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Fundamental Causes Of Racial And Ethnic Covid-19-Related Health Disparities, Hana Neutz 2021 Chapman University

Fundamental Causes Of Racial And Ethnic Covid-19-Related Health Disparities, Hana Neutz

Student Scholar Symposium Abstracts and Posters

Underserved low-income communities of color in the U.S. have endured an unequal burden of COVID-19 morbidity and mortality. This pattern of pandemic-related health disparities has been pervasive throughout history. However, no known studies have simultaneously examined social and biological factors that contribute to these concerning health disparities. Therefore, this paper aims to bridge the gap by employing a scoping literature review of (1) the deleterious impacts of systemic racism on COVID-19-related outcomes; and (2) the cellular and molecular mechanisms connecting COVID-19 and hypertension (a comorbidity known to exacerbate COVID-19 severity). My findings indicate that systemic racism manifests in inequitable ...


216— Loss Of Function Mutation For Tp53 Does Not Rescue The Chaf1bNt2 Small-Eye Phenotype In Danio Rerio, Alex Parks 2021 SUNY Geneseo

216— Loss Of Function Mutation For Tp53 Does Not Rescue The Chaf1bNt2 Small-Eye Phenotype In Danio Rerio, Alex Parks

GREAT Day

In Zebrafish, the chromosome assembly factor 1b (chaf1b) gene is in part responsible for the development of the eye. In homozygous chaf1bt24412 mutants retinal cell death is promoted through cell-death promoting activity of the gene, tumor suppressor protein p53 (tp53), resulting in a small-eye phenotype. Another allele chaf1bnt2, was found to also result in the small-eye phenotype when in a homozygous state. We found that knockdown of Tp53 protein via morpholino antisense oligonucleotide injection of 1-2 cell stage embryos failed to rescue retinal cell death of chaf1bnt2 homozygous mutants as detected by TUNEL labeling. Because morpholinos may fail to fully ...


Structure Of Clostridium Perfringens Type Iv Pili, Alexander R. Meyer 2021 University of Nebraska - Lincoln

Structure Of Clostridium Perfringens Type Iv Pili, Alexander R. Meyer

Honors Theses, University of Nebraska-Lincoln

Type IV pili (T4P) are thin, hair-like bacterial appendages composed of protein subunits polymerized into a helical fiber. T4P perform diverse functions such as host cell adhesion, biofilm formation, natural competence, and twitching motility. While T4P are well characterized in Gram-negative bacteria, they have more recently been found in Gram-positive bacteria as well. In this work we aimed to solve the crystal structure of the type IV major pilin protein PilA2 from Clostridium perfringens, the predominant pilus subunit which makes up about 99% of the pilus fiber. We report expression, purification, and crystallization conditions which are sufficient for X-ray diffraction ...


Cohesin Mutations Alter Dna Damage Repair And Chromatin Structure And Create Therapeutic Vulnerabilities In Mds/Aml, Zuzana Tothova, Anne-Laure Valton, Sergey V. Venev, Job Dekker, Benjamin L. Ebert 2021 Dana-Farber Cancer Institute

Cohesin Mutations Alter Dna Damage Repair And Chromatin Structure And Create Therapeutic Vulnerabilities In Mds/Aml, Zuzana Tothova, Anne-Laure Valton, Sergey V. Venev, Job Dekker, Benjamin L. Ebert

Open Access Publications by UMMS Authors

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven ...


The N Terminus Of Myosin-Binding Protein C Extends Toward Actin Filaments In Intact Cardiac Muscle, Sheema Rahmanseresht, Kyoung H. Lee, Thomas S. O'Leary, James W. McNamara, Sakthivel Sadayappan, Jeffrey Robbins, David M. Warshaw, Roger W. Craig, Michael J. Previs 2021 University of Vermont

The N Terminus Of Myosin-Binding Protein C Extends Toward Actin Filaments In Intact Cardiac Muscle, Sheema Rahmanseresht, Kyoung H. Lee, Thomas S. O'Leary, James W. Mcnamara, Sakthivel Sadayappan, Jeffrey Robbins, David M. Warshaw, Roger W. Craig, Michael J. Previs

Radiology Publications

Myosin and actin filaments are highly organized within muscle sarcomeres. Myosin-binding protein C (MyBP-C) is a flexible, rod-like protein located within the C-zone of the sarcomere. The C-terminal domain of MyBP-C is tethered to the myosin filament backbone, and the N-terminal domains are postulated to interact with actin and/or the myosin head to modulate filament sliding. To define where the N-terminal domains of MyBP-C are localized in the sarcomere of active and relaxed mouse myocardium, the relative positions of the N terminus of MyBP-C and actin were imaged in fixed muscle samples using super-resolution fluorescence microscopy. The resolution of ...


The C. Neoformans Cell Wall: A Scaffold For Virulence, Christine Chrissian 2021 The Graduate Center, City University of New York

The C. Neoformans Cell Wall: A Scaffold For Virulence, Christine Chrissian

Dissertations, Theses, and Capstone Projects

Cryptococcus neoformans is a globally distributed opportunistic fungal pathogen and the causative agent of life threatening cryptococcal meningoencephalitis in immunocompromised individuals, resulting in ~180,000 deaths each year worldwide. A primary virulence-associated trait of this organism is the production of melanin. Melanins are a class of diverse pigments produced via the oxidation and polymerization of aromatic ring compounds that have a characteristically complex, heterogenous, and amorphous structure. They are synthesized by representatives of all biological kingdoms and share a multitude of remarkable properties such as the ability to absorb ultraviolet (UV) light and protect against ionizing radiation. Melanin production in ...


Nad(H) Phosphates Mediate Tetramer Assembly Of Human C-Terminal Binding Protein (Ctbp), Jeffry C. Nichols, Celia A. Schiffer, William E. Royer 2021 University of Massachusetts Medical School

Nad(H) Phosphates Mediate Tetramer Assembly Of Human C-Terminal Binding Protein (Ctbp), Jeffry C. Nichols, Celia A. Schiffer, William E. Royer

University of Massachusetts Medical School Faculty Publications

C-terminal binding proteins (CtBPs) are co-transcriptional factors that play key roles in cell fate. We have previously shown that NAD(H) promotes the assembly of similar tetramers from either human CtBP1 and CtBP2 and that CtBP2 tetramer destabilizing mutants are defective for oncogenic activity. To assist structure-based design efforts for compounds that disrupt CtBP tetramerization, it is essential to understand how NAD(H) triggers tetramer assembly. Here, we investigate the moieties within NAD(H) that are responsible for triggering tetramer formation. Using multi-angle light scattering (MALS) we show that ADP is able to promote tetramer formation of both CtBP1 and ...


Separation And Identification Of Permethylated Glycan Isomers By Reversed Phase Nanolc-Nsi-Ms(N), Simone Kurz, M. Osman Sheikh, Shan Lu, Lance Wells, Michael Tiemeyer 2021 University of Georgia

Separation And Identification Of Permethylated Glycan Isomers By Reversed Phase Nanolc-Nsi-Ms(N), Simone Kurz, M. Osman Sheikh, Shan Lu, Lance Wells, Michael Tiemeyer

Open Access Publications by UMMS Authors

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 ...


Unique Structural Solution From A Vh3-30 Antibody Targeting The Hemagglutinin Stem Of Influenza A Viruses, Wayne D. Harshbarger, Derrick Deming, Gordon J. Lockbaum, Nattapol Attatippaholkun, Maliwan Kamkaew, Shurong Hou, Mohan Somasundaran, Jennifer P. Wang, Robert W. Finberg, Quan Karen Zhu, Celia A. Schiffer, Wayne A Marasco 2021 Dana-Farber Cancer Institute

Unique Structural Solution From A Vh3-30 Antibody Targeting The Hemagglutinin Stem Of Influenza A Viruses, Wayne D. Harshbarger, Derrick Deming, Gordon J. Lockbaum, Nattapol Attatippaholkun, Maliwan Kamkaew, Shurong Hou, Mohan Somasundaran, Jennifer P. Wang, Robert W. Finberg, Quan Karen Zhu, Celia A. Schiffer, Wayne A Marasco

Schiffer Lab Publications

Broadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined ...


Crystal Structure Of Sars-Cov-2 Main Protease In Complex With The Non-Covalent Inhibitor Ml188, Gordon J. Lockbaum, Archie C. Reyes, Jeong Min Lee, Ronak Tilvawala, Ellen A. Nalivaika, Akbar Ali, Nese Kurt Yilmaz, Paul R. Thompson, Celia A. Schiffer 2021 University of Massachusetts Medical School

Crystal Structure Of Sars-Cov-2 Main Protease In Complex With The Non-Covalent Inhibitor Ml188, Gordon J. Lockbaum, Archie C. Reyes, Jeong Min Lee, Ronak Tilvawala, Ellen A. Nalivaika, Akbar Ali, Nese Kurt Yilmaz, Paul R. Thompson, Celia A. Schiffer

COVID-19 Publications by UMMS Authors

Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (M(pro)) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 M(pro), and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 M(pro) at 2.5 microM, which is ...


Arabinoxylan Structural Profiling Of Cool-Season Pasture Grasses Via High-Performance Anion-Exchange Chromatography With Pulsed Amperometric Detection (Hpaec-Pad) Analysis Of Endoxylanase Digests, Glenna Erin Joyce 2021 University of Kentucky

Arabinoxylan Structural Profiling Of Cool-Season Pasture Grasses Via High-Performance Anion-Exchange Chromatography With Pulsed Amperometric Detection (Hpaec-Pad) Analysis Of Endoxylanase Digests, Glenna Erin Joyce

Theses and Dissertations--Animal and Food Sciences

Arabinoxylan (AX) is a major structural polysaccharide found in the cell walls of monocots such as cereal grains and pasture grasses. The variety of AX structural components and substitution patterns contribute to AX structural diversity between different monocot species as well as plant tissues.

The rumen is the first digestion site of masticated food material in cattle and provides 70% of energy to host through fermentation of forage. There are many species of pasture grasses that act as a forage source. Differences in AX structure found in these pasture grasses may impact rumen microbial fermentation. Understanding the AX structure of ...


Interactions Of Post-Pks Enzymes Of The Mithramycin Biosynthetic Pathway, Ryan Wheeler 2021 University of Kentucky

Interactions Of Post-Pks Enzymes Of The Mithramycin Biosynthetic Pathway, Ryan Wheeler

Theses and Dissertations--Pharmacy

Combinatorial biosynthesis is a powerful tool for generating new, more active drug analogues to combat disease. But in order for combinatorial biosynthesis to be employed to its full potential, a deep understanding of the enzymes that produce the parent molecule must be had. The goals of the work presented in this thesis are to characterize the reaction catalyzed by MtmW, the final enzyme in the mithramycin (MTM) biosynthetic pathway, and to discover the interaction between MtmW and MtmOIV.

MtmW is an aldol-ketoreductase responsible for reducing the most distal carbonyl on the MTM pentyl side chain. It forms an octamer that ...


On The Structure And Function Of Mitochondrial Uncoupling Proteins: The Case Of Ucp2, Afshan Ardalan 2021 Wilfrid Laurier University

On The Structure And Function Of Mitochondrial Uncoupling Proteins: The Case Of Ucp2, Afshan Ardalan

Theses and Dissertations (Comprehensive)

Uncoupling proteins (UCPs) are regulated proton transporters of the mitochondrial inner membrane. UCP-mediated proton leak negatively impacts the rate of ATP synthesis. Despite the importance of their physiological role(s) in certain tissues, molecular aspects of UCPs’ structure-function relationships are not fully understood. The current study explores the tertiary and quaternary structure of UCP2, as well as its proton transport mechanism in lipid membranes. The proteins were expressed in the E. coli inner membrane, purified and reconstituted into liposomes. Proteins were characterized by semi-native SDS-PAGE. Circular dichroism spectroscopy (CD) and fluorescence quenching assays were utilized to study the conformation of ...


Structural Basis For +1 Ribosomal Frameshifting During Ef-G-Catalyzed Translocation [Preprint], Gabriel Demo, Anna B. Loveland, Egor Svidritskiy, Howard B. Gamper, Ya-Ming Hou, Andrei A. Korostelev 2020 University of Massachusetts Medical School

Structural Basis For +1 Ribosomal Frameshifting During Ef-G-Catalyzed Translocation [Preprint], Gabriel Demo, Anna B. Loveland, Egor Svidritskiy, Howard B. Gamper, Ya-Ming Hou, Andrei A. Korostelev

University of Massachusetts Medical School Faculty Publications

Frameshifting of mRNA during translation provides a strategy to expand the coding repertoire of cells and viruses. Where and how in the elongation cycle +1-frameshifting occurs remains poorly understood. We captured six ∼3.5-Å-resolution cryo-EM structures of ribosomal elongation complexes formed with the GTPase elongation factor G (EF-G). Three structures with a +1-frameshifting-prone mRNA reveal that frameshifting takes place during translocation of tRNA and mRNA. Prior to EF-G binding, the pre-translocation complex features an in-frame tRNA-mRNA pairing in the A site. In the partially translocated structure with EF-G, the tRNA shifts to the +1-frame codon near the P site, whereas ...


Systematic Evaluation Of Chromosome Conformation Capture Assays [Preprint], Betul Akgol-Oksuz, Liyan Yang, Sergey V. Venev, Nils Krietenstein, Krishna M. Parsi, Hakan Ozadam, Marlies E. Oomen, Ankita Nand, Hui Mao, Ryan M.J. Genga, Rene Maehr, Oliver J. Rando, Johan H. Gibcus, Job Dekker 2020 University of Massachusetts Medical School

Systematic Evaluation Of Chromosome Conformation Capture Assays [Preprint], Betul Akgol-Oksuz, Liyan Yang, Sergey V. Venev, Nils Krietenstein, Krishna M. Parsi, Hakan Ozadam, Marlies E. Oomen, Ankita Nand, Hui Mao, Ryan M.J. Genga, Rene Maehr, Oliver J. Rando, Johan H. Gibcus, Job Dekker

University of Massachusetts Medical School Faculty Publications

Chromosome conformation capture (3C)-based assays are used to map chromatin interactions genome-wide. Quantitative analyses of chromatin interaction maps can lead to insights into the spatial organization of chromosomes and the mechanisms by which they fold. A number of protocols such as in situ Hi-C and Micro-C are now widely used and these differ in key experimental parameters including cross-linking chemistry and chromatin fragmentation strategy. To understand how the choice of experimental protocol determines the ability to detect and quantify aspects of chromosome folding we have performed a systematic evaluation of experimental parameters of 3C-based protocols. We find that different ...


Linker Histone H1.8 Inhibits Chromatin-Binding Of Condensins And Dna Topoisomerase Ii To Tune Chromosome Compaction And Individualization [Preprint], Pavan Choppakatla, Bastiaan Dekker, Erin E. Cutts, Alessandro Vannini, Job Dekker, Hironori Funabiki 2020 Rockefeller University

Linker Histone H1.8 Inhibits Chromatin-Binding Of Condensins And Dna Topoisomerase Ii To Tune Chromosome Compaction And Individualization [Preprint], Pavan Choppakatla, Bastiaan Dekker, Erin E. Cutts, Alessandro Vannini, Job Dekker, Hironori Funabiki

University of Massachusetts Medical School Faculty Publications

DNA loop extrusion by condensins and decatenation by DNA topoisomerase II (topo II) drive mitotic chromosome compaction and individualization. Here, we reveal that the linker histone H1.8 regulates chromatin levels of condensins and topo II. In vitro chromatin reconstitution experiments demonstrate that H1.8 inhibits binding of condensins and topo II to nucleosome arrays. Accordingly, H1.8 depletion in Xenopus egg extracts increased condensins and topo II levels on mitotic chromatin. Chromosome morphology and Hi-C analyses suggest that H1.8 depletion makes chromosomes thinner and longer likely through shortening the average loop size and reducing DNA amount in each ...


The Shape Of U: Mapping Out Protective Elements In Mrna Escapees, Jacob Miles 2020 University of Massachusetts Amherst

The Shape Of U: Mapping Out Protective Elements In Mrna Escapees, Jacob Miles

Masters Theses

A crucial step of the viral life cycle of Kaposi’s Sarcoma Herpesvirus (KSHV) lytic infection is the triggering of a massive RNA decay event termed “Host Shutoff”. Host Shutoff is driven by the viral endonuclease SOX which leads to the destruction of over 70% of the total transcriptome. This process cripples cellular gene expression and allows for viral reprograming of the cell for the purpose of viral replication. Co-evolution has led to the host developing a multitude of antiviral defenses aimed at preserving certain cellular RNAs linked to antiviral responses. One such defense are RNA secondary structures located within ...


A Rational Design Approach To Developing Second Generation Fabry Disease Treatments, Matthew Metcalf 2020 University of Massachusetts Amherst

A Rational Design Approach To Developing Second Generation Fabry Disease Treatments, Matthew Metcalf

Doctoral Dissertations

Fabry disease is an X-linked lysosomal storage disorder that affects

approximately 1 in 40,000 males in its classical form and as many as 1:4,600 in its

late-onset form [1]. The disease is caused by mutations in the gene encoding α-

galactosidase (α-GAL), which results in deficient levels of α-GAL activity in the

lysosomes of patients [2, 3]. This lack of enzymatic activity causes macromolecular

substrates to accumulate in tissues, and can result in a wide range of symptoms such

as impaired renal and cardiac function [4]. The severity of disease is linked to the

amount of residual ...


Simultaneous Epigenetic Perturbation And Genome Imaging Reveal Distinct Roles Of H3k9me3 In Chromatin Architecture And Transcription, Ying Feng, Yao Wang, Xiangnan Wang, Xiaohui He, Chen Yang, Ardalan Naseri, Thoru Pederson, Jing Zheng, Shaojie Zhang, Xiao Xiao, Wei Xie, Hanhui Ma 2020 East China University of Science and Technology

Simultaneous Epigenetic Perturbation And Genome Imaging Reveal Distinct Roles Of H3k9me3 In Chromatin Architecture And Transcription, Ying Feng, Yao Wang, Xiangnan Wang, Xiaohui He, Chen Yang, Ardalan Naseri, Thoru Pederson, Jing Zheng, Shaojie Zhang, Xiao Xiao, Wei Xie, Hanhui Ma

Open Access Publications by UMMS Authors

INTRODUCTION: Despite the long-observed correlation between H3K9me3, chromatin architecture, and transcriptional repression, how H3K9me3 regulates genome higher-order organization and transcriptional activity in living cells remains unclear.

RESULT: Here, we develop EpiGo (Epigenetic perturbation induced Genome organization)-KRAB to introduce H3K9me3 at hundreds of loci spanning megabases on human chromosome 19 and simultaneously track genome organization. EpiGo-KRAB is sufficient to induce genomic clustering and de novo heterochromatin-like domain formation, which requires SETDB1, a methyltransferase of H3K9me3. Unexpectedly, EpiGo-KRAB-induced heterochromatin-like domain does not result in widespread gene repression except a small set of genes with concurrent loss of H3K4me3 and H3K27ac. Ectopic ...


Degree Of Conservation Of Methionines Found To Be Oxidized In The Human Urinary Proteome, Alexis Hall 2020 University of Arkansas, Fayetteville

Degree Of Conservation Of Methionines Found To Be Oxidized In The Human Urinary Proteome, Alexis Hall

Theses and Dissertations

In previous work from this laboratory, methionine containing peptides from the human urinary proteome were examined by mass spectrometry for the degree of methionine oxidation to the sulfoxide form. While this demonstrated that many of the methionines detected were capable of being oxidized, the question of whether these methionines are important in the structure and/or function of the parent proteins came about. In some proteins, methionine oxidation has been linked to conformational changes and alteration of function and thus can serve as a mechanism for reversible regulation of activity. It is hypothesized that methionines which might serve a regulatory ...


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