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

University of Massachusetts Medical School Faculty Publications

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. 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 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 H3K9me3 appears to spread ...


Structural Analysis Of Potent Hybrid Hiv-1 Protease Inhibitors Containing Bis-Tetrahydrofuran In A Pseudo-Symmetric Dipeptide Isostere, Linah Rusere, Gordon J. Lockbaum, Mina Henes, Sook-Kyung Lee, Ean Spielvogel, Desaboini Nageswara Rao, Klajdi Kosovrasti, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali 2020 University of Massachusetts Medical School

Structural Analysis Of Potent Hybrid Hiv-1 Protease Inhibitors Containing Bis-Tetrahydrofuran In A Pseudo-Symmetric Dipeptide Isostere, Linah Rusere, Gordon J. Lockbaum, Mina Henes, Sook-Kyung Lee, Ean Spielvogel, Desaboini Nageswara Rao, Klajdi Kosovrasti, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali

University of Massachusetts Medical School Faculty Publications

The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the ...


Lmea, A Conserved Cell-Envelope Protein In Mycobacteria, Is Important For Antibiotic Resistance And Cell Envelope Permeability, Sarah Hassan Osman 2020 University of Massachusetts Amherst

Lmea, A Conserved Cell-Envelope Protein In Mycobacteria, Is Important For Antibiotic Resistance And Cell Envelope Permeability, Sarah Hassan Osman

Masters Theses

The cell envelope of mycobacteria is critical for the survival and virulence of pathogenic species during infection, and its biosynthesis has been a proven drug target. Therefore, finding new targets in the biosynthetic pathway of cell envelope components is of great interest. Mycobacterium smegmatis is a model organism for the study of the devastating pathogen Mycobacterium tuberculosis. Previously, lipomannan elongation factor A (LmeA) has been identified as a cell envelope protein that is critical for the control of mannan chain length of lipomannan (LM) and lipoarabinomannan (LAM), lipoglycan components of the cell envelope. The deletion mutant, ∆lmeA, accumulates abnormal LM ...


Gene Expression Regulation In The Mouse Liver By Mechanistic Target Of Rapamycin Complexes I And Ii, Anthony Poluyanoff 2020 University of Massachusetts Amherst

Gene Expression Regulation In The Mouse Liver By Mechanistic Target Of Rapamycin Complexes I And Ii, Anthony Poluyanoff

Masters Theses

The mechanistic target of rapamycin (mTOR) is a key serine/threonine protein kinase that functions in complexes mTORC1 and mTORC2. mTORC1, originally discovered due to its sensitivity towards the mTOR inhibitor rapamycin, responds to extracellular growth factor signaling, WNT signaling, and nutrient abundance via glucose and amino acid-triggered signaling. Downstream effectors of mTORC1 include autophagy, mitochondrial metabolic function, protein synthesis, and ribosome biogenesis. mTORC2, initially discovered as a rapamycin-insensitive complex of mTOR, responds to insulin, growth factor signaling, and inflammatory signaling such as tumor necrosis factor-alpha, with its downstream effectors being Akt, a key serine/threonine kinase that functions in ...


Jnk-Mediated Disruption Of Bile Acid Homeostasis Promotes Intrahepatic Cholangiocarcinoma, Elisa Manieri, Tamera Barrett, Julie Cavanagh-Kyros, Roger J. Davis, Alfonso Mora, Guadalupe Sabio 2020 National Centre for Cardiovascular Research, Spain

Jnk-Mediated Disruption Of Bile Acid Homeostasis Promotes Intrahepatic Cholangiocarcinoma, Elisa Manieri, Tamera Barrett, Julie Cavanagh-Kyros, Roger J. Davis, Alfonso Mora, Guadalupe Sabio

University of Massachusetts Medical School Faculty Publications

Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARalpha. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in ...


Nutrient Sensing Pathways Mediating Igfbp1 Phosphorylation In Fgr, Shapnil Bhuiyan 2020 The University of Western Ontario

Nutrient Sensing Pathways Mediating Igfbp1 Phosphorylation In Fgr, Shapnil Bhuiyan

Electronic Thesis and Dissertation Repository

Impairment of fetal oxygen levels and nutrient delivery contributes to fetal growth restriction (FGR), which affects 20% of pregnancies. Such cellular stress induces hepatic Insulin-like Growth Factor Binding Protein 1 (IGFBP1) phosphorylation, which sequesters Insulin-like Growth Factor 1 (IGF-I) and markedly reduces fetal growth signaling. IGFBP1 hyperphosphoryaltion in hypoxia is mediated through the mTOR signaling pathway and through the Amino Acid Response (AAR) pathway during amino acid deprivation. Hypoxia stimulates upstream mTORC1 regulators, AMPK and REDD1 which are well-established upstream regulators of one of the two mTOR complexes, mTORC1. The molecular mechanisms by which upstream mTORC1-driven processes regulate IGFBP1 phosphorylation ...


Hem1 Deficiency Disrupts Mtorc2 And F-Actin Control In Inherited Immunodysregulatory Disease, Sarah A. Cook, William A. Comrie, Morgan Similuk, Andrew J. Oler, Aiman J. Faruqi, Sheng Yang, D. Eric Anderson, Susan Price, Margery Smelkinson, Baoyu Chen, V. Koneti Rao, Michael J. Lenardo, et al. 2020 National Institutes of Health

Hem1 Deficiency Disrupts Mtorc2 And F-Actin Control In Inherited Immunodysregulatory Disease, Sarah A. Cook, William A. Comrie, Morgan Similuk, Andrew J. Oler, Aiman J. Faruqi, Sheng Yang, D. Eric Anderson, Susan Price, Margery Smelkinson, Baoyu Chen, V. Koneti Rao, Michael J. Lenardo, Et Al.

Biochemistry, Biophysics and Molecular Biology Publications

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss ...


Plankton Dynamics In An Urban, Subtropical Lake Prior To Lake Restoration, Jennifer C. Pulsifer 2020 Louisiana State University and Agricultural and Mechanical College

Plankton Dynamics In An Urban, Subtropical Lake Prior To Lake Restoration, Jennifer C. Pulsifer

LSU Master's Theses

This research assessed plankton dynamics in two urban, subtropical lakes (University Lake and City Park Lake) shortly before a proposed and approved lake restoration project. Plankton dynamics were determined in University Lake by the dilution method to attempt to quantify growth rates of phytoplankton and grazing rates of zooplankton. Landry and Hassett’s (1982) dilution method has been widely used in marine systems to estimate rates of growth and grazing. In many marine systems, nutrients must be added to prevent nutrient limitation. However, it is assumed, due to the hypereutrophic conditions, that nutrients would not be a limitation in University ...


Regulation Of The Mammalian Swi/Snf Family Of Chromatin Remodeling Enzymes By Phosphorylation During Myogenesis, Teresita Padilla-Benavides, Pablo Reyes-Gutierrez, Anthony N. Imbalzano 2020 University of Massachusetts Medical School

Regulation Of The Mammalian Swi/Snf Family Of Chromatin Remodeling Enzymes By Phosphorylation During Myogenesis, Teresita Padilla-Benavides, Pablo Reyes-Gutierrez, Anthony N. Imbalzano

University of Massachusetts Medical School Faculty Publications

Myogenesis is the biological process by which skeletal muscle tissue forms. Regulation of myogenesis involves a variety of conventional, epigenetic, and epigenomic mechanisms that control chromatin remodeling, DNA methylation, histone modification, and activation of transcription factors. Chromatin remodeling enzymes utilize ATP hydrolysis to alter nucleosome structure and/or positioning. The mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) family of chromatin remodeling enzymes is essential for myogenesis. Here we review diverse and novel mechanisms of regulation of mSWI/SNF enzymes by kinases and phosphatases. The integration of classic signaling pathways with chromatin remodeling enzyme function impacts myoblast viability and proliferation as well ...


Chromosome-Scale Assembly Of The Coral Endosymbiont Symbiodinium Microadriaticum Genome Provides Insight Into The Unique Biology Of Dinoflagellate Chromosomes [Preprint], Ankita Nand, Ye Zhan, Octavio R. Salazar, Manuel Aranda, Christian R. Voolstra, Job Dekker 2020 University of Massachusetts Medical School

Chromosome-Scale Assembly Of The Coral Endosymbiont Symbiodinium Microadriaticum Genome Provides Insight Into The Unique Biology Of Dinoflagellate Chromosomes [Preprint], Ankita Nand, Ye Zhan, Octavio R. Salazar, Manuel Aranda, Christian R. Voolstra, Job Dekker

University of Massachusetts Medical School Faculty Publications

Dinoflagellates are major primary producers in the world’s oceans, the cause of harmful algal blooms, and endosymbionts of marine invertebrates. Much remains to be understood about their biology including their peculiar crystalline chromosomes. Here we used Hi-C to order short read-based sub-scaffolds into 94 chromosome-scale scaffolds of the genome of the coral endosymbiont Symbiodinium microadriaticum. Hi-C data show that chromosomes are folded as linear rods within which loci separated by up to several Mb are highly packed. Each chromosome is composed of a series of structural domains separated by boundaries. Genes are enriched towards the ends of chromosomes and ...


Acidic Ph Triggers Lipid Mixing Mediated By Lassa Virus Gp, Uriel Bulow, Ramesh Govindan, James B. Munro 2020 Tufts University

Acidic Ph Triggers Lipid Mixing Mediated By Lassa Virus Gp, Uriel Bulow, Ramesh Govindan, James B. Munro

Open Access Articles

Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever, a lethal disease endemic to Western Africa. LASV entry is mediated by the viral envelope glycoprotein (GP), a class I membrane fusogen and the sole viral surface antigen. Previous studies have identified components of the LASV entry pathway, including several cellular receptors and the requirement of endosomal acidification for infection. Here, we first demonstrate that incubation at a physiological temperature and pH consistent with the late endosome is sufficient to render pseudovirions, bearing LASV GP, non-infectious. Antibody binding indicates that this loss of infectivity is due to a conformational ...


Collaborative, Multidisciplinary Evaluation Of Cancer Variants Through Virtual Molecular Tumor Boards Informs Local Clinical Practices., Shruti Rao, Beth Pitel, Alex H Wagner, Simina M Boca, Matthew McCoy, Ian King, Samir Gupta, Ben Ho Park, Jeremy L Warner, James Chen, Peter Rogan, Debyani Chakravarty, Malachi Griffith, Obi L Griffith, Subha Madhavan 2020 The University of Western Ontario

Collaborative, Multidisciplinary Evaluation Of Cancer Variants Through Virtual Molecular Tumor Boards Informs Local Clinical Practices., Shruti Rao, Beth Pitel, Alex H Wagner, Simina M Boca, Matthew Mccoy, Ian King, Samir Gupta, Ben Ho Park, Jeremy L Warner, James Chen, Peter Rogan, Debyani Chakravarty, Malachi Griffith, Obi L Griffith, Subha Madhavan

Biochemistry Publications

PURPOSE: The cancer research community is constantly evolving to better understand tumor biology, disease etiology, risk stratification, and pathways to novel treatments. Yet the clinical cancer genomics field has been hindered by redundant efforts to meaningfully collect and interpret disparate data types from multiple high-throughput modalities and integrate into clinical care processes. Bespoke data models, knowledgebases, and one-off customized resources for data analysis often lack adequate governance and quality control needed for these resources to be clinical grade. Many informatics efforts focused on genomic interpretation resources for neoplasms are underway to support data collection, deposition, curation, harmonization, integration, and analytics ...


Investigation Of The Role Of Heparin-Binding Pocket In Amyloid Fibrils Formation Of Fgf-1, I Gusti Ayu Agung Septiari 2020 University of Arkansas, Fayetteville

Investigation Of The Role Of Heparin-Binding Pocket In Amyloid Fibrils Formation Of Fgf-1, I Gusti Ayu Agung Septiari

Theses and Dissertations

Human acidic fibroblast growth factor (aFGF/hFGF-1) is one of the promising molecules to be investigated to generate an in-depth understanding of the pathological mechanism of Alzheimer's disease (AD) neurodegenerative disorder characterized by the presence of amyloid fibrils. Some in vivo and human brain tissue studies proved the correlation of high-level expression of FGF-1-induced neuroinflammation and the occurrence of AD. The presence of amyloid fibrils as a hallmark of AD can be related to the generic property of the proteins to form amyloid fibrils; High level of FGF-1, in this case, may contribute to the formation of amyloid fibrils ...


Unpacking Pi Stacking: How Electrostatic Interactions And Aromaticity Can Be Utilized To Aid Triplex Formation In Double Helical Rna, John M. Talbott 2020 Elizabethtown College

Unpacking Pi Stacking: How Electrostatic Interactions And Aromaticity Can Be Utilized To Aid Triplex Formation In Double Helical Rna, John M. Talbott

Summer Scholarship, Creative Arts and Research Projects (SCARP)

No abstract provided.


Elucidating Collagen Degradation Synergy Between Col G And Col H From Hathewaya (Clostridium) Histolytica And Identifying Novel Structural Features In Hpt And Rec Domains From Vars Histidine Kinase In V. Alginolyticus, Perry Caviness 2020 University of Arkansas, Fayetteville

Elucidating Collagen Degradation Synergy Between Col G And Col H From Hathewaya (Clostridium) Histolytica And Identifying Novel Structural Features In Hpt And Rec Domains From Vars Histidine Kinase In V. Alginolyticus, Perry Caviness

Theses and Dissertations

In this research the mechanisms by which Hathewaya (Clostridia) histolytica collagenases are secreted and work together to degrade collagens are investigated. While H. histolytica collagenases Col G and Col H have similar multi-domain structures the difference in number of and orientation of the domains hint that the two target different regions in collagen. Study small angle x-ray scattering (SAXS) was used to give a low-resolution envelope of full-length Col G and Col H and Col G/Col H non-catalytic domains bound to a collagen-like peptide (mini-collagen). SAXS derived envelopes along with structural information was used to tease out the mechanisms ...


Structural Analysis Of The Multifunctional Spoiie Regulatory Protein Of Clostridioides Difficile., Blythe Emily Bunkers 2020 University of Arkansas, Fayetteville

Structural Analysis Of The Multifunctional Spoiie Regulatory Protein Of Clostridioides Difficile., Blythe Emily Bunkers

Theses and Dissertations

Clostridioides (formally Clostridium) difficile is a medically relevant pathogen pertinent to infectious disease research. C. difficile is distinctly known for its ability to produce two toxins, enterotoxin A and cytotoxin B, and the propensity to colonize the mammalian gastrointestinal tract. It is known that metabolism is tightly correlated with sporulation in endospore producers such as C. difficile, but an interesting and novel regulatory relationship found by the Ivey lab has yet to be understood. The relationship explored in this study is observed between the sporulation factor, SpoIIE, which represses expression of an ABC peptide transporter, app. In this study, two ...


Secretion Of Proteins And Antibody Fragments From Transiently Transfected Endothelial Progenitor Cells, Loree Heller, Reynald Thinard, Melanie Chevalier, Sezgi Arpag, Yu Jing, Ruth Greferath, Richard Heller, Claude Nicolau 2020 Old Dominion University

Secretion Of Proteins And Antibody Fragments From Transiently Transfected Endothelial Progenitor Cells, Loree Heller, Reynald Thinard, Melanie Chevalier, Sezgi Arpag, Yu Jing, Ruth Greferath, Richard Heller, Claude Nicolau

Bioelectrics Publications

In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, neuroinflammation can lead to blood-brain barrier (BBB) breakdown. After intravenous or intra-arterial injection into mice, endothelial progenitor cells (EPCs) home to the damaged BBB to promote neurovascular repair. Autologous EPCs transfected to express specific therapeutic proteins offer an innovative therapeutic option. Here, we demonstrate that EPC transfection by electroporation with plasmids encoding the reporter protein GFP or an anti-beta-amyloid antibody fragment (Fab) leads to secretion of each protein. We also demonstrate the secreted anti-beta-amyloid Fab protein functions in beta-amyloid aggregate solubilization.


Viral Membrane Fusion And The Transmembrane Domain, Chelsea T. Barrett, Rebecca Ellis Dutch 2020 University of Kentucky

Viral Membrane Fusion And The Transmembrane Domain, Chelsea T. Barrett, Rebecca Ellis Dutch

Molecular and Cellular Biochemistry Faculty Publications

Initiation of host cell infection by an enveloped virus requires a viral-to-host cell membrane fusion event. This event is mediated by at least one viral transmembrane glycoprotein, termed the fusion protein, which is a key therapeutic target. Viral fusion proteins have been studied for decades, and numerous critical insights into their function have been elucidated. However, the transmembrane region remains one of the most poorly understood facets of these proteins. In the past ten years, the field has made significant advances in understanding the role of the membrane-spanning region of viral fusion proteins. We summarize developments made in the past ...


Coronavirus Infographic, Angela Messmer-Blust 2020 University of Massachusetts Medical School

Coronavirus Infographic, Angela Messmer-Blust

RTI Children's Resources

To help give children a better understanding of the coronavirus that is causing the COVID-19 disease and the disruption in our daily lives, the RNA Therapeutics Institute (RTI) at UMass Medical created this infographic just for kids. We hope parents and teachers can use it to help explain this complex situation, while also teaching the wonders of science.


Abcs Of Covid-19 Coloring Page, Angela Messmer-Blust 2020 University of Massachusetts Medical School

Abcs Of Covid-19 Coloring Page, Angela Messmer-Blust

RTI Children's Resources

To help give children a better understanding of the coronavirus that is causing the COVID-19 disease and the disruption in our daily lives, the RNA Therapeutics Institute (RTI) at UMass Medical created this coloring page just for kids. We hope parents and teachers can use it to help explain this complex situation, while also teaching the wonders of science.


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