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

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

Doctoral Dissertations

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


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 ...


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 ...


Sars-Cov-2 Spike Protein Variant D614g Increases Infectivity And Retains Sensitivity To Antibodies That Target The Receptor Binding Domain [Preprint], Leonid Yurkovetskiy, Thomas Nyalile, Yetao Wang, William E. Diehl, Ann Dauphin, Claudia Carbone, Kristen Veinotte, Shawn B. Egri, Pardis C. Sabeti, Christos Kyratsous, James B. Munro, Kuang Shen, Jeremy Luban 2020 University of Massachusetts Medical School

Sars-Cov-2 Spike Protein Variant D614g Increases Infectivity And Retains Sensitivity To Antibodies That Target The Receptor Binding Domain [Preprint], Leonid Yurkovetskiy, Thomas Nyalile, Yetao Wang, William E. Diehl, Ann Dauphin, Claudia Carbone, Kristen Veinotte, Shawn B. Egri, Pardis C. Sabeti, Christos Kyratsous, James B. Munro, Kuang Shen, Jeremy Luban

COVID-19 Publications by UMMS Authors

Virus genome sequence variants that appear over the course of an outbreak can be exploited to map the trajectory of the virus from one susceptible host to another. While such variants are usually of no functional significance, in some cases they may allow the virus to transmit faster, change disease severity, or confer resistance to antiviral therapies. Since the discovery of SARS-CoV-2 as the cause of COVID-19, the virus has spread around the globe, and thousands of SARS-CoV-2 genomes have been sequenced. The rate of sequence variation among SARS-CoV-2 isolates is modest for an RNA virus but the enormous number ...


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 ...


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 ...


Crispr Deletion Of The C9orf72 Promoter In Als/Ftd Patient Motor Neurons Abolishes Production Of Dipeptide Repeat Proteins And Rescues Neurodegeneration, Gopinath Krishnan, Yu Zhang, Yuanzheng Gu, Mark W. Kankel, Fen-Biao Gao, Sandra Almeida 2020 University of Massachusetts Medical School

Crispr Deletion Of The C9orf72 Promoter In Als/Ftd Patient Motor Neurons Abolishes Production Of Dipeptide Repeat Proteins And Rescues Neurodegeneration, Gopinath Krishnan, Yu Zhang, Yuanzheng Gu, Mark W. Kankel, Fen-Biao Gao, Sandra Almeida

Open Access Articles

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Brain tissues from affected individuals show characteristic nuclear RNA foci containing the expanded repeat RNAs, as well as neuronal inclusions containing dipeptide repeat (DPR) proteins [poly(GA), poly(GP), poly(GR), poly(PR), and poly(PA)] resulting from the translation of both sense and antisense repeat RNAs in all reading frames. Although reduced C9ORF72 protein function may contribute to disease, the more likely drivers of disease are mechanisms related to a gain of toxic function ...


Dgat1 Is A Lipid Metabolism Oncoprotein That Enables Cancer Cells To Accumulate Fatty Acid While Avoiding Lipotoxicity [Preprint], Daniel J. Wilcock, Melissa Kasheta, Craig J. Ceol 2020 University of Manchester

Dgat1 Is A Lipid Metabolism Oncoprotein That Enables Cancer Cells To Accumulate Fatty Acid While Avoiding Lipotoxicity [Preprint], Daniel J. Wilcock, Melissa Kasheta, Craig J. Ceol

University of Massachusetts Medical School Faculty Publications

Dysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone ...


Hydrazines As Versatile Chemical Biology Probes And Drug-Discovery Tools For Cofactor-Dependent Enzymes [Preprint], Zongtao Lin, Xie Wang, Katelyn A. Bustin, Lin He, Radu M. Suciu, Nancy Schek, Mina Ahmadi, Kai Hu, Erika J. Olson, William H. Parsons, Eric S. Witze, Paul D. Morton, Ann M. Gregus, Matthew W. Buczynski, Megan L. Matthews 2020 University of Pennsylvania

Hydrazines As Versatile Chemical Biology Probes And Drug-Discovery Tools For Cofactor-Dependent Enzymes [Preprint], Zongtao Lin, Xie Wang, Katelyn A. Bustin, Lin He, Radu M. Suciu, Nancy Schek, Mina Ahmadi, Kai Hu, Erika J. Olson, William H. Parsons, Eric S. Witze, Paul D. Morton, Ann M. Gregus, Matthew W. Buczynski, Megan L. Matthews

University of Massachusetts Medical School Faculty Publications

Known chemoproteomic probes generally use warheads that tag a single type of amino acid or modified form thereof to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electron-poor enzyme cofactors, transient intermediates and chemically-labile regulatory modifications, but probes for such species are underdeveloped. Here, we have innovated a versatile class of chemoproteomic probes for this less charted hemisphere of the proteome by using hydrazine as the common chemical warhead. Its electron-rich nature allows it to react by both polar and radicaloid mechanisms and to target multiple, pharmacologically important functional classes of enzymes bearing diverse organic ...


Clinicopathologic Features Of Endometrial Cancer With Mismatch Repair Deficiency, Sushmita Gordhandas, Ryan M. Kahn, Charlotte Gamble, Nizam Talukdar, Brandon Maddy, Becky Baltich Nelson, Gulce Askin, Paul J. Christos, Kevin Holcomb, Thomas A. Caputo, Eloise Chapman-Davis, Melissa K. Frey 2020 Weill Cornell Medical College

Clinicopathologic Features Of Endometrial Cancer With Mismatch Repair Deficiency, Sushmita Gordhandas, Ryan M. Kahn, Charlotte Gamble, Nizam Talukdar, Brandon Maddy, Becky Baltich Nelson, Gulce Askin, Paul J. Christos, Kevin Holcomb, Thomas A. Caputo, Eloise Chapman-Davis, Melissa K. Frey

Open Access Articles

The inclusion of DNA mismatch repair (MMR) evaluation as a standard of care for endometrial cancer management will result in a growing population of patients with MMR deficiency and negative germline Lynch syndrome testing (MMR-deficient). In this systematic review and study, the clinicopathologic features of endometrial cancer in patients with MMR-intact, MLH1 methylation positive, MMR-deficient or Lynch syndrome are evaluated. A systematic search of online databases between 1990 and 2018 identified studies of endometrial cancer patients with tumour testing (MMR protein immunohistochemistry or microsatellite instability) and germline assessment for Lynch syndrome. Extracted data included tumour testing, germline genetic testing, age ...


Proteomic Identification Reveals The Role Of Ciliary Extracellular‐Like Vesicle In Cardiovascular Function, Ashraf M. Mohieldin, Rajasekharreddy Pala, Rinzhin T. Sherpa, Madhawi Alanazi, Ashwaq Alanazi, Kiumars Shamloo, Amir Ahsan, Wissam A. AbouAlaiwi, James J. Moresco, John R. Yates III, Surya M. Nauli 2020 Chapman University

Proteomic Identification Reveals The Role Of Ciliary Extracellular‐Like Vesicle In Cardiovascular Function, Ashraf M. Mohieldin, Rajasekharreddy Pala, Rinzhin T. Sherpa, Madhawi Alanazi, Ashwaq Alanazi, Kiumars Shamloo, Amir Ahsan, Wissam A. Aboualaiwi, James J. Moresco, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Primary cilia are shown to have membrane swelling, also known as ciliary bulbs. However, the role of these structures and their physiological relevance remains unknown. Here, it is reported that a ciliary bulb has extracellular vesicle (EV)‐like characteristics. The ciliary extracellular‐like vesicle (cELV) has a unique dynamic movement and can be released by mechanical fluid force. To better identify the cELV, differential multidimensional proteomic analyses are performed on the cELV. A database of 172 cELV proteins is generated, and all that examined are confirmed to be in the cELV. Repressing the expression of these proteins in vitro and ...


Transgenic Goats Producing An Improved Version Of Cetuximab In Milk [Preprint], Götz Laible, Sally Cole, Brigid Brophy, Paul Maclean, Li How Chen, Dan P. Pollock, Lisa A. Cavacini, Nathalie Fournier, Christophe De Romeuf, Nicholas C. Masiello, William G. Gavin, David N. Wells, Harry M. Meade 2020 University of Auckland

Transgenic Goats Producing An Improved Version Of Cetuximab In Milk [Preprint], Götz Laible, Sally Cole, Brigid Brophy, Paul Maclean, Li How Chen, Dan P. Pollock, Lisa A. Cavacini, Nathalie Fournier, Christophe De Romeuf, Nicholas C. Masiello, William G. Gavin, David N. Wells, Harry M. Meade

University of Massachusetts Medical School Faculty Publications

Therapeutic monoclonal antibodies (mAbs) represent one of the most important classes of pharmaceutical proteins to treat human diseases. Most are produced in cultured mammalian cells which is expensive, limiting their availability. Goats, striking a good balance between a relatively short generation time and copious milk yield, present an alternative platform for the cost-effective, flexible, large-scale production of therapeutic mAbs. Here, we focused on cetuximab, a mAb against epidermal growth factor receptor, that is commercially produced under the brand name Erbitux and approved for anti-cancer treatments. We generated several transgenic goat lines that produce cetuximab in their milk. Two lines were ...


Longitudinal Biomarkers In Amyotrophic Lateral Sclerosis, Fen Huang, Yuda Zhu, Jennifer Hsiao-Nakamoto, Xinyan Tang, Jason C. Dugas, Miriam Moscovitch-Lopatin, Jonathan D. Glass, Robert H. Brown Jr., Shafeeq S. Ladha, David Lacomis, Jeffrey M. Harris, Kimberly Scearce-Levie, Carole Ho, Robert Bowser, James D. Berry 2020 Denali Therapeutics

Longitudinal Biomarkers In Amyotrophic Lateral Sclerosis, Fen Huang, Yuda Zhu, Jennifer Hsiao-Nakamoto, Xinyan Tang, Jason C. Dugas, Miriam Moscovitch-Lopatin, Jonathan D. Glass, Robert H. Brown Jr., Shafeeq S. Ladha, David Lacomis, Jeffrey M. Harris, Kimberly Scearce-Levie, Carole Ho, Robert Bowser, James D. Berry

Open Access Articles

OBJECTIVE: To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects.

METHODS: De-identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n = 108; 85 with samples from > /=2 visits) and controls without neurological disease (n = 41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n = 35) were obtained from multiple sources. We stratified PALS into fast- and ...


Comparative Molecular Transporter Properties Of Cyclic Peptides Containing Tryptophan And Arginine Residues Formed Through Disulfide Cyclization, Eman H. M. Mohammed, Dindyal Mandal, Saghar Mozaffari, Magdy Abdel-Hamied Zahran, Amany Mostafa Osman, Rakesh Kumar Tiwari, Keykavous Parang 2020 Chapman University

Comparative Molecular Transporter Properties Of Cyclic Peptides Containing Tryptophan And Arginine Residues Formed Through Disulfide Cyclization, Eman H. M. Mohammed, Dindyal Mandal, Saghar Mozaffari, Magdy Abdel-Hamied Zahran, Amany Mostafa Osman, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

We have previously reported cyclic cell-penetrating peptides [WR]5 and [WR]4 as molecular transporters. To optimize further the utility of our developed peptides for targeted therapy in cancer cells using the redox condition, we designed a new generation of peptides and evaluated their cytotoxicity as well as uptake behavior against different cancer cell lines. Thus, cyclic [C(WR)xC] and linear counterparts (C(WR)xC), where x = 4–5, were synthesized using Fmoc/tBu solid-phase peptide synthesis, purified, and characterized. The compounds did not show any significant cytotoxicity (at 25 µM) against ovarian (SK-OV-3), leukemia (CCRF-CEM), gastric ...


Comparative Molecular Transporter Properties Of Cyclic Peptides Containing Tryptophan And Arginine Residues Formed Through Disulfide Cyclization, Eman H. M. Mohammed, Dindyal Mandal, Saghar Mozaffari, Magdy Abdel-Hamied Zahran, Amany Mostafa Osman, Rakesh Kumar Tiwari, Keykavous Parang 2020 Chapman University

Comparative Molecular Transporter Properties Of Cyclic Peptides Containing Tryptophan And Arginine Residues Formed Through Disulfide Cyclization, Eman H. M. Mohammed, Dindyal Mandal, Saghar Mozaffari, Magdy Abdel-Hamied Zahran, Amany Mostafa Osman, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

We have previously reported cyclic cell-penetrating peptides [WR]5 and [WR]4 as molecular transporters. To optimize further the utility of our developed peptides for targeted therapy in cancer cells using the redox condition, we designed a new generation of peptides and evaluated their cytotoxicity as well as uptake behavior against different cancer cell lines. Thus, cyclic [C(WR)xC] and linear counterparts (C(WR)xC), where x = 4–5, were synthesized using Fmoc/tBu solid-phase peptide synthesis, purified, and characterized. The compounds did not show any significant cytotoxicity (at 25 µM) against ovarian (SK-OV-3), leukemia (CCRF-CEM), gastric ...


Recombinant Human Proteoglycan-4 Mediates Interleukin-6 Response In Both Human And Mouse Endothelial Cells Induced Into A Sepsis Phenotype, Holly A. Richendrfer, Mitchell M. Levy, Khaled A. Elsaid, Tannin A. Schmidt, Ling Zhang, Ralph Cabezas, Gregory D. Jay 2020 Brown University

Recombinant Human Proteoglycan-4 Mediates Interleukin-6 Response In Both Human And Mouse Endothelial Cells Induced Into A Sepsis Phenotype, Holly A. Richendrfer, Mitchell M. Levy, Khaled A. Elsaid, Tannin A. Schmidt, Ling Zhang, Ralph Cabezas, Gregory D. Jay

Pharmacy Faculty Articles and Research

Objectives:

Sepsis is a leading cause of death in the United States. Putative targets to prevent systemic inflammatory response syndrome include antagonism of toll-like receptors 2 and 4 and CD44 receptors in vascular endothelial cells. Proteoglycan-4 is a mucinous glycoprotein that interacts with CD44 and toll-like receptor 4 resulting in a blockade of the NOD-like receptor pyrin domain-containing-3 pathway. We hypothesized that endothelial cells induced into a sepsis phenotype would have less interleukin-6 expression after recombinant human proteoglycan 4 treatment in vitro.

Design:

Enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction to measure interleukin-6 protein and gene expression.

Setting ...


Plcg2 Protective Variant P.P522r Modulates Tau Pathology And Disease Progression In Patients With Mild Cognitive Impairment, Luca Kleineidam, Michael T. Heneka, Alfredo Ramirez 2020 University of Cologne

Plcg2 Protective Variant P.P522r Modulates Tau Pathology And Disease Progression In Patients With Mild Cognitive Impairment, Luca Kleineidam, Michael T. Heneka, Alfredo Ramirez

Open Access Articles

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-gamma2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Abeta1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate ...


Core Binding Factor Leukemia Hijacks T-Cell Prone Pu.1 Antisense Promoter [Preprint], E. van der Kouwe, Lucio H. Castilla, D. G. Tenen, P. B. Staber 2020 Medical University of Vienna

Core Binding Factor Leukemia Hijacks T-Cell Prone Pu.1 Antisense Promoter [Preprint], E. Van Der Kouwe, Lucio H. Castilla, D. G. Tenen, P. B. Staber

University of Massachusetts Medical School Faculty Publications

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of the hematopoietic master regulator PU.114. PU.1 gene expression is regulated through enhancer-promoter interactions within a topologically associated domain (TAD)5,6. PU.1 levels increase during myeloid differentiation while failure to do so results in myeloid leukemia7. In contrast, T-cell differentiation requires PU.1 to be completely switched off810. Little is known about the precise mechanisms of PU.1 repression, physiological as in T-cell differentiation, or pathological as in leukemia. Here we ...


A Specific Neuroligin3-Αneurexin1 Code Regulates Gabaergic Synaptic Function In Mouse Hippocampus [Preprint], Motokazu Uchigashima, Kohtarou Konno, Emily Demchak, Amy Cheung, Takuya Watanabe, David G. Keener, Manabu Abe, Timmy Le, Kenji Sakimura, Toshikuni Sasaoka, Takeshi Uemura, Yuka Imamura Kawasawa, Masahiko Watanabe, Kensuke Futai 2020 University of Massachusetts Medical School

A Specific Neuroligin3-Αneurexin1 Code Regulates Gabaergic Synaptic Function In Mouse Hippocampus [Preprint], Motokazu Uchigashima, Kohtarou Konno, Emily Demchak, Amy Cheung, Takuya Watanabe, David G. Keener, Manabu Abe, Timmy Le, Kenji Sakimura, Toshikuni Sasaoka, Takeshi Uemura, Yuka Imamura Kawasawa, Masahiko Watanabe, Kensuke Futai

University of Massachusetts Medical School Faculty Publications

Synapse formation and regulation require interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here, we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the ...


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