Medicine and Health Sciences Commons^™

High Affinity Binding Of H3k14ac Through Collaboration Of Bromodomains 2, 4 And 5 Is Critical For The Molecular And Tumor Suppressor Functions Of Pbrm1., Lili Liao, Nilda L. Alicea-Velázquez, Lauren Langbein, Xiaohua Niu, Weijia Cai, Eun-Ah Cho, Meiling Zhang, Celeste B. Greer, Qin Yan, Michael S. Cosgrove, Haifeng Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Polybromo-1 (PBRM1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains (BDs), which are specialized structures that recognize acetyl-lysine residues. While BD2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BDs collaborate with BD2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM1 is also unknown. We discovered that full-length PBRM1, but not its individual BDs, strongly binds H3K14ac. BDs 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative …

In Vitro Growth Of Human Ovarian Follicles For Fertility Preservation, Diego Marin, Min Yang, Tianren Wang

Department of Biochemistry and Molecular Biology Faculty Papers

Young female cancer survival rates significantly increased due to the great progress of cancer therapy. In fact, cryostorage and transplantation of ovarian tissue have already resulted in the birth of healthy babies. Follicle in vitro growth (IVG) has the great potential of restoring fertility by achieving functional oocytes from the most immature stages to maturation. This is suitable for a wide range of patients, from pubertal to perimenopause women. Notable achievements have been achieved in human follicle IVG in the past decade. Mature oocytes have been successfully collected from long-term sequential follicle IVG. However, it is still a major challenge …

Trypanosoma Brucei Prmt1 Is A Nucleic Acid Binding Protein With A Role In Energy Metabolism And The Starvation Stress Response., Lucie Kafková, Chengjian Tu, Kyle L. Pazzo, Kyle P. Smith, Erik W. Debler, Kimberly S. Paul, Jun Qu, Laurie K. Read

Department of Biochemistry and Molecular Biology Faculty Papers

In Trypanosoma brucei and related kinetoplastid parasites, transcription of protein coding genes is largely unregulated. Rather, mRNA binding proteins, which impact processes such as transcript stability and translation efficiency, are the predominant regulators of gene expression. Arginine methylation is a posttranslational modification that preferentially targets RNA binding proteins and is, therefore, likely to have a substantial impact on T. brucei biology. The data presented here demonstrate that cells depleted of T. brucei PRMT1 (TbPRMT1), a major type I protein arginine methyltransferase, exhibit decreased virulence in an animal model. To understand the basis of this phenotype, quantitative global proteomics was employed …

Highly Efficient 5' Capping Of Mitochondrial Rna With Nad+ And Nadh By Yeast And Human Mitochondrial Rna Polymerase, Jeremy G Bird, Urmimala Basu, David Kuster, Aparna Ramachandran, Ewa Grudzien-Nogalska, Atif Towheed, Douglas C. Wallace, Megerditch Kiledjian, Dmitry Temiakov, Smita S. Patel, Richard H. Ebright, Bryce E. Nickels

Department of Biochemistry and Molecular Biology Faculty Papers

Bacterial and eukaryotic nuclear RNA polymerases (RNAPs) cap RNA with the oxidized and reduced forms of the metabolic effector nicotinamide adenine dinucleotide, NAD+ and NADH, using NAD+ and NADH as non-canonical initiating nucleotides for transcription initiation. Here, we show that mitochondrial RNAPs (mtRNAPs) cap RNA with NAD+ and NADH, and do so more efficiently than nuclear RNAPs. Direct quantitation of NAD+- and NADH-capped RNA demonstrates remarkably high levels of capping in vivo: up to ~60% NAD+ and NADH capping of yeast mitochondrial transcripts, and up to ~15% NAD+ capping of human mitochondrial transcripts. The capping efficiency is determined by promoter …

Levels Of Par-1 Kinase Determine The Localization Of Bruchpilot At The Drosophila Neuromuscular Junction Synapses., Kara R. Barber, Martin Hruska, Keegan M. Bush, Jade A. Martinez, Hong Fei, Irwin B. Levitan, Matthew B. Dalva, Yogesh P. Wairkar

Farber Institute for Neuroscience Faculty Papers

Functional synaptic networks are compromised in many neurodevelopmental and neurodegenerative diseases. While the mechanisms of axonal transport and localization of synaptic vesicles and mitochondria are relatively well studied, little is known about the mechanisms that regulate the localization of proteins that localize to active zones. Recent finding suggests that mechanisms involved in transporting proteins destined to active zones are distinct from those that transport synaptic vesicles or mitochondria. Here we report that localization of BRP-an essential active zone scaffolding protein in Drosophila, depends on the precise balance of neuronal Par-1 kinase. Disruption of Par-1 levels leads to excess accumulation of …

Development Of Onchocerca Volvulus In Humanized Nsg Mice And Detection Of Parasite Biomarkers In Urine And Serum., John B. Patton, Sasisekhar Bennuru, Mark L. Eberhard, Jessica A. Hess Ligas, April R. Torigian, Sara Lustigman, Thomas B. Nutman, David Abraham

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: The study of Onchocerca volvulus has been limited by its host range, with only humans and non-human primates shown to be susceptible to the full life cycle infection. Small animal models that support the development of adult parasites have not been identified.

METHODOLOGY/PRINCIPAL FINDINGS: We hypothesized that highly immunodeficient NSG mice would support the survival and maturation of O. volvulus and alteration of the host microenvironment through the addition of various human cells and tissues would further enhance the level of parasite maturation. NSG mice were humanized with: (1) umbilical cord derived CD34+ stem cells, (2) fetal derived liver, …

A Virus-Encoded Type I Interferon Decoy Receptor Enables Evasion Of Host Immunity Through Cell-Surface Binding., Bruno Hernáez, Juan Manuel Alonso-Lobo, Imma Montanuy, Cornelius Fischer, Sascha Sauer, Luis J. Sigal, Noemí Sevilla, Antonio Alcamí

Department of Microbiology and Immunology Faculty Papers

Soluble cytokine decoy receptors are potent immune modulatory reagents with therapeutic applications. Some virus-encoded secreted cytokine receptors interact with glycosaminoglycans expressed at the cell surface, but the biological significance of this activity in vivo is poorly understood. Here, we show the type I interferon binding protein (IFNα/βBP) encoded by vaccinia and ectromelia viruses requires of this cell binding activity to confer full virulence to these viruses and to retain immunomodulatory activity. Expression of a variant form of the IFNα/βBP that inhibits IFN activity, but does not interact with cell surface glycosaminoglycans, results in highly attenuated viruses with a virulence similar …

Parp-1 Regulates Dna Repair Factor Availability., M J Schiewer, Amy C. Mandigo, Nicolas Gordon, Fangjin Huang, Sanchaika Gaur, Renée De Leeuw, Shuang G Zhao, Joseph Evans, Sumin Han, Theodore Parsons, Ruth Birbe, Peter Mccue, Christopher Mcnair, Saswati N. Chand, Ylenia Cendon-Florez, Peter Gallagher, Jennifer J Mccann, Neermala Poudel Neupane, Ayesha A Shafi, Emanuela Dylgjeri, Lucas J Brand, Tapio Visakorpi, Ganesh V Raj, Costas D. Lallas, Edouard J Trabulsi, Leonard G Gomella, Adam Dicker Md, Phd, William Kevin Kelly, Benjamin E Leiby, Beatrice Knudsen, Felix Y Feng, Karen E Knudsen

Department of Cancer Biology Faculty Papers

PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted …

The Single Mitochondrion Of The Kinetoplastid Parasite Crithidia Fasciculata Is A Dynamic Network., John Dimaio, Gordon Ruthel, Joshua J. Cannon, Madeline F. Malfara, Megan L. Povelones

Department of Medical Laboratory Sciences & Biotechnology Faculty Papers

Mitochondria are central organelles in cellular metabolism. Their structure is highly dynamic, allowing them to adapt to different energy requirements, to be partitioned during cell division, and to maintain functionality. Mitochondrial dynamics, including membrane fusion and fission reactions, are well studied in yeast and mammals but it is not known if these processes are conserved throughout eukaryotic evolution. Kinetoplastid parasites are some of the earliest-diverging eukaryotes to retain a mitochondrion. Each cell has only a single mitochondrial organelle, making them an interesting model for the role of dynamics in controlling mitochondrial architecture. We have investigated the mitochondrial division cycle in …

Trna 3'-Amino-Tailing For Stable Amino Acid Attachment., Howard Gamper, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Amino acids are attached to the tRNA 3'-end as a prerequisite for entering the ribosome for protein synthesis. Amino acid attachment also gives tRNA access to nonribosomal cellular activities. However, the normal attachment is via an ester linkage between the carboxylic group of the amino acid and the 3'-hydroxyl of the terminal A76 ribose in tRNA. The instability of this ester linkage has severely hampered studies of aminoacyl-tRNAs. Although the use of 3'-amino-3'-deoxy A76 in a 3'-amino-tailed tRNA provides stable aminoacyl attachment via an amide linkage, there are multiple tailing protocols and the efficiency of each relative to the others …

Non-Neutralizing Antibodies Elicited By Recombinant Lassa-Rabies Vaccine Are Critical For Protection Against Lassa Fever., Tiago Abreu-Mota, Katie R. Hagen, Kurt Cooper, Peter B. Jahrling, Gene Tan, Christoph Wirblich, Reed F. Johnson, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

Lassa fever (LF), caused by Lassa virus (LASV), is a viral hemorrhagic fever for which no approved vaccine or potent antiviral treatment is available. LF is a WHO priority disease and, together with rabies, a major health burden in West Africa. Here we present the development and characterization of an inactivated recombinant LASV and rabies vaccine candidate (LASSARAB) that expresses a codon-optimized LASV glycoprotein (coGPC) and is adjuvanted by a TLR-4 agonist (GLA-SE). LASSARAB elicits lasting humoral response against LASV and RABV in both mouse and guinea pig models, and it protects both guinea pigs and mice against LF. We …

Sumo-Mediated Regulation Of Nlrp3 Modulates Inflammasome Activity., Rachael Barry, Sidonie Wicky John, Gianmaria Liccardi, Tencho Tenev, Isabel Jaco, Chih-Hong Chen, Justin Choi, Paulina Kasperkiewicz, Teresa Fernandes-Alnemri, Emad S Alnemri, Marcin Drag, Yuan Chen, Pascal Meier

Department of Biochemistry and Molecular Biology Faculty Papers

The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, …

Dna Methylation-Based Age Prediction And Telomere Length In White Blood Cells And Cumulus Cells Of Infertile Women With Normal Or Poor Response To Ovarian Stimulation., Scott J. Morin, Xin Tao, Diego Marin, Yiping Zhan, Jessica Landis, Jenna Bedard, Richard T. Scott, Emre Seli

Department of Biochemistry and Molecular Biology Faculty Papers

An algorithm assessing the methylation levels of 353 informative CpG sites in the human genome permits accurate prediction of the chronologic age of a subject. Interestingly, when there is discrepancy between the predicted age and chronologic age (age acceleration or "AgeAccel"), patients are at risk for morbidity and mortality. Identification of infertile patients at risk for accelerated reproductive senescence may permit preventative action. This study aimed to assess the accuracy of the "epigenetic clock" concept in reproductive age women undergoing fertility treatment by applying the age prediction algorithm in peripheral (white blood cells [WBCs]) and follicular somatic cells (cumulus cells …

Micu1 Interacts With The D-Ring Of The Mcu Pore To Control Its Ca2+ Flux And Sensitivity To Ru360, Melanie Paillard, György Csordás, Kai-Ting Huang, Peter Várnai, Suresh K. Joseph, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Proper control of the mitochondrial Ca²⁺ uniporter’s pore (MCU) is required to allow Ca²⁺ dependent activation of oxidative metabolism and to avoid mitochondrial Ca²⁺ overload and cell death. The MCU’s gatekeeping and cooperative activation is mediated by the Ca²⁺ sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU’s DIME motif, the selectivity filter. This led us to recognize in MICU1’s sequence, a putative DIME Interacting Domain (DID) which is required for …

Distinct Role Of Il-27 In Immature And Lps-Induced Mature Dendritic Cell-Mediated Development Of Cd4, Fang Zhou, Guang-Xian Zhang, A. M. Rostami

Department of Neurology Faculty Papers

Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4⁺ T cell-mediated immune responses have not yet been elucidated. Here we show that IL-27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS-stimulated DCs. IL-27 treatment facilitates development of the CD4⁺ CD127⁺3G11⁺ regulatory T cell subset …

Redox Regulation Of Type-I Inositol Trisphosphate Receptors In Intact Mammalian Cells., Suresh K. Joseph, Michael P. Young, Kamil Alzayady, David I. Yule, Mehboob Ali, David M. Booth, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

A sensitization of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release is associated with oxidative stress in multiple cell types. These effects are thought to be mediated by alterations in the redox state of critical thiols in the IP3R, but this has not been directly demonstrated in intact cells. Here, we utilized a combination of gel-shift assays with MPEG-maleimides and LC-MS/MS to monitor the redox state of recombinant IP3R1 expressed in HEK293 cells. We found that under basal conditions, ∼5 of the 60 cysteines are oxidized in IP3R1. Cell treatment with 50 μm thimerosal altered gel shifts, indicating oxidation of ∼20 cysteines. …

Potential Role Of Csf Cytokine Profiles In Discriminating Infectious From Non-Infectious Cns Disorders., Danielle Fortuna, D. Craig Hooper, Amity L. Roberts, Larry A. Harshyne, Michelle Nagurney, Mark T. Curtis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states. Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may be helpful. We undertook this preliminary proof-of-concept study using multiplex ELISA to measure CSF cytokine levels in various CNS disorders (infections, autoimmune/demyelinating diseases, lymphomas, and gliomas) to determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases. Both …

Metabolic Reprogramming Of Murine Cardiomyocytes During Autophagy Requires The Extracellular Nutrient Sensor Decorin., Maria A. Gubbiotti, Erin L. Seifert, Ulrich Rodeck, Jan B. Hoek, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The extracellular matrix is a master regulator of tissue homeostasis in health and disease. Here we examined how the small, leucine-rich, extracellular matrix proteoglycan decorin regulates cardiomyocyte metabolism during fasting in vivo. First, we validated in Dcn^-/- mice that decorin plays an essential role in autophagy induced by fasting. High-Throughput metabolomics analyses of cardiac tissue in Dcn^-/- mice subjected to fasting revealed striking differences in the hexosamine biosynthetic pathway resulting in aberrant cardiac O-β-N-Acetylglycosylation as compared with WT mice. Functionally, Dcn^-/- mice maintained cardiac function at a level comparable with nonfasted animals whereas fasted WT mice showed …

Role Of The Fractalkine Receptor In Cns Autoimmune Inflammation: New Approach Utilizing A Mouse Model Expressing The Human Cx3cr1, Sandra M. Cardona, Sangwon V. Kim, Kaira A. Church, Vanessa O. Torres, Ian A. Cleary, Andrew S. Mendiola, Stephen P. Saville, Stephanie S. Watowich, Jan Parker-Thornburg, Alejandro Soto-Ospina, Pedronel Araque, Richard M. Ransohoff, Astrid E. Cardona

Department of Microbiology and Immunology Faculty Papers

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) is the leading cause of non-traumatic neurological disability in young adults. Immune mediated destruction of myelin and oligodendrocytes is considered the primary pathology of MS, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function during CNS inflammation, our laboratory focuses on the fractalkine/CX3CR1 signaling as a regulator of microglia neurotoxicity in various models of neurodegeneration. Fractalkine (FKN) is a transmembrane chemokine expressed in the CNS by neurons and signals through its unique receptor CX3CR1 present in microglia. During …

Causality Analysis And Cell Network Modeling Of Spatial Calcium Signaling Patterns In Liver Lobules., Aalap Verma, Anil Noronha Antony, Babatunde A. Ogunnaike, Jan B. Hoek, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Dynamics as well as localization of Ca2+ transients plays a vital role in liver function under homeostatic conditions, repair, and disease. In response to circulating hormonal stimuli, hepatocytes exhibit intracellular Ca2+ responses that propagate through liver lobules in a wave-like fashion. Although intracellular processes that control cell autonomous Ca2+ spiking behavior have been studied extensively, the intra- and inter-cellular signaling factors that regulate lobular scale spatial patterns and wave-like propagation of Ca2+ remain to be determined. To address this need, we acquired images of cytosolic Ca2+ transients in 1300 hepatocytes situated across several mouse liver lobules over a period of …

Cellular Network Modeling And Single Cell Gene Expression Analysis Reveals Novel Hepatic Stellate Cell Phenotypes Controlling Liver Regeneration Dynamics, Daniel Cook, Sirisha Achanta, Jan B. Hoek, Babatunde A. Ogunnaike, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Recent results from single cell gene and protein regulation studies are starting to uncover the previously underappreciated fact that individual cells within a population exhibit high variability in the expression of mRNA and proteins (i.e., molecular variability). By combining cellular network modeling, and high-throughput gene expression measurements in single cells, we seek to reconcile the high molecular variability in single cells with the relatively low variability in tissue-scale gene and protein expression and the highly coordinated functional responses of tissues to physiological challenges. In this study, we focus on relating the dynamic changes in distributions of hepatic stellate cell …

Control Of Ccnd1 Ubiquitylation By The Catalytic Saga Subunit Usp22 Is Essential For Cell Cycle Progression Through G1 In Cancer Cells., Victoria J. Gennaro, Timothy J. Stanek, Amy R. Peck, Yunguang Sun, Feng Wang, Shuo Qie, Karen E. Knudsen, Hallgeir Rui, Tauseef Butt, J. Alan Diehl, Steven B. Mcmahon

Department of Biochemistry and Molecular Biology Faculty Papers

Overexpression of the deubiquitylase ubiquitin-specific peptidase 22 (USP22) is a marker of aggressive cancer phenotypes like metastasis, therapy resistance, and poor survival. Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional cofactor complex. Challenging the dogma, we report here a nontranscriptional role for USP22 via a direct effect on the …

Polymicrobial Sepsis Influences Nk-Cell-Mediated Immunity By Diminishing Nk-Cell-Intrinsic Receptor-Mediated Effector Responses To Viral Ligands Or Infections., Isaac J. Jensen, Christina S. Winborn, Micaela G. Fosdick, Peng Shao, Mikaela M. Tremblay, Qiang Shan, Sandeep Kumar Tripathy, Christopher M. Snyder, Hai-Hui Xue, Thomas S. Griffith, Jon C. Houtman, Vladimir P. Badovinac

Department of Microbiology and Immunology Faculty Papers

The sepsis-induced cytokine storm leads to severe lymphopenia and reduced effector capacity of remaining/surviving cells. This results in a prolonged state of immunoparalysis, that contributes to enhanced morbidity/mortality of sepsis survivors upon secondary infection. The impact of sepsis on several lymphoid subsets has been characterized, yet its impact on NK-cells remains underappreciated-despite their critical role in controlling infection(s). Here, we observed numerical loss of NK-cells in multiple tissues after cecal-ligation-and-puncture (CLP)-induced sepsis. To elucidate the sepsis-induced lesions in surviving NK-cells, transcriptional profiles were evaluated and indicated changes consistent with impaired effector functionality. A corresponding deficit in NK-cell capacity to produce …

The Anti-Cancer Effect Of Retinoic Acid Signaling In Crc Occurs Via Decreased Growth Of Aldh+ Colon Cancer Stem Cells And Increased Differentiation Of Stem Cells, Shirin R. Modarai, Anindita Gupta, Lynn M. Opdenaker, Ryan Kowash, Gabriel Masters, Vignesh Viswanathan, Tao Zhang, Jeremy Z. Fields, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and …

Pediatric Obesity: Influence On Drug Dosing And Therapeutics, Barbara Ameer Pharmd, Mba, Bcps, Fcp, Michael Weintraub Md

Department of Medicine Faculty Papers

Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of US children and adolescents. Severe obesity (³120% of the 95^th percentile of BMI-for-age, or a BMI of ³35 kg/m²) is the fastest growing subgroup and now approaches 6% of all US youth. Health consequences (e.g., type 2 diabetes, coronary heart disease) are related in a dose-dependent manner to severity of obesity. Since therapeutic interventions are less effective in severe obesity, prevention is a high priority.

Treatment plans involving combinations of …

Extracellular Interactions Between Fibulins And Transforming Growth Factor (Tgf)-Β In Physiological And Pathological Conditions., Takeshi Tsuda

Department of Pediatrics Faculty Papers

Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell⁻matrix interactions, including thrombospondins, SPARC (Secreted Protein …

Pepducin-Mediated Cardioprotection Via Β-Arrestin-Biased Β2-Adrenergic Receptor-Specific Signaling, Laurel A. Grisanti, Toby P. Thomas, Rhonda L. Carter, Claudio De Lucia, Erhe Gao, Walter J. Koch, Jeffrey L. Benovic, Douglas G. Tilley

Department of Biochemistry and Molecular Biology Faculty Papers

Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in …

A Neurotheological Approach To Spiritual Awakening, Andrew B. Newberg, Mark R. Waldman

Marcus Institute of Integrative Health Faculty Papers

A neurotheological approach suggests an analysis of spiritual awakening experiences by combining phenomenological data with neuroscience. This paper presents a synthesis combining information on the thoughts, feelings, and experiences associated with spiritual awakening experiences and neurophysiological data, primarily from neuroimaging studies, to help assess which brain structures might be associated with these experiences. Brain structures involved with emotions correlate with emotional responses while areas of the brain associated with the sense of self appear to correlate with the key feature of these experiences in which an individual loses the sense of self and feels intimately connected with God, universal consciousness, …

Listeria Monocytogenes As A Vector For Cancer Immunotherapy: Current Understanding And Progress, John C. Flickinger, Ulrich Rodeck, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Listeria monocytogenes, a Gram-positive facultative anaerobic bacterium, is becoming a popular vector for cancer immunotherapy. Indeed, multiple vaccines have been developed utilizing modified Listeria as a tool for generating immune responses against a variety of cancers. Moreover, over a dozen clinical trials testing Listeria cancer vaccines are currently underway, which will help to understand the utility of Listeria vaccines in cancer immunotherapy. This review aims to summarize current views on how Listeria-based vaccines induce potent antitumor immunity and the current state of Listeria-based cancer vaccines in clinical trials. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

Mir-196b Target Screen Reveals Mechanisms Maintaining Leukemia Stemness With Therapeutic Potential., Sara E. Meyer, David E. Muench, Andrew M. Rogers, Tess J. Newkold, Emily Orr, Eric O'Brien, John P. Perentesis, John G. Doench, Ashish Lal, Patrick J. Morris, Craig J. Thomas, Judy Lieberman, Edwina Mcglinn, Bruce J. Aronow, Nathan Salomonis, H. Leighton Grimes

Department of Cancer Biology Faculty Papers

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27^Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27^Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation …