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All Articles in Biochemistry, Biophysics, and Structural Biology

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The Dhodh Inhibitor Ptc299 Arrests Sars-Cov-2 Replication And Suppresses Induction Of Inflammatory Cytokines [Preprint], Jeremy Luban, Caterina Strambio De Castilla, Yetao Wang, Allan Jacobson, Stuart Peltz 2020 University of Massachusetts Medical School

The Dhodh Inhibitor Ptc299 Arrests Sars-Cov-2 Replication And Suppresses Induction Of Inflammatory Cytokines [Preprint], Jeremy Luban, Caterina Strambio De Castilla, Yetao Wang, Allan Jacobson, Stuart Peltz

University of Massachusetts Medical School Faculty Publications

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known ...


Separation And Identification Of Permethylated Glycan Isomers By Reversed Phase Nanolc-Nsi-Msn [Preprint], Simone Kurz, M. Osman Sheikh, Shan Lu, Lance Wells, Michael Tiemeyer 2020 University of Georgia

Separation And Identification Of Permethylated Glycan Isomers By Reversed Phase Nanolc-Nsi-Msn [Preprint], Simone Kurz, M. Osman Sheikh, Shan Lu, Lance Wells, Michael Tiemeyer

University of Massachusetts Medical School Faculty Publications

High performance liquid chromatography has been employed for decades to enhance detection sensitivity and quantification of complex analytes within biological mixtures. Among these analytes, glycans released from glycoproteins and glycolipids have been characterized as underivatized or fluorescently tagged derivatives by HPLC coupled to various detection methods. These approaches have proven extremely useful for profiling the structural diversity of glycoprotein and glycolipid glycosylation but require the availability of glycan standards and secondary orthogonal degradation strategies to validate structural assignments. A robust method for HPLC separation of glycans as their permethylated derivatives, coupled with in-line MSn fragmentation to assign structural features independent ...


Atomistic Mechanism Of Force Generation, Translocation, And Coordination In A Viral Genome Packaging Motor [Preprint], Joshua Pajak, Erik Dill, Mark A. White, Brian A. Kelch, Paul Jardine, Gaurav Arya, Marc C. Morais 2020 Duke University

Atomistic Mechanism Of Force Generation, Translocation, And Coordination In A Viral Genome Packaging Motor [Preprint], Joshua Pajak, Erik Dill, Mark A. White, Brian A. Kelch, Paul Jardine, Gaurav Arya, Marc C. Morais

University of Massachusetts Medical School Faculty Publications

Double-stranded DNA viruses package their genomes into pre-assembled protein capsids using virally-encoded ATPase ring motors. While several structures of isolated monomers (subunits) from these motors have been determined, they provide little insight into how subunits within a functional ring coordinate their activities to efficiently generate force and translocate DNA. Here we describe the first atomic-resolution structure of a functional ring form of a viral DNA packaging motor and characterize its atomic-level dynamics via long timescale molecular dynamics simulations. Crystal structures of the pentameric ATPase ring from bacteriophage asccφ28 show that each subunit consists of a canonical N-terminal ASCE ATPase domain ...


Melting Dsdna Donor Molecules Potentiates Precision Genome Editing In C. Elegans [Preprint], Krishna S. Ghanta, Craig C. Mello 2020 University of Massachusetts Medical School

Melting Dsdna Donor Molecules Potentiates Precision Genome Editing In C. Elegans [Preprint], Krishna S. Ghanta, Craig C. Mello

University of Massachusetts Medical School Faculty Publications

CRISPR genome editing has revolutionized genetics in many organisms. In the nematode Caenorhabditis elegans one injection into each of the two gonad arms of an adult hermaphrodite exposes hundreds of meiotic germ cells to editing mixtures, permitting the recovery of multiple indels or small precision edits from each successfully injected animal. Unfortunately, particularly for long insertions, editing efficiencies can vary widely, necessitating multiple injections, and often requiring co-selection strategies. Here we show that melting double stranded DNA (dsDNA) donor molecules prior to injection increases the frequency of precise homology-directed repair (HDR) by several fold for longer edits. We describe troubleshooting ...


Characterization Of Human Pyrroline-5-Carboxylate Reductase Enzymes Responsible For L-Proline Biosynthesis, Sagar Patel 2020 University of Nebraska - Lincoln

Characterization Of Human Pyrroline-5-Carboxylate Reductase Enzymes Responsible For L-Proline Biosynthesis, Sagar Patel

Theses and Dissertations in Biochemistry

Pyrroline-5-carboxylate reductases (EC 1.5.1.2) are important housekeeping enzymes of L-proline biosynthesis, which generate L-proline and influence redox cycling of NAD(P)H/NAD(P)+ to support cellular growth in all domains of life. Structural evidence from X-ray crystal structures of HsPYCR1 (PDB codes 5UAT, 5UAU, and 5UAV) shows both NADPH bound in the N-terminal Rao-Rossmann fold motif and an important hydrogen bond or proton donor role for Thr238 with L-P5C. The Thr238Ala mutation results in 10-fold loss in catalytic efficiency with varied L-P5C relative to the wild-type enzyme, thus indicating Thr238’s potential hydrogen bond and proton ...


Urban Air Quality Modeling: Evaluating Impacts Of Ecoroofs On Urban Air Quality In Portland, Oregon, Danlyn L. Brennan, Selina Teng 2020 Portland State University

Urban Air Quality Modeling: Evaluating Impacts Of Ecoroofs On Urban Air Quality In Portland, Oregon, Danlyn L. Brennan, Selina Teng

altREU Projects

In this work, the authors present a mathematical model simulating the impact of ecoroof vegetation on air quality in an urban microclimate. An ecoroof is a layer of vegetation established on rooftops to reduce stormwater runoff, mitigate heat, and enhance air quality. Certain plant species in ecoroofs may however have a detrimental effect on air quality, due to their emission of biogenic volatile organic compounds (BVOCs), which include potentially reactive species such as isoprene. These chemical species can interact with urban air pollution, particularly NOx produced by car traffic, to create other harmful pollutants such as ozone and particulate matter ...


Silencing Innovation: The Patent Eligibility Of Sirna Therapeutics, Alexander M. Walker 2020 University of Minnesota Law School

Silencing Innovation: The Patent Eligibility Of Sirna Therapeutics, Alexander M. Walker

Minnesota Journal of Law, Science & Technology

No abstract provided.


Dimerization Of The Notch Intracellular Domain Results In Distinct Signaling Activity, Jacob Jeffery Crow 2020 Boise State University

Dimerization Of The Notch Intracellular Domain Results In Distinct Signaling Activity, Jacob Jeffery Crow

Boise State University Theses and Dissertations

The Notch signaling pathway is a core component of multicellularity; enabling cells to directly communicate with both their neighbors and the surrounding microenvironment. These signals are translated directly through the Notch proteins, where a fragment of Notch transitions into the nucleus to act as a co-transcription factor, setting into motion a host of physiological responses. Commonly involved in pathways that define a cell’s identity and fate decisions, what appears to be a simplistic pathway instead exists in a state of high-tunability and strict control. Missteps in this pathway are generally embryonically lethal or lead to a suite of congenital ...


Comparative Transcriptomics Of Rice Genotypes With Contrasting Responses To Nitrogen Stress Reveals Genes Influencing Nitrogen Uptake Through The Regulation Of Root Architecture, Prasanta K. Subudhi, Richard S. Garcia, Sapphire Coronejo, Ronald Tapia 2020 Louisiana State Univ, Agr Ctr, Sch Plant Environm & Soil Sci, Baton Rouge, LA

Comparative Transcriptomics Of Rice Genotypes With Contrasting Responses To Nitrogen Stress Reveals Genes Influencing Nitrogen Uptake Through The Regulation Of Root Architecture, Prasanta K. Subudhi, Richard S. Garcia, Sapphire Coronejo, Ronald Tapia

Faculty Publications

The indiscriminate use of nitrogenous fertilizers continues unabated for commercial crop production, resulting in air and water pollution. The development of rice varieties with enhanced nitrogen use efficiency (NUE) will require a thorough understanding of the molecular basis of a plant's response to low nitrogen (N) availability. The global expression profiles of root tissues collected from low and high N treatments at different time points in two rice genotypes, Pokkali and Bengal, with contrasting responses to N stress and contrasting root architectures were examined. Overall, the number of differentially expressed genes (DEGs) in Pokkali (indica) was higher than in ...


Connexin-46/50 In A Dynamic Lipid Environment Resolved By Cryoem At 1.9 Å, Jonathan A. Flores, Bassam G. Haddad, Kimberly A. Dolan, Janette Bernadette Myers, Craig C. Yoshioka, Jeremy Yoshioka, Daniel M. Zuckerman, Steve L. Reichow 2020 Oregon Health & Science University

Connexin-46/50 In A Dynamic Lipid Environment Resolved By Cryoem At 1.9 Å, Jonathan A. Flores, Bassam G. Haddad, Kimberly A. Dolan, Janette Bernadette Myers, Craig C. Yoshioka, Jeremy Yoshioka, Daniel M. Zuckerman, Steve L. Reichow

Chemistry Faculty Publications and Presentations

Gap junctions establish direct pathways for cells to transfer metabolic and electrical messages. The local lipid environment is known to affect the structure, stability and intercellular channel activity of gap junctions; however, the molecular basis for these effects remains unknown. Here, we incorporate native connexin-46/50 (Cx46/50) intercellular channels into a dual lipid nanodisc system, mimicking a native cell-to-cell junction. Structural characterization by CryoEM reveals a lipid-induced stabilization to the channel, resulting in a 3D reconstruction at 1.9 Å resolution. Together with all-atom molecular dynamics simulations, it is shown that Cx46/50 in turn imparts long-range stabilization to ...


Protease Oma1 Modulates Mitochondrial Bioenergetics And Ultrastructure Through Dynamic Association With Micos Complex, Martonio P. Viana 2020 University of Nebraska - Lincoln

Protease Oma1 Modulates Mitochondrial Bioenergetics And Ultrastructure Through Dynamic Association With Micos Complex, Martonio P. Viana

Theses and Dissertations in Biochemistry

Remodeling of mitochondrial ultrastructure is a complex dynamic process that is critical for a variety of mitochondrial functions and apoptosis. Although the key regulators of this process - mitochondrial contact site and cristae junction organizing system (MICOS) and GTPase Optic Atrophy 1 (OPA1) have been characterized, the mechanisms behind this regulation remain incompletely defined. Here, we found that in addition to its role in mitochondrial division, metallopeptidase OMA1 is required for maintenance of contacts between the inner and outer membranes through a dynamic association with MICOS. This association is independent of OPA1, appears to be mediated via the MIC60 MICOS subunit ...


Investigating Evolutionary Innovation In Yeast Heat Shock Protein 90, Pamela Cote-Hammarlof 2020 University of Massachusetts Medical School

Investigating Evolutionary Innovation In Yeast Heat Shock Protein 90, Pamela Cote-Hammarlof

GSBS Dissertations and Theses

The Heat Shock Protein 90 (Hsp90) is an essential and highly conserved chaperone that facilitates the maturation of a wide array of client proteins, including many kinases. These clients in turn regulate a wide array of cellular processes, such as signal transduction, and transcriptional reprogramming. As a result, the activity of Hsp90 has the potential to influence physiology, which in turn may influence the ability to adapt to new environments. Previous studies using a deep mutational scanning approach, (EMPIRIC) identified multiple substitutions within a 9 amino acid substrate-binding loop of yeast Hsp90 that provides a growth advantage for yeast under ...


Building The Interphase Nucleus: A Study On The Kinetics Of 3d Chromosome Formation, Temporal Relation To Active Transcription, And The Role Of Nuclear Rnas, Kristin N. Abramo 2020 University of Massachusetts Medical School

Building The Interphase Nucleus: A Study On The Kinetics Of 3d Chromosome Formation, Temporal Relation To Active Transcription, And The Role Of Nuclear Rnas, Kristin N. Abramo

GSBS Dissertations and Theses

Following the discovery of the one-dimensional sequence of human DNA, much focus has been directed on microscopy and molecular techniques to learn about the spatial organization of chromatin in a 3D cell. The development of these powerful tools has enabled high-resolution, genome-wide analysis of chromosome structure under many different conditions. In this thesis, I focus on how the organization of interphase chromatin is established and maintained following mitosis. Mitotic chromosomes are folded into helical loop arrays creating short and condensed chromosomes, while interphase chromosomes are decondensed and folded into a number of structures at different length scales ranging from loops ...


No Oxygen, No Water: The Unique Physiology Of Annual Killifish Embryos Across Development, Daniel Erik Zajic 2020 Portland State University

No Oxygen, No Water: The Unique Physiology Of Annual Killifish Embryos Across Development, Daniel Erik Zajic

Dissertations and Theses

For most vertebrates, an abundance of oxygen is necessary for the production of ATP and the maintenance of cellular homeostasis. The absence of oxygen, even for brief periods, quickly leads to ATP depletion which can lead to irreparable damages to sensitive organs, such as the brain and heart. However, certain vertebrates demonstrate an extraordinary ability to thrive and recover fully from periods of no oxygen (anoxia). The annual killifish (Austrofundulus limnaeus) lives in ephemeral ponds in the Maracaibo basin of Venezuela and their embryos have the remarkable ability to not only survive anoxic periods for months, but also dehydrating conditions ...


Tactviz: A Vmd Plugin For Tactile Visualization Of Protein Structures, Olivia R. Shaw, Jodi A. Hadden-Perilla 2020 University of Delaware

Tactviz: A Vmd Plugin For Tactile Visualization Of Protein Structures, Olivia R. Shaw, Jodi A. Hadden-Perilla

Journal of Science Education for Students with Disabilities

Scientific disciplines spanning biology, biochemistry, and biophysics involve the study of proteins and their functions. Visualization of protein structures represents a barrier to education and research in these disciplines for students who are blind or visually impaired. Here, we present a software plugin for readily producing variable-height tactile graphics of proteins using the free biomolecular visualization software Visual Molecular Dynamics (VMD) and protein structure data that is publicly available through the Protein Data Bank. Our method also supports interactive tactile visualization of proteins with VMD on electronic refreshable tactile display devices. Employing our method in an academic laboratory has enabled ...


Characterization And Enzyme Engineering Of A Hyperthermophilic Laccase Toward Improving Its Activity In Ionic Liquid, Joseph Craig Stevens, David W. Rodgers, Claire Dumon, Jian Shi 2020 University of Kentucky

Characterization And Enzyme Engineering Of A Hyperthermophilic Laccase Toward Improving Its Activity In Ionic Liquid, Joseph Craig Stevens, David W. Rodgers, Claire Dumon, Jian Shi

Biosystems and Agricultural Engineering Faculty Publications

Ionic liquids (ILs) are organic salts molten at room temperature that can be used for a wide variety of applications. Many ILs, such as 1-ethyl-3-methylimidazolium acetate ([C2C1Im][OAc]), have been shown to remove a significant fraction of the complex biopolymer lignin from biomass during pretreatment. Valorizing lignin via biological pathways (e.g., enzymes) holds promise but is limited by the low biocompatibility of many ILs used for pretreatment. The discovery of thermostable enzymes and the application of enzyme engineering techniques have yielded biocatalysts capable of withstanding high concentrations of ILs. Converting lignin from a waste product ...


Basement Membrane Damage By Ros- And Jnk-Mediated Mmp2 Activation Drives Macrophage Recruitment To Overgrown Tissue, Neha Diwanji, Andreas Bergmann 2020 University of Massachusetts Medical School

Basement Membrane Damage By Ros- And Jnk-Mediated Mmp2 Activation Drives Macrophage Recruitment To Overgrown Tissue, Neha Diwanji, Andreas Bergmann

Open Access Articles

Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model ("undead" model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging ...


Structure Function Analysis Of Mitochondrial Dna Polymerase Ic Reveals Multiple Roles In Kinetoplast Maintenance, Jonathan Miller 2020 University of Massachusetts Amherst

Structure Function Analysis Of Mitochondrial Dna Polymerase Ic Reveals Multiple Roles In Kinetoplast Maintenance, Jonathan Miller

Doctoral Dissertations

Kinetoplastid organisms including medically relevant species like Trypanosoma brucei, Trypanosoma cruzi, and Leishmania are distinguished by their single flagellum and unique mitochondrial DNA called kDNA, among other features. While there is heterogeneity in copy number and sequence classes among different species, kDNA is most often found as a network of thousands of DNA molecules catenated together. This unique biological property of disease-causing organisms has been a subject of study as a potential drug target since it is essential for parasite survival. Trypanosoma brucei is the causative agent of African Sleeping Sickness in humans and related diseases in other mammals and ...


Structural Analysis Of Protein Therapeutics Using Covalent Labeling – Mass Spectrometry, Patanachai Limpikirati 2020 University of Massachusetts Amherst

Structural Analysis Of Protein Therapeutics Using Covalent Labeling – Mass Spectrometry, Patanachai Limpikirati

Doctoral Dissertations

Using mass spectrometry (MS) to obtain information about a higher order structure of protein requires that a protein’s structural properties are encoded into the mass of that protein. Covalent labeling (CL) with reagents that can irreversibly modify solvent accessible amino acid side chains is an effective way to encode structural information into the mass of a protein, as this information can be read-out in a straightforward manner using standard MS-based proteomics techniques. The differential reactivity of proteins under two or more conditions can be used to distinguish protein topologies, conformations, and/or binding sites. CL-MS methods have been effectively ...


Comparison Of Accelerated Solvent Extraction (Ase) And Energized Dispersive Guided Extraction (Edge) For The Analysis Of Pesticides In Leaves, Ashlie D. Kinross, Kimberly J. Hageman, William J. Doucette, Alexandria L. Foster 2020 Utah State University

Comparison Of Accelerated Solvent Extraction (Ase) And Energized Dispersive Guided Extraction (Edge) For The Analysis Of Pesticides In Leaves, Ashlie D. Kinross, Kimberly J. Hageman, William J. Doucette, Alexandria L. Foster

Chemistry and Biochemistry Faculty Publications

Various techniques have been evaluated for the extraction and cleanup of pesticides from environmental samples. In this work, a Selective Pressurized Liquid Extraction (SPLE) method for pesticides was developed using a Thermo Fisher Scientific Accelerated Solvent Extraction (ASE) system. This instrument was compared to the newly introduced (2017) extraction instrument, the Energized Dispersive Guided Extraction (EDGE) system, which combines Pressurized Liquid Extraction (PLE) and dispersive Solid Phase Extraction (dSPE). We first optimized the SPLE method using the ASE instrument for pesticide extraction from alfalfa leaves using layers of Florisil and graphitized carbon black (GCB) downstream of the leaf homogenate in ...


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