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Biochemistry, Biophysics, and Structural Biology Commons

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Physiology

2015

University of Massachusetts Medical School

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Articles 1 - 19 of 19

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Endothelial Protein Kinase Map4k4 Promotes Vascular Inflammation And Atherosclerosis, Rachel J. Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, Myriam Aouadi, G. Nana Hagan, Joseph Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P. Cooper, Timothy P. Fitzgibbons, Leonard Buckbinder, Michael P. Czech Dec 2015

Endothelial Protein Kinase Map4k4 Promotes Vascular Inflammation And Atherosclerosis, Rachel J. Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, Myriam Aouadi, G. Nana Hagan, Joseph Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P. Cooper, Timothy P. Fitzgibbons, Leonard Buckbinder, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic ...


Systematic Dissection Of Roles For Chromatin Regulators In Dynamics Of Transcriptional Response To Stress In Yeast: A Dissertation, Hsiuyi V. Chen Dec 2015

Systematic Dissection Of Roles For Chromatin Regulators In Dynamics Of Transcriptional Response To Stress In Yeast: A Dissertation, Hsiuyi V. Chen

GSBS Dissertations and Theses

The following work demonstrates that chromatin regulators play far more pronounced roles in dynamic gene expression than they do in steady-state. Histone modifications have been associated with transcription activity. However, previous analyses of gene expression in mutants affecting histone modifications show limited alteration. I systematically dissected the effects of 83 histone mutants and 119 gene deletion mutants on gene induction/repression in response to diamide stress in yeast. Importantly, I observed far more changes in gene induction/repression than changes in steady-state gene expression. The extensive dynamic gene expression profile of histone mutants and gene deletion mutants also allowed me ...


Homozygous Knockout Of The Piezo1 Gene In The Zebrafish Is Not Associated With Anemia, Boris E. Shmukler, Nicholas C. Huston, Jonathan N. Thon, Chih-Wen Ni, George Kourkoulis, Nathan D. Lawson, Barry H. Paw, Seth L. Alper Dec 2015

Homozygous Knockout Of The Piezo1 Gene In The Zebrafish Is Not Associated With Anemia, Boris E. Shmukler, Nicholas C. Huston, Jonathan N. Thon, Chih-Wen Ni, George Kourkoulis, Nathan D. Lawson, Barry H. Paw, Seth L. Alper

Molecular, Cell and Cancer Biology Publications

We have now examined the erythroid phenotype in this zebrafish strain carrying a ZFN genomic knockout of piezo1. Genotyping was performed as previously described. In contrast to the anemic phenotype observed in zebrafish subjected to morpholino knockdown of piezo, the genomic ZFN knockout of piezo1 did not segregate either with anemia in the 3-dpf embryo or with dysmorphic erythrocyte morphology in the adult fish.


Direct Visualization Of Hiv-1 Replication Intermediates Shows That Capsid And Cpsf6 Modulate Hiv-1 Intra-Nuclear Invasion And Integration, Christopher R. Chin, Jill Perreira, George Savidis, Jocelyn M. Portmann, Aaron M. Aker, Eric M. Feeley, Miles C. Smith, Abraham L. Brass Nov 2015

Direct Visualization Of Hiv-1 Replication Intermediates Shows That Capsid And Cpsf6 Modulate Hiv-1 Intra-Nuclear Invasion And Integration, Christopher R. Chin, Jill Perreira, George Savidis, Jocelyn M. Portmann, Aaron M. Aker, Eric M. Feeley, Miles C. Smith, Abraham L. Brass

Microbiology and Physiological Systems Publications and Presentations

Direct visualization of HIV-1 replication would improve our understanding of the viral life cycle. We adapted established technology and reagents to develop an imaging approach, ViewHIV, which allows evaluation of early HIV-1 replication intermediates, from reverse transcription to integration. These methods permit the simultaneous evaluation of both the capsid protein (CA) and viral DNA genome (vDNA) components of HIV-1 in both the cytosol and nuclei of single cells. ViewHIV is relatively rapid, uses readily available reagents in combination with standard confocal microscopy, and can be done with virtually any HIV-1 strain and permissive cell lines or primary cells. Using ViewHIV ...


Roles Of Protein Arginine Methyltransferase 7 And Jumonji Domain-Containing Protein 6 In Adipocyte Differentiation: A Dissertation, Yu-Jie Hu Oct 2015

Roles Of Protein Arginine Methyltransferase 7 And Jumonji Domain-Containing Protein 6 In Adipocyte Differentiation: A Dissertation, Yu-Jie Hu

GSBS Dissertations and Theses

Regulation of gene expression comprises a wide range of mechanisms that control the abundance of gene products in response to environmental and developmental changes. These biological processes can be modulated by posttranslational modifications including arginine methylation. Among the enzymes that catalyze the methylation, protein arginine methyltransferase 7 (PRMT7) is known to modify histones to repress gene expression. Jumonji domain-containing protein 6 (JMJD6) is a putative arginine demethylase that potentially antagonize PRMT7. However, the biological significance of these enzymes is not well understood. This thesis summarizes the investigation of both PRMT7 and JMJD6 in cell culture models for adipocyte differentiation. The ...


Hcm1 Integrates Signals From Cdk1 And Calcineurin To Control Cell Proliferation, Heather E. Arsenault, Jagoree Roy, Claudine E. Mapa, Martha S. Cyert, Jennifer A. Benanti Oct 2015

Hcm1 Integrates Signals From Cdk1 And Calcineurin To Control Cell Proliferation, Heather E. Arsenault, Jagoree Roy, Claudine E. Mapa, Martha S. Cyert, Jennifer A. Benanti

Molecular, Cell and Cancer Biology Publications

Cyclin-dependent kinase (Cdk1) orchestrates progression through the cell cycle by coordinating the activities of cell-cycle regulators. Although phosphatases that oppose Cdk1 are likely to be necessary to establish dynamic phosphorylation, specific phosphatases that target most Cdk1 substrates have not been identified. In budding yeast, the transcription factor Hcm1 activates expression of genes that regulate chromosome segregation and is critical for maintaining genome stability. Previously we found that Hcm1 activity and degradation are stimulated by Cdk1 phosphorylation of distinct clusters of sites. Here we show that, upon exposure to environmental stress, the phosphatase calcineurin inhibits Hcm1 by specifically removing activating phosphorylations ...


Cfap54 Is Required For Proper Ciliary Motility And Assembly Of The Central Pair Apparatus In Mice, Casey W. Mckenzie, Branch Craige, Tiffany V. Kroeger, Rozzy Finn, Todd A. Wyatt, Joseph H. Sisson, Jacqueline A. Pavlik, Lara Strittmatter, Gregory M. Hendricks, George B. Witman, Lance Lee Sep 2015

Cfap54 Is Required For Proper Ciliary Motility And Assembly Of The Central Pair Apparatus In Mice, Casey W. Mckenzie, Branch Craige, Tiffany V. Kroeger, Rozzy Finn, Todd A. Wyatt, Joseph H. Sisson, Jacqueline A. Pavlik, Lara Strittmatter, Gregory M. Hendricks, George B. Witman, Lance Lee

Cell and Developmental Biology Publications

Motile cilia and flagella play critical roles in fluid clearance and cell motility, and dysfunction commonly results in the pediatric syndrome primary ciliary dyskinesia (PCD). CFAP221, also known as PCDP1, is required for ciliary and flagellar function in mice and Chlamydomonas reinhardtii, where it localizes to the C1d projection of the central microtubule apparatus and functions in a complex that regulates flagellar motility in a calcium-dependent manner. We demonstrate that the genes encoding the mouse homologues of the other C. reinhardtii C1d complex members are primarily expressed in motile ciliated tissues, suggesting a conserved function in mammalian motile cilia. The ...


Weekly Treatment Of 2-Hydroxypropyl-Beta-Cyclodextrin Improves Intracellular Cholesterol Levels In Ldl Receptor Knockout Mice, Sofie M.A. Walenbergh, Tom Houben, Tim Hendrikx, Mike L.J. Jeurissen, Patrick J. Van Gorp, Nathalie Vaes, Steven W.M. Olde Damink, Fons Verheyen, Ger H. Koek, Dieter Lutjohann, Alena Grebe, Eicke Latz, Ronit Shiri-Sverdlov Sep 2015

Weekly Treatment Of 2-Hydroxypropyl-Beta-Cyclodextrin Improves Intracellular Cholesterol Levels In Ldl Receptor Knockout Mice, Sofie M.A. Walenbergh, Tom Houben, Tim Hendrikx, Mike L.J. Jeurissen, Patrick J. Van Gorp, Nathalie Vaes, Steven W.M. Olde Damink, Fons Verheyen, Ger H. Koek, Dieter Lutjohann, Alena Grebe, Eicke Latz, Ronit Shiri-Sverdlov

Open Access Articles

Recently, the importance of lysosomes in the context of the metabolic syndrome has received increased attention. Increased lysosomal cholesterol storage and cholesterol crystallization inside macrophages have been linked to several metabolic diseases, such as atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Two-hydroxypropyl-beta-cyclodextrin (HP-B-CD) is able to redirect lysosomal cholesterol to the cytoplasm in Niemann-Pick type C1 disease, a lysosomal storage disorder. We hypothesize that HP-B-CD ameliorates liver cholesterol and intracellular cholesterol levels inside Kupffer cells (KCs). Hyperlipidemic low-density lipoprotein receptor knockout (Ldlr(-/-)) mice were given weekly, subcutaneous injections with HP-B-CD or control PBS. In contrast to control injections, hyperlipidemic mice ...


Determination Of Fatty Acid Oxidation And Lipogenesis In Mouse Primary Hepatocytes, Thomas E. Akie, Marcus P. Cooper Aug 2015

Determination Of Fatty Acid Oxidation And Lipogenesis In Mouse Primary Hepatocytes, Thomas E. Akie, Marcus P. Cooper

GSBS Student Publications

Lipid metabolism in liver is complex. In addition to importing and exporting lipid via lipoproteins, hepatocytes can oxidize lipid via fatty acid oxidation, or alternatively, synthesize new lipid via de novo lipogenesis. The net sum of these pathways is dictated by a number of factors, which in certain disease states leads to fatty liver disease. Excess hepatic lipid accumulation is associated with whole body insulin resistance and coronary heart disease. Tools to study lipid metabolism in hepatocytes are useful to understand the role of hepatic lipid metabolism in certain metabolic disorders. In the liver, hepatocytes regulate the breakdown and synthesis ...


Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky Aug 2015

Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky

GSBS Dissertations and Theses

During stress, eukaryotes regulate protein synthesis in part through formation of cytoplasmic, non-membrane-bound complexes called stress granules (SGs). SGs transiently store signaling proteins and stalled translational complexes in response to stress stimuli (e.g. oxidative insult, DNA damage, temperature shifts and ER dysfunction). The functional outcome of SGs is proper translational regulation and signaling, allowing cells to overcome stress.

The fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) develops in an age-related manner and is marked by progressive neuronal death, with cytoplasmic protein aggregation, excitotoxicity and increased oxidative stress as major hallmarks. Fused in Sarcoma/Translocated in Liposarcoma (FUS) is ...


Inducible Deletion Of Protein Kinase Map4k4 In Obese Mice Improves Insulin Sensitivity In Liver And Adipose Tissues, Laura V. Danai, Rachel J. Roth Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Michael P. Czech Jul 2015

Inducible Deletion Of Protein Kinase Map4k4 In Obese Mice Improves Insulin Sensitivity In Liver And Adipose Tissues, Laura V. Danai, Rachel J. Roth Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with ...


A Major Role Of Insulin In Promoting Obesity-Associated Adipose Tissue Inflammation, David J. Pedersen, Adilson L Guilherme, Laura V. Danai, Lauren Heyda, Anouch Matevossian, Jessica L. Cohen, Sarah M. Nicoloro, Juerg R. Straubhaar, Hye Lim Noh, Dae Young Jung, Jason K. Kim, Michael P. Czech May 2015

A Major Role Of Insulin In Promoting Obesity-Associated Adipose Tissue Inflammation, David J. Pedersen, Adilson L Guilherme, Laura V. Danai, Lauren Heyda, Anouch Matevossian, Jessica L. Cohen, Sarah M. Nicoloro, Juerg R. Straubhaar, Hye Lim Noh, Dae Young Jung, Jason K. Kim, Michael P. Czech

Open Access Articles

OBJECTIVE: Adipose tissue (AT) inflammation is associated with systemic insulin resistance and hyperinsulinemia in obese rodents and humans. A longstanding concept is that hyperinsulinemia may promote systemic insulin resistance through downregulation of its receptor on target tissues. Here we tested the novel hypothesis that insulin also impairs systemic insulin sensitivity by specifically enhancing adipose inflammation.

METHODS: Circulating insulin levels were reduced by about 50% in diet-induced and genetically obese mice by treatments with diazoxide or streptozotocin, respectively. We then examined AT crown-like structures, macrophage markers and pro-inflammatory cytokine expression in AT. AT lipogenesis and systemic insulin sensitivity was also monitored ...


Role Of Protein Kinase Map4k4 In Energy Metabolism: A Dissertation, Laura V. Danai Apr 2015

Role Of Protein Kinase Map4k4 In Energy Metabolism: A Dissertation, Laura V. Danai

GSBS Dissertations and Theses

Systemic glucose regulation is essential for human survival as low or chronically high glucose levels can be detrimental to the health of an individual. Glucose levels are highly regulated via inter-organ communication networks that alter metabolic function to maintain euglycemia. For example, when nutrient levels are low, pancreatic α-cells secrete glucagon, which signals to the liver to promote glycogen breakdown and glucose production. In times of excess nutrient intake, pancreatic β-cells release insulin. Insulin signals to the liver to suppress hepatic glucose production, and signals to the adipose tissue and the skeletal muscle to take up excess glucose via insulin-regulated ...


Highly Selective In Vivo Labeling Of Subcutaneous White Adipocyte Precursors With Prx1-Cre, Joan Sanchez-Gurmaches, Wen-Yu Hsiao, David A. Guertin Apr 2015

Highly Selective In Vivo Labeling Of Subcutaneous White Adipocyte Precursors With Prx1-Cre, Joan Sanchez-Gurmaches, Wen-Yu Hsiao, David A. Guertin

Program in Molecular Medicine Publications and Presentations

The origins of individual fat depots are not well understood, and thus, the availability of tools useful for studying depot-specific adipose tissue development and function is limited. Cre drivers that selectively target only brown adipocyte, subcutaneous white adipocyte, or visceral white adipocyte precursors would have significant value because they could be used to selectively study individual depots without impacting the adipocyte precursors or intrinsic metabolic properties of the other depots. Here, we show that the majority of the precursor and mature subcutaneous white adipocytes in adult C57Bl/6 mice are labeled by Prx1-Cre. In sharp contrast, few to no brown ...


Presynaptic C-Jun N-Terminal Kinase 2 Regulates Nmda Receptor-Dependent Glutamate Release, Robert Nistico, Fulvio Florenzano, Dalila Mango, Caterina Ferraina, Massimo Grilli, Silvia Di Prisco, Annalisa Nobili, Stefania Saccucci, Marcello D'Amelio, Michela Morbin, Mario Marchi, Nicola B. Mercuri, Roger J. Davis, Anna Pittaluga, Marco Feligioni Mar 2015

Presynaptic C-Jun N-Terminal Kinase 2 Regulates Nmda Receptor-Dependent Glutamate Release, Robert Nistico, Fulvio Florenzano, Dalila Mango, Caterina Ferraina, Massimo Grilli, Silvia Di Prisco, Annalisa Nobili, Stefania Saccucci, Marcello D'Amelio, Michela Morbin, Mario Marchi, Nicola B. Mercuri, Roger J. Davis, Anna Pittaluga, Marco Feligioni

Davis Lab Publications

Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for ...


Myosin-Binding Protein C Corrects An Intrinsic Inhomogeneity In Cardiac Excitation-Contraction Coupling, Michael J. Previs, Benjamin L. Prosser, Ji Young Mun, Samantha Beck Previs, James Gulick, Kyounghwan Lee, Jeffrey Robbins, Roger Craig, W J. Lederer, David M. Warshaw Feb 2015

Myosin-Binding Protein C Corrects An Intrinsic Inhomogeneity In Cardiac Excitation-Contraction Coupling, Michael J. Previs, Benjamin L. Prosser, Ji Young Mun, Samantha Beck Previs, James Gulick, Kyounghwan Lee, Jeffrey Robbins, Roger Craig, W J. Lederer, David M. Warshaw

Cell and Developmental Biology Publications

The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by ...


Fhl1 Reduces Dystrophy In Transgenic Mice Overexpressing Fshd Muscular Dystrophy Region Gene 1 (Frg1), Sandra J. Feeney, Meagan J. Mcgrath, Absorn Sriratana, Stefan M. Gehrig, Gordon S. Lynch, Colleen E. D'Arcy, John T. Price, Catriona A. Mclean, Rossella Ginevra Tupler, Christina A. Mitchell Feb 2015

Fhl1 Reduces Dystrophy In Transgenic Mice Overexpressing Fshd Muscular Dystrophy Region Gene 1 (Frg1), Sandra J. Feeney, Meagan J. Mcgrath, Absorn Sriratana, Stefan M. Gehrig, Gordon S. Lynch, Colleen E. D'Arcy, John T. Price, Catriona A. Mclean, Rossella Ginevra Tupler, Christina A. Mitchell

Open Access Articles

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To ...


Drug-Resistant Hiv-1 Protease Regains Functional Dynamics Through Cleavage Site Coevolution, Nevra Ozer, Aysegul Ozen, Celia A. Schiffer, Turkan Haliloglu Feb 2015

Drug-Resistant Hiv-1 Protease Regains Functional Dynamics Through Cleavage Site Coevolution, Nevra Ozer, Aysegul Ozen, Celia A. Schiffer, Turkan Haliloglu

University of Massachusetts Medical School Faculty Publications

Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in ...


Uncoupling Lifespan And Healthspan In Caenorhabditis Elegans Longevity Mutants, Ankita Bansal, Lihua Julie Zhu, Kelvin Yen, Heidi A. Tissenbaum Jan 2015

Uncoupling Lifespan And Healthspan In Caenorhabditis Elegans Longevity Mutants, Ankita Bansal, Lihua Julie Zhu, Kelvin Yen, Heidi A. Tissenbaum

Molecular, Cell and Cancer Biology Publications

Aging research has been very successful at identifying signaling pathways and evolutionarily conserved genes that extend lifespan with the assumption that an increase in lifespan will also increase healthspan. However, it is largely unknown whether we are extending the healthy time of life or simply prolonging a period of frailty with increased incidence of age-associated diseases. Here we use Caenorhabditis elegans, one of the premiere systems for lifespan studies, to determine whether lifespan and healthspan are intrinsically correlated. We conducted multiple cellular and organismal assays on wild type as well as four long-lived mutants (insulin/insulin-like growth factor-1, dietary restriction ...