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Articles 1 - 30 of 1388

Full-Text Articles in Amino Acids, Peptides, and Proteins

Coevolution, Dynamics And Allostery Conspire In Shaping Cooperative Binding And Signal Transmission Of The Sars-Cov-2 Spike Protein With Human Angiotensin-Converting Enzyme 2, Gennady M. Verkhivker Nov 2020

Coevolution, Dynamics And Allostery Conspire In Shaping Cooperative Binding And Signal Transmission Of The Sars-Cov-2 Spike Protein With Human Angiotensin-Converting Enzyme 2, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of ...


Prevention Of Mitochondrial Impairment By Inhibition Of Protein Phosphatase 1 Activity In Amyotrophic Lateral Sclerosis, So Yoen Choi, Ju-Hyun Lee, Ah-Young Chung, Youhwa Jo, Joo-Ho Shin, Hae-Chul Park, Hyun Kim, Rodrigo Lopez-Gonzalez, Jae Ryun Ryu, Woong Sun Oct 2020

Prevention Of Mitochondrial Impairment By Inhibition Of Protein Phosphatase 1 Activity In Amyotrophic Lateral Sclerosis, So Yoen Choi, Ju-Hyun Lee, Ah-Young Chung, Youhwa Jo, Joo-Ho Shin, Hae-Chul Park, Hyun Kim, Rodrigo Lopez-Gonzalez, Jae Ryun Ryu, Woong Sun

Open Access Articles

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood. In this study, we found that Dynamin-related protein 1 (Drp1) was dephosphorylated in several ALS models, including those with SOD1 and TDP-43 mutations, and the dephosphorylation was mediated by the pathological induction of protein phosphatase 1 (PP1) activity in these models. Suppression of the PP1-Drp1 cascade effectively prevented ALS-related symptoms ...


Extracellular Micrornas In Human Circulation Are Associated With Mirisc Complexes That Are Accessible To Anti-Ago2 Antibody And Can Bind Target Mimic Oligonucleotides, Hirosha Geekiyanage, Shima Rayatpisheh, James A. Wohlschlegel, Robert H. Brown Jr., Victor R. Ambros Sep 2020

Extracellular Micrornas In Human Circulation Are Associated With Mirisc Complexes That Are Accessible To Anti-Ago2 Antibody And Can Bind Target Mimic Oligonucleotides, Hirosha Geekiyanage, Shima Rayatpisheh, James A. Wohlschlegel, Robert H. Brown Jr., Victor R. Ambros

Open Access Articles

MicroRNAs (miRNAs) function cell-intrinsically to regulate gene expression by base-pairing to complementary mRNA targets while in association with Argonaute, the effector protein of the miRNA-mediated silencing complex (miRISC). A relatively dilute population of miRNAs can be found extracellularly in body fluids such as human blood plasma and cerebrospinal fluid (CSF). The remarkable stability of circulating miRNAs in such harsh extracellular environments can be attributed to their association with protective macromolecular complexes, including extracellular vesicles (EVs), proteins such as Argonaut 2 (AGO2), or high-density lipoproteins. The precise origins and the potential biological significance of various forms of miRNA-containing extracellular complexes are ...


Cytokine-Targeted Therapeutics For Kshv-Associated Disease, Nedaa Alomari, Jennifer Totonchy Sep 2020

Cytokine-Targeted Therapeutics For Kshv-Associated Disease, Nedaa Alomari, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Kaposi’s sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a significant inflammatory component, current therapy for KSHV-associated disease is associated with significant off-target effects. However, recent advances in our understanding of the pathogenesis of KSHV have produced new insight into the use of cytokines as potential therapeutic targets. Better understanding of the role of cytokines during KSHV infection and tumorigenesis may lead to new preventive ...


Seroprevalence Of Sars-Cov-2-Specific Igg Antibodies Among Adults Living In Connecticut: Post-Infection Prevalence (Pip) Study [Preprint], Shiwani Mahajan, Lokinendi V. Rao, Harlan M. Krumholz Sep 2020

Seroprevalence Of Sars-Cov-2-Specific Igg Antibodies Among Adults Living In Connecticut: Post-Infection Prevalence (Pip) Study [Preprint], Shiwani Mahajan, Lokinendi V. Rao, Harlan M. Krumholz

University of Massachusetts Medical School Faculty Publications

Background: A seroprevalence study can estimate the percentage of people with SARS-CoV-2 antibodies in the general population, however, most existing reports have used a convenience sample, which may bias their estimates.

Methods: We sought a representative sample of Connecticut residents, aged ≥18 years and residing in non-congregate settings, who completed a survey between June 4 and June 23, 2020 and underwent serology testing for SARS-CoV-2-specific IgG antibodies between June 10 and July 29, 2020. We also oversampled non-Hispanic Black and Hispanic subpopulations. We estimated the seroprevalence of SARS-CoV-2-specific IgG antibodies and the prevalence of symptomatic illness and self-reported adherence to ...


Fancj Compensates For Rap80 Deficiency And Suppresses Genomic Instability Induced By Interstrand Cross-Links, Sanket Awate, Joshua A. Sommers, Arindam Datta, Sumeet Nayak, Marina A. Bellani, Olivia Yang, Christopher A. Dunn, Claudia M. Nicolae, George-Lucian Moldovan, Michael M. Seidman, Sharon B. Cantor, Robert M. Brosh Sep 2020

Fancj Compensates For Rap80 Deficiency And Suppresses Genomic Instability Induced By Interstrand Cross-Links, Sanket Awate, Joshua A. Sommers, Arindam Datta, Sumeet Nayak, Marina A. Bellani, Olivia Yang, Christopher A. Dunn, Claudia M. Nicolae, George-Lucian Moldovan, Michael M. Seidman, Sharon B. Cantor, Robert M. Brosh

Open Access Articles

FANCJ, a DNA helicase and interacting partner of the tumor suppressor BRCA1, is crucial for the repair of DNA interstrand crosslinks (ICL), a highly toxic lesion that leads to chromosomal instability and perturbs normal transcription. In diploid cells, FANCJ is believed to operate in homologous recombination (HR) repair of DNA double-strand breaks (DSB); however, its precise role and molecular mechanism is poorly understood. Moreover, compensatory mechanisms of ICL resistance when FANCJ is deficient have not been explored. In this work, we conducted a siRNA screen to identify genes of the DNA damage response/DNA repair regime that when acutely depleted ...


Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster Sep 2020

Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster

Open Access Articles

Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral replication, and increased morbidity. Contrastingly, Cxcr2 (CXCL1 receptor)-deficient mice exhibit markedly reduced neutrophil recruitment, BBB ...


Flexible Usage And Interconnectivity Of Diverse Cell Death Pathways Protect Against Intracellular Infection, Marcel Doerflinger, Milton Pereira, Andreas Strasser, Sammy Bedoui, Marco J. Herold Sep 2020

Flexible Usage And Interconnectivity Of Diverse Cell Death Pathways Protect Against Intracellular Infection, Marcel Doerflinger, Milton Pereira, Andreas Strasser, Sammy Bedoui, Marco J. Herold

Open Access Articles

Programmed cell death contributes to host defense against pathogens. To investigate the relative importance of pyroptosis, necroptosis, and apoptosis during Salmonella infection, we infected mice and macrophages deficient for diverse combinations of caspases-1, -11, -12, and -8 and receptor interacting serine/threonine kinase 3 (RIPK3). Loss of pyroptosis, caspase-8-driven apoptosis, or necroptosis had minor impact on Salmonella control. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and their macrophages, demonstrating that host defense can employ varying components of several cell death pathways to limit intracellular infections. This flexible use of distinct cell death ...


Caspase-8 Mediates Inflammation And Disease In Rodent Malaria, Larissa M. N. Pereira, Patricia Aparecida Assis, Natalia M. De Araujo, Danielle Fernandes Durso, Caroline Junqueira, Marco Antonio Ataide, Dhelio B. Pereira, Egil Lien, Katherine A. Fitzgerald, Dario S. Zamboni, Douglas T. Golenbock, Ricardo T. Gazzinelli Sep 2020

Caspase-8 Mediates Inflammation And Disease In Rodent Malaria, Larissa M. N. Pereira, Patricia Aparecida Assis, Natalia M. De Araujo, Danielle Fernandes Durso, Caroline Junqueira, Marco Antonio Ataide, Dhelio B. Pereira, Egil Lien, Katherine A. Fitzgerald, Dario S. Zamboni, Douglas T. Golenbock, Ricardo T. Gazzinelli

Open Access Articles

Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFalpha and IL-1beta and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find ...


Antibody Responses In Covid-19 Patients, Shuying Liu, Shan Lu Sep 2020

Antibody Responses In Covid-19 Patients, Shuying Liu, Shan Lu

COVID-19 Publications by UMMS Authors

Measuring virus-specific antibody responses to emerging pathogens is a well-established and highly useful tool to diagnose such infections, understand interactions between the immune system and pathogens, and provide potential clues for the development of vaccines or therapeutic agents against such pathogens. Since the beginning of 2020, the discovery of SARS-CoV-2 as the emerging virus responsible for the COVID-19 pandemic has provided new insight into the complexity of antibody responses to this dangerous virus. The current review aims to sort out diverse and sometimes seemingly confusing findings to put together a cohesive understanding on the profile of antibody responses elicited in ...


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 Sep 2020

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 Articles

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 ...


Osteoblast-Osteoclast Communication And Bone Homeostasis, Jung-Min Kim, Chujiao Lin, Zheni Stavre, Matthew B. Greenblatt, Jae-Hyuck Shim Sep 2020

Osteoblast-Osteoclast Communication And Bone Homeostasis, Jung-Min Kim, Chujiao Lin, Zheni Stavre, Matthew B. Greenblatt, Jae-Hyuck Shim

Open Access Articles

Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P ...


Contributions Of Ifn-Gamma And Granulysin To The Clearance Of Plasmodium Yoelii Blood Stage, Natalia Satchiko Hojo-Souza, Patrick Orestes De Azevedo, Julia Teixeira De Castro, Andrea Teixeira-Carvalho, Judy Lieberman, Caroline Junqueira, Ricardo T. Gazzinelli Sep 2020

Contributions Of Ifn-Gamma And Granulysin To The Clearance Of Plasmodium Yoelii Blood Stage, Natalia Satchiko Hojo-Souza, Patrick Orestes De Azevedo, Julia Teixeira De Castro, Andrea Teixeira-Carvalho, Judy Lieberman, Caroline Junqueira, Ricardo T. Gazzinelli

Open Access Articles

P. vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8+ T cells and killed by granulysin (GNLY) and granzymes. However, how Plasmodium infection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps control Plasmodium infection in vivo has not been studied. Here, we examine these questions using rodent infection with the P. yoelii 17XNL strain, which has tropism for Retics. Infection with P. yoelii caused extramedullary erythropoiesis, reticulocytosis and expansion of CD8+CD44+CD62L- IFN-gamma-producing T cells that form immune synapses with iRetics. We now provide evidence that MHC-I expression by iRetic ...


Bcl11a Enhancer Edited Hematopoietic Stem Cells Persist In Rhesus Monkeys Without Toxicity, Selami Demirci, Jing Zeng, Yuxuan Wu, Naoya Uchida, Anne H. Shen, Danilo Pellin, Jackson Gamer, Morgan Yapundich, Claire Drysdale, Jasmine Bonanno, Aylin C. Bonifacino, Allen Krouse, Nathaniel Seth. Linde, Theresa Engels, Robert E. Donahue, Juan J. Haro-Mora, Alexis Leonard, Tina Nassehi, Kevin Luk, Shaina N. Porter, Cicera R. Lazzarotto, Shengdar Q. Tsai, Mitchell Weiss, Shondra M. Pruett-Miller, Scot A. Wolfe, Daniel E. Bauer, John F. Tisdale Sep 2020

Bcl11a Enhancer Edited Hematopoietic Stem Cells Persist In Rhesus Monkeys Without Toxicity, Selami Demirci, Jing Zeng, Yuxuan Wu, Naoya Uchida, Anne H. Shen, Danilo Pellin, Jackson Gamer, Morgan Yapundich, Claire Drysdale, Jasmine Bonanno, Aylin C. Bonifacino, Allen Krouse, Nathaniel Seth. Linde, Theresa Engels, Robert E. Donahue, Juan J. Haro-Mora, Alexis Leonard, Tina Nassehi, Kevin Luk, Shaina N. Porter, Cicera R. Lazzarotto, Shengdar Q. Tsai, Mitchell Weiss, Shondra M. Pruett-Miller, Scot A. Wolfe, Daniel E. Bauer, John F. Tisdale

Open Access Articles

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from sickle cell disease (SCD) patients induces fetal hemoglobin (HbF) without detectable toxicity as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer edited HSPCs in four non-human primates. We utilized a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits ...


Ino80c Remodeler Maintains Genomic Stability By Preventing Promiscuous Transcription At Replication Origins, Salih Topal, Christopher Van, Yong Xue, Michael F. Carey, Craig L. Peterson Sep 2020

Ino80c Remodeler Maintains Genomic Stability By Preventing Promiscuous Transcription At Replication Origins, Salih Topal, Christopher Van, Yong Xue, Michael F. Carey, Craig L. Peterson

Open Access Articles

The proper coordination of transcription with DNA replication and repair is central for genomic stability. We investigate how the INO80C chromatin remodeling enzyme might coordinate these genomic processes. We find that INO80C co-localizes with the origin recognition complex (ORC) at yeast replication origins and is bound to replication initiation sites in mouse embryonic stem cells (mESCs). In yeast, INO80C recruitment requires origin sequences but does not require ORC, suggesting that recruitment is independent of pre-replication complex assembly. In both yeast and ESCs, INO80C co-localizes at origins with Mot1 and NC2 transcription factors, and genetic studies suggest that they function together ...


2'-O-Methyl At 20-Mer Guide Strand 3' Termini May Negatively Affect Target Silencing Activity Of Fully Chemically Modified Sirna, Sarah M. Davis, Jacquelyn Sousa, Lorenc Vangjeli, Matthew R. Hassler, Dimas Echeverria, Emily G. Knox, Anton A. Turanov, Julia F. Alterman, Anastasia Khvorova Sep 2020

2'-O-Methyl At 20-Mer Guide Strand 3' Termini May Negatively Affect Target Silencing Activity Of Fully Chemically Modified Sirna, Sarah M. Davis, Jacquelyn Sousa, Lorenc Vangjeli, Matthew R. Hassler, Dimas Echeverria, Emily G. Knox, Anton A. Turanov, Julia F. Alterman, Anastasia Khvorova

Open Access Articles

Small interfering RNAs (siRNAs) have the potential to treat a broad range of diseases. siRNAs need to be extensively chemically modified to improve their bioavailability, safety, and stability in vivo. However, chemical modifications variably impact target silencing for different siRNA sequences, making the activity of chemically modified siRNA difficult to predict. Here, we systematically evaluated the impact of 3' terminal modifications (2'-O-methyl versus 2'-fluoro) on guide strands of different length and showed that 3' terminal 2'-O-methyl modification negatively impacts activity for >60% of siRNA sequences tested but only in the context of 20- and not 19- or ...


Cell Type Impacts Accessibility Of Mrna To Silencing By Rna Interference, Chantal M. Ferguson, Dimas Echeverria, Matthew R. Hassler, Socheata Ly, Anastasia Khvorova Sep 2020

Cell Type Impacts Accessibility Of Mrna To Silencing By Rna Interference, Chantal M. Ferguson, Dimas Echeverria, Matthew R. Hassler, Socheata Ly, Anastasia Khvorova

Open Access Articles

RNA interference (RNAi) is a potent mechanism that silences mRNA and protein expression in all cells and tissue types. RNAi is known to exert many of its functional effects in the cytoplasm, and thus, the cellular localization of target mRNA may impact observed potency. Here, we demonstrate that cell identity has a profound impact on accessibility of apolipoprotein E (ApoE) mRNA to RNAi. We show that, whereas both neuronal and glial cell lines express detectable ApoE mRNA, in neuronal cells, ApoE mRNA is not targetable by RNAi. Screening of a panel of thirty-five chemically modified small interfering RNAs (siRNAs) did ...


Click-Free Synthesis Of A Multivalent Tricyclic Peptide As A Molecular Transporter, Sumit Kumar, Dindyal Mandal, Shaima Ahmed El-Mowafi, Saghar Mozaffari, Rakesh Kumar Tiwari, Keykavous Parang Sep 2020

Click-Free Synthesis Of A Multivalent Tricyclic Peptide As A Molecular Transporter, Sumit Kumar, Dindyal Mandal, Shaima Ahmed El-Mowafi, Saghar Mozaffari, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]4 and c[WR]5 consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in ...


Effect Of High Glucose On Ocular Surface Epithelial Cell Barrier And Tight Junction Proteins, Saleh M. Alfuraih, Ashley Barbarino, Christopher Ross, Kiumars Shamloo, Vishal Jhanji, Miao Zhang, Ajay Sharma Sep 2020

Effect Of High Glucose On Ocular Surface Epithelial Cell Barrier And Tight Junction Proteins, Saleh M. Alfuraih, Ashley Barbarino, Christopher Ross, Kiumars Shamloo, Vishal Jhanji, Miao Zhang, Ajay Sharma

Pharmacy Faculty Articles and Research

PURPOSE. Patients with diabetes mellitus are reported to have ocular surface defects, impaired ocular surface barrier function, and a higher incidence of corneal and conjunctival infections. Tight junctions are critical for ocular surface barrier function. The present study was designed to investigate the effect of high glucose exposure on human corneal and conjunctival epithelial cell barrier function and tight junction proteins.

METHODS. Human corneal and conjunctival epithelial cells were exposed to 15 mM and 30 mM glucose for 24 and 72 hours. The barrier function was measured using transepithelial electrical resistance (TEER). The cell migration was quantified using scratch assay ...


Histone Exchange Is Associated With Activator Function At Transcribed Promoters And With Repression At Histone Loci, Sari Kassem, Paolo Ferrari, Amanda L. Hughes, Julien Soudet, Oliver J. Rando, Michel Strubin Sep 2020

Histone Exchange Is Associated With Activator Function At Transcribed Promoters And With Repression At Histone Loci, Sari Kassem, Paolo Ferrari, Amanda L. Hughes, Julien Soudet, Oliver J. Rando, Michel Strubin

Open Access Articles

Transcription in eukaryotes correlates with major chromatin changes, including the replacement of old nucleosomal histones by new histones at the promoters of genes. The role of these histone exchange events in transcription remains unclear. In particular, the causal relationship between histone exchange and activator binding, preinitiation complex (PIC) assembly, and/or subsequent transcription remains unclear. Here, we provide evidence that histone exchange at gene promoters is not simply a consequence of PIC assembly or transcription but instead is mediated by activators. We further show that not all activators up-regulate gene expression by inducing histone turnover. Thus, histone exchange does not ...


Thioredoxin Interacting Protein Is Required For A Chronic Energy-Rich Diet To Promote Intestinal Fructose Absorption, Anu Shah, Sezin Dagdeviren, Jordan P. Lewandowski, Angela B. Schmider, Elisabeth M. Ricci-Blair, Niranjana Natarajan, Henna Hundal, Hye Lim Noh, Randall H. Friedline, Charles Vidoudez, Jason K. Kim, Amy J. Wagers, Roy J. Soberman, Richard T. Lee Sep 2020

Thioredoxin Interacting Protein Is Required For A Chronic Energy-Rich Diet To Promote Intestinal Fructose Absorption, Anu Shah, Sezin Dagdeviren, Jordan P. Lewandowski, Angela B. Schmider, Elisabeth M. Ricci-Blair, Niranjana Natarajan, Henna Hundal, Hye Lim Noh, Randall H. Friedline, Charles Vidoudez, Jason K. Kim, Amy J. Wagers, Roy J. Soberman, Richard T. Lee

Open Access Articles

Increased consumption of fats and added sugars has been associated with an increase in metabolic syndromes. Here we show that mice chronically fed an energy-rich diet (ERD) with high fat and moderate sucrose have enhanced the absorption of a gastrointestinal fructose load, and this required expression of the arrestin domain protein Txnip in the intestinal epithelial cells. ERD feeding induced gene and protein expression of Glut5, and this required the expression of Txnip. Furthermore, Txnip interacted with Rab11a, a small GTPase that facilitates the apical localization of Glut5. We also demonstrate that ERD promoted Txnip/Glut5 complexes in the apical ...


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 Sep 2020

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 ...


Znf410 Represses Fetal Globin By Devoted Control Of Chd4/Nurd [Preprint], Divya S. Vinjamur, Qiuming Yao, Mitchel A. Cole, Connor Mcguckin, Chunyan Ren, Jing Zeng, Mir Hossain, Kevin Luk, Scot A. Wolfe, Luca Pinello, Daniel E. Bauer Aug 2020

Znf410 Represses Fetal Globin By Devoted Control Of Chd4/Nurd [Preprint], Divya S. Vinjamur, Qiuming Yao, Mitchel A. Cole, Connor Mcguckin, Chunyan Ren, Jing Zeng, Mir Hossain, Kevin Luk, Scot A. Wolfe, Luca Pinello, Daniel E. Bauer

University of Massachusetts Medical School Faculty Publications

Major effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to the γ-globin genes but rather its chromatin occupancy is solely concentrated at CHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ...


Ribosome Inhibition By C9orf72-Als/Ftd-Associated Poly-Pr And Poly-Gr Proteins Revealed By Cryo-Em [Preprint], Anna B. Loveland, Egor Svidritskiy, Denis Susorov, Soojin Lee, Alexander Park, Gabriel Demo, Fen-Biao Gao, Andrei A. Korostelev Aug 2020

Ribosome Inhibition By C9orf72-Als/Ftd-Associated Poly-Pr And Poly-Gr Proteins Revealed By Cryo-Em [Preprint], Anna B. Loveland, Egor Svidritskiy, Denis Susorov, Soojin Lee, Alexander Park, Gabriel Demo, Fen-Biao Gao, Andrei A. Korostelev

University of Massachusetts Medical School Faculty Publications

Toxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥ 20 repeats inhibit the ribosome’s peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel ...


Nano-Vesicle (Mis)Communication In Senescence-Related Pathologies, Sherin Saheera, Ajay Godwin Potnuri, Prasanna Krishnamurthy Aug 2020

Nano-Vesicle (Mis)Communication In Senescence-Related Pathologies, Sherin Saheera, Ajay Godwin Potnuri, Prasanna Krishnamurthy

COVID-19 Publications by UMMS Authors

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising of exosomes, apoptotic bodies, and microvesicles. Of the extracellular vesicles, exosomes are the most widely sorted and extensively explored for their contents and function. The size of the nanovesicular structures (exosomes) range from 30 to 140 nm and are present in various biological fluids such as saliva, plasma, urine etc. These cargo-laden extracellular vesicles arise from endosome-derived multivesicular bodies and are known to carry proteins and nucleic acids. Exosomes are involved in multiple physiological and pathological processes, including cellular senescence. Exosomes mediate signaling crosstalk and play a critical role ...


Cyclic Peptide-Gadolinium Nanoparticles For Enhanced Intracellular Delivery, Amir Nasrolahi Shirazi, Shang Eun Park, Shirin Rad, Luiza Baloyan, Dindyal Mandal, Muhammad Imran Sajid, Ryley Hall, Sandeep Lohan, Khalid Zoghebi, Keykavous Parang, Rakesh Tiwari Aug 2020

Cyclic Peptide-Gadolinium Nanoparticles For Enhanced Intracellular Delivery, Amir Nasrolahi Shirazi, Shang Eun Park, Shirin Rad, Luiza Baloyan, Dindyal Mandal, Muhammad Imran Sajid, Ryley Hall, Sandeep Lohan, Khalid Zoghebi, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

A cyclic peptide containing one cysteine and five alternating tryptophan and arginine amino acids [(WR)5C] was synthesized using Fmoc/tBu solid-phase methodology. The ability of the synthesized cyclic peptide to produce gadolinium nanoparticles through an in situ one-pot mixing of an aqueous solution of GdCl3 with [(WR)5C] peptide solution was evaluated. Transmission electron microscopy showed the formed peptide-Gd nanoparticles in star-shape morphology with a size of ~250 nm. Flow cytometry investigation showed that the cellular uptake of a cell-impermeable fluorescence-labeled phosphopeptide (F′-GpYEEI, where F′ = fluorescein) was approximately six times higher in the presence of ...


Host Immunity Increases Mycobacterium Tuberculosis Reliance On Cytochrome Bd Oxidase [Preprint], Yi Cai, Eleni Jaecklein, Jared Mackenzie, Kadamba Papavinasasundaram, Michigan State University, Xinchun Chen, Africa Health Research Institute, Christopher M. Sassetti Aug 2020

Host Immunity Increases Mycobacterium Tuberculosis Reliance On Cytochrome Bd Oxidase [Preprint], Yi Cai, Eleni Jaecklein, Jared Mackenzie, Kadamba Papavinasasundaram, Michigan State University, Xinchun Chen, Africa Health Research Institute, Christopher M. Sassetti

University of Massachusetts Medical School Faculty Publications

In order to sustain a persistent infection, Mycobacterium tuberculosis (Mtb) must adapt to a changing environment that is shaped by the developing immune response. This necessity to adapt is evident in the flexibility of many aspects of Mtb metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the bc1/aa3 complex appears to play a dominant role, while the alternative bd oxidase is largely redundant. However, presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the ...


A Cross-Reactive Human Iga Monoclonal Antibody Blocks Sars-Cov-2 Spike-Ace2 Interaction, Ejemel Monir, Qi Li, Shurong Hou, Zachary Schiller, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Jacqueline R. Toomey, Ryan Schneider, Anudeep S. Ramchetty, Chandrashekar Ganesa, Lisa Cavacini, Mark S. Klempner, Celia A. Schiffer, Yan Wang Aug 2020

A Cross-Reactive Human Iga Monoclonal Antibody Blocks Sars-Cov-2 Spike-Ace2 Interaction, Ejemel Monir, Qi Li, Shurong Hou, Zachary Schiller, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Jacqueline R. Toomey, Ryan Schneider, Anudeep S. Ramchetty, Chandrashekar Ganesa, Lisa Cavacini, Mark S. Klempner, Celia A. Schiffer, Yan Wang

COVID-19 Publications by UMMS Authors

COVID-19 caused by SARS-CoV-2 has become a global pandemic requiring the development of interventions for the prevention or treatment to curtail mortality and morbidity. No vaccine to boost mucosal immunity, or as a therapeutic, has yet been developed to SARS-CoV-2. In this study, we discover and characterize a cross-reactive human IgA monoclonal antibody, MAb362. MAb362 binds to both SARS-CoV and SARS-CoV-2 spike proteins and competitively blocks ACE2 receptor binding, by overlapping the ACE2 structural binding epitope. Furthermore, MAb362 IgA neutralizes both pseudotyped SARS-CoV and SARS-CoV-2 in 293 cells expressing ACE2. When converted to secretory IgA, MAb326 also neutralizes authentic SARS-CoV-2 ...


Broad Host Range Of Sars-Cov-2 Predicted By Comparative And Structural Analysis Of Ace2 In Vertebrates, Joana Damas, Elinor K. Karlsson, Harris A. Lewin Aug 2020

Broad Host Range Of Sars-Cov-2 Predicted By Comparative And Structural Analysis Of Ace2 In Vertebrates, Joana Damas, Elinor K. Karlsson, Harris A. Lewin

COVID-19 Publications by UMMS Authors

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike ...


Reduced Neurog3 Gene Dosage Shifts Enteroendocrine Progenitor Toward Goblet Cell Lineage In The Mouse Intestine, Joyce H. Li, Subir Ray, Alper Kucukural, Gerard Gradwohl, Andrew B. Leiter Aug 2020

Reduced Neurog3 Gene Dosage Shifts Enteroendocrine Progenitor Toward Goblet Cell Lineage In The Mouse Intestine, Joyce H. Li, Subir Ray, Alper Kucukural, Gerard Gradwohl, Andrew B. Leiter

University of Massachusetts Medical School Faculty Publications

BACKGROUND and AIMS: Transient expression of Neurog3 commits intestinal secretory progenitors to become enteroendocrine-biased progenitors and hence drive enteroendocrine differentiation. Loss of Neurog3 in mouse resulted in the depletion of intestinal enteroendocrine cells (EECs) and an increase in goblet cells. Earlier studies in developing mouse pancreas showed Neurog3 gene dosage in endocrine and exocrine cell fate allocation. We aimed to determine whether Neurog3 gene dosage controls fate choice of enteroendocrine progenitors.

METHODS: We acquired mutant Neurog3 reporter mice carrying 2, 1, or null Neurog3 alleles to study Neurog3 gene dosage effect by lineage tracing. Cell types arising from Neurog3+ progenitors ...