315 Questions
Which molecule is fat stored as in adipose tissue?
Triglycerol
Which process produces 106 ATPs from the oxidation of fatty acids?
Fatty acid oxidation
What activates lipase for the breakdown of triglycerides in adipose tissue?
Glucagon
Which molecule is used as a source of energy and hydrated during the breakdown of triglycerides?
Glycerol
Which hormone activates lipase for the breakdown of triglycerides in adipose tissue?
Leptin
What is the primary storage form of fat in adipose tissue?
Triglycerol
Which organ is described as an 'energy storage organ' and an 'endocrine organ' in the text?
Adipose tissue
What is the primary storage form of energy in muscle?
Glycogen
What is the breakdown product of triglycerides in adipose tissue?
Fatty acids and glycerol
Where are fatty acids transported after being released from the breakdown of triglycerides?
Blood
Which molecule is primarily stored as glycogen in muscle?
Glucose
What activates hormone-sensitive lipase for the breakdown of triglycerides in adipose tissue?
Hormone-signaled phosphorylation
What is the endocrine function of adipose tissue?
Secretion of adipocytokines
Which protein is found in the A band of the sarcomere?
Myosin
What is the functional unit of a muscle cell?
Sarcomere
What happens to the I band when the sarcomere contracts?
It shortens
What is the primary event that triggers muscle contraction?
Opening of Ca2+ channels in the sarcoplasmic reticulum
What is the main mechanism for muscle relaxation?
Pumping of calcium back into the sarcoplasmic reticulum
What triggers contraction in smooth muscle cells?
Binding of calmodulin to Ca2+
What is the role of Na+/K+-ATPase pumps in muscle cells?
Maintain the low calcium content in the sarcoplasm
What is the function of calsequestrin in the sarcoplasmic reticulum?
Maintaining low calcium content until neural stimulation
What triggers both myosin-actin interactions and myosin ATPase activity in muscle cells?
Influx of Ca2+ into the cytosol
What is the source of the increased [Ca2+] in the muscle cytosol during muscle contraction?
Influx of Na+ into the muscle cell
What is the role of troponin C in muscle contraction?
Binding of troponin C to Ca2+
What is the function of the sarcoplasmic reticulum in muscle cells?
Maintaining low calcium content until neural stimulation
What is the role of the Ca2+-ATPase pump in the sarcoplasmic reticulum?
Pumping calcium back into the sarcoplasmic reticulum
Which type of muscle does not have neuromuscular junctions?
Smooth muscle
What is an additional requirement for heart muscle contraction, besides SR calcium release?
Extracellular calcium
What type of muscle responds to both neural and circulating factors?
Smooth muscle
What is the primary cause of skeletal muscle contraction?
Stimulation via acetylcholine at the neuromuscular junction
What is the additional requirement for heart muscle contraction, besides SR calcium release?
Extracellular calcium
Which type of muscle responds to both neural and circulating factors?
Smooth muscle
Match the following components of muscle contraction with their roles:
Myosin head group = Interacts with actin after tropomyosin movement Tropomyosin = Inhibits myosin-actin interaction at low [Ca2+] Calcium (Ca2+) = Causes conformational shift in Tn-I, leading to tropomyosin movement ATP = Breaks actinomyosin cross-bridge and conserves free energy from hydrolysis
Match the following events in muscle contraction with their consequences:
Binding of calcium to Tn-C = Causes a conformational shift in Tn-I Release of ADP and Pi from myosin = Causes a major conformational change in myosin, producing a 'power stroke' Uptake of calcium back in the SR = Causes ATP to bind myosin and break the actinomyosin cross-bridge Contraction of actin chain = Increases their overlap and causes muscle contraction
Match the following molecules with their functions in muscle contraction:
ADP and Pi bound to myosin head group = Myosin head group is in a high-energy conformation but unable to bind actin ATP binding to myosin = Breaks actinomyosin cross-bridge and conserves free energy from hydrolysis Ca2+ in resting muscle = Low levels prevent myosin-actin interaction due to tropomyosin inhibition Tn-C in muscle contraction = Causes a conformational shift in Tn-I, leading to tropomyosin movement
What is the role of calcium in muscle contraction?
Calcium binds to Tn-C, causing a conformational shift in Tn-I, which is transmitted through Tn-T to tropomyosin, allowing myosin to interact with actin and initiating the power stroke.
Describe the sequence of events that leads to muscle contraction.
In resting muscle, myosin head group is in a high-energy conformation but unable to bind actin due to tropomyosin inhibition at low [Ca2+]. When calcium enters the sarcoplasm, it binds to Tn-C, causing a conformational shift in Tn-I, which is transmitted through Tn-T to tropomyosin, allowing myosin to interact with actin and initiating the power stroke. The release of ADP and Pi causes a major conformational change in myosin, producing a “power stroke” that moves the actin chain, increasing their overlap and causing contraction.
What happens to myosin after the power stroke during muscle contraction?
The release of ADP and Pi causes a major conformational change in myosin, producing a “power stroke” that moves the actin chain, increasing their overlap and causing contraction.
Which process provides a means to rapidly convert ADP back to ATP in muscle cells?
Creatine phosphate shuttle
What is the source of ATP in muscle cells during exercise?
Anaerobic glycolysis
Which ATPase is needed for muscle contraction to maintain the intracellular concentration of ATP?
Na+/K+-ATPase
What is the primary function of the combined action of creatine phosphokinase and adenylate kinase (myokinase) in muscle cells?
Regenerate the supply of ATP
What is the major contributor to energy utilization during later stages of short-duration, high-power output muscle contractions?
Glycogen
For longer duration, low intensity muscle contractions, what becomes the primary source of energy?
Oxygen supply and aerobic metabolism of fatty acids
What is the primary source of energy for fast-twitch muscle fibers during short bursts of contraction?
Anaerobic glycolysis
Which muscle fiber type is well perfused with blood, rich in mitochondria, and myoglobin?
Slow-twitch (slow-oxidative)
What is the color of fast-twitch muscle fibers due to?
Less blood flow and lower myoglobin content
What is the primary storage form of energy in slow-twitch muscle fibers?
Fatty acid oxidation
New skeletal muscle fibers form by fusion of myoblasts
True
Myoblasts will continue to proliferate as long as certain growth factors such as FGF or HGF are present
True
Once the growth factors are removed, the myoblasts rapidly stop dividing, differentiate, and eventually fuse to form fibers
True
New skeletal muscle fibers form by fusion of myoblasts:
True
Myoblasts will continue to proliferate as long as certain growth factors such as FGF or HGF are present:
True
Once the growth factors are removed, the myoblasts rapidly stop dividing, differentiate, and eventually fuse to form fibers:
True
What are satellite cells in relation to muscle fibers?
Stem cells of adult skeletal muscles stored near mature muscle fibers
What happens to satellite cells when muscle is damaged?
They are activated to proliferate and their progeny can fuse to repair damaged muscle
What is the primary role of satellite cells in muscle tissue?
Repairing damaged muscle fibers
Which protein is part of a complex with sarcoglycans and dystroglycans, and its loss results in the destabilization of the entire dystroglycan-glycoprotein complex?
Dystrophin
Which protein does dystroglycan bind to, along with F-actin?
ß-dystroglycan
What is the primary role of dystrophin in muscle cells?
Stabilizing the dystroglycan-glycoprotein complex
What is the primary consequence of mutations in sarcoglycans?
Disruption of the dystroglycan-glycoprotein complex
Which protein do sarcoglycans bind to, contributing to muscle membrane stability?
Dystrobrevin
What is the function of sarcospan in relation to sarcoglycans?
Enhances the function of sarcoglycans in muscle membrane stability
What is the function of alpha-dystroglycan in the DGC?
Binds to laminin 2 and other extracellular matrix proteins with laminin globular (LG) domains
Which protein binds to dystrophin inside the cell and to alpha-dystroglycan outside the cell?
Beta-dystroglycan
What is the primary role of dystroglycan in the DGC?
Provides the link between the cytoskeleton and the basal lamina (ECM)
What is the primary function of matriglycan in muscle cells?
Acting as a glycosaminoglycan-like polymer
Which enzymes define the different forms of M3-type O-Man glycans?
Mannosyltransferases
What distinguishes matriglycan from traditional glycosaminoglycans (GAGs)?
Presence of amino sugars like GlcNAc or GalNAc
What is the unique feature of the glycan associated with LARGE2?
Repeating disaccharide structure
What is the primary reason for the immense amount of specific gene transcription and energy utilization devoted to the production of this glycan?
It is only found on one protein
What physicochemical property makes the glycan useful as a linker?
Flexibility
What limits the regenerative response of satellite cells in muscle tissue?
Progressive shortening of telomeres
What replaces muscle cells when satellite cell regenerative response cannot keep pace with the damage?
Connective tissue and fibroblasts
What is the consequence of loss of dystrophin and other components of the DGC in muscle tissue?
Replacement of muscle cells by connective tissue and fibroblasts
What is the primary challenge in delivering genes to most of the striated muscle in the body for Duchenne muscular dystrophy?
Efficient delivery of the new gene to most of the striated muscle in the body
What is the interesting approach mentioned for delivering genes to muscle tissue?
Modify viral coat proteins to alter their natural tropism or selectivity for certain tissues
Why are viral vectors still the best choice for delivering genes to muscle tissue despite problems with antigenicity?
Viral vectors have the best delivery efficiency despite antigenicity problems
What would be a crude delivery method for genes to muscle tissue, as mentioned in the text?
Hundreds of intramuscular injections
Explain the challenges in delivering genes to most of the striated muscle in the body for Duchenne muscular dystrophy.
The challenge lies in the efficient delivery of the new gene to most of the striated muscle in the body, which constitutes over 40% of the body mass. Additionally, the design of viral vectors to carry the large genes to be replaced, such as the 2.4 Mb dystrophin gene, is a significant challenge. Muscle transduction with viruses must also not trigger toxic or immunological reactions that can further damage the weakened muscle. The tight packing of muscles makes delivery difficult, and crude delivery methods like hundreds of intramuscular injections are not feasible for critical muscles like the heart and diaphragm.
What are the potential approaches for delivering genes to muscle tissue and the associated drawbacks?
The potential approaches for delivering genes to muscle tissue include viral vectors and crude delivery methods, each with its drawbacks. Viral vectors, although the best choice, may still pose problems with antigenicity, thus triggering immunological reactions. Crude delivery methods, such as hundreds of intramuscular injections, are suitable for certain muscles involved in mobility but are challenging to use for critical muscles like the heart and diaphragm.
What is the interesting approach mentioned for modifying viral vectors, and how does it aim to address the existing problems?
The interesting approach mentioned involves modifying viral coat proteins to alter their natural tropism or selectivity for certain tissues. By doing so, the aim is to address the problems associated with viral vectors, such as antigenicity and immunological reactions, by altering their natural tropism or selectivity for certain tissues.
What promising therapeutic approaches are being explored for muscular dystrophy, and what challenges do they present?
Gene therapy and substrate replacement therapy for certain partially functional enzymes are promising therapeutic approaches for muscular dystrophy. However, they present challenges in terms of efficient delivery of the new gene to most of the striated muscle in the body, designing viral vectors to carry large genes to be replaced, and avoiding toxic or immunological reactions during muscle transduction with viruses.
What are some potential therapeutic approaches for muscular dystrophy?
Some potential therapeutic approaches for muscular dystrophy include gene therapy, exon skipping to restore dystrophin expression, and stem cell therapy.
What controls the heart rate by creating rhythmic impulses?
Pacemaker cells
What is responsible for the atrial propagation of the electrical potential in the heart?
Sinoatrial (SA) node
What is the average resting cardiac rate in adult humans approximately?
70 beats per minute
What happens when there are congenital defects in the heart valves?
Imbalance of blood flow
What is the primary source of energy for the heart?
Continuous supply of energy
What is the primary role of the valves in the heart?
Control the flow of blood through the heart chambers
What is the function of the sinoatrial (SA) node in the heart?
Responsible for atrial propagation of electrical potential
What controls the native rate of the heart's rhythmic impulses?
Sympathetic and parasympathetic nerve fibers
What is the initiating factor for atherogenesis?
Damage to the endothelium
What is the main component of the plaque formed during atherogenesis?
Cholesterol-containing foam cells
What mitigates the formation of foam cells during atherogenesis?
Adiponectin from adipose tissue
What presents the biggest threat during atherogenesis?
Formation of a blood clot or thrombus
Monocytes (precursors of macrophages) are attracted to the damaged ______ and migrate into the arterial wall
endothelium
These macrophages begin to ingest LDL (cholesterol-containing) particles that have entered the damaged ______ and become oxidized
site
Plaque can rupture and form a blood clot or ______ (this presents the biggest threat)
thrombus
Main components of atherogenesis are endothelial dysfunction, lipid deposition and inflammation in the vascular ______
wall
What does MCV stand for in the context of anemia?
Mean corpuscular volume
What does Hct measure in the blood?
Percent of whole blood that is red blood cells
What does it mean when red blood cells are hypochromic?
Lower than normal hemoglobin concentration
What is the inheritance pattern of the deficiency described in the text?
X-linked recessive
Which of the following medications is NOT listed as a precipitating factor for oxidative damage and hemolysis in individuals with the described deficiency?
Antibiotics
What is the primary protective mechanism that is compromised in individuals with the described deficiency under increased oxidative conditions?
Production of NADPH
What is the only real cure for hemolysis due to damage of red blood cells as they pass through defective periprosthetic valve?
Valve replacement
In treating hemolysis due to damage of red blood cells as they pass through defective periprosthetic valve, what can be used to decrease the force of contraction and reduce shear stress?
Beta blockers
In some cases of hemolysis due to damage of red blood cells as they pass through defective periprosthetic valve, what may be warranted if MCV is low?
Iron supplementation
What is the primary consequence of B12 deficiency?
Decreased nucleotide synthesis leading to arrested red blood cell development and larger cells
What is the primary consequence of thalassemia?
Decreased synthesis of globin protein leading to decrease in hemoglobin and anemia
What is the primary consequence of sickle cell anemia?
Variants of the globin gene resulting in polymerization of hemoglobin and abnormal red blood cell structure
What is the primary treatment for thalassemia?
Blood transfusions and iron chelation therapy
During which stage of life does primitive erythropoiesis occur?
During fetal development
What is the primary source of erythrocyte metabolism?
Glycolysis
What is the main reason for the nucleation of primitive erythrocytes?
Delivery of oxygen to the developing fetus
What is the process of erythropoiesis?
Formation of erythrocytes
Where does erythropoiesis occur in fetal development?
Liver
What triggers the production of erythropoietin (EPO)?
Hypoxia
Which transcription factor is involved in coordinated expression of globin and heme synthesis?
GATA-1
What is the primary fuel source for erythrocyte metabolism?
Glucose
What is the primary function of the Pentose Phosphate Pathway in erythrocytes?
Produces NADPH and glycolytic intermediates
What is the role of carbonic anhydrase in erythrocytes?
Converts CO2 to carbonic acid
What is the primary component of erythrocyte structure?
Hemoglobin
What are the mechanisms of senescent cell destruction?
Extravascular and intravascular hemolysis
What is the primary role of erythrocytes in gas exchange?
Facilitate oxygen delivery and CO2 removal
What are the primary components of heme synthesis?
Glycine, succinyl-CoA, and iron
What cellular changes occur in erythropoiesis?
Decrease in cell size and loss of organelles
What is the primary role of senescent erythrocytes?
Undergo changes in membrane, leading to decreased deformability
Which of the following is the expected laboratory finding in a patient with B12 deficiency anemia?
Elevated mean corpuscular volume (MCV)
What is the primary pathophysiology of thalassemia?
Defective globin chain synthesis
In sickle cell anemia, what is the expected laboratory finding?
Elevated unconjugated serum bilirubin
What is the expected treatment for B12 deficiency anemia?
Oral vitamin B12 supplementation
What is the primary pathophysiology of thalassemia?
Defective globin chain synthesis
What is the primary pathophysiology of sickle cell anemia?
Abnormal erythrocyte shape due to hemoglobin S
What is the expected laboratory finding in thalassemia?
Decreased mean corpuscular volume (MCV)
What is the primary treatment for sickle cell anemia?
Hydroxyurea therapy
What is the expected laboratory finding in B12 deficiency anemia?
Elevated mean corpuscular volume (MCV)
What is the pathophysiology of thalassemia?
Defective synthesis of globin chains in hemoglobin
What is the expected laboratory finding in sickle cell anemia?
Elevated unconjugated bilirubin
What is the treatment for B12 deficiency anemia?
Vitamin B12 supplementation
What is the primary pathophysiology of thalassemia?
Defective synthesis of globin chains in hemoglobin
What is the primary treatment for sickle cell anemia?
Hydroxyurea therapy
What is the expected laboratory finding in thalassemia?
Decreased mean corpuscular volume (MCV)
What is the primary treatment for thalassemia?
Blood transfusion
What is the max recommended dietary intake of iron for adults?
18 mg/d
Where is iron primarily absorbed in the body?
Duodenum and upper jejunum
What is the primary iron transport protein in the body?
Transferrin
What regulates iron release from enterocytes and macrophages?
Hepcidin
What is the recommended dietary intake of iron for adults?
8-18 mg/d
Which protein is responsible for iron transport in the body?
Transferrin
What is the primary cellular consequence of abnormal iron metabolism?
Generation of free radicals
What is the role of hepcidin in iron metabolism?
Regulates iron release from enterocytes and macrophages
What is the recommended dietary intake of copper for adults?
5-10 mg/d
Which transporter is defective in Wilson disease, leading to copper accumulation in the liver?
Atp7b
What are the primary symptoms of porphyrias?
Photosensitivity and acute attacks with neurological symptoms
What is the primary consequence of hemochromatosis?
Iron overload in the body
What is the primary excretory route for copper in the body?
Bile
In which syndrome do inherited defects or immaturity of hepatocyte enzymes result in jaundice?
Crigler-Najjar syndrome
What is the primary breakdown product of heme?
Bilirubin
What is the primary cause of neonatal jaundice?
Bilirubin excretion deficiency
What is the diagnosis for a 57-year-old man with high transferrin saturation and serum ferritin, showing symptoms of weakness, ascites, and jaundice?
Hepatocellular carcinoma
What is the likely trigger for a 34-year-old woman's porphyria, as indicated by elevated porphyrin and aminolevulinic acid levels?
Antibiotics
What are the key aspects of metabolism illustrated by the cases?
Porphyrias and copper transport
Which transporter defect leads to copper accumulation in the liver and causing hepatic and neurological symptoms?
Atp7b
What is the primary cause of hemochromatosis?
Abnormal iron absorption
What is the primary function of heme in the body?
Important in many cellular proteins
What is the end product of heme catabolism?
Stercobilins
Which condition is characterized by high transferrin saturation and serum ferritin, leading to a diagnosis of hepatocellular carcinoma?
Hemochromatosis
Which disorder is likely triggered by antibiotics and is indicated by elevated porphyrin and aminolevulinic acid levels?
Porphyria
What are the primary products of bilirubin excretion in bile?
Urobilinogens and stercobilins
Which condition involves high total serum bilirubin and unconjugated bilirubin levels in a baby?
Neonatal jaundice
What is the primary cause of jaundice in conditions like Crigler-Najjar syndrome and Gilbert syndrome?
Bilirubin excretion deficiency
What can cause porphyrias, leading to photosensitivity and acute attacks with neurological symptoms?
Defects in heme synthesis
What is the recommended dietary intake of copper for adults?
1-10 mg/d
Which micronutrient, like iron, is reactive and can participate in the generation of free radicals, but is excreted in bile?
Copper
What is the recommended dietary intake of copper for adults?
5-10 mg/d
Which transporter is defective in Wilson disease, leading to copper accumulation in the liver?
Atp7b
What are the products of heme catabolism?
Bilirubin and urobilinogens
What can defects in heme synthesis cause?
Porphyrias
What is the primary cause of neonatal jaundice?
Inherited defects or immaturity of hepatocyte enzymes
Which disease is characterized by iron overload in the body?
Hemochromatosis
What are the symptoms of Wilson disease?
Hepatic and neurological symptoms
What are the initial symptoms of porphyrias?
Photosensitivity and acute attacks
What is the final excretory form of bilirubin?
Urobilinogens
What is the primary diagnosis for a 57-year-old man showing high transferrin saturation and serum ferritin?
Hemochromatosis
What is the likely trigger for the porphyria in Case 2?
Antibiotics
What is the primary cause of neonatal jaundice in Case 3?
Inherited defects or immaturity of hepatocyte enzymes
What is the primary function of collagens in the extracellular matrix?
Providing flexibility and strength to tissues
What is the chemical composition of collagen that contributes to its unique structure?
33% glycine, 13% proline, 10% hydroxyproline
Which type of collagen is primarily found in cartilage?
Type II
What is the main function of the extracellular matrix (ECM)?
Surrounding and supporting cells
Which macromolecule is NOT a major component of the extracellular matrix (ECM)?
Hyaluronic acid
What is the primary role of elastin in the extracellular matrix (ECM)?
Providing elasticity to tissues
Which class of macromolecules in the ECM is responsible for cell adhesion and migration?
Fibronectin and laminin
What is the function of proteoglycans in the extracellular matrix (ECM)?
Regulating water balance and ion movement
Which protein is implicated in the altered cell behavior during tissue morphogenesis in Marfan syndrome?
Fibrillin-1
What is the major growth factor involved in bone development and remodeling, as mentioned in the text?
Transforming growth factor-beta (TGF-ß)
Which drug is thought to rescue the Marfan phenotypes by either decreasing the expression of TGF-beta receptor or decreasing expression of TGF-ß activators?
Losartan
What is the primary role of fibrillin-1 in regulating TGF-beta bioactivity?
Binding to latent TGF-ß binding proteins (LTBPs)
Which organ showed loss of tissue integrity similar to emphesyma in mice with defective fibrillin-1?
Lung
What is the approved drug that acts as an angiotensin receptor blocker and is thought to rescue the Marfan phenotypes?
Losartan
Which therapeutic strategy for Marfan vascular disease involves the use of drugs to block the activation of TGF-ß?
Beta-adrenergic blockers
What do mutations in fibrillin-1 lead to?
Loss of microfibrils
Which protein is more hydrophobic than collagen?
Elastin
What is the primary structure of elastin composed of?
Alternating hydrophobic (valine-rich) and hydrophilic (lysine-rich) domains
Which glycoprotein is a dimeric protein with binding sites for heparin, collagen, and other molecules?
Fibronectin
Which component of the ECM is mainly comprised of carbohydrates and not protein?
Proteoglycans
Which cells synthesize type I collagen and other proteins that control bone mineralization?
Osteoblasts
Which protein is responsible for the attachment of hydroxyapatite to collagen in bone matrix?
Glycoproteins
Which growth factors induce the differentiation of osteoblasts?
BMP (bone morphogenetic proteins) and Wnt proteins
Which monoclonal antibody binds to RANKL and mimics the effect of osteoprotegerin?
Denosumab
Which condition is characterized by progressive loss of bone density and increased susceptibility to fractures?
Osteoporosis
What is the primary role of drugs that decrease osteoclast activity in the treatment of osteoporosis?
To decrease bone resorption
Which hormone is essential for the development and maintenance of bone mass?
Parathyroid hormone (PTH)
Which cell type must be activated before it is capable of resorbing bone?
Osteoclasts
Which vitamin is essential for maintaining the enzyme prolyl hydroxylase in its active form?
Vitamin C
What is the primary cause of Marfan syndrome?
Mutations in the ECM protein, fibrillin-1
What is the primary function of vitamin D in the body?
Regulating calcium absorption from the intestine
Which vitamin deficiency leads to the disease mechanism and pathophysiology of Scurvy?
Vitamin C
What is the main role of Denosumab (Prolia®) in the treatment of osteoporosis?
Increasing bone density
What is the primary effect of insufficiency or inefficient action of activated vitamin D during childhood?
Rickets
Which vitamin deficiency causes sailors at sea for long periods to develop scurvy?
Vitamin C
What is the primary consequence of vitamin D deficiency?
Rickets
Which vitamin acts as a reducing agent and is essential for maintaining the enzyme prolyl hydroxylase in its active form?
Vitamin C
What is the primary role of Odanacatib (MK-0822, MK-822) in the treatment of osteoporosis?
Inhibiting cathepsin K
What is the primary cause of osteoporosis?
Decreased bone density
What is the main effect of bisphosphonate therapy (FosamaxTM) in the treatment of osteoporosis?
Increasing bone density
Which drug, approved by the FDA in 1995, is thought to rescue the Marfan phenotypes by either decreasing the expression of TGF-beta receptor or decreasing expression of TGF-ß activators?
Losartan
Which therapeutic strategy for Marfan vascular disease involves drugs that block the activation of TGF-ß?
Losartan
Which type of drugs are used to slow aortic growth in Marfan vascular disease?
Beta-adrenergic blockers
Which of the following is true regarding peripheral activation of Tc cells?
Peripheral activation can produce more Tc cells and/or induce Tc cells to express higher levels of cytotoxic factors.
What is the consequence of engagement of Tc TCR and MHC-I without co-receptor activation or supporting cytokine signaling?
Induces Tc anergy or Tc cell death.
What is the role of B7-1 on APCs in relation to T cells?
B7-1 binds CD28 on T cells, stimulating T-cell survival and further activation.
What happens when PD-L1 (B7-H1) binds PD-1 at the T-cell surface?
PD-1’s ITIM and ITSM motifs become phosphorylated and recruit SHP1 phosphatase, reducing signal through the TCR receptor.
Which process contributes to the high mutation rate of the HIV genome?
Antigenic variation through random mutation of its GP120/GP40 surface receptors
Which molecule inhibits NK cell cytotoxicity in HIV-infected cells?
HLA-E
What is the primary role of the HIV protein Nef?
Reduce CD4 expression and enhance Fas ligand expression on infected cells
What is the consequence of killing of infected CD4+ T-cells by HIV infection?
Reduction in T-cell count leading to inadequate immune defenses
What contributes to the progression of HIV infection towards AIDS?
Opportunistic pathogens taking advantage of expanding niches
What is the main function of the immune system in the context of HIV infection?
To raise responses against and clear viruses
Which molecule actively decreases expression of CD4 and MHC-I at the surface of infected cells?
Vpu
What contributes to the avoidance of immune elimination by HIV?
Antigenic variation through random mutation of its GP120/GP40 surface receptors
What is the consequence of the loss of MHC-I on HIV-infected cells?
Reduced NK cell killing
What is the ultimate consequence of killing of CD4+ T-cells by HIV infection?
Too few T-cells exist to mount appropriate defenses against pathogens
What contributes to the progression of HIV infection towards AIDS?
Opportunistic pathogens taking advantage of expanding niches
What is the impact of cytokine storms resulting from runaway immune activation in HIV infection?
Multiple organ dysfunctions
What is the purpose of the immunological synapse?
To provide a stable platform for extended signaling between cells, ensuring multiple opportunities to abort the activation/killing process
What is the primary role of APCs in relation to T cells?
To activate Th1 and Th2 cells, supporting the differentiation of Tc cells expressing TCRs capable of recognizing peptides derived from the pathogen
What enhances the killing potential of activated Tc cells?
Cytokines released by activated Tc cells
What is the primary function of class switching in B-cells?
To allow the Fc effector region of an IgM to be swapped for another Fc type, initiated at Switch regions by deamination of C residues by AID, regulated by cytokines
What happens to the recombined chromosome during class switching in B-cells?
It contains new junctions within intronic DNA sequence that will be spliced out of the final Ig mRNA
What can a B-cell that has undergone class switching from IgM to another Ig type do?
Undergo additional class switching with any downstream Fc domains remaining within the heavy chain gene cluster
What is the primary consequence of loss of MHC-I on HIV-infected cells?
Enhanced immune recognition and elimination of infected cells
What is the primary role of dystroglycan in the DGC?
To support muscle membrane stability
What is the primary storage form of energy in muscle?
Glycogen
What can defects in heme synthesis cause?
Porphyria
What contributes to the progression of HIV infection towards AIDS?
Impaired immune response
What is the primary treatment for thalassemia?
Blood transfusions
Peripheral activation of Tc cells produces more ________ cells and/or induces Tc cells to express higher levels of cytotoxic factors.
Tc
Engagement of Tc TCR and MHC-I without co-receptor activation or without supporting cytokine signaling induces Tc ________ or Tc cell death.
anergy
Co-receptor engagement can be stimulatory or inhibitory (if MHC-TCR binding has already occurred). B7-1 expressed on APCs binds CD28 on T cells (CD4+ or CD8+), which stimulates T-cell ________ and further activation.
survival
PD-L1 (aka B7-H1) on APCs binds PD-1 on T cells and inhibits T-cell ________ and further activation.
survival
CTLA4 signaling may be similar to PD-1 or CTLA4 may reduce CD3 signaling by out-competing ______ for B7-1 binding.
CD28
CD28 activation of ______ results in the production of PIP3/DAG and activation of AKT and NF-kB, enhancing T cell survival and function.
PI3K
B-cells are initially activated by antigen interactions with the BCR and become fully activated by engagement of appropriate ______ found on the B-Cell and Th2 cells.
co-receptors
Signaling between B-cells and T-cells, or between other APCs and T-cells, occurs at the ______, a structured domain of signaling molecules and adhesion molecules localized within a lipid domain enriched in specific lipids and glycolipids.
immunological synapse
The purpose of the immunological synapse is to provide a ______ platform for extended signaling between cells, ensuring multiple opportunities to abort the activation/killing process.
stable
Coordinated activation of humoral and cellular immunity to the same pathogen challenge arises from ______ of B-cells and T cells with overlapping binding specificity.
clonal selection
APCs activate Th1 and Th2 cells, supporting the ______ of Tc cells expressing TCRs capable of recognizing peptides derived from the pathogen.
differentiation
Activated Tc cells initiate the demise of target cells through ______ vesicles or CD95L engagement, and their killing potential is enhanced by cytokines released by activated Tc cells.
lytic
B-cells initially express IgM but mature their antibody response by ______ and affinity maturation in response to cytokine activation.
class switching
Class switching allows the Fc effector region of an IgM to be swapped for another Fc type, initiated at Switch regions by deamination of C residues by ______, regulated by cytokines.
AID
The recombined chromosome contains new junctions within intronic DNA sequence that will be ______ out of the final Ig mRNA.
spliced
A B-cell that has ______ne class switching from IgM to another Ig type can ______ additional class switching with any downstream Fc domains remaining within the heavy chain gene cluster.
undergo
Antibody affinity maturation utilizes the same enzymes as ______ to generate regions of Somatic Hypermutation within the complementarity determining region of the heavy and light chain variable domains.
class-switching
The major coat proteins of the HIV virus (GP120 and GP40) are not present at high levels at the virion surface. Therefore, the predominant molecules at the surface of the HIV virion are self-derived ______.
membrane lipids
The high mutation rate of the HIV genome ensures that very early in the infection the immune system is presented with an array of viruses that possess mutations at almost every ______ within the HIV genome.
nucleotide
Proteins encoded in the HIV genome (Vpu and Nef) actively decrease expression of CD4 and MHC-I at the surface of infected cells, effectively blinding the immune system to the presence of the virus and blocking the ability of infected cells to ______.
signal
The HIV protein Nef, which reduces CD4 expression, enhances Fas ligand expression on infected cells, inducing cell death in local T-cells through Fas- ______ interactions.
FasL
Down-regulation of MHC-I on HIV-infected cells should enhance NK cell killing since loss of MHC-I is a signal of altered ______.
self
The same molecular and cellular mechanisms that allow us to identify and destroy pathogens or cancer cells also contribute to the maintenance of ______ tissue functions.
normal
Allelic diversity in various HLA loci underlies the concept of human haplotypes and might explain individual-to-individual variation in disease susceptibility or severity when underlying pathology results from inflammatory or ______ responses.
immune
Decreased surface expression of CD4 and MHC on infected cells is a strategy used by HIV to ______ immune elimination.
avoid
Cytokine storms that result from runaway immune activation produce multiple organ ______.
dysfunctions
Vascular permeability altered by cytokine signaling causes fluid leakage and blood coagulation in the lungs, grossly interfering with gas exchange and leading to suffocation, and ultimately ______ failure.
multi-organ
The same molecular and cellular mechanisms that allow us to identify and destroy pathogens or cancer cells also contribute to the maintenance of ______ tissue functions.
normal
Which of the following is true about the engagement of Tc TCR and MHC-I without co-receptor activation?
It induces Tc anergy or Tc cell death
What is the consequence of PD-L1 (B7-H1) binding PD-1 at the T-cell surface?
It inhibits T-cell survival and further activation
What happens when B7-1 on APCs binds CTLA4 on T cells?
It inhibits T-cell survival and further activation
What is the consequence of sufficient IFN-g and IL-2 generated by local Th1 cells in the periphery?
It allows Tc cells to be fully activated at sites of inflammation
What is the major coat protein of the HIV virus?
GP120 and GP40
What is the primary mechanism by which HIV avoids immune elimination?
Antigenic variation through random mutation
What is the role of the HIV protein Nef in infected cells?
Reduces CD4 expression and enhances Fas ligand expression
How does the low abundance of HIV-encoded proteins on the virion surface contribute to immune evasion?
Reduces the likelihood of virus clearance
What is the consequence of the high mutation rate of the HIV genome?
Presents an array of viruses with mutations at almost every nucleotide
How does the HIV virus induce immune evasion through MHC molecules?
Induces the expression of HLA-C and HLA-E
What is the primary consequence of the killing of CD4+ T-cells by HIV infection?
Reduction in T-cell count leading to immune deficiency
How do opportunistic pathogens contribute to the progression of HIV infection towards AIDS?
Take advantage of expanding niches due to reduced T-cell count
What is the consequence of cytokine storms resulting from runaway immune activation in HIV infection?
Multiple organ dysfunctions
What is the impact of immune activation in HIV infection on tissue functions?
Impacts normal functions of cells in almost all tissues
What underlies the concept of human haplotypes and might explain individual-to-individual variation in disease susceptibility?
Allelic diversity in various HLA loci
What is the primary role of Somatic Hypermutation in antibody affinity maturation?
Generates regions of mutation within the complementarity determining region
Which molecule is primarily responsible for the production of PIP3/DAG and activation of AKT and NF-kB, enhancing T cell survival and function?
PI3K
How are B-cells initially activated?
By antigen interactions with the BCR
What is the purpose of the immunological synapse?
To provide a stable platform for extended signaling between cells
What supports the differentiation of Tc cells expressing TCRs capable of recognizing peptides derived from the pathogen?
Activated B-cells
Which enzyme is responsible for initiating class switching in B-cells?
AID
What happens to the recombined chromosome during class switching in B-cells?
It contains new junctions within intronic DNA sequence that will be spliced out of the final Ig mRNA
What enhances the killing potential of activated Tc cells?
Cytokines released by activated Tc cells
What is the primary cause of neonatal jaundice?
Bilirubin overproduction
What is the primary role of APCs in relation to T cells?
To present antigens to T cells
What is the primary function of heme in the body?
Oxygen transport
What contributes to the progression of HIV infection towards AIDS?
Loss of MHC-I on infected cells
What presents the biggest threat during atherogenesis?
Plaque rupture
Study Notes
Erythropoiesis and Erythrocytes: Key Points
- Erythropoiesis occurs in fetal liver and spleen and shifts to bone marrow near birth
- Erythropoietin (EPO) is produced by the kidney and liver in response to hypoxia
- GATA-1 is a transcription factor involved in coordinated expression of globin and heme synthesis
- Cellular changes in erythropoiesis involve a decrease in cell size and loss of organelles
- Heme is synthesized from glycine, succinyl-CoA, and iron
- Erythrocytes facilitate oxygen delivery and CO2 removal, and have an anti-inflammatory role
- Glucose is the fuel source for erythrocyte metabolism
- The Pentose Phosphate Pathway produces NADPH and glycolytic intermediates
- Carbonic Anhydrase in erythrocytes converts CO2 to carbonic acid
- Erythrocyte structure includes hemoglobin, membrane lipids, proteins, and glycoconjugates
- Senescent erythrocytes undergo changes in membrane, leading to decreased deformability
- Extravascular and intravascular hemolysis are mechanisms of senescent cell destruction
Heme, Iron, and Copper Metabolism Overview
- Hemochromatosis is a disease causing iron overload in the body, with various genetic classes leading to abnormal iron absorption.
- Copper is an essential micronutrient, with a recommended dietary intake of 1-10 mg/d for adults and plays a crucial role in the body.
- Copper, like iron, is reactive and can participate in the generation of free radicals, but it is excreted in bile.
- Atp7b, a transporter in the golgi, is defective in Wilson disease, leading to copper accumulation in the liver and causing hepatic and neurological symptoms.
- Heme is an iron-containing cofactor important in many cellular proteins and is synthesized from glycine, succinyl-CoA, and iron.
- Defects in heme synthesis can cause porphyrias, leading to photosensitivity and acute attacks with neurological symptoms.
- Heme is catabolized to biliverdin, then bilirubin, which is excreted in bile and converted by intestinal bacteria to fecal urobilinogens and stercobilins.
- Inherited defects or immaturity of hepatocyte enzymes can result in jaundice, as seen in conditions like Crigler-Najjar syndrome and Gilbert syndrome.
- Case 1 describes a 57-year-old man with symptoms of weakness, ascites, and jaundice, showing high transferrin saturation and serum ferritin, with a diagnosis of hepatocellular carcinoma.
- Case 2 presents a 34-year-old woman with abdominal pain, photosensitivity, and elevated porphyrin and aminolevulinic acid levels, indicating a porphyria likely triggered by antibiotics.
- Case 3 involves a baby boy with neonatal jaundice, as evidenced by high total serum bilirubin and unconjugated bilirubin levels.
- The cases illustrate different aspects of heme, iron, and copper metabolism, including disorders like hemochromatosis, porphyrias, and neonatal jaundice.
Integrated Immune Response
- CTLA4 signaling may be similar to PD-1 and may reduce CD3 signaling by out-competing CD28 for B7-1 binding
- CD28 activates PI3K resulting in the production of PIP3/DAG and activation of AKT and NF-kB, enhancing T cell survival, function, and effector functions
- B-cells are activated by antigen interactions with the BCR and become fully activated by engagement of appropriate co-receptors (e.g., CD40 on the B-cell and CD40L on the T cell) and Th2 cytokines
- B cell activation requires sequential activation-to-survival-to-differentiation supported by appropriate signaling and co-receptor engagement
- Signaling between immune cells occurs at the immunological synapse, a structured domain of signaling and adhesion molecules
- The mature immunological synapse is characterized by a central signaling domain surrounded by adhesive proteins
- The purpose of the immunological synapse is to provide a stable platform for extended signaling between cells
- Coordinated activation of humoral and cellular immunity to the same pathogen arises from clonal selection of B-cells and activation of Th1 and Th2 cells
- APCs activate Th1 cells that support the differentiation of Tc cells, leading to the formation of an immunological synapse between Tc and the target cell
- Activated Tc cells initiate the demise of target cells through apoptosis, with two pathways that converge on apoptosis
- The killing potential of Tc cells is enhanced by the direct action of cytokines on target cells
- B-cells initially express IgM but mature their antibody response by class switching and affinity maturation, regulated by cytokines
Immunological Synapse and Immune Cell Activation
- CTLA4 signaling may be similar to PD-1 or CTLA4 may reduce CD3 signaling by out-competing CD28 for B7-1 binding.
- CD28 activation of PI3K results in the production of PIP3/DAG and activation of AKT and NF-kB, enhancing T cell survival and function.
- B-cells are initially activated by antigen interactions with the BCR and become fully activated by engagement of appropriate co-receptors found on the B-Cell and Th2 cells.
- Signaling between B-cells and T-cells, or between other APCs and T-cells, occurs at the immunological synapse, a structured domain of signaling molecules and adhesion molecules localized within a lipid domain enriched in specific lipids and glycolipids.
- The purpose of the immunological synapse is to provide a stable platform for extended signaling between cells, ensuring multiple opportunities to abort the activation/killing process.
- Coordinated activation of humoral and cellular immunity to the same pathogen challenge arises from clonal selection of B-cells and T cells with overlapping binding specificity.
- APCs activate Th1 and Th2 cells, supporting the differentiation of Tc cells expressing TCRs capable of recognizing peptides derived from the pathogen.
- Activated Tc cells initiate the demise of target cells through lytic vesicles or CD95L engagement, and their killing potential is enhanced by cytokines released by activated Tc cells.
- B-cells initially express IgM but mature their antibody response by class switching and affinity maturation in response to cytokine activation.
- Class switching allows the Fc effector region of an IgM to be swapped for another Fc type, initiated at Switch regions by deamination of C residues by AID, regulated by cytokines.
- The recombined chromosome contains new junctions within intronic DNA sequence that will be spliced out of the final Ig mRNA.
- A B-cell that has undergone class switching from IgM to another Ig type can undergo additional class switching with any downstream Fc domains remaining within the heavy chain gene cluster.
Immunological Synapse and Immune Cell Activation
- CTLA4 signaling may be similar to PD-1 or CTLA4 may reduce CD3 signaling by out-competing CD28 for B7-1 binding.
- CD28 activation of PI3K results in the production of PIP3/DAG and activation of AKT and NF-kB, enhancing T cell survival and function.
- B-cells are initially activated by antigen interactions with the BCR and become fully activated by engagement of appropriate co-receptors found on the B-Cell and Th2 cells.
- Signaling between B-cells and T-cells, or between other APCs and T-cells, occurs at the immunological synapse, a structured domain of signaling molecules and adhesion molecules localized within a lipid domain enriched in specific lipids and glycolipids.
- The purpose of the immunological synapse is to provide a stable platform for extended signaling between cells, ensuring multiple opportunities to abort the activation/killing process.
- Coordinated activation of humoral and cellular immunity to the same pathogen challenge arises from clonal selection of B-cells and T cells with overlapping binding specificity.
- APCs activate Th1 and Th2 cells, supporting the differentiation of Tc cells expressing TCRs capable of recognizing peptides derived from the pathogen.
- Activated Tc cells initiate the demise of target cells through lytic vesicles or CD95L engagement, and their killing potential is enhanced by cytokines released by activated Tc cells.
- B-cells initially express IgM but mature their antibody response by class switching and affinity maturation in response to cytokine activation.
- Class switching allows the Fc effector region of an IgM to be swapped for another Fc type, initiated at Switch regions by deamination of C residues by AID, regulated by cytokines.
- The recombined chromosome contains new junctions within intronic DNA sequence that will be spliced out of the final Ig mRNA.
- A B-cell that has undergone class switching from IgM to another Ig type can undergo additional class switching with any downstream Fc domains remaining within the heavy chain gene cluster.
Immunological Synapse and Immune Cell Activation
- CTLA4 signaling may be similar to PD-1 or CTLA4 may reduce CD3 signaling by out-competing CD28 for B7-1 binding.
- CD28 activation of PI3K results in the production of PIP3/DAG and activation of AKT and NF-kB, enhancing T cell survival and function.
- B-cells are initially activated by antigen interactions with the BCR and become fully activated by engagement of appropriate co-receptors found on the B-Cell and Th2 cells.
- Signaling between B-cells and T-cells, or between other APCs and T-cells, occurs at the immunological synapse, a structured domain of signaling molecules and adhesion molecules localized within a lipid domain enriched in specific lipids and glycolipids.
- The purpose of the immunological synapse is to provide a stable platform for extended signaling between cells, ensuring multiple opportunities to abort the activation/killing process.
- Coordinated activation of humoral and cellular immunity to the same pathogen challenge arises from clonal selection of B-cells and T cells with overlapping binding specificity.
- APCs activate Th1 and Th2 cells, supporting the differentiation of Tc cells expressing TCRs capable of recognizing peptides derived from the pathogen.
- Activated Tc cells initiate the demise of target cells through lytic vesicles or CD95L engagement, and their killing potential is enhanced by cytokines released by activated Tc cells.
- B-cells initially express IgM but mature their antibody response by class switching and affinity maturation in response to cytokine activation.
- Class switching allows the Fc effector region of an IgM to be swapped for another Fc type, initiated at Switch regions by deamination of C residues by AID, regulated by cytokines.
- The recombined chromosome contains new junctions within intronic DNA sequence that will be spliced out of the final Ig mRNA.
- A B-cell that has undergone class switching from IgM to another Ig type can undergo additional class switching with any downstream Fc domains remaining within the heavy chain gene cluster.
Test your knowledge of energy storage in the body with this quiz. Explore how fat is stored as triglycerol in adipose tissue and how muscle stores glycogen. Learn about the role of adipose tissue as an energy storage and endocrine organ, and its secretion of adipocytokines such as visfatin, resistin, leptin, and adiponectin. Delve into the mobilization of triglycerides to meet the body's energy demands.
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