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Pad2 Dysregulation And Abnormal Protein Citrullination In Als Disease Models, Issa Yusuf, Tao Qiao, Ronak Tilvawala, Paul R. Thompson, Zuoshang Xu 2020 University of Massachusetts Medical School

Pad2 Dysregulation And Abnormal Protein Citrullination In Als Disease Models, Issa Yusuf, Tao Qiao, Ronak Tilvawala, Paul R. Thompson, Zuoshang Xu

University of Massachusetts Medical School Publications

Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disease characterized by loss of motor neurons, paralysis and eventual death. The mechanism of ALS is still incompletely understood, and the disease is to date without an effective remedy. Protein arginine deiminase 2 (PAD2) converts peptidyl-Arginine into peptidyl-Citrulline, a post-translational modification referred to as citrullination. Aberrant expression of PAD2 and protein citrullination are increased in several neurodegenerative conditions. Whether this increase is involved in ALS is unknown. In this study, we investigated PAD2 and protein citrullination in two genetic mouse models of ALS expressing human mutant SOD1G93A and PFN1C71G, respectively ...


Rad21 Is Involved In Corneal Stroma Development By Regulating Neural Crest Migration, Bi Ning Zhang, Yu Liu, Qichen Yang, Pui Ying Leung, Chengdong Wang, Thomas Chi Wong Bun, Clement C. Tham, Sun On Chan, Chi Pui Pang, Li Jia Chen, Job Dekker, Hui Zhao, Wai Kit Chu 2020 The Chinese University of Hong Kong

Rad21 Is Involved In Corneal Stroma Development By Regulating Neural Crest Migration, Bi Ning Zhang, Yu Liu, Qichen Yang, Pui Ying Leung, Chengdong Wang, Thomas Chi Wong Bun, Clement C. Tham, Sun On Chan, Chi Pui Pang, Li Jia Chen, Job Dekker, Hui Zhao, Wai Kit Chu

Open Access Publications by UMMS Authors

Previously, we identified RAD21(R450C) from a peripheral sclerocornea pedigree. Injection of this rad21 variant mRNA into Xenopus laevis embryos disrupted the organization of corneal stroma fibrils. To understand the mechanisms of RAD21-mediated corneal stroma defects, gene expression and chromosome conformation analysis were performed using cells from family members affected by peripheral sclerocornea. Both gene expression and chromosome conformation of cell adhesion genes were affected in cells carrying the heterozygous rad21 variant. Since cell migration is essential in early embryonic development and sclerocornea is a congenital disease, we studied neural crest migration during cornea development in X. laevis embryos. In ...


Multivalent Interactions Drive Nucleosome Binding And Efficient Chromatin Deacetylation By Sirt6, Wallace H. Liu, Jie Zheng, Jessica L. Feldman, Mark A. Klein, Vyacheslav I. Kuznetsov, Craig L. Peterson, Patrick R. Griffin, John M. Denu 2020 University of Wisconsin-Madison

Multivalent Interactions Drive Nucleosome Binding And Efficient Chromatin Deacetylation By Sirt6, Wallace H. Liu, Jie Zheng, Jessica L. Feldman, Mark A. Klein, Vyacheslav I. Kuznetsov, Craig L. Peterson, Patrick R. Griffin, John M. Denu

Open Access Publications by UMMS Authors

The protein deacetylase SIRT6 maintains cellular homeostasis through multiple pathways that include the deacetylation of histone H3 and repression of transcription. Prior work suggests that SIRT6 is associated with chromatin and can substantially reduce global levels of H3 acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we describe an exquisitely tight interaction between SIRT6 and nucleosome core particles, in which a 2:1 enzyme:nucleosome complex assembles via asymmetric binding with distinct affinities. While both SIRT6 molecules associate with the acidic patch on the nucleosome, we find that the intrinsically disordered SIRT6 C-terminus promotes binding ...


Peptidylarginine Deiminase 2 Has Potential As Both A Biomarker And Therapeutic Target Of Sepsis, Yuzi Tian, Santanu Mondal, Paul R. Thompson, Yongqing Li 2020 Central South University

Peptidylarginine Deiminase 2 Has Potential As Both A Biomarker And Therapeutic Target Of Sepsis, Yuzi Tian, Santanu Mondal, Paul R. Thompson, Yongqing Li

Open Access Publications by UMMS Authors

Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression ...


A Label-Free Assay For Aminoacylation Of Trna, Howard Gamper, Ya-Ming Hou 2020 Thomas Jefferson University

A Label-Free Assay For Aminoacylation Of Trna, Howard Gamper, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Aminoacylation of tRNA generates an aminoacyl-tRNA (aa-tRNA) that is active for protein synthesis on the ribosome. Quantification of aminoacylation of tRNA is critical to understand the mechanism of specificity and the flux of the aa-tRNA into the protein synthesis machinery, which determines the rate of cell growth. Traditional assays for the quantification of tRNA aminoacylation involve radioactivity, either with a radioactive amino acid or with a [3'-32P]-labeled tRNA. We describe here a label-free assay that monitors aminoacylation by biotinylation-streptavidin (SA) conjugation to the α-amine or the α-imine of the aminoacyl group on the aa-tRNA. The conjugated aa-tRNA product ...


Estimating Partial Body Ionizing Radiation Exposure By Automated Cytogenetic Biodosimetry, Ben Shirley, Peter Rogan 2020 Cytognomix

Estimating Partial Body Ionizing Radiation Exposure By Automated Cytogenetic Biodosimetry, Ben Shirley, Peter Rogan

Biochemistry Publications

Purpose: Inhomogeneous exposures to ionizing radiation can be detected and quantified with the dicentric chromosome assay (DCA) of metaphase cells. Complete automation of interpretation of the DCA for whole-body irradiation has significantly improved throughput without compromising accuracy, however, low levels of residual false positive dicentric chromosomes (DCs) have confounded its application for partial-body exposure determination.

Materials and methods: We describe a method of estimating and correcting for false positive DCs in digitally processed images of metaphase cells. Nearly all DCs detected in unirradiated calibration samples are introduced by digital image processing. DC frequencies of irradiated calibration samples and those exposed ...


Caenorhabditis Elegans Methionine/S-Adenosylmethionine Cycle Activity Is Sensed And Adjusted By A Nuclear Hormone Receptor, Gabrielle E. Giese, Melissa D. Walker, Olga Ponomarova, Hefei Zhang, Xuhang Li, Gregory Minevich, Albertha J. M. Walhout 2020 University of Massachusetts Medical School

Caenorhabditis Elegans Methionine/S-Adenosylmethionine Cycle Activity Is Sensed And Adjusted By A Nuclear Hormone Receptor, Gabrielle E. Giese, Melissa D. Walker, Olga Ponomarova, Hefei Zhang, Xuhang Li, Gregory Minevich, Albertha J. M. Walhout

Open Access Publications by UMMS Authors

Vitamin B12 is an essential micronutrient that functions in two metabolic pathways: the canonical propionate breakdown pathway and the methionine/S-adenosylmethionine (Met/SAM) cycle. In Caenorhabditis elegans, low vitamin B12, or genetic perturbation of the canonical propionate breakdown pathway results in propionate accumulation and the transcriptional activation of a propionate shunt pathway. This propionate-dependent mechanism requires nhr-10 and is referred to as 'B12-mechanism-I'. Here, we report that vitamin B12 represses the expression of Met/SAM cycle genes by a propionate-independent mechanism we refer to as 'B12-mechanism-II'. This mechanism is activated by perturbations in the Met/SAM cycle, genetically or due ...


Changes In Lipid Profiles Of Epileptic Mouse Mode, Alicia Johnson, Ryan A. Grove, Deepak Madhavan, Cory H.T. Boone, Camila Pereira Braga, Hannah Kyllo, Kaeli K. Samson, Kristina A. Simeone, Timothy A. Simeone, Tomáš Helikar, Corrine K. Hanson, Jiri Adamec 2020 University of Nebraska-Lincoln

Changes In Lipid Profiles Of Epileptic Mouse Mode, Alicia Johnson, Ryan A. Grove, Deepak Madhavan, Cory H.T. Boone, Camila Pereira Braga, Hannah Kyllo, Kaeli K. Samson, Kristina A. Simeone, Timothy A. Simeone, Tomáš Helikar, Corrine K. Hanson, Jiri Adamec

Biochemistry -- Faculty Publications

Introduction Approximately 1% of the world’s population is impacted by epilepsy, a chronic neurological disorder characterized by seizures. One-third of epileptic patients are resistant to AEDs, or have medically refractory epilepsy (MRE). One non-invasive treatment that exists for MRE includes the ketogenic diet (KD), a high-fat, low-carbohydrate diet. Despite the KD’s success in seizure attenuation, it has a few risks and its mechanisms remain poorly understood. The KD has been shown to improve metabolism and mitochondrial function in epileptic phenotypes. Potassium channels have implications in epileptic conditions as they have dual roles as metabolic sensors and control neuronal ...


A Review Of The Preclinical And Clinical Efficacy Of Remdesivir, Hydroxychloroquine, And Lopinavir-Ritonavir Treatments Against Covid-19, Dawid Maciorowski, Samir Z. El Idrissi, Yash Gupta, Brian J. Medernach, Michael B. Burns, Daniel P. Becker Ph.D., Ravi Durvasula, Prakasha Kempaiah 2020 Loyola University Chicago Stritch School of Medicine

A Review Of The Preclinical And Clinical Efficacy Of Remdesivir, Hydroxychloroquine, And Lopinavir-Ritonavir Treatments Against Covid-19, Dawid Maciorowski, Samir Z. El Idrissi, Yash Gupta, Brian J. Medernach, Michael B. Burns, Daniel P. Becker Ph.D., Ravi Durvasula, Prakasha Kempaiah

Chemistry: Faculty Publications and Other Works

In December of 2019, an outbreak of a novel coronavirus flared in Wuhan, the capital city of the Hubei Province, China. The pathogen has been identified as a novel enveloped RNA beta-coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus SARS-CoV-2 is associated with a disease characterized by severe atypical pneumonia known as coronavirus 2019 (COVID-19). Typical symptoms of this disease include cough, fever, malaise, shortness of breath, gastrointestinal symptoms, anosmia, and, in severe cases, pneumonia.1 The high-risk group of COVID-19 patients includes people over the age of 60 years as well as people with existing cardiovascular ...


Physico-Chemical And Adsorption Properties Of Activated Adsorbents Obtained On The Basis Of Wood Stems, Rakhimjon Paygamov, Izzat Eshmetov, Shakhnoza Kuldasheva, Hamdam Akbarov, Feruza Jurayeva 2020 Institute of general and inorganic chemistry of Academy of Sciences of the Republic of Uzbekistan

Physico-Chemical And Adsorption Properties Of Activated Adsorbents Obtained On The Basis Of Wood Stems, Rakhimjon Paygamov, Izzat Eshmetov, Shakhnoza Kuldasheva, Hamdam Akbarov, Feruza Jurayeva

Bulletin of National University of Uzbekistan: Mathematics and Natural Sciences

As a result of the investigations, the adsorbents of activated coal at different temperatures and with water vapor were extracted from plane-tree, ash-tree, Cherry, Apricot, nut stems were received and their physico-chemical and adsorption properties were determined. The results have shown that the adsorption efficiency and adsorption properties of the plane-tree adsorbents are significantly higher than those of other trees. It can be seen that heating the resulting coal adsorbents from 400 to 800°, that is, thermal activation, almost has double their pore volume. The adsorption properties of adsorbents were determined in the following orders, for thermally activated coals at ...


Differentiation Of Membrane Active Crown Ethers On The Multilamellar Layers, Ulugbek Mirkhodjaev, Oleg Yarishkin, Umida Sharafutdinova, Uktam Toyirov, Nafisa Atamuratova, Anisa Tashmukhamedova, Bekdjan Tashmukhamedov 2020 National University of Uzbekistan

Differentiation Of Membrane Active Crown Ethers On The Multilamellar Layers, Ulugbek Mirkhodjaev, Oleg Yarishkin, Umida Sharafutdinova, Uktam Toyirov, Nafisa Atamuratova, Anisa Tashmukhamedova, Bekdjan Tashmukhamedov

Bulletin of National University of Uzbekistan: Mathematics and Natural Sciences

Investigation of the interaction of crown ethers, which are have different structure and mechanism of membrane action, with multilamellar dispersions makes it possible to establish a difference in their effect on the rearrangement of the initial structure of lipid bilayers. Investigation of the restructuring of lipid bilayers during interaction of complexons, ionophores and channel-formers with a membrane allows obtaining important information on the mechanisms of transmembrane ion transport.


Large Domains Of Heterochromatin Direct The Formation Of Short Mitotic Chromosome Loops, Maximilian H. Fitz-James, Pin Tong, Alison L. Pidoux, Hakan Ozadam, Liyan Yang, Sharon A. White, Job Dekker, Robin C. Allshire 2020 University of Edinburgh

Large Domains Of Heterochromatin Direct The Formation Of Short Mitotic Chromosome Loops, Maximilian H. Fitz-James, Pin Tong, Alison L. Pidoux, Hakan Ozadam, Liyan Yang, Sharon A. White, Job Dekker, Robin C. Allshire

Open Access Publications by UMMS Authors

During mitosis chromosomes reorganise into highly compact, rod-shaped forms, thought to consist of consecutive chromatin loops around a central protein scaffold. Condensin complexes are involved in chromatin compaction, but the contribution of other chromatin proteins, DNA sequence and histone modifications is less understood. A large region of fission yeast DNA inserted into a mouse chromosome was previously observed to adopt a mitotic organisation distinct from that of surrounding mouse DNA. Here, we show that a similar distinct structure is common to a large subset of insertion events in both mouse and human cells and is coincident with the presence of ...


Indoline‐6‐Sulfonamide Inhibitors Of The Bacterial Enzyme Dape, Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz, Daniel P. Becker Ph.D. 2020 Loyola University Chicago

Indoline‐6‐Sulfonamide Inhibitors Of The Bacterial Enzyme Dape, Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz, Daniel P. Becker Ph.D.

Chemistry: Faculty Publications and Other Works

Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG).


Rethinking Fda Regulation Of Complex Products, Philip E. Alford 2020 University of Minnesota Law School

Rethinking Fda Regulation Of Complex Products, Philip E. Alford

Minnesota Journal of Law, Science & Technology

No abstract provided.


Estimating Partial Body Ionizing Radiation Exposure By Automated Cytogenetic Biodosimetry, Peter Rogan 2020 The University of Western Ontario

Estimating Partial Body Ionizing Radiation Exposure By Automated Cytogenetic Biodosimetry, Peter Rogan

Biochemistry Publications

Purpose: Inhomogeneous exposures to ionizing radiation can be detected and quantified with the Dicentric Chromosome Assay (DCA) of metaphase cells. Complete automation of interpretation of the DCA for whole body irradiation has significantly improved throughput without compromising accuracy, however low levels of residual false positive dicentric chromosomes (DCs) have confounded its application for partial body exposure determination.

Materials and Methods: We describe a method of estimating and correcting for false positive DCs in digitally processed images of metaphase cells. Nearly all DCs detected in unirradiated calibration samples are introduced by digital image processing. DC frequencies of irradiated calibration samples and ...


Electronic-Cigarette Vehicles And Flavoring Affect Lung Function And Immune Responses In A Murine Model, Brittany N. Szafran, Rakeysha Pinkston, Zakia Perveen, Matthew K. Ross, Timothy Morgan, Daniel B. Paulsen, Arthur L. Penn, Barbara L. F. Kaplan, Alexandra Noel 2020 Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Ctr Environm Hlth Sci, Mississippi State, MS

Electronic-Cigarette Vehicles And Flavoring Affect Lung Function And Immune Responses In A Murine Model, Brittany N. Szafran, Rakeysha Pinkston, Zakia Perveen, Matthew K. Ross, Timothy Morgan, Daniel B. Paulsen, Arthur L. Penn, Barbara L. F. Kaplan, Alexandra Noel

Faculty Publications

The use of electronic nicotine delivery systems (ENDS), also known as electronic-cigarettes (e-cigs), has raised serious public health concerns, especially in light of the 2019 outbreak of e-cig or vaping product use-associated acute lung injury (EVALI). While these cases have mostly been linked to ENDS that contain vitamin E acetate, there is limited research that has focused on the chronic pulmonary effects of the delivery vehicles (i.e., without nicotine and flavoring). Thus, we investigated lung function and immune responses in a mouse model following exposure to the nearly ubiquitous e-cig delivery vehicles, vegetable glycerin (VG) and propylene glycol (PG ...


Genome Scan Detection Of Selective Sweeps Among Biotypes Of The Soybean Aphid, Aphis Glycines, With Differing Virulence To Resistance To A. Glycines (Rag) Traits In Soybean, Glycine Max, Brad S. Coates, Jessica D. Hohenstein, Rosanna Giordano, Ravi Kiran Donthu, Andrew P. Michel, Erin W. Hodgson, Matthew E. O'Neal 2020 U.S. Department of Agriculture

Genome Scan Detection Of Selective Sweeps Among Biotypes Of The Soybean Aphid, Aphis Glycines, With Differing Virulence To Resistance To A. Glycines (Rag) Traits In Soybean, Glycine Max, Brad S. Coates, Jessica D. Hohenstein, Rosanna Giordano, Ravi Kiran Donthu, Andrew P. Michel, Erin W. Hodgson, Matthew E. O'Neal

Entomology Publications

Multiple biotypes of soybean aphid, Aphis glycines, occur in North America adapted for survival (virulence) on soybean, Glycine max, with one or more different resistance to A. glycines (Rag) traits. The degree of genome-wide variance between biotypes and the basis of virulence remains unknown, but the latter is hypothesized to involve secreted effector proteins. Between 167,249 and 217,750 single nucleotide polymorphisms (SNPs) were predicted from whole genome re-sequencing of A. glycines avirulent biotype 1 (B1) and virulent B2, B3 and B4 colony-derived iso-female lines when compared to the draft B1 genome assembly, Ag_bt1_v6.0. Differences in nucleotide diversity ...


Pressure Driven Desalination Utilizing Nanomaterials, Fangyou Xie 2020 calpoly san luis obispo

Pressure Driven Desalination Utilizing Nanomaterials, Fangyou Xie

Master's Theses

Nanomaterials such as graphene oxide and carbon nanotubes, have demonstrated excellent properties for membrane desalination, including decrease of maintenance, increase of flux rate, simple solution casting, and impressive chemical inertness. Here, two projects are studied to investigate nanocarbon based membrane desalination. The first project is to prepare hybrid membranes with amyloid fibrils intercalated with graphene oxide sheets. The addition of protein amyloid fibrils expands the interlayer spacing between graphene oxide nanosheets and introduces additional functional groups in the diffusion pathways, resulting in increase of flux rate and rejection rate for the organic dyes. Amyloid fibrils also provide structural assistance to ...


The Bromodomains Of The Mammalian Swi/Snf (Mswi/Snf) Atpases Brahma (Brm) And Brahma Related Gene 1 (Brg1) Promote Chromatin Interaction And Are Critical For Skeletal Muscle Differentiation [Preprint], Anthony N. Imbalzano, Hanna Witwicka, Tapan Sharma 2020 University of Massachusetts Medical School

The Bromodomains Of The Mammalian Swi/Snf (Mswi/Snf) Atpases Brahma (Brm) And Brahma Related Gene 1 (Brg1) Promote Chromatin Interaction And Are Critical For Skeletal Muscle Differentiation [Preprint], Anthony N. Imbalzano, Hanna Witwicka, Tapan Sharma

University of Massachusetts Medical School Faculty Publications

Skeletal muscle differentiation induces changes in the epigenome of myoblasts as they proceed towards a myogenic phenotype. mSWI/SNF chromatin remodeling enzymes coordinate with lineage-determining transcription factors and are key regulators of differentiation. Three mSWI/SNF proteins, the mutually exclusive ATPases, BRG1 and BRM, and the BAF180 protein (Polybromo1, PBRM1) contain bromodomains belonging to the same structural subfamily. Bromodomains bind to acetylated lysines on histone N-terminal tails and on other proteins. Pharmacological inhibition of mSWI/SNF bromodomain function using the selective inhibitor PFI-3 reduced differentiation, decreased expression of myogenic genes, and increased the expression of cell cycle-related genes and the ...


Machine Learning Applications For Drug Repurposing, Hansaim Lim 2020 The Graduate Center, City University of New York

Machine Learning Applications For Drug Repurposing, Hansaim Lim

Dissertations, Theses, and Capstone Projects

The cost of bringing a drug to market is astounding and the failure rate is intimidating. Drug discovery has been of limited success under the conventional reductionist model of one-drug-one-gene-one-disease paradigm, where a single disease-associated gene is identified and a molecular binder to the specific target is subsequently designed. Under the simplistic paradigm of drug discovery, a drug molecule is assumed to interact only with the intended on-target. However, small molecular drugs often interact with multiple targets, and those off-target interactions are not considered under the conventional paradigm. As a result, drug-induced side effects and adverse reactions are often neglected ...


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