Strep and MRSA: Bacteria and Treatment

-The ability to evade immune phagocytosis, often by formation of a protective capsule or by entry into cells

-Once inside a cell, the ability to resist breakdown by lysosomal enzymes

-Secretion of exotoxins that enter the bloodstream to disrupt function of nearby and remote tissues

-Release of endotoxin that stimulates intense immune system activation

-Expression of superantigens that stimulate intense immune system activation

1. Attachment to target cells, often due to highly specific recognition sites on the outer surface of the viral particle that bind specific target cell types.

2. Entering the host cell by endocytosis.

3.Removal of capsid coat to expose nucleic acid.

4. Replication of viral DNA in the nucleus of the host cell, or replication of viral RNA in the cytoplasm of the host cell.

5 and 6. Transcription and translation of viral proteins.

7. Virion assembly: Capsomere subunits often self-assemble surrounding the nucleic acid core.

8. Release may be by cell lysis, killing the host cell. For enveloped viruses, the virions acquire a membrane coat by budding off from the host cell.

Tests for a specific pathogen or a toxin of a specific pathogen are often carried out with immune-based methods (enzyme immunoassays) based on commercial development of antibodies to that particular target.

S. pyogenes, a gram-positive, group A β-hemolytic streptococcus

can lead to rheumatic heart disease

skin infections with s. pyogenes would lead to cellulitis or necrotizing fascitis

PCN

produces an altered PBP, PBP2a, which makes the bacteria unresponsive to penicillin and other β-lactam-containing antibiotics

the accumulation of macrophages and T cells creates a granuloma that surrounds the tubercle bacilli. Although the granuloma serves to limit bacterial replication and spread, it also allows the bacteria to persist, as latent TB infection, within the host.

sputum culture

A chest x-ray showing areas of infiltration and cavity formation

and using NAAT for diagnosing and identifying pharmacological susceptibility

isoniazid, rifampin, ethambutol, and pyrazinamide

Antibiotic treatment, particularly with broad- spectrum antibiotics that deplete the normal microbiota
Proton pump inhibitors, as gastric acid secretion may suppress CDI
Hospitalization or nursing home environments
Older age—older adults are more likely to be colonized by C. difficile, and CDI is generally more severe in this population
C. difficile ingestion from contaminated food

Initial transmission of B. burgdorferi occurs during the larval feeding, when a tick engorges on an infected animal (usually a white-footed mouse). The bacteria enter the gut of the tick and remain there until the next blood meal. A fraction of the spirochetes will exit the tick gut, migrate to the salivary glands, and await transfer to the new host. Once the ticks molt into their nymph stage, they feed on additional animal hosts, including mice, deer, and humans, who thereby become new infectious reservoirs.

Influenza A envelopes contain prominent spike hemagglutinin (HA) and neuraminidase (NA) proteins used to characterize the strains by the H/N system

transcription of DNA from an RNA template

-Virus attachment occurs when GP120 binds to target cells, primarily macrophages and CD4+ T-helper lymphocytes. The host cell membrane protein CD4 is the initial docking site for GP120, and this binding is complemented by binding to a co-receptor, either CCR5 or CXCR4.

-The first stage of binding allows the transmembrane protein GP41 to bind to the host cell and draw the virion close to the target cell, initiating fusion and entry of the nucleocapsid into the host cell.

-Uncoating releases the single-stranded viral RNA and enzyme reverse transcriptase.

-The proviral nucleic acid is synthesized—double-stranded DNA coding for HIV proteins.

-Proviral DNA is integrated into the host's chromosomal DNA by the viral integrase protein. Transcription of messenger RNA (mRNA) for viral proteins begins; additional transcription reproduces the viral RNA needed to produce daughter virions

-Translation produces the viral pro-protein—a single transcript containing all of the required viral proteins as one long polypeptide strand.

-Limited proteolysis by viral protease produces the proteins that will be packaged inside the virion, including reverse transcriptase, integrase, and protease. Additional translation produces GP120 and GP41 for insertion into the host cell membrane.

-Budding gives the nucleocapsid a membrane coat that contains the appropriate glycoproteins.

After a 2- to 3-week incubation period, many individuals develop an acute flu-like illness lasting about 2 weeks. During this period, the virus is replicating rapidly and the number of CD4+ T cells rapidly declines. As the host immune response begins, viral load (the measured number of circulating viral particles) decreases and the CD4 T-cell count recovers. During the subsequent chronic phase of the infection, CD4 T-cell numbers slowly decline

malaria

Additional tests include PCR amplification of parasite DNA, an immune-based rapid diagnostic test (RDT) for parasite antigens, and measures of host antibody response to parasite antigens by immunofluorescene assay (IFA).

vertical transmission

a host response by macrophages, mast cells, and neutrophils [release of cytokins (particularly interleukin-1 and tumor necrosis factor alpha)

lipid ergosterol- target of antifungal drugs

synthesizes catalase that neutralizes neutrophil reactive oxygen species &lysosome enzymes

-produces B-lactamase that degrades PCN and similar drugs

Stages of infection:
1.Droplets containing MTB bacilli are inhaled and deposited in the alveoli.
2.Macrophages are activated leading to cytokine release, attracting additional immune cells, including T & B lymphocytes, natural killer cells and neutrophils.
3.A solid granuloma forms around the core of the infected macrophages, foams cells, giant cells, epithelioid macrophages, and dendritic cells, surrounding by lymphocytes, neutrophils, and natural killer cells.
4.Macrophage death leads to transition of the solid granuloma to a caseating granuloma with a liquefying center.
5.From this stage, the granuloma may ultimately collapse, releasing the bacilli into the circulation and perpetuating spread of the infection.

called the GHON bodies

. Inhibition or loss of these mechanisms, by proton pump inhibitors that reduce gastric acid secretion, or changes in microbiota due to aging or antibiotic use, can initiate the transition from the spore colonization state to the active expansion state of the C. difficile bacteria. This results in infection and diarrhea production.

Early symptoms bulls-eye rash; later constitutional symptoms such as headache, malaise, musculoskeletal pain, fever, and lymphadenopathy.
Severe but rare complications include meningitis, cranial and peripheral neuropathies, Lyme carditis (heart blocks), myocarditis, LV dysfunction.

•Retrovirus
•RNA-based virus
•Reverse transcriptase enzyme converts to single-strand, then double-strand DNA
•Integrase inserts into host cell genome

circulating protein molecules produced and secreted by immune cells to promote proliferation and activation of other immune cells

second layer of immune defense- comprises of fast acting cells and molecules that recognize common features of pathogens

i.e circulating white blood cells and tissue-resident scavenger cells orchestrate this - molecules of innate immunity include proteins of the complement cascade. a system attacking and lysing bacteria [Phagocytes (macrophages, dendritic cells); granulocytes (neutrophils, eosinophils, mast cells, basophils); innate lymphoid cells (NK cells and ILCs)]


made from bone marrow stem cells

B cells recognize free antigen located in extracellular compartments of the body

can recognize both intracellular and extracellular peptide antigen but require other cells to present the peptides to them on cell-surface molecules called the major histocompatibility complex (MHC)

they synthesize and secrete highly specific Y-shaped molecules called antibodies that can inactivate, neutralize, or label pathogens or toxins

produce cytokines, which can activate innate cells and support B-cell and CD8 T-cell responses.

function to lyse cells infected by intracellular bacteria, virus-infected cells, or tumor cells.

thymus gland

bone marrow

provides T and B cells with the ability to recirculate through the tissues, lymph, and blood, allowing them to constantly patrol and survey the body for signs of infection.

Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, dendritic cells, and megakaryocytes or platelets. .

T and B lymphocytes
natural killer cells
innate lymphoid cells

for B-cell production in the bone marrow:

cells of the adaptive immune system physically cut out small regions of DNA and then paste the remaining pieces of DNA back together in an error-prone way.

Lymphoid follicles are predominantly populated with B cells, and as B cells respond and proliferate in response to antigen they form circular structures known as germinal centers within the B-cell follicle. The germinal center is highly dynamic, increasing in size as the immune response progresses and decreasing in size as the response resolves.

composed of red pulp, where damaged or senescent red blood cells are removed, and scattered nodules of white pulp, in which T and B cells respond to blood-borne antigen

activated mast cells and macrophages at the site of injury /infection release histamine to increase blood vessel permeability causing local blood vessels to dilate- increasing blood flow to the area

neutrophils, eosinophils, basophils

lymphocytes and monocytes

neutrophils

The relative increase in immature cells detected in the blood sample is the result of rapid movement of mature neutrophils into tissues, and increased bone marrow production and release of immature neutrophils. The immature cells, called band or stab cells, are easily recognizable by the characteristic shape of their nucleus.

Activated neutrophils in the process of dying release their DNA into the extracellular space .At this point, chromatin from many neutrophils starts to aggregate, generating a sticky trap for bacteria. Antimicrobial enzymes and ROS contained in neutrophil granules are also released in the extracellular compartment, targeting the entrapped bacteria for destruction.

histamine and cytokines respectively

cytoplasm is filled with granules containing toxic enzymes released by exocytosis onto specific targets

cytotoxic cells that kill parasites

in patients with allergies- vulnerable tissues usually have eosinophils present

cytokines, particularly IL-1 and tumor necrosis factor

Antigen-presenting cells. They live under the skin and in mucosa.

CD4 because they do not neutralize infections but rather trigger the body's response to infections

NK cells (and cytotoxic T cells) use perforins (create pores in the cell membrane) and granzymes (induce apoptosis).

Armed by a series of surface receptors and cytoplasmic granules containing toxic substances, NK cells scan for the presence of unusual ligands on cell plasma membranes. Ligand and receptor interactions can modulate NK cell effector properties

PAMPs/DAMPs activate endothelial cells, ILCs, and macrophages to release histamine, prostaglandins, kinins, and leukotrienes to cause vasodilation, increased capillary permeabillity and stimulated pain fibers

Cytokines are released by macrophages and IL-1 and TNF are released into the circulation to stimulate bone marrow to produce more leukocytes and liver to secrete acute phase proteins [CRP and serum amyloid A protein]

activity of antiinflammatory macrophages increases, resulting in increased levels of platelet-derived growth factor (PDGF), vascular endothelial growth factor alpha (VEGF-α ), and TGF-β 1

promote cell proliferation and development of blood vessels

serum proteins produced by the liver that assist the immune system in destroying microbes

antibody or the acute phase protein CRP binds to a pathogen- the antibody/CRP bound bacterium then interacts with the C1 protein complex triggering its activation and releasing an active protease. C3 converstase is made

part of the innate immunity

pathogen + young C3 leads to the formation of C3 Convertase

MBL binds to of Manas a carbohydrate and becomes activated to turn into inactivated C3 convertase

smaller proteins C3A and C5A- potent inflammatory signals; known as anaphylatoxins because they promote mast cell degranulation with histamine release.

forms the membrane attack complex;

they form cyllinder-shaped large pores in the cell wall or membrane of the invading pathogen, allowing water to move into the pathogen causing swelling and cell death

in APC cells: dendritic cells, b cells, and macrophages

can be expressed by nearly all nucleated cells

from phagocytized material of extracellular organisms

sourced from intracellular pathogens such as viruses or intracellular bacteria

CD8

CD4

the antigenic differences between the host MHC and donor MHC can lead to an immune response initiated against the graft

hematopoietic stem cells used in bone marrow transplantation can develop into T cells that recognize the host MHC as a foreign antigen

-may neutralize target proteins
-coating a microbe with antibodies as a form of opsonization facilitating phagocytosis and destruction by neutrophils and macrophages
-activates classical complement pathway

IgG only

IgA

IgE

it activates both B and T cells

it is necessary for the CD8 cell to work

reperfusion tissue injury

an autoimmune disorder where adaptive immune cells activate innate immune cells in joints

once lymphocytes have been stimulated by their unique antigen- they generate memory cells that can proliferate when the same antigen is encountered again

-B cell receptors can detect soluble antigen (e.g., a vaccine) or antigen attached to a particular pathogen (influenza virus, pneumococcus bacteria)

-B cell activation results in proliferation of that specific B cell (clonal expansion), generating antibody-secreting cells and memory cells

-The first encounter with antigen results in B cell secreting immunoglobulin M (IgM)

-B cell proliferates and differentiates into plasma cells secreting large amounts of antibody

1.Neutralization - antibody binding may neutralize target proteins. Antibody binds with toxins to prevent their effects on the body.

2.Coating of microbe with antibodies to facilitate phagocytosis with macrophages and neutrophils

3.Activate the classical complement pathway to kill bacterial

new infection

Good at activating the complement cascade and eliminating pathogen, promoting opsonization and (Membrane attack complex) MAC formation on microbe surfaces. Half-life 3 weeks (considered long acting). Most efficient for promoting opsonization and phagocytosis. ONLY one to cross the placenta providing protection to the fetus during pregnancy. Also responsible for fetal loss if there are IgG antibodies against the blood type of the fetus.

(A) Opsonization and complement- or antibody receptor-mediated phagocytosis or cell lysis through membrane attack complex (MAC).

(B) Complement- and antibody receptor-mediated inflammation resulting from recruitment and activation of inflammation-producing leukocytes (neutrophils and monocytes).

(C) Antibody-mediated cellular dysfunction, in which antibody against the thyroid-stimulating hormone (TSH) receptor increases thyroid hormone production, and

(D) antibody to acetylcholine receptor inhibits receptor binding of the neurotransmitter in myasthenia gravis.

Type III, immune complex reactions involving complement-activating IgG or IgM immunoglobulins with (1) formation of blood-borne immune complexes that are (2) deposited in tissues. Complement activation at the site of immune complex deposition (3) leads to attraction of leukocytes that are responsible for vessel and tissue injury.

(A) direct cell-mediated cytotoxicity in which CD8+ T cells kill the antigen-bearing target cells and (B) delayed-type hypersensitivity reactions in which presensitized CD4+ cells release cell-damaging cytokin

When self-reactive T and B cells are not properly regulated in the BM or thymus and make it to the lymphoid organs here they then begin to cause tissue damage

result from loss of function mutations in immune cell receptors, cytokines, chemokines, transcription factors, or complement components

During the interphase prior to meiosis, chromosomes replicate.

proteins that regulate the cell cycle

fluctuations in the levels determine cell cycle orderly progression, controlled by other proteins at critical check points (promotes cell division)

after completing their role, cycline are readily degraded to prevent abnormal cell cycling

enzymes that bind to cyclin and do the work

unable to function unless level of their specific cylin increases (promotes cell division)

Can be activated by signals like P21 protein and half CDK activity and cell cycle progression when surveillance indicates a problem at a given stage (inhibits cell division)

CDKs are a family of kinase proteins that when active, phosphorylate a specific set of protein substrates. These phosphorylation events set in motion various stages and transition points in the cell cycle by activating or inhibiting a multitude of proteins at key times. Dependent on the binding of cyclins (increase CDK function). Various CDKs have roles in the cell cycle and different combination's of CDKs and their cyclins are important for regulation

Benign—grows slowly, well demarcated, noninfiltrating

Dysplasia—abnormal appearing cells, can transition to malignancy

Carcinoma in situ—abnormal cells that remain within basement membrane, noninvasive

Malignant—poorly defined margins, invasive

Cancer of blood cells (sometimes called liquid tumors)—proliferate in bone marrow then travel in circulation, no solid tumor present

epithelial origin: Squamous cell tumor arises from squamous cells

Adenocarcinoma—from glandular epithelial cells: e.g. adenocarcinoma of the lung is derived from glandular epithelial cells lining the tracheobronchial tree in the lungs.

Small cell carcinoma—from neuroendocrine cells: For example, a small cell carcinoma of the lung arises from neuroendocrine cells in lung tissue.

originate from mesenchymal tissue

Cartilage, smooth muscle, skeletal muscle, blood vessels

leukemias and lymphomas

- abnormal proliferation of cells in the bone marrow, peripheral blood, or other hematopoietic tissues such as lymph nodes, spleen, or liver.

Lymphoma - refers to a malignant tumor that results from a monoclonal proliferation of lymphoid cells such as B lymphocytes or T-lymphocytes; Leukemia - monoclonal proliferation of blast cells in the bone marrow + an arrest in normal maturation of cells.

germ cells:

Dermoid cyst - AKA mature cystic teratoma - may occur in the testes or ovaries and be composed of an aggregate of mature tissue representing various organs in the body. Others include ectoderm (skin and hair), lungs and intestines (endoderm), and bone and cartilage (mesoderm)

-Encode proteins that promote cell division

-Highest activity during embryonic development and childhood accelerated growth

-Essentially shut off when no longer needed

-Mutations can reactivate them, creating oncogenes

-gain of function (release from inhibition) allows unregulated production of growth factors, growth factor receptors, intracellular signals that upregulate cell proliferation pathways

loss of function (mutation in both alleles causing loss of functional protein) promotes unregulated growth—includes cell cycle suppressors (Rb, p53, p21) and many DNA repair genes

Hallmarks of cancer:
1.Uncontrolled proliferative signaling

2.Evading growth suppressors

3.Genomic instability

4.Enabling cell immortality

5.Resisting cell death

6.Hijacking or generating blood supply for nourishment

7.Acquiring invasive and metastatic abilities

important intracellular signaling protein responsible for cell growth (briefly activated then turned off).
Mutated RAS - continuous stimulation allowing for tumor growth.

part of a growth promoting tyrosine kinases. Mutated forms or increased levels frequently present in cancer.

- Mutated tumor suppressor genes that lead to cancer

- RB1 → retinoblastoma tumor suppressor mutation

- p53 → mutated in 50% of cancer cells, regulates 50 other genes so all of those get messed up too

A DNA repair defect that causes hypersensitivity to UV light and has a 1000x increased risk of skin cancer.

extremely dry skin and "pigmentosum" refers to the freckles and dark spots

skin cancer

sun protection, sun screen

Increased expression of EMT transcriptional regulators results in a loss of adherence, and associated conversion from an epithelial to a fibroblastic or spindle-like morphology, expression of matrix-degrading enzymes, and increased cell motility. E-cadherin (key adhesion molecule) is lost in many cancer cells, allow tumor cells to detach from surrounding cells and increasing the risk of invasion and metastasis

Cytokine elevation causes fever, suppresses appetite, and promoting clotting. Hypercoagulability is common in early cancer and may lead to a diagnosis of Cancer.

a constellation of clinical findings and effects from a primary malignancy. These syndromes are mediated by hormones secreted by the malignant cells and/or the immune response the hormones trigger. Common is SIADH from tumor-produced vasopressin associated with lung cancers
Hyper-parathyroid hormone-related protein - causes hypercalcemia and bone loss.

An acute generalized reaction associated with massive cell death caused by cancer treatment. Usually associated with a round of chemotherapy that results in robust and rapid killing of malignant cells.

Can result in cardiac dysrhythmias and seizures. Also can result in acute renal failure.

uInitiation of chemotherapy that causes many cells to die at one time, overloading the body with damage-associated molecular patterns and causing fluid and electrolyte imbalance

-Hyperkalemia
-Hyperphosphatemia
-Hypocalcemia
-Hyperuricemia

can result in acute renal failure

Patient factors such as Fluid and electrolyte balance and renal function as well as estimating tumor volume, cell lysis potential associated with the treatment. Treatment for tumor lysis syndrome include fluid + reducing uric acid, phosphate, and potassium.

Other complications include pain, anemia, neutropenia, thrombocytopenia, nausea and vomiting, stomatitis, fatigue, radiation-induced tissue injury, sleep disturbances and dysphoria.

widened QRS due to hypokalemia

must give calcium

Mismatch repair genes assist in ensuring that there is accurate pairing of DNA base pairs. Microsatellites are short DNA sequences that may be altered due to mutations in the mismatch repair genes which then result in a genomic instability. Mismatch repair gene mutations also pose an increased risk from the development of colorectal and endometrial cancers, cancers in organs such as the duodenum, kidneys, liver, stomach, and ovaries.

Li-Fraumeni syndrome increased risk for the development of tumors at an early age. Tumors include sarcoma of the bone and soft tissue, breast cancer, brain tumors, and tumors of the adrenal cortex.

BRCA1 and BRCA2 are tumor suppressor genes that are often germline mutations and a copy of the mutated gene significantly increases the risk for the development of early breast/ovarian cancer.

Translocation of chromosomes 9 and 22

The chromosomal translocation between the breakpoint cluster region gene BCR on chromosome 22 and the ABL gene on chromosome 9 results in the generation of the Philadelphia Chromosome. This abnormal gene produces oncoproteins that have proliferation-promoting tyrosine kinase activity that can no longer switched off resulting in uncontrolled proliferation of granulocytic cells and development of chronic myeloid leukemia.

continued unexplained weight loss

headaches- often with early morning vomiting

increased swelling or persistent pain in bones, joints, back or legs

Lump or mass, especially in the abdomen, neck, chest, pelvis, or armpits

development of excessive bruising, bleeding or rash

constant infections

a whitish color behind the pupil

nausea

constant tiredness or noticeable paleness

eye or vision changes that occur suddenly and persist

recurrent or persistent fevers of unknown origin.
focus on manifestations of cancers in children,

-Cdks.
-enzymes that drive the cell cycle; activated only when bound by a cyclin. Activate target proteins by phosphorylation.

uncontrolled proliferative signaling, evading growth suppressors, genomic instability, enabling cell immortality, resisting cell death, hijacking or generating blood supply sources for nourishment, and acquiring invasive and metastatic abilities.

Ras is an important intracellular signaling protein (oncogene) that, when properly stimulated, transmits signals that activate cell growth for a brief time before being turned off. Mutated Ras results in continuous stimulation that fuels tumor growth

a process that allows transformed epithelial cells to invade tissues, resist apoptosis, and spread

massive cell death that leads to hyperkalemia, hyperphosphatemia, hyperuricemia

electrolyte imbalance leading to instability of excitable tissues resulting cardiac arrhythmias and neurological seizures

ribosomes in the cytoplasm

proteins, signaling molecules, and messenger RNA molecules

Protein synthesis for intracellular use or for export from cell- the site of chaperone proteins that detect the progress of protein folding and that mark misfolded proteins for destruction, through the unfolded protein response

steroid synthesis and detoxification of drugs and poisons

and major site of cellular calcium homeostasis, sequestering calcium to keep cytoplasmic free calcium levels low most of the time, and releasing calcium in response to membrane receptor signaling,

functions to release calcium ions that initiate muscle cell contraction, subsequently taking up calcium ions and causing muscle cell relaxation.

flattened stacks that process, package, and deliver proteins and lipids from the ER

It functions to sort, modify, and package proteins and lipids that are delivered in vesicles from the nearby endoplasmic reticulum. After proceeding through the Golgi stacks, these substances may leave the cell by exocytosis or be delivered to different intracellular locations. The Golgi apparatus also forms other organelles that are vesicle-type organelles, including lysosomes and other secretory vesicles, as well as being a source of plasma membrane.

degradative enzymes that break down aging cell organelles and molecules.

Vesicles that have enzymes that digest fatty acids and amino acids through the use of oxygen for their reactions

sodium is high extracellularly and potassium is high intracellularly.

J = flux, the amount of substance that moves across the barrier from a region of higher concentration to a region of lower concentration
D = the diffusion constant for the substance
A = the surface area for diffusion
Δc = concentration gradient for the substance across a barrier
Δx = thickness of the diffusion barrier

Endo= into the cell (engulf). Exo= out of the cell (excrete).

malfunction of LDL receptors that do not trigger endocytosis- this disorder manifests with extremely high cholesterol levels, tissue cholesterol accumulation and early-onset atherosclerosis

after proteins are synthesized they end up getting secreting through exocytosis

a process in which a molecule or protein destined for secretion is held in intracellular vesicles until a specific event triggers exocytotic release.

depolarization can occur in response to increased cellular glucose metabolism similarly opening voltage-gated calcium channels, stimulating regulated exocytosis of vesicles containing the hormone insulin.

a mechanism by which hydrophilic polar and charged substances can move across cell membranes down their concentration gradients.[membrane protein transporters- binding a molecule of the substance on the side of higher concentration and releasing it on the side of lower concentration]

A cell membrane protein that uses energy to pump sodium out of the cell and transports potassium into the cell

The concentration gradient for sodium created by the Na+/K+ pump is a source of potential energy in that other solutes can be transported against their concentration gradients by transporters that link their movement to sodium influx into cells.

Beginning with the step of sodium binding, three cytoplasmic sodium ions bind to sites facing the intracellular fluid. ATP then binds to the transport protein and is split, donating a high-energy phosphate group and changing the pump's configuration. The protein shifts its orientation and releases the sodium ions to the extracellular fluid, subsequently binding two potassium ions. This is followed by release of potassium to the intracellular fluid and release of the bound phosphate.

voltage difference across membrane of resting cell- most cells have this potential difference as the inside of the cell is electrically negative with respect to the extracellular fluid, with the cell membrane able to separate the charge- maintaining the voltage difference

The electrical potential across a cell membrane that exactly opposes the net diffusion of a particular ion through the membrane following its concentration gradient.

Potassium (K+) is high in the ICF and low in the ECF. (a) If fluids with this composition are separated by a solid membrane, no ion movement will occur. (b) If potassium channels are inserted in the membrane, K+ will move from ICF to ECF, down its concentration gradient. This will generate a membrane potential difference, with the inside negative with respect to the outside.

depolarization can open voltage gated channels producing action potential

Large electrical spikes of depolarization that can be propagated for long distances along axons and ultimately release neurotransmitter molecules into synapses. electrical impulse that travels down the axon triggering the release of neurotransmitters

proteins accept chemical messengers from other cells (i.e. hormones)

parasympathetic system [postganglionic neurons are cholinergic]

Sympathetic system [postganglionic neurons are adrenergic]

Found on all cells, GPCRs are the most common mechanism by which hormones and neurotransmitters influence cell and organ function.
Signaling is amplified as a small group of receptors can activate a larger group of G proteins, ultimately stimulating membrane-bound enzyme production of many molecules of second messengers.
Second messengers act by turning on protein kinase enzymes that phosphorylate intracellular proteins to change their function to meet the body's changing needs.
Phosphorylation of some proteins increases their activity, while phosphorylation of other proteins decreases their activity, but in both cases a change in the protein's activity produces the final effect of hormoneeceptor signaling.
The strength and duration of GPCR effects are limited by various inhibitory and off-switches, including inhibitory receptors themselves, an intrinsic timing function of the GTPase activity of G proteins, and protein phosphatase enzymes that remove phosphate groups from proteins.
Finally, the second messengers can be metabolized, terminating their action. For example, a phosphodiesterase cleaves cAMP and converts it into 5′-AMP, which is inactive.

an enzyme that adds a phosphate group onto target proteins- alters target protein activity level and thus change cell function

After the ligand binds and activates the receptor, the G protein α subunit GDP is replaced by GTP; the α subunit dissociates from the βγ pair and activates or inhibits the relevant enzyme (adenylyl cyclase or phospholipase C). As the second messenger is generated, the α subunit is also breaking down the bound GTP, leaving GDP bound to the α protein, returning the βγ proteins to their initial state of binding to α, and turning off second messenger production.

an enzyme that catalyzes the transfer of a phosphate group from ATP to the amino acid tyrosine on a substrate protein

after the self activation- the tyrosine kinase portions of the receptor begin to phosphorylate additional proteins- some attach and build up complex of proteins along the intracellular portion of the receptor

Involved in mediating cell-to-cell communication and controlling a wide range of complex biological functions, including cell growth, motility, differentiation, and metabolism.

Ligand binding to the extracellular RTK domain stimulates dimerization of RTKs, and the cytosolic domains cross-phosphorylate one another to activate the kinase domains.

Ligand binding stabilizes the dimerization of cytosolic domains of RTKs, and the intracellular domains can trans-phosphorylate one another (autophosphorylate) to activate the kinase domains.

Binding to the receptor activates the G protein which activates the effector.

-Subunits (a, b, & g) that dissociate when a ligand binds to its receptor, allowing the a subunit to activate or inhibit an enzyme
-GTPase activity of the a subunit that serves as a timing switch to terminate receptor signaling after a defined period of time

molecules that bind to receptors

connections that go from cell to cell

can tell you if from own body or foreign

programmed cell death

two-layer membrane, contains: a nucleolus, most of DNA, enzymes, and nucleotides of replication and transcription, transcription factors, pre-mRNAs
Each cell in the body contains a single nucleus, with the exception of red blood cells (contain no nucleus), and skeletal muscle cells (multinucleated)

Ribosomes—manufactured in the nucleus, migrate to the cytoplasm, synthesize proteins in the process of translation, travel freely or bound to endoplasmic reticulum (forming rough endoplasmic reticulum)

system of membranous compartments dispersed throughout the cell, contains enzymes of metabolism, steroid synthesis, major role in cell calcium storage,

packages newly synthesized proteins and other solutes for transport within the cell or export from the cell, forms new intracellular vesicles

inherited only through mother- Daughter

two membrane layers, produces ATP through Krebs cycle and oxidative phosphorylation, contains its own DNA, has enzymes for synthesis of steroids and other reactions, stores calcium, can signal cell to undergo apoptosis

contain degradative enzymes: proteases and phospholipases, highly developed in phagocytic white blood cells (neutrophils and macrophages), contribute to breakdown of aging cell components

conduct oxidative metabolic reactions, can generate and detoxify reactive oxygen species such as hydrogen peroxide

= Small hydrophilic molecules when movement is down a concentration gradient

through diffusion down their concentration gradient

exocytosis or endocytosis

facilitated diffusion [if movement is down a concentration gradient] or secondary active transport [if movement is against a concentration gradient]

ion channels [if movement is down a concentration gradient], by secondary active transport (mainly sodium), and by active transport (if movement is against a concentration gradient)

produces albumin and other plasma proteins, coagulation factors, hormone binding proteins

hydrophilic or polar substances

[e.g glucose entry into the cells: GLUT are glucose transporters that moves glucose at high rates specifically for control of circulating glucose]

plasma membrane and endoplasmic reticulum membrane.

hydrolyzes ATP to obtain energy for transport

pump is found in the stomach, produces stomach acid; also found in the kidneys, regulating acid-base balance. This proton pump is the target of drugs that inhibit gastric acid secretion PPI e.g. Rabeprazole sodium (Aciphex), Omeprazole (Prilosec)

hydrolyzes ATP to obtain energy for transport

in kidney tubulues and GI tract- all glucose can be absorbed by a sodium- glucose cotransporter that allows sodium to enter the cell at the same time

: sodium, potassium, chloride, calcium are most common

these channels have the ability to slow/quicken narrow or widen and control the amount that passes through

-Most cell membranes have potassium "leak" channels—K+ diffuses out, down its concentration gradient, leaving behind intracellular negative charges
-An electrical potential difference builds up across the membrane, inside negative relative to the outside of the cell (b)
-Open channel allows ions to freely move until 1) pore closes or 2) reaches electrochemical equilibrium.

based on the distribution of ions across the cell membrane (Na concentration higher in the extracellular environment, K+ higher inside). In resting conditions the cell is resistant to most cellular charges - most permeable to K+.

chloride channel dysfunction

through cAMP

Stimulatory and inhibitory AC-linked receptors. AC can be stimulated or inhibited,αdepending on the type of receptor activated. Stimulatory receptors (R-stim) work through Gs to increase AC activity and cyclic adenosine monophosphate (cAMP) production; inhibitory receptors (R-inh) work through Gi to decrease AC activity and cAMP production.
AC, adenylyl cyclase.

biomarkers- chemical messengers produced in response to a stimulus

they are immune signaling molecules produced by white blood cells and other cells to activate other immune target cells, including promoting proliferation during immune responses

can turn on/off genes,

•Cells throughout the body are controlled by extracellular signals generated by the autonomic nervous and endocrine systems, as well as by immune cytokines and local damage signals

most signaling agents are hydrophilic and mediated by cell surface receptors usually G protein receptors.

•Ligands promoting cell division during embryonic growth and other times of accelerated cell proliferation (including immune activation) work through enzyme-linked receptors having a tyrosine kinase mechanism

calcium and ATP

sarcolemma

sarcoplasmic reticulum

•Calcium binds to troponin and shifts tropomyosin, exposing actin's myosin-binding site and initiating crossbridge formation

1.Rapid loss of ATP production, resulting in diminished membrane potential
2.Depressed NA/K pump activity
3.Intracellular calcium overload
4.Cell swelling with membrane rupture
5.Loss of antioxidant function
6.Accumulation of oxygen-deprived free radicals (AKA reactive oxygen species [ROS]
7.Acidosis
8.Activation of degradative enzymes that contribute to membrane rupture and spread of the damage to adjacent cells.
●
9.Restoring blood flow by reperfusion of the area may worsen cell death by providing oxygen to fuel production of ROS and by recruiting WBCs that continue the inflammatory response.

•Cell death in a variety of disease processes or due to injury can be characterized as necrotic (cells swell, rupture, spill signals of tissue danger, initiate inflammation), apoptotic (cells shrink, small blebs containing contents break off, noninflammatory- cell suicide and collapses onto itself) and autophagic (some cells digest their own contents, provide nutrients for other cells in the surrounding region, noninflammatory)

Shrinking and condensation of the nucleus and cytoplasm occur. The chromatin aggregates at the nuclear envelope, and DNA fragmentation occurs. Then, the cell becomes fragmented into multiple apoptotic bodies in a manner that maintains the integrity of the plasma membrane and does not initiate inflammation. Changes in the plasma membrane induce phagocytosis of the apoptotic bodies by macrophages and other cells, thereby completing the degradation process.

shrinking of the cell structures (A), condensation and fragmentation of the nuclear chromatin (B and C), separation of nuclear fragments and cytoplasmic organelles into apoptotic bodies (D and E), and engulfment of apoptotic fragments by phagocytic cell (F).

•Increased workload can result in organ growth by hypertrophy (muscles) or hyperplasia (kidney, liver)

impaired calcium homeostasis

increase in cytosolic calcium because of increased influx across the cell membrane and the release of calcium from intracellular stores. The increased calcium level may inappropriately activate a number of enzymes with potentially damaging effects. These enzymes include the phospholipases, responsible for damaging the cell membrane; proteases that damage the cytoskeleton and membrane proteins; ATPases that break down ATP and hasten its depletion; and endonucleases that fragment chromatin. Although it is known that injured cells accumulate calcium, it is unknown whether this is the ultimate cause of irreversible cell injury.

sarcopenia

-muscle loss with aging

another cyclic nucleotide that is involved in G protein signaling events. G protein activates cGMP phosphodiesterase that lowers [cGMP]i; this in turn closes cGMP-gated nonselective cation channels

cGMP has two major physiologically defined roles.
1. Synthesized in retinal photoreceptor cells; critical role in vision.
2. Acts in vascular smooth muscle a a potent vasodilator.

The enzyme that produces cGMP is called guanylyl cyclase. It occurs in two forms 1) in vascular smooth muscle cells (particulate guanylyl cyclase)- part of the membrane-bound receptors for natriuretic hormones, and 2) soluble guanylyl cyclase found in the cytoplasm. The latter is activated by ER- produced nitric oxide. The nitric oxide diffuses to the blood vessel's smooth muscle layer. End result is vasodilation and lowered blood pressure.

The nitric oxide diffuses into the smooth muscle to cause vasodilation

primary active transport

necrosis

1.Rapid loss of ATP production, resulting in diminished membrane potential
2.Depressed NA/K pump activity
3.Intracellular calcium overload
4.Cell swelling with membrane rupture
5.Loss of antioxidant function
6.Accumulation of oxygen-deprived free radicals (AKA reactive oxygen species [ROS]
7.Acidosis
8.Activation of degradative enzymes that contribute to membrane rupture and spread of the damage to adjacent cells.
9.Restoring blood flow by reperfusion of the area may worsen cell death by providing oxygen to fuel production of ROS and by recruiting WBCs that continue the inflammatory response.

cells shrink, small blebs containing contents break off, noninflammatory

some cells digest their own contents, provide nutrients for other cells in the surrounding region, noninflammatory

simple diffusion

lysosomal autophagy

a polymer of nucleotides and consists of a series of bases attached to a sugar-phosphate backbone, making up a strand with the bases projecting away from the backbone. Of the four DNA bases, two are larger purines (adenine, guanine) and two are smaller pyrimidines (cytosine, thymine)

he backbones have a polarity based on the free ends of the chain, one of which is a phosphate attached to the 5′ (five prime) carbon of the ribose sugar, and the other of which is a hydroxyl attached to the 3′ carbon of the ribose sugar

proteins that DNA wraps around

interphase, mitosis, cytokinesis

include the G1 or gap 1 phase, the S or synthesis phase, and the G2 or gap 2 phase

prophase, metaphase, anaphase, telophase

chromosomes becomes visible spindle forms, nucleus disappears, nucleoli disappear

chromosomes line up (single file) along center of spindle

and the attachment of the spindle fibers is checked

Chromatids are pulled apart

sister chromatids separate and migrate towrds the poles of the cell

The nuclear envelope re forms around the chromosomes at each pole and the chromosomes begin to decondense into chromatin

23; sperm and ova

primary spermatocyte in males, or primary oocyte in females. Has 46 chromosomes

You start with 46 chromosomes/ 92 chromatids.

offspring of meiosis I leads to 23 chromosomes/46 chromatids.

"Grandchildren" of this turns into 23 chromosomes/23 chromatids

1: Helicase unwinds DNA
2: single stranded binding proteins bind to DNA strands to keep them separated and stabilizing the structure at the replication fork
3: primase creates primer
4: DNAV polymerase begins to build by adding DNA bases after digesting the primer
5. short lagging strand segments must be joined by DNA ligase

Relatively short fragment of DNA synthesized on the lagging strand during DNA replication.

DNA polymerases; these enzymes proofread the sequence of neucleotides and when an error is located, excise the incorrect nucleotide and replace it with the correct one

transcription of a gene or a portion of a gene into pre-mRNA, post transcriptional processing to create mRna, transport of the mRNA out of the cell nucleus, translation of the mRNA into a polypeptide chain of amino acids, and finally post-translational processing to create a finished functional protein

RNA polymerase adds complementary neucleotides to the growing RNA strand, substituting uracil for thymine.

The strand of DNA being copied; because of the complementary nature of DNA and RNA, the RNA molecule will be the same sequence of nucleotides as the nontemplate strand.

a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.

Sequences that are not translated into part of the protein, and must be removed.

they come in between on interefere with the exons

a 5' cap is added to one end of the molecule and a poly- A tail to the other. It is used as an anchor for the ribosome to attach to the mRNA to begin the process of translation

sometimes adenine bases are added to the end of the pre-RNA [adding tot he stability of the mRNA molecule] extending the time it takes before the molecule is degraded by enzymes in the cytoplasm

the process in which ribosomes in a cell's cytoplasm create proteins, following transcription of DNA to RNA in the cell's nucleus. It occurs in cytoplasm

mRNA message and synthesize protein chains base on the message

transfer tRNA carries amino acids one by one to the ribosome where each amino acid is added to the growing polypeptide chain

a sequence of three nucleotides that together form a unit of genetic code in a DNA or RNA molecule.

UAA, UAG, UGA

AUG (methionine) and it signals beginning of translation

the ribosome attaches to the 5' cap of the mRNA and travels down the mRNA molecule until the AUG start codon is encountered.

tRNA with the anticodon UAC aligns with the codon and leaves its methionine to begin the peptide sequence

initiation: transitional complex forms, and tRNA brings first amino acid in polypeptide chain to bind to start codon on mRNA

elongation: tRNAs bring amino acids one by one to add to the polypeptide chain

termination: release factor recognizes stop codon, translational complex dissociates, and completed polypeptide is released

a specific location of a gene along the chromosome

Different forms of a gene

When the DNA sequence is altered so the protein becomes more active or takes on a new function (usually dominant inheritance)

A mutation which causes reduced or no protein function

genotype: the unique sequence of nucleotides in his or her genes

phenotype: the physical expression associated with that train or disorder (straight or curly hair)

single nucleotide polymophisms that reside in the coding region of a gene but do not affect the amino acid sequence of the protein product

single nucleotide polymophisms that reside in the coding region of a gene and change the amino acid sequence of the protein product, often impacting the structure or function

One base pair is added or deleted, everything shifts, most of the amino acids will change.

caused by an expansion of the triplet "CAG" repeated several times within the sequence of the gene. Over time the mutant huntington protein accumulates damaging neurons and causing neurodegeneration.

The accumulation is an example of genetic anticipation- in which each generate tends to have a worse phenotype and earlier presentation

polymorphisms in which short sequences of nucleotides within the DNA are repeated either in or near a gene

only one copy of the abnormal gene is required for the phenotype to present in the individual

if one parent has the disorder- there is a 50% chance he or she will pass on the abnormal copy of the gene to each offspring

If one parent is a carrier and the other is not affected and is not a carrier, with each pregnancy there is a 50% chance that their offspring will be carriers

If both parents are carriers but neither has the disorder, there is a 25% chance with each pregnancy that the offspring will have the disorder, a 50% chance their offspring will be a carrier, and a 25% chance the offspring will be a nonaffected noncarrier

If an affected individual mates with a nonaffected, noncarrier person, all of the offspring will be carriers but none will be affected or nonaffected noncarriers. The nonaffected, noncarrier parent only has the nonmutated gene to donate and the affected parent only has the mutated gene to donate, so the offspring has one copy of each parent's gene

If an affected individual mates with a carrier, with each pregnancy there is a 50% chance their offspring will be affected and a 50% chance the offspring will be a carrier. In this scenario, there is no chance of the offspring being a nonaffected noncarrier because the affected parent always donates a mutated gene.

one copy of the normal gene on the X chromosome is sufficient to prevent the disease from expressing. All males inheriting the abnormal gene on the X chromosome will be affected as they have no other X chromosome to make that protein.

The percentage of individuals with a specific genotype who also express the expected phenotype

the degree to which a trait is expressed

Family
Multiple family members are affected across multiple generations. But note that lack of a family history does not rule out genetic causes.

G—Groups of anomalies
The presence of multiple anomalies increases the probability of an underlying genetic syndrome. Several anomalies clustered together should raise the index of suspicion and may warrant referral of the patient to a geneticist or genetic counselor. The cluster of anomalies will likely not be diagnostic, as many genetic disorders have similar dysmorphic findings, and further testing may be necessary.

E—Early or extreme presentation of illnesses
Onset of diseases at an earlier-than-expected age or in the uncharacteristic sex likely indicates a genetic basis for the disease. Breast cancer occurring in women before the age of 60 or breast cancer in males is one such occurrence. Early onset of cardiovascular disease is another example. Cardiovascular disease in males before age 60 or women before age 65 should lead the clinician to consider a more thorough genetic assessment.

N—Neurodevelopmental delay or neurodegenerative diseases
Neurodevelopmental delay in infants and children should prompt consideration of a genetic disorder, particularly when the delay is found in combination with other red flags such as congenital dysmorphologies.

E—Exceptional pathology
Among these pathologies would be finding in either organs or structures of paired or bilateral organs. Another example of exceptional pathology would be to find several different cancers in the same patient simultaneously.

S—Surprising laboratory values
An example would be extremely high lipid levels in a young, otherwise healthy person.

The gradual shortening of telomeres, signaling removal of the cell.

Telomeres are protective structures present at the ends of linear chromosomes that are important in preventing genome instability. Telomeres shorten as a result of cellular replication, leading to a permanent cell cycle arrest, also known as replicative senescence

telomeres become too short, permanent withdrawal from the cell cycle; prevents impending DNA damage from DNA coding being damaged

after 60th division- non dividing - prevents cancers and tumors

enzymes that work with DNA to either replace primers, repair, or elongate a new strand

They identify errors in the sequences of nucleotdies and when an error is identified. The polymerase removes the incorrect nucleotide and replace it with a correct one

P = short arm
Q= long arm

Location of a gene on a chromosome

a particular version of a gene, with an identified sequence

the identified DNA sequence for an individual

the physical expression of a characteristic that may be altered by genotype

having identical alleles of the gene on both homologous chromosomes

Mitosis phases: prophase, metaphase, anaphase, during which nuclear membrane dissolves, chromosome pairs line up along midline, spindle fibers pull chromosomes toward opposite ends of the cell

Prophase - chromosomes condense and appear in paired sets

Metaphase -sister chromatids line up along the center of the cell; attachment of spindle fibers is checked.

Anaphase - spindles pull back from

Telophase—nuclear membranes reforms and encloses chromosomes, DNA disperses

Cytokinesis - plasma membrane invaginates, completes separation into 2 daughter cells

In females -mesosis begins during the first 6 months of fetal development and is interrupted at prophase of meiosis. At the time of ovulation, each oocyte completes meiosis I and stops during prophase of meiosis II. When the egg is fertilized, the cell rapidly completes meiosis II. Meiosis will not be competed if egg is not fertilized. Males - division results in 4 mature spermatids; in females - one large oocyte with most of cytoplasm and a second cells with essentially no cytoplasm = polar body. Adult female will produce ~400 primary oocytes

1.During G1 phase, the cell readies itself for the s phase. The representative chromosome pair is one chromosome from the mother, a second from the father.

2.DNA is copied, similar to the S phase of mitosis. The duplicated homologous chromosome (sister chromatids) are adjacent and because of the similarities, cross over can occur with segmental swapping between maternal and paternal versions (see slide 12). This allows for genetic diversity.

3.At telophase I and cytokinesis, the new versions of the chromosome pairs are separated into daughter cells.

4.A second cell division occurs for each daughter cell. This reduces the chromosome number to1 with the random chance that the gamete will have 1) paternal chromosome, 2) maternal chromosome, 3) a chromosome made of combination of maternal and paternal segments.

5.Mature egg and sperm have 23 chromosome and are termed haploid. When fertilization occurs, the resulting zygote has 46 chromosomes and cell division (embryogenesis begins.

Heterozygous—having different alleles (variations in sequence) of the gene on the maternal and paternal chromosomes

Wild-type—having the version of the gene that does not contain any mutations, associated with normal phenotype

sequence variations that affect only one nucleotide - SNP

more than one copy of a gene exists (copy number variation)

short sequences repeated a variable number of times

1.Spontaneous
2.Consequence of chemical or radiation induced injury
1.Reactive oxygen species
2.Chemical mutations from environmental or occupational exposures
3.Radiation (e.g. sun exposure)
4.Failure of cellular protective strategies.

May include gain of function (protein is more active) versus loss of function (protein is less active.

change in genotype does not change phenotype

altering a nucleotide changes one amino acid in the protein product

altering a nucleotide inserts a premature stop codon, protein is truncated and nonfunctional

Marfan's Syndrome and Neurofibromatosis

Autosomal dominant-Multiple cutaneous neurofibromas are noted on the face and trunk.
The presence of large (usually ≥15 mm in diameter), flat cutaneous pigmentations, known as café au lait spots. They are usually a uniform light brown in whites and darker brown in people of color, with sharply demarcated edges. Although small single lesions may be found in normal children, larger lesions or six or more spots larger than 1.5 cm in diameter suggest NF-1.7 S
Skin pigmentations become more evident with age as the melanosomes in the epidermal cells accumulate melanin.

•Children with NF-1 are also susceptible to neurologic complications. There is an increased incidence of learning disabilities, attention deficit disorders, and abnormalities of speech among affected children.
•Complex partial and generalized tonic-clonic seizures are a frequent complication.
•Malignant neoplasms are also a significant problem in people with NF-1. One of the major complications of NF-1, occurring in 3% to 5% of people, is the appearance of a neurofibrosarcoma in a neurofibroma, usually a larger plexiform neurofibroma.4 NF-1 is also associated with increased incidence of other neurogenic tumors, including meningiomas, optic gliomas, and pheochromocytomas.
•Type 2 NF is characterized by tumors of the acoustic nerve. Most often, the disorder is asymptomatic through the first 15 years of life. This type of NF occurs less frequently, at a rate of 1 in 50,000 people. The most frequent symptoms are headaches, hearing loss, and tinnitus. There may be associated intracranial and spinal meningiomas. Surgery may be indicated for debulking or removal of the tumors.5

exerts dominance, therefore only one copy is needed to exhibit the trait or disorder. There are gender related differences in inheritance risk.
A heterozygous mother will have the phenotype of the disorder and there is a 50% chance she will pass it to her offspring regardless of gender. If the father has the disorder there is a 50% change he will pass it on his female offspring but no chance he will pass it to his male. Some disorders with an X-linked dominant inheritance patter include Rhett syndrome, fragile X syndrome, X-linked hypophosphatemia (Vitamin D-resistant rickets).

In this inheritance pattern - one copy of the normal gene on the x-chromosome is succificent to prevent the disease from expressing. All males inheriting the abnormal gene on the X-chromosome will be affected because they have no other X-chromosome to make the necessary protein. The risk is variable depending on which parent has the trait e.g. if the father is affected, all female offpring will be carriers but his sons will NOT have the disorder. If the mother is affected - 50% of the male offspring will have the disorder while 50% of the female children will be carriers. Hemophilia (A & B); Duchene's Muscular Dystrophy; glucose-6-phosphate dehydrogenase (G6PD) deficiency;

Because mtDNA is inherited only from the mother, all disorders of mtDNA are also inherited on the maternal line. Maternal inheritance is explained by the processes occurring during conception. Ova contain numerous mitochondria in their abundant cytoplasm, whereas spermatozoa contain few, if any, mitochondria. Thus, the mtDNA in the zygote is derived solely from the mother. The zygote and its daughter cells have many mitochondria, each of which contains multiple copies of the maternally derived mtDNA. During growth of the fetus or later, it is likely that some cells will contain only normal or mutant mtDNA (a situation called homoplasmy), whereas others receive a mixture of normal and mutant DNA (heteroplasmy). In turn, the clinical expression of a disease produced by a given mutation of mtDNA depends on the total content of mitochondrial genes and the proportion that is mutant. The fraction of mutant mtDNA must exceed a critical value for a mitochondrial disease to become symptomatic. This threshold varies in different organs and is presumably related to the energy requirements of the cells.

Mitochondrial DNA mutations generally affect tissues that are dependent on oxidative phosphorylation to meet their high needs for metabolic energy. Thus, mtDNA mutations frequently affect the neuromuscular system and produce disorders such as encephalopathies, myopathies, retinal degeneration, loss of extraocular muscle function, and deafness. The range of mitochondrial diseases is broad, however, and may include liver dysfunction, bone marrow failure, and pancreatic islet cell dysfunction and diabetes, among other disorders.

Penetrance—Describes the likelihood that the individual with genotype associated with a disease actually presents with the disease. Many genetic disorders are 100% penetrant (sickle cell disease, Huntington disease). Other disorders have variable penetrance, including long QT syndrome, hemochromatosis, and deafness.

Expressivity—Describes variability of phenotype among those with a disease-related genotype. Presentation can be mild, moderate, or severe, but if the disorder is 100% penetrant, all those with the mutated gene have the disease to some degree. Cystic fibrosis and osteogenesis imperfecta are examples of genetic disorders with variable expressivity.

•Phenotype - tall stature, aortic dilation and dissection, scoliosis, joint hypermobility, arachnodactyly, pectus excavatum or carinatum, and mitral valve prolapse.

•BRCA-1 is located at 17q12-21 (>900 mutations); lifetime breast cancer risk is 55% to 65%
•BRCA-2 is found at 13q12-13 and has approximately the same number of mutation. <50% (slightly) with a 15% risk of Ovarian Cancer.
•BRCA risk among men is 7% for breast cancer and 20% risk of prostate cancer.
•Cancer develops at an earlier age.
•An affected individual receives one mutated allele from one parent which increases the risk of developing cancer but most alleles must be mutated for cancer to develop.

family history/pedigree

Family "GENES" mnemonic:
-Groups of anomalies are present
-Early or extreme illness presentation
-Neurodevelopmental delay or neurodegenerative diseases
-Exceptional pathology
-Surprising laboratory values

Tissue sample taken, exposed to conditions that promote mitosis, then arrested in metaphase—chromosomes are arranged by size, stained and photographed

Uses of karyotyping:
Determine chromosome number (two copies of each? Trisomy?)
Determine chromosome size?
Evaluate for translocations, inversions, insertions, deletions

-Identifies transcripts that are increased in tumor cells (could be driving tumor growth)
-Other transcripts are decreased in tumor cells (lack of these could be permissive)
-Some transcripts are unchanged between normal and tumor cells—not likely to be involved in tumor growth

the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself.

-Certain patterns of gene expression are heritable without requiring a change in DNA sequence
uModifications of DNA and histone proteins can alter the likelihood of gene expression in a way that can be retained during DNA replication and formation of daughter cells
Examples are
-Histone modification by acetylation (makes genes more accessible) and deacetylation (decreases likelihood of transcription)
-DNA methylation stabilizes DNA and reduces transcription rates—hypomethylation can be a marker of abnormal transcription in disease states

if an individual has two copies of mutation -

The sequence ATCTTT, with complimentary strand TAGAAA, is the normal sequence for a segment of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and codes for isoleucine (position 507) and phenylalanine (position 508). A relatively small deletion of the C-G pair and two T-A pairs (in red) changes that sequence to ...ATT... at position 507, which is translated into isoleucine; however, the next codon is lost, so phenylalanine is missing from the protein sequence. This specific example results in a misfolded CFTR protein that cannot insert into the cell membrane and is degraded.

One base pair is added or deleted, everything shifts, most of the amino acids will change.

polymorphisms in which short sequences of nucleotides within the DNA are repeated, either in or near a gene

Sexes are equally likely to be affected and to transmit the gene.
An affected person will have at least one affected parent.
Numbers of affected individuals in a pedigree are higher than would be expected for autosomal recessive and sex-linked inheritance patterns

-Affected individuals are usually born to unaffected carriers. The risk of an offspring having an autosomal recessive disorder requires that both parents carry a copy of the mutated gene
-Both sexes are equally affected.
-Overall, there are fewer affected individuals in a family pedigree

cystic fibrosis, PKU, sickle cell anemia, and Tay-Sachs disease.

A heterozygous mother will have the phenotype of the disorder, and there is a 50% chance she will pass it on to each of her offspring regardless of sex (Figure 3.23a).
If the father has the disorder, there is a 100% chance he will pass it on to his female offspring, but no chance he will pass it on to his male offspring because he donates the Y chromosome (Figure 3.23b). Some disorders with an X-linked dominant inheritance pattern include Rett syndrome, fragile X syndrome, and X-linked hypophosphatemia (vitamin D-resistant rickets).

All males inheriting the abnormal gene on the X chromosome will be affected as they have no other X chromosome to make that protein.

If the father is affected, all female offspring will be carriers but his sons will not have the disorder. If the mother is a carrier, 50% of male offspring will have the disorder while 50% of all female offspring will be carriers.

hemophilia A, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Duchenne muscular dystrophy.

autosomal dominant

mutation of the FBN1 gene

results in excess activation of transformin growth factor beta- destabilizing the connective tissue

the lifetime breast cancer risk for women with a BRCA1 mutation is 55% to 65%, with a 40% risk of ovarian cancer. A BRCA2 mutation imparts a breast cancer risk of slightly less than 50%, with a 15% risk of ovarian cancer.