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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. 2018 University of Massachusetts Medical School

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 2018 University of Massachusetts Medical School

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 2018 University of Massachusetts Medical School

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 2018 York University

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 2018 University of Massachusetts Medical School

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 ...


Behavioral Insights Into Nociceptor Function: A Systematic Approach To Understanding Postsurgical And Neuropathic Pain Mechanisms In Rats, Max Odem 2018 The Univesity of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Behavioral Insights Into Nociceptor Function: A Systematic Approach To Understanding Postsurgical And Neuropathic Pain Mechanisms In Rats, Max Odem

UT GSBS Dissertations and Theses (Open Access)

Postsurgical and neuropathic pain are each clinically common, and often associated with ongoing pain. Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors. Preclinical studies using rodent neuropathic models have concentrated on allodynia driven by OA generated in non-nociceptive Aβ fibers, but little attention has been paid to postsurgical pain in sham controls or to C-fiber nociceptor OA promoting ongoing pain.

Operant assays that reveal negative motivational and cognitive aspects of voluntary pain-related behavior may be particularly sensitive to pain-related alterations. In the mechanical conflict (MC) test, rodents can freely choose to escape from a brightly ...


Methanogens, Plausible Extraterrestrial Life Forms On Mars, And Their Tolerance To Increasing Concentrations Of Illite Clay, Chandler Kern 2018 University of Arkansas, Fayetteville

Methanogens, Plausible Extraterrestrial Life Forms On Mars, And Their Tolerance To Increasing Concentrations Of Illite Clay, Chandler Kern

Biological Sciences Undergraduate Honors Theses

Methanogens, some of Earth’s most primitive prokaryotic organisms, are candidates for possible life forms capable of inhabiting Mars. Specifically, four different species (Methanobacterium formicicum, Methanococcus maripaludis, Methanosarcina barkeri, Methanothermobacter wolfeii) were analyzed for their tolerance to the presence of illite clay. Illite is a crystalline mineral that has been identified from regions of Mars’s surface. Results indicated that all four species grew with some success in the illite at different concentrations. This experimentation with methanogens’ abilities to survive and reproduce in the presence of illite allows for a more accurate understanding of the potential capability of microbial growth ...


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 2018 University of Massachusetts Medical School

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 2018 Harvard Medical School

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 2018 University of Massachusetts Medical School

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 ...


Activation Of The Apoptotic Pathway During Prolonged Prometaphase Blocks Daughter Cell Proliferation, Yumi Uetake, Greenfield Sluder 2018 University of Massachusetts Medical School

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 ...


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 2018 University of Massachusetts Medical School

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 ...


Modified Cantilever Arrays Improve Sensitivity And Reproducibility Of Nanomechanical Sensing In Living Cells, Samadhan B. Patil, Rajai M. Al-Jehani, Hashem Etayash, Valerian Turbe, Keren Jiang, Joe Bailey, Walid Al-Akkad, Rania Soudy, Kamaljit Kaur, Rachel A. McKendry, Thomas Thundat, Joseph W. Ndieyira 2018 University College London

Modified Cantilever Arrays Improve Sensitivity And Reproducibility Of Nanomechanical Sensing In Living Cells, Samadhan B. Patil, Rajai M. Al-Jehani, Hashem Etayash, Valerian Turbe, Keren Jiang, Joe Bailey, Walid Al-Akkad, Rania Soudy, Kamaljit Kaur, Rachel A. Mckendry, Thomas Thundat, Joseph W. Ndieyira

Pharmacy Faculty Articles and Research

Mechanical signaling involved in molecular interactions lies at the heart of materials science and biological systems, but the mechanisms involved are poorly understood. Here we use nanomechanical sensors and intact human cells to provide unique insights into the signaling pathways of connectivity networks, which deliver the ability to probe cells to produce biologically relevant, quantifiable and reproducible signals. We quantify the mechanical signals from malignant cancer cells, with 10 cells per ml in 1000-fold excess of non-neoplastic human epithelial cells. Moreover, we demonstrate that a direct link between cells and molecules creates a continuous connectivity which acts like a percolating ...


Effects Of Maternal Protein Restriction On The Pulmonary Surfactant System During The Early Life And Adulthood, Reza Khazaee 2018 The University of Western Ontario

Effects Of Maternal Protein Restriction On The Pulmonary Surfactant System During The Early Life And Adulthood, Reza Khazaee

Electronic Thesis and Dissertation Repository

Fetal growth restriction (FGR) is defined by low birth weight and contributes to a variety of adult-onset diseases with different severities between males and females. However, the effects of FGR on the pulmonary surfactant are not fully elucidated. In this thesis, first, we investigated the FGR effects on the lung function and the surfactant system at the early postnatal life. It was hypothesized that FGR contributes to alterations of lung mechanics and the surfactant system during the neonatal period. Second, we assessed the FGR effects on the surfactant system in response to sepsis in adulthood. It was hypothesized that FGR ...


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 2018 University of Massachusetts Medical School

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 ...


Calcium Signaling In The Sperm Head, Julie Simons, Lisa Fauci 2018 The California Maritime Academy

Calcium Signaling In The Sperm Head, Julie Simons, Lisa Fauci

Annual Symposium on Biomathematics and Ecology: Education and Research

No abstract provided.


Endothelial Glycocalyx Shedding In Pediatric Diabetic Ketoacidosis, Rufina Ning 2018 The University of Western Ontario

Endothelial Glycocalyx Shedding In Pediatric Diabetic Ketoacidosis, Rufina Ning

Electronic Thesis and Dissertation Repository

Diabetic ketoacidosis (DKA) is a state of severe insulin deficiency resulting in hyperglycemia, ketoacidosis, and inflammation. Children with DKA have an increased risk of microvascular complications (e.g. stroke). The glycocalyx maintains the anti-thrombotic properties of endothelial cells (ECs), however the glycocalyx status is unknown in DKA. We quantified major glycocalyx components: hyaluronic acid (HA), heparan sulfate (HS), chondroitin sulfate (CS), and syndecan-1 in DKA plasma and correlated them with DKA severity. HA/HS were significantly increased in the plasma of DKA patients in comparison to insulin-controlled type-1 diabetics, but only HA correlated to DKA severity. Exogenous addition or removal ...


Mechanisms Underlying Freeze Tolerance In The Spring Field Cricket, Gryllus Veletis, Jantina Toxopeus 2018 The University of Western Ontario

Mechanisms Underlying Freeze Tolerance In The Spring Field Cricket, Gryllus Veletis, Jantina Toxopeus

Electronic Thesis and Dissertation Repository

Freeze tolerance has evolved repeatedly across insects, facilitating survival in low temperature environments. Internal ice formation poses several challenges, but the mechanisms that mitigate these challenges in freeze-tolerant insects are not well understood. To better understand how insects survive freezing, I describe a novel laboratory model, the spring field cricket Gryllus veletis (Orthoptera: Gryllidae). Following acclimation to six weeks of decreasing temperature and photoperiod (mimicking autumn), G. veletis juveniles becomes moderately freeze-tolerant, surviving freezing at -8 °C for up to one week, and surviving temperatures as low as -12 °C. Acclimation is associated with increased control of the temperature and ...


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 2018 University of Massachusetts Medical School

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 2018 Albert Ludwigs University

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 ...


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