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Bleeding Disorder Referrals To Hematology Clinic: A Single Institution Experience, Zuri Hudson 2021 Children's Mercy Kansas City

Bleeding Disorder Referrals To Hematology Clinic: A Single Institution Experience, Zuri Hudson

Research Days

Background: Our center receives hundreds of referrals yearly for bleeding disorder evaluation both due to bleeding symptoms and secondary to routine preoperative laboratory testing. The evaluation for a bleeding disorder can be challenging due to the wide variability of symptoms as well as the need for accurately interpreting lab results. Bhasin et al showed that 4% of patients referred to hematology based on a preoperative coagulation evaluation had a clinically relevant bleeding disorder. Currently there is little published about the referral patterns to pediatric hematology and the outcomes of these referrals.

Objectives/Goal: To characterize our hematology referrals for bleeding ...


A Novel Dna And Protein Combination Covid-19 Vaccine Formulation Provides Full Protection Against Sars-Cov-2 In Rhesus Macaques, Yuzhong Li, Guangnan Hu, Shixia Wang, Qihan Li, Shan Lu, Wei Cun 2021 Peking Union Medical College

A Novel Dna And Protein Combination Covid-19 Vaccine Formulation Provides Full Protection Against Sars-Cov-2 In Rhesus Macaques, Yuzhong Li, Guangnan Hu, Shixia Wang, Qihan Li, Shan Lu, Wei Cun

COVID-19 Publications by UMMS Authors

The current study aims to develop a safe and highly immunogenic COVID-19 vaccine. The novel combination of a DNA vaccine encoding the full-length Spike (S) protein of SARS-CoV-2 and a recombinant S1 protein vaccine induced high level neutralizing antibody and T cell immune responses in both small and large animal models. More significantly, the co-delivery of DNA and protein components at the same time elicited full protection against intratracheal challenge of SARS-CoV-2 viruses in immunized rhesus macaques. As both DNA and protein vaccines have been proven safe in previous human studies, and DNA vaccines are capable of eliciting germinal center ...


Human Antibody Immune Responses Are Personalized By Selective Removal Of Mhc-Ii Peptide Epitopes [Preprint], Matias Gutiérrez-González, Padma P. Nanaware, Liying Lu, Lawrence J. Stern, Brandon J. DeKosky 2021 University of Kansas

Human Antibody Immune Responses Are Personalized By Selective Removal Of Mhc-Ii Peptide Epitopes [Preprint], Matias Gutiérrez-González, Padma P. Nanaware, Liying Lu, Lawrence J. Stern, Brandon J. Dekosky

University of Massachusetts Medical School Faculty Publications

Human antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody development in vivo. Large-scale antibody sequence analysis and experimental validation of peptide binding revealed that MHC-II epitope removal from BCRs is linked to genetic signatures of T cell help, and donor-specific antibody repertoire modeling demonstrated that somatic hypermutation selectively targets the personalized MHC-II epitopes in antibody variable regions. Mining of ...


T Cells In The Brain Enhance Neonatal Mortality During Peripheral Lcmv Infection, Laurie L. Kenney, Erik P. Carter, Anna Gil, Liisa K. Selin 2021 University of Massachusetts Medical School

T Cells In The Brain Enhance Neonatal Mortality During Peripheral Lcmv Infection, Laurie L. Kenney, Erik P. Carter, Anna Gil, Liisa K. Selin

Open Access Publications by UMMS Authors

In adult mice the severity of disease from viral infections is determined by the balance between the efficiency of the immune response and the magnitude of viral load. Here, the impact of this dynamic is examined in neonates. Newborns are highly susceptible to infections due to poor innate responses, lower numbers of T cells and Th2-prone immune responses. Eighty-percent of 7-day old mice, immunologically equivalent to human neonates, succumbed to extremely low doses (5 PFU) of the essentially non-lethal lymphocytic choriomeningitis virus (LCMV-Armstrong) given intraperitoneally. This increased lethality was determined to be dependent upon poor early viral control, as well ...


Sars-Cov-2 Receptors Are Expressed On Human Platelets And The Effect Of Aspirin On Clinical Outcomes In Covid-19 Patients [Preprint], Aditya Sahai, Milka Koupenova-Zamor, Jane E. Freedman, Scott Cameron 2020 Case Western Reserve University

Sars-Cov-2 Receptors Are Expressed On Human Platelets And The Effect Of Aspirin On Clinical Outcomes In Covid-19 Patients [Preprint], Aditya Sahai, Milka Koupenova-Zamor, Jane E. Freedman, Scott Cameron

COVID-19 Publications by UMMS Authors

Coronavirus disease-2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of anti-platelet agents in attenuating thrombosis is unknown. We aimed to determine if human platelets express the known SARS-CoV-2 receptor-protease axis on their cell surface and assess whether the anti-platelet effect of aspirin may mitigate risk of myocardial infarction (MI), cerebrovascular accident (CVA), and venous thromboembolism (VTE) in COVID-19. Expression of ACE2 and TMPRSS2 on human platelets were detected by immunoblotting and confirmed by confocal microscopy. We ...


The Long Non-Coding Rna Lucat1 Is A Negative Feedback Regulator Of Interferon Responses In Humans, Shiuli Agarwal, Tim Vierbuchen, Sreya Ghosh, Jennie Chan, Zhaozhao Jiang, Richard K. Kandasamy, Emiliano Ricci, Katherine A. Fitzgerald 2020 University of Massachusetts Medical School

The Long Non-Coding Rna Lucat1 Is A Negative Feedback Regulator Of Interferon Responses In Humans, Shiuli Agarwal, Tim Vierbuchen, Sreya Ghosh, Jennie Chan, Zhaozhao Jiang, Richard K. Kandasamy, Emiliano Ricci, Katherine A. Fitzgerald

Open Access Publications by UMMS Authors

Long non-coding RNAs are important regulators of biological processes including immune responses. The immunoregulatory functions of lncRNAs have been revealed primarily in murine models with limited understanding of lncRNAs in human immune responses. Here, we identify lncRNA LUCAT1 which is upregulated in human myeloid cells stimulated with lipopolysaccharide and other innate immune stimuli. Targeted deletion of LUCAT1 in myeloid cells increases expression of type I interferon stimulated genes in response to LPS. By contrast, increased LUCAT1 expression results in a reduction of the inducible ISG response. In activated cells, LUCAT1 is enriched in the nucleus where it associates with chromatin ...


Neutrophil Infiltration Regulates Clock-Gene Expression To Organize Daily Hepatic Metabolism, Maria Crespo, Norman J. Kennedy, Roger J. Davis, Nuria Matesanz, Magdalena Leiva, Guadalupe Sabio 2020 Spanish National Cardiovascular Research Centre

Neutrophil Infiltration Regulates Clock-Gene Expression To Organize Daily Hepatic Metabolism, Maria Crespo, Norman J. Kennedy, Roger J. Davis, Nuria Matesanz, Magdalena Leiva, Guadalupe Sabio

University of Massachusetts Medical School Faculty Publications

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 ...


Changes In Selected Haematological Parameters Associated With Jak1/Jak2 Inhibition Observed In Patients With Rheumatoid Arthritis Treated With Baricitinib, Jonathan Kay, Masayoshi Harigai, Josh Rancourt, Christina Dickson, Thomas Melby, Maher Issa, Inmaculada de la Torre, Yoshitaka Isaka, Anabela Cardoso, Chadi Saifan, Edward C. Keystone, Ronald F. van Vollenhoven, Jon T. Giles, Tom Wj. Huizinga, Joel M. Kremer 2020 University of Massachusetts Medical School

Changes In Selected Haematological Parameters Associated With Jak1/Jak2 Inhibition Observed In Patients With Rheumatoid Arthritis Treated With Baricitinib, Jonathan Kay, Masayoshi Harigai, Josh Rancourt, Christina Dickson, Thomas Melby, Maher Issa, Inmaculada De La Torre, Yoshitaka Isaka, Anabela Cardoso, Chadi Saifan, Edward C. Keystone, Ronald F. Van Vollenhoven, Jon T. Giles, Tom Wj. Huizinga, Joel M. Kremer

Open Access Publications by UMMS Authors

OBJECTIVE: To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.

METHODS: Data were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).

RESULTS: Mean absolute neutrophil counts decreased (-1.36x10(9)/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period ...


Extracellular Micrornas In Human Circulation Are Associated With Mirisc Complexes That Are Accessible To Anti-Ago2 Antibody And Can Bind Target Mimic Oligonucleotides, Hirosha Geekiyanage, Shima Rayatpisheh, James A. Wohlschlegel, Robert H. Brown Jr., Victor R. Ambros 2020 University of Massachusetts Medical School

Extracellular Micrornas In Human Circulation Are Associated With Mirisc Complexes That Are Accessible To Anti-Ago2 Antibody And Can Bind Target Mimic Oligonucleotides, Hirosha Geekiyanage, Shima Rayatpisheh, James A. Wohlschlegel, Robert H. Brown Jr., Victor R. Ambros

Open Access Publications by UMMS Authors

MicroRNAs (miRNAs) function cell-intrinsically to regulate gene expression by base-pairing to complementary mRNA targets while in association with Argonaute, the effector protein of the miRNA-mediated silencing complex (miRISC). A relatively dilute population of miRNAs can be found extracellularly in body fluids such as human blood plasma and cerebrospinal fluid (CSF). The remarkable stability of circulating miRNAs in such harsh extracellular environments can be attributed to their association with protective macromolecular complexes, including extracellular vesicles (EVs), proteins such as Argonaut 2 (AGO2), or high-density lipoproteins. The precise origins and the potential biological significance of various forms of miRNA-containing extracellular complexes are ...


Caspase-8 Mediates Inflammation And Disease In Rodent Malaria, Larissa M. N. Pereira, Patricia Aparecida Assis, Natalia M. de Araujo, Danielle Fernandes Durso, Caroline Junqueira, Marco Antonio Ataide, Dhelio B. Pereira, Egil Lien, Katherine A. Fitzgerald, Dario S. Zamboni, Douglas T. Golenbock, Ricardo T. Gazzinelli 2020 University of Massachusetts Medical School

Caspase-8 Mediates Inflammation And Disease In Rodent Malaria, Larissa M. N. Pereira, Patricia Aparecida Assis, Natalia M. De Araujo, Danielle Fernandes Durso, Caroline Junqueira, Marco Antonio Ataide, Dhelio B. Pereira, Egil Lien, Katherine A. Fitzgerald, Dario S. Zamboni, Douglas T. Golenbock, Ricardo T. Gazzinelli

Open Access Publications by UMMS Authors

Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFalpha and IL-1beta and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find ...


Contributions Of Ifn-Gamma And Granulysin To The Clearance Of Plasmodium Yoelii Blood Stage, Natalia Satchiko Hojo-Souza, Patrick Orestes de Azevedo, Julia Teixeira de Castro, Andrea Teixeira-Carvalho, Judy Lieberman, Caroline Junqueira, Ricardo T. Gazzinelli 2020 Oswaldo Cruz Foundation

Contributions Of Ifn-Gamma And Granulysin To The Clearance Of Plasmodium Yoelii Blood Stage, Natalia Satchiko Hojo-Souza, Patrick Orestes De Azevedo, Julia Teixeira De Castro, Andrea Teixeira-Carvalho, Judy Lieberman, Caroline Junqueira, Ricardo T. Gazzinelli

Open Access Publications by UMMS Authors

P. vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8+ T cells and killed by granulysin (GNLY) and granzymes. However, how Plasmodium infection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps control Plasmodium infection in vivo has not been studied. Here, we examine these questions using rodent infection with the P. yoelii 17XNL strain, which has tropism for Retics. Infection with P. yoelii caused extramedullary erythropoiesis, reticulocytosis and expansion of CD8+CD44+CD62L- IFN-gamma-producing T cells that form immune synapses with iRetics. We now provide evidence that MHC-I expression by iRetic ...


Non-Neutralizing Antibody Responses Following A(H1n1)Pdm09 Influenza Vaccination With Or Without As03 Adjuvant System, Damien Friel, Mary Dawn T. Co, Thierry Ollinger, Bruno Salaun, Anne Schuind, Ping Li, Karl Walravens, Francis A. Ennis, David W. Vaughn 2020 GlaxoSmithKline, Belgium

Non-Neutralizing Antibody Responses Following A(H1n1)Pdm09 Influenza Vaccination With Or Without As03 Adjuvant System, Damien Friel, Mary Dawn T. Co, Thierry Ollinger, Bruno Salaun, Anne Schuind, Ping Li, Karl Walravens, Francis A. Ennis, David W. Vaughn

Open Access Publications by UMMS Authors

BACKGROUND: Non-neutralizing antibodies inducing complement-dependent lysis (CDL) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity may contribute to protection against influenza infection. We investigated CDL and ADCC responses in healthy adults randomized to receive either non-adjuvanted or AS03-adjuvanted monovalent A(H1N1)pdm09 vaccine (containing 15 microg/3.75 mug of hemagglutinin, respectively) on a 2-dose schedule 21 days apart.

METHODS: We conducted an exploratory analysis of a subset of 106 subjects having no prior history of A(H1N1)pdm09 infection or seasonal influenza vaccination enrolled in a previously reported study (NCT00985673). Antibody responses against the homologous A/California/7/2009 (H1N1) vaccine ...


In-Vitro Sorbent-Mediated Removal Of Edoxaban From Human Plasma And Albumin Solution, Alexandra A. Angheloiu, Yanglan Tan, Cristian Ruse, Scott A. Shaffer, George O. Angheloiu 2020 Temple University

In-Vitro Sorbent-Mediated Removal Of Edoxaban From Human Plasma And Albumin Solution, Alexandra A. Angheloiu, Yanglan Tan, Cristian Ruse, Scott A. Shaffer, George O. Angheloiu

Open Access Publications by UMMS Authors

BACKGROUND AND OBJECTIVE: Based on previous experience of sorbent-mediated ticagrelor, dabigatran, and radiocontrast agent removal, we set out in this study to test the effect of two sorbents on the removal of edoxaban, a factor Xa antagonist direct oral anticoagulant.

METHODS: We circulated 100 mL of edoxaban solution during six first-pass cycles through 40-mL sorbent columns (containing either CytoSorb in three passes or Porapak Q 50-80 mesh in the remaining three passes) during experiments using human plasma and 4% bovine serum albumin solution as drug vehicles. Drug concentration was measured by liquid chromatography-tandem mass spectrometry.

RESULTS: Edoxaban concentration in two ...


Editorial: Macrophages In Liver Disease, Ruchi Bansal, Pranoti Mandrekar, Sujit K. Mohanty, Ralf Weiskirchen 2020 University of Twente

Editorial: Macrophages In Liver Disease, Ruchi Bansal, Pranoti Mandrekar, Sujit K. Mohanty, Ralf Weiskirchen

Open Access Publications by UMMS Authors

Macrophages constitute a key component of our immune system and play an important role in immune surveillance. Hepatic macrophages are a heterogeneous population of immune cells that mainly comprises of embryonically-derived resident Kupffer cells (KCs), and circulating monocyte-derived macrophages (MoMFs). They play a critical role in disease initiation and progression as well as contribute to disease resolution. Traditionally, macrophages were defined by two broad subsets: classically-activated pro-inflammatory M1 or alternatively-activated anti-inflammatory M2 macrophages. However, it has been recognized that macrophages can differentiate into multiple phenotypes with distinct functions based on the tissue microenvironment.


Mycobacterium Tuberculosis Evasion Of Guanylate Binding Protein-Mediated Host Defense In Mice Requires The Esx1 Secretion System [Preprint], Andrew J. Olive, Clare M. Smith, Christina E. Baer, Jörn Coers, Christopher M. Sassetti 2020 Michigan State University

Mycobacterium Tuberculosis Evasion Of Guanylate Binding Protein-Mediated Host Defense In Mice Requires The Esx1 Secretion System [Preprint], Andrew J. Olive, Clare M. Smith, Christina E. Baer, Jörn Coers, Christopher M. Sassetti

University of Massachusetts Medical School Faculty Publications

Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis (Mtb) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against Mtb, it is not capable of fully eradicating Mtb infection. This suggests that Mtb evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms Mtb resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown ...


Basement Membrane Damage By Ros- And Jnk-Mediated Mmp2 Activation Drives Macrophage Recruitment To Overgrown Tissue, Neha Diwanji, Andreas Bergmann 2020 University of Massachusetts Medical School

Basement Membrane Damage By Ros- And Jnk-Mediated Mmp2 Activation Drives Macrophage Recruitment To Overgrown Tissue, Neha Diwanji, Andreas Bergmann

Open Access Publications by UMMS Authors

Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model ("undead" model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging ...


Current Insights In Cutaneous Lupus Erythematosus Immunopathogenesis, Colton J. Garelli, Maggi Ahmed Refat, Padma P. Nanaware, Zaida G. Ramirez-Ortiz, Medhi Rashighi, Jillian M. Richmond 2020 University of Massachusetts Medical School

Current Insights In Cutaneous Lupus Erythematosus Immunopathogenesis, Colton J. Garelli, Maggi Ahmed Refat, Padma P. Nanaware, Zaida G. Ramirez-Ortiz, Medhi Rashighi, Jillian M. Richmond

Open Access Publications by UMMS Authors

Cutaneous Lupus Erythematosus (CLE) is a clinically diverse group of autoimmune skin diseases with shared histological features of interface dermatitis and autoantibodies deposited at the dermal-epidermal junction. Various genetic and environmental triggers of CLE promote infiltration of T cells, B cells, neutrophils, antigen presenting cells, and NK cells into lesional skin. In this mini-review, we will discuss the clinical features of CLE, insights into CLE immunopathogenesis, and novel treatment approaches.


In Vitro Immune Activation By Treponema Pallidum And The Effect On Osteoclastogenesis: First Experimental Step Towards An Integration Between Osteoimmunology And Paleopathology., Emily Ann Rich 2020 University of Louisville

In Vitro Immune Activation By Treponema Pallidum And The Effect On Osteoclastogenesis: First Experimental Step Towards An Integration Between Osteoimmunology And Paleopathology., Emily Ann Rich

College of Arts & Sciences Senior Honors Theses

The presence of pathogens in the human body influences the expression of pro-inflammatory cytokines by activated immune cells. These cytokines, and other factors, regulate osteoclastogenesis and osteoclast activity. Through experimental osteoimmunology, interactions between the inflammatory response and bone cell physiology may provide insight into how immune processes can be translated into the lesions or abnormalities observed in the osteological record. In this research, our objective was to determine if the cytokines produced by activated immune cells increase osteoclastogenesis and osteoclast activity. To evaluate this hypothesis, we used two main protocols, one for immune activation and one for osteoclastogenesis, that utilized ...


A Systematic Re-Examination Of Processing Of Mhci-Bound Antigenic Peptide Precursors By Er Aminopeptidase 1, George Mavridis, Richa Arya, Alexander Domnick, Jerome Zoidakis, Manousos Makridakis, Antonia Vlahou, Anastasia Mpakali, Angelos Lelis, Dimitris Georgiadis, Robert Tampe, Athanasios Papakyriakou, Lawrence J. Stern, Efstratios Stratikos 2020 National Center for Scientific Research Demokritos

A Systematic Re-Examination Of Processing Of Mhci-Bound Antigenic Peptide Precursors By Er Aminopeptidase 1, George Mavridis, Richa Arya, Alexander Domnick, Jerome Zoidakis, Manousos Makridakis, Antonia Vlahou, Anastasia Mpakali, Angelos Lelis, Dimitris Georgiadis, Robert Tampe, Athanasios Papakyriakou, Lawrence J. Stern, Efstratios Stratikos

Open Access Publications by UMMS Authors

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in pre-formed MHCI-peptide complexes, but which mode is more relevant to its biological function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in solution or when bound to three MHCI alleles, HLA-B*58, HLA-B*08 and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination ...


Regulation Of Adipose Tissue Inflammation By Interleukin 6, Myoung Souk Han, Alexis White, Rachel J. Perry, Joao-Paulo Camporez, Juan Hidalgo, Gerald I. Shulman, Roger J. Davis 2020 University of Massachusetts Medical School

Regulation Of Adipose Tissue Inflammation By Interleukin 6, Myoung Souk Han, Alexis White, Rachel J. Perry, Joao-Paulo Camporez, Juan Hidalgo, Gerald I. Shulman, Roger J. Davis

Open Access Publications by UMMS Authors

Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the Il6 gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These ...


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