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Size, Shape, And Sequence-Dependent Immunogenicity Of Rna Nanoparticles, Sijin Guo, Hui Li, Mengshi Ma, Jian Fu, Yizhou Dong, Peixuan Guo 2017 The Ohio State University

Size, Shape, And Sequence-Dependent Immunogenicity Of Rna Nanoparticles, Sijin Guo, Hui Li, Mengshi Ma, Jian Fu, Yizhou Dong, Peixuan Guo

Center for Research on Environmental Disease Faculty Publications

RNA molecules have emerged as promising therapeutics. Like all other drugs, the safety profile and immune response are important criteria for drug evaluation. However, the literature on RNA immunogenicity has been controversial. Here, we used the approach of RNA nanotechnology to demonstrate that the immune response of RNA nanoparticles is size, shape, and sequence dependent. RNA triangle, square, pentagon, and tetrahedron with same shape but different sizes, or same size but different shapes were used as models to investigate the immune response. The levels of pro-inflammatory cytokines induced by these RNA nanoarchitectures were assessed in macrophage-like cells and animals. It ...


A Hyperthermophilic Phage Decoration Protein Suggests Common Evolutionary Origin With Herpesvirus Triplex Proteins And An Anti-Crispr Protein, Nicholas P. Stone, Brendan J. Hilbert, Daniel Hidalgo, Kevin T. Halloran, Brian A. Kelch 2017 University of Massachusetts Medical School

A Hyperthermophilic Phage Decoration Protein Suggests Common Evolutionary Origin With Herpesvirus Triplex Proteins And An Anti-Crispr Protein, Nicholas P. Stone, Brendan J. Hilbert, Daniel Hidalgo, Kevin T. Halloran, Brian A. Kelch

University of Massachusetts Medical School Faculty Publications

Virus capsid proteins reproducibly self-assemble into regularly-shaped, stable shells that protect the viral genome from external environmental assaults, while maintaining the high internal pressure of the tightly packaged viral genome. To elucidate how capsids maintain stability under harsh conditions, we investigated the capsid components of a hyperthermophilic virus, phage P74-26. We determined the structure of a capsid protein gp87 and show that it has the same fold as trimeric decoration proteins that enhance the structural stability of capsids in many other phage, despite lacking significant sequence homology. We also find that gp87 is significantly more stable than its mesophilic homologs ...


Guidelines For Morpholino Use In Zebrafish, Didier Y. R. Stainier, Nathan D. Lawson, Cecilia B. Moens 2017 Max Planck Institute for Heart and Lung Research

Guidelines For Morpholino Use In Zebrafish, Didier Y. R. Stainier, Nathan D. Lawson, Cecilia B. Moens

Open Access Articles

The zebrafish (Danio rerio) has emerged as a powerful model to study vertebrate development and disease. Its short generation time makes it amenable to genetic manipulation and analysis, and its small size and high fecundity make it especially well suited for large-scale forward genetic and chemical screens. Fast-developing zebrafish embryos are transparent, facilitating live imaging of a variety of developmental processes in wild-type and mutant animals. ...

This brief document provides an updated set of guidelines regarding morpholino use in zebrafish that we anticipate will be of value for experimentalists as well as journal and grant reviewers, and decision makers.


Mutsβ Abundance And Msh3 Atp Hydrolysis Activity Are Important Drivers Of Ctg•Cag Repeat Expansions, Norma Keogh, Kara Y. Chan, Guo-Min Li, Robert S. Lahue 2017 National University of Ireland Galway, Ireland

Mutsβ Abundance And Msh3 Atp Hydrolysis Activity Are Important Drivers Of Ctg•Cag Repeat Expansions, Norma Keogh, Kara Y. Chan, Guo-Min Li, Robert S. Lahue

Toxicology and Cancer Biology Faculty Publications

CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutSβ (Msh2-Msh3 heterodimer). To evaluate properties of MutSβ that drive expansions, previous studies have tested under-expression, ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems. Additionally, some variants destabilize MutSβ, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutSβ. Msh3−/− cells are severely defective for CTG•CAG repeat expansions but show full activity on contractions. Msh3−/− cells provide a single, isogenic system ...


Synthesis And Photophysical Studies Of Pyrrolocytosine Derivatives, Atefeh Rouhi 2017 The University of Western Ontario

Synthesis And Photophysical Studies Of Pyrrolocytosine Derivatives, Atefeh Rouhi

Electronic Thesis and Dissertation Repository

Pyrrolocytosine (pC) derivatives are used in the study of nucleic acid structure, function and in the design of the hybridization probes. They have unique properties including small size and Watson-Crick base pairing capability and impressive fluorescent properties. However, they exhibit variation in the fluorescence properties upon incorporation into single-stranded DNA and double-stranded DNA.

This study analyzes the effect of the nearest neighbours on the fluorescence properties of phenylpyrrolocytosine (PhpC) and provides a guide to the proper design of the PhpC containing fluorescent probes. Moreover, the possibility of photoinduced electron transfer (PET) as the underlying mechanism of the unusual photophysical behavior ...


Epigenetic Instability Induced By Dna Base Lesion Via Dna Base Excision Repair, Zhongliang Jiang 2017 Florida International University

Epigenetic Instability Induced By Dna Base Lesion Via Dna Base Excision Repair, Zhongliang Jiang

FIU Electronic Theses and Dissertations

DNA damage can cause genome instability, which may lead to human cancer. The most common form of DNA damage is DNA base damage, which is efficiently repaired by DNA base excision repair (BER). Thus BER is the major DNA repair pathway that maintains the stability of the genome. On the other hand, BER mediates DNA demethylation that can occur on the promoter region of important tumor suppressor genes such as Breast Cancer 1 (BRCA1) gene that is also involved in prevention and development of cancer. In this study, employing cell-based and in vitro biochemical approaches along with bisulfite DNA sequencing ...


Flt1 And Transcriptome-Wide Polyadenylation Site (Pas) Analysis In Preeclampsia, Ami Ashar-Patel, Yasin Kaymaz, Augustine Rajakumar, Jeffrey A. Bailey, S. Ananth Karumanchi, Melissa J. Moore 2017 University of Massachusetts Medical School

Flt1 And Transcriptome-Wide Polyadenylation Site (Pas) Analysis In Preeclampsia, Ami Ashar-Patel, Yasin Kaymaz, Augustine Rajakumar, Jeffrey A. Bailey, S. Ananth Karumanchi, Melissa J. Moore

Open Access Articles

Maternal symptoms of preeclampsia (PE) are primarily driven by excess anti-angiogenic factors originating from the placenta. Chief among these are soluble Flt1 proteins (sFlt1s) produced from alternatively polyadenylated mRNA isoforms. Here we used polyadenylation site sequencing (PAS-Seq) of RNA from normal and PE human placentae to interrogate transcriptome-wide gene expression and alternative polyadenylation signatures associated with early-onset PE (EO-PE; symptom onset < 34 weeks) and late-onset PE (LO-PE; symptom onset > 34 weeks) cohorts. While we observed no general shift in alternative polyadenylation associated with PE, the EO-PE and LO-PE cohorts do exhibit gene expression profiles distinct from both each other and from normal placentae. The only two genes upregulated ...


Crispr/Cas9 Editing Reveals Novel Mechanisms Of Clustered Microrna Regulation And Function, Lazaros Lataniotis, Andreas Albrecht, Fatma O. Kok, Clinton A. L. Monfries, Lorena Benedetti, Nathan D. Lawson, Simon M. Hughes, Kathleen Steinhofel, Manuel Mayr, Anna Zampetaki 2017 King's College London

Crispr/Cas9 Editing Reveals Novel Mechanisms Of Clustered Microrna Regulation And Function, Lazaros Lataniotis, Andreas Albrecht, Fatma O. Kok, Clinton A. L. Monfries, Lorena Benedetti, Nathan D. Lawson, Simon M. Hughes, Kathleen Steinhofel, Manuel Mayr, Anna Zampetaki

Open Access Articles

MicroRNAs (miRNAs) are important regulators of diverse physiological and pathophysiological processes. MiRNA families and clusters are two key features in miRNA biology. Here we explore the use of CRISPR/Cas9 as a powerful tool to delineate the function and regulation of miRNA families and clusters. We focused on four miRNA clusters composed of miRNA members of the same family, homo-clusters or different families, hetero-clusters. Our results highlight different regulatory mechanisms in miRNA cluster expression. In the case of the miR-497~195 cluster, editing of miR-195 led to a significant decrease in the expression of the other miRNA in the cluster ...


5-Vinylphosphonate Improves Tissue Accumulation And Efficacy Of Conjugated Sirnas In Vivo, Reka A. Haraszti, Loic Roux, Andrew H. Coles, Anton A. Turanov, Julia F. Alterman, Dimas Echeverria, Bruno M. D. C. Godinho, Neil Aronin, Anastasia Khvorova 2017 University of Massachusetts Medical School

5-Vinylphosphonate Improves Tissue Accumulation And Efficacy Of Conjugated Sirnas In Vivo, Reka A. Haraszti, Loic Roux, Andrew H. Coles, Anton A. Turanov, Julia F. Alterman, Dimas Echeverria, Bruno M. D. C. Godinho, Neil Aronin, Anastasia Khvorova

Open Access Articles

5-Vinylphosphonate modification of siRNAs protects them from phosphatases, and improves silencing activity. Here, we show that 5-vinylphosphonate confers novel properties to siRNAs. Specifically, 5-vinylphosphonate (i) increases siRNA accumulation in tissues, (ii) extends duration of silencing in multiple organs and (iii) protects siRNAs from 5-to-3 exonucleases. Delivery of conjugated siRNAs requires extensive chemical modifications to achieve stability in vivo. Because chemically modified siRNAs are poor substrates for phosphorylation by kinases, and 5-phosphate is required for loading into RNA-induced silencing complex, the synthetic addition of a 5-phosphate on a fully modified siRNA guide strand is expected to be beneficial. Here, we show ...


Regulation And Modulation Of Human Dna Polymerase Δ Activity And Function, Marietta Y W T Lee, Xiaoxiao Wang, Sufang Zhang, Zhongtao Zhang, Ernest Y C Lee 2017 New York Medical College

Regulation And Modulation Of Human Dna Polymerase Δ Activity And Function, Marietta Y W T Lee, Xiaoxiao Wang, Sufang Zhang, Zhongtao Zhang, Ernest Y C Lee

NYMC Faculty Publications

This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on the mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions ...


Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried 2017 University of Kentucky

Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried

Center for Structural Biology Faculty Publications

Human O6-alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O6-alkylguanine and O4-alkylthymine adducts in single-stranded and duplex DNAs. The search for these lesions, through a vast excess of competing, unmodified genomic DNA, is a mechanistic challenge that may limit the repair rate in vivo. Here, we examine influences of DNA secondary structure and twist on protein–protein interactions in cooperative AGT complexes formed on lesion-free DNAs that model the unmodified parts of the genome. We used a new approach to resolve nearest neighbor (nn) and long-range (lr) components from the ensemble-average cooperativity, ωave. We found that ...


Single-Molecule Fish In Drosophila Muscle Reveals Location Dependent Mrna Composition Of Megarnps, Akiko Noma, Carlas Smith, Maximiliaan Huisman, Robert M. Martin, Melissa J. Moore, David Grünwald 2017 University of Massachusetts Medical School

Single-Molecule Fish In Drosophila Muscle Reveals Location Dependent Mrna Composition Of Megarnps, Akiko Noma, Carlas Smith, Maximiliaan Huisman, Robert M. Martin, Melissa J. Moore, David Grünwald

University of Massachusetts Medical School Faculty Publications

Single-molecule fluorescence in-situ hybridization (smFISH) provides direct access to the spatial relationship between nucleic acids and specific subcellular locations. The ability to precisely localize a messenger RNA can reveal key information about its regulation. Although smFISH is well established in cell culture or thin sections, methods for its accurate application to tissues are lacking. The utility of smFISH in thick tissue sections must overcome several challenges, including probe penetration of fixed tissue, accessibility of target mRNAs for probe hybridization, high fluorescent background, spherical aberration along the optical axis, and image segmentation of organelles. Here we describe how we overcame these ...


Essential Role For Non-Canonical Poly(A) Polymerase Gld4 In Cytoplasmic Polyadenylation And Carbohydrate Metabolism, Jihae Shin, Ki Young Paek, Mariya Ivshina, Emily E. Stackpole, Joel D. Richter 2017 University of Massachusetts Medical School

Essential Role For Non-Canonical Poly(A) Polymerase Gld4 In Cytoplasmic Polyadenylation And Carbohydrate Metabolism, Jihae Shin, Ki Young Paek, Mariya Ivshina, Emily E. Stackpole, Joel D. Richter

Open Access Articles

Regulation of gene expression at the level of cytoplasmic polyadenylation is important for many biological phenomena including cell cycle progression, mitochondrial respiration, and learning and memory. GLD4 is one of the non-canonical poly(A) polymerases that regulates cytoplasmic polyadenylation-induced translation, but its target mRNAs and role in cellular physiology is not well known. To assess the full panoply of mRNAs whose polyadenylation is controlled by GLD4, we performed an unbiased whole genome-wide screen using poy(U) chromatography and thermal elution. We identified hundreds of mRNAs regulated by GLD4, several of which are involved in carbohydrate metabolism including GLUT1, a major ...


Identification Of A Nucleoside Analog Active Against Adenosine Kinase-Expressing Plasma Cell Malignancies, Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J. Barelli, Michelle A. Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H. Shoemaker, J. David Warren, Olivier Elemento, Kenneth M. Kaye, Ethel Cesarman 2017 Weill Cornell Medical College

Identification Of A Nucleoside Analog Active Against Adenosine Kinase-Expressing Plasma Cell Malignancies, Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J. Barelli, Michelle A. Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H. Shoemaker, J. David Warren, Olivier Elemento, Kenneth M. Kaye, Ethel Cesarman

Pharmacy Faculty Articles and Research

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase–inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further ...


Accuracy, Reproducibility And Bias Of Next Generation Sequencing For Quantitative Small Rna Profiling: A Multiple Protocol Study Across Multiple Laboratories, Maria D. Giraldez, Kahraman Tanriverdi, Jane E. Freedman, Muneesh Tewari 2017 University of Michigan

Accuracy, Reproducibility And Bias Of Next Generation Sequencing For Quantitative Small Rna Profiling: A Multiple Protocol Study Across Multiple Laboratories, Maria D. Giraldez, Kahraman Tanriverdi, Jane E. Freedman, Muneesh Tewari

University of Massachusetts Medical School Faculty Publications

Small RNA-seq is increasingly being used for profiling of small RNAs. Quantitative characteristics of long RNA-seq have been extensively described, but small RNA-seq involves fundamentally different methods for library preparation, with distinct protocols and technical variations that have not been fully and systematically studied. We report here the results of a study using common references (synthetic RNA pools of defined composition, as well as plasma-derived RNA) to evaluate the accuracy, reproducibility and bias of small RNA-seq library preparation for five distinct protocols and across nine different laboratories. We observed protocol-specific and sequence-specific bias, which was ameliorated using adapters for ligation ...


Diversity Oriented Synthesis, Characterization And Anti-Cancer Activity Of Killer Peptide Nucleolipid Bioconjugates, Niki K. Rana 2017 Seton Hall University

Diversity Oriented Synthesis, Characterization And Anti-Cancer Activity Of Killer Peptide Nucleolipid Bioconjugates, Niki K. Rana

Seton Hall University Dissertations and Theses (ETDs)

The killer peptide sequence D-(KLAKLAK)2 has been originally designed and developed as an antibacterial agent. Despite having excellent cytotoxicity towards bacteria, this sequence maintains low cell cytotoxity in malignant mammalian cell types such as cancer. The chemical basis for its selectivity has been attributed to its poly(cationic) amphiphilic nature, which facilitates cell permeability across the negatively charged bacterial membrane, but with limited permeability across the zwitterionic membrane of mammalian cells. The positively charged D-(KLAKLAK)2 sequence has been found to accumulate on the surface of the mitochondria causing dissipation of the negatively charged mitochondrial membrane potential ...


Investigating The Mechanism Of Novel Anticancer Agent, As1411 : Does Metabolism To Guanine Play A Role?, Parker T Howard 2017 University of Louisville

Investigating The Mechanism Of Novel Anticancer Agent, As1411 : Does Metabolism To Guanine Play A Role?, Parker T Howard

College of Arts & Sciences Senior Honors Theses

AS1411 is an oligonucleotide that has shown promising results in lab experiments and clinical trials as an anti-cancer drug, Likewise, treatments with guanine based purine compounds (GBPCs) have demonstrated similar anti-proliferative effects in vitro. This activity is dependent on the HGPRT enzyme. Similarities in activity and physical structure has led us to believe that AS1411 and GBPCs operate by a similar mechanism. To test this, we compare the activity of both in the presence of HGPRT siRNAs and HGPRT deficient cells. While siRNA treatment was unable to alter the activity of GBPCs or AS1411 in our cell lines, HGPRT deficient ...


Functionalization Of Peptide Nucleic Acids Via Post-Synthetic Click Chemistry, Xiaoxiao Wang 2017 The University of Western Ontario

Functionalization Of Peptide Nucleic Acids Via Post-Synthetic Click Chemistry, Xiaoxiao Wang

Electronic Thesis and Dissertation Repository

Peptide Nucleic Acid (PNA) has shown great potential in molecular diagnostics, antisense/antigene therapy and nanotechnology. Like other synthetic nucleic acids and artificial analogues, PNA has been extensively modified to achieve better performance in these applications. To efficiently develop PNA probes for molecular diagnosis, this thesis is focused on versatile functionalization of PNA via post-synthetic click chemistry.

Chapter 2 presents the synthesis of quencher-free PNA molecular beacons (MBs) targeting a cystic fibrosis transmembrane conductance regulator (CFTR) sequence mutation. To avoid the tedious synthesis of functionalized PNA monomers for probe development, a simple approach to modify PNA oligomers by post-synthetic on-resin ...


Diverse Role Of Survival Motor Neuron Protein, Ravindra N. Singh, Matthew D. Howell, Eric W. Ottesen, Natalia N. Singh 2017 Iowa State University

Diverse Role Of Survival Motor Neuron Protein, Ravindra N. Singh, Matthew D. Howell, Eric W. Ottesen, Natalia N. Singh

Biomedical Sciences Publications

The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners ...


Liquid Crystal Phase Behavior Of A Dna Dodecamer And Sunset Yellow, Joseph Theis 2017 University of Colorado, Boulder

Liquid Crystal Phase Behavior Of A Dna Dodecamer And Sunset Yellow, Joseph Theis

Undergraduate Honors Theses

The organic molecule Sunset Yellow, a chromonic dye, and reverse Dickerson dodecamer DNA, a self-complementary, 12 base pair strand of nucleic acids, both self-assemble into rod shaped aggregates that exhibit liquid crystal phases in solution. The sunset yellow molecules and the nano-DNA duplexes have similar structure with hydrophobic cores and peripheral hydrophilic ions. The focus of this research is on mixtures of these two aggregates in miscible liquid crystal states and the phase separation that occurs at higher concentrations in the columnar phase. The structure and phase space of this mixture was determined using polarized optical microscopy and x-ray diffraction ...


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