 and the Mediterannean Fever gene PYRIN as among the genes most differentially expressed following infection with coronaviruses. These data reveal unprecedented mobilization of nucleic acid sensors during coronavirus infection.

scholarly journals Seminal Plasma: Relevant for Fertility?

2021 ◽  
Vol 22 (9) ◽  
pp. 4368
Author(s):  
Heriberto Rodriguez-Martinez ◽  
Emilio A. Martinez ◽  
Juan J. Calvete ◽  
Fernando J. Peña Vega ◽  
Jordi Roca
Keyword(s):  
Seminal Plasma ◽  
Current Knowledge ◽  
Inorganic Ions ◽  
Vitro Fertilization ◽  
Dna And Rna ◽  
Model Animal ◽  
Sexual Glands ◽  
Species Specific

Seminal plasma (SP), the non-cellular component of semen, is a heterogeneous composite fluid built by secretions of the testis, the epididymis and the accessory sexual glands. Its composition, despite species-specific anatomical peculiarities, consistently contains inorganic ions, specific hormones, proteins and peptides, including cytokines and enzymes, cholesterol, DNA and RNA—the latter often protected within epididymis- or prostate-derived extracellular vesicles. It is beyond question that the SP participates in diverse aspects of sperm function pre-fertilization events. The SP also interacts with the various compartments of the tubular genital tract, triggering changes in gene function that prepares for an eventual successful pregnancy; thus, it ultimately modulates fertility. Despite these concepts, it is imperative to remember that SP-free spermatozoa (epididymal or washed ejaculated) are still fertile, so this review shall focus on the differences between the in vivo roles of the SP following semen deposition in the female and those regarding additions of SP on spermatozoa handled for artificial reproduction, including cryopreservation, from artificial insemination to in vitro fertilization. This review attempts, including our own results on model animal species, to critically summarize the current knowledge of the reproductive roles played by SP components, particularly in our own species, which is increasingly affected by infertility. The ultimate goal is to reconcile the delicate balance between the SP molecular concentration and their concerted effects after temporal exposure in vivo. We aim to appraise the functions of the SP components, their relevance as diagnostic biomarkers and their value as eventual additives to refine reproductive strategies, including biotechnologies, in livestock models and humans.

Regulation of RNA helicase activity: principles and examples

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Pascal Donsbach ◽  
Dagmar Klostermeier
Keyword(s):  
Atp Hydrolysis ◽  
Wide Spectrum ◽  
Mrna Translation ◽  
Rna Degradation ◽  
Rna Helicases ◽  
Interaction Partners ◽  
Rna Duplexes ◽  
Self Association

Abstract RNA helicases are a ubiquitous class of enzymes involved in virtually all processes of RNA metabolism, from transcription, mRNA splicing and export, mRNA translation and RNA transport to RNA degradation. Although ATP-dependent unwinding of RNA duplexes is their hallmark reaction, not all helicases catalyze unwinding in vitro, and some in vivo functions do not depend on duplex unwinding. RNA helicases are divided into different families that share a common helicase core with a set of helicase signature motives. The core provides the active site for ATP hydrolysis, a binding site for the non-sequence-specific interactions with RNA, and in many cases a basal unwinding activity. Its activity is often regulated by flanking domains, by interaction partners, or by self-association. In this review, we summarize the regulatory mechanisms that modulate the activities of the helicase core. Case studies on selected helicases with functions in translation, splicing, and RNA sensing illustrate the various modes and layers of regulation in time and space that harness the helicase core for a wide spectrum of cellular tasks.

scholarly journals Base-edited CAR T cells for combinational therapy against T cell malignancies

Leukemia ◽  
2021 ◽  
Author(s):  
Christos Georgiadis ◽  
Jane Rasaiyaah ◽  
Soragia Athina Gkazi ◽  
Roland Preece ◽  
Aniekan Etuk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Specific Binding ◽  
Base Editing ◽  
Car T Cells ◽  
Dna And Rna ◽  
Car T ◽  
T Cell Malignancies

AbstractTargeting T cell malignancies using chimeric antigen receptor (CAR) T cells is hindered by ‘T v T’ fratricide against shared antigens such as CD3 and CD7. Base editing offers the possibility of seamless disruption of gene expression of problematic antigens through creation of stop codons or elimination of splice sites. We describe the generation of fratricide-resistant T cells by orderly removal of TCR/CD3 and CD7 ahead of lentiviral-mediated expression of CARs specific for CD3 or CD7. Molecular interrogation of base-edited cells confirmed elimination of chromosomal translocations detected in conventional Cas9 treated cells. Interestingly, 3CAR/7CAR co-culture resulted in ‘self-enrichment’ yielding populations 99.6% TCR−/CD3−/CD7−. 3CAR or 7CAR cells were able to exert specific cytotoxicity against leukaemia lines with defined CD3 and/or CD7 expression as well as primary T-ALL cells. Co-cultured 3CAR/7CAR cells exhibited highest cytotoxicity against CD3 + CD7 + T-ALL targets in vitro and an in vivo human:murine chimeric model. While APOBEC editors can reportedly exhibit guide-independent deamination of both DNA and RNA, we found no problematic ‘off-target’ activity or promiscuous base conversion affecting CAR antigen-specific binding regions, which may otherwise redirect T cell specificity. Combinational infusion of fratricide-resistant anti-T CAR T cells may enable enhanced molecular remission ahead of allo-HSCT for T cell malignancies.

IMMU-53. STING-ING GLIOBLASTOMA WITH SPHERICAL NUCLEIC ACIDS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi104-vi105
Author(s):  
Akanksha Mahajan ◽  
Lisa Hurley ◽  
Serena Tommasini-Ghelfi ◽  
Corey Dussold ◽  
Alexander Stegh ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
High Surface ◽  
Biological Properties ◽  
Innate Immune ◽  
Limiting Factors ◽  
Nucleic Acid Delivery ◽  
Sting Pathway ◽  
Spherical Nucleic Acids

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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