Topic 13: Innate Defense System

  • Overview of Host Resistance

    • immune system
    • composed of wide variety of cells, tissues, and organs
    • recognizes foreign substances or microbes and acts to neutralize or destroy them
    • “probiotic—up to 500 species”, “prebiotic” – up to ¾ immune system reside in your gut
      • probiotic line intestine (mental health importance; dependent on nutrition)
      • said will not ask # of species
      • know difference between the two?
    • compromised by stress, health problems & unhealthy food / lifestyle
    • immunity
    • ability of host to resist a particular disease or infection
    • immunology
    • science concerned with immune responses
  • Terminology

    • Susceptibility: Lack of resistance to a disease
    • Immunity: Ability to ward off disease
    • Innate immunity: Defenses against any pathogen
    • “nonspecific immunity”
    • Adaptive immunity: Immunity, resistance to a specific pathogen
  • Types of immune responses

    • Innate (nonspecific) defense system
    • responds quickly, offers resistance to any microbe or foreign substance, lacks immunological memory, and consists of:
      • First line of defense – skin and membranes
      • Second line of defense – antimicrobial proteins, phagocytes, and other cells
      • Inhibit spread of invaders throughout the body (stop the invaders)
      • Inflammation is its hallmark and most important mechanism (cause of swelling, heat, redness)
      • Where did you hear phagocytosis?
        • WBC will “eat” them; bacterias with capsule resistant to phagocytosis
  • Immunity

    • Innate Immunity
    • First Line of Defense
      • Intact skin
      • Mucous membranes and their secretions
      • Normal Microbiota (antagonism)
      • antagonism is your normal bacteria on skin that keeps you “clean” → will be “mean/antagonize” new bacteria
    • Second Line of Defense
      • Natural Killer cells and phagocytic WBC
      • Inflammation
      • Fever
      • Antimicrobial substances
    • Adaptive Immunity (“specific”)
    • Third Line of Defense
      • Specialized lymphocytes: T and B cells (T cells are HIV’s target; B cells give antibodies)
      • Antibodies
      • received by getting sick and producing B cells or getting vaccine with B cells
  • Adaptive (specific) defense system

    • Also called acquired or induced immunity, has immunological memory, responds to a very particular foreign substance (why some substances last a shorter time than others? they don’t know yet; COVID is one that doesn’t have a long memory)
    • about 2 weeks to produce antibodies (don’t get vaccine when people are already sick, do it sooner)
    • Third line of defense
    • Takes longer to react than the innate system
    • Works in conjunction with the innate system

    Covid 19 target is B cells; donation of plasma was needed because it has B cells; B cells have lock and key neutralization of covid; acquired side = adapative; covid 19 vaccine causing autoimmune diseases?

  • Components of the Innate Immune System

    • Skin (biggest organ)
    • Mucous
    • most pathogens go through mucous membrane (eyes, nose, mouth)
    • Covid going for respiratory; cytocines? caused continous inflammation
    • Chemical
    • stomach acid
    • food poisiong indicates eating a lot of bacteria
    • bacteria can go up through urinary tract and cause UTI, if not treated the bacteria can travel upwards
    • lysozyme cuts galasidic bond?
    • smokers cough in morning because paralysis of cilia (cilia moves the fluid upwards)
  • Innate (non-specific) defense systems

    • Surface Barriers: Skin, mucous membranes, and their secretions make up the first line of defense
    • sebaceous glands → oils (sebum)

    Use preparation H for when you get burned (its a hemmeroid cream); pain is good thing because it means the nerve endings are still intact; once infection reaches bone, doctors are unable to do anything to treat other than amputation; burn victims suspectible to infections becasue skin is exposed

  • Skin

    • Largest organ (20 sqft), 10+/- pounds
    • strong mechanical barrier to microbial invasion
    • keratin produced by keratinocytes (=basal cells) in outer layer
    • resists absorption of water and most inorganic chemicals; allows absorption of many organic and a few inorganic chemicals
  • Skin infection/reaction by microbes

    • Cellulitis: inflammation due to infection
    • does not have to be an open cut
    • Warts: viral infection cause excess skin growth
    • Herpes: HSV-1&HSV-2, periodic blisters around lips or genitals
    • cold sores
    • Hives: allergic reaction – not infection
    • Tinea: skin mycosis
    • fungal skin infection
    • Shingles: varicella zoster virus (linear DNA, lipid enveloped, herpes group)
    • DNA virus, enveloped, hide when young but “come out” when older
    • younger people can get it as well
  • Skin = inhospitable environment for many microbes

    • attached organisms removed by shedding of outer skin cells = part of your soap scum, eww
    • pH 3-5 = acidic
    • high NaCl concentration = why?
    • skin bacteria have a high salt toleration and dryness (mannitol salt agar!)
    • subject to periodic drying
    • Lysozyme in saliva and tears – function
    • prevents infection
    • Fungistatic fatty acids in sebum
    • Transferrin** in blood (who’s the bad guy?)
    • *Antagonisms: competitive exclusion of normal microbiota (our bacteria)
    • **iron-binding blood glycoproteins
  • More about Skin

    • specialized cells called skin-associated lymphoid tissue (SALT)
    • Langerhans cell---NOT islet of Langerhans in pancreas!!!
      • dendritic cell that can phagocytose antigens
      • have lots of branches; can eat the pathogens (bring inside cell)
      • differentiates into interdigitating dendritic cell–presents antigen to and activates T cells
      • uses piece of pathogen to present to T cell
  • Antimicrobial Secretions

    • lysozyme
    • How?: tears, saliva
      • cut 1-4 galoscidic bond
    • lactoperoxidase
    • produces superoxide radicals: toxic
    • mammary and salivary gland (saliva)
  • The Eye

    • flushing action of tears
    • lysozyme, lactoferrin and secretory IgA in tears
    • lactoferrin - transferrin (good?)
    • Lactoferrin: multifunctional protein (antimicrobial)
    • IgA = antibody
    • cover antibodies later
  • Mucous Membranes

    • form protective covering that resists penetration and traps many microbes
    • are often bathed in antimicrobial secretions which contain a variety of antimicrobial substances
    • contain mucosal-associated lymphoid tissue (MALT)
    • mucous can trap bacteria
  • Mucosal-Associated Lymphoid Tissue (MALT)

    • specialized immune barrier
    • gut-associated lymphoid tissue (GALT)
    • bronchial-associated lymphoid tissue (BALT)
      • two types of MALT
  • Respiratory system

    • turbulent air flow deposits microbes onto mucosal surfaces
    • COVID 19 TARGET
    • Mucociliary blanket
    • mucous secretions that traps microbes
    • once trapped, microbes transported away from the lungs (mucociliary escalator)
      • can be expelled by coughing or sneezing
      • salivation washes microbes to stomach (pH 3-5)
    • alveolar macrophages
    • phagocytic cells in alveoli of lungs
      • capsule bacteria prevent digestion by phagotcytic cells
  • When you smoke…

    • Cilia paralized, smoker’s cough
    • being moved upwards
    • Smokers are sick more often because……
    • cilia is paralized therefore cilia isn’t moving upwards
    • Morning cough
    • 80% lung cancer – due to smoking, 13% survive 5+ years
    • includes 2nd hand smoking
    • P53 gene – nose, liver, colon, myloid leukemia
    • cancer suppressing gene
    • Tobacco smoke contains a deadly mix of more than 7,000chemicals. Hundreds are toxic. About 70 can cause cancer. Here are some of the chemicals. (said wouldn’t ask about chemicals, just information)
    • Cancer-Causing Chemicals
      • Formaldehyde: Used to embalm dead bodies
      • Benzene: Found in gasoline
      • Polonium 210: Radioactive and very toxic
      • Vinyl chloride: Used to make pipes
    • Toxic Metals
      • Chromium: Used to make steel
      • Arsenic: Used in pesticides
      • Lead: Once used in paint
      • Cadmium: Used to make batteries
    • Poison Gases
      • Carbon monoxide: Found in car exhausts
      • Hydrogen cyanide: Used in chemical weapons
      • Ammonia: Used in household cleaners
      • Butane: Used in lighter fluid
      • Toluene: Found in paint thinners
  • Helicobacter pylori –in the disease packet

    • Gram -, Curved rod, Microaerophilic
    • microaerophilic - likes less oxygen (strept throat test)
    • 80% of infected people = asymptomatic
    • Gastritis, linked to duodenal and stomach cancer – stress was to blame before the discovery
    • burrow into stomach
    • high salt diet dissolves membrane in stomach (high salt diet = higher chance of stomach cancer)
    • Stomach acid gradient chemotaxis
    • urea in stomach acid
    • Urease –Ammonia production, ph?
    • metabolize protein, pH increases
    • 1st infection – antibody test
    • 2nd and after – Urea or stool test
    • because possible antibodies from last infection

    Picture: blood has plasma and cells (red blood cells, platelets, and white blood cells); centrifuge separates layers

  • Blood Plasma – approx. 55%

    • Glucose, fat
    • Protein – (antibodies 1/3)
    • Clotting factor
    • Electrolytes, vitamins
    • Hormones
    • BP, pH
    • less fluid increase BP; neutral pH
    • CO2

    Will not ask # or %; know majority is red blood cells; Acronym for remembering white blood cells - know the relative # in comparison to others (i.e basophils have the least amount of cells)

  • Donations

    • Blood donation ---- NO NO
    • Have tested positive for hepatitis B or hepatitis C, lived with or had sexual contact in the past 12 months with anyone who has hepatitis B or symptomatic hepatitis C.
    • After donation, test for ….HIV, hepatitis, syphilis, Human T-lymphotropic virus
    • Platelets donation – not from mama. Why????
    • pregnant - may have antibody from baby
    • Plasma donation – no tuberculosis, malaria, sickle cell anemia, cancer etc..
    • screening
  • White Blood Cells and the Nonspecific and Specific Responses

    • white blood cells (WBCs) - major role in the innate and specific responses
    • Hematopoesis – hematopoetic stem cell differentiation process (all blood components)
    • stem cells that differenate
    • umblitical cord has stem cells
      • development of white blood cells in bone marrow of mammals
      • WBCs that mature prior to leaving bone marrow, e.g. macrophages and dendritic cells, become part of innate immune system and will respond to all antigens
      • WBCs that are not fully functional after leaving bone marrow become part of the adaptive immune response, e.g.B and T cells and could differentiate in response to specific antigens
        • know the differences

  • Monocytes and macrophages

    • highly phagocytic cells, 6% of WBC
    • engulf pathogen, lysosome digests pathogen
    • make up monocyte-macrophage system
    • monocytes
    • are mononuclear phagocytic leukocytes
    • after circulating for ~8 hours, mature into macrophages
    • macrophages
    • reside in specific tissues
    • have a variety of surface receptors
      • senses the pathogens
    • named according to tissue in which they reside

    Bring inside and combine with lysosome to digest and do exocyotis; capsule bacteria may not die here and may continue to live inside the cell

  • Dendritic Cells: Antigen-presenting cells (APC)

    • present in small numbers in blood, skin, and mucous membranes of nose, lungs, and intestines
    • contact, phagocytose and process antigens → display foreign antigens on their surfaces (antigen presentation)
      • bring antigen/pathogen to surface to show other cells (i.e macrophages)
  • Basophils

    • stain bluish-black with basic dyes, 1% of WBC
    • Non-phagocytic
    • release histamine, heparin, prostaglandins, serotonin, and leukotrienes from granules
    • histamine most important
    • play important role in development of allergies and hypersensitivities (inflammation)
    • antihistamines
  • Eosinophils

    • stain red with acidic dyes, 3% of WBC
    • defend against parasites (protozoan and helminthes)
    • play a role in asthma/allergic reactions along with mast cells
  • Neutrophils

    • stain at neutral pH
    • 60% of WBC - majority
    • highly phagocytic - 1st to go to site
    • circulate in blood then migrate to sites of tissue damage
    • sequeeze through capillary walls
    • kill ingested microbes with lytic enzymes and reactive oxygen metabolites
    • high neutrophil count = bacterial infection
    • pus is normally dead neutrophils
  • Mast Cells

    • differentiate in blood and connective tissue
    • contain granules containing histamine, heparin, and other pharmacologically active chemicals, over 200+ chemicals
    • play important role in development of allergies and hypersensitivities
    • Mast cell activation syndrome
    • idopathic - don’t know what it is, may be genetic
  • Lymphocytes

    • major cells of the immune system, 30% of WBC
    • major populations include T cells, B cells, and natural killer (NK) cells
    • B and T lymphocytes differentiate in bone marrow from stem cells
  • B Lymphocytes

    • B cells (B lymphocytes)
    • mature mostly in lymph nodes and other lymph tissues
    • circulate in blood
    • can settle in lymphoid organs
    • after maturation and activation are called plasma cells and produce antibodies
      • memory and antibodies (after ~10 days)
      • outside of pathogens
  • T Lymphocytes

    • T cells (T lymphocytes)
    • Mature primarily in the thymus gland
    • can remain in thymus, circulate in blood, or reside in lymphoid tissue
    • like B cells, require antigen binding to surface receptors for activation and continuation of replication
      • need a signal (i.e antigen presenting cell - dendritic cell)
      • they have no memory or antibodies
    • cytokines, chemicals that have effects on other cells, are produced and secreted by activated T cells
  • Natural Killer (NK) Cells

    • small population of large non-phagocytic granular lymphocytes
    • kill malignant cells and cells infected with pathogens
    • two ways of recognizing target cells
    • bind to antibodies which coat infected or malignant cells (antibody-dependent cell-mediated cytotoxicity (ADCC))
    • recognizes cells that have lost their class I major histocompatibility (MHC) antigen due to presence of virus or cancer
      • organ transplant

    ADCC process

  • Cytotoxic T Cells and Natural Killer Cells

    • Cytotoxic T-cells : the specific antigens presented by their MHC class I molecule
    • recognize receptor and present it
    • NK cells : the absence of MHC class I molecules, specific types of antibodies, and \n some type of cellular stress
    • Know the difference!

    is an open system

  • Primary Lymphoid Organs and Tissues

    • immature undifferentiated lymphocytes (generated in the bone marrow) → mature
    • obtain a specific antigenic specificity within the primary lymphoid organs and tissues, bone marrow and thymus gland
    • unique to pathogens
  • Secondary Lymphoid Organ/Tissue

    • Secondary lymphoid tissue includes: lymph nodes, tonsils, adenoids, Peyer’s patches (intestine), spleen
    • throughout the body
    • interface between innate and acquired host immunity (overlap)
    • act as areas of antigen sampling and processing
      • determine if the threat needs to be neutralized
    • some lymphoid cells are found closely associated with specific tissues
      • e.g., skin-associated lymphoid tissue (SALT)
      • e.g., mucous-associated lymphoid tissue (MALT)
      • e.g. bronchial associated lymphoid tissue (BALT)
  • Secondary Lymphoid Organ/Tissue

    • spleen
    • highly organized lymphoid organ
    • filters blood - scanning
    • trap microbes and antigens
      • present antigens to B and T cells
      • most common way that lymphocytes become activated to carry out their immune functions
    • lymph nodes
    • highly organized lymphoid tissue
    • filter lymph
    • microbes and antigens trapped and phagocytosed by macrophages and dendritic cells
    • B cells differentiate into memory and plasma cells within lymph nodes
  • Phagocytosis

    • process by which phagocytic cells (monocytes, tissue macrophages, dendritic cells and neutrophils) recognize, ingest and kill extracellular microbes
    • How bacteria resist?
    • capsule

    yeast is eukaryotic cell

  • Phagocytosis

    • two mechanisms for recognition of microbe by phagocyte
    • opsonin-independent (nonopsonic) recognition
    • opsonin-dependent (opsonic) recognition
    • phagocytosis can be greatly increased by opsonization
  • Opsonization (stopped here w/ anki)

    • opsonin – Greek: prepare for eating
    • opson – Greek: delicious side dish
    • process in which microbes are coated by serum components in preparation for recognition/ingestion by phagocytic cells
    • molecules that carry out above are called opsonins = antibodies, complement molecules
    • some complement proteins are opsonins
    • bind to microbial cells, coating them for phagocyte recognition
  • Opsonin-Independent Mechanism

    • involves nonspecific and specific receptors on phagocytic cells
    • four main forms:
    • recognition by lectin-carbohydrate interactions
    • recognition by protein-protein interactions (PPI)
    • recognition by hydrophobic interactions
    • detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs, e.g., toll-like receptors)
      • *lectin: carbohydrate binding proteins
      • *PPI: Alzheimer’s, CJD, Cancer
  • Pathogen-Associated Molecular Patterns (PAMPs)

    • PAMPs are unique to microbes, not present in host
    • Examples of unqiue features
      • e.g., lipopolysaccharide (LPS) of gram negative bacteria
      • e.g., peptidoglycan of gram positive bacteria
    • PAMPs recognized by pattern recognition receptors (PRRs) on phagocytic cells
  • Toll-Like Receptors (TLRs)

    • recognize and bind unique PAMPs of viruses, bacteria or fungi
    • Innate
    • Macrophages, Dendritic cells
    • on these cells
  • Intracellular Digestion

    • phagolysosome
    • vacuole which results from fusion of phagosome with lysosome
    • presence of toxic chemicals
      • e.g., degradative enzymes
      • e.g., toxic reactive oxygen intermediates (ROIs) (kills microorganisms)
      • e.g., reactive nitrogen intermediates (RNIs)

    cytokines are the message that recruit for help from other immune cells; cytokines produce inflammation; cytokines killed a lot of people at the beginning of COVID; bacteria's weapon is leukocidins - kills WBCs; pus is dead WBCs; lysosome is chemical that helps kill the bacteria inside macrophage

  • Neutrophils – after digesting microbial fragments

    • also phagocytic - 1st to be at site of injury
    • Exocytosis
      • process used by neutrophils to expel microbial fragments after they have been digested
      • phagolysosome unites with cell membrane
      • results in extracellular release of microbial fragments
  • Inflammation (innate side)

    • nonspecific response to tissue injury
    • can be caused by pathogen or physical trauma
    • acute inflammation is the immediate response of body to injury or cell death
    • cardinal signs---PRISH (reactions from inflammation)
    • Pain – release of chemicals such as histamine
    • Redness – increased blood flow
    • Immobility - altered or loss of function
    • Swelling – edema (accumulation of fluid)
      • application of ice pack (no more than 20 min because it slows the process of blood flow which gets rid of the waste)
    • Heat – increased blood flow
  • Acute Inflammatory Response

    • Vascular phase first, then cellular phase
    • vascular is the fluid
    • the release of inflammatory mediators from injured tissue cells initiates a cascade of events which result in the signs of inflammation
    • involves chemical mediators
    • chemokines - signaling proteins/cytokines
      • released by injured cells
    • selectins
      • cell adhesion molecules on activated capillary endothelial cells
    • integrins
      • adhesion receptors on neutrophils
      • blood vessel will get loose because of histamine and neutrophils can squeeze through
  • Inflammatory Response Vascular Permeability

    • Vasodilation
    • Chemicals released by the inflammatory response stimulate mast cells next to capillaries
    • Mast cells release histamines to increase permeability of capillaries
    • histamines make you “leaky”
    • Plasma seeps into tissue (interstitial) spaces causing local edema (swelling), which contributes to the sensation of pain
    • *pain – Na+channel
      • lidocaine blocks Na+ channel
  • Inflammatory Response Phagocytic Mobilization

    • Margination – neutrophils cling to the walls of capillaries in the injured area
    • Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis
    • know margination and diapedesis
    • Chemotaxis – inflammatory chemicals attract neutrophils to the injury site

    gram + bacteria on skin; histamine relase -> loose capilaries -> neutrophils squeeze through; siderophores "bad guys" - take Fe and transferrins "good guys" - hold on Fe; platelets help clot bleeding; acute inflammation

  • Chronic Inflammation

    • slow process
    • may not notice
      • rhuematoid arthrisis
      • excema
    • involves formation of new connective tissue
    • usually causes permanent tissue damage
    • dense infiltration of lymphocytes and macrophages at site of inflammation
    • granuloma
      • walled off area formed when phagocytic cells can’t destroy pathogen

    Don't need to know this Flowchart of Events in Inflammation; summary chart; vasodilation - local loose capillary

  • ~~Opsonization~~

    • ~~process in which microbes are coated by serum components in preparation for recognition/ingestion by phagocytic cells~~
    • ~~molecules that carry out above are called opsonins~~
    • ~~make pathogen more visible~~
    • ~~some complement proteins are opsonins~~
    • ~~bind to microbial cells, coating them for phagocyte recognition~~
  • Pus

    • Dead leukocytes (mostly neutrophils)
    • Color varies
    • Abscess=enclosed in tissue
    • Pimple=visible collection within/beneath the epidermis
    • Pus causing bacteria = pyogenic
    • Example from your lab: Staphylococcus aureus (pink eye), S. epidermidis, S. pyogenes (strept throat) (Gram+, β-hemolysis, catalase-), Escherichia coli, Pseudomonas aeruginosa
  • The Complement System (or cascade)

    • composed of >30 serum proteins – mainly produced in liver (pro-proteins)
    • augments (or “complements”) the antibacterial activity of antibody
    • part of innate immunity, will NOT change over ones lifetime, does not adaptable
    • genetic, pre-determined
    • aide in getting rid of pathogen

    C3b is complement protein; combination of both opsonin increases visibility and recogniation of bacteria, increases binding

  • Other Functions of Complement Proteins

    • function as chemotactic signals that recruit phagocytes to their activation site
    • puncture cell membranes causing cell lysis
    • important function
    • many complement activities unite the nonspecific and specific arms of the immune system to destroy and remove invading pathogens
  • Complement Activation Pathways (innate)

    • specific proteins are unique to the first part of each of the three complement activation pathways, but all complement pathways have the same outcome
    • Opsonization - phagocytosis
    • stimulation of inflammatory mediators
    • lysis of microbes by membrane attack
    • all pathways are activated as a cascade; the activation of one protein results in the activation of the next
    • all complement proteins are in the inactive state until activation when the host is challenged by an invading microbe

    don't need to memorize; classic involves antibodies (adaptive); processes make different results like membrane attack complex (one that punctures cell wall) don't need to memorize details; showing the puncture of cell wall; all proteins in the complex need to be working in order to function correctly - reason for bacterial infections increase

  • Cytokines

    • soluble proteins or glycoproteins that are released by one cell population that act as intercellular mediators or signaling molecules
    • monokines
    • released from mononuclear phagocytes
    • i.e macrophages
    • lymphokines
    • released from T lymphocytes
    • interleukins
    • released from one leukocyte and act on another leukocyte
    • colony stimulating factors (CSFs)
    • act on hemopoietic stem cell, stimulate growth and differentiation of immature leukocytes in bone marrow
  • Interferons (IFNs) =type of cytokines

    • regulatory cytokines produced by some eukaryotic cells in response to viral infection
    • viral infection is important (acute)
      • do not prevent virus entry into host cells, but defend against viruses by preventing viral replication and assembly
    • also help to regulate the immune response
    • responsible for “flu-like” symptoms
    • clinical use for viral infection, MS and cancer treatment
    • cancer treatment: elicit T cells (side effects: thinning hair, flu-like symptoms); T cells attack cancer

    lytic cycle, interferons; process to treat cancer

  • Fever

    • 37.5-38.3 °C (99.5-100.9°F) or above
    • dr starts to get worried at 105
    • most common cause of fever is viral or bacterial infection or bacterial toxins
    • Viral --- DO NOT ask for antibiotics!!!!
    • Thermostat set point located in hypothalamus
  • More About Fever

    • in most cases, the endogenous pyrogen, a cytokine produced in response to pathogen, directly triggers fever production
    • after release, pyrogens → hypothalamus and induce production of prostaglandins which reset hypothalamus to a higher temperature
    • increase temp
    • When the hypothalamus is reset, what has to happen to increase body temperature?
    • *Pyrogen = a fever inducing substance
    • **Prostaglandins = found in every tissue, hormone-like effect, lipid derived
    • ***Physical activity is needed to increase metabolic rate, heat production = This accomplished by shivering thermogenesis.
    • know where body’s thermostat is
  • Should fever be reduced with medicines?

    • Yes! Because……
    • Febrile seizure (epileptic seizure) – can be dangerous
      • some people can get seizures from fever (temperature increases too quickly)
    • Feeling awful/miserable – treating the symptom, not the cause
      • fever caused by infection
      • bacterial infection treated by antibiotics, no treatment for viral infection
    • No! because……….
    • Not high enough fever
      • may hinder immune system
    • Research (2014) has shown that using fever-suppressing drugs may allow patients to mistakenly feel better quicker than normal resulting in their premature return to the population
    • Concerning influenza, it is estimated that this will result in a 1% increase in the number of cases and about 700 more deaths each year in the U.S.
    • contributes to spread

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