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Physiology

2017

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Articles 1 - 30 of 84

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

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O’Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O’Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

Molecular and Cellular Biochemistry Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

University of Massachusetts Medical School Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers Dec 2017

Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers

UMass Metabolic Network Publications

Recent structural studies suggest that glucose transporter 1 (GLUT1)-mediated sugar transport is mediated by an alternating access transporter that successively presents exofacial (e2) and endofacial (e1) substrate-binding sites. Transport studies, however, indicate multiple, interacting (allosteric), and co-existent, exo- and endofacial GLUT1 ligand-binding sites. The present study asks whether these contradictory conclusions result from systematic analytical error or reveal a more fundamental relationship between transporter structure and function. Here, homology modeling supported the alternating access transporter model for sugar transport by confirming at least four GLUT1 conformations, the so-called outward, outward-occluded, inward-occluded, and inward GLUT1 conformations. Results from docking analysis ...


Attaching-And-Effacing Pathogens Exploit Junction Regulatory Activities Of N-Wasp And Snx9 To Disrupt The Intestinal Barrier, John J. Garber, Emily M. Mallick, Karen M. Scanlon, Jerrold R. Turner, Michael S. Donnenberg, John M. Leong, Scott B. Snapper Dec 2017

Attaching-And-Effacing Pathogens Exploit Junction Regulatory Activities Of N-Wasp And Snx9 To Disrupt The Intestinal Barrier, John J. Garber, Emily M. Mallick, Karen M. Scanlon, Jerrold R. Turner, Michael S. Donnenberg, John M. Leong, Scott B. Snapper

Open Access Articles

Background and Aims: Neural Wiskott-Aldrich Syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton in epithelial tissues and is poised to mediate cytoskeletal-dependent aspects of apical junction complex (AJC) homeostasis. Attaching-and-effacing (AE) pathogens disrupt this homeostasis through translocation of the effector molecule early secreted antigenic target-6 (ESX)-1 secretion-associated protein F (EspF). Although the mechanisms underlying AJC disruption by EspF are unknown, EspF contains putative binding sites for N-WASP and the endocytic regulator sorting nexin 9 (SNX9). We hypothesized that N-WASP regulates AJC integrity and AE pathogens use EspF to induce junction disassembly through an N-WASP- and SNX9-dependent ...


Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo Dec 2017

Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo

University of Massachusetts Medical School Faculty Publications

Purpose: The apoptotic mechanisms responsible for secondary cone death in retinitis pigmentosa (RP) remain largely unknown. The cone-enriched apoptotic protease caspase-7 (Casp7) is thought to be triggered by endoplasmic reticulum (ER) stress and plays a pivotal role in mice deficient in the cone cyclic nucleotide-gated channels, a deficiency that causes achromatopsia in humans and in mice with autosomal dominant rhodopsin mutations, in particular the T17M mutation. Thus, we tested in two mouse models of RP whether the cone-enriched Casp7 plays a role during secondary cone death.

Methods: Casp7 knockout mice were crossed to two different RP mouse models with significantly ...


Regulation Of Liver Mitochondrial Metabolism During Hibernation By Post-Translational Modification, Katherine E. Mathers Dec 2017

Regulation Of Liver Mitochondrial Metabolism During Hibernation By Post-Translational Modification, Katherine E. Mathers

Electronic Thesis and Dissertation Repository

Hibernation, characterized by a seasonal reduction in metabolism and body temperature, allows animals to conserve energy when environmental conditions (e.g. temperature, food availability) are unfavourable. During hibernation, small mammals such as the 13-lined ground squirrel (Ictidomys tridecemlineatus) cycle between two distinct metabolic states: torpor, where metabolic rate is suppressed by >95% and body temperature falls to ~5 °C, and interbout euthermia (IBE), where metabolic rate and body temperature rapidly increase and are maintained at euthermic levels several hours. Suppression of metabolism during entrance into torpor is paralleled by rapid suppression of liver mitochondrial metabolism. In my thesis, I aimed ...


Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel Dec 2017

Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel

University of Massachusetts Medical School Faculty Publications

Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver ...


The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio Dec 2017

The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio

UMass Metabolic Network Publications

Increases in lipid peroxidation can cause ferroptosis, a form of cell death triggered by inhibition of glutathione peroxidase 4 (GPX4), which catalyzes the reduction of lipid peroxides and is a target of ferroptosis inducers, such as erastin. The alpha6beta4 integrin protects adherent epithelial and carcinoma cells from ferroptosis induced by erastin. In addition, extracellular matrix (ECM) detachment is a physiologic trigger of ferroptosis, which is evaded by alpha6beta4. The mechanism that enables alpha6beta4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, alpha6beta4-mediated activation of Src and STAT3 suppresses expression of ACSL4, an ...


Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon Dec 2017

Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon

UT GSBS Dissertations and Theses (Open Access)

Salt inducible kinase 1 (SIK1) has been considered a stress-inducible kinase since it was first cloned in 1999. Continued efforts since this time have been dedicated to characterizing the structure and function of SIK1. Such research has laid the ground work for our understanding of SIK1 action and regulation in tissue and stimuli dependent manners. The fundamental findings of this dissertation continue in this tradition and include investigations of SIK1 regulatory mechanisms in skeletal muscle cells, the cellular and physiological effects of SIK1 loss of function in vitro and in vivo, and intracellular metabolic and mitochondrial regulation by this kinase ...


Cellular Mechanisms Of Ionoregulation In The Gill Of Japanese Medaka And Rainbow Trout, Rebecca Jo Bollinger Dec 2017

Cellular Mechanisms Of Ionoregulation In The Gill Of Japanese Medaka And Rainbow Trout, Rebecca Jo Bollinger

Theses and Dissertations

Euryhaline fishes are capable of adapting to a wide range of salinities such as freshwater, brackish water or seawater. Through the combined effort of the gill, kidney and intestine, they are able to osmoregulate to maintain a constant internal hydromineral balance. As the gill is in direct contact with the external environment, it is continuously working to maintain ion and acid/base balance, gas exchange and eliminate nitrogenous waste. Fish in freshwater are subjected to osmotic water gain and diffusional ion loss across the gill and experience the opposite in seawater. Therefore, the gill exhibits extreme plasticity when experiencing a ...


Temporal Regulation Of Chromatin During Myoblast Differentiation, Akihito Harada, Yasuyuki Ohkawa, Anthony N. Imbalzano Dec 2017

Temporal Regulation Of Chromatin During Myoblast Differentiation, Akihito Harada, Yasuyuki Ohkawa, Anthony N. Imbalzano

UMass Metabolic Network Publications

The commitment to and execution of differentiation programmes involves a significant change in gene expression in the precursor cell to facilitate development of the mature cell type. In addition to being regulated by lineage-determining and auxiliary transcription factors that drive these changes, the structural status of the chromatin has a considerable impact on the transcriptional competence of differentiation-specific genes, which is clearly demonstrated by the large number of cofactors and the extraordinary complex mechanisms by which these genes become activated. The terminal differentiation of myoblasts to myotubes and mature skeletal muscle is an excellent system to illustrate these points. The ...


Jnk Promotes Epithelial Cell Anoikis By Transcriptional And Post-Translational Regulation Of Bh3-Only Proteins, Nomeda Girnius, Roger J. Davis Nov 2017

Jnk Promotes Epithelial Cell Anoikis By Transcriptional And Post-Translational Regulation Of Bh3-Only Proteins, Nomeda Girnius, Roger J. Davis

UMass Metabolic Network Publications

Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here, we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that ...


Bivalent Epigenetic Control Of Oncofetal Gene Expression In Cancer, Sayyed K. Zaidi, Seth E. Frietze, Jonathan A. Gordon, Jessica L. Heath, Terri Messier, Deli Hong, Joseph R. Boyd, Mingu Kang, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Gary S. Stein Nov 2017

Bivalent Epigenetic Control Of Oncofetal Gene Expression In Cancer, Sayyed K. Zaidi, Seth E. Frietze, Jonathan A. Gordon, Jessica L. Heath, Terri Messier, Deli Hong, Joseph R. Boyd, Mingu Kang, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Gary S. Stein

UMass Metabolic Network Publications

Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency ...


Casein Kinase 2-Mediated Phosphorylation Of Brahma-Related Gene 1 Controls Myoblast Proliferation And Contributes To Swi/Snf Complex Composition, Teresita Padilla-Benavides, Brian T. Nasipak, Amanda L. Paskavitz, Dominic T. Haokip, Jake M. Schnabl, Jeffrey A. Nickerson, Anthony N. Imbalzano Nov 2017

Casein Kinase 2-Mediated Phosphorylation Of Brahma-Related Gene 1 Controls Myoblast Proliferation And Contributes To Swi/Snf Complex Composition, Teresita Padilla-Benavides, Brian T. Nasipak, Amanda L. Paskavitz, Dominic T. Haokip, Jake M. Schnabl, Jeffrey A. Nickerson, Anthony N. Imbalzano

UMass Metabolic Network Publications

Transcriptional regulation is modulated in part by chromatin-remodeling enzymes that control gene accessibility by altering chromatin compaction or nucleosome positioning. Brahma-related gene 1 (Brg1), a catalytic subunit of the mammalian SWI/SNF chromatin-remodeling enzymes, is required for both myoblast proliferation and differentiation, and the control of Brg1 phosphorylation by calcineurin, PKCbeta1, and p38 regulates the transition to differentiation. However, we hypothesized that Brg1 activity might be regulated by additional kinases. Here, we report that Brg1 is also a target of casein kinase 2 (CK2), a serine/threonine kinase, in proliferating myoblasts. We found that CK2 interacts with Brg1, and mutation ...


Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto Nov 2017

Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto

UMass Metabolic Network Publications

In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target ...


Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice, Tony Jourdan, Sarah M. Nicoloro, Zhou Zhou, Yuefei Shen, Jie Liu, Nathan J. Coffey, Resat Cinar, Grzegorz Godlewski, Bin Gao, Myriam Aouadi, Michael P. Czech, George Kunos Nov 2017

Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice, Tony Jourdan, Sarah M. Nicoloro, Zhou Zhou, Yuefei Shen, Jie Liu, Nathan J. Coffey, Resat Cinar, Grzegorz Godlewski, Bin Gao, Myriam Aouadi, Michael P. Czech, George Kunos

UMass Metabolic Network Publications

OBJECTIVE: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types ...


Hdac3 Regulates Lymphovenous And Lymphatic Valve Formation, Harish P. Janardhan, Zachary J. Milstone, Masahiro Shin, Nathan D. Lawson, John F. Keaney Jr., Chinmay M. Trivedi Nov 2017

Hdac3 Regulates Lymphovenous And Lymphatic Valve Formation, Harish P. Janardhan, Zachary J. Milstone, Masahiro Shin, Nathan D. Lawson, John F. Keaney Jr., Chinmay M. Trivedi

UMass Metabolic Network Publications

Lymphedema, the most common lymphatic anomaly, involves defective lymphatic valve development; yet the epigenetic modifiers underlying lymphatic valve morphogenesis remain elusive. Here, we showed that during mouse development, the histone-modifying enzyme histone deacetylase 3 (Hdac3) regulates the formation of both lymphovenous valves, which maintain the separation of the blood and lymphatic vascular systems, and the lymphatic valves. Endothelium-specific ablation of Hdac3 in mice led to blood-filled lymphatic vessels, edema, defective lymphovenous valve morphogenesis, improper lymphatic drainage, defective lymphatic valve maturation, and complete lethality. Hdac3-deficient lymphovenous valves and lymphatic vessels exhibited reduced expression of the transcription factor Gata2 and its target ...


Association Of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study, Ravi V. Shah, Ashish S. Yeri, Venkatesh L. Murthy, Joe M. Massaro, Ralph Sr. D'Agostino, Jane E. Freedman, Michelle T. Long, Caroline S. Fox, Saumya Das, Emelia J. Benjamin, Ramachandran S. Vasan, Christopher J. O'Donnell, Udo Hoffmann Nov 2017

Association Of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study, Ravi V. Shah, Ashish S. Yeri, Venkatesh L. Murthy, Joe M. Massaro, Ralph Sr. D'Agostino, Jane E. Freedman, Michelle T. Long, Caroline S. Fox, Saumya Das, Emelia J. Benjamin, Ramachandran S. Vasan, Christopher J. O'Donnell, Udo Hoffmann

UMass Metabolic Network Publications

Importance: Increased ability to quantify anatomical phenotypes across multiple organs provides the opportunity to assess their cumulative ability to identify individuals at greatest susceptibility for adverse outcomes.

Objective: To apply unsupervised machine learning to define the distribution and prognostic importance of computed tomography-based multiorgan phenotypes associated with adverse health outcomes.

Design, Setting, and Participants: This asymptomatic community-based cohort study included 2924 Framingham Heart Study participants between July 2002 and April 2005 undergoing computed tomographic imaging of the chest and abdomen. Participants are from the offspring and third-generation cohorts.

Exposures: Eleven computed tomography-based measures of valvular/vascular calcification, adiposity, and muscle ...


Role Of Granulocyte-Macrophage Colony-Stimulating Factor Production By T Cells During Mycobacterium Tuberculosis Infection, Alissa C. Rothchild, Britni L. Stowell, Girija Goyal, Claudio Nunes-Alves, Qianting Yang, Kadamba Papavinasasundaram, Christopher M. Sassetti, Glenn Dranoff, Xinchun Chen, Jinhee Lee, Samuel M. Behar Oct 2017

Role Of Granulocyte-Macrophage Colony-Stimulating Factor Production By T Cells During Mycobacterium Tuberculosis Infection, Alissa C. Rothchild, Britni L. Stowell, Girija Goyal, Claudio Nunes-Alves, Qianting Yang, Kadamba Papavinasasundaram, Christopher M. Sassetti, Glenn Dranoff, Xinchun Chen, Jinhee Lee, Samuel M. Behar

UMass Metabolic Network Publications

Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF(-/-)) are highly susceptible to infection with Mycobacterium tuberculosis, and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T ...


Age-Associated Microrna Expression In Human Peripheral Blood Is Associated With All-Cause Mortality And Age-Related Traits, Tianxiao Huan, George Chen, Chunyu Liu, Anindya Bhattacharya, Jian Rong, Brian H. Chen, Sudha Seshadri, Kahraman Tanriverdi, Jane E. Freedman, Martin G. Larson, Joanne M. Murabito, Daniel Levy Oct 2017

Age-Associated Microrna Expression In Human Peripheral Blood Is Associated With All-Cause Mortality And Age-Related Traits, Tianxiao Huan, George Chen, Chunyu Liu, Anindya Bhattacharya, Jian Rong, Brian H. Chen, Sudha Seshadri, Kahraman Tanriverdi, Jane E. Freedman, Martin G. Larson, Joanne M. Murabito, Daniel Levy

UMass Metabolic Network Publications

Recent studies provide evidence of correlations of DNA methylation and expression of protein-coding genes with human aging. The relations of microRNA expression with age and age-related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 x 10(-4) (Bonferroni-corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age-associated mRNA expression possibly driven by age-associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict 'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Deltaage) and found that Deltaage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 x 10(-5) adjusted for sex and chronological age). Additionally, Deltaage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age-related diseases. Wiley and Sons Ltd.


A Protein Scaffold Coordinates Src-Mediated Jnk Activation In Response To Metabolic Stress, Shashi Kant, Claire L. Standen, Caroline Morel, Dae Young Jung, Jason K. Kim, Wojciech Swat, Richard A. Flavell, Roger J. Davis Sep 2017

A Protein Scaffold Coordinates Src-Mediated Jnk Activation In Response To Metabolic Stress, Shashi Kant, Claire L. Standen, Caroline Morel, Dae Young Jung, Jason K. Kim, Wojciech Swat, Richard A. Flavell, Roger J. Davis

UMass Metabolic Network Publications

Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH2-terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV. These interactions are required for SRC-induced activation ...


A Synthetic Biology Approach To Probing Nucleosome Symmetry, Yuichi Ichikawa, Caitlin M. Connolly, Hsin-Jung Chou, Yuanyuan Chen, Upasna Sharma, Hsuiyi V. Chen, Vineeta Bajaj, Daniel Na. Bolon, Oliver J. Rando, Paul D. Kaufman Sep 2017

A Synthetic Biology Approach To Probing Nucleosome Symmetry, Yuichi Ichikawa, Caitlin M. Connolly, Hsin-Jung Chou, Yuanyuan Chen, Upasna Sharma, Hsuiyi V. Chen, Vineeta Bajaj, Daniel Na. Bolon, Oliver J. Rando, Paul D. Kaufman

UMass Metabolic Network Publications

The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo. We also demonstrate the utility of this ...


A Dual Role Of Caspase-8 In Triggering And Sensing Proliferation-Associated Dna Damage, A Key Determinant Of Liver Cancer Development, Yannick Boege, Roger J. Davis, Achim Weber Sep 2017

A Dual Role Of Caspase-8 In Triggering And Sensing Proliferation-Associated Dna Damage, A Key Determinant Of Liver Cancer Development, Yannick Boege, Roger J. Davis, Achim Weber

UMass Metabolic Network Publications

Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in ...


The N-Terminus Of Ift46 Mediates Intraflagellar Transport Of Outer Arm Dynein And Its Cargo-Adaptor Oda16, Yuqing Hou, George B. Witman Sep 2017

The N-Terminus Of Ift46 Mediates Intraflagellar Transport Of Outer Arm Dynein And Its Cargo-Adaptor Oda16, Yuqing Hou, George B. Witman

Radiology Publications and Presentations

Cilia are assembled via intraflagellar transport (IFT). The IFT machinery is composed of motors and multi-subunit particles, termed IFT-A and IFT-B, that carry cargo into the cilium. Knowledge of how the IFT subunits interact with their cargo is of critical importance for understanding how the unique ciliary domain is established. We previously reported a Chlamydomonas mutant, ift46-1, that fails to express the IFT-B protein IFT46, has greatly reduced levels of other IFT-B proteins, and assembles only very short flagella. A spontaneous suppression of ift46-1 restored IFT-B levels and enabled growth of longer flagella, but the flagella lacked outer dynein arms ...


The Mitochondrial Unfolded Protein Response: Signaling From The Powerhouse, Mohammed A. Qureshi, Cole M. Haynes, Mark W. Pellegrino Aug 2017

The Mitochondrial Unfolded Protein Response: Signaling From The Powerhouse, Mohammed A. Qureshi, Cole M. Haynes, Mark W. Pellegrino

UMass Metabolic Network Publications

Mitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPRmt). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPRmt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.


Critical Role For Arginase 2 In Obesity-Associated Pancreatic Cancer, Tamara Zaytouni, Pei-Yun Tsai, Daniel S. Hitchcock, Cory D. Dubois, Elizaveta Freinkman, Lin Lin, Vicente Morales-Oyarvide, Patrick J. Lenehan, Brian M. Wolpin, Mari Mino-Kenudson, Eduardo M. Torres, Nicholas Stylopoulos, Clary B. Clish, Nada Y. Kalaany Aug 2017

Critical Role For Arginase 2 In Obesity-Associated Pancreatic Cancer, Tamara Zaytouni, Pei-Yun Tsai, Daniel S. Hitchcock, Cory D. Dubois, Elizaveta Freinkman, Lin Lin, Vicente Morales-Oyarvide, Patrick J. Lenehan, Brian M. Wolpin, Mari Mino-Kenudson, Eduardo M. Torres, Nicholas Stylopoulos, Clary B. Clish, Nada Y. Kalaany

UMass Metabolic Network Publications

Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of (15)N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of ...


Nrg4 Promotes Fuel Oxidation And A Healthy Adipokine Profile To Ameliorate Diet-Induced Metabolic Disorders, Zhimin Chen, Guo-Xiao Wang, Sara L. Ma, Dae Young Jung, Hyekyung Ha, Tariq Altamimi, Xu-Yun Zhao, Liang Guo, Peng Zhang, Chun-Rui Hu, Ji-Xin Cheng, Gary D. Lopaschuk, Jason K. Kim, Jiandie D. Lin Aug 2017

Nrg4 Promotes Fuel Oxidation And A Healthy Adipokine Profile To Ameliorate Diet-Induced Metabolic Disorders, Zhimin Chen, Guo-Xiao Wang, Sara L. Ma, Dae Young Jung, Hyekyung Ha, Tariq Altamimi, Xu-Yun Zhao, Liang Guo, Peng Zhang, Chun-Rui Hu, Ji-Xin Cheng, Gary D. Lopaschuk, Jason K. Kim, Jiandie D. Lin

UMass Metabolic Network Publications

OBJECTIVE: Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and ...


Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno Aug 2017

Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno

UT GSBS Dissertations and Theses (Open Access)

Triple-negative (TNBC) and inflammatory (IBC) breast cancer are the most aggressive forms of breast cancer, accounting for 20% and 10% of cancer-related deaths, respectively. Among IBC cases, 30% are additionally classified with TNBC molecular pathology, a diagnosis that significantly worsens patient’s prognosis. The current lack of TNBC and IBC molecular understanding prevents the development of effective therapeutic strategies. To identify effective treatments, we explored aberrant apoptosis pathways and cell membrane fluidity as novel therapeutic targets.

We first identified an effective therapeutic strategy against TNBC and IBC by pro-apoptotic protein NOXA-mediated inhibition of the anti-apoptotic protein MCL1 following inhibition of ...


Cross-Sectional Relations Of Whole-Blood Mirna Expression Levels And Hand Grip Strength In A Community Sample, Joanne M. Murabito, Jian Rong, Kathryn L. Lunetta, Tianxiao Huan, Honghuang Lin, Qiang Zhao, Jane E. Freedman, Kahraman Tanriverdi, Daniel Levy, Martin G. Larson Aug 2017

Cross-Sectional Relations Of Whole-Blood Mirna Expression Levels And Hand Grip Strength In A Community Sample, Joanne M. Murabito, Jian Rong, Kathryn L. Lunetta, Tianxiao Huan, Honghuang Lin, Qiang Zhao, Jane E. Freedman, Kahraman Tanriverdi, Daniel Levy, Martin G. Larson

UMass Metabolic Network Publications

MicroRNAs (miRNAs) regulate gene expression with emerging data suggesting miRNAs play a role in skeletal muscle biology. We sought to examine the association of miRNAs with grip strength in a community-based sample. Framingham Heart Study Offspring and Generation 3 participants (n = 5668 54% women, mean age 55 years, range 24, 90 years) underwent grip strength measurement and miRNA profiling using whole blood from fasting morning samples. Linear mixed-effects regression modeling of grip strength (kg) versus continuous miRNA 'Cq' values and versus binary miRNA expression was performed. We conducted an integrative miRNA-mRNA coexpression analysis and examined the enrichment of biologic pathways ...


Removal Of Endocrine Disrupting Compounds Using Membrane Bioreactor, Mohanad Ali Abdulsahib Kamaz Aug 2017

Removal Of Endocrine Disrupting Compounds Using Membrane Bioreactor, Mohanad Ali Abdulsahib Kamaz

Theses and Dissertations

The presence of endocrine disrupting compounds (EDCs) and pharmaceutically active compounds (PhAC) such as pesticides, personal care products, antibiotics and pharmaceutical compounds, in sewage, industrial, and domestic waters has extensively become the major concern for health and environmental organizations. These compounds have the ability to interact with mammalian endocrine system and disrupting their functions. The traditional activated sludge processes are designed to degrade solids, organic carbon and nitrogen loading. Although several treatment steps in a wastewater treatment plant can contribute to partial removal of EDCs, effective removal has been a challenge due to their resistant chemical and biological degradation and ...