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Full-Text Articles in Molecular Biology

Mechanisms By Which Mnte-2-Pyp Suppresses Prostate Cancer Cell Growth, Yuxiang Zhu Dec 2020

Mechanisms By Which Mnte-2-Pyp Suppresses Prostate Cancer Cell Growth, Yuxiang Zhu

Theses & Dissertations

Prostate cancer patients are often treated with radiotherapy. MnTE-2-PyP, is a superoxide dismutase (SOD) mimic and a known radioprotector of normal tissues. Our recent work demonstrates that MnTE-2-PyP also inhibits prostate cancer progression with radiotherapy; however, the mechanisms remain unclear. In this thesis, we identified that MnTE-2-PyP-induced intracellular H2O2 levels are critical in inhibiting growth of prostate cancer cells. We found that MnTE-2-PyP induced protein oxidations in PC3 cells and one major group of oxidized protein targets were involved in energy metabolism. The oxidative phosphorylation rates were significantly enhanced in both PC3 and LNCaP cells with MnTE-2-PyP treatment, but mitochondrial ...


Engineering Mesothelin-Binding Proteins As Targeted Cancer Diagnostics And Therapeutics, Allison Rita Sirois Dec 2020

Engineering Mesothelin-Binding Proteins As Targeted Cancer Diagnostics And Therapeutics, Allison Rita Sirois

Doctoral Dissertations

Cancer is a significant global health concern; and traditional therapies, including chemotherapeutics, are often simultaneously toxic yet ineffective. There is a critical need to develop targeted cancer therapeutics which specifically inhibit molecules or molecular pathways essential for tumor growth and maintenance. Furthermore, a targeted therapy is only effective when a patient's tumor expresses the molecular target; therefore, companion diagnostics, including molecular imaging agents, are a necessary counterpart of targeted therapies.

Mesothelin (MSLN) is a cell surface protein overexpressed in numerous cancers, including triple-negative breast, pancreatic, ovarian, liver, and lung, with limited expression in normal tissues. Aberrant MSLN expression promotes ...


P53 Drives A Transcriptional Program That Elicits A Non-Cell-Autonomous Response And Alters Cell State In Vivo, Sydney Moyer Dec 2020

P53 Drives A Transcriptional Program That Elicits A Non-Cell-Autonomous Response And Alters Cell State In Vivo, Sydney Moyer

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Cell stress and DNA damage activate the tumor suppressor p53, triggering transcriptional activation of a myriad of target genes. The molecular, morphological, and physiological consequences of this activation remain poorly understood in vivo. We activated a p53 transcriptional program in mice by deletion of Mdm2, a gene which encodes the major p53 inhibitor. By overlaying tissue-specific RNA-sequencing data from pancreas, small intestine, ovary, kidney, and heart with existing p53 ChIP-sequencing, we identified a large repertoire of tissue-specific p53 genes and a common p53 transcriptional signature of seven genes which included Mdm2 but not p21. Global p53 activation caused a metaplastic ...


A 4-Base-Pair Core-Enclosing Helix In Telomerase Rna Is Essential For Activity And For Binding To The Telomerase Reverse Transcriptase Catalytic Protein Subunit, Melissa A. Mefford, Evan P. Hass, David C. Zappulla Nov 2020

A 4-Base-Pair Core-Enclosing Helix In Telomerase Rna Is Essential For Activity And For Binding To The Telomerase Reverse Transcriptase Catalytic Protein Subunit, Melissa A. Mefford, Evan P. Hass, David C. Zappulla

Open Access Publications by UMMS Authors

The telomerase ribonucleoprotein (RNP) counters the chromosome end replication problem, completing genome replication to prevent cellular senescence in yeast, humans, and most other eukaryotes. The telomerase RNP core enzyme is composed of a dedicated RNA subunit and a reverse transcriptase (telomerase reverse transcriptase [TERT]). Although the majority of the 1,157-nucleotide (nt) Saccharomyces cerevisiae telomerase RNA, TLC1, is rapidly evolving, the central catalytic core is largely conserved, containing the template, template-boundary helix, pseudoknot, and core-enclosing helix (CEH). Here, we show that 4 bp of core-enclosing helix is required for telomerase to be active in vitro and to maintain yeast telomeres ...


Dormancy-To-Death Transition In Yeast Spores Occurs Due To Gradual Loss Of Gene-Expressing Ability, Theo Maire, Tim Allertz, Max A. Betjes, Hyun Youk Nov 2020

Dormancy-To-Death Transition In Yeast Spores Occurs Due To Gradual Loss Of Gene-Expressing Ability, Theo Maire, Tim Allertz, Max A. Betjes, Hyun Youk

Open Access Publications by UMMS Authors

Dormancy is colloquially considered as extending lifespan by being still. Starved yeasts form dormant spores that wake-up (germinate) when nutrients reappear but cannot germinate (die) after some time. What sets their lifespans and how they age are open questions because what processes occur-and by how much-within each dormant spore remains unclear. With single-cell-level measurements, we discovered how dormant yeast spores age and die: spores have a quantifiable gene-expressing ability during dormancy that decreases over days to months until it vanishes, causing death. Specifically, each spore has a different probability of germinating that decreases because its ability to-without nutrients-express genes decreases ...


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 Publications by UMMS Authors

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 ...


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 Oct 2020

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 ...


Bta-Mir-23a Regulates The Myogenic Differentiation Of Fetal Bovine Skeletal Muscle-Derived Progenitor Cells By Targeting Mdfic Gene, Xin Hu, Yishen Xing, Ling Ren, Yahui Wang, Qian Li, Qiyuan Yang, Min Du, Lingyang Xu, Luc Willems, Junya Li, Lupei Zhang Oct 2020

Bta-Mir-23a Regulates The Myogenic Differentiation Of Fetal Bovine Skeletal Muscle-Derived Progenitor Cells By Targeting Mdfic Gene, Xin Hu, Yishen Xing, Ling Ren, Yahui Wang, Qian Li, Qiyuan Yang, Min Du, Lingyang Xu, Luc Willems, Junya Li, Lupei Zhang

Open Access Publications by UMMS Authors

miR-23a, a member of the miR-23a/24-2/27a cluster, has been demonstrated to play pivotal roles in many cellular activities. However, the mechanisms of how bta-miR-23a controls the myogenic differentiation (MD) of PDGFRalpha(-) bovine progenitor cells (bPCs) remain poorly understood. In the present work, bta-miR-23a expression was increased during the MD of (PDGFRalpha-) bPCs. Moreover, bta-miR-23a overexpression significantly promoted the MD of (PDGFRalpha-) bPCs. Luciferase reporter assays showed that the 3'-UTR region of MDFIC (MyoD family inhibitor domain containing) could be a promising target of bta-miR-23a, which resulted in its post-transcriptional down-regulation. Additionally, the knockdown of MDFIC by siRNA ...


Fine-Tuning Of Alanyl-Trna Synthetase Quality Control Alleviates Global Dysregulation Of The Proteome, Paul Kelly, Arundhati Kavoor, Michael Ibba Oct 2020

Fine-Tuning Of Alanyl-Trna Synthetase Quality Control Alleviates Global Dysregulation Of The Proteome, Paul Kelly, Arundhati Kavoor, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

One integral step in the transition from a nucleic acid encoded-genome to functional proteins is the aminoacylation of tRNA molecules. To perform this activity, aminoacyl-tRNA synthetases (aaRSs) activate free amino acids in the cell forming an aminoacyl-adenylate before transferring the amino acid on to its cognate tRNA. These newly formed aminoacyl-tRNA (aa-tRNA) can then be used by the ribosome during mRNA decoding. In Escherichia coli, there are twenty aaRSs encoded in the genome, each of which corresponds to one of the twenty proteinogenic amino acids used in translation. Given the shared chemicophysical properties of many amino acids, aaRSs have evolved ...


Modeling Tissue-Relevant Caenorhabditis Elegans Metabolism At Network, Pathway, Reaction, And Metabolite Levels, L. Safak Yilmaz, Xuhang Li, Shivani Nanda, Bennett Fox, Frank Schroeder, Albertha J. M. Walhout Oct 2020

Modeling Tissue-Relevant Caenorhabditis Elegans Metabolism At Network, Pathway, Reaction, And Metabolite Levels, L. Safak Yilmaz, Xuhang Li, Shivani Nanda, Bennett Fox, Frank Schroeder, Albertha J. M. Walhout

Open Access Publications by UMMS Authors

Metabolism is a highly compartmentalized process that provides building blocks for biomass generation during development, homeostasis, and wound healing, and energy to support cellular and organismal processes. In metazoans, different cells and tissues specialize in different aspects of metabolism. However, studying the compartmentalization of metabolism in different cell types in a whole animal and for a particular stage of life is difficult. Here, we present MEtabolic models Reconciled with Gene Expression (MERGE), a computational pipeline that we used to predict tissue-relevant metabolic function at the network, pathway, reaction, and metabolite levels based on single-cell RNA-sequencing (scRNA-seq) data from the nematode ...


The Lipid Handling Capacity Of Subcutaneous Fat Is Programmed By Mtorc2 During Development, Wen-Yu Hsiao, Su Myung Jung, Yuefeng Tang, John A. Haley, Rui Li, Huawei Li, Camila Martinez Calejman, Joan Sanchez-Gurmaches, Chien-Min Hung, Amelia K. Luciano, Victoria Demambro, Kathryn E. Wellen, Clifford J. Rosen, Lihua Julie Zhu, David A. Guertin Oct 2020

The Lipid Handling Capacity Of Subcutaneous Fat Is Programmed By Mtorc2 During Development, Wen-Yu Hsiao, Su Myung Jung, Yuefeng Tang, John A. Haley, Rui Li, Huawei Li, Camila Martinez Calejman, Joan Sanchez-Gurmaches, Chien-Min Hung, Amelia K. Luciano, Victoria Demambro, Kathryn E. Wellen, Clifford J. Rosen, Lihua Julie Zhu, David A. Guertin

Open Access Publications by UMMS Authors

Overweight and obesity are associated with type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal, as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictor upregulate mature adipocyte markers but develop a striking lipid storage defect resulting in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness ...


Sonoporation-Mediated Loading Of Trehalose In Cells For Cryopreservation., Charles W. Shaffer Iv, David F. Grimm, Michael A. Menze, Jonathan A. Kopechek Sep 2020

Sonoporation-Mediated Loading Of Trehalose In Cells For Cryopreservation., Charles W. Shaffer Iv, David F. Grimm, Michael A. Menze, Jonathan A. Kopechek

Undergraduate Research Events

Trehalose, a non-reducing disaccharide, is present in many microorganisms and metazoans. In these organisms, trehalose acts as a stress protectant and helps preserve lipid membranes of cells during states of desiccation and freezing. Trehalose is required on both sides of the cell membrane to achieve a significant cryoprotective effect. Specific loading methods for trehalose are required since this sugar is impermeant to mammalian cells. Trehalose loading in mammalian cells has been achieved by fluid-phase endocytosis and genetic modification for the expression of trehalose transporters, however cryoprotective outcomes are unable to compete with established methods of cryopreservation for mammalian cells. Sonoporation ...


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 Publications by UMMS Authors

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 ...


Tdp-43 Mediated Blood-Brain Barrier Permeability And Leukocyte Infiltration Promote Neurodegeneration In A Low-Grade Systemic Inflammation Mouse Model, Frank Zamudio, Anjanet R. Loon, Shayna Smeltzer, Khawla Benyamine, Nanda K. Navalpur Shanmugam, Nicholas J. F. Stewart, Daniel C. Lee, Kevin Nash, Maj-Linda B. Selenica Sep 2020

Tdp-43 Mediated Blood-Brain Barrier Permeability And Leukocyte Infiltration Promote Neurodegeneration In A Low-Grade Systemic Inflammation Mouse Model, Frank Zamudio, Anjanet R. Loon, Shayna Smeltzer, Khawla Benyamine, Nanda K. Navalpur Shanmugam, Nicholas J. F. Stewart, Daniel C. Lee, Kevin Nash, Maj-Linda B. Selenica

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases.

METHODS: To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then ...


Artificial Intron Technology To Generate Conditional Knock-Out Mice, Amber N. Thomas-Gordon Aug 2020

Artificial Intron Technology To Generate Conditional Knock-Out Mice, Amber N. Thomas-Gordon

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Genetic engineering has been re-shaped by the invention of new tools in modern biotechnology in a way that offers precision and efficiency in modifying the genome at a single nucleotide level and/or allowing precise control of gene expression. Such gene manipulation brings about significant findings and revelations in comprehending more about embryonic development, cellular and physiological functions, and disease pathology. Current methods used to produce conditional knockouts have limitations on conditional allele placement and modification varies among genes in different organisms. Thus, a system for generating conditional alleles with fidelity remains a challenge. My goal was to examine an ...


Building The Interphase Nucleus: A Study On The Kinetics Of 3d Chromosome Formation, Temporal Relation To Active Transcription, And The Role Of Nuclear Rnas, Kristin N. Abramo Jul 2020

Building The Interphase Nucleus: A Study On The Kinetics Of 3d Chromosome Formation, Temporal Relation To Active Transcription, And The Role Of Nuclear Rnas, Kristin N. Abramo

GSBS Dissertations and Theses

Following the discovery of the one-dimensional sequence of human DNA, much focus has been directed on microscopy and molecular techniques to learn about the spatial organization of chromatin in a 3D cell. The development of these powerful tools has enabled high-resolution, genome-wide analysis of chromosome structure under many different conditions. In this thesis, I focus on how the organization of interphase chromatin is established and maintained following mitosis. Mitotic chromosomes are folded into helical loop arrays creating short and condensed chromosomes, while interphase chromosomes are decondensed and folded into a number of structures at different length scales ranging from loops ...


Basement Membrane Damage By Ros- And Jnk-Mediated Mmp2 Activation Drives Macrophage Recruitment To Overgrown Tissue, Neha Diwanji, Andreas Bergmann Jul 2020

Basement Membrane Damage By Ros- And Jnk-Mediated Mmp2 Activation Drives Macrophage Recruitment To Overgrown Tissue, Neha Diwanji, Andreas Bergmann

Open Access Publications by UMMS Authors

Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model ("undead" model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging ...


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

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 ...


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 Jul 2020

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.


Ribosome Engineering Reveals The Importance Of 5s Rrna Autonomy For Ribosome Assembly, Shijie Huang, Nikolay A. Aleksashin, Anna B. Loveland, Dorota Klepacki, Kaspar Reier, Amira Kefi, Teresa Szal, Jaanus Remme, Luc Jaeger, Nora Vazquez-Laslop, Andrei A. Korostelev, Alexander S. Mankin Jun 2020

Ribosome Engineering Reveals The Importance Of 5s Rrna Autonomy For Ribosome Assembly, Shijie Huang, Nikolay A. Aleksashin, Anna B. Loveland, Dorota Klepacki, Kaspar Reier, Amira Kefi, Teresa Szal, Jaanus Remme, Luc Jaeger, Nora Vazquez-Laslop, Andrei A. Korostelev, Alexander S. Mankin

Open Access Publications by UMMS Authors

5S rRNA is an indispensable component of cytoplasmic ribosomes in all species. The functions of 5S rRNA and the reasons for its evolutionary preservation as an independent molecule remain unclear. Here we used ribosome engineering to investigate whether 5S rRNA autonomy is critical for ribosome function and cell survival. By linking circularly permutated 5S rRNA with 23S rRNA we generated a bacterial strain devoid of free 5S rRNA. Viability of the engineered cells demonstrates that autonomous 5S rRNA is dispensable for cell growth under standard conditions and is unlikely to have essential functions outside the ribosome. The fully assembled ribosomes ...


Dictyostelium Discoideum Protein Kinase C-Orthologue Pkca Regulates The Actin Cytoskeleton Through Interaction With Phospholipase D And P21-Activated Kinase, Sean Singh Jun 2020

Dictyostelium Discoideum Protein Kinase C-Orthologue Pkca Regulates The Actin Cytoskeleton Through Interaction With Phospholipase D And P21-Activated Kinase, Sean Singh

Dissertations, Theses, and Capstone Projects

Proper regulation of the actin cytoskeleton is crucial to many cellular processes. Many of these processes are regulated by extracellular signaling cues, which direct changes in the actin cytoskeleton, resulting in changes to cellular morphology, and directed motility. The social amoeba, Dictyostelium discoideum, is used as a simple model system to study the translation of extracellular signals to the actin cytoskeleton. When starved, these unicellular amoebae undergo a multicellular developmental process characterized by a tightly regulated sequence of signaling events. This results in chemotaxis and formation of a multicellular aggregate, and ultimately cell differentiation and the formation of a fruiting ...


Mutagenesis Of The Btea Gene Encoding A Bordetella Virulence Protein, Xiaolei Mao May 2020

Mutagenesis Of The Btea Gene Encoding A Bordetella Virulence Protein, Xiaolei Mao

2020 Symposium Posters

Bordetella Type III Secretion System Effector A (BteA) is a virulence protein found in members of the genus Bordetella which include important pathogens of humans and other mammals. Bordetella pertussis is a causative agent of the whooping cough, a highly contagious respiratory disease that is especially dangerous, and sometimes deadly, for infants. The BteA protein appears to be an important factor in the ability of these pathogens to cause disease, as it leads to rapid killing of a wide range of mammalian cells. The aim of this project is to determine which regions of the DNA are important for mediating ...


Neuroligin3 Splice Isoforms Shape Inhibitory Synaptic Function In The Mouse Hippocampus, Motokazu Uchigashima, Ming Leung, Takuya Watanabe, Amy Cheung, Timmy Le, Sabine Pallat, Alexandre Luis Marques Dinis, Masahiko Watanabe, Yuka Imamura Kawasawa, Kensuke Futai May 2020

Neuroligin3 Splice Isoforms Shape Inhibitory Synaptic Function In The Mouse Hippocampus, Motokazu Uchigashima, Ming Leung, Takuya Watanabe, Amy Cheung, Timmy Le, Sabine Pallat, Alexandre Luis Marques Dinis, Masahiko Watanabe, Yuka Imamura Kawasawa, Kensuke Futai

Open Access Publications by UMMS Authors

Synapse formation is a dynamic process essential for the development and maturation of the neuronal circuitry in the brain. At the synaptic cleft, transsynaptic protein-protein interactions are major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity, and dysregulation of the E-I balance has been implicated in neurodevelopmental disorders, including autism spectrum disorders. However, the molecular mechanisms underlying the E-I balance remain to be elucidated. Here, using single-cell transcriptomics, immunohistochemistry and electrophysiology approaches to murine CA1 pyramidal neurons obtained from organotypic hippocampal slice cultures, we investigate Neuroligin (Nlgn) genes that ...


Control Of Adipocyte Thermogenesis And Lipogenesis Through Beta3-Adrenergic And Thyroid Hormone Signal Integration, Adilson L. Guilherme, Batuhan Yenilmez, Alexander H. Bedard, Felipe Henriques, Dianxin Liu, Alexandra Lee, Lauren Goldstein, Mark Kelly, Sarah M. Nicoloro, Min Chen, Lee Weinstein, Sheila Collins, Michael P. Czech May 2020

Control Of Adipocyte Thermogenesis And Lipogenesis Through Beta3-Adrenergic And Thyroid Hormone Signal Integration, Adilson L. Guilherme, Batuhan Yenilmez, Alexander H. Bedard, Felipe Henriques, Dianxin Liu, Alexandra Lee, Lauren Goldstein, Mark Kelly, Sarah M. Nicoloro, Min Chen, Lee Weinstein, Sheila Collins, Michael P. Czech

Open Access Publications by UMMS Authors

Here, we show that beta adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsalphaKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, beta3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo. We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL ...


Single Cell Rna Profiling Reveals Adipocyte To Macrophage Signaling Sufficient To Enhance Thermogenesis [Preprint], Felipe Henriques, Alexander H. Bedard, Adilson L. Guilherme, Mark Kelly, Lawrence M. Lifshitz, Karl D. Bellve, Leslie Rowland, Batuhan Yenilmez, Shreya Kumar, Yetao Wang, Jeremy Luban, Michael P. Czech May 2020

Single Cell Rna Profiling Reveals Adipocyte To Macrophage Signaling Sufficient To Enhance Thermogenesis [Preprint], Felipe Henriques, Alexander H. Bedard, Adilson L. Guilherme, Mark Kelly, Lawrence M. Lifshitz, Karl D. Bellve, Leslie Rowland, Batuhan Yenilmez, Shreya Kumar, Yetao Wang, Jeremy Luban, Michael P. Czech

University of Massachusetts Medical School Faculty Publications

The “browning” of inguinal white adipose tissue (iWAT) through increased abundance of thermogenic beige/brite adipocytes is induced by cold exposure and many other perturbations in association with beneficial systemic metabolic effects. Adipose browning is reported to require activation of sympathetic nerve fibers (SNF), aided by alternately activated macrophages within iWAT. Here we demonstrate the first example of a non-cell autonomous pathway for iWAT browning that is fully independent of SNF activity. Thus, the strong induction of thermogenic adipocytes prompted by deletion of adipocyte fatty acid synthase (iAdFASNKO mice) was unaffected by denervation or the deletion of SNF modulator Neuregulin-4 ...


Cloning, Expression, Purification And Characterization Of Heparin-Binding Pocket Of Recombinant Fgf1, Quratulayn Ashraf May 2020

Cloning, Expression, Purification And Characterization Of Heparin-Binding Pocket Of Recombinant Fgf1, Quratulayn Ashraf

Theses and Dissertations

Fibroblast growth factors are polypeptide members of the FGF family, which to date comprises of at least 22 members. They belong to a group of growth factors and are involved in a variety of cellular processes including wound healing, angiogenesis, differentiation and development (organogenesis). Amongst FGF members, human acidic FGF-1 and basic FGF-2 are the most characterized. FGF-1 and FGF-2 are known to share more than 80% sequence similarity and have an identical structural fold. However, their biological roles are quite different. FGFs bind to heparin and heparan sulfate ligands through their heparin-binding pockets. The interactions are primarily electrostatic in ...


A Putative Cystathionine Beta-Synthase Homolog Of Mycolicibacterium Smegmatis Is Involved In De Novo Cysteine Biosynthesis, Saroj Kumar Mahato May 2020

A Putative Cystathionine Beta-Synthase Homolog Of Mycolicibacterium Smegmatis Is Involved In De Novo Cysteine Biosynthesis, Saroj Kumar Mahato

Theses and Dissertations

Mycobacteria include serious pathogens of humans and animals. Mycolicibacterium smegmatis is a non-pathogenic model that is widely used to study core mycobacterial metabolism. This thesis explores mycobacterial pathways of cysteine biosynthesis by generating and study of genetic mutants of M. smegmatis. Published in vitro biochemical studies had revealed three independent routes to cysteine synthesis in mycobacteria involving separate homologs of cysteine synthase, namely CysK1, CysK2, and CysM. However, in vivo data were lacking. The M. smegmatis genome encodes only a CysM homolog and lacks orthologs for CysK1 or CysK2. The gene that codes for CysM is a part of an ...


Cloning, Protein Expression, And Characterization Of Interleukin 1 Alpha, Musaab Habeeb Ali Al Ameer May 2020

Cloning, Protein Expression, And Characterization Of Interleukin 1 Alpha, Musaab Habeeb Ali Al Ameer

Theses and Dissertations

Recombinant DNA technology and the ability to produce recombinant proteins have significantly changed the world of pharmaceutical market. Recombinant DNA technology using E. coli cells has successfully produced many therapeutic proteins. In this study, the designed tag Ark-RUBY-tag facilitates rapid, and reproducible purification of recombinant proteins expressed as inclusion bodies in E. coli cells. Purification of Ark-RUBY-fused recombinant protein(s) can be obtained by using imidazole fractions. Target protein can be easily removed from the Ark-RUBY-tag by enzymatic cleavage. Ark-RUBY-fused recombinant proteins can be quantitatively detected using polyclonal antibodies. Ark-RUBY-tag can be used to purify small peptides. By using Ark-RUBY-tag ...


A Study Of Matr3 And Its Effects On The Neural Progenitor Cells Of Xenopus Laevis Tadpoles, Kendall Branham May 2020

A Study Of Matr3 And Its Effects On The Neural Progenitor Cells Of Xenopus Laevis Tadpoles, Kendall Branham

Undergraduate Honors Theses

Understanding the genes and mechanisms that regulate the highly important process of neurogenesis in the developing nervous system is crucial to uncovering why disease arises when this system is disrupted. Neural progenitor cells and their multipotent nature allow for the growth of a large pool of stem cells in the early stages of development, but the signal that leads these cells to the irreversible fate of becoming a neuron is unclear. The gene matr3 has been implicated in having a role in the maintenance of undifferentiated neural stem cells but its role needs further investigation to fully reveal how its ...


Investigating The Redox Sensitivity Of Mitf Splice Variants, Rachel Berryman May 2020

Investigating The Redox Sensitivity Of Mitf Splice Variants, Rachel Berryman

Senior Theses

Within pigment-producing cells known as melanocytes, the transcription factor MITF is intimately involved in regulating genes associated with cell cycle maintenance and melanocyte differentiation. Research, however, has provided conflicting results on the relationship between the expression levels of MITF and melanocyte cell fate. To complicate matters, two splice variants of MITF exist, differing by only 18 base pairs. These variants have been observed at variable levels of expression in melanocyte and melanoma cells, raising the question as to their functional purpose. Building upon previous research by the Leachman/Cassidy lab that identified the redox sensitivity of MITF while additionally establishing ...