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Full-Text Articles in Life Sciences

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling And Increases Survival In Cancer Cachexia Syndrome, Felipe Henriques, Magno A. Lopes, Felipe O. Franco, Pamela Knobl, Kaltinaitis B. Santos, Luana L. Bueno, Victor A. Correa, Alexander H. Bedard, Adilson L. Guilherme, Alexander Birbrair, Sidney B. Peres, Stephen R. Farmer, Miguel L. Batista Jr. Dec 2018

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling And Increases Survival In Cancer Cachexia Syndrome, Felipe Henriques, Magno A. Lopes, Felipe O. Franco, Pamela Knobl, Kaltinaitis B. Santos, Luana L. Bueno, Victor A. Correa, Alexander H. Bedard, Adilson L. Guilherme, Alexander Birbrair, Sidney B. Peres, Stephen R. Farmer, Miguel L. Batista Jr.

Open Access Articles

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that both genetic ablation and pharmacological inhibition of TLR4 were able to attenuate the main clinical markers of cachexia in mice bearing Lewis lung carcinoma (LLC). AT remodelling was not found in LLC tumor-bearing (TB) TLR4(-/-) mice due to reduced macrophage infiltration and adipocyte atrophy. TLR4(-/-) mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 (Atorvastatin) reproduced the main protective effect against AT remodeling found in ...


Cpla2alpha-/- Sympathetic Neurons Exhibit Increased Membrane Excitability And Loss Of N-Type Ca2+ Current Inhibition By M1 Muscarinic Receptor Signaling, Liwang Liu, Joseph V. Bonventre, Ann R. Rittenhouse Dec 2018

Cpla2alpha-/- Sympathetic Neurons Exhibit Increased Membrane Excitability And Loss Of N-Type Ca2+ Current Inhibition By M1 Muscarinic Receptor Signaling, Liwang Liu, Joseph V. Bonventre, Ann R. Rittenhouse

Open Access Articles

Group IVa cytosolic phospholipase A2 (cPLA2alpha) mediates GPCR-stimulated arachidonic acid (AA) release from phosphatidylinositol 4,5-bisphosphate (PIP2) located in plasma membranes. We previously found in superior cervical ganglion (SCG) neurons that PLA2 activity is required for voltage-independent N-type Ca2+ (N-) current inhibition by M1 muscarinic receptors (M1Rs). These findings are at odds with an alternative model, previously observed for M-current inhibition, where PIP2 dissociation from channels and subsequent metabolism by phospholipase C suffices for current inhibition. To resolve cPLA2alpha's importance, we have investigated its role in mediating voltage-independent N-current inhibition (~40%) that follows application of the muscarinic agonist oxotremorine-M ...


Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti Dec 2018

Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti

Open Access Articles

Two efficient recombination systems were combined to produce a versatile method for chromosomal engineering that obviates the need to prepare double-stranded DNA (dsDNA) recombination substrates. A synthetic "targeting oligonucleotide" is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annealase. This oligonucleotide contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a "payload plasmid" that contains a cognate recombination site and a selectable marker. The targeting oligonucleotide and payload plasmid are cotransformed into a RecT- and Int-expressing strain, and drug-resistant homologous recombinants are selected in a single step ...


The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski Dec 2018

The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski

Open Access Articles

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegans BRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of ...


Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer Dec 2018

Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer

Open Access Articles

In their natural settings, CRISPR-Cas systems play crucial roles in bacterial and archaeal adaptive immunity to protect against phages and other mobile genetic elements, and they are also widely used as genome engineering technologies. Previously we discovered bacteriophage-encoded Cas9-specific anti-CRISPR (Acr) proteins that serve as countermeasures against host bacterial immunity by inactivating their CRISPR-Cas systems (A. Pawluk, N. Amrani, Y. Zhang, B. Garcia, et al., Cell 167:1829-1838.e9, 2016, https://doi.org/10.1016/j.cell.2016.11.017). We hypothesized that the evolutionary advantages conferred by anti-CRISPRs would drive the widespread occurrence of these proteins in nature (K ...


Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker Nov 2018

Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker

Open Access Articles

S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress-responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat ...


Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong Nov 2018

Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong

Open Access Articles

Glycosylation is a fundamental modification of proteins and membrane lipids. Toxins that utilize glycans as their receptors have served as powerful tools to identify key players in glycosylation processes. Here, we carried out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-mediated genome-wide loss-of-function screens using two related bacterial toxins, Shiga-like toxins (Stxs) 1 and 2, which use a specific glycolipid, globotriaosylceramide (Gb3), as receptors, and the plant toxin ricin, which recognizes a broad range of glycans. The Stxs screens identified major glycosyltransferases (GTs) and transporters involved in Gb3 biosynthesis, while the ricin screen identified GTs and transporters involved in N-linked ...


The Nf-Kappab Factor Relish Regulates Atg1 Expression And Controls Autophagy, Anubhab Nandy, Lin Lin, Panagiotis D. Velentzas, Louisa P. Wu, Eric H. Baehrecke, Neal S. Silverman Nov 2018

The Nf-Kappab Factor Relish Regulates Atg1 Expression And Controls Autophagy, Anubhab Nandy, Lin Lin, Panagiotis D. Velentzas, Louisa P. Wu, Eric H. Baehrecke, Neal S. Silverman

Open Access Articles

Macroautophagy and cell death both contribute to innate immunity, but little is known about how these processes integrate. Drosophila larval salivary glands require autophagy for developmentally programmed cell death, and innate immune signaling factors increase in these dying cells. Here, we show that the nuclear factor kappaB (NF-kappaB) factor Relish, a component of the immune deficiency (Imd) pathway, is required for salivary gland degradation. Surprisingly, of the classic Imd pathway components, only Relish and the PGRP receptors were involved in salivary gland degradation. Significantly, Relish controls salivary gland degradation by regulating autophagy but not caspases. In addition, expression of either ...


Crispr-Delivery Particles Targeting Nuclear Receptor-Interacting Protein 1 (Nrip1) In Adipose Cells To Enhance Energy Expenditure, Yuefei Shen, Jessica L. Cohen, Sarah M. Nicoloro, Mark Kelly, Batuhan Yenilmez, Felipe Henriques, Emmanouela Tsagkaraki, Yvonne J. K. Edwards, Xiaodi Hu, Randall H. Friedline, Jason K. Kim, Michael P. Czech Nov 2018

Crispr-Delivery Particles Targeting Nuclear Receptor-Interacting Protein 1 (Nrip1) In Adipose Cells To Enhance Energy Expenditure, Yuefei Shen, Jessica L. Cohen, Sarah M. Nicoloro, Mark Kelly, Batuhan Yenilmez, Felipe Henriques, Emmanouela Tsagkaraki, Yvonne J. K. Edwards, Xiaodi Hu, Randall H. Friedline, Jason K. Kim, Michael P. Czech

Open Access Articles

RNA-guided, engineered nucleases derived from the prokaryotic adaptive immune system CRISPR-Cas represent a powerful platform for gene deletion and editing. When used as a therapeutic approach, direct delivery of Cas9 protein and single-guide RNA (sgRNA) could circumvent the safety issues associated with plasmid delivery and therefore represents an attractive tool for precision genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fatty acid oxidation, and secretion of bioactive factors through a "browning" process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed "CRISPR-delivery particles," denoted CriPs, composed of nano-size complexes of Cas9 ...


Activation Of The Apoptotic Pathway During Prolonged Prometaphase Blocks Daughter Cell Proliferation, Yumi Uetake, Greenfield Sluder Nov 2018

Activation Of The Apoptotic Pathway During Prolonged Prometaphase Blocks Daughter Cell Proliferation, Yumi Uetake, Greenfield Sluder

Radiology Publications and Presentations

When untransformed human cells spend >1.5 hr. in prometaphase under standard culture conditions, all daughters arrest in G1 despite normal division of their mothers. We investigate what happens during prolonged prometaphase that leads to daughter cell arrest in the absence of DNA damage. We find that progressive loss of anti-apoptotic MCL-1 activity and oxidative stress act in concert to partially activate the apoptosis pathway resulting in the delayed death of some daughters and senescence for the rest. At physiological oxygen levels, longer prometaphase durations are needed for all daughters to arrest. Partial activation of apoptosis during prolonged prometaphase leads ...


Inhibition Of Triggering Receptor Expressed On Myeloid Cells 1 Ameliorates Inflammation And Macrophage And Neutrophil Activation In Alcoholic Liver Disease In Mice, David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo Oct 2018

Inhibition Of Triggering Receptor Expressed On Myeloid Cells 1 Ameliorates Inflammation And Macrophage And Neutrophil Activation In Alcoholic Liver Disease In Mice, David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo

Open Access Articles

Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage- and pathogen-associated molecular patterns contribute to a self-perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a surface receptor that amplifies inflammation induced by toll-like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM-1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand-independent TREM-1 inhibitory peptides that were formulated into human high-density lipoprotein (HDL)-mimicking complexes GF9-HDL and GA ...


Reduced Gut Microbiome Protects From Alcohol-Induced Neuroinflammation And Alters Intestinal And Brain Inflammasome Expression, Patrick P. Lowe, Benedek Gyongyosi, Abhishek Satishchandran, Arvin Iracheta-Vellve, Yeonhee Cho, Aditya Ambade, Gyongyi Szabo Oct 2018

Reduced Gut Microbiome Protects From Alcohol-Induced Neuroinflammation And Alters Intestinal And Brain Inflammasome Expression, Patrick P. Lowe, Benedek Gyongyosi, Abhishek Satishchandran, Arvin Iracheta-Vellve, Yeonhee Cho, Aditya Ambade, Gyongyi Szabo

Open Access Articles

BACKGROUND: The end-organ effects of alcohol span throughout the entire body, from the gastrointestinal tract to the central nervous system (CNS). In the intestine, alcohol use changes the microbiome composition and increases gut permeability allowing translocation of microbial components into the circulation. Gut-derived pathogen-associated signals initiate inflammatory responses in the liver and possibly elsewhere in the body. Because previous studies showed that the gut microbiome contributes to alcohol-induced liver disease, we hypothesized that antibiotic administration to reduce the gut microbiome would attenuate alcohol-induced inflammation in the brain and small intestine (SI).

METHODS: Six- to 8-week-old C57BL/6J female mice were ...


Red Wine And Green Tea Flavonoids Are Cis-Allosteric Activators And Competitive Inhibitors Of Glut1-Mediated Sugar Uptake, Ogooluwa A. Ojelabi, Kenneth P. Lloyd, Julie K. De Zutter, Anthony Carruthers Oct 2018

Red Wine And Green Tea Flavonoids Are Cis-Allosteric Activators And Competitive Inhibitors Of Glut1-Mediated Sugar Uptake, Ogooluwa A. Ojelabi, Kenneth P. Lloyd, Julie K. De Zutter, Anthony Carruthers

Open Access Articles

The anti-oxidant, flavonoid-rich content of red wine and green tea is reported to offer protection against cancer, cardiovascular disease and diabetes. Some studies, however, show that flavonoids inhibit GLUT1-mediated, facilitative glucose transport raising the possibility that their interaction with GLUT1 and subsequent, downstream effects on carbohydrate metabolism may also impact health. The present study explores the structure/function relationships of flavonoid-GLUT1 interactions. We find that low concentrations of flavonoids act as cis-allosteric activators of sugar uptake while higher concentrations competitively inhibit sugar uptake and noncompetitively inhibit sugar exit. Studies with heterologously expressed human GLUTs 1, 3 and 4 reveal that ...


Fxr And Tgr5 Agonists Ameliorate Liver Injury, Steatosis, And Inflammation After Binge Or Prolonged Alcohol Feeding In Mice, Arvin Iracheta-Vellve, Charles D. Calenda, Jan Petrasek, Aditya Ambade, Karen Kodys, Luciano Adorini, Gyongyi Szabo Oct 2018

Fxr And Tgr5 Agonists Ameliorate Liver Injury, Steatosis, And Inflammation After Binge Or Prolonged Alcohol Feeding In Mice, Arvin Iracheta-Vellve, Charles D. Calenda, Jan Petrasek, Aditya Ambade, Karen Kodys, Luciano Adorini, Gyongyi Szabo

Open Access Articles

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT-777, and INT-767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in ...


Intestinal P-Glycoprotein Exports Endocannabinoids To Prevent Inflammation And Maintain Homeostasis, Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. Mccormick Aug 2018

Intestinal P-Glycoprotein Exports Endocannabinoids To Prevent Inflammation And Maintain Homeostasis, Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. Mccormick

Open Access Articles

Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted ...


Identification Of A Novel Anoikis Signalling Pathway Using The Fungal Virulence Factor Gliotoxin, Florian Haun, Simon Neumann, Lukas Peintner, Katrin Wieland, Juri Habicht, Carsten Schwan, Kristine Ostevold, Maria Magdalena Koczorowska, Martin Biniossek, Matthias Kist, Hauke Busch, Melanie Boerries, Roger J. Davis, Ulrich Maurer, Oliver Schilling, Klaus Aktories, Christoph Borner Aug 2018

Identification Of A Novel Anoikis Signalling Pathway Using The Fungal Virulence Factor Gliotoxin, Florian Haun, Simon Neumann, Lukas Peintner, Katrin Wieland, Juri Habicht, Carsten Schwan, Kristine Ostevold, Maria Magdalena Koczorowska, Martin Biniossek, Matthias Kist, Hauke Busch, Melanie Boerries, Roger J. Davis, Ulrich Maurer, Oliver Schilling, Klaus Aktories, Christoph Borner

Open Access Articles

Anoikis is a form of apoptosis induced by cell detachment. Integrin inactivation plays a major role in the process but the exact signalling pathway is ill-defined. Here we identify an anoikis pathway using gliotoxin (GT), a virulence factor of the fungus Aspergillus fumigatus, which causes invasive aspergillosis in humans. GT prevents integrin binding to RGD-containing extracellular matrix components by covalently modifying cysteines in the binding pocket. As a consequence, focal adhesion kinase (FAK) is inhibited resulting in dephosphorylation of p190RhoGAP, allowing activation of RhoA. Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim. Cells in ...


A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder Aug 2018

A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder

Open Access Articles

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell ...


Are Membranes Non-Apoptotic Compartments For Apoptotic Caspases, Andreas Bergmann Aug 2018

Are Membranes Non-Apoptotic Compartments For Apoptotic Caspases, Andreas Bergmann

Open Access Articles

Critical mediators of apoptotic cell death are caspases, a highly specialized class of Cys-proteases that cleave substrates after Asp residues. Under normal conditions, caspases are cytosolic proteins. After their activation, they cleave a large number of cytosolic proteins and execute apoptosis (Figure 1, left). However, in addition to their well-studied role in apoptosis, caspases also have many non-apoptotic functions [1, 2]. It is not very well understood how cells escape the potential harmful action of caspases when they perform nonapoptotic functions. In our recent work, we now show that epithelial cells may prevent apoptosis by sequestration of caspases at the ...


Jnk Regulates Muscle Remodeling Via Myostatin/Smad Inhibition, Sarah J. Lessard, Tara L. Macdonald, Prerana Pathak, Myoung Souk Han, Vernon G. Coffey, Johann Edge, Donato A. Rivas, Michael F. Hirshman, Roger J. Davis, Laurie J. Goodyear Aug 2018

Jnk Regulates Muscle Remodeling Via Myostatin/Smad Inhibition, Sarah J. Lessard, Tara L. Macdonald, Prerana Pathak, Myoung Souk Han, Vernon G. Coffey, Johann Edge, Donato A. Rivas, Michael F. Hirshman, Roger J. Davis, Laurie J. Goodyear

Open Access Articles

Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass. Conversely, when muscle JNK activation is suppressed, an alternative remodeling program is initiated, resulting in smaller, more oxidative muscle fibers, and enhanced aerobic fitness. When muscle is exposed to mechanical stress, JNK initiates muscle growth via phosphorylation of the transcription factor ...


A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Aug 2018

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

University of Massachusetts Medical School Faculty Publications

Persistence detection is a mechanism that ensures a physiological output is only executed when the relevant input is sustained. Gene regulatory network circuits known as coherent type 1 feed forward loops (FFLs) with an AND-logic gate have been proposed to generate persistence detection. In such circuits two transcription factors (TFs) are both required to activate target genes and one of the two TFs activates the other. While numerous FFLs have been identified, examples of actual persistence detectors have only been described for bacteria. Here, we discover a transcriptional persistence detector in Caenorhabditis elegans involving the nuclear hormone receptors nhr-10 and ...


Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr. Jul 2018

Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr.

Open Access Articles

Cancer cachexia (CC) is a multifactorial syndrome with an unknown etiology. The primary symptom is the progressive reduction of the body weight. Recently, down-regulation of adipogenic and lipogenic genes were demonstrated to be early affected during cachexia progression in adipose tissue (AT), resulting in AT remodeling. Thus, this study aimed to evaluate in a co-culture system the influence of the Lewis Lung Carcinoma (LLC) tumor cells (c/c-LLC) in an established pre-adipocyte cell line 3T3-L1 adipogenic capacity. c/c-LLC in the presence of 3T3-L1 caused a reduction in lipids accumulation, suggesting that secretory tumor cells products may affect adipogenesis. Interestingly ...


Quantitative Profiling Of The Lymph Node Clearance Capacity, Cristina C. Clement, Wei Wang, Monika Dzieciatkowska, Marco Cortese, Kirk C. Hansen, Aniuska Becerra, Sangeetha Thangaswamy, Irina Nizamutdinova, Jee-Young Moon, Lawrence J. Stern, Anatoliy A. Gashev, David Zawieja, Laura Santambrogio Jul 2018

Quantitative Profiling Of The Lymph Node Clearance Capacity, Cristina C. Clement, Wei Wang, Monika Dzieciatkowska, Marco Cortese, Kirk C. Hansen, Aniuska Becerra, Sangeetha Thangaswamy, Irina Nizamutdinova, Jee-Young Moon, Lawrence J. Stern, Anatoliy A. Gashev, David Zawieja, Laura Santambrogio

Open Access Articles

Transport of tissue-derived lymphatic fluid and clearance by draining lymph nodes are pivotal for maintenance of fluid homeostasis in the body and for immune-surveillance of the self- and non-self-proteomes. Yet a quantitative analysis of nodal filtration of the tissue-derived proteome present in lymphatic fluid has not been reported. Here we quantified the efficiency of nodal clearance of the composite proteomic load using label-free and isotope-labeling proteomic analysis of pre-nodal and post-nodal samples collected by direct cannulation. These results were extended by quantitation of the filtration efficiency of fluorophore-labeled proteins, bacteria, and beads infused at physiological flow rates into pre-nodal lymphatic ...


Inhibition Of Protein Arginine Methyltransferase 5 Enhances Hepatic Mitochondrial Biogenesis, Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M. Najjar, Mary M. Lee, Joae Qiong Wu Jul 2018

Inhibition Of Protein Arginine Methyltransferase 5 Enhances Hepatic Mitochondrial Biogenesis, Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M. Najjar, Mary M. Lee, Joae Qiong Wu

Open Access Articles

Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved ...


Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis Jun 2018

Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis

Davis Lab Publications

Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more ...


Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Donald A. Morgan, Kamal Rahmouni, Michael P. Czech Jun 2018

Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Donald A. Morgan, Kamal Rahmouni, Michael P. Czech

Open Access Articles

OBJECTIVE: Crosstalk between adipocytes and local neurons may be an important regulatory mechanism to control energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) expands sympathetic neurons within white adipose tissue (WAT) and stimulates the appearance of "beige" adipocytes. Here we tested whether WAT DNL activity can also influence neuronal regulation and thermogenesis in brown adipose tissue (BAT).

METHODS AND RESULTS: Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. This ...


The Cjun Nh2-Terminal Kinase (Jnk) Signaling Pathway Promotes Genome Stability And Prevents Tumor Initiation, Nomeda A. Girnius, Yvonne J. K. Edwards, David S. Garlick, Roger J. Davis Jun 2018

The Cjun Nh2-Terminal Kinase (Jnk) Signaling Pathway Promotes Genome Stability And Prevents Tumor Initiation, Nomeda A. Girnius, Yvonne J. K. Edwards, David S. Garlick, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor ...


Rna Polymerase Ii Transcription Attenuation At The Yeast Dna Repair Gene, Def1, Involves Sen1-Dependent And Polyadenylation Site-Dependent Termination, Courtney Whalen, Christine Tuohy, Thomas Tallo, James W. Kaufman, Claire Moore, Jason N. Kuehner May 2018

Rna Polymerase Ii Transcription Attenuation At The Yeast Dna Repair Gene, Def1, Involves Sen1-Dependent And Polyadenylation Site-Dependent Termination, Courtney Whalen, Christine Tuohy, Thomas Tallo, James W. Kaufman, Claire Moore, Jason N. Kuehner

Open Access Articles

Termination of RNA Polymerase II (Pol II) activity serves a vital cellular role by separating ubiquitous transcription units and influencing RNA fate and function. In the yeast Saccharomyces cerevisiae, Pol II termination is carried out by cleavage and polyadenylation factor (CPF-CF) and Nrd1-Nab3-Sen1 (NNS) complexes, which operate primarily at mRNA and non-coding RNA genes, respectively. Premature Pol II termination (attenuation) contributes to gene regulation, but there is limited knowledge of its prevalence and biological significance. In particular, it is unclear how much crosstalk occurs between CPF-CF and NNS complexes and how Pol II attenuation is modulated during stress adaptation. In ...


Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo May 2018

Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo

University of Massachusetts Medical School Faculty Publications

Aerobic glycolysis accounts for approximately 80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic ...


Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo May 2018

Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo

Open Access Articles

Aerobic glycolysis accounts for approximately 80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic ...


Syndromic Congenital Myelofibrosis Associated With A Loss-Of-Function Variant In Rbsn, Pilar L. Magoulas, Silvia Corvera, Luis M. Franco May 2018

Syndromic Congenital Myelofibrosis Associated With A Loss-Of-Function Variant In Rbsn, Pilar L. Magoulas, Silvia Corvera, Luis M. Franco

University of Massachusetts Medical School Faculty Publications

The human proteins rabenosyn-5 and VPS45 form a complex that plays a key role in early endocytosis. Pathogenic variants in VPS45 cause severe congenital neutropenia (SCN) with impaired neutrophil function, reticulin fibrosis of the bone marrow, and extramedullary hematopoiesis (OMIM: 615285). Patients with a specific VPS45 variant (p.Glu238Lys) also have intellectual disability and bilateral optic nerve hypoplasia. To date, the only evidence of a potential role for RBSN in human disease is the report of a homozygous missense variant (p.Gly425Arg) in a patient with intellectual disability, seizures, microcephaly, osteopenia, mild reticulin fibrosis of the bone marrow, and transient ...