MCAT2015

Biology
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CELLS 1
—————————————Cell Membrane Overview—————————————
CELL MEMBRANE AND PHOSPHOLIPIDS INTRODUCTION
• Cell membranes protect us from the outside world, compartmentalize organelles and reactions, etc.
• They are made largely of phospholipids- which themselves contain a glycerol backbone, phospholipid
head, and 2 fatty acid tails
• Phosphate head is polar, hydrophilic. Fatty acid tails are nonpolar and hydrophobic.
• In aqueous solutions, these phospholipids spontaneously form membrane bilayers with hydrophobic
interiors.
• The formation of a phospholipid bilayer is primarily driven by an increase in entropy of surrounding
water molecules.
• Lipids cause water to arrange in an ordered, unfavorable cage-like structure (called a Clathrate
cage). Forcing lipids into a bilayer reduces this effect, thus increasing entropy.
• The membrane is semi-permeable. What can pass?
• Small nonpolar molecules (mostly gases, such as O2 and CO2) go through fairly quickly. This is
called passive diffusion
• Small polar molecules (such as ethanol, H2O) can also go through, but much more slowly
• Large, nonpolar molecules (such as benzeze) also go through the membrane, but also slowly
• Large, polar molecules, such as glucose, cannot pass through the membrane
• Charged molecules (such as Cl–, Na+, many ions and amino acids) also cannot pass through the
membrane
• Phospholipids often bond with another head group via a phosphodiester bond:
• phosphotidyl serine • phosphotidyl choline
• phosphotidyl ethanolamine • phosphotidyl inositol
• diphosphotidyl glycerol (aka cardiolipin)
• The fatty acid “R” group is made of long fatty acids, which can sometimes have double bonds.
• If cis double bonds, they’ll have a kink, which affects cell membrane

CELL MEMBRANE PROTEINS AND THE FLUID MOSAIC MODEL

• Recall, the main component of cell membranes is phospholipids, but it can have other molecules in it,
as well.
• cholesterol: maintains fluidity (at low temps, especially) and integrity (at high temps) of membrane
• proteins: carry out membrane processes. Two main types
• integral / transmembrane proteins: crosses the whole membrane. Strongly bonded
(hydrophobic) with the phospholipids and must be removed by a detergent. They also have
polar and nonpolar regions (Charged parts are on outside, in aqueous environments.)
• peripheral proteins: noncovalently bonded to outside of membrane. Can come and go as it is
needed
• lipid bound protein: found within the interior of the bilayer. These are rare because they don’t
really have access to either side of the membrane and thus don’t play a role in membrane
performing its duties.
• Channel Protein: One of the main types of integral proteins that have a channel / hole that allows
things (such as ions) to pass through.
• can also pump things out
• generally don’t require energy, or ATP, and thus go down a concentration gradient
• One type of channel protein is the aquaporin protein, which selectively allows water through
• Carrier Protein: Will protect the substance so it can carry the molecule in,
• Can go against the concentration gradient if needed (which uses ATP)
• Glucose typically enters the cell through facilitated diffusion via a carrier protein
• Glycoprotein: membrane proteins that are also bound to carbohydrates (glycoproteins); these play a
big role in cell-cell communication, and signaling with / recognizing other cells.
• carbohydrates are always on the outside of the cell membrane for this reason
• There also can be glycolipids, carbohydrates covalently bonded to a lipid that anchors it
CELLS 2
• fluid mosaic model (1972) - cell is made of many different components that are relatively fluid, the
different “pieces” can undergo rapid lateral diffusion around their layer

CELL MEMBRANE FLUIDITY

• Temperature:
• As temperature decreases, fluidity decreases. (The phospholipids will cluster together and not
have energy to move around a lot. At very low temps, this is called a crystallized state.)
• membrane is rigid and may break
• As temperature increases, fluidity increases. (More space in between phospholipids).
• membrane won’t hold shape
• Cholesterol: sort of a buffer, allows the membrane to maintain a certain level of fluidity
• At low temps, cholesterol can help maintain fluidity by creating space between phospholipids
• At high temps, cholesterol can help maintain integrity (b/c phospholipids want to get closer to
cholesterol molecules)
• Unsaturated or Saturated fatty acids in the phospholipids:
• Saturated fatty acid chains pack tighter than unsaturated, and thus will have lower fluidity than the
kinked unsaturated fatty acid chains.

MEMBRANE DYNAMICS: How do phospholipids move in the cell membrane?

• Uncatalyzed movement:
• Transbilayer, or “flip flop” diffusion — when a phospholipid goes from the inner leaflet to outer
leaflet, or vice versa. This is very slow and uncommon.
• Lateral diffusion — phospholipids move all around their own leaflet. Very fast and common.
• Catalyzed movement:
• Flippase protein — catalyzes the movement of a phospholipid from outer leaflet to the inner,
using ATP. Fast compared to transbilayer diffusion
• Floppase protein — catalyzes the movement of a phospholipid from inner leaflet to outer leaflet,
using ATP
• Scramblase — catalyzes the simultaneous movement of one phospholipid from inner —> outer
leaflet, and a second phospholipid from outer —> inner leaflet. Does not require ATP.
What happens when there is a problem with the cell membrane’s ability to uptake/export
important molecules or communicate?
• There are many diseases associated with problems in the ability of the phospholipid bilayer to perform
these functions. One of these is Alzheimer’s disease, characterized by brain shrinkage and memory
loss. One idea explaining why Alzheimer’s disease occurs is the forming of plaque sticking to the
phospholipid bilayer of the brain neurons. These plaques block communication between the brain
neurons, eventually leading to neuron death and in turn causing the symptoms of Alzheimer’s, such
as poor short-term memory.

——————————————Cell–Cell Interaction——————————————
CELL JUNCTIONS
• Three main ways for cells to connect to each other: gap junctions, tight junctions, and desmosomes
• Gap Junctions are essentially tubes that join two cells together.
• These tubes create a connection that allows for the transport of water and
ions to and from the connecting cells.
• Gap junctions allow action potentials to spread between cardiac (or neural)
cells by permitting the passage of ions between cells, producing depolarization
of the heart muscle (or nerve).
• Tight Junctions form when cells are squished up against one another.
• The cell membranes are connected, but the contents of each cell are not
connected in any way; there is an impermeable layer in between the cells.
CELLS 3
• Tight junctions are useful in places that need to contain certain fluids, like in the
bladder, the intestines or the kidneys.
• Desmosomes are thread-like substances that connect cells across the space in between cells.
• Also called macula adherens.
• Like tight junctions, desmosomes physically hold the cells together, but
do not allow fluids or materials to pass from the inside of one cell to the next.
• These connections are also attached to the cytoskeleton (aka the scaffolding
of the cell) to help with structural support.
• The space in between the cells allows for water and solutes to flow freely between each cell
without compromising the connection.
• This is convenient for areas of our body that experience high stress like in our skin or our
intestines because the space in between the cells offer flexibility that the other junctions can’t.
• What happens when cell junctions don’t work properly?
• Gap junctions are most commonly found in the skin, so mistakes in their functions can lead to a
variety of diseases that make up ectodermal dysplasia, a series of genetic disorders affecting the
development or function of the teeth, hair, nails and sweat glands.
• Additionally, errors in specific gap junction genes called, Cx43 and Cx56.6, can lead to the
breakdown of some of our brain tissue called white matter which makes up 60% of our brain.
• This is involved in diseases such as multiple sclerosis & Huntington’s disease
• Mistakes in our genes that produce desmosomes cause skin blistering.

MEMBRANE RECEPTORS
• Membrane receptors = integral proteins that interact with outside environment
• Signaling molecules (aka ligands) such as neurotransmitters, hormones, etc. bind to the membrane
receptor (with specificity) and make a ligand-receptor complex
• This complex then triggers a response in the cell, explaining how hormones function, how / when
cells divide, when they die, etc. Also explains how cells communicate with each other
• Membrane receptors are a common target for pharmaceutical drugs; this is why some cells can
target specific cells (like your liver or heart)
• Signal transduction — an extracellular signal molecule (ligand) binds to membrane receptor, which
then triggers and intracellular response
• The binding causes protein to chain, causes conformational chain, causes cascade of signals in
the cell, causing it to perform a certain function.
• Each receptor can only bind with specific / certain types of molecules. This is especially important in
hormonal signaling.
• Used to be called lock-and-key, but induced fit is now the model, which means the ligand and
receptor can change shape to better fit one another.
• Three main types of membrane receptors:
• Ligand gated ion channels
• G-protein coupled receptors
• Enzyme linked receptors

LIGAND GATED ION CHANNELS

• Also called ion channel linked receptors, these are transmembrane ion channels that open or close in
response to the binding of a ligand.
• Commonly found in excitable cells like neurons, because these channels react quickly to binding of a
ligand, and thus the cells can respond quickly to stimulus.
• Only specific ligands can bind to specific channels (lock and key / induced fit)
• Note, binding site is no where near actual channel.. ligand binds to allosteric site and alters opening /
closing by conformational change.
• The allosteric binding site can be inside the cell, but that’s rare.
• Also possible for there to be multiple binding sites for ligands.
• Once the ions move in or out of the cell, an intracellular electrical signal happens
CELLS 4
• Ligand gated ion channels are not the same as voltage gated ion channels.. those only depend on a
different in membrane potential, not the binding of a ligand
• Ligand gated ion channels are also different from stretch activated ion channels.. which open /
close in response to deformation or stretching of the cell membrane

G-PROTEIN COUPLED RECEPTORS

• Only found in eukaryotes; are the largest class of membrane receptors. Each is specific to a specific
function, but are
• Ligands that bind to these range from light sensitive compounds to pheromones, hormones,
neurotransmitters, etc.
• GCPRs can regulate immune system, growth, sense of smell / taste / behavioral / visual and our
moods. Many G-proteins and GCPRs still have unknown functions.
• Most important characteristics:
• GCPRs have 7 transmembrane alpha helices.
• They’re also linked to G-proteins, which have the ability to bind to GTP / GDP and be activated
• G-proteins have 3 subunits: G α , G ß , and G γ . G α and G γ are attached by lipid anchors.
• (1) When the ligand binds to the GCPR, it undergoes a conformational change.
(2) Because of the conformational change, the G α exchanges its GDP for a GTP, becoming activated.
(3) The GTP causes the G α subunit to dissociate and move away from G ßγ dimer.
(4) G α subunit then goes on to regulate target proteins
(5) Target protein then relays signal via second messenger.
• So target protein could be an enzyme that produces second messengers, or an ion channel that
let ions be second messengers
• Some G-proteins stimulate activity, others inhibit.
• This chain of events, with a G α protein subunit dissociating and going on to activate further response
in the cell, will happen repeatedly as long as the ligand is bound. So how do we turn it off?
(6) GTP on the G α is hydrolyzed to GDP
• This often occurs internally, by GTPase within the G α –protein itself, but can also be regulated
(accelerated) by an RGS protein
• Ex with epinephrine (aka adrenaline):
• Epi binds to ß-adrenergic receptor (GCPR),
which causes it to undergo conformational
change and switch GDP to GTP on the G α
subunit of the G-protein.
• The G α subunit dissociates and binds to
adenylate cyclase, which then makes the secondary messenger cAMP from AMP.
• cAMP goes on to increase heart rate, dilate blood vessels, and break down glycogen —> glucose

ENZYME LINKED RECEPTORS

• Are transmembrane proteins that uniquely function as receptors for signaling molecules and enzymes
• also called catalytic receptors
• General structure has extracellular “ligand binding domain” and intracellular “enzymatic domain”
• Most common enzyme linked receptors are tyrosine kinases (also called RTKs), which regulate cell
growth differentiation and survival; and they can bind and respond to ligands such as growth factors.
• Unique because Tyrosine is on the enzymatic intracellular receptor. RTKs have ability to transfer
phosphate groups to intracellular proteins, which activates them, and they go on to trigger
additional change.
• RTKs occur in pairs. When ligands bind, the RTKs come together and act together in a cross-linked
dimer. This helps activate the Tyr.
• Each Tyrosine in one dimer activates a Tyrosine on the other dimer! This is cross phosphorylation.
• Tyr causes an ATP —> ADP + Pi
• Other Tyr then pick up the free phosphate group.
• Once activated, these phosphorylated Tyr allow different proteins to come by and attach
themselves to them.
CELLS 5
• The only thing these proteins need to dock is an SH2 domain, which allows them to bind.
• Multiple docking of different proteins allows changes to different intracellular signaling pathways at
the same time. It often ends at the nucleus, with the signal from the docking protein affecting
transcription.
• RTKs are useful / famous for their role in growth factors, such as in regulating surface proteins called
ephrines, which can guide developmental processes in tissue architecture, placement of nerve
endings, and blood vessel maturation. Other growth factors (like platelet derived) and hormones (such
as insulin) also bind to RTKs.
• When the RTKs fail to regulate properly, they can cause issues in cell growth and differentiation.
Many cancers involve mutations of RTKs
• Many chemotherapies thus target RTKs. For example, the breast cancer drug Herceptin binds to
and inhibit an RTK that is overexpressed in many breast cancers.

———————————Transport Across a Cell Membrane———————————

• Recall, cell membranes are semipermeable, meaning they have control over what molecules can or
cannot pass through it.
• The bigger the passenger (molecule) we need to get across the membrane, the bigger car (vesicle /
transport mechanism) we’ll need.
PASSIVE TRANSPORT
• In passive transport, no energy is required. This includes:
• diffusion • osmosis
• filtration • facilitated diffusion
• Diffusion is when molecules move down their gradients (higher concentration —> lower
concentration) through the membrane.
• No matter what the situation, the cell it will try to stabilize / equalize concentrations
• Simple Diffusion occurs when small & nonpolar molecules pass through the membrane, down their
gradient, without the use of energy or any membrane transporter.
• This diffusion can be disrupted if the diffusion distance is increased.
• Ex: if the alveoli in our lungs fill with fluid (pulmonary edema), the distance the gases must travel
increases, so their transport decreases. Risk of pulmonary edema can be decreased by
decreasing hydrostatic pressure and increasing osmotic pressure
• Osmosis is when water undergoes simple diffusion; water can easily pass through cell membranes.
• Facilitated diffusion is diffusion with the help of a membrane transport channel.
• These channels are glycoproteins (proteins w/ carbohydrates attached) that allow molecules to
pass through the membrane. They’re almost always specific for a certain molecule (or a certain
type of molecule, if they’re an ion channel), thus are tightly linked to certain physiologic functions.
• Ex: K+ leak channel — potassium has a much higher concentration inside the cell than outside,
so K+ ions will flow down their gradient via this K+ leak channel in the membrane.
• Ex: Chloride transporter that flips its conformation from outside to inside of the cell after binding
chloride. Once the chloride is released into the cell, the transporter flips again to outside of cell.
• Ex: GLUT4 is a glucose transporter found in fat and skeletal muscle.
• Insulin triggers GLUT4 to insert into membranes of these cells so glucose can be taken in.
• Being a passive mechanism, the amount of sugar entering our cells is proportional to how
much sugar we consume, up to saturation point
• In type II diabetes mellitus, cells do not respond as well to the presence of insulin, and so do
not insert GLUT4 into their membranes. This can lead to soaring blood glucose levels.
• Primary Active Transport: directly uses ATP for energy.
• Since these are so costly in terms of energy, they’re more rare than other kinds of transporters.
• Ex: Proton-potassium exchanger (H+/K+ ATPase) found in the stomach. These proton pumps are
responsible for creating the acidic environment of the stomach, and can cause acid reflux. Proton
pump inhibitors like omeprazole are used to treat ulcers or acid reflux because they help reduce
the acidity of the gut.
CELLS 6
• Ex: sodium-potassium pump (Na+/K+ ATPase) helps maintain resting potential in the cell.
• Sodium-Potassium Pump (also called Na+/K+ ATPase) maintains a voltage gradient across a cell or
neuron’s membrane.
• This protein uses the energy released from hydrolysis of ATP to pump three sodium ions out of
and two potassium ions into the cell.
• Three sodiums bond and ATP —> ADP (This is why it’s an ATPase). This causes the transport
protein to flip and open on other side, where Na+ ions are released. Once empty (and facing
outside), two K+ ions bind, causing the transport protein to again flip (this time to the inside) and
releases K+ into the cell.
• Na+ concentration is thus higher outside the cell, K+ concentration is higher inside the cell.
• The outside of the cell is also more positive than inside, b/c for every exchange, we add a net +1
charge to the outside. This creates an electropotential gradient, which eventually stabilizes
because of facilitated diffusion.
• Secondary active transport moves multiple molecules across the membrane, powering the uphill
movement of one molecule(s) with the downhill movement of the other(s).
• Uses a gradient (which is set up using energy) instead of ATP for energy
• Ex: SGLT2 is a glucose symporter transporter that allows glucose into our cells against its
gradient by bringing in a sodium molecule down its gradient at the same time.
• Na+ wants to get inside the cell, and the energy released by it traveling down its gradient is
enough to power glucose into the cell in the same direction (against its gradient).
• Ex: Sodium/calcium exchanger used to
restore cardiomyocyte (heart cell) calcium
concentrations after an action potential. An
influx of calcium causes the heart to
contract. The transporter then pushes
calcium out against its gradient, while
bringing in a sodium ion to relax the heart.
• This type of transporter that allow
molecules to go in opposite directions is
an antiporter

• Secondary active transport also occurs in the neurons (see organ systems section for more).
• SSRIs (used to treat depression) block a specific sodium-neurotransmitter symporter (why?) in the
pre-synaptic neuron to keep the neurotransmitter in the synaptic cleft for a longer period of time.

ENDOCYTOSIS:
• When an extracellular molecule(s) is too large to pass through the bilayer (but it’s still needed in the
cell), the membrane folds inward, causing a new vesicle to bud off into the interior of the cell.
• Phagocytosis — cell engulfs a molecule in order to move it to the interior of the cell.
• A molecule binds to specific receptors on the surface of the cell membrane, triggering the cell
membrane to reshape and surround the molecule. (This process is specific.)
• Then, the the two ends of the cell fuse, creating a vesicle
that surrounds the molecule. Eventually the membrane
around the molecule will be “digested “and its contents will
be used.
• Ex: white blood cells recognize pathogens, such as viruses or bacterial cells, outside of the cell
and will use phagocytosis to bring it in to destroy it!
• Phagocytosis has proteins involved that end up getting hijacked by an HIV virus, such that the virus
can then spread its genetic material and infect throughout the body.
• Ex: our body has helper T-cells (which target and kill bad things in the body) that have a receptor
on them call CXCR4. This receptor is targeted by the HIV virus protein GP41, which binds to
CXCR4. Some people have a genetic alteration in the CXCR4 that does not allow GP41 to bind;
these individuals are immune to HIV!
CELLS 7
• Pinocytosis — cell engulfs dissolved ions & other solutes in the liquid medium surrounding the cell.
• This is different than phagocytosis, which brings in full, undissolved or insoluble molecules, but the
distortion of the cell membrane is similar.
• Pinocytosis is not specific to what is carried into the cell, just brings in a bunch of ions and solutes.
This means that it can accidentally bring in bacteria or pathogens; pinocytosis is how salmonella
infects an individual.
• Receptor-Mediated Endocytosis — very specific (even more so than phagocytosis) importation of
molecules into the cell, lock-and-key
• Receptors embedded in the cell membrane, when bound by molecules with an exact match in
shape, size, or other physical attribute, will allow those molecule to enter into the cell through the
same engulfment process as phagocytosis or pinocytosis
EXOCYTOSIS:
• The golgi body (which has its own membrane) releases a waste protein or molecule into a vesicle.
• Once the vesicle has enclosed the waste proteins, it moves towards the cell membrane and merges
with it, opening the bubble-like structure and ejecting its contents into the surrounding environment.
• Exocytosis can also embed proteins in the cell membrane ————>
• The new protein is formed inside the cell and becomes a part
of a vesicle’s membrane
• The vesicle, now containing the new protein in its phospholipid
bilayer, fuses with cell membrane, allowing the proteins to
become directly integrated with it.
DETAILS ON PHAGOCYTOSIS:
• Phagocytosis is a when a cell (often an immune system cell) binds to the item it wants to engulf on
the cell surface and draws the item inward while engulfing around it.
• Often happens when the cell is trying to destroy something, like a virus or an infected cell
• Very specific process that depends on the cell being able to bind by engulfing surface receptors
• Won’t happen unless the cell is in physical contact with the particle it wants to engulf.
• Cell surface receptors used for phagocytosis depends on the type of cell that’s phagocytizing.
The most common cell receptors are:
• Opsonin receptors — bind bacteria or other particles that have been coated with immunoglobulin G
(or “IgG”) antibodies by the immune system.
• Immune system coats potential threats in antibodies so other cells know it should be destroyed.
• Immune system can use something called the “complement system”, a group of proteins used to
tag the bacteria… basically another way for the immune system to destroy pathogens and threats.
• Scavenger receptors — bind to extracellular matrix produced by bacteria itself.
• Most bacteria and other cellular species produce a matrix of proteins surrounding themselves…
It’s a perfect way for immune system to identify foreign species, because human cells do not
produce the same protein matrix.
• Toll-like receptors — bind to specific molecules produced by bacteria
• Once they’re bound to a bacterial pathogen, the innate immune system recognizes these toll
receptors and activates the immune response.
• Many different types of toll-like receptors are produced by the body, which bind diff. molecules.
• Antibodies — Some immune cells make antibodies that can bind to specific antigens.
•
• Antigens are specific to their pathogens, they help immune system know what threat it has to fight.
• This process is similar to how toll-like receptors recognize and identify what type of bacteria is
infecting the host.
Details of phagocytosis:
• The virus and the cell need to come into contact with each other.
(1) Sometimes the immune cell accidentally bumps into a virus in the blood stream. Other times, cells
move via chemotaxis, in response to a chemical stimulus.
• Many immune system cells move in response to cytokines, small proteins that signal cells to
move to certain area in the body where the particle (e.g. a virus) is found.
CELLS 8
• Common in infections that are specific to a certain area (e.g. skin wound infected by bacteria).
(2) The virus binds to the cell surface receptors on the macrophage.
• Recall, different cell types express different receptors. Some are general, meaning they can
identify a self-produced molecule versus a potential threat (and that’s about it); others are very
specific, like toll-like receptors or antibodies.
• The macrophage will not initiate phagocytosis without successful binding of cell surface receptors.
• Viruses can also have surface receptors specific to those on the macrophage.
• Viruses need to access the host cell’s cytoplasm or nucleus in order to replicate and cause an
infection, so they use their surface receptors to interact with immune system cells and exploit
the immune response for entry into the cell.
• Sometimes, when a virus and a host cell interact, the host cell is able to successfully destroy the
virus and stop the spread of infection.
• Other times, the host cell engulfs the virus, and the virus tricks the cell, gaining access to what it
needs to replicate. Once this happens, the infected cell is identified and destroyed by other cells
of the immune system in order to stop viral replication and infection.
(3) The macrophage starts to invaginate around the virus, engulfing it into a pocket.
• Instead of passing it through the membrane, phagocytosis uses invagination (turns it inside out or
folds back on itself to form a cavity / pouch) to draw the particle inward while closing in around it.
(4) Invaginated virus becomes enclosed in a phagasome (bubble-like structure) within the cytoplasm.
• The lips of the pocket, formed by invagination, extend towards each other to close the gap.
• The plasma membrane then moves around and encases the particle.
(5) The phagosome fuses with a lysosome, becoming a “phagolysosome”.
• Lysosomes are similar to phagosomes, which process wastes inside the cell.
• “Lysis” means “to break down”, making it easy to remember the function of a lysosome.
• Without fusing with a lysosome, the phagosome wouldn’t be able to do anything with its contents.
(6) Phagolysosome lowers the pH to break down its contents.
• A lysosome or phagolysosome is able to break down its contents by drastically lowering the pH of
its internal environment. The strong acidity is an effective way of killing or neutralizing whatever is
inside the phagolysosome so it cannot infect the cell.
• Some viruses actually exploit this lowered pH to escape the phagolysosome and start replicating
inside the cell. Ex: influenza uses the drop in pH to activate a conformational change, allowing it to
escape into the cytoplasm.
(7) Once the contents have been neutralized, the phagolysosome forms a residual body that contains
the waste products from the phagolysosome. The residual body is eventually discharged from the cell.

Phagocytosis and the Immune System

• Phagocytosis is a critical part of the immune system, allowing cells to ingest and destroy pathogens
(e.g. viruses, bacteria) and infected cells. This limits how quickly the infection can spread and
multiply.
• The act of phagocytizing pathogenic or foreign particles also allows immune system cells to know
what they are fighting against… then the cells of the immune system can specifically target similar
particles circulating in the body.
• Several types of cells of the immune system perform phagocytosis, such as neutrophils,
macrophages, dendritic cells, and B lymphocytes.
• Phagolysosomes create an acidic environment to destroy or neutralize its contents, but immune
system cells that perform phagocytosis can also use other mechanisms to destroy pathogens inside
the phagolysosome, such as:
• Oxygen Radicals — highly reactive molecules that react with proteins, lipids and other biological
molecules. During physiological stress, the amount of oxygen radicals in a cell can increase
dramatically, causing oxidative stress, which can destroy cell structures.
• Nitric Oxide — a reactive substance, similar to oxygen radicals, that reacts with superoxide to
create further molecules that damage various biological molecules.
• Antimicrobial Proteins — proteins that specifically damage or kill bacteria.
CELLS 9
• ex: antimicrobial proteins such as proteases, which kill various bacteria by destroying essential
proteins; and lysozyme, which attacks the cell walls of gram positive bacteria
• Antimicrobial Peptides — similar to antimicrobial proteins in that they attack and kill bacteria.
Some antimicrobial peptides, like defensins, attack bacterial cell membranes.
• Binding Proteins — competitively bind to proteins or ions that would have otherwise been
beneficial to bacteria or viral replication. They’re important players in the immune system
• ex: lactoferrin, a binding protein found in mucosal membranes, binds iron ions, which are
necessary for growth of bacteria.
• Some species of amoebas, algae, and other single-celled organisms use endocytosis & phagocytosis
to eat. These engulfing mechanisms allow larger species to consume smaller species easily.
• Many of these single-celled organisms don’t express specific binding receptors. Instead, cilia
(hair-like structures) is used to capture / entangle smaller species and initiate phagocytosis.

MEMBRANE POTENTIALS:
• Recall, cells have a high concentration of K+ (much higher inside then outside)..
Let’s say it’s around 150mMol/L inside, and 5mMol/L outside.
• This is set up by the Na+/K+ ATPase — move 2 K+ in and 2 Na+ out.
• Net charge of a cell is neutral, though, because every cation has an anion.
• The concentration gradient across the membrane makes K+ move outside the
cell via specific ion channels in the membrane.
• When K+ moves out of the cell by these channels, the anions that were bound to
it are left, creating a big negative charge within the cell. This membrane potential
charge makes K+ want to move back in to neutralize the cell..
• Eventually, an equilibrium is reached such that K+ out = K+ in . This typically happens around –92mV
for K+, but is different for every ion (and for different types of cells)
• Note: technically speaking, at some point you will have more K+ ions outside than inside, but the
concentration, which we measure in mols, will stay relatively constant compared to those ion amounts
• The cell will always revert to its equilibrium potential.
• Let’s say we pour a bunch of positive charge into the cell that raises the membrane potential to -
46mV. The K+ will continue to leave because of the concentration gradient, but the lesser negative
charge means they won’t be drawn back in as quick… so the cell returns to -92mV potential.
• As long as you maintain concentration gradient (150mM inside and 5mM outside) and permeability,
the cell will stabilize at its equilibrium! Without both a desire to leave and a way to leave, though, the
concentration gradient won’t happen. (It would be 0mV)
• How do we get calculate V M (membrane potential)?
• V M = 61.5 x log ( [K+ out ] / [K+ in ] )
• Examples of membrane potentials for different ions (for a cell that’s was only permeable to one ion):
• K+ = -67mV (positive ions moving outside cell) • Na+ = +67mV (positive ions moving into cell)
• Cl– = -87mV (negative ions moving into cell) • Ca2+ = 123mV (positive ions moving into cell)
2+
• note that because Ca has a 2+ charge, the 61.5 gets changed to 30.75 in our V M equation.
PERMEABILITY AND MEMBRANE POTENTIALS:
• Permeability is all ions crossing back and forth across the membrane. How do we figure out what this
membrane potential of the cell is?
• Look at what percentage of the “border crossings” are from each ion?
• Let’s say 95% K+, 1% Na+, 2% Cl–, 2% Ca2+
• Multiply this percentage by the ions ideal membrane potential and add them all together.
• -87.4mV (K+) + 0.7mV (Na+) – 1.7mV (Cl–)+ 2.5mV (Ca2+) = – 85.9mV cell membrane potential
• note that equilibrium potential of K+ most influenced the cell membrane’s overall potential,
because it has the highest permeability. If Na+ had the highest permeability by far, the cell’s total
membrane potential would be positive.

————————————————Cell Theory————————————————
1600s:
CELLS 10
• In the 1600s, Anton Von Leeuwenhoek (“Father of Biology”) was looking at a bunch of stuff under the
microscopic, including gunk from his own teeth. He discovered bacteria and named them animacules.
• Also in the 1600s, Robert Hooke also looked at stuff under a microscopic, including a thin sliver of
cork. He noticed the array of their internal structure and discovered & named cells.
• Other scientists around this time looked at animal tissues, and also noticed similar cells.
• This all led to 1st tenet of cell theory: The cell is the basic unit of life.
Early 1800s:
• Scientists continued to research bacteria and noticed that they all had the same sort of structure.
• In 1830s, a botanist named Schleiden also noticed that no matter what kind of plant he was looking
at, they all had those cells that Hooke noticed. Him and Schwann discovered sort of the same thing…
• Schwann researched animal nervous systems, and noticed that even different species of animals
had the same kind of cells. He published a book in 1837 that laid out the 2nd tenet of cell theory:
• All living organisms are composed of cells.
Late 1800s:
• It was known that a man and a woman could reproduce, and thus that animals come from animals.
• It was also known that trees produce seeds, which can be planted to make similar trees, and thus
plants come from plants.
• But no one really knew where bacteria came from… predominant theory at the time was abiogenesis.
• Abiogenesis was a theory of spontaneous generation… Scientists thought that there was some
unknown substance in the air that would combine with non-living material (e.g. a rock) to produce life.
• In late 1800s, scientists studying the cells began to refute this theory. One such scientist was
Virchow.
• Virchow was a German physician and pathologist who observed that some bacteria, if he was
watching them at the right time, divided into 2 bacteria cells that were seemingly identical to the
parent. (We know now this is binary fission, and it’s how bacteria reproduce.)
• Virchow published “ominis cellula e cellula” — cells produce cells. (Though it’s worth noting he
didn’t coin this phrase and probably wasn’t the first / real discoverer of binary fission.
• Virchow was highly criticized… people thought abiogenesis could still explain what he saw.
• Louis Pasteur (1860s) finally really disproved abiogenesis with his swan-neck bottle experiment
• At this time, a well-known experiment that “proved” abiogenesis involved filling a bottle necked
flask with broth (which likely contained bacteria). The broth was boiled to kill any bacteria, and
then left alone… without anything being added to the flask, scientists noted there was growth/life.
• Pasteur thought that maybe there was some sort of bacteria particles in the air that were getting
into the broth and causing the growth… So he invented his own swan necked bottle flask. This still
allowed the broth to be open to the air, but if any microorganisms fell in they would be collected in
the curve of the neck instead of going into the broth. Lo and behold, after the boiling / sterilization
of broth in this sort of swan-necked bottle, and it was left alone for a while, there was no growth.
• This established the 3rd tenet of cell theory: All cells come from pre-existing cells.
• Note: viruses are not considered living organisms because they violate 3rd tenet of cell theory
———————————————Eukaryotic Cells———————————————
CHARACTERISTICS OF EUKARYOTIC CELLS:
• Eukaryotes are usually much large than prokaryotes, and often found in multicellular organisms.
• Also have compartmentalization, membrane-bound organelles, a nucleus, and divide by mitosis.
• Compartmentalization: different parts of the cell are divided from one another so they have
different functions. In prokaryotic cells, everything is just sort of floating around.
• These compartments are called membrane bound organelles.
• Nucleus is very important membrane bound organelle that contains all the genetic material.
• Because prokaryotes are not compartmentalized, they can divide by simply making 2 copies of
everything and dividing down the middle through binary fission.
• Eukaryote division is more complicated, and requires a process called mitosis.
• Nucleus is the “control” center of the cell. It’s where DNA is and where DNA —> mRNA
• Mitrochondria is the cells “power plant” it’s the site of cell respiration where glucose —> ATP
CELLS 11
• Endoplasmic Reticulum is a complex pattern of folded membranes that surrounds the nucleus. It is
the primary site for protein synthesis, and is thus the “factory” of the cell.
• Golgi Apparatus is the “mail room” of the cell. It receives proteins from the ER and then sends them
wherever they need to go, to a different organelle or even out of the cell.
• Lysosomes and Peroxisomes — cells can have multiple of both of these “recycling centers”. The
environment inside of these is very different than the cytoplasm. Lysosomes breaks down things.
Peroxisomes reduce reactive oxygen species (like peroxides) into non-toxic forms.

THE NUCLEUS
• Most important function of the nucleus is to contain genetic material.
• It is enclosed by two membranes (inner & outer), which allows its nucleoplasm to be separate from
the cell’s cytoplasm.
• The nuclear membrane has a nuclear pore that spans both membranes. This allows complexes in
the cytoplasm (such as polymerases) to be transported in, and allows other molecules (like mRNA) to
leave. The nuclear pore is very selective, only recognizing/allowing in molecules w/ certain receptors.
• Nuclear envelope = the combination of inner/outer membranes and the nuclear pores.
• Within the nucleus is a very dense region known as the nucleolus. This is the site of ribosome
assembly, so it’s densely packed with regions of DNA that produce rRNA.
• Proteins needed for rRNA synthesis can come into the nucleus through the nuclear pore.
• After synthesis, complete rRNA can exit back through the nuclear pore into the cytoplasm.
• The outer membrane of the nucleus is continuous with the membrane of the endoplasmic reticulum,
and thus the intermembrane space of the nucleus is continuous with the lumen of the ER.

MITOCHONDRIA
• Mitochondria are responsible for producing ATP, which provides energy for the whole cell.
• They have a double membrane:
• Outer membrane is made of a lipid bilayer that is only permeable to small molecules (which pass
through via facilitator proteins).
• Inner membrane is also a lipid bilayer, but it is not permeable to small molecules. It also has many
folds called cristae, which help increase the surface area of this membrane.
• Increased surface area means more space for membrane proteins involved in ATP production
• In between these two membranes is the intermembrane space
• At the center of the mitochondria is the matrix.
• Let’s go through the steps of cellular respiration:
• (1) Glycolysis splits glucose (6C) into 2 pyruvate (3C each) — in cytoplasm
• (2) PDH (Pyruvate Dehydrogenase Complex) converts pyruvate to Acetyl-CoA — in mt matrix
• (3) Krebs Cycle reacts A-CoA in a series of reactions producing NADH and FADH2 — in mt matrix
• (4) Electron transport chain makes ATP with help of electron carriers — inner mt membrane.
• In the electron transport chain, NADH is oxidized to NAD+ by complex I, and FADH 2 is oxidized to
FAD by complex II. In each of these, the resulting electrons from oxidation are delivered to Cyt. Q,
which shuffles them through complex III to cyt. c, and the electrons are eventually delivered to
complex IV, which uses them to reduce O 2 to H 2 O.
• When the electrons move from protein to protein, they’re going from a higher energy state to a lower
energy state, releasing energy in the process. This energy is used to pump H+ ions out of the matrix
into the intermembrane space.
• The intermembrane thus becomes acidic while the matrix becomes basic, creating a concentration
and electropotential gradient. The H+ ions will want to go back down their gradient, but remember
the inner membrane is impermeable. So the H+ must go through the ATP synthase enzyme.
• ATP synthase has special channels for H+ ions. When H+ goes through them, it causes the axle of
ATP synthase to spin, which results in ADP being combined with a phosphate group to make
ATP.
• chemiosmosis = H+ ions passing through channel in ATP synthase to make ATP
• Mitochondria are also unique in the following ways; they…
CELLS 12
• Have their own circular piece of DNA (multiple copies of it), contained in the matrix.
• Are self-replicating and, because they have their own genome, can make their own rRNA, tRNA,
proteins involved in ETC, and some proteins involved in ATP synthesis.
• Use a different system of transcription and translation
• Have their own unique genetic code.

ENDOPLASMIC RETICULUM AND GOLGI APPARATUS

• The endoplasmic reticulum is made of the Rough ER (has ribosomes) and the Smooth ER.
• Rough ER has ribosomes and is thus the site of protein synthesis.
• Recall: Protein synthesis also happens in the cytoplasm. Proteins made there might end up in the
nucleus, mitochondria, peroxisomes, or just stay in the cytoplasm.
• In contrast, proteins made in the RER will be secreted into the environment, become integral
proteins in the cell membrane, or remain in the ER, golgi body, or in lysosomes.
• The Rough ER is also responsible for post-translational modifications of proteins, such as the
formation of disulfide bridges.
• Proteins that are secreted from the cell or that become part of the membrane follow the secretary
pathway (involves the ER—> golgi —> lysosome or cell membrane). How does it know to follow this?
• All proteins begin to be translated in the cytoplasm, but those that need to follow the secretory
pathway have a signal sequence that’s detected early on in translation. This sequences causes
the protein / polypeptide that’s being translated to be pushed into the RER.
• Smooth ER synthesizes lipids, including those that end up being part of the cell membrane and those
that are eventually secreted from the cell, such as steroid hormones.
• It also metabolizes carbohydrates and aids in the detoxification of drugs.
• Smooth ER It is more tubular than rough ER, and may not be continuous with nuclear envelope.
• Every cell has a smooth ER, but the amount will vary with cell function. (ex: The liver, which is
responsible for most of the body’s detoxification, has larger amount of smooth ER.
• Muscle cells contain sarcoplasmic reticulum, a modified smooth ER that helps store calcium.
• The golgi apparatus is organelle found near the ER; looks like a stack of pancakes. The golgi body
modifies proteins made in the RER, sorts and sends proteins to proper destinations, and synthesizes
certain molecules for secretion.
• Different molecules have different fates upon entering the Golgi. This determination is done by
tagging the proteins with specific sugar molecules that set the protein on one of four paths:
• Cytosol: proteins that enter the Golgi by mistake are sent back into the cytosol
• Cell membrane: proteins destined for the cell membrane are processed continuously. Once the
vesicle is made, it moves to the cell membrane and fuses with it. Molecules in this pathway are
often protein channels or cell identifiers.
• Secretion: proteins meant to be secreted from the cell must accumulate in number and acquire a
special chemical signal before their vesicles can fuse with the cell membrane for release.
• Lysosome: The final destination for proteins coming through the Golgi is the lysosome. Vesicles
sent to this acidic organelle contain enzymes that will hydrolyze the lysosome’s content.
• Let’s look at a protein made in the RER. What will happens to it? For starters, we know it ends up
being secreted or going into a lysosome or the cell membrane.
• First step after synthesis is for the protein to bud off the RER into a vesicle.
• This vesicle merges with the cis stack of the Golgi apparatus (the first part, closest to ER), then
goes through the medial stack, and eventually ends up in the trans stack (furthest from the ER.)
• From the trans stack, the protein-containing vesicle buds off into the cytoplasm and can take
several directions.. It might merge with a lysosome so the protein ends up in it; it might expel its
contents via exocytosis, or might merge with the membrane in such a way that the protein is
embedded in the cell membrane.

LYSOSOMES AND PEROXIDES

• Lysosomes are membrane bound organelles in the cell that digest (“lyse”) small molecules and
substances via two processes: autophagy and crinophagy.
CELLS 13
• Autophagy = self-eating. This is when the lysosomes digest parts of the cell itself or other cells.
• ex: If some organelles in the cell are no longer functional, lysosomes will break them down
• ex: Macrophages in the immune system break down viruses via lysosome autophagy.
• Crinophagy is when lysosomes digest excess secretory product.
• ex: if cells produce extra of a hormone that needs to be secreted, lysosomes will break down that
extra via crinophagy.
• In both processes, after the lysosome breaks down the molecules, it will release the building blocks
into the cytoplasm to be reused.
• Enzymes in the lysosomes are known as acid hydrolases; they require an acidic environment to
work properly. The pH in a lysosome is ~5, which acts as a safety mechanism for the cell.
• If for some reason a lysosome were to burst, it would release into the cell’s cytoplasm all the acid
hydrolases that break down organelles and other molecules… but those hydrolases wouldn’t be
able to work because the pH of cytoplasm is ~7.4!
• Yes, the lysosome would release some of its internal acid into the cell upon bursting, but not
enough to have any significant impact on the pH of the cytoplasm overall.
• If many lysosomes burst at once, though, that would make the cytoplasm more acidic, and that
might make the acid hydrolases start to work, which would not be good for the cell.
• Peroxisomes are responsible for variety of metabolic activities… they break down fatty acids, help
liver cells detoxify chemical and drugs, and neutralize reactive oxygen species (ROS)
• ROSs are molecules like oxygen ions or peroxides that are created as a byproduct of normal
cellular metabolism, but also by radiation, tobacco, and drugs.
• They cause oxidative stress in the cell by reacting with and damaging DNA and lipid-based
molecules like cell membranes.
• In the peroxisome, an ROS such as H 2 O 2 is broken down by catalases into H 2 O and O 2 .

EPITHELIAL AND CONNECTIVE TISSUE

• Four different types of animal tissues are made of eukaryotic cells:
• epithelial • connective
• muscle • nervous
• Epithelial tissue makes up various linings in the body (both outer and inner) and the glands.
• Linings: outer layer of skin, outer layer of organs, lumen of organs, inside of an organism’s cavities
• ex: epithelial cells are found in the tissue lining the mouth, esophagus, GI tract, and kidney
tubules; as well as in the lining of blood and lymphatic vessels, where it’s called endothelium
• Exocrine glands (release hormones / substances directly to target organ)
• Endocrine glands (release hormones to bloodstream)
• Epithelial tissue can be simple (one layer thick), or stratified (2+ layers):
• Simple epithelial tissue is found where substances needs to diffuse from two different sites
• ex: Alveoli of lungs are lined with simple epithelium so O 2 and CO 2 can diffuse from alveoli
• Stratified epithelial tissue can be found in places that need to resist chemical/mechanical stress
• ex: The esophagus intakes food that may be sharp, hot, large, etc.. stratified cells protect it.
• Epithelial cells are attached to a basement membrane that is made of different kinds of fibers (e.g.
collagen) rather than cells.
• The basement membrane is semi-permeable to certain substances, which is important because
epithelial cells are avascular; they have no blood vessels.
• Instead, epithelial cells get nutrients from underlying tissue. Nutrients diffuse from tissue through
basement membrane into epithelial cells.
• Connective tissue supports tissues, connects tissues, and separates different tissues from each other.
• ex: bones, cartilage, blood, lymphs, adipose, membranes covering brain and spinal cord
• Connective tissues have 3 key components: cells, ground substance (a viscous type of fluid), & fibers:
• The ground substance + fiber = matrix. (matrix is usually produced by the connective tissue cells)
• Examples of connective tissue, many of which provide some sort of support for tissues and organs:
• Areolar tissue - binds to different types of tissue and provides flexibility and cushioning.
• Adipose tissue - basically fat; it provides cushioning from the body and stores energy.
CELLS 14
• Adipose does not have fibers (is an exception to the rule)
• Fibrous connective tissue — very strong. provides support and shock absorption for bones and
organs.
• Fibrous connective tissues is found in dermis (middle layer of the skin), tendons, and ligaments
• Blood — also doesn’t have fibers, and the matrix is the plasma.
• Osseous-bone — cells are osteocytes; matrix is bone mineral / hydroxyapatite (the latter is basically
collagen with different minerals in it such as Mg2+, Cl–, etc.)
• Hyaline cartilage — cells are chondrocytes; found in surfaces of joints.

————————————————Cytoskeleton————————————————
INTRODUCTION TO CYTOSKELETON (ANIMAL CELLS):
• Cytoskeleton of the cell provides structural support, helps with cell movement, and helps with
transport within the cell.
• Below are three components of the cytoskeleton, which are all made of proteins:
• Microtubules have a diameter of ~25nm.
• Involved in the mitotic spindle of mitosis, they make up cilia (hairlike projections on outside of cell
that help sweep things up) and flagella (tail-like projections that help move the cell), and aid in
transport across the cell
• Microtubules are made of two proteins, α-tubulin and ß-tubulin that come together to form a dimer.
• These dimers then form long chains/ polymers, which then come together to form a sheet, and
that sheet is rolled up to form the microtubule.
• Intermediate filaments have a diameter of ~10 nm
• Provide structural support to the cell and help resist mechanical stress. Help cell retain its shape.
• In contrast to microtubules and microfilaments, these are made of many different kind of proteins
that are strung together into polymers, which then twist together to make intermediate filaments.
• Also unlike microtubules and microfilaments, intermediate filaments are pretty permanent. Once
they’re made in the cell they stay put (Microtubules & microfilaments are dynamic)
• Microfilaments have a diameter of ~7 nm
• Involved in the gross movement of the cell. Note that this gross movement comes from within the
cell (as opposed to cilia & flagella, which help move the cell from the outside).
• Microfilaments are found in the cytoplasm.
• They’re composed of a protein called actin. Many molecules of actin join together to form an actin
polymer; many actin polymers twist around each other to form actin filaments.
MICROFILAMENTS DETAILS
• Recall, Microfilaments are mainly involved in the gross movement of the cell. They can lengthen and
shorten very frequently (in that sense they’re similar to microtubulues)
• become longer through actin polymerization
• become shorter through actin depolymerization
• This polymerization / depolymerization process is what moves the cell.
• Actin is both flexible and strong, making it a useful protein in cell movement. In the heart, contraction
is mediated through an actin-myosin system.
• ex: Microfilaments help the cell divide; they help make the pinched shape & help actual division occur.
• ex: Microfilament are responsible for the ameboid movement of macrophages (e.g. white blood cell
engulfing a pathogen).. An amoeba has projections known as pseudopods, which reach out to grab
•
food and ingest it. Pseudopod movement is aided by microfilaments.
MICROTUBULES DETAILS
• These tubules are found in cilia & flagella, and also provide pathways for secretory vesicles to move
through the cell. Microtubules are very important in cell division; they help form the mitotic spindle.
• One end of the microtubule is anchored to the microtubule organizing center (MTOC). At the other
end, additional dimers can be added or subtracted to length or shorten the microtubule as needed.
• Examples of MTOC include centrosomes and basal bodies.
CELLS 15
• The centrosome is an organelle that’s found near the nucleus of the cell, it’s made of many different
proteins, including two very important rods (blue) called centrioles (centrosome + proteins).
• Centrioles are made of triplets of microtubules; 9 triplets make up one centriole (so 27
microtubules = 1 centriole)
• When a cell is dividing, the centrioles duplicate and one pair
ends up on each side of the cell.
• At the center of the mitotic spindles are the chromosomes,
and at the center of those chromosomes is the
centromere. A protein kinetichore structure surrounds
the centromere and serves as an anchoring site for the
kinetichore fibers which come out of the kinetichore.
• Those kinetichore fibers are what turn into microtubules.
• Interpolar microtubules are between different poles of the cell. (anchored by centrosomes)
• Astral microtubules are those coming out of the centrioles that bind to the kinetichores
— named because the unit of centrioles + fibers coming out of it (/sort of behind it) is called an aster.
• During the next phase of mitosis (anaphase), microtubules become shorter so the chromosomes are
pulled apart — one half of each chromosome ends up on either side of the cell and eventually the cell
is split down the middle.
• A Basal body has pretty much the same structure as a centrioles; they are MTOC in cells that have
cilia or flagella anchored to them.
• Cilium and flagellum are made of microtubules in a specific 9 + 2 arrangmenet. Looking at a cross
section, we would see 9 pairs around the edge of the tubule, and one pair at the center.
• Between the pairs of microtubules is a protein called nexin, which helps keep them in their place.
• Coming out of the microtubules is a protein called dynein, which breaks down ATP and helps the
microtubles move past each other. This is what moves the flagellum or cilium.
Microtubules also play a very important role in neurons.
• Most substances in a nerve cell are made in its soma, and then have to travel through the axon and
get out the synaptic terminal… this process also happens with the help of microtubules.
• Microtubules form a network (sort of like a railroad track) from the soma; different substances are
moved along this track with the help of two proteins: kinesin and dynein.
• substances that are shuttled down this track include synaptic vesicles (which contain
neurotransmitters), proteins, lipids, even organelles.
• Kinesin and Dynein can move substances in either direction: soma <——> synaptic terminal
• this is called axonal transport / axoplasmic transport

——————————————Prokaryotes / Bacteria——————————————
OVERVIEW OF ARCHAEA, PROTISTA, AND BACTERIA:
• In the phylogenetic tree of life, one of the main divisions is between prokaryotes and eukaryotes.
• Protists are eukaryotes (have nucleus)
• Bacteria and archaea are prokaryotes (“before nucleus,” they don’t have one)
Archaea
• Some of the oldest organisms still in existence, and are thus used to extreme environments
• Three types of archaea: thermophiles (thrive in extreme temperatures), halophiles (thrive in very salty
environments), methanogens (thrive in high concentrations of swamp gas)
• In order to live in these types of environments, archaea have very different cell membranes / walls
Protists
• Protists are basically any eukaryote (organism with a nucleus) that is not a plant, fungi, or animal.
• All protists like moist / aquatic environments.
• Characterized as photosynthesizing or non-photosynthesizing
• Photosynthesizing protists are closely related to plants, and are called algae.
• Nonphotosynthesizing protists are closely related to fungi (fungi-like) and animals (protozoa)
• fungi-like protists include slime molds
CELLS 16
• protozoa include amoebas
• These protists have evolved unique ways of getting nutrients and of moving — including movement
by cilia, flagella, and amoeba-like movements
Bacteria
• Can be found in more diverse environments than protists
and archaea.. Bacteria can both help and harm us.
• Outside structure of bacteria:
• Outermost layer is a capsule or a slime layer.
(Slime layer can be washed off, capsule can’t be)
• Beneath the capsule / slime layer is the cell wall.
The thickness of this wall is different for gram positive
and gram negative bacteria
• Under the cell wall is plasma membrane (lipid bilayer)
• Attached to the outermost layer of bacteria are
structures that aid in movement, such as prokaryotic
flagella (which is different from eukaryotic flagella in
that it’s made of the protein flagellin rather than
microtubules). These help bacteria move toward nutrients via chemotaxis (sensing chemicals and
moving towards / away from it)
• Some bacteria also have hair-like structures on the outside, called fimbriae / pili
• Inside the bacteria, we have cytoplasm, ribosomes, etc., and an area not bound by the nucleus where
the chromosome resides; this is the nucleoid
• Recall: bacterial chromosomes are made of circular double stranded DNA
• Some bacteria also have plasmids, basically extra pieces of DNA that give bacteria important
genetic advantages
• Bacteria also have inclusion bodies that store stuff (e.g. nutrients) for the bacteria. This is important
in prokaryotes because they have no membrane-bound organelles. Instead of synthesizing energy
like the mitochondria make ATP, they must get all their nutrients from the environment and store them
in inclusion bodies. (Bacteria use chemotaxis to get to these nutrients or avoid toxins.)
• Aerobes are bacteria that require oxygen in their environment; anaerobes do not. There are several
different types of anaerobes:
• Aerotolerant anaerobes cannot use oxygen, but can tolerate it in the environment.
• Obligate anaerobes are negatively affected by the presence of oxygen.
• Facultative anaerobes can make ATP by aerobic respiration if oxygen is available, but are
capable of switching to fermentation or anaerobic respiration if oxygen is absent.

BACTERIAL CHARACTERISTICS — GRAM STAINING:

• There are three main shapes of bacteria:
• Coccus (cocci) bacteria are spherical
• Bacillus (bacilli) bacteria are rod shaped
• Spirochete (spirilla) are sort of a squiggle, they actually don’t show up in the same way and must
be stained differently.
• The gram stain is purple in color. After being exposed to the stain, the bacteria sample is washed.
• Gram-positive bacteria hold the stain well and thus show up purple under the microscope.
• Gram-negative bacteria can’t old the stain well and thus show up as a pink color.
• The outer layers of bacteria are very different for gram-positive and gram-negative bacteria.
• Gram-positive have (from inside —> out) a plasma membrane, a very thick cell-wall, & a capsule
• plasma membrane is lipid bilayer
• cell wall is thick peptidoglycan layer (sugar-chains connected by proteins)
• capsule / slime layer
• Gram-negative have two plasma membranes + a layer of glycosylated lipids. From inside —> out:
• inner plasma membrane (lipid bilayer)
• thin cell wall (peptidoglycan layer)
CELLS 17
• outer plasma membrane
• lipopolysaccharide, or LPS, layer (lipid area with sugar chains attached)
• capsule
• Gram-negative bacteria is more likely to cause a systemic effect (such as sepsis) in the body,
because its outer membrane may protect if from the effects of antibiotics
• There is some space between the plasma membrane (or inner membrane in gram negative bacteria)
and the peptidoglycan layer called the periplasmic space.
• Gram stain sticks much better to gram positive bacteria because it can get into the thick cell wall.
Gram negative bacteria have such a thin cell wall, it doesn’t hold the stain well.

BACTERIAL GROWTH CURVE:

• Bacteria reproduce by an asexual reproduction process called binary fission
• Bacteria do this well because they’re small and have a small chromosome
• Because bacterial DNA is circular (and double-stranded) it can have just one origin of replication.
• At this origin, the initiator protein comes in, then 2 DNA polymerases enter to start replication in
opposite directions… They eventually just run into each other on the circle.
• After the replication of genetic material, in order to make a copy of themselves, bacteria start growing
and making a new cell wall… When that wall is complete, the bacteria pull apart and split.
• Each resulting bacteria share the ribosomes / cytoplasm of parent, but have their own cell wall.
• How do bacteria grow as a population? Let’s look at a bacterial growth chart:
• Lag phase: Bacteria takes some time to adapt to its environment, so any replication is slow
• Exponential growth: Once accustomed, the population divides exponentially & growth shoots up
• Stationary phase: The plateau after grown slows because the bacteria population has grown to
capacity and are using all the nutrients available. number of bacteria grown = number that die
• Death phase: At some point, the population gets so crowded that a toxic environment (with no
nutrients) is created and everything dies off.,
• Note: Some gram-positive bacteria can escape the death phase because by forming an endospore.
Recall, gram-positive bacteria have a super thick cell wall. When they start to sense the toxicity in the
environment, some can change their wall chemistry to be super reinforced and seal itself off.. this
endospore is then resistant to heat, radiation, toxic chemicals, etc… it can even survive in boiling
water for an hour! The endospore “rescues” the bacteria until it gets in an environment that has
nutrients again and can be activated

BACTERIAL GENETIC RECOMBINATION:

• How does bacteria get new genetic info? (e.g. pass on antibiotic resistance) — through the plasmid
• (1) Transformation = the bacteria takes up naked DNA from the environment.
• This can be forced in the lab by heating up the bacteria or breaking its membrane with chemicals,
creating pores that are too small for the big chromosome but ok for the plasmid to get through…
• Other bacteria can then pick up the plasmid floating around through their pores and then when the
heat / chemical is removed, the bacteria repairs its membrane and is perfectly functional.
• (2) Conjugation = one bacteria with a plasmid (that is fertility+, it has a fertility factor) and one without
plasmid (f-). A bacteria that has a fertility factor in the plasmid and is fertility positive (F+) will create a
sex pilus — basically a protein tube — that connects the f+ bacterium to an f- bacterium.
• Once connected, the plasmid makes a copy of itself, travels across the sex pilus, and is
circularized / incorporated again in the next DNA
• This is good for traits like antibiotic resistance, because it doesn’t require that the original plasmid
die or be removed like in transformation
• (3) Transduction = a bacteriophage (virus that infects bacteria) injects its genetic material into the
bacteria and the viral genetic info is taken up by the chromosome or plasmid.
• The virus eventually will lyse the cell and leave after reproducing. Before doing so, though, it
needs to repackage its DNA. In transduction, when the virus repackages its own DNA it will also
pick up either the plasmid’s or the chromosomal DNA.
CELLS 18
• Then, when the virus goes on to infect the next cell, it will bring either the plasmid’s or the
chromosome’s genetic information into the next cell.

————————————————Viruses————————————————
VIRUSES ARE NOT LIVING (BUT ALSO NOT DEAD)
• Death is what happens when a living organism stops performing biological functions.. this doesn’t
really apply to viruses, as most biologists would say viruses were never alive.
• Viruses are not made out of cells, they can’t keep themselves in a stable state (homeostasis), and
they don’t grow.
• Viruses also cannot make their own energy or reproduce on their own (they must use a host).
• Even though they have different levels of organization and adapt to their environment, viruses are
more like androids than real living organisms.
VIRUS STRUCTURE AND CLASSIFICATION:
• Four things characterize a virus: size, shape, nucleic acids, and type of host
1) Size.
• A typical virus is >100x times smaller than a bacterium, and >1000x smaller than a eukaryotic
cells. than one
• Size is also a way to tell viruses apart — some are super tiny, other are just very small
2) Shape
• All viruses have a capsid, or protein coat, made of capsomere building blocks.
• Capsomeres are identical for a particular virus, but different types of viruses have different
capsomeres, and thus unique capsids. (Although capsids can be categorized by their 3-D shape.)
• Icosahedral — classic, 6-sided diamond shape
• Helical shape — looks like a cylinder, but is twisted like a helix
• Spherical shape — occurs when an envelope covers the capsid and makes it look spherical
• Some of the capsomeres may help determine the antigenicity of a virus.
3) Nucleic acids.
• Viruses can contain one of four types of nucleic acid:
• dsDNA, dsRNA, ssDNA, ssRNA
• The different types help identify viruses.
• This genetic info is stored inside the protein coat. A nucleocapsid = protein coat + nucleic acid.
4) Type of host.
• A bacteriophage is the name of the viruses that infect bacteria. Viruses that infect eukaryotic cells
are all unique and specific and have their own names (e.g. pox virus).
• Viruses are obligate intracellular parasites. They’re very small (just proteins + nucleic acids), don’t
have organelles, can’t make energy for themselves, and can’t replicate. They’re not a living thing.
Instead they sneak into larger cells and hijack their replication. How do they enter?
• Bacteriophages have a complex shape in that they’re not just icosahedral or helical… They might
have nucleocapsid at the top with the head portion shape containing nucleic acid, but viruses also
have a sheath that acts like a needle (shoots nucleic acid down it), and a tail that attaches to the
bacteria.
• Receptor-mediated endocytosis: If a virus can’t attach and inject its nucleic acid like a
bacteriophage, it sneaks in by tricking cell receptors.
• Some receptors can’t tell the difference between normal cells and viruses or bacterias. A virus
simply enters the cell by binding with (and tricking) receptors and entering via endocytosis.
• Direct fusion: If a virus has that membrane envelope that give the virus a spherical shape, it has
an extra option to get in. Enveloped viruses can still enter via receptor-mediated endocytosis, or
they can get in by direct fusion, which is when the envelope around the virus fuses with the
membrane and gets virus in that way.
VIRAL REPLICATION: LYTIC VS. LYSOGENIC
• Recall that viruses have to get inside other cells to use their ATP and organelles to copy themselves
• once they get in the cell, viruses either go off to copy themselves or wait awhile.
CELLS 19
• Lytic Pathway — Impatient viruses go ahead and take over the cells machinery to immediately start
making copies of their genetic material and their protein (for the protein coat).
• These building blocks then self-assemble in the cytoplasm.
• As the cell continues to make more and more virions, it becomes quite full and eventyally lyses;
then the viruses spread to nearby cells to infect them.
• This cycle is especially good if there are many hosts nearby and viruses need an army fast.
• Lysogenic Pathway — Patient viruses wait for a while because maybe their isn’t a host nearby, in
which case there’s no need to destroy their only host by lysing it. Instead, the virus will just combine
with the host’s genetic info so it can’t really tell that it’s there.
• Viral genetic info is combined into the host cell’s DNA, but it is repressed, not transcribed; it’s
dormant/latent.. but continues being replicated by the host cell.
• Every 1/10,000 times that this happens (or if something like exposure to UV light spurs it), the
repressor gene malfunctions and the cell will try to respond to this “mistake,” or what it thinks is a
mutation, by excising or splicing out the “mutated,” aka the viral, nucleic acids.
• When the cell splices these out and sends them into the cytoplasm, the virus is activated; it self-
assembles, and again eventually grows in population to lyse the cell.
• All lytic viruses destroy the cell while lysogenic viruses may be replicated along with the host cell.
Therefor the host will generate new daughter cells that are infected with the virus, eventually leading
to a neoplasm (aka tumor). Thus oncoviruses are lysogenic.
RETROVIRUSES
• Retroviruses don’t really fit the box of lytic / lysogenic.
• Retroviruses are enveloped ssRNA virus. Three special proteins (reverse transcriptase, integrase,
protease) are also carried in the envelope.
• Recall, enveloped viruses can enter in one of two ways, by endocytosis or fusion.
• HIV, for example, enters via fusion by binding to CD4 receptor cells. This allows then CCR5
receptor to grab hold of the envelope, pull it in, and eventually the virus membrane will fuse with
the cell membrane to release its genetic material into the host cell
• After entering the cell, the retroviruses undergoes a step called uncoating, meaning the capsid is
dissolved. Everything inside this coat is released.
• Reverse transcriptase then binds to the viral RNA and (reading from 3’ to 5’) makes a
complementary DNA strand (cDNA). It then produces a second complementary strand, this time
by reading the new strand of cDNA. This creates two DNA strands that can combine to make
double-stranded DNA. The viral RNA then gets degraded.
• Note that reverse transcriptase makes frequently errors… this mutation of the HIV virus makes
it very hard to treat.
• Integrase protein then comes along and clips off each of the 3’ ends of the viral DNA, forming
sticking ends. It then carries the viral DNA into the nucleus and integrates it into the host DNA,
similar to the lysogenic pathway. (This is the provirus stage)
• Unlike the regular lysogenic cycle, though, the retroviral cDNA does not have the typical
lysogenic repressor gene. It is thus actively transcribed whenever the host DNA is, and turned
into mRNA that’s exported to the cytosol. Outside the nucleus, the mRNA goes through
translation to make campsomere proteins and the other three necessary proteins / building
blocks (though they come out as one polypeptide). Viruses are then self-assembled and head
to the membrane of the cell with the other three proteins.
• As the immature virus leaves the cell via exocytosis, protease cleaves those functional three
proteins. The act of leaving via exocytosis means the virion can retain the cell membrane
envelope around it.
SUBVIRAL PARTICLES: VIROIDS AND PRIONS
• Viruses and subviral particles are categorized as nonliving infections agents; they need a host.
• Viroids are only made of a single strand of circular RNA
• Viroids were previously thought to only be in plants, but now they’ve been found in humans in the
case of hepatitis D.
CELLS 20
• Viroids make more of their own genetic material because their RNA is catalytic, meaning it can
make or break covalent bonds and can thus self-cleave to make other viroid RNA.
• Note: don’t confuse the viroid subviral particles with a virion. Virions are what we call whole virus
(protein coat + RNA + maybe an envelope), but viriods are much smaller and even less complex.
• Prions come from the word “proteinacious infections particles”
• Prions have no genetic material at all! They’re only made of proteins.
• A normal protein is in the shape of an alpha helix. A prion protein (PRP) tends to be in a ß-sheet
• We don’t know much about them but it’s thought that because the normal and prion proteins are
made of same amino acids, so when the prion ß-sheet comes in contact with alpha helix, it will
convert the helix to a ß-sheet.
• As this happens over and over, and more alpha helices become ß–sheets, protein deposits are
created. These are bad in general, but especially bad in something like the brain because the
body will want to clean up these protein deposits.. and in “cleaning them up” (via cleavage or
other damage repair mechanisms) would leaves holes in your brain and cause disease.

———————————————Cell Division———————————————
CELL CYCLE PHASES
• A cell has a diameter of just 100 µm (1/1000000 of the
size of a human)
• The cell cycle can be thought of as seasons in a year.
• Two main “seasons” = interphase and mitosis

• Interphase — cell grows but does not divide. Cells spent most of their life in this phase (unless
they’re cancer cells). There are several sub-seasons of interphase..
• G 1 — extra organelles, such as ribosomes and proteins, are produced. This is the longest phase
of the cell cycle.
• After this, if a cell wants to move towards division it enters S phase. If not, it goes into G 0 phase,
where there is no more division. (This is likely to happen in cells like neurons… Once the brain is
formed, there’s no need for neurons to divide more; instead they just grow)
• S phase — DNA synthesis occurs, and all 23 chromosomes are replicated so we now have 46
• G 2 phase — cell prepares for mitosis through processes like making microtubules (which are
used to pull chromatids apart)
• Mitosis — time of active cell division
• Once the cell divides and produces 2 cells, each of those daughter cells enter the daughter G1
phase.

CELL CYCLE CONTROL

• There are two key places or checkpoints of excessive regulation:
(1) between G1 and S phase, to regulate cell before DNA replication
(2) between G2 and mitosis, to regulate cell before mitosis / division
• Two main proteins regulate these checkpoints:
• Cyclin dependent kinases (add phosphates to other enzymes to activate / inactivate them)
• Cyclins
• All the different types of CDKs are always present in the cell, but their default function is for them to
be inactive. They must be activated by cyclins.
• Specific cyclins are made at specific times. This is important because CDKs are only active when
bound to a specific cyclin, so if the cell hasn’t reached a certain stage of cyclin production, CDKs are
inactive and the cell won’t pass the checkpoints.
• In G1, cyclins G (which CDK2 binds to) and D (which CDK4 binds to) are produced. These,
specifically CDK4, phosphorylate a protein called Rb.
CELLS 21
• Rb normally inhibits DNA replication, but phosphorylation inactivates it so DNA replication can
occur.
• In S phase, Cyclin A is produced, which binds to CDK2. This complex helps activate DNA replication
• In G2 phase, Cyclin B is produced and binds to CDK1. This is able to activate mitosis.
• In order to pass the checkpoints, these cyclin complexes must be present.
LOSS OF CELL CYCLE IN CANCER
• There are higher levels of regulation that occur that occur with a couple of key proteins in addition to
Rb. One of these other proteins is p53, which is the “guardian of the genome.”
• p53 directly binds to DNA to produce proteins that block production of the cell cycle. This includes
proteins like p21, which inhibits CDK, and Rb which inhibits DNA replication.
• These proteins are made from tumor-suppressor genes.
• If the tumor suppressor genes are defected or have a loss of function, you tend to get cancer.
• > 50% of tumors have a defect in p53
• Rb got its name because a defect in this tumor suppressor gene causes a tumor of the eye called
retinoblastoma.
• p21 is unusual in that it doesn’t actually lead to cancer when it’s defective. Instead, mice who lack
p21 are able to regenerate limbs!

FERTILIZATION TERMINOLOGY: GAMETES, ZYGOTES, HAPLOID/DIPLOID

• Fertilization = sperm combines with an ovum. (200-300 million sperm try to get to ovum; only 1 wins)
• Gametes = sex cells (sperm and ovum). Each gamete has just half the number of chromosomes as
somatic cells in your body.
• Sperm cells have a nucleus with 23 chromosomes in it from your father. The last one is sex-
determining… if your father contributes an X, you’ll be female; if he contributes a Y you’ll be male.
• In the nucleus of the ovum there’s also a nucleus with 23 chromosomes; mother contributes an X
sex chromosome
• Zygote = fertilized egg, the fused cell of sperm + egg. This has 46 chromosomes (23 from each
parent; mom and dad chromosomes pair up). This cell can now keep replicating and differentiating
into different cells that make you you.
• The mom and dad chromosomes pair up as homologous chromosomes. This means they have
different variations of codes for the same proteins. 46 chromosomes = 23 homologous pairs.
• Diploid = having the full number of chromosomes. Zygotes are diploid.
• Haploid refers to when you have half the number of chromosomes as a normal cell. For humans, this
23 chromosomes; sperm and ova gametes are haploid.
• When people speak in general about cells, they’ll refer to haploid number as n, and diploid as 2n.

ZYGOTE DIFFERENTIATING INTO SOMATIC AND GERM CELLS

• After fertilization, the zygote keeps replicating through mitosis.
• After one round, you have 2 cells that each still have 2n chromosomes. Then those divide over and
over… 2 —> 4 —> 8 —> 16 —> 32 —> 64.…
• Eventually you have millions of these cells, all of which have 2n chromosomes!
• These cells can then continue to replicate and differentiate into different parts of a body.. this makes a
human fetus!
• Most of the cells produced via mitosis are body / somatic cells; they differentiate into your heart,
lung, brain, etc. Some, though, differentiate into germ cells, into your gonads (ovaries or testes).
• These differentiated germ cells in the gonads produce, through meosis, sperm or ova.
• If you have a mutation in one of your somatic cells like heart or lung, it might affect you / your ability to
survive or reproduce, but it won’t effect genetic info in the gametes. You won’t pass it on. If a mutation
happens in the germ cells, though, that actually has a chance of being pass down to your offspring.

MITOSIS
• Recall, bulk of cell’s life cycle is in interphase. Mitosis is the process by which the one nucleus turns
into 2 nuclei that each have original genetic info and then splits in 2, so 1 diploid cell—> 2 diploid cells
CELLS 22
• Recall, before mitosis is interphase, where the DNA strand of a chromosome is replicated, and this
copied strand is attached to the original strand at the centromere.
• This new structure is called a bivalent chromosome. A bivalent chromosome consists
of two sister chromatids. When a chromosome exists as just one chromatid, just one
DNA strand (and its associated proteins), it is called a monovalent chromosome.
• Prophase
• DNA goes from being in chromatin form, where it’s all spread out into their chromatid
form that is a condensed, distinct shape. (one chromosome = two sister chromatids,
connected by centromere.)
• The nuclear membrane starts to go away, and the centrosomes (organelles that
organize microtubules) start to migrate to opposite sides of the cell.
• Metaphase
• Nuclear membrane is completely gone and chromosomes line up at the cell’s center.
• Centrosomes are fully on opposite ends of the cell. (Each centrosome has two
centrioles, cylindrical-looking structures that aid in extending microtubules).
• Microtubules grow out of centrosomes and attach at the centromere, forming the
mitotic spindle
• Anaphase
• The microtubules (coming out of the kinetochore) begin pulling on the chromosomes.
• The sister chromatids separate and are pulled to opposite sides of the cell. (Note:
These are still called chromosomes b/c a chromosome unit is defined by centromere)
• Telophase
• The newly separated chromosomes on opposite ends of the cell start to unwind into chromatin
• Nuclear membrane starts to reform around the chromosomes (centrosome stays in the cytosol)
• When mitosis is complete, the cell has two groups of 46 chromosomes, each enclosed with their own
nuclear membrane. It then splits via cytokinesis, creating two clones of the original cell.

MEIOSIS
• Germ cells (cells in the gonads) can either undergo mitosis to produce other germ cells, or they can
undergo meiosis to produce gametes. (This is not part of the cell cycle.)
• The purpose of meiosis is to make haploid gametes
• Like mitosis, meiosis starts with a cell that has a diploid number of chromosomes (because during
interphase the DNA replicates).
• Meiosis I yields 2 germ cells that each have a haploid number of chromosomes.
• Meiosis II yields 2 haploid cells from each of the original daughter cells. Now we have 4 haploid
cells that may not have the same genetic info (because of crossover).
• If these are egg cells, only 1 of those 4 will become an ova, the other will become polar cells.
• Oogenesis & spermatogenesis describe the process of meiosis in females and males, respectively.
Meiosis I:
• Let’s start with a germ cell that has 2 chromosomes from the father and two from the mother. (2n = 4)
• With interphase, the DNA and centrosomes are replicated.
• Prophase I:
• Chromosomes condense into distinct homologous pairs of sister chromatids attached by a
centromere. Note: In each pair, you have four chromatids (and two centromeres), so a
homologous pair is sometimes called a tetrad.
• These chromosomes are homologous in that they might contain different sequences, but they
code for the same genes / characteristics (hair color, eye color, height, etc.)
• Nuclear envelope begins to dissolve, and centrosomes start to migrate to the ends of the cell.
• Also in prophase, recombination occurs! Homologous chromosomes switch gene sequences.
This is a way to get more variation into the offspring population. (See Biomolecules document for
details on the different types of recombination).
• Metaphase I:
• Nuclear membrane is gone and the centrosomes are on opposite sides of the cell
CELLS 23
• Homologous pairs of chromosomes line up along the center axis of the cell, aka bivalent
chromosomes lined up two-by-two. Different from mitosis metaphase which has them single file.
• Microtubules extend from kinetichore fibers and attach to the chromosome centromeres.
• Anaphase I:
• The two homologous pairs (aka the tetrad) get pulled apart. This is unlike the anaphase in mitosis,
which splits into sister chromatids rather than full chromosomes!
• How they split is random, which also adds to genetic variation. The gametes produced will all have
different gene sequences.
• Telophase I:
• Homologous pairs are fully separated into opposite ends of the cell and begin to unravel into their
chromatin state.
• Nuclear membranes reform and microtubules dissolve.
• Cytokinesis occurs, creating two haploid germ cells from the one diploid germ cell. The
centrosomes replicate themselves again.
Meiosis II (very similar to what happens in mitosis b/c it preserves # of chromosomes):
• Sometimes, after meiosis I, we might have an interphase II that’s basically a rest period between the
two phases of meiosis. Otherwise the two daughter cells go right into meiosis II.
• Prophase II:
• Nuclear envelope dissolves again and the chromosomes again condense into sister chromatids.
• Centrosomes start to migrate to opposite ends of the cell.
• Metaphase II
• Our centrosomes are on opposite ends of the cell, our nuclear membrane is gone, and the
chromosomes line up at the cell’s equator.
• Microtubules grow out of the kinetochores and attach to the centromeres.
• Anaphase II
• The sister chromatids get pulled apart by the microtubules to opposite ends of the cell (different
from anaphase I!).
• Telophase II
• Daughter chromosomes begin to unravel into chromatin form, and nuclear envelope re-forms.
• Microtubules dissolve and cytokinesis begins, yielding a total of 4 haploid gametes.
• Note that the resulting daughter chromosomes are not homologous; they code for different genes.
If they merge with a sperm (or egg) to form a zygote, only then will they have 23 homologous
pairs, aka the diploid 46 chromosomes. In addition, because of recombination all the gametes will
have different genomes!
• If the chromosomes aren’t split correctly during anaphase II, you get aneuploidy — a term that refers
to mistakes in the number of chromosomes in an organism. For example, if one gamete has an extra
copy of chromosomes 21 (as a result of the bivalent chromosome not being separated into sister
chromatids in anaphase II), the resulting offspring will have Down syndrome.
• Cells can be karotyped during metaphase to check for certain chromosomal mutations.

EMBRYONIC STEM CELLS

• How does the fertilized egg develop after it becomes a diploid zygote?
• Immediately after fertilization, the zygote undergoes several rounds of mitosis to become a mass of
cells (all with the same genetic info) called a morula.
• Once the morula gets to 16 cells or so (takes 4-5 days), it starts differentiating into a blastomere.
• trophoblasts = layer of outer cells
• embryoblasts = inner cells
• The cells keep dividing as fluid then comes in between the trophoblasts and embryoblasts
• Trophoblasts form an outer circle of cells called a trophosphere, while embryoblasts clump
together inside it, forming an inner cell mass against one side of the trophoblast sphere.
• The rest of the space is filled with fluid (called blastocoel). This whole structure is called the
blastocyst in humans (or blastula, blastosphere in other animal… those don’t necessarily have
the inner cell mass there.)
CELLS 24
• This inner cell mass is what turns into the organism! The outer cells, troposphere, is what turns
into the placenta.
• Cells (blastospheres) of the inner call mass, which have not yet differentiated, are called embryonic
stem cells. These have plasticity, which means they could potentially turn into any type of cell!
• The theory is that if you have some damage in your body, stem cells could go that site and
grow/differentiate to replace this damage. Very exciting and promising research for all sorts of
diseases!
• We also have somatic stem cells throughout out body (e.g. in the bone marrow to make red blood
cells), but those are not as plastic.. they can’t make any cell in the human body. Somatic stem
cells won’t turn into human beings if implanted, embryonic cells can.
• Stem cells are controversial because to harvest them (for research, etc), you must kill the developing
embryo. Some think this is bad because that embryo had the potential to turn into a human.
• If you get just one stem cell, you can put it in a petri dish and grow it into an embryonic stem cell
line. This does destroy the embryo, but so do other processes such as in vitro fertilization.
• In vitro fertilization is when some eggs are taken out of the mother, fertilized with semen so they all
become zygotes, and then allow them to develop to the blastocyst stage (such that they have embryo
and blastocoel space). Then a few of the healthiest looking blastocysts are implanted into the mother.
• The embryos they don’t implant also have the potential to create human beings, but most places
just destroy those embryos!
CANCER
• In regular circumstances: cells undergo mitosis and grow until they get a little crowded.. then they
recognized that they’re crowded and stop dividing. (This is called contact inhibition.)
• If something were to mutate in one of those cells, it recognizes this error and destroys itself via
apoptosis.
• There are ~100 billion new cells made in the body every day! and ~100 trillion total cells in a
human body.
• If you have a mutation in a cell and it doesn’t destroy itself, though, this causes problems. Let’s say a
the cell has two mutations, one that prevents apoptosis and one that makes the cell defective in
another way.
• This cell will start dividing more and more and not realize contact inhibition that normally stops /
slows cell growth… instead you’ll have an ever-growing cluster of these mutated cells called a
neoplasm. If this group of cells form a lump of abnormal cells, it’s called a tumor.
• A benign tumor will continue to replicate itself, but not really affect anything around it.
• Cancer occurs when the mutation causes the neoplast of cells to become invasive and start
infiltrating everything, including other tissues, organs. This is invasive super-growth; cancer cells
crowd out other cells and use up nutrients and continue replicating at high speeds. Note that as the
cell continues replicating, it will not only pass on its own mutation, but probably also develop other
mutations (especially if one of the first mutations affects transcription).
• One mutation might eventually cause those cells to break off and travel to infect other parts of the
body. This is metastasis.
• Cancer is thus especially hard to cure because it’s not like a virus or bacterial infection where we can
target a specific protein or pathogen, it’s a whole system of mutations… Even if you target one
specific type of the cells, they can mutate and then that medicine won’t be effective for those cells.
• Common theme behind chemotherapy is to attack things that are quickly growing.

——————————————Cellular Development——————————————
STEM CELLS
• The zygote starts to divide until it reaches the blastocyst stage. Recall, this stage involves an inner
grouping of cells called the inner cell mass, which go on to become the embryo.
• This inner grouping is made of embryonic stem cells, which are pluripotent, meaning they can go
on to differentiate into any different cell type (if/when given proper stimulation)
• We also have somatic stem cells, which are used more as a repair system for the body. They aren’t
quite pluripotent and thus can’t repair everything, but can help some things recover / replenish.
CELLS 25
• ex: epidermal stem cells regenerate our skin as we slough of the outer layer of epidermis.
• Mature cells are not the same as stem cells; they are already specialized but stem cells are not.
• In order to be considered a stem cell (of any kind), you must possess two main qualities:
(1) Continuous production of stem cells — As the cell divides over and over, at least one of the
offspring must still be a stem cell
(2) Differentiation into specialized cells when the time comes
• There are several different types of stem cells, and some are more potent than others in terms of
what they can specialize into
• ex: Epidermal cells are unipotent; they can only differentiate into more epidermal cells
• ex: Our red blood cells have a lifespan of about 4 months, and thus need to be replenished.
Hematopoietic stem cells in bone marrow are multipotent, meaning they can differentiate into
many different types of cells, but only ones within a specific family. (in this case, blood cells)
• In blood diseases like leukemia, certain blood cells grow uncontrollably within a patient’s bone
marrow and crowd out the stem cells. To treat this, the blood cells are removed from marrow by
chemo or radiation, and then doctors can put more hematopoietic stem cells in the bone marrow
to replenish the good blood cells.
• We also have multipotent neural stem cells (give rise to neural types of cells) and multipotent
mesenchymal cells (which give rise to bone, cartilage, adipose)
• Why aren’t these stem cells being used up as they divide? Two mechanisms:
• Obligate asymmetric replication: when stem cells divide, they divide into one cell that’s identical
to the mother cell, and one daughter cell that is differentiated. The mother is still a plastic stem
cell, while the daughter can go on to divide to make more specialized cells.
• Stochastic differentiation: If a stem cell messes up and divides into two daughter cells, another
stem cell will recognize that difference and make up for it by undergoing mitosis to make two
mother stem cell copies.
• Induced pluripotent stem cells (iPS) are a third kind of stem cells… they arise when specific genes
are introduced into the genes of already specialized somatic cells genes. This causes the cells to sort
of forget what kind they are, and revert back into a pluripotent stem cell like an embryonic stem cell.
• This is hugely important / exciting in medicine! iPS cells are the core of regenerative medicine (a
sort of new field where the goal is to repair damage in tissues of a person by giving them their own
line of pluripotent stem cells). Not only would a patient be able to get a new organ/tissue, but
there’d be no immune system rejection because the organ is made of their own cells!
• Cord blood is another source of stem cells; it comes from blood taken from the umbilical cord and
placenta after a baby is born.
What causes stem cells to differentiate?
• Every cell in our body has originated from a common group of stem cells during development. They
have the same DNA, but a neural cell looks very different from a muscle cell, for example, because it
is expressing different genes.
• In order to differentiate, stem cells must turn on one set of “muscle / neural / etc.” genes, and turn off
other genes. Once the cell specializes into a certain type, it can’t go back and re-specialize (at least
not on its own).
• How does a cell turn off and on genes and know what to become? Cues from the environment:
• Asymmetrical Segregation of Cellular Determinants (Internal environmental cue):
• Zygotes, have transcription factors (and mRNA precursors) floating around in the cytoplasm.
• These TFs, which activate certain genes and turn them on, are clustered in one region of the cell.
• This means that when the zygote divides, some of the resulting daughter cells will have those TFs
to turn on certain genes so they’ll specialize into a certain type of cell; other cells won’t have those
TFs and thus won’t specialize to that certain cell.
• Inductive Signaling: peer pressure… one group of cells can influence another group to differentiate
• The influencing group can send signals to other cells via diffusion (paracrine signaling) where
they bind receptors on the other group and cause differentiation
• The group of cells can also influence by direct contact, or by passing chemical signals via gap
junctions (collectively connexon proteins) to induce differentiation.
CELLS 26
• The goal of the transcription factors and of the signals of induction is to get cells to change their gene
expression, which is ultimately what causes them to differentiate.

CELLULAR COMMUNICATION
• Evolutionarily, cells being able to communicate is a major reason we’re so complex.
• Cells communicate directly with one another via direct cell-cell communication, aka direct binding:
• Ex: When macrophages see a pathogen, then can ingest it and break it down. They then show off
a little piece of the pathogen, called an antigen, on their surface. This antigen is basically a a note
to pass to friends; it sends a message that this type of pathogen is around.
• Another white blood cell such as a helper T-cell may come along, then, and grab that antigen with
one of its own membrane receptor proteins. The T-cell thus receives the message and, depending
on what antigen it is, can decide whether or not to start a full-blown immune response.
• Cells communicate over short distances by neural communication or paracrine signaling:
• Neural Communication: Neurons need to communicate with other neurons close by, but the end
of one doesn’t quite touch the head of the next neuron; it leaves a gap called the synaptic cleft.
So neurons can release neurotransmitters that travel from the axon of the first neuron, through
the synaptic cleft, and are then absorbed into the dendrite of the next neuron.
• Paracrine Signaling: This is how one cell can also talk to a small group of cells locally (huddle).
Ex: Just under our skin in, e.g. in our nose, we have skin cells called mast cells that are very
important in mediating allergic reactions. When you breathe in something you’re allergic to, like
pollen, that allergen will bind to receptors in our mast cells. Mast cells then release histamines
that travel to other cells in the area and lets them know to start preparing for an allergic reaction.
• Cells communicate over long distances via endocrine signaling with hormones.
• Ex: Hormones are created by cell bodies and released into the blood stream. They can then travel
through the body and get to any place needed! Not every organ is responsive to them, of course,
because not all have the appropriate receptors, but this allows cells to communicate long-distance

MITOCHONDRIA, APOPTOSIS, AND OXIDATIVE STRESS

• The mitochondria is most well known for producing ATP, but it also plays a big role in apoptosis —
programmed cell death.
• There’s another type of cell death called necrosis, which is more of an “uncontrolled” cell death
that usually occurs in response to extreme stress like an infection or extreme trauma.
• Apoptosis, in contrast, is considered to be more controlled. Even though the cell is dying it will
likely benefit the body / system in some way.
• ex: early on in our development, our hand just sort of looks like a blob of knuckles.. through
apoptosis, the cells in between those ‘knuckles’ die and we get 5 distinct fingers.
• Reasons / situations in which apoptosis is triggered:
• Development (like example above)
• DNA damage — the cell has mechanisms in place to repair damage, but the DNA damage may be
too extensive or our repair mechanisms may not be working, in which case our last resort is
apoptosis. Of course, apoptosis is also good here because we wouldn’t want a damaged cell
passing on damaged DNA to offspring cells.
• Infection — especially by viruses. Often times, our immune cells can recognize specific proteins
on cells surface that indicate is has been infected with a virus(es). Immune cells then send a
signal to the infected cell to undergo apoptosis and prevent the virus from spreading.
• Stress — due to deprivation of oxygen, nutrients, or even disruption of cell-to-cell connections
• In order to continue surviving, cells need to receive signals that it is attached or in close
proximity to other cells around it. If those are taken away, it might undergo cell death.
• Many cells are also often receiving signals from growth factors. If these are removed
somehow, the cell might see it as a sign to go into programmed cell death.
• Ultimately, cells can undergo cell death if their environment is unfavorable.
• Reactive oxygen species (ROS) — These are oxygen species that have acquired extra electrons
are are unstable.
CELLS 27
• Oxygen is important in the cell because its the final electron acceptor in oxidative phosphorylation.
However, about 1/4 are improperly (partially) reduced in this process.
• This leads to the production of ROS, such as superoxides like O 2 –, OH (no negative charge = only
1 lone electron), and H 2 O 2
• How do cells prevent interaction between ROS and important stuff? Cells have enzymes and
antioxidants try to turn ROS into less reactive species or trap it and neutralize / destroy it.
• All ROS will have an effect on mitochondria, though, which play a role in initiating apoptosis. ROS
make the mitochondria membrane more permeable than before. The proteins that regulate the
permeability of this outer mitochondrial membrane are known as the BCL-2 family of protein.
• BCL-2 proteins can be pro-apoptotic or anti-apoptotic; these activate and inhibit the process,
respectively. When things are going well in the cell and its not receiving apoptotic signal, the
balance of these proteins is in favor of anti-apoptic ones; they prevent mitochondria from initiating
apoptosis. When the mitochondria receive signals downstream from apoptotic signals, the balance
shifts in favor of pro-apoptotic proteins, which facilitate increased permeability of outer membrane.
• Why is the permeability of the mt membrane increased to initiate apoptosis? Doing so allows
cytochrome c to exit the intermembrane space and enter the cytoplasm. Recall, cytochrome C is part
of oxidative phosphorylation; it helps shuttle electrons between complex III and IV.
• Cyt C in the cytoplasm also activates a family of enzymes called caspases (c-asp-ase = break
down cytoplasmic proteins by attacking their aspartate residues with a caspase cysteine residue).
• Apoptosis utilizes caspase enzymes, but necrosis doesn’t. These caspase enzymes set off a
controlled cascade of action; their activation of one protein will cause that protein to go on and
activate/degrade another, and on and on. Caspases will activate other types of enzymes like
nucleases (break down DNA).
• These degraded polymers inside the cell can then be recycled to neighboring cells, which will use
phagocytosis to eat up the “building blocks” and use them in their own cell.

TELOMERES AND CELL SENESCENCE

• In your body, you have a couple overarching types of cells called mitotic and post-mitotic.
• Mitotic cells: actively able to divide by mitosis to replenish / regenerate tissues they’re a part of
• Ex: epithelial cells (skin), fibroblast cells (make up scaffolding of organs), endothelial cells (line
blood vessels), stem cells
• Post-mitotic cells: don’t undergo mitosis and are thus incapable of proliferation. They have a
limited ability to repair / regenerate the systems they’re a part of. They can do it with the help of
stem cells, but it happens very slowly.
• Ex: neurons, heart muscle cells
• Recall that in mitotic division, DNA must be replicate. And every time DNA is replicated, their
telomeres get slightly shorter.
• This happens because of the way DNA must be synthesized in the 5’ —> 3’ direction. The lagging
strand is made of Okazaki fragments separated by RNA primers, which are later turned replaced
with actual DNA by DNA polymerase. The final RNA primer, however, cannot be converted to
DNA because there’s no where for the polymerase to bind. Thus that last primer is just degraded
and the copy of DNA is slightly shorter than its template.
• Telomeres on the end of DNA strands prevent actual coding genes from being shortened / mutated,
but a cell can only divide 60-70 times before its telomeres are too short and important coding DNA is
at risk. Once this happens, cell initiates a DNA damage response and sort of gives up its ability to
divide; it becomes a senescent cell.
• Senescence is a change from a happy, active, often dividing cell state — to a state of non-division
that may or may not be happy. The senescent cell starts expressing genes it wasn’t expressing before
and starts to look different / respond differently to cells around it.
• If a cell reaches senescence because its telomere is too short (as described above), it is called
replicative senescence.
• A cell can also go into senescence if their telomeres malfunction in some way, or if DNA mutates
(even in a post-mitotic cell), etc
CELLS 28
• The number of times a cell can divide before it reaches senescence is called Hayflick limit (~60)
• Cells transform to a senescent state to stop division & prevent impending DNA damage
• On one hand, this prevents tumors and cancer from happening by preventing division of damaged
cells. On the other hand, as we age we get more senescent cells that can’t divide and our tissue
can’t repair itself as well. This leads to all sorts of age-related
diseases, like cataracts.
• On a graph of cell division capacity vs. number of doublings:
• Somatic/mitotic cells start out with a high cell division capacity
and move down.. As they continue to divide, their capacity to
divide lessens because telomeres are getting shorter.
• Stem cells maintain a high capacity to divide because they
express the telomerase enzyme!
• Every time a stem cell undergoes replication / division and the telomere gets shorter, telomerase will
replenish it.
• Sometimes somatic cells can have a mutation that allows them to express telomerase, and then their
cell division capacity gets increases and they escape senescence. This can cause cancer.

CELLULAR MOVEMENT
• Some cells have to move around the body (not blood cells, they’re just pumped along) on their own.
• Cell migration / movement is super important
• In development, cells move around the embryo to form distinct organs and limbs.
• As an adult, cell movement is critical for the immune system
• Recall, a sperm’s life is pretty much all about movement, which they do through a flagellum.
• The flagellum is made of microtubules connected by dynein proteins; that all work together to
create a whipping movement of the flagellum
• There are prokaryotic flagellae in bacteria and archaea too, but they’re made slightly differently,
from a protein called flagellin.
• Movement of other cells, such as the neutrophil (a white blood cell, major part of our immune
system) is dependent on the cytoskeleton.
• Neutrophils respond to signals from tissues “in danger” by sticking to the endothelial cells lining
the blood vessel and rolling along for a bit until, at some point, they duck between two endothelial
cells and go into the tissue where they’re needed. There are two major theories / mechanisms for
how these immune system cells roll along the endothelium:

• Cytoskeletal model of movement: The cell quickly polymerizes / puts together actin filaments (made
of actin protein) on the leading edge of the cell. This is how the front of the cell is advanced. In the
back of the cell, we have microtubules that sort of act as a rudder to steer the cell where it needs to
go, and can act as an anchor
• If microtubules are in their flexible / dynamic state, they steer the cell.
• If microtubules are in their stubborn / fixed state, they anchor the cell and it won’t move even if
there’s actin filaments pushing the leading edge forward.
• Membrane-flow model: Bits of the plasma membrane enter the cell in the back via endocytosis, and
they move to the front of the cell and recombine via exocytosis. These vesicles can just be plasma
membrane, or they can contain integrin proteins that act as feet and sort of anchor the cell where they
are; the combination of these types of vesicles move the protein along.
CELLS 29

————————————————Embryology————————————————
Egg and Sperm Structure:
• The entire purpose of the male’s gamete, the sperm, is to transfer the male’s genetic material into the
woman’s gamete, the ovum. The structure is like a torpedo, conducive to this aim:
• Pointed head allows it to travel in the forward direction
• Flagellum tail propels the sperm. It requires a lot of energy
and thus remains dormant until sperm enters the vagina.
• At the base of the head, wrapped around the flagellum, is
a middle section full of mitochondria that provide energy
to propel the sperm towards the egg.
• Inside the head of the sperm is the genetic material, within a nuclear envelope
• The head also has a “warhead” at its front called an acrosome, important for fertilization
• Recall, the sperm is haploid; it contains one set of 23 chromosomes. Meiosis creates 4 sperm from a
single germ cell. Sperm are ejaculated in semen, a basic fluid with a pH of about 7.4 (isotonic)
• The ovum is round, not designed for active mobility. It’s also about 10,000 bigger than the sperm, so
big that it’s often visible to the human eye!
• Like sperm, the egg cell has its genetic material within a
nuclear envelope.
• It also has a thick, protective layer of glycoproteins (peptides with
chains of sugars coming off of them) called the zona pellucida.
• Beneath the zona pellucida is the plasma membrane. Once the
sperm penetrates that, fertilization has occurred.
• The egg is the source of cytosol and organelles, particularly
mitochondria (of which is has 100,000 - 200,000 present), for the future zygote.
• Unlike sperm, the egg has not completed meiosis - it’s stuck in the Metaphase II stage of division.
This means that the egg is haploid but with sister chromatids still attached to each other.
• Also unlike sperm, the meiotic division to create eggs, oogenesis, only makes one viable egg.

FERTILIZATION
• Egg and sperm travel in opposite directions to ultimately meet in (most often) the fallopian tubes.
• During ovulation, ovaries release an egg into one of the fallopian tubes, and the egg proceeds down
the tube toward the uterus, which is being prepared for possible implantation.
• Part of this preparation involves elevated levels of estrogen and luteinizing hormone (LH).
• LH triggers the ovaries to release the egg, while higher blood estrogen levels stimulate the vaginal
membrane to secrete glycogen, which is then metabolized to lactate.
• Cervical mucus may prevent sperm from passing into the uterus, but during ovulation when estrogen
is released and the egg is released from the ovaries, the mucus gets thinner and lower in pH.
• This lower vaginal pH (to as low as 3.8), creates an acidic environment hostile to pathogens (like the
ones that cause sexually transmitted infections).
• However, this environment can also be toxic to sperm, though the semen (a basic fluid) can buffer
the vaginal acidity to preserve sperm cells.
• As the semen mixes with vaginal secretions, the pH settles at a point that is not harmful for sperm,
and this new environment is the trigger to activate sperm flagella and increase sperms’ motility.
• Only about 1 in a million sperm that are ejaculated into the vagina will reach the site of fertilization.
• Increased estrogen causes cervical mucus to become watery and more alkaline, as well as relaxes
the cervix, and stimulates uterine contractions – all of which help sperm reach the egg.
CELLS 30
Steps of fertilization:
1. Sperm binding: A sperm comes in contact with the zona pellucida and becomes bound to it
2. Acrosome Reaction: The binding of the sperm to the zona pellucida sets off release of acrosomal
enzymes (from the head of the sperm) into the zona pellucida, where they start to digest it.
• This allows the sperm head to dive in deeper towards the plasma membrane
• Without the acrosomal reaction allowing the sperm to penetrate the egg, sterility is expected.
3. Cortical Reaction (blocks polyspermy): Eventually the sperm head makes it to the plasma
membrane, and when the two make contact, it it triggers a release of calcium ions, which then cause
cortical granules (right under the plasma membrane) to fuse with the egg’s membrane.
• These granules then release their enzymes into the zona pellucida, and digest its glycoproteins,
specifically the ones that allow other sperm to bind.
• This makes the zona pellucida unable to bind more sperm, while other molecules found in the
granules create a new protective layer around the fertilized egg.
• The cortical reaction thus prevents polyspermy, or the fertilization of a single egg by multiple
sperm. Any sperm that torpedo into the egg after the first one binds will just bounce off now.
• If cortical reaction does not occur, more than one sperm may enter, increasing the risk of trisomy.
4. Genetic transfer: The plasma membranes of the sperm and egg cell become fully used and all the
genetic material within the nucleus of the sperm is released into the egg. This is fertilization.
• A note on Copper IUDs: IUDs in general trigger a mild inflammatory reaction that brings in immune
cells that make it even harder for the sperm to complete their journey.
• The copper released by copper IUDs, specifically, is a natural spermicide (and ovicide, though it
more strongly affects sperm). The copper ions reduce sperm’s motility, ability to trigger the
acrosomal reaction, and general viability.
• Though the devices release less copper than what could be found in our diets, the copper build-up
in the mucous lining of the cervix and uterine is enough to halt the movement of sperm.

EARLY EMBRYOGENESIS: CLEAVAGE, BLASUTLATION, GASTRULATION, AND NEURULATION:

• Let’s start with a zygote, an egg that’s just been fused with a sperm and received its genetic material.
Cleavage:
• You want to become an embryo and need to divide really fast… so fast you don’t have time to grow.
• Cleavage occurs, where the zygote splits into two cells, over and over (still within zone of pellucida).
• After you’ve reached 32 cells (still ~ same size as the zygote), this clump of cells is called a morula.

Blastulation: mass of cells forms a hollow ball; cells begin to differentiate and form cavities.
• The cells of the morula, still stuck within the zone of pellucida, start to get closer to each other,
compact, and the cells start to differentiate.
• Two layers develop: an outer shell layer known as the trophoblast, and an inner collection of cells
called embryoblasts, which make up a clump called the inner cell mass.
• Rather than being arranged in a solid sphere of cells, the inner cell mass is pushed off to one side of
the sphere formed by the trophoblast. The rest of the fluid-filled cavity is called the blastocoel. The
whole setup now resembles a snow globe, and is collectively called the blastocyst.
• Outer trophoblast will develop into structures that help the growing embryo implant in the uterus.
• The inner cell mass will continue to differentiate and parts of it will eventually become the embryo.
CELLS 31
• At this point, cells in the inner cell mass are pluripotent, meaning they can
eventually turn into the cells of any body tissue (muscle, brain, bone, etc).
• This is also the time when the zona pellucida begins to disappear, allowing the
blastocyst to grow and change shape.
• During the 2nd week, these cells differentiate further into the epiblast and the
hypoblast, which make up the two layers of the bilaminar disc. This disc is a
flat slice across the developing sphere; it splits the environment into two cavities.
• The hypoblast is the layer facing the blastocoel; epiblast is on the other side.
• Cavities then expand within the hypoblast and epiblast cells to fill the space.
• The primary yolk sac develops where the blastocoel used to be, on the side of the hypoblast.
• The amniotic cavity develops on the side of epiblast, and is what will eventually surround the fetus.
Gastrulation: Three germ layers form; the primitive streak forms
• A primitive streak of epiblasts then forms (~ day 16) on the bilaminar disc. This streak is actually the
movement of epiblast cells towards the hypoblast layer. The cells (and thus the streak) start from the
caudal (anus) end and migrate toward the end that will eventually become the head.
• This streak determines the midline of the body, and separates the left and right sides.
• This streak will end up as a “waterfall” of cells in between the epiblast layer and the hypoblast.
• If we imagine this motion of the primitive streak formation as a waterfall, the first layer to invaginate
dives the deepest and ends up closest to the hypoblast – this is the endoderm.
• The next layers will become the mesoderm, and the cells of the epiblast that continue to border the
amniotic cavity are the ectoderm.
• We now have three germ layers, making up a trilaminar disc.

• Directly beneath the primitive streak, the mesoderm (middle germ layer) then forms a thin rod of cells
known as the notochord.
• The notochord helps define the major axis of our bodies, and its main purpose is in inducing the
next step of embryogenesis, when we finally start to make our tubes!
• The notochord is also what eventually becomes our intervertebral discs in adults

Neurulation: Notocord forms; tubes form into a neurula; notochord induces formation of the neural
plate, which folds back on itself to make the neural tube and neural crest.
1. The formation of the notochord causes a sort of thickening within the
ectoderm, forming a thick flat plate of cells called the neural plate. The
neural plate extends the length of the rostral-caudal axis.
• The neural plate border separates the ectoderm from the neural plate.
2./3. The neural plate then bends back on itself and seals itself into a tube
known as the neural tube, that fits underneath the ectoderm. The neural tube
will become the brain and spinal cord.
CELLS 32
• In the process, the borders of where the neural plate get pulled under
with the ectoderm and become the neural crest.
• The closure of the neural tube disconnects the neural crest from the
epidermis. Neural crest cells differentiate to form most of the peripheral
nervous system — the sympathetic and parasympathetic nervous
systems, melanocytes, Schwann cells, even some of the bones and
connective tissue of the face.
4. The notochord degenerates and only persists as part of the intervertebral
discs. Other mesoderm cells differentiate into the somites, the precursors of
the axial skeleton and skeletal muscle.
• Actually, the whole mesoderm can be subdivided into axial,
paraxial, intermediate, and lateral plate mesoderms.
• The notochord came from the axial mesoderm.
• The paraxial mesoderm will give rise to somites, which will differentiate
into muscle, cartilage, bone, and dermis.

• The intermediate mesoderm is the origin of our

urogenital system – our kidneys, gonads, adrenal glands,
and the ducts that connect them.
• The lateral plate mesoderm will give rise to the heart
(the first organ to develop!), blood vessels, the body wall,
and the muscle in our organs.

• Also at the same time, the endoderm is rolling into a tube as well – the digestive tract. The digestive
tract is subdivided into the foregut, midgut, and hindgut. Each subdivision has its own nerve and blood
supply. Organs related to the GI tract actually start off as outpouchings of this tube.
• The foregut gives rise to the esophagus, stomach, part of the duodenum, and the respiratory bud,
which will eventually develop into the lungs.
• The second half of the duodenum through to the transverse colon arise from the midgut.
• The remainder of the GI tract, including the rest of the transverse colon, the descending colon, the
sigmoid colon, and the rectum are formed from the hindgut.

• Consider: The gut tube is the only developmental

tube that is supposed to remain an open cylinder.
CELLS 33
If the neural tube does not close, it creates a life-
threatening condition known as spina bifida.
• Spina bifida can occur due to genetic factors,
but may also be caused by a lack of folic acid
during pregnancy or if the mother has
uncontrolled diabetes.
• Spina bifida can lead to weakness and
paralysis of the legs, bladder and bowel
control issues, and other physical problems.
Children with spina bifida often struggle
academically, potentially due to problems in
development of the central nervous system.
• While there is no known cure for spina bifida,
the introduction of folic acid into everyday foods like cereal and bread has drastically reduced the
incidence of neural tube defects in newborns.
IMPLANTATION:
• As the zona pellucida around a blastocyst begins to disintegrate (blastulation), the endometrial lining
of the uterus anticipates implantation and begins to grow. It develops valleys called crypts, in which
the blasocyst eventually rests. Apposition = process of a blastocyst coming into contact with a crypt.
• The blastocyst is not firmly embedded at this point, though, and must become really bound before it
can start nutrient transfer. So trophoblasts on the outside of the blastocyst (now that zona pellucida is
dissolved) start to multiply and invade surrounding endometrium in a process called adhesion.
• The endometrium cells also continue to divide so pretty soon the blastocyst is entirely surrounded by
endometrial tissues.
• In the endometrium are blood vessels (fed by vessels from uterine arteries) that start to grow and
coalesce and form large pools of blood.
• At the same time, the trophoblasts continue dividing and getting bigger and start to fuse to form
multinuclear cells that extend out into the endometrium — called syncitiotrophoblasts. The
remaining trophoblasts are then called cytotrophoblasts (they’ve maintating their unicellularity)
• Syncitiotrophoblasts continue to grow and form finger-like projections called villi within the
endometrium. The blood vessels also continue to grow together.
• Within the villi, tiny fetal blood vessels start to grow as well. These are in really close contact to the
uterine blood vessels.
• The vessels aren’t actually mixing together (because there’s a membrane of trophoblasts between
them), but they’re close enough that nutrients from uterine blood vessels can be transferred to
fetal blood vessels, and waste from fetal blood vessels can be transferred to uterine vessels.
• Eventually this structure of villi and coalesced uterine blood vessels near fetal blood vessels forms
around almost the whole uterus. This is called the placenta.

GESTATION:
• Gestation is often used synonymously with pregnancy; it lasts about 9 months and ends at birth.
• Gestation can be divided into three trimesters, or into weeks.
• Week 0 = Last menstrual period (LMP)
• Week 2 = Fertilization.. sperm meets egg and genetic material is combined
• Weeks 2-10 = Embryogenesis. (+ organogenesis, because in this stage all organs are formed.
• After week 10, the embryo is considered a fetus, and it undergoes fetal development for the
remainder of gestation.
• At ~24 weeks, we hit a milestone of 50% survival outside the womb. If you’re born at 24 weeks, you
have 50% chance of survival. After this, the rate of complications significantly decreases
• Full term is considered to be at 40 weeks (with ~2-3 weeks on either side). If you’re born before this,
it’s considered pre-term. If you’re born after this period, it’s considered post-term.
• There are complications to being born both pre and post term.
CELLS 34
GERM LAYER DERIVATIVES (RECAP):
• After gastrulation, you’ve formed your three major germ layers: endoderm, mesoderm, and ectoderm.
• Endoderm turns into the gastrointestinal and pulmonary systems.
• At the top of the gastrointestinal track/tube are holes from which the lungs actually form, as well as
the liver, and the pancreas.
• And of course that tube goes on to form the stomach, esophagus, large intestines and small
intestines.
• The mesoderm forms the muscle, skeletal, and genitourinary systems.
• Some of the inner layers of skin, as well as muscles and bones, including cardiac muscle, the
kidneys, bladder, and ovaries/testes.
• The ectoderm forms the outer layer of skin, and some skin related items like sweat glands and hair. It
also forms our nervous system.
• The order of formation of germ layers is first ectoderm, then endoderm, then mesoderm. Thus the
order of embryological cells —> tissues is spine formation first, followed by the lungs, then muscle.
ORGAN SYSTEMS 1
——————————————The Nervous System——————————————
STRUCTURE OF THE NERVOUS SYSTEM
• Central Nervous System is made of brain and spinal cord
• Brain can be divided into:
• cerebrum — the top and the biggest part of the brain;
it has two distinct left and right hemispheres
• brain stem — hooks onto the spinal cord, is itself
divided into midbrain (top), Pons (middle), and
Medulla (bottom, also called medulla oblongata; this
connects to the spinal cord)
• cerebellum — sits behind the brain stem and is
connected to it
• Brain structures are sometimes referred to by what they developed from in the embryo:
• forebrain (aka prosencephalon) — becomes cerebrum (temporal lobe, frontal lobe, occipital
lobe, parietal lobse)
• midbrain (aka mesencephalon) — becomes midbrain (top of the brain stem), substantia niagra
• hindbrain (aka rhombencephalon) — becomes the rest of the brain – pons, medulla, cerebellum
• Peripheral Nervous System is made of nerves and ganglia
• Nerves carry the axons of neurons, while ganglia are lumps attached to nerves that contain the
somas of neurons
• Afferent neurons carry information into the central nervous system
• Efferent neurons carry information away from the central nervous system to the periphery.
• An impulse moving through a neuron that carries info from PNS —> CNS is an afferent neuron
impulse moving proximally
• Nerves can be divided into different categories (and are in pairs on each side of the body):
• Cranial Nerves — exit the skull, primarily coming out of the brain and pass through the skull
on the way between the central and periphery nervous system. (12 pairs)
• Spinal Nerves — come out of the spinal cord and pass through the spine on their way between
the central and peripheral nervous systems. (23 pairs)
• Spinal nerves form from spinal nerve roots.
• Efferent neurons (carrying info away) go through spinal nerve root in the front while
afferent neurons (carrying into in) go through spinal nerve roots in the back.
• These come together in the spinal nerves, which we call mixed nerves.
• As any of the nerves travel from their proximal (close to center of the body) to their distal ends,
they branch repeatedly, getting smaller and smaller.

FUNCTIONS OF THE NERVOUS SYSTEM

• Can be divided into basic (lower) functions and higher (complex) functions
• Patterns of abnormal functions are called syndromes. Some syndromes are more common than
others because they’re caused by neurological or psychiatric disorders that occur more frequently.
• Functions are performed by both
• Cranial nerves primarily perform basic functions for the head and neck
• Spinal nerves primarily perform basic functions for the limbs and trunk
• Basic functions are performed by central and periphery nervous systems. Basic functions are associated
with the senses, movement, and automatic function. Three main categories:
• Motor: control of skeletal muscle. These functions cause movement, tone, and posture.
• Sensory: deals with all senses (more than 5!), anything that the nervous system can detect
ORGAN SYSTEMS 2
• Automatic: don’t require conscious involvement — includes reflexes, control of some body
systems, etc. aka. Sweating
• Higher functions are performed by parts of the brain. Higher functions are associated with cognition,
emotion, or consciousness.Three main categories:
• Cognition: thinking functions of the brain — thinking, learning, memory, language, exec.
functions
• Emotions: feelings — play a major role in our experience of life ex. fear
• Consciousness: related to awareness of being a person, experiencing life, and controlling actions
MOTOR UNIT
• Lower motor neurons — efferent neurons of peripheral nervous system (carry info away); they
synapse on and control skeletal muscle, which is the main muscle type of our body.
• One lower motor neuron unit = one lower motor neuron (soma, axon, and axon terminals) AND all the
skeletal muscle cells that it contacts and controls.
• The place where a neuron contacts its target cell is a synapse.
• The synapse between a lower motor neuron and skeletal muscle cell is specifically called the
neuromuscular junction. Lower motor neurons will typically have many neuromuscular
junctions.
• When the neuron fires, all of these skeletal cells are activated and contracted together.
• The somas of LMNs are in the spinal cord or in the brain stem. Their axons pass out of the spine /
brain stem from the spinal nerves / cranial nerves, respectively.
• These axons then continue to branch until they reach and synapse on all the skeletal muscle cells in
their motor unit.
• The lower motor neurons in the cranial nerves primarily control skeletal muscle in the head and neck,
while lower motor neurons in the spinal nerves primarily control muscles of the limbs and trunk.
• Small muscles that need rapid precise control (e.g. in the eyes or fingers) tend to have small motor
units (synapse on few cells). Large muscles that don’t need precise control (e.g. those in the trunk or
thighs) typically have large motor units — may include up to control hundreds of skeletal muscle cells.
• When there is any abnormality of a motor unit, symptoms may include weakness, or loss of strength of
contraction of skeletal muscle.
• Abnormalities of the lower motor neurons, specifically, cause Lower Motor Neuron Signs (LMN
signs):
• Atrophy — decreased bulk of skeletal muscle
• If muscle cells aren’t periodically stimulated by LMNs, the cells degenerate or are lost.
• Extreme weakness and shrunken muscle is an example of atrophy, which is a sign of lower
motor neuron dysfunction.
• Fasciculations — involuntary twitches of skeletal muscle that can occur after some problem of the
motor neurons. The occasional fasciculation is normal, but if we see a lot in one spot that suggests
there could be something wrong with an LMN.
• Apparently, if muscle cells don’t receive periodic input from LMNs, the cells might start to
contract on their own, without any input.
• Hypotonia — decrease in tone of skeletal muscle. Tone is how much a muscle contracts when
you’re trying to relax it. (Ex: Remember the old picture of a doctor and patient. In a normal patient,
even if doc tells the patient to relax, when he tries to move their leg he will feel a little resistance.
With hypotonia, the leg will be especially floppy and not resistant to movement.)
• Hyporeflexia — decreased muscle stretch reflexes (MSR), which normally happen if you rapidly
flex a skeletal muscle (like a pin hammer on a knee).
• Note: ALS affects both upper and lower motor neurons.
PERIPHERAL SOMATOSENSATION
• Somatosensation is simply senses of the body. We can divide this into five categories.
ORGAN SYSTEMS 3
• Position — sense of body parts relative to each other (ex: If we close our eyes and someone moves
our arm over our head, we can know it’s over our head without seeing it.)
• Vibration — can feel vibrations (may be tested on a patient with a tuning fork)
• Touch • Pain • Temperature
• To detect these things, we have a bunch of somatosensory receptors, which can be found in a number
of places. We group these into 3 categories:
• Mechanoreceptors — respond to stimuli. Can detect position, vibration, and touch.
• These receptors have special structures (sort of look like a disc) at the end of the axon that help
take information back to the central nervous system.
• Ex: Mechanoreceptors in the skin detect touch and vibration; those in the deep tissue of
muscles can detect stretch.
• Other mechanoreceptors in the tendons and capsules around joints are important for position
sense because they can send info back to central nervous system about the position of joints
• Nociceptors — can detect a number of different stimuli that give rise to the experience of pain.
• Thermoreceptors — detect temperature.
• Nocireceptor and Thermoreceptors don’t usually have a specific structure at the end like
mechanoreceptors. Instead the axon just ends in uncovered terminals called bare nerve endings.
• Once a somatosensory receptor detects a stimuli it’s specific for, it will send that information back to
the central nervous system in axons of the peripheral nervous system. These are a type of afferent
neuron called somatosensory neurons.
• Most of these have their somas in ganglia close to either the spinal cord or brain stem,
depending on what they’re entering.
• There are several different types of somatosensory neurons:
• Position, vibration, and some touch information tends to travel in certain neurons with large
diameter axons, with a thick myelin sheath. The Schwann cells that create myelin sheath are thus
wrapped around the axon in many layers.
• Pain, temp, and the rest of touch tend to travel in other specific neurons with a smaller diameter,
and either a thin myelin sheath (with less wrapping of Schwann cell membranes around the axon)
or no myelin sheath at all.
• Because axons with a larger diameter and a thicker myelin sheath conduct action potentials more
rapidly, the somatosensory neurons for position, vibration and some touch will conduct action
potential much faster than the others.
• The sense of touch is a funny one because it travels in both types of neurons. Fine touch sense
information tends to travel faster than larger, gross touch sense.

MUSCLE STRETCH REFLEX

• Reflex is a response to a stimulus that doesn’t require the involvement of consciousness.
• All reflexes have two parts:
• afferent — brings info about the stimulus into central nervous system
• efferent — carries info away from CNS to cause a response/effect in the periphery.
• Some reflexes, like the muscle stretch reflex, happen on the same side of the body. Others (especially
those in the brain stem) have an afferent limb that comes in on one side, and efferent responses that
come out to both sides.
• If a muscle is rapidly stretched, the muscle stretch reflex will cause it to contract quickly. This type of
reflex is what is tested when the doctor hits the tendon just below your kneecap with a little rubber
hammer.
ORGAN SYSTEMS 4
• Knee jerk reflex is a monosynaptic stretch reflex. A tap to the tendon that connects the
quadriceps to the patella activates a sensory neuron that directly snyapses with the motor
neuron in the spinal cord, causing the quadriceps to contract.

• When your doctor hits you in the tendon, it actually stretches (not very far, but rapidly) the group of
muscles on the front of your thigh contract, the ones that make your leg extend.
• The receptors in skeletal muscle are called muscle spindles. Specialized little fibers in the muscle
spindle get stretched when the muscle does, and special axons wrapped around these fibers can detect
the stretch. They then send that info back through nerves of the peripheral system and enter the spinal
cord or the brain stem.
• This afferent (stimulus) part of the reflex is caused by somatosensory neurons.
• Inside the central nervous system, these somatosensory neurons carrying muscle stretch info from an
excitatory stimulus synapse with another nerve whose soma is in the CNS. This neuron sends an axon
out through nerves of the PNS back to the same muscle that was stretched. It synapses on and excites
skeletal muscle cells there to contract, causing a response.
• This efferent (response) is caused by the lower motor neurons.
• Recall, one LMN sign is hyporeflexia — occurs if LMN is unable to communicate with the muscle, so
it won’t know to contact in response to the stimulus. But you can also have diminished muscle stretch
reflex if the somatosensory neurons aren’t functioning.
• This is true of all reflexes. If there is an abnormality or malfunction in the afferent or efferent
part, you may have a diminished reflex response.
• Higher parts of the nervous system (cerebrum, e.g.) don’t ever have to get involved for a reflex like
this to occur.
• When the muscles on the top of the thigh are contracted, the ones at the back that cause leg bending are
relaxing. This is because the same somatosensory neuron that sends info of stimulus back to CNS
inhibits the LMNs of the back thigh muscle.
• This isn’t necessary for the muscle to occur, but it does increase the response.

AUTONOMIC NERVOUS SYSTEM

• ANS controls things without involving the consciousness.
• It consists of efferent neurons in the peripheral nervous system that control three types of cells:
• Smooth muscle
• Cardiac muscle
• Gland cells
• We can divide the autonomic nervous system into sympathetic & parasympathetic.
• The autonomic nervous system has two functional differences. The sympathetic nervous system is
associated with fight or flight, and the parasympathetic nervous system is associated with rest and digest.
• Rest and digest means that body functions promoting homeostasis are activated.
• Fight or flight means that body functions promoting survival are activated.
• When one system is activated, the other decreases activities.
• Sympathetic nervous system:
• Starts in the middle part of the spinal cord
• The first neuron off the soma of the spinal cord has a short axon and synapses in a ganglia
close to the spinal cord. The second neuron has a longer axon that then goes toward the desired
target — i.e. a tissue that contains smooth, cardiac muscle, gland cells
• The chain of ganglia coming out of the first, short axons off the spinal cord is called the
sympathetic chain.
ORGAN SYSTEMS 5
• Sympathetic nerves originate in the center of the spinal cord and have a short axon to the
synapse of another neuron. From there, there is a long axon to the target neuron.
• Parasympathetic nervous system:
• Starts either in the brain stem or at the bottom of the spinal cord
• First neuron sends a long axon out to synapse in a ganglion at a lengthy distance from the first
neuron soma. The second neuron then sends a shorter axon to the target cell.
• The parasympathetic nerves originate in the brainstem or at the bottom of the spinal cord.
Parasympathetic nerves have long axons to the synapse of another neuron, then a short axon to
the target neuron.
• Functions of sympathetic nervous system: “Fight or flight”
• causes changes that will help us fight or run away when threatened
• Functions of parasympathetic nervous system: “Rest and digest”
• causes changes more important for homeostasis
• Consider the blood flow to the the gastrointestinal system, which plays a big role in the amount of
digestion that can happen and the amount of blood available for other muscles.
• When the sympathetic nervous system “fight or flight” is activated, blood flow to the intestines is
decreased and redirected towards skeletal muscle
• Most of the time, though, when you’re in a non-threatening situation and can “rest and digest,” the
parasympathetic nervous system is activated which diverts blood away from skeletal muscle and
brings it towards the intestines to help you digest food.
• Consider the heart output, or how much blood is pumped out in a give time period:
• When sympathetic nervous system is activated, heart output is increased to increased blood
availability for skeletal muscle.
• When parasympathetic nervous system is activated, heart output is decreased because you don’t
need as much blood flow to the rest of the muscles if you’re not using them.
• These examples of blood flow involve the activity of smooth muscle, which makes up blood vessels,
and cardiac muscle, which obviously affects the heart.
• Consider the glands:
• When sympathetic nervous system is activated, sweat glands are activated — this cools us down
and allows us to move faster and farther.
• When the parasympathetic nervous system is activated, salivary glands are activated — helps us
digest food.
• Most of the things the SNS does increases the ability of the body to turn stored energy into movement!
Whereas most of the paraSNS activities allows us to conserve energy and digest food.
• Autonomic neurons also play a role in changing pupil size of the eyes, in sexual functions, and more.

GRAY AND WHITE MATTER — GREY = SOMA; WHITE = AXONS

• In the CNS, which is mostly the brain and spinal cord, gray matter contains most of the neuron
somas, and white matter contains most of the myelinated axons.
• Looking at different cross-sections of the spinal cord, we see that most of the gray matter (butterfly or
H-shape) is on the inside of the spinal cord, and most of the white matter is on the outside.
• Looking at cross sections of the brain, we see that gray matter is mostly on the outside of the brain!
This is called cortex. The gray matter over the cerebrum is thus called the cerebral cortex, while gray
matter on the cerebellum is called cerebellar cortex. Most of the neuron somas are here.
• Most of the white matter of the brain is on the inside of the brain, under the cerebral cortex.
• There are some other areas deep in the brain that have also gray matter, which we call nuclei.
ORGAN SYSTEMS 6
• In the white matter of the CNS are collections of axons that travel together through the CNS; we call
them tracts. (One tract can have many axons in it, often carrying similar sorts of information from one
part of the CNS to another part).
• In addition to neurons involved in motor, sensory, and automatic functions, the CNS also has many
neurons participating in higher functions of consciousness, cognition, and emotion. These take place
particularly in the cerebral cortex.

UPPER MOTOR NEURONS

• Recall, the LMNs have their somas in the brain or spinal cord and they send nerves out to skeletal
muscles. LMNs that pass through spinal nerves primarily control cells in the limbs and trunk, while
LMNs that pass through cranial nerves primarily control cells in the head and neck.
• Turns out that while the LMNs control what muscles contract and when, the Upper Motor Neurons
(UMNs) control the lower motor neurons!
• Somas of the UMNs are found mainly in the cerebral cortex (gray matter over cerebrum), and their
axons descend down to synapse on LMNs in the brain stem or the spinal cord, depending on tract.
• Let’s think about a LMN at the top of a spinal cord on the left side. The soma will be in the spinal
cord, and send an axon out into the muscles. The UMN that controls this LMN will start in the cerebral
cortex on the opposite side, and send its axon down through the deep white matter, and into the brain
stem (through the midbrain, pons, and medulla). Where the brain stem meets the spinal cord, most of
these axons will cross over to the other side and travel down the appropriate left side until they reach
the LMN to synapse on it and control it.
• We call this the corticospinal tract.
• The left side of the brain controls, for the most part, the right side of the body.
• Because of the crossover, we see that if there’s dysfunction of a tract at the spinal cord site, there
will be weakness on that same side of the body. If, however, there’s dysfunction in a neuron at the
site of the cerebral cortex, there will be weakness on the opposite side of the body.
• Ex of LMN in the brain stem — one extends to each side of the head or neck. To reach these, some
UMNs start in the cerebral cortex and send an axon down in a similar way as the corticospinal tract
and they will similarly cross over and affect the LMN on the other side of the brain stem. We also see,
however, that some UMNs will travel down to affect an LMN on the same side of the brain stem.
• We call this the corticobulbar tract. It includes UMN axons that innervate LMNs in brain stem.
We can get different patterns of weakness with abnormalities of this tract.. more on that later.
• Dysfunction in either the UMNs or the LMNs can cause weakness.
• Upper Motor Neuron signs can occur with or without weakness. These signs can help us understand, if
a patient does have weakness, whether the problem is in the upper or lower motor neurons.
• Hyperreflexia — an increase in the muscle stretch reflexes (opposite of LMN sign hyporreflexia).
Would cause a patient to have an exaggerated response to a knee tap.
• Cause of hyperreflexia is not known. But apparently when muscle spindles (receptors in
skeletal muscle which are activated and their info is carried back by somatosensory receptors to
elicit a response by UMNs), are not periodically stimulated by the UMNs, the LMNs may
become super sensitive. This may mean a normal signal from a UMN causes an LMN to have
an exaggerated reflex.
• Clonus — rhythmic contraction of antagonist muscles, which have an opposite effect on a joint.
• ex: Antagonist muscles in the front of your shin cause you to pull your foot up, while the
counter muscles in the back of the leg cause you to push your foot down (like a gas pedal). If a
doctor grabs the foot of a patient who has UMN dysfunction and rapidly pulls it upward, the
foot may go into this involuntary movement (clonus) where it starts going up and down and up
and down over and over.
ORGAN SYSTEMS 7
• The cause of clonus is likely just hyperreflexia… each time the foot goes one way the muscles
on the other side are stretched; and the muscles end up triggering each other
• The involuntary rhythmic contraction of antagonist muscles is known as clonus and is a sign of
upper motor neuron dysfunction.
•
• Hypertonia — Increased tone (resistance) of skeletal muscles (opposite of LMN sign hypotonia).
• This can cause muscle spasms, different from the fasciculation of LMN degeneration.
• Muscle spasticity is a feature of hypertonia, or increased tone of skeletal muscle, and is an upper
motor neuron sign.
• Extensor Plantar Response (aka Babinski sign) — If you take a hard object and scrape along the
bottom of the foot, the normal plantar response is flexor, to have the toes curl down towards the
bottom of the foot. If a person has UMN dysfunction and you do this to them, though, the foot will
respond with extensor, meaning the toes will extend away from the bottom of the foot. The
extensor plantar response (or babinski reflex) is a sign of upper motor neuron dysfunction and can be
seen when a noxious stimuli is placed on the bottom of the foot, causing the toes to go into extension
away from the bottom of the foot, rather than flexing down in the direction of the bottom of the foot.

SOMATOSENSORY TRACTS
• Somatosensory tracks are groups of axons that carry information about the environment back to CNS.
• Recall, the different types of somatosensory information tend to travel in different pathways:
• Position sense, Vibration sense, and fine touch sense — these signals travel in large diameter,
heavily myelinated axons. Fast response.
• Pain sense, Temperature, and Gross, or less precise, touch sense — these signals travel in smaller
diameter, thinly myelinated (if at all) axons. Slower response.
• Somatosensory info from most of the body travels to CNS through (afferent) nerves in the PNS and
then through spinal nerves that enter the spinal cord and deliver that info.
• Somatosensory info from the face will usually travel into the brainstem through cranial nerves.
• What happens once the info is delivered into the brainstem or spinal cord?
• For the somatosensory pain, temperature, and gross touch info — Inside the spinal cord, neural
axons carry that information up to the brain in one of the somatosensory tracts that’s specific to
that type of sensation.
• If, e.g. a noxious stimuli is experienced on the left side of the body, an axon will carry that pain
sensation across to the right side of the spinal cord, and then up through the brain stem until it
comes to a place deep down in the cerebrum. It enters the cerebral hemisphere on the other side
from the part of the body where the receptor is on.
• The same is true for the somatosensations of the other category (position, vibration, fine touch),
although their axons cross to the other side a little further up the body in the brain stem (instead of
in the spinal cord)
• Pain, temp, gross touch, etc. sensations from receptors in the face (and some other parts of the head)
can come into the brainstem through cranial nerves that will travel through axons that go down first,
and then cross and then go up to about the same place in the cerebral hemisphere that the info from the
rest of the body came from.
• This tract is also the case for position, vibration, and fine touch. They come into the brain stem
from cranial nerves, go down first and then cross and then go up to about the same place.
• In this place deep in the cerebral hemisphere, all these different types of somatosensory information
come back together and stay close to each other as they send that information on to areas of the
cerebral cortex that will do more processing of the information.
• Because these somatosensory tracts have this sort of anatomy, if there’s an injury or disease to one side
of the brain’s hemisphere, the other side of the body can have somatosensory loss.
ORGAN SYSTEMS 8

CEREBELLUM
• Recall, the cerebellum is behind the brainstem, underneath the cerebrum. It is also divided into left and
right hemispheres, and has many different functions.
• Cerebellum is most notable for coordinating movement; it smooths moves out & increases accuracy.
• Three parts to how information travels into and out of the cerebellum to let it coordinate movement:
• Motor Plan — this involves which muscles need to contract and at what intensity and duration.
• While the movement is actually being executed by UMN through LMN, information about the
motor plan is delivered from the cerebrum to the cerebellum, as well.
• Position Sense — Muscle spindles, e.g. will send info through somatosensory neurons. Once it
enters brain stem and cerebellum, the latter can tell if it’s going according to plan or if corrections
are necessary. Usually that is the case, it needs some sort of correction to make the movement
match the motor plan, so the cerebellum needs to send feedback..
• Feedback — After receiving info about the position sense, the cerebellum may send feedback
back to the motor areas of the cerebrum, the areas that came up with the motor plan in the first
place, to try and correct the movement while it’s occurring by changing activity of the UMN.
• Note: cerebellum is set up such that the middle of the cerebellum tends to coordinate movement of the
middle body, most notably walking. The part of the cerebellum more on the side is more involved in
movement of the limbs. Many parts of the cerebellum also coordinate movements of speech and of our
eyes.

BRAINSTEM
• Brainstem basically connects all parts of the nervous system: the cerebrum, cerebellum, and spinal
cord. It also connects all the cranial nerves.
• Inside of the brain stem has some similarities to the spinal cord, particularly in the medulla. Most of
the white matter is on the outside and most of the gray matter is on the inside, but it’s more mixed than
in the spinal cord.
• Much of the brain stem gray matter are sort of distributed or scattered neurons not in distinct
groups or bundles. This is the reticular formation of the brain stem. It plays an important role in
many autonomic functions, such as circulation, respiration, and digestion.
• Reticular formation also sends lots of axons up to the cerebrum and it plays a role in some of the
higher functions, as well, including cognition, emotion, and consciousness.
• A lot of the white matter passing through the brain stem is actually connecting different parts of the
nervous system. Long tracts are collections of axons that often connect the cerebrum to the spinal cord.
Two big categories of long tracts to which the brain stem plays host:
• Upper Motor Neuons (important for movement)
• Somatosensory
• Most of the 12 pairs of cranial nerves humans have are attached to the brain stem.
• These nerves perform motor functions, sensory functions (many different kinds of sense functions),
and a number of automatic functions.
• These nerves are related to a lot of the gray matter inside the brain stem. In addition to the reticular
formation, there are collections of neuron somas that are distinct nuclei. Cranial nerves often carry
info into or away from these nuclei. — ex: nuclei have neuron somas and axons leave the brain
stem through cranial nerves to perform motor functions.
• Cranial nerves mostly perform their functions in the head and neck, but there are a few that travel
down the brainstem all the way to the body and perform functions in the trunk and limbs
• Ex of cranial nerve functions: sensation of the face, movements of the eyes / face / jaw / throat,
influence the heart and intestines.
ORGAN SYSTEMS 9

SUBCORTICAL CEREBRUM
• This is the deep part of the cerebrum, under the cortex of gray matter. Deep white
matter and deep gray matter (which are called nuclei) are subcortical
• Lots of white matter deep in the cerebrum, which contains axons going from cerebral
cortex gray matter and/or from deeper nuclei and/or to and from the brainstem
• Internal capsule (pink) - subcortical band of white matter, shaped like a V (if looking
top-down). Contains corticospinal tract of UMN.
• Basal ganglia (blue) — collection of subcortical nuclei that function
together; play a major role in motor functions. (They don’t contain UMN
themselves but help out the motor areas of cerebral cortex). Also
contributes to cognition and emotion.
• Corpus callosum (purple) — band of white matter connecting left and
right hemisphere, allows info to travel across them.
• Thalamus (Diencephalon) (yellow) — Under the corpus callosum.
Plays an important role in sensory functions. Almost all the senses have
pathways that travel to the thalamus for sensory processing and then
travel further on to areas of the cerebral cortex.
• Thalamus is also very important for all higher functions of the brain (cognition, emotion, and
consciousness) bc it is connected to many brain areas and plays a role in passing info around
between them and other areas / subcortical structures.
• Hypothalamus (green) — Under the thalamus. It is connected to and controls the pituitary gland
(circled in green), aka “the master gland” that links nervous and endocrine systems and plays a major
role in controlling glands. The hypothalamus is also involved in higher functions.

CEREBRAL CORTEX
• Cerebral cortex is layer of gray matter on outside of the cerebrum. It has many ridges called gyri
(sing: gyrus), and small grooves on either side of a gyrus called sulci (sing: sulcus).
• Large grooves separating lobes are called fissures.
• Cerebral cortex is divided into lobes, named for the bones of the
skull right above them.
• Frontal — logic and decision making
• Parietal — proprioception and sensory
• Temporal — language and memory, olfactory, auditory
• Occipital — vision
• A few senses and motor functions of cerebral cortex on one side of
the brain tend to be involved with the other side of the body.
• Visual information coming in on the right side of a body will be
processed on the left side of the brain (in the occipital lobe),
and vice versa
• Somatosensory information, such as a hot or cold something applied to the skin on the right side,
will end up being processed and brought to consciousness in the parietal cortex
• Motor functions for, e.g., the right leg will be processed on the left side of the brain (specifically,
the back part of the frontal lobe).
• Other senses (besides vision and somatosensation) tend to get processed in areas of the cerebral cortex
on both sides
ORGAN SYSTEMS 10
• We can divide the areas of the cerebral cortex based on the function of that area:
• Primary cortex: performs basic motor or sensory functions
• Association cortex: associates different types of info to do more complex processing and
functions.
• ex: For areas of motor cortex, there’s primary motor cortex/cortices that do basic motor functions,
and then association motor cortices do more complex functions like planning of movements. Some
areas of association motor cortices take in different types of information and integrate / process it
to do higher level complex motor or sensory functions, and to produce higher functions of the
nervous system such as cognition and emotion.
• One aspect of cognition is language (ability to turn thoughts into words), performed by certain areas of
cerebral cortex in left hemisphere.
• Cerebral cortex on both sides plays a role in attention but, for most people, the right cerebral
hemisphere’s cortex plays a role in paying attention to both sides of the body and the environment.
(The left hemisphere just seems to pay more attention to the right side of the body).

NEUROTRANSMITTER ANATOMY
• Recall, neurotransmitters are molecules that communicate between neurons and their target cells at
chemical synapses.
• Some neurotransmitters are released by neurons that are distributed throughout the nervous system.
• Ex: glutamate (most common excitatory neurotransmitter), GABA (inhibitory, in the
brain), and glycine (inhibitory, in spinal cord)
• Other neurotransmitters are more specific to certain areas.
• Areas of the brain that have collections of neurons send axons diffusely to release specific
neurotransmitters into the cerebral cortex. (Also other areas, but mostly that)
• These widespread projections coming up towards the cerebral cortex dump lots of a specific
neurotransmitter all over certain areas of the cerebral cortex; and they’re very important for
functions of the higher nervous system (i.e. cognition, emotion, and consciousness).
• Glutamate — Some particular areas in the reticular formation of the brain stem and parts of the
thalamus that project axons diffusely to cerebral cortex and release glutamate all over cerebral cortex.
• Reticular activating system = collection of neurons that have diffuse projection of glutamate
• Without this system, there is no consciousness
• Acetylcholine — The basalis and septal nuclei send diffuse projections of acetylcholine all over the
cerebral cortex. [affects peripheral nervous system.]
• Lower motor neurons that come out of CNS and have axons that synapse on skeletal muscle cells
release acetylcholine
• Most neurons of the autonomic nervous system also release acetylcholine, a smaller number release
norepinephrine as their neurotransmitter.
• Histamine — There are a number of neurons in the hypothalamus that send projections to release
histamine all over the cerebral cortex.
• Norepinephrine — The local ceuruleus is an area in the pons section of the brainstem that sends
neurons releasing norepinephrine all over the cerebral cortex. [affects peripheral nervous system]
• Most neurons of the autonomic nervous system also release acetylcholine, a smaller number
release norepinephrine as their neurotransmitter.
• Serotonin — A number of raphe nuclei are present at all levels of the brain stem (midbrain, pons
and medulla) that release serotonin up to cortex and other parts of the immune system.
• Dopamine —The ventral tegmental area is in the midbrain, and it diffusely projects dopamine onto
the cortex. [affects central nervous system]
ORGAN SYSTEMS 11
• There are also a couple of projection systems of dopamine that aren’t into the cerebral cortex but
that are important for functions of the central nervous system, and can become problems for
medications that affect dopamine neurotransmission.
• One such collection of neurons in the midbrain is called the substantia nigra, and it’s projecting
dopamine to another part of the basal ganglia (specifically to a couple of nuclei deep in the cerebral
hemisphere) called the striatum.
• Problems with this system of dopamine getting from substantia nigra to the striatum appear to
be a big part of what happens in Parkinsons’ disease.
• There are also dopaminergic neurons in the hypothalamus that send dopamine down to the pituitary
gland to control the release of prolactin.
• All these diffuse projection systems are very important to the higher functions of the nervous system.
• Many psychiatric disorders appear to involve dysfunction of these neurotransmitter systems and thus,
many psychiatric drugs influence these systems.

• Dopamine is released from the ventral tegmentum (also known as the ventral tegmental area) to the limbic system
through the nucleus accumbens. Dopamine is released from the substantia nigra to the striatum. Dopamine is released
from the hypothalamus to the pituitary gland.

One specific type of antidepressant medication works by blocking the removal of neurotransmitters. Which of the
following neurotransmitters is most likely the target of the antidepressant medication?
• The neurotransmitter must be classified as one of the types that is associated with attention, cognition, and
emotion.
• The medication works by blocking the removal of the neurotransmitter; acetylcholine is not removed from the
receptor, but is broken down by enzymes.
• Selective Serotonin Reuptake Inhibitors (SSRI’s) function by blocking the reuptake of serotonin, which
allows more serotonin to be present.

EARLY METHODS OF STUDYING THE BRAIN

• Old study of phrenology thought brain areas were divided into different tasks / characteristics, and this
created bumps on the skull. By studying bumps, they thought they could learn about a person. Wrong.
• Autopsies — told scientists a lot about different structures of the brain, but was limited in that it can’t
show how the brain functions or controls the body.
• Wait until someone has some kind of brain injury and then study the effect it has on the
• Ex: Phineas Gage in 1848 got a metal rod from the railroad through his head but survived!
Actually walked away from the accident despite losing brain matter and lots of blood. However,
the injury completely changed his personality (for the worse).
• Scientists learned cerebral localization from these types of studies — the idea that specific areas
of the brain control specific aspects of behavior and emotion, even personality.
• We didn’t have much control over these types of studies though. Because strokes / accidents typically
cause a lot of damage, it’s hard to tell what area is responsible for what behavioral change. But there
are some areas around it.
• Paul Broca studied a patient he called “tan” who lost the ability to speak (except for that word), yet
didn’t seem to suffer any other type of mental impairment. When the patient died, Broca discovered he
ORGAN SYSTEMS 12
had damage in a very particular part of the left frontal lobe. Broca then studied autopsied brains for
a number of patients with speech impairment and while the type of damage varied, it was all in this
particular region. He discovered this area must be involved in speech production.
• We now call this region in the left frontal lobe Broca’s area,
• Aphasia = loss of ability to understand or express speech.
• Broca’s aphasia = trouble with speech production because of damage to Broca’s area.
• Problem with these methods is the long time span (waiting until someone dies means they may outlive
doctor, may sustain other brain injuries by then, may lose touch with doctor, etc) and the lack of
control over the types of injuries / damage done.

LESION STUDIES AND EXPERIMENTAL ABLATION

• Ablation studies — method of deliberately destroying tissues (making lesions) in order to see what
effect this will have on an animals’s behavior. (This research obviously not done with humans.)
• Functions that can no longer be performed after the damage must be the ones that were controlled
by those damaged regions.
Different methods of creating lesions:
• Surgical removal, with a scalpel or aspiration (literally sucking out brain tissue).
• This is limited in that it can only remove structures on the surface of the brain.
• Also, scientists aren’t always interested in actually removing tissue, but instead damaging the
tissue in place (e.g. through the following methods… less invasive)
• Severing the nerve with a scalpel — inhibits signals from the nerves so it can’t do its job
• Radio frequency lesions — can destroy tissue both on the surface and deep inside
• A wire that’s insulated except at the very tip, is inserted to a pre-determined area in the brain. Then
a high frequency current is passed through the wire, which heats up and destroys tissue just around
the wire’s tip.
• This allows scientists to vary the intensity and duration of current to control size of resulting
lesion. However, it destroys everything in the area — not just the cell bodies of neurons in that
area, but also the axons of other neurons just passing through. Hard to determine which is
responsible for any behavior change.
• Neurochemical lesions — very precise, and can be created through many different methods, including
excitotoxic lesions… Excitotoxins are chemicals that bind to glutamate receptors and cause such an
influx of Ca2+ ions that it kills the neuron, essentially exciting it to death.
• Ex: kainic acid. This method destroys cell bodies of neurons but not those of axons passing by, so
you don’t need to worry about severing connections like in radio frequency lesions or knife cuts.
• Ex: Oxidopamine (6-hydroxydopamine) — selectively destroys dopaminergic neurons (release
dopamine) and noradrenergic neurons (release norepinephine or adrenaline).
• Say you have a presynaptic cell that’s releasing dopamine to the synaptic cleft between cells.
After dopamine binds with post-synaptic cell, the body wants to get rid of it or recycle it. It
does this through re-uptake, where basically a little vacuum on the pre-synaptic cell sucks all
the neurotransmitter back in. Oxidopamine looks a lot like dopamine, so when released into an
area, it’s also taken up by re-uptake channels.. then it kills those cells.
• This is extremely useful because it gives us a lot of control, allowing us to destroy cell bodies
(not axons) and to target specific populations of neurons in specific areas of the brain.
• Ex: researchers use this to model Parkinsons disease in lab animals (by targeting and
destroying neurons in substantia nigra)
ORGAN SYSTEMS 13
• Cortical cooling (cryogenic blockade) — cools down neurons until they stop firing / functions. Can
be done many different ways, including with use of a cryoloop. This device is surgically implanted
between skull and brain, and then a chilled liquid is circulated through the loop.
• Unlike other ablation techniques mentioned thus far, this is reversible!!
• Temporary lesions can also be created through neurochemical means…
• Ex: A drug called muscimol temporarily binds with GABA receptors and winds up temporarily
inhibiting those neurons so they can’t fire.

MODERN WAYS OF STUDYING THE BRAIN

• Can be divided into two types of studies: those that tell us structures and those that tell us function.
Structural Recording:
• CAT scans or CT scans (Computerized Axial Tomography) — Uses X-rays to create images of brain.
• Can show us if there’s a tumor or abnormal swelling in the brain.
• Can’t tell us what areas are active at a given time.
• Magnetic Resonance Imaging (MRI) — Uses radio waves to get picture of brain.
• A person’s head is exposed to a strong magnetic field, which aligns the atoms in their brain in a
certain direction. Then a radio wave is added to the magnetic field, which disrupts that alignment.
• As the atoms then move back to realign with the magnetic field, they emit a signal. Different types
of atoms emit different signals!
• This allows for a creation of a (much more) detailed picture of the brain.
• Still can’t tell us anything about brain function, though.
Functional Recording:
• Electroencephalography (EEG) — measures electrical activity generated by neurons in the brain
• Done by placing electrodes on someone’s scalp at predetermined positions (usually by using a cap
with electrodes that are filled with a conductive gel.
• Pro: non-invasive. Con: Because it’s non-invasive, EEGs can’t really tell us anything about
specific neurons or groups of neurons; just looks at sum total electrical fields generated from the
brain.
• Unlike structural methods (CT scans, MRIs), we don’t get a picture of the brain- just lots of
squiggly lines that show if a person is awake/asleep or if they’re engaged in certain cognitive tasks
• Magnetoencephalography (MEG) — Records the magnetic fields produced by electrical currents in
the brain.
• These fields are measured using SQUID (superconductive quantum interface devices).
• Gives better resolution than EEG, but this method is also more rare (especially in social
sciences)… It needs a much bigger and more expensive set-up.
Combined methods:
• fMRI (functional MRI) — gives the same structural images from the MRI, but can also look at which
structures are active.
• Does this by measuring relative amounts of oxygenated / deoxygenated blood in the brain, because
neurons that are firing a lot require more oxygen than those that aren’t active. fMRIs thus tell us
what parts of the brain are active, what parts we’re using to do a certain task.
ORGAN SYSTEMS 14
• Positron Emission Tomography (PET scans) — On their own can’t give us a detailed structure of
the brain, but are combined with CAT scans and MRIs.
• Involves radioactive glucose that’s injected into a person. Since active cells naturally use more
glucose because they need more energy, we can see (with CAT or MRI scans) what areas of the
brain are more active at a given point in time.
• fMRI is more popular (at least in social sciences), probably because PET scans are more invasive.

————————————————Neural Cells————————————————
TYPES OF NEURAL CELLS
• Two types of neural cells: neurons (aka nerve cells) and glia (aka neuroglia, glial cells).
• Central nervous system = brain & spinal cord
• Peripheral nervous system = nerves coming out of spinal cord
• Nerves of PNS are made of neurons, glial cells, and other cells (which is why calling neurons
“nerve cells” is problematic)
• Neurons are in both CNS and PNS, but different types of glial cells are just in one or the other.
• Most neurons and glia found in the CNSs are derived from neural stem cells, while most neurons and
glia in the PNS are derived from neural crest cells.
• Both types arise early in embryo development, in the ectoderm.
• Most types of neurons and glia share structural features:
• soma — main body of cell that contains nucleus and most organelles
• long processes / projections that come out of the soma and vary in number, length, thickness,
degree of branching, and terminal structures, as well as in their function.
• Function of neurons is to process and transmit information. Function of glia is to support the neurons
in a variety of ways. (Even more glia than neurons.)

NEURON STRUCTURE
• Neurons consist of soma and projections called neurites, which are divided into dendrites & axons.
• Dendrites are short, branched projections often covered in small spines that increase their surface area
and perform other functions
• Axons are longer and unbranched until it reaches its end. Might be short, or as long as 1 m or more.
• The end of the axon branches to create multiple axon terminals.
• Axon hillock = area where Axon leaves the soma
• Axon initial segment (trigger zone) = right after hillock, the first part of the axon projection
• Large axons are usually wrapped in a myelin sheath. Gaps that regularly interrupt the segments of
myelin are called nodes of Ranvier.
• Axon terminals come close to the target cells (which might be another neuron, muscle cells, gland
cells, or even capillaries (if releasing hormones to bloodstream), but don’t touch. This junction is
called a synapse.
• Unipolar neurons — have soma and one projection (and axon)
• In the CNS — these start as neural stem cells, which can become any cell of nervous system, and
then differentiate into (structurally similar) neuroblasts, which can only become neural cells.
• Neuroblasts then migrate away from other neural stem cells to the location their soma will be
after development. They extend an axon, tipped with a growth cone, toward the target cell,
which grows by following guidance cues in the environment until it reaches the target cell.
• In the PNS — both the original and migrating cells are neural crest cells instead of neural stem
cells and neuroblasts
ORGAN SYSTEMS 15
• Unipolar neurons are found in humans during fetal development, but not after.
• Bipolar neurons — have a soma, one axon, and one dendrite
• Multipolar neurons — have a soma, one axon, and multiple dendrites. This is most common type.
• Pseudounipolar neurons —have a soma, with short process coming out of soma that then divides
into two long processes going in different directions. These are axons and the one bringing information
in from the periphery is called peripheral axon, and axon bringing information into the CNS is called
central axon.
• End of peripheral axon acts like dendrites do on other types of neurons. The part of the peripheral
axon near the end is the initial segment / trigger zone, and the axon terminals are at the other end of
the central axon.

Multipolar = motor neurons. motor neurons that conduct motor commands from the cortex to the spinal cord or from
the spinal cord to the muscles

Pseudo-unipolar = sensory neurons. sensory neurons that receive sensory signals from sensory organs and send
them via short axons to the central nervous system. Uni (one brain). Psuedo =PNS.

Bipolar neuron. Interneuron = . interneurons that interconnect various neurons within the brain or the spinal cord

NEURON FUNCTION
• Function of neurons is to process and transmit information.
• Most neurons have a resting membrane potential — a stable electrical charge difference across their
membrane (more negative in the cell).
• This potential is how the neuron is able to be excited and to respond to input.
• Neurons receive excitatory or inhibitory input from other cells or from physical stimuli.
ORGAN SYSTEMS 16
• Input info usually comes in through the dendrites, less often through soma or axon. The info from the
input is transmitted to the axon with graded potentials — changes to membrane potential away from
the resting potential. These are small in size, brief, in duration, and travel short distances.
• The size and duration of the graded potential is proportional to the size and duration of input.
• Summation = adding together of all the excitatory and inhibitory graded potentials at any moment in
time. This summation occurs at the trigger zone, the initial axon segment, and is how neurons process
information from their input.
• If the membrane potentials at the trigger zone crosses a threshold potential, information will be
fired down the axon.
• Graded potentials are like a finger on the gun.. once pulled back a certain distance, information
(bullet) will be fired down the axon.
• Action potential — a different change in membrane potential that allows information to be fired down
the axon. These are usually large in size and brief in duration (they travel quickly), and can be
conducted down the entire length of the axon, no matter how long
• Action potentials are usually the same size and duration for any particular of neuron. This is unlike
graded potentials, whose size and duration depend on size and duration of input
• Action potentials travel faster down larger (bigger diameter) and more myelinated axons. When it
reaches axon terminals, information (i.e. neurotransmitters) crosses the synapse gap to target cell.
• Neurotransmitters are released at axon terminal to bind to receptors on the target cell to maybe
change that target cell’s behavior.
• Neurotransmitters are then removed from the synapse (via re-uptake channels) to reset system.
• Input information that was converted to size and duration of graded potentials is converted to the
temporal pattern of firing of action potentials down the axon. This firing info is then converted to the
amount and temporal pattern of neurotransmitter release at the synapse.
• Above is the general way neurons function, but there are multiple types of neurons:
• Afferent / sensory neuron— pseudounipolar that neuron brings info (about a stimulus) into CNS
• Efferent neurons — carry info away from CNS to PNS. Two main kinds of efferent neurons:
• motor neurons (aka somatomotor neurons) — control skeletal muscle
• autonomic neurons (aka visceromotor neurons) — control smooth muscle (e.g. around blood
vessels), cardiac muscle, and gland cells.
• Autonomic neurons innervating the heart are responsible for releasing norepinephrine, a
neurotransmitter of the sympathetic nervous system
• Most neurons of CNS aren’t like afferent/efferent, but are interneurons — they connect other neurons
and form complex pathways for information to travel.

ASTROCYTES:
• Astrocytes are star shaped glial cells in the central nervous system (come from neural stem cells)
• Most common type of cell int the CNS
• Have lots of highly branched processes, at the end of which are end feet.
• They perform many many functions, possibly the greatest variety of functions, including the
following:
(1) Form the scaffold for the whole CNS - give structural support to other cells in brain/spinal cord.
(2) Gliosis / astrogliiosis - involved in the repair and scarring process of the brain and spinal cord
following traumatic injuries.
• If there’s an injury to the brain and/or spinal cord, astrocytes will divide and form more of
themselves, migrate over to site of injury, and surround it.
• Their many projections then become hypertrophied and form a glial scar.
(3) Homeostasis of interstitial fluid — astrocytes take in or release necessary ions to keep
environment for neural cells in homeostasis.
ORGAN SYSTEMS 17
• Also release lactate (made from astrocyte glycogen) into interstitial fluid because neurons have
very little internal energy in their cells and need that for energy.
(4) Blood-brain barrier - The end-feet of astrocytes are plastered all over blood vessels of CNS.
These end-feet structures, along with components of the vessels themselves, form an effective
barrier that prevents large molecules from leaving blood to enter CNS unless they want it
(5) Clears out synapses between neurons — Astrocytes place their end feet all over synapses and
clear out neurotransmitters to reset the synapse for the next signal.
(6) Influence neurons and other glia through exchanging substances.
Most common cell type in the brain.
Astrocytes have structural, metabolic, regulatory, and repair functions, and are the most
abundant cell in the brain.
Astrocytes are found in areas of brain scarring.
Astrocytes can supply lactate if the energy need arises.
Astrocytes are involved in strengthening the blood brain barrier, but do not monitor the interstitial
fluid for foreign pathogens. This is the job of the microglia.

MICROGLIA:
• Derived from mesoderm, instead of the ectoderm like all the other neural cells.
• Resting microglia have small soma and many highly branched processes heading out in every
direction. In this state, they’re basically just monitoring the interstitial fluid looking for inflammation
(from injury or infection). When they detect trouble, they convert to active microglia.
• The active microglia are just larger and sort of blob shapes. They act like macrophages and
scavenge the CNS for plaques, damaged neurons, and infectious agents.
• Microglia are the resident macrophages of the of the brain and spinal cord, and thus act as the first and
main form of active immune defense in the central nervous system. They do this by:
(1) Secreting cytotoxins — If a microglia finds a foreign cell it can secrete cytotoxic substances like
reactive oxygen species that can kill a cell.
(2) Phagocytosis — After macrophages kill the bacteria, it becomes debris. Microglia eat up all kinds of
debris, from foreign or from its own cell and break it all down. yum.
• Note: these processes don’t necessarily happen in order… They could phagocytose something and
then secrete a cytotoxin.
(3) Antigen presentation — After consuming debris, microglia will take a tiny pieces of it and stick
tjos antigen out on its surface for other cells (specifically those of the immune system) to see.
• Ex: Lymphocytes can then recognize the antigens, and potentially increase inflammation and/or
make it more specific to whatever foreign cell the microglia has identified.
• Thus microglia is both activated by inflammation and it contributes to it.
(4) other cells of the immune system through exchange of substances.
Microglia arise from monocytes, and are a part of the immune system, which arises from the
mesoderm. However, the majority of the nervous system arises from ectoderm (CNS) or neural crest cells
(PNS).
Microglia are the macrophages, or phagocytes, of the central nervous system (CNS, or the brain).
They will proliferate if there is an infection, such as bacterial meningitis.

EPENDYMAL CELLS:
• These cells line the CSF-filled ventricles in the brain and the central canal of the spinal cord.
• Derived from neural stem cells
• Ependymal cells are simple (one layer) columnar, cuboid epithelium-like cells.
ORGAN SYSTEMS 18
• The side of the ependymal cell that faces the cerebral spinal fluid has many microvilli and cilia.
• Main functions:
(1) Form barrier between CSF and interstitial fluid of the tissue itself, though it’s a relatively leaky
area (this leakiness if helpful because it means doctors can sample it).
(2) Secrete CSF — Specialized ependymal cells and capillaries form tufts in some of these brain
ventricles. This is where CSF is secreted across ependymal cells to create cerebral spinal fluid.
Ependymal cells help form the barrier that holds in and produces CSF, cerebrospinal fluid. Ependymal
cells not only help form the barrier that separates CSF from the rest of the body, but help secrete
it as well.
The brain and spinal cord are cushioned by cerebrospinal fluid (CSF), which is kept separate from blood
and lymph fluid.

OLIGODENDROCYTES:
• Similar structure to astrocytes, but with fewer projections. Also in the central nervous system.
• main function: produce myelin sheath in the CNS
• Each oligodendrocyte has maybe a dozen projections that extend towards nearby axons of neurons.
The structure at the end of these oligodendrocyte projections is myelin sheath.
• Each oligodendrocyte can produce myelin sheaths for multiple neurons (each projection makes one
segment of the sheath, but they have multiple projections)
• The myelin sheath for a single neuron can come from multiple oligodendrocytes.
• Myelin sheath is made mostly of a lipid, the same substance that makes up fat, of course. It’s basically
the cell membrane for an axon… sort of like the rubber coating on a wire.
• Oligodendrocytes also influence other glial cells.
Each nerve cell can have multiple myelin sheaths, which help speed conduction. Oligodendrocytes are myelin
sheaths that wrap around nerve axons to help speed conduction.
•

SCHWANN CELLS:
• Schwann cells are glia of the PNS, derived from neural crest cells. They come in different shapes.
• Nonmyelinating Schwann cells are fairly shapeless, but have troughs on their surface. Small diameter
neurons can just sort of sit their axons in these troughs.
• These types of Schwann cells provide some support for PNS axons, but don’t myelinate them.
• The main function of normal Schwann cells is to produce the myelin sheath for PNS neurons.
• Not all peripheral neurons have a myelin sheath, but most of those with a larger diameter do. The
structure and function of these myelin segments are the same in the PNS and in the CNS, but are
produced by different cells.
• Schwann cells are also different from the oligodendrocytes of the CNS in that a single Schwann cell
produces the myelin for a single segment of a single axon. They’re not myelinating multiple neurons
like oligodendrocytes.
• Almost all the cell membrane of a Schwann cell is the myelin wrapped around an axon. It has just a
little lump outside this wrapping, though, that contains the nucleus and cytoplasm for the Schwann cell
• Schwann cells also influence neurons, and vice versa, through exchange of various substances.
• Gangliosides are found on Schwann cells, the myelin sheath cells of the peripheral nervous
system
• The majority of immune cells cannot cross the blood-brain barrier.
• Conduction potential velocity increases with increased axon diameter and myelination.
• Multiple sclerosis is an inflammatory disease, and is characterized by an increase in antibodies and a
decrease in myelination.
ORGAN SYSTEMS 19

Other:
• Tetanus is the maximum sustained contraction of skeletal muscle cells.
• Heart rate is controlled by the autonomic nervous system.
• Afferent nerve fibers bring signals back to the central nervous system.
• A local nerve block would be an anesthetic, as it would block sensation, but would not affect movement.
Sometimes a nerve block is used to dull tooth pain when pain medication is contra-indicated.

————————————Neuron Membrane Potentials————————————

NEURON RESTING POTENTIAL — DESCRIPTION:
• Positively charged cations are in layer all over outside of the cell membrane; negatively charged
anions are in a layer all over the inside of the cell membrane.
• Well, really, there are anions and cations on both sides of the membrane… but more cations on
the outside and more anions on the inside.
• Outside is called 0, and difference between outside and inside is usually around -60mV
• Resting potential is related to the concentration differences, or gradients, of different ions across the
membrane
• Most important cations that are K+ Na+ and Ca+
• Most important anions are Cl- and organic anions (e.g. proteins)
• Organic anions and K+ have a bigger concentration inside than outside the neuron.
• Na+, Cl-, and Ca2+ have a bigger concentration outside than inside the neuron.
• Each ion is therefore acted on by two forces:
• Electrical potential — ions will be attracted to the side with opposite charge
• ex: OA- electrical force will try to drive it out of the neuron; K+ electrical force will try to
drive those ions in (because inside is more negative)
• Diffusion potential — ions will be attracted to the side with lower concentration
• ex: OA- diffusion force has matched diffusion force with electrical force, wanting to drive it
out. K+ has opposite diffusion force to electrical force; diffusion force wants to drive it out of
cell (even though the inside is more negative).

NEURON RESTING POTENTIAL — MECHANISM:

• Let’s consider a neuron with no resting potential — it’s not more positive outside or more negative
inside the membrane, and all the key ions have the same [ ] inside and outside…
• Organic ions are created in the cell for release into the cytoplasm. As this happens, the OA- build
up in the cell, creating a small negative membrane potential, but not enough for neuron to function.
OA- ions now have electrochemical forces that make it want to leave but it can’t. so there are not
further
• For other ions, they can pass through the membrane (unlike OA- ions) through leaky channels that
are open all the time.
• The Na+/K+ pump is also in the neuron membrane, and it transports 3 Na+ out and 2 K+ in. This
also makes the membrane potential more negative, and increases diffusion gradient/potential for
sodium and potassium as more K+ and less Na+ is inside the cell
ORGAN SYSTEMS 20
• The concentration changed inside the cell but not outside because the extracellular fluid is
huge, with tons of ions such that any movement into it is negligible.
• For K+, at typical neuron ion concentrations its diffusion force is bigger than smaller electrical force,
causing a net movement of K+ out through the leak channels. As they leave, it makes the membrane
potential more negative; until equilibrium is reached with K+ ions. This typically occurs around -70
mV which is more than enough for the neuron to function.
• Equilibrium potential / reversible potential = the membrane potential at which there is no net
movement of ions across the membrane.
• Doesn’t actually take much for this equilibrium potential to be reached with K+ (maybe 1% of all
K+ ions in the cell have to leave), but it does take some time for them to get through leak channels
• For Na+, at typical neuron ion concentrations, Na+ diffusion force and electrical force drive Na+ into
the cell. If we had a cell that was only permeable to Na+, it would be driven into the cell to the extent
that the membrane potential would switch to positive.
• It would have to be quite positive inside the neuron for the electrical force to balance this diffusion
force. Equilibrium potential of sodium is ~ +50 mV.
• Without input, when membrane is at rest, the permeability of the membrane to sodium is much less
than permeability to potassium.. It does affect potential a little bit through, so the equilibrium
potential is around -60 mV instead of the -70 it would be with just potassium.
• For a cell whose membrane is permeable to multiple ions with electrochemical driving forces, the
overall resting membrane potential is a weighted average of those ions’ equilibrium potentials.
(weighted by permeability).
• The resting membrane usually has an intermediate permeability to Cl- ions. In contrast to Na+ and K+
whose concentration gradients determine resting membrane potential, the resting membrane potential
determines the concentration gradient of Cl- ions. Membrane potential drives Cl- out of the ions until
the concentration gradient is big enough to balance it.
• So normally there’s a very small concentration of Cl- inside the cell compared to outside.
• One way chloride is driven out is by the Cl-/K+ symporter, drives Cl- out by harnessing K+ ions’
diffusion force to leave the cell.
• Because of this, equilibrium conc. for chloride is slightly less than resting potential, usually -
70mV.. this is usually negligible for overall resting potential, though.
• Ca2+ is also driven out of the cell so that there’s a small concentration of Ca2+ ions inside compared
to outside. One way this is down is by the Ca2+/Na2+ exchanger, which harnesses the electrical and
diffusion forces acting on Na+ (to bring Na+ in the cell) in order to pump Ca2+ out of the cell.
• This creates strong electrical and chemical gradients for Ca2+ that want to drive it into the cell.
• Equilibrium force of Ca2+ is ~ +120mV, very high, but permeability is very low, so it doesn’t
really have an effect on resting potential.

• A neuron at rest (or resting potential) has a stable separation of charges across the membrane.
• At resting potential, there are more positive charges on the layer directly outside of the membrane, and more negative
charges on the inside of the membrane.
• This separation of charges refers to polarization. The membrane potential of a neuron at rest is slightly negative, thus
it is polarized.

NEURON GRADED POTENTIAL — DESCRIPTION:

• Graded potentials occur in response to input.
• Resting neurons have a stable charge separation across entire membrane, where a layer of cations is on
the outside of the membrane (0) and a layer of anions is on the inside of the membrane (~ -60 mV)
ORGAN SYSTEMS 21
• These potentials can be graphed as time vs. potential.
• Inputs from certain types of stimuli may increase or decrease the membrane potential for a brief period
of time before it goes back to the resting potential — these are graded potentials
• Tend to occur in the dendrites and soma of the neuron
• Size and duration of graded potential is determined by size and duration of the inputs
• Most graded potentials don't pass into the axons of neurons but instead most axons have a different
membrane potential change called the axon potential.
• Axon potentials start at the trigger zone and occur when the combined effect (summation) of the
graded potentials brings the membrane potential of this trigger zone (the initial part of the axon)
across a certain value called the threshold potential.
• Threshold potential varies between neurons (but a common one is around -50 mV)
• Summation at the trigger zone is how neurons process information from their inputs.
• Most neurons respond to inputs from other neurons in the form of neurotransmitter molecules released
at synapses. Neurotransmitters then bind to receptors on other neuron to produce a graded potential
called synaptic potentials.
• Depending on the neurotransmitter and receptor, it could be an excitatory or inhibitory input.
• Other neurons (and neuron-like cells) may also generate graded potentials from physical stimuli, such
a slight or odorant molecules. These are receptor potentials.
• Depolarization / excitatory potentials = a graded potential that moves the membrane potential closer
to zero (less negative). This moves it closer to the threshold, increasing likelihood of response.
• Hyperpolarization / inhibitory potential = graded potential that moves the membrane potential
further away from the threshold, or in the more negative direction. Increases charge separation of the
membrane, and decreases likelihood of an axon potential starting.
• Graded potentials decay with time and distance, such that their effect is brief and localized.
• The closer the potential is to the trigger zone, the greater likelihood there will be of it inducing an
action potential.
• Therefore a synapse that’s closer to the trigger zone will have a greater influence on the behavior
of the neuron
• Temporal Summation:
• If two depolarizations happen slightly separated from one another, they wont’ have any effect.
• But if two happen right around the same time, we get an added effect called a temporal summation
that could produce a depolarization twice the size.
• Spatial Summation:
• As graded potentials spread from the dendrites that accepted the neurotransmitters across the soma,
they also decay.. so by the time the potential reaches the trigger zone it may not have much of an
effect.
• If two graded potentials happen sort of far away from each other, they might not have any effect.
But if two graded potentials occur close to each other on the membrane, it could cause spatial
summation so you get a depolarization twice the size.
• If you have excitatory input and inhibitory input at the same time and sort of the same place, they may
cancel each other out
• Synaptic potentials tend to be quite small, < 1mV in size. So neurons require the temporal and spatial
summation of 10 synapses or more to reach threshold and have an effect.

• Electrical synapses do not have a gap between the neuron and target cell - the cells are physically connected.
• Chemical synapses have a gap between the neuron and target to facilitate communication.
• electrical synapses have very different mechanisms to relay information from the neuron to the target cell.
ORGAN SYSTEMS 22
•

NEURON GRADED POTENTIAL — MECHANISM:

• Neurotransmitter receptors are found at synapses and are what the neurotransmitters released from
other neurons bind to.
• Many neurotransmitter receptors are a type of ligand gated ion channel
• The graded potential produced depends on:
• What kind of ions pass into membrane (some channels allow just one type in, others allow
multiple)
• How many channels are opened (depends on amount of neurotransmitter released into synapse and
how long it stays in the synapse)
• If a channel opens that is selective for only one type of ion, the membrane permeability for that ion is
increased, which causes the membrane potential for that ion to change around that synapse.
• If Na+ or Ca2+ channels cause a depolarization or excitatory potential, because the cations flow into
the neuron and bring positive ions into the more negative internal environment of the cell.
• Force of diffusion and electrical difference drives it in.
• Na+ channel is most common type of depolarization channel.
• If Cl- channel, hyperpolarization usually occurs because it flows into the cell and makes it more
negative. (This is most common type of inhibitory channel.)
• Force of diffusion ([ ] outside cell much bigger than in) overcomes the electrical force to drive
Cl– ions in.
• K+ channels also cause hyperpolarization because its larger diffusion overcomes small electrical
force to drive it out of the cell once the channel if opened, which again makes the internal
membrane more negative
• When a neurotransmitter, such as Na+, binds to the receptor and allows, for example, Na+ inside, there
will be a small cluster of Na+ ions around that channel that causes membrane potential there to
increase.
• It doesn’t just continue increasing, though, because the neurotransmitter leaves and the ion channel
closes again. This causes the graded potential to plateau.
• Why do they decay? The Na+ ions diffuse throughout the cell (because of electrical and chemical
diffusion) and the depolarization decreases. Eventually that piece of the membrane goes back to its
resting potential.

• The sodium-potassium pump pulls potassium ions in and moves sodium ions out of the cell.
• Because potassium is positively charged and the inside of the cell is negatively charged, the electrical gradient tends
to pull potassium in, not out.
• When a membrane is at rest, sodium ions or more concentrated outside of the neuron; potassium ions are
more concentrated inside. Concentration gradients move potassium ions out of the cell.
• negative sign on a resting potential signifies a relative difference in charge, not an absolute difference.
• Potassium cation is found in greatest concentration inside a neuron in the resting state
• At the resting potential, negatively charged ions will feel an electrical force pushing them out of the neuron,

Graded potentials cause action potentials.

The size of a graded potential must reach a certain threshold in order to cause an action potential.
The size of the action potential is independent of the size of the graded potential (this is known as the all-or-nothing
rule). Amplitude doesn’t change.
The best-fit line of the results most likely has the equation y = c.
ORGAN SYSTEMS 23

Difference between action and graded potential:

All potentials are determined by the flow of charged molecules across the neuron membrane.
The difference between graded potentials and action potentials first and foremost has to do with where they occur.
Action potentials occur in axons, while graded potentials occur in the dendrites and soma.

NEURON ACTION POTENTIAL — DESCRIPTION:

• Multiple excitatory / depolarizing potentials are needed with temporal and spatial summation to push
the membrane of the trigger zone over its threshold potential. When this happens (often around -50
mV), an action potential well be conducted down the whole axon.
• Axon potentials are unlike graded potentials in that they’re the same size for a given neuron (though
total size may vary between neurons), and that they’re unchanged (don’t degrade) as they go down the
axon, no matter how long it is.
• Shape of an action potential is fairly characteristic:
• After graded potentials reach threshold potential, action potential begins with a rising phase that
depolarizes the membrane so much the charge inside the cell membrane is positive, ~ +40mV
• Small plateau
• Rapid falling phase that goes even more negative than normal resting potential, to ~ -70 mV
• Slowly settles back up to resting potential of ~ -60 mV
• All-or-none property of an action potential — you either get one or you don’t (b/c size doesn’t vary
for a particular neuron. Doesn’t matter how far over the threshold a graded potential gets, will cause
the same size action potential)
• Duration of action potential is also pretty consistent for any particular neuron.
• (Graded potentials have a wider range of duration depending on the duration of their inputs.)
• Speed at which action potentials are conducted can be very fast (1 - 100 m/s).
• Faster speeds usually happen in larger-diameter and more myelinated axons.
• Saltatory conduction — speed of an action potential down a myelinated axon is not consistent — it is
conducted faster at the myelinated segments than through the nodes of Ranvier.

NEURON ACTION POTENTIAL — MECHANISM:

• The membranes of axons have leak channels and voltage-gated channels (which open when the
membrane potential crosses a certain threshold potential)
• Na+ channels are voltage-gated. So when a summation of graded potentials causes depolarization of
the trigger zone membrane past the threshold, Na+ flows in. This causes further depolarization at the
trigger zone membrane, which then leads to more Na+ channels opening a little further down, and this
effects cascades in a wave down the axon.
• Trigger zone has greatest density of Na+ voltage gated channels, which is why the action potential
starts there.
• Membrane potential dramatically rises as it tries to increase membrane potential to Na+ eq.
potential (around +50 mV). This is rising phase, and the inside of the cell membrane becomes
positive.
• After the membrane potential gets depolarized to a certain extent, the Na+ voltage gated channels
close, so the membrane potential never actually reaches +50 mV, usually just to +40 mV.
• After they close, they’re in an inactivated state — ion channels are unable to open for a certain
period of time.
• After the rising phase and plateau, an exit of K+ through leak channels
and voltage gated channels causes the falling phase of the membrane
ORGAN SYSTEMS 24
potential and it plummets to an even more negative potential (-70 mV)
than at resting state.
• K+ leak channels — some K+ leaves when the membrane is at rest
(without input), but after the membrane potential becomes so
positive, both electrical and diffusion force drive K+ out of the
membrane through leak channels quite quickly.
• Voltage-gated K+ channels — also open after membrane potential
crosses threshold, but do so more slowly than the Na+ ones.
• So first, Na+ rushes in causing rising phase, then K+ voltage
channels open (and exit through leak channels increases), causing the falling phase
• Once the membrane potential inside is negative again, it stops falling further because K+ leak channels
drive out K+ much slower then, and because the negative potential causes voltage gated K+ channels
to close automatically, though again a bit slower than Na+ voltage channels did at positive potential, so
the falling action extends past the resting potential for a bit until it settles back.
• This extension past resting potential is called the after-hyperpolarization, or refractory period
(called refractory because it’s difficult or impossible to start a new action potential during this
period).
• Refractory period has two parts: absolute and relative
• absolute refractory period — when the voltage gated Na+ channels are first closed and they’re in
an inactive state. No matter how strong a graded potential comes in, it won’t trigger another action
potential.
• relative refractory period — when the voltage gated Na+ channels are functional again, but
membrane potential is hyper-polarized. It would take more excitatory input than normal to cause
an action potential.
• relative refractory periods can help us figure out how intense a stimulus is — cells in your
retina will send signals faster in bright light than in dim light, because the trigger is stronger.
• An effect of refractory period is that action potentials travel down the axon from the trigger zone, and
can’t travel immediately back.
• Refractory period determines the maximum frequency at which a single neuron can send action
potentials.
• Movement of sodium and potassium ions across the membrane starts at trigger zone and spreads in
waves. First wave of depolarization all down the axon, then of hyperpolarization, & eventually
settling.

• Resting potentials are not associated with refractory periods. Graded potentials are not associated with refractory
periods. Refractory periods (both relative and absolute) are times when a membrane is resistant to starting
another action potential.

EFFECTS OF AXON DIAMETER AND MYELINATION:

• Axon with larger diameter offers less resistance to ions moving down the axon (more pathways
through the cytoplasmic around other cell structures), and therefore allows action potential to be
conducted faster (because speed of action potential is related to speed of ions moving down axon).
• Action potentials move faster in myelinated segments because the capacitance of the membrane is
reduced. This decreases the number of ions and the time needed to change the membrane potential in
these areas.
ORGAN SYSTEMS 25
• Capacitance (in this context) = total number of charges along the membrane, or number of ions
that can be stored in the layers on both sides of the membrane at any given potential (because
potential represents strength of the charge separation for any particular ion carrier).
• The closer charges are to each other, the more charge can be stored.
• At the nodes of Ranvier, an anion on the inside layer is strongly attracted to cation on opposite side; It
overcomes the repulsion of nearby like charges on either side of the membrane and thus in these nodes
(at resting potential) more cations/anions can be packed in on either side. (low capacitance)
• In the myelinated segments, the membrane is essentially much thicker, so distance is much greater
between oppositely charged ions on opposite sides of the membrane and strength of that charge is
less. In myelinated segments you can thus put fewer cations/anions on either side. (high
capacitance)
• This means that as an action potential comes rushing by, it is easier to depolarize the areas that are
sheathed, because there are fewer negative ions to counteract.
• As our action potential travels down the membrane, sometimes ions are lost as they cross the
membrane and exit the cell. The presence of myelin makes this escape pretty much impossible, and so
it also helps to preserve the action potential.
• Myelination also decreases the membrane permeability to ions, so fewer total ions cross the membrane
during an action potential. Thus fewer ions than normal need to be pumped out through Na+/K+ pump
after the action potential.
• Recall that these pumps require energy, myelination actually increases the efficiency of action
potential conduction in terms of the energy needed to maintain these ion concentrations after action
potentials.
• Myelinated axons have most of their voltage-gated ion channels at the nodes of Ranvier, so they can
regenerate the full size of the action potential and keep it strong all the way down the axon.
• More myelin and larger = faster

• Voltage-gated sodium channels are found in lower concentration towards axon terminals.
• Voltage-gated sodium channels are found in greatest concentration in the trigger zones.

Reduced permeability of potassium leak channels would affect the time to reach maximum
repolarization in a neuron. (more K+ would remain inside).

• In myelinated axons, action potentials only form in nodes.

• Nodes that are close together might cause action potentials to slow down.
• Nodes that are far apart might cause action potentials to stop.
• Saltatory conduction refers to the the movement of action potentials from node to node.
• Myelinated axons are axons covered with a myelin sheath.
• Myelin sheaths are broken up by small nodes.
• Saltatory conduction is the conduction of action potentials along myelinated axons.

ACTION POTENTIAL PATTERNS:

• Some neurons fire no action potentials until there is sufficient excitatory inputs. And then the size /
duration of depolarization over threshold is converted into the frequency and duration of a series, aka a
train of action potentials
• Used by motor neurons that synapse on skeletal muscles.
ORGAN SYSTEMS 26
• Other neurons fire action potentials at a regular rate without any input. This happens because they have
differences in their leak channels and/or voltage-gated ion channels that spontaneously depolarize the
membrane to threshold at a regular interval.
• Similar to pacemaker cells in the heart.
• With these types of neurons, excitatory input will cause them to fire action potentials more
frequently when excited; and when that goes away they go back to their regular rate of firing.
Firing is slowed down during inhibition
• During absence of input, some neurons fire clusters of bursts of action, pause for a bit, and then fire
more bursts.
• Excitatory input can increases frequency of these bursts (and maybe increase space between them)
• In the last two systems, where neuron fire regularly or in bursts, at resting potentials is that
information passed along to target cells can be fine tuned in either direction. (unlike first case, which
must be no action potential or train of action potential).
• The last two systems can also pass along info in a more fine-grained fashion.
• The different temporal patterns of action potentials are then converted to the amounts and temporal
patterns of neurotransmitter release at the synapse.

• At the peak of an action potential, there is more sodium inside of the membrane than outside.
• Resting potential is approximately -70mV.
• Action potentials peak around 40mV.
• Sodium equilibrium potentials are around 50mV. Thus, the membrane potential is slightly less positive than
the sodium equilibrium potential at the peak of an action potential.
• Dendrites receive an action potential.
• Axons transmit action potentials.

• Potassium leak channels allow potassium to exit a neuron in response to depolarization.

• Reduced permeability of a leak channel to its natural ion means that the rate the ions are able to cross the channel is
reduced.
• Reduced permeability of potassium leak channels would affect the time to reach maximum repolarization in a
neuron.

• Voltage-gated potassium channels play a central role in action potentials.

• Voltage-gated sodium channels also play a central role in action potentials.
• Voltage-gated calcium channels are central to the release of neurotransmitters into the synaptic cleft.
•

DEMYELINATION DISEASES:
• Demyelination diseases degrade the myelin coating on cells.
• Ex: Guillain-Barre syndrome and Multiple Sclerosis.
• Guillain-Barre syndrome is the destruction of Schwann cells (in the peripheral nervous system)
• MS is caused by a loss of oligodendrocytes (in the brain and spinal column).
• These disorders have different causes and presentations, but both involve muscle weakness and
numbness or tingling.
• These symptoms occur because the nerves aren’t sending information the right way. When the myelin
coating of nerves degenerates, the signals are either diminished or completely destroyed.
ORGAN SYSTEMS 27
• If the nerves are afferent (sensory) fibers, the destruction of myelin leads to numbness or tingling,
because sensations aren’t traveling the way they should.
• When efferent (motor) nerves are demyelinated, this can lead to weakness because the brain is
expending a lot of energy but is still unable to actually move the affected limbs.
• Limbs are especially affected, because they have the longest nerves, and the longer the nerve, the more
myelin it has that can potentially be destroyed.

——————————————Neuronal Synapses——————————————
SYNAPSE STRUCTURE:
• Recall, synapses are the junction between a neuron’s axon terminal(s) and the target cell.
• Chemical synapses have a gap b/n the neuron’s axon and target. Neurotransmitters are used.
• Electrical synapses are when the axon terminal and target cell are physically connected. Gap
junctions allow ions to flow between them. (These are fairly rare in humans)
• A typical neuron receives up to thousands of signals from other neurons. These synapses most often
occur at the dendrites (part of the reason they’re branched is to increase surface area for synapses).
• However, there can also be synapses on the soma or the axon (usually the axon terminals)
• In the central nervous system, end feet of astrocytes cover most of the synapses.
• Synaptic cleft = gap between axon terminal and target cell
• It is bordered by the pre-synaptic membrane (of the axon terminal) and post-synaptic
membrane (of the target cell)
• Just on the inside of the pre-synaptic membrane are synaptic vesicles, bubble-like structures that are
full of neurotransmitters.
• The pre-synaptic axon terminal also has voltage-gated calcium channels that allow Ca2+ in.
• On the post-synaptic membrane are receptors that are specific for the neurotransmitters.

NEUROTRANSMITTER RELEASE:
• A protein known as complexin acts like a brake, and stop the vesicles from fusing into the membrane
and releasing their contents [remember: complexin complicates the process of vesicle fusion]
• The vesicle protein synaptotagmin can bind and release complexin in the presence of calcium
• As the action potential travels down the axon, positive ions continue to flood the cell. Eventually, this
influx reaches the very end of the neuron – the axon terminal. When this happens, the membrane
potential of the axon terminal is depolarized.
• This opens the Ca2+ to channels at the axon terminal; and calcium flows into the axon (because/c of
its diffusion gradient)
• The calcium ions can then activate synaptotagmin to release the brake, and the vesicles fuse with the
cell membrane, and the vesicle contents (neurotransmitters) are released into the synaptic cleft.
• Neurotransmitter then diffuses across the cleft and binds to receptors on the target cell.
• An increased frequency of axon potentials reaching the terminal causes increased opening of Ca2+
voltage gated ion channels. This causes more Ca2+ to enter the cell, which means more synaptic
vesicles fuse and more neurotransmitter is released.
• Increased duration of axon potential means neurotransmitter is released for a longer duration.
• These two things (frequency & duration) affect how much neurotransmitter is in the synaptic cleft
for how long, which in turn affects the cell it is firing on.
• When the train of action potentials stops firing, voltage-gated ion channels will close, Ca2+ will stop
entering cell, and Ca2+ will start to exit via usual methods; neurotransmitter will stop being released.

Action potentials determine how much information is released into the synaptic cleft.
Action potentials also determine how long information is present in the synaptic cleft.
ORGAN SYSTEMS 28
Action potentials open voltage gated calcium channels, which results in calcium flowing into the axon terminal.
Action potentials do not result in calcium leaving the target cell at the post synaptic membrane.

TYPES OF NEUROTRANSMITTERS:
• Neurons tend to have just one type of neurotransmitter that they release, but many neurotransmitters
can bind to multiple types receptors.
Amino Acid Neurotransmitters:
• Have an amino group and carboxylic acid group.
• Glutamate — most common excitatory neurotransmitter of the nervous system
• GABA and Glycine — most common inhibitory neurotransmitters of the nervous system.
• GABA the most common inhibitory neurotransmitter in brain
• Glycine is most common in spinal cord

• Glycine is the most common inhibitory neurotransmitter in the spinal cord

• Glutamate is the most common excitatory neurotransmitter in the nervous system.
• Gamma-aminobutyric acid, or GABA, is the most common inhibitory neurotransmitter in the brain.

•
• These AA neurotransmitters are involved in most processes of the nervous system
Peptide Neurotransmitters:
• Peptides are polymers of amino acids; they’re much larger than other types of other neurotransmitters
• One group of peptide neurotransmitters are called the opiods. (ex: endorphin)
• These play a big role in our perception of pain, and thus those types of neurotransmitters are a
target for many pain meds.
Monoamine Neurotransmitters (aka biogenic amines):
• Organic molecules with an amino group connected to an aromatic group by a 2-carbon chain.
• Serotonin, Histamine, Dopamine, Epinephrine, and Norepinephrine
• Three monoamines (dopamine, epinephrine, norepinephrine) are specifically called catecholamines;
they have a catechole group (benzene + two hydroxyl groups)
• Are involved in many processes, especially in the brain; including process of consciousness, attention,
cognition and emotion
• Norepinephrine in particular is released by some autonomic neurons in the PNS
• Many disorders of the nervous system involve abnormalities of the monoamine transmitters; and thus
they are often a target for drugs.
Other:
• Acetylcholine — one of the most important nervous system that is not a monoamine or peptide.
• Performs a number of functions in the brain of the CNS
• In the PNS, this is released by most neurons in autonomic nervous system, and by motor neurons.

TYPES OF NEUROTRANSMITTER RECEPTORS:

• Combination of neurotransmitter released and receptor on post-synaptic membrane that determines
whether a signal to the target cell is excitatory or inhibitory
• Many neurotransmitters can bind to multiple types of receptors; some cause excitatory response
and others cause inhibitory response.
• When the target cell is another neuron, excitatory or inhibitory synapses can be scattered all over the
neuron, or there are many neurons where the dendrites receive predominately excitatory synapses and
ORGAN SYSTEMS 29
the soma receives inhibitory synapses at the soma. And when the synapse happens on another neuron’s
axon terminal, there’s a mix of excitatory and inhibitory synapses.
• This allows fine-tuning of neuron output at multiple levels, from the dendrite to soma to the axon
terminals.
• Two major types of neurotransmitter receptors:
• Ionotropic — ligated gated ion channels. When the ligand (neurotransmitter) binds to the receptor,
they open and let certain ions pass through.
• These ionotopic receptors cause graded potentials (brief, local) when they open.
• Excitatory response is usually caused in target cell if the ionotropic ion channel allows Na+ or Ca2+
in (because their positive charges cause depolarization)
• Inhibitory response is usually caused in the target cell if the ionotopic ion channel allows Cl_ or K+
ions to pass. (Cl goes in to the already negative cell; K+ travels out)
• Metabotropic — When neurotransmitter binds, it activates second messengers inside the neuron
• Second messengers can open ion channels, change protein activity, or affect gene transcription.
• When metabotropic receptors are activated, the response is slower than with ionotropic ones, but
the overall effect may be larger and more widespread because of the amplification that secondary
messengers can cause.
• Overall response of target cell after a metabotropic receptor binds a neurotransmitter may be brief,
or it may affect the cell permanently.
•
• Metabotropic neurotransmitter receptors move more slowly than ionotropic neurotransmitter receptors.
Metabotropic neurotransmitter receptors move more slowly than ionotropic receptors, but their
results may be larger and more widespread.
• Ionotropic neurotransmitter receptors are the type of receptor that directly allows ions to pass through the membranes.
• Metabotropic neurotransmitter receptors are the type of receptor that activate a second messenger inside the neuron.
•

NEUROTRANSMITTER REMOVAL:
• As action potentials travel down axons, the information they contain is really contained in the
frequency of firing and duration of the chains of axon potentials.
• When the action potential reaches the axon terminal, neurotransmitter is released to bind to receptors
on target cell. Eventually, it needs to be removed from the receptors and from the synaptic cleft:
• If neurotransmitter lingers in the synaptic cleft, it will mostly continue to bind to the receptor, and
the duration of the trains of action potential signals won’t be able to be transmitted.
• The synapse will not be functional.
ORGAN SYSTEMS 30
• Structure of neurotransmitter may be changed before it’s removed, so that it is not recognized by
the receptor. Ex: acetylcholine (in motor neurons) is deactivated by acetylcholinesterase, which is
an enzyme that breaks down acetylcholine into choline and acetate.
• Neurotransmitter removal can be by diffusion — leftover neurotransmitter just passively diffuses out
of the synapse. This only works action potentials are firing slowly.
• If action potentials are firing quickly, the rate of neurotransmitter release may be greater than the
rate at which neurotransmitters can diffuse.
• Neurotransmitter removal can also be active:
(1) Enzymes break down the neurotransmitter
in the synapse into its component parts
(2) Reuptake pumps — some pre-synaptic
membranes contain special active transport
channels that actively pump neurotransmitters
back into the axon, where it can be recycled &
used in future releases.
(3) Astrocyte end-feet — in CNS, astrocytes
put their end feet all over synapses. The end
feet also contain pumps/channels that actively
pump the neurotransmitter out of synapse and into the astrocyte.
• Sometimes the neurotransmitter will be broken down or used in the astrocyte, or parts of it may be
transferred by the astrocyte back to the axon terminal of the neuron so it can be recycled.
• All these methods allow the synapse to be rapidly turned on and off, so it can convey more information
from neuron to target cell.

• When the structure of a neurotransmitter is changed, it is not recognized by the receptor.

Acetylcholine is deactivated by acetylcholinesterase, which is an enzyme that breaks down acetylcholine into
choline and acetate.

NEUROPLASTICITY:
• Neuroplasticity refers to how the nervous system changes in response to experience.
• Nervous system is constantly changing (e.g. when we form new memories).
• This involves changes in synapses and/or other parts of neurons that affect how information is
processed and transmitted int he nervous system
• Potentiation — increase in the strength of info flowing through a particular part of the nervous system
• Each action potential has a larger effect on target cell
• Happens with parts of neurons and chains of neurons that are used often; they grow stronger
• Depression — decrease in the strength of info flowing through a particular part of the nervous system
• Each action potential has less of an effect on target cell
• Happens with parts of neurons and chains of neurons that are used rarely; they grow weaker
• Amount of neuroplasticity is highest when the nervous system is developing (and lower afterward), but
it’s present throughout life. Also increases transiently in response to nervous system injury.
Synaptic neuroplasticity — neuroplasticity changes that happen at the synapse
• Potentiation changes from lots of activity: increase in target cell response for each action potential
• For each action potential reaching the axon terminal, more neurotransmitter may be released in the
synapse, so a bigger response is seen in the target cell.
ORGAN SYSTEMS 31
• May be an increase in the number or type of membrane receptors in the post-synaptic membrane, or
in the responses that occur through second messengers so that for any given amount of
neurotransmitter released from the axon, the target cell has a bigger response because it is more
sensitive to that neurotransmitter
• Seems like there’s communication going from axon terminal to post-synaptic membrane and
backwards… details haven’t been figured out yet.
• Depression changes from inactivity: decrease in target cell response for each action potential
• For each action potential reaching the axon terminal, less neurotransmitter may be released in the
synapse, so a lower / depressed response is seen in the target cell.
• Neurotransmitter receptors may decrease in number, or change type to a less responsive receptor; or
there may be changes in the response of second messengers such that they elicit a weaker response
than they used to.
Structural neuroplasticity — neuroplasticity changes that happen at the level of an entire cell, where
the total number of synapses between a neuron and its target cell are changed.
• If two neurons are firing together frequently (one often stimulated by the other), we may see an
increase in the number of synapses between pre-synaptic neuron and post-synaptic neuron
• Dendrites may get longer or growing more branches; dendritic tree becomes more complex
• Pre-synaptic neuron may sprout more axon branches and terminals so it forms more synaptic
connections with dendritic tree.
• If two neurons are not firing together very frequently, we may see a decrease in the number of
synapses between pre-synaptic neuron and post-synaptic neuron
• Dendrites may get shorter or lose branches, such that the dendritic tree becomes simpler
• Pre-synaptic neuron may lose some of its axon terminals.
• If this neuron is not firing very often at all, we might even lose the whole neuron:
• Pruning — process of losing neurons or parts of neurons because they’re not very active
• Potentiation and depression can happen over a wide spectrum of time.. We often categorize it into
short term changes (over the course of seconds or minutes) or long term (over months or years).
• Synaptic neuroplasticity can contribute to both short term & long term potentiation and depression
• Structural neuroplasticity tends to be more associated with long term potentiation and depression
• By changing the strength of information flow between individual synapses or the between cells by
changing the total number of synapses, neuroplasticity plays a very important role in the development
of the nervous system as it’s wiring itself together based on the experience it’s receiving during its
formative time.
• Neuroplasticity also plays a huge role in memory and learning, as well as recovery from injury to the
nervous system

Depression refers to neuroplasticity that results in activity and response growing weaker.
Potentiation refers to neuroplasticity that activity and response growing stronger.
Synaptic refers to neuroplasticity that occurs at a synapse.
Structural refers to neuroplasticity that affects whole neurons or groups of neurons.

————————————————Biosignaling————————————————
MEMBRANE RECEPTORS
• Membrane receptors = integral proteins that interact with outside environment
ORGAN SYSTEMS 32
• Signaling molecules (aka ligands) such as neurotransmitters, hormones, etc. bind to the membrane receptor
(with specificity) and make a ligand-receptor complex.
• This complex then triggers a response in the cell.
• This process explains how hormones function, how / when cells divide, when they die, etc. Also explains
how cells communicate with each other
• Membrane receptors are a common target for pharmaceutical drugs; this is why some cells can target specific
cells (like your liver or heart)
• Signal transduction — an extracellular signal molecule (ligand) binds to membrane receptor, which then
triggers an intracellular response
• The binding causes conformational change in the protein, which induces other changes that eventually lead
to a cascade of signals in the cell, trigger a specific response.
• Each receptor can only bind with specific / certain types of molecules. This is especially important in hormonal
signaling.
• Used to be called lock-and-key, but induced fit is now the model, which means the ligand and receptor can
change shape to better fit one another.
• Three main types of membrane receptors:
• Ligand gated ion channels
• G-protein coupled receptors
• Enzyme linked receptors

LIGAND GATED ION CHANNELS

• Also called ion channel linked receptors, these are transmembrane ion channels that open or close in
response to the binding of a ligand.
• Commonly found in excitable cells like neurons, because these channels react quickly to binding of a
ligand, and thus the cells can respond quickly to a stimulus.
• Only specific ligands can bind to specific channels (lock and key / induced fit)
• Note that the binding site of a ligand is not in/on the actual ion channel… the ligand binds to allosteric site on
the receptor, and causes opening / closing of the channel by conformational change.
• The receptor allosteric binding site can also be inside the cell, but that’s rare.
• It’s also possible for there to be multiple binding sites for ligands.
• Once the ions move in or out of the cell, an intracellular electrical signal happens
• Ligand gated ion channels are not the same as voltage gated ion channels.. those only depend on a
different in membrane potential, not the binding of a ligand
• Ligand gated ion channels are also different from stretch activated ion channels.. which open / close
in response to deformation or stretching of the cell membrane.

• Generally, ligands are not directly involved in any aspect of intracellular signaling.
• Ligands do not directly influence the production of cyclic AMP and do not hydrolyze GTP to GDP.
• A ligand is a small molecule, usually a protein, that binds to a membrane-bound receptor, which
triggers downstream changes within the cell.
• A molecule that attaches to a receptor, triggering changes within the cell is the correct answer.
ORGAN SYSTEMS 33

• Cells that respond to mechanic forces typically possess stretch-activated ion channels. An example would be a
cardiac cell.
• Terminally differentiated cells comprise multiple cell types, some of which may possess ion channels, but this is
not the best choice here.
• The importance of the ligand-gated ion channel is that it allows for rapid response to a stimulus, so cells that need
to respond quickly (like neurons) are those that possess ligand-gated ion channels.
• Cells that need to respond quickly to external stimuli is the correct answer.
• Allosteric binding is an important feature of ligand-gated ion channels.
• Ligand-gated ion channels actually can have intracellular binding sites. React quickly to stimuli or ligand

G-PROTEIN COUPLED RECEPTORS

• Only found in eukaryotes; are the largest class of membrane receptors. Each has a specific function
• Ligands that bind to these range from light sensitive compounds to pheromones, hormones,
neurotransmitters, etc.
• GCPRs can regulate immune system, growth, sense of smell / taste / behavioral / visual and our
moods. Many G-proteins and GCPRs still have unknown functions.
• Most important characteristics:
• GCPRs have 7 transmembrane alpha helices.
• They’re also linked to G-proteins, which have the ability to bind to GTP / GDP and be activated
• G-proteins have 3 subunits: G α , G ß , and G γ . G α and G γ are attached by lipid anchors.
(1) When the ligand binds to the GCPR, it undergoes a conformational change.
(2) Because of the conformational change, the G α exchanges its GDP for a GTP, becoming activated.
(3) The GTP causes the G α subunit to dissociate and move away from G ßγ dimer.
(4) G α subunit then goes on to regulate target proteins
(5) Target protein then relays signal via second messenger.
• So target protein could be an enzyme that produces second messengers (e.g. adenylase making
cAMP), or an ion channel that lets ions be second messengers
• Some G-proteins stimulate activity, others inhibit.
• This chain of events, with a G α protein subunit dissociating and going on to activate further response
in the cell, will happen repeatedly as long as the ligand is bound. So how do we turn it off?
(6) GTP on the G α is hydrolyzed to GDP
• This often occurs internally, by GTPase
within the G α –protein itself, but can also
be regulated (accelerated) by RGS protein
• Ex with epinephrine (aka adrenaline):
• Epi binds to ß-adrenergic receptor (GCPR),
which causes it to undergo conformational
change and switch GDP to GTP on the G α
subunit of the G-protein.
ORGAN SYSTEMS 34
• The G α subunit dissociates and binds to adenylate cyclase, which then makes the secondary
messenger cAMP from AMP.
• cAMP goes on to increase heart rate, dilate blood vessels, and break down glycogen —> glucose

ENZYME LINKED RECEPTORS (aka catalytic receptors)

• Enzyme-linked receptors are transmembrane proteins that uniquely function as receptors for signaling
molecules and enzymes — binding of ligand activates enzymatic activity.
• General structure includes extracellular “ligand binding domain” and intracellular “enzymatic domain”
• Shaped sort of like a Y (the V part is extracellular, where ligand binds)
• Most common enzyme linked receptors are tyrosine kinases (also called RTKs), which regulate cell
growth differentiation and survival; and they can bind and respond to ligands such as growth factors.
• Unique because Tyrosine is on the enzymatic intracellular receptor.
• RTKs have ability to transfer phosphate groups to intracellular proteins, which activates them, and
they go on to trigger additional change.
• RTKs occur in pairs. When ligands bind, the RTKs come together and act together in a cross-linked
dimer. This helps activate the Tyr phosphorylation activity.

• Each Tyrosine in one dimer activates a Tyrosine on the other dimer! This is cross phosphorylation.
• Tyr causes an ATP —> ADP + Pi
• Other Tyr then pick up the free phosphate group.
• Once activated, these phosphorylated Tyr allow different proteins to come by and attach
themselves to them.
• The only thing these proteins need to dock is an SH2 domain, which allows them to bind.
• Multiple docking of different proteins allows changes to multiple different intracellular signaling
pathways at the same time.
• The cellular changes often end at nucleus, signal from docking protein affecting transcription.
ORGAN SYSTEMS 35

• RTKs are useful / famous for their role in growth factors, such as in regulating surface proteins called
epinephrines, which can guide developmental processes in tissue architecture, placement of nerve
endings, and blood vessel maturation. Other growth factors (like platelet derived) and hormones (such
as insulin) also bind to RTKs.
• When the RTKs fail to regulate properly, they can cause issues in cell growth and differentiation.
Many cancers involve mutations of RTKs
• Many chemotherapies thus target RTKs. For example, the breast cancer drug Herceptin binds to
and inhibit an RTK that is overexpressed in many breast cancers.
RTKs are often associated with growth factors.
———————————————Endocrine System———————————————
ENDOCRINE GLAND HORMONE REVIEW
• How do different parts of the body communicate with each other? Some communicate through nerves,
but not everything is connected by nerves. The endocrine system connects everything!
• Endocrine system is a system of glands that secrete hormones (chemical messages) and release them
into the bloodstream so they can circulate to different parts of the body and initiate an effect.
• Hypothalamus — major endocrine gland in the forebrain, is about the size of a grape
• As a member of the forebrain, it receives many nerve signals from the brain.
• Called “control center” b/c it directs pituitary and plays a dual role b/n nervous & endocrine
system
• In addition to stimulating the pituitary gland, the hypothalamus makes hormones:
• ADH - antidiuretic hormone, mainly regulates fluid volume in our body
• Oxytocin — stimulates uterus to contract for females during pregnancy
• note: although hypothalamus makes these, they’re stored in & secreted from posterior pituitary
• Pituitary gland — right below the hypothalamus, is about the size of a green pea
• Called “master gland” because it takes signal from hypothalamus and directs it to almost all the
other endocrine glands, such that their function is ultimately dependent on the pituitary
• Thyroid gland – located in the neck, wraps around trachea (windpipe)
• receives signal from pituitary and regulates metabolism through thyroid hormones T3
(triiodothyronine) and T4 (thyroxine); it uses these to stimulate the body’s metabolism
• Parathyroid - four spots, right behind the thyroid
• responsible for regulating our body’s blood calcium level. (recall: calcium is involved in muscle
contraction, bone growth, and other important, sensitive functions)
• Adrenal glands — located on top of the kidneys
• cortex (outer part): makes adrenal cortical steroids, such as cortisol and aldosterone
• cortisol is a stress hormone that increases blood sugar in times of stress so we have energy;
also has anti-inflammatory functions
• aldosterone is major regulator of our body’s blood volume
• medulla (inner part): makes catecholamines such as epinephrine and norepinephrine, which are
involved in our body’s fight or flight response.
• Gonads — release sex hormones, which are mainly involved in development of secondary sex
characteristics and developmental stages associated with those characteristics (puberty, menopause)
• Ovaries in females produce estrogen and progesterone; testes in male produce testosterone
ORGAN SYSTEMS 36
• Pancreas — isn’t as directly involved with the pituitary as other glands but still uses its hormones
(insulin and glucagon) to stimulate an effect: control of blood glucose levels.
• How do hormones get to their destination organs when there’s so many hormones around the body?
• Hormones won’t be received unless there’s a specific receptor on the target cell
• The receptor and its location are important in determining hormone function
• Hormone classes help us identify which hormones have which functions:
• autocrine hormones function at the cell that makes them
• ex: T cells in the immune system secrete leukine hormones that signal the T cell itself to
increase effectiveness and immune function
• paracrine hormones function regionally
• ex: hormones released by hypothalamus that affect the pituitary
• endocrine hormones function at a distance
• ex: pituitary gland stimulating the gonads

HYPOTHALAMUS AND THE PITUITARY GLAND (AND THEIR HORMONES)

• The pituitary has 2 parts, which the hypothalamus interacts with in different ways.
• Hypothalamus gets signals from the brain and sends hormones / signals to different parts of the
pituitary. Hormones it sends include:
• Gonadotropin releasing hormone (GnRH)
• Corticotrophin releasing hormone (CRH)
• Thyrotropin-releasing hormone (TRH)
• Growth hormone releasing hormone (GHRH)
• Prolactin inhibitory factor (PIF) — unlike other hormones, PIH is constantly being released and
when it stops being released, the pituitary gland is signaled to release prolactin
Anterior pituitary — hypothalamus interacts with this primarily through the hypophyseal portal
system, a capillary system into which the hypothalamus secretes hormones [paracrine signaling]
• Some anterior pituitary hormones go on to stimulate other endocrine glands; others have a direct effect
on parts of the body. Use the pneumonic FLAT PEG to remember which is which.
• FLAT hormones (FSH / LH, ACTH, and TSH) are tropic hormones - they stimulate other
endocrine glands
• PEG hormones (Prolactin, Endorphins (which are not unique to the anterior pituitary), and GH) are
direct hormones - they directly stimulate a part of the body
• GnRH received by anterior pituitary stimulates release of follical stimulating hormone (FSH) and
luteinizing hormone (LH), which travel to the gonads & stimulates them to release their hormones
• CRH from the hypothalamus stimulates the release of adrenocorticotrophic hormone (ACTH),
which travels to the adrenal gland and stimulates it to release its own hormones
• TRH from hypothalamus stimulates anterior pituitary to release thyroid stimulating hormone (TSH),
which travels to thyroid and stimulates it to release its own hormones (T3 & T4, namely)
• When PIH stops being released from the hypothalamus, the pituitary gland is then stimulated to release
prolactin, which is involved in milk production in moms
ORGAN SYSTEMS 37
• GHRH from hypothalamus stimulates anterior pituitary to release growth hormone (GH), which
travels directly to the long bones and big muscles in our body to stimulate growth
Posterior Pituitary — hypothalamus interacts with this primarily through the stimulation of nerves that
run down the pituitary stalk.
• The nerve stimuli from the hypothalamus causes the posterior pituitary to release hormones that are
actually made in the hypothalamus but stored in the pituitary, including:
• ADH (antidiuretic hormone) — stimulates collecting ducts in the kidneys to retain water
• Oxytocin — involved in uterine contractions in women

HORMONE METABOLISM AND REGULATION

• One of the ways hormone concentration is controlled is through metabolism and excretion:
• liver — metabolizes extra / unneeded hormones and turns them into bile, which is ultimately
excreted in the digestive system
• kidneys — filter your blood all the time and remove waste products in the blood through urine
• blood — some hormones are just broken down in the blood (and their products go on to the liver or
kidneys)
• sweat — some hormones can just be sweat out
• Concentrations are also controlled through negative feedback loops — conditions resulting from the
hormone’s action suppress further release of those hormones
• Example of negative feedback loop with thyroid hormones:
• The hypothalamus releases TRH (thyrotropin releasing hormone) into the pituitary gland and, in
response to TRH, the pituitary then releases its hormone TSH (thyroid stimulating hormone) which
travels to the thyroid gland.
• The thyroid gland then releases its hormones T3 (triiodothyronine) and T4 (thyroxine), which
travel all throughout the body in search of their receptors to, e.g., upregulate metabolism.
• Some of the receptors of T3 and T4 are located on the pituitary gland and hypothalamus. When/as
the thyroid hormones reach those receptors, it signals the hypothalamus and pituitary to stop
producing TRH and TSH, respectively; more thyroid hormones are clearly not needed.
• Why does the pituitary gland need to be turned off if the hypothalamus is? Redundancy is just
indicative of how important feedback regulation is, to keep level of hormones in the body controlled.
TYPES OF HORMONES
• Hormones can be classified by where they function (autocrine, paracrine, endocrine) and, more
importantly, can also be classified by their structure.
• Structure is key to how a hormone works.
• There are three major types of hormones based on structure:
1) Proteins and Polypeptides
• Made of amino acids linked by peptide bonds
• P & P type hormones are most of the body’s hormones
• They range in size from small (3 AA) to large (many hundreds of AA). After about 50 AAs, we go
from calling them polypeptides to proteins.
• These are made in the rough endoplasmic reticulum (RER) of the cell and then go to the golgi
apparatus, where they’re repackaged into vesicles that can eventually be excreted from cell.
ORGAN SYSTEMS 38
• Because proteins and polypeptides are made of AAs, they’re typically charged. This makes them water
soluble but also makes it difficult to cross cell membranes. For this reason, P & P hormone receptors
are usually located in or on a cell surface
• When they bond to a receptor, P & P hormones can initiate a response inside the cell by initiating
of a cascade of secondary messengers
• ex: insulin is a relatively large protein hormone
2) Steroids
• largely used for signaling
• made from lipids (mostly from cholesterol), and thus have a characteristic structure that they all share:
a four-ringed carbon backbone (three cyclohexane, one cyclopentane)
• Because they’re made from lipids, steroids can enter a cell without much trouble. Unlike proteins and
polypeptides, the receptors for steroid hormones are thus located inside the cell.
• Steroids act as primary messengers; they’re doing the signaling themselves. Receptors are often in the
cytoplasm or the nucleus of the cell.
• Steroids can effect change at the level of DNA transcription and translation, make new proteins form.
• ex: hormones from adrenal cortex (cortisol, etc) and from gonads (testosterone, estrogen, etc.)
3) Tyrosine Derivatives
• Recall: Tyrosine is an amino acid.
• Why is it not of the polypeptides and proteins type, then? Well, they’re only
made of derivatives from a single amino acid. Additionally, they
sometimes act like P & P hormones, but other times act like steroids.
They’re a class of their own.
• ex: thyroid gland hormones like T3 (triiodothyronine) and T4 (thyroxine); these stimulate metabolism
• act very similarly to steroids, and bind to receptors inside the cell
• ex: catecholamines like epinephrine and norepinephrine, which are produced in the medulla and are
involved in our fight or flight response.
• act very similarly to P & P proteins in that they bind to the outside of a cell and stimulate
secondary messengers inside the cell.
• Act like proteins

CELLULAR MECHANISM OF HORMONE ACTION

• After traveling through the body, a hormone eventually reaches the receptor on a target cell
• One mechanism: action by secondary messengers — Hormone binds to a receptor on the outside of a
cell. Instead of stimulating an effect directly, it sets off a chain of secondary messengers within the cell
that themselves stimulate the effect.
• When hormone binds with receptor, it causes the receptor to change conformation and interact with
the G-protein to form a complex. When this happens, the GDP bound to G-protein is transformed
to GTP .
• This transformation to GTP allows the G-protein to move through the membrane and activate the
adenylate cyclase. The adenylate cyclase then transforms ATP —> cyclicAMP (cAMP).
• cAMP is then what triggers the effect inside the cell that the hormone is targeting in the first place.
ORGAN SYSTEMS 39
• Signal amplification: in theory one hormone can bind to a receptor, which sets off chain reaction
leading to a lot of cAMP being produced.
• Because we are unable to communicate directly
• Second mechanism: action by primary messenger — Certain hormones like steroids and thyroid
hormones can cross the cell membrane and effect change themselves.
• Steroid and thyroid hormones can typically cross the membrane on their own because, unlike other
polypeptide hormones, e.g., they are lipid based.
• Hormone crosses cell membrane and binds to a receptor in the cytoplasm or the nucleus.
• When the hormone binds to this receptor, it directly affects transcription (if receptor is in nucleus)
or translation (if in cytoplasm) of the protein that’s being activated by the hormone.

TERPENES, CHOLESTEROL, AND STEROIDS

• Terpenes are a class of lipid molecules made from repeating isoprene units
• An Isoprene unit has 5 carbons — 4 are bonded in a chain, the 5th branches off a middle carbon
• monoterpene = 2 isoprene units, forming 10-C molecule (ex: menthol)
• sesquiterpene = 3 isoprenes form a 15-C molecule (ex: ginger)
• diterpene = 4 isoprenes (essentially 2 monoprenes) form 20 carbon molecule
• sesterterpene = 5 isoprenes form a 25 carbon molecule
• triterpene = 6 isoprenes form a 30 carbon molecule (ex: squalene)
• Biosynthesis of steroids uses isoprene pyrophosphate (recall: pyrophosphate is a weak base and makes
a good leaving group)
• Dimethylallyl pyrophosphate and isopentyl pyrophosphate combine head-to-tail (displacing a
pyrophosphate in the process) to make geranyl pyrophosphate, a 10-C molecule
• Geranyl pyrophosphate then combines head-to-tail with a third isoprene to make 15-C farnesyl
pyrophosphate; another pyrophosphate is released.
• Two farnesyl pyrophosphates combine head-to-head to make 30 carbon squalene. Squalene is the
precursor for all the steroid hormones.
• After a series of ring-closing reactions, squalene turns into cholesterol, a four-ringed molecule.
• In the case of endocrine organs that use steroid hormones to communicate, cholesterol can be altered
to form the characteristic steroid backbone
• Two important classes of steroids for endocrine glands: sex hormones and adrenal cortex steroids:
• Sex hormones: estrogens (estradiol and estrone, made in ovaries); progesterone (pregnancy
hormone); androgens (testosterone, androsterone)
• Adrenal Cortex: cortison and cortisol (stress hormones, have various effects from anti-
inflammatory to increasing carbohydrate metabolism); aldosterone (one of the main hormones that
regulates blood pressure and fluid volume).

——————————————Circulatory System——————————————
THE HEART
Intro
ORGAN SYSTEMS 40
• Thorax = includes heart enclosed within ribcage, a lung on either side, & diaphragm muscle
underneath
Jobs of the heart:
(1) Systemic flow — Delivers the oxygen, nutrients, and other things that the cell needs to live; and
takes away its waste (like CO 2 ).
• Blood enters hear through the superior / inferior vena cava; the aorta sends it back out.
• Systemic flow includes coronary blood vessels around the heart that serve the heart cells itself.
(2) Pulmonary flow — Before sending blood out through the aorta, the heart sends it through the right
and left lungs so it becomes oxygenated.

Flow through the Heart

• Blood comes down from arms, neck, head (upper half) into superior vena cava of the heart, while
blood from the legs, belly (lower half) into inferior vena cava. Both enter into the right atrium.
• After the right atrium, blood flows down into the right ventricle (through the tricuspid valve).
• From the right ventricle, blood passes through the pulmonary valve into left and right pulmonary
arteries. These arteries travel through the lungs, where CO 2 is exchanged for O 2 .
• The newly oxygenated blood then re-enters the heart through the pulmonary vein to enter the left
atrium, after which it flows through the mitral valve to enter the left ventricle.
• From the left ventricle, blood flows through the aortic valve to enter the aorta, which sends it out to the
body (aorta has branches into head/neck and each arm, through the midsection and then into each leg).

Layers of the Heart

• Blood flow: RA —> RV —> lungs —> LA —> LV
• Atrioventricular valves help keep blood flowing (they’re the two valves between atria and ventricles).
• tricuspid — RA/RV
• mitral — LA/LV
• These valves face downward; are tethered to the walls by chordae tendinae (chords) and papillary,
that keep the valves from flapping back and forth. Without these, blood would flow back in wrong
direction during systole (ventricular contraction).
• The intraventricular septum is basically a wall that divides the left and right ventricles of the heart
• Has two different areas: membraneous area closer to the atria, and muscular area.
• One of the most common heart defects in infants is a hole in the membraneous intraventricular
septum, so blood flows from left ventricle to right ventricle (big problem) — this is a called VSD.
• Heart muscle has three layers (starting inside heart —> out)
• Endocardium — thin layer that’s very similar to the lining of blood vessels; is what the red blood
cells bump up against
• Myocardium — thickest layer. This is where all the contractile muscle is, and thus where a lot of
the energy is being used up.
• Pericardium — a little thinner, has two layers with a gap in between them. There might be a little
fluid in that gap, but no cells.
ORGAN SYSTEMS 41
• This happens when the heart is growing in a fetus, it grows into a sort of ballon sac so a
pancaked balloon surrounds the heart
• Visceral pericardium — layer closer to the heart
• Parietal pericardium — layer further from the heart

Lub Dub of the heart:

• Four valves of the heart: tricuspid, pulmonary, mitral, aortic.
• As blood flows from RA —> RV, blood (from a previous cycle) also flows form LA —> LV
• Mitral and tricuspid valves [atrioventricular valves] thus open simultaneously. And when these are
open, the pulmonary and aortic valves [semilunar valves] are closed.
• Ventricles are then filled with blood, and so they squeeze (contract) to pump it out.
• Blood then flows through pulmonary and aortic valves from the ventricles. When those are open, the
pulmonary and aortic valves snap shut.
• The shutting of valves makes the lub dub noise.
• Lub = first heart sound (S1) —> caused by T and M valves snapping shut
• S1 is when semilunar valves open; blood has just emptied from the atria into the ventricles.
• Dub = second heart sound (S2) —> caused by P and A valves snapping shut
• S2 is when tricuspid and mitral (atrioventricular) valves open. Immediately after S2, the atria
and ventricles fill with blood.
• S2 indicates the beginning of diastole, so at the end of it; all valves are closed.
• Diastole is a complete relaxation of the ventricles, and represents the time lag between pairs of lub
dubs, when the blood refilled from the atriums into ventricles
• Systole is the time lag between S1 and S2, during which heart pumps blood from the ventricles out, so
AV valves are closed to prevent regurgitation into the atria..

BLOOD VESSELS
Layers of a Blood Vessel
• Tunica Intima — The lumen of the blood vessel is surrounded by a layer of endothelial cells. These
are the first type of cells that blood will interact with. Outside of that layer of endothelial cells is a
layer of protein (e.g. collagen), called a basement membrane, that keeps everything from falling out
of place.
• Tunica Media (middle) — a layer of smooth muscle cells outside the basement membrane
• Tunica Externa (adventia) — on the very outside is another layer of protein. It’s like the basement
membrane but a different composition (still lots of collagen though).
• On larger vessels, you sometimes find vasa vasorum, tiny blood vessels that supply the tunica
externa itself. It also has nerve endings.
• Veins — have all three layers, pretty straight forward.
• Large / middle size arteries — Have a normal tunica intima layer, but the tunica media is much
larger; a thick layer of smooth muscle that also contain elastin, a protein that makes arteries more
elastic for high pressures. Tunica externa is then pretty normal (with vasa vasorum and nerve endings)
• Small arterioles — Also have a normal tunica intima and a large tunica media. Instead of having
elastin in the media layer, though, it just has a ton of smooth muscle cell which makes it very strong.
ORGAN SYSTEMS 42
Makes sense because arterioles are the vessels that create resistance to change blood pressure. Tunica
externa is also pretty normal (with vasa vasorum and nerve endings)
• Capillary — unlike the veins and arteries, this is down to the single cell level. So the endothelial layer
is made of just one cell that envelopes the lumen.

Arteries vs Veins
• Systemic circulation: Arteries take blood from the heart out to all the capillary beds in all parts of the
body; then veins bring the (now deoxygenated blood) back to the heart.
• Pulmonary circulation: Pulmonary artery takes deoxygenated blood to the lungs; pulmonary vein
brings it back. arteries take blood
• Note: In the lungs there is mixing b/n pulmonary & systemic circulation - lungs receive oxygenated
blood from Bronchial Arteries, which are a part of the systemic circulation. Some of the blood drains
back through the Bronchial Veins, but some of it joins the deoxygenated blood in the lungs from the
Pulmonary Arteries, becomes re-oxygenated, & re-enters heart through Pulmonary Veins..
• Direction of flow between arteries and veins is different:
• Arteries — take blood away from heart. Veins take it towards the heart.
• Type of blood the arteries and veins carry is different:
• Usually Veins carry deoxygenated blood, and Arteries carry of oxygenated blood.
• exception: Pulmonary artery carries deoxygenated blood; pulmonary vein carries oxygenated
blood.
• Pressure and volume in veins and arteries different:
• Arteries are high pressure (like a fast flowing river), and don’t carry much volume.
• Veins are low pressure, and carry a lot of volume.
• How much blood is where in your body? ~ 5% in the heart, ~ 5% in the capillaries, & 10% in the
lungs. Only 15% is in the arteries, then the remaining 65% of body’s blood is in the veins at any given
time.
• Veins have valves; arteries do not.
• In veins, the valves keep the blood flowing in the right direction.
• This is not really necessary for arteries because the pressure is so high. But that means if you cut an
artery, you just have a fountain of blood spewing out. If you cut the vein, you get more of a pool of
blood that eventually clots.
• The papillary muscles contract during systole to prevent blood from flowing backwards within
the heart.
• Semilunar valves are not actively closed.
• Instantly after second heart sound, all valves are closed
• All blood vessels have a tunica intima. This layer is made of endothelial cells, and is an essential
structural component.
• Intracellular calcium is the cellular messenger resulting in the contraction of smooth muscle.
• The tunica media is a muscular layer, which can be contracted and relaxed to enact changes in blood
pressure.
• A thick tunica media is characteristic of large systemic arteries.
• A thick tunica media explains the responsiveness of large systemic arteries to changes in
intracellular calcium concentrations.
• P =QR
ORGAN SYSTEMS 43

PRESSURE, FLOW, RESISTANCE

• Dr. Poiseuille: If you know the length (L) and radius (r) of a tube, as well as the viscosity (eta, η)
of the fluid, you can calculate the resistance (R) of flow through that tube.
• R = 8Lη / πr4

• So, if two tubes have same length and are carrying the same fluid, resistance is proportional
to 1/r4
• So for a tube with half the radius (r/2) of another tube with radius r, resistance will be 16
times greater in the smaller radius tube.
• In arterioles, when smooth muscle is relaxed (vaso-dilation), the radius of the tube is much
greater than when it is constricted (vaso-constriction). This means we have low resistance of
blood flow during vaso-dilation, and high resistance during vaso-constriction.
• Flow: blood flows from aorta to brachial artery, then to an artery, eventually a capillary bed
where it comes out the other side, now deoxygenated, in a venule and then a vein, and eventually
gets back to the heart through the superior vena cava.
• The pressure that blood is exerting at any given point on the blood vessel walls can be described
by systolic vs. diastolic pressure, upper and lower range. Below, let’s look at average pressure
over time as the blood flows through the body:

• Overall pressure continues to

decrease as blood flows through
the body.
• The biggest drop occurs when
flowing from the arteriole into the
capillary bed.

• Consider resistance to flow? ∆P = Q x R

• ∆P = pressure at the beginning of a tube (P S ) – pressure at the end of the tube (P E )
• Q is blood flow in volume / min
• Q = stroke volume x heart rate, aka the volume of blood that’s pumped out in each beat,
and the beats per min. (volume / beat) x (beat / min) = volume / min
• For an average male, there are 70 mL / beat, and 70 beats / min, so Q = 4900 mL/min =
5L/min
• R is proportional to 1 / r4
• What is total body resistance? Well we know that when blood comes out the aorta, the pressure
is 95 mmHg, and when it goes back in through the vena cava, it is about 5 mmHg.
• ∆P = Q x R
• 95 – 5 mmHg = 5L/min x R
• R = 90/5 = 18 mmHg*min / L

THERMOREGULATION IN THE CIRCULATORY SYSTEM

• How does your body maintain its core temperature when, e.g. you’re exercising under the hot
sun? One way is by sweating. Another way involves in the skin.
• Below the skin is blood vessels, an arteriole supplies your skin with blood and oxygen through
capillary beds, very fine blood vessels with high surface area.
ORGAN SYSTEMS 44
• For our purposes, the skin acts as insulation. [Think of a house, with walls that insulate it] But
capillaries go into the skin layer and lose heat easily. [windows in the house]
• When your body is hot, it will dilate the capillaries in your skin [open the windows] to allow
more heat out. When capillaries are vasodilated, more blood can pass through them, and thus
more heat is lost to the surroundings.
• When it’s cold out, your capillaries will vasoconstrict, so you lose less heat to the environment.
This also means you have less heat at the surface of your skin, then, which is why partly your
skin gets so cold.
• Body regulates the size of blood vessels through the smooth muscles cells, which are told to
contract or relax through nerves.

———————————————Hematologic System—————————————
——
WHAT’S INSIDE OF BLOOD?
• Blood is drawn into a tube that’s lined with a chemical so the blood doesn’t clot, then it’s
centrifuged so the blood parts separate out. There are now three different layers.
• Plasma is the least dense and the largest layer, making up about 55% of the blood.
• It’s made of 90% water, 8% proteins (Albumin, antibody, fibrinogen [+ other clotting
factors]) and 2% hormones, electrolytes, nutrients.
• Note: Plasma and serum are very similar, but serum does not have fibrinogen.
• The next layer (< 1%) is white blood cells / platelets.
• Hemoglobin is the last, most dense layer, making up about 45% of the blood (lots of hemoglobin)
• Hematocrit = volume of RBC / total volume. What a normal hematocrit level is changes
depending on your age, sex, and even if you live at a high altitude.
• polycythemia = person has a really high level of red blood cells
• anemia = person has a really low volume of red blood cells.
HEMOGLOBIN
• Oxygen enters a blood vessel from the alveolus in the lung, and within blood vessel diffuses into
a RBC.
• Hemoglobin protein has 4 parts to it, and each part can bind a protein.
• Once a single O 2 is bound, it’s easier for other O 2 to bind. (cooperativity)
• Two ways O 2 transported in blood: HbO 2 (oxyhemoglobin; most common) or O 2 dissolved in
plasma.
• A muscle cell has high pC O 2 , and low p O 2 - so when oxyhemoglobin enters it releases O 2
• Also inclined to released O 2 because protons (H+) and CO 2 compete with O 2 for hemoglobin:
• When CO 2 enters the red blood cell, it reacts with a water molecule (catalyzed by carbonic
anhydrase in a reversible reaction) to become HCO 3 - and H+
• The HCO 3 - exits the cell, and the H+ binds to hemoglobin, causing the oxygen to fall away.
• Note: An increase in HCO 3 - would remove free H+ ions from blood and thus increase its
pH, ultimately increases O 2 affinity for Hb.
• When CO 2 binds to red blood cells (competing with O 2 ), a proton is also created.
• When blood is returning to the lung, what is it carrying with it?
• Hb-COO- (carbaminohemoglobin)
• H+Hb (with corresponding HCO 3 - in the plasma)* biggest way CO2 comes back
• CO2 dissolved in plasma.
ORGAN SYSTEMS 45
• When in the lung, an oxygen rich tissue, O 2 diffuses into the red blood cell and tries to enter
hemoglobin; we basically push the reactions to the left and O 2 competes for hemoglobin again.
• When carbaminohemoglobin enters the lung, with high pO 2 and low pCO 2 , it releases CO 2
• Also inclined to release CO 2 because O 2 competes with H+ / CO 2 for Hb
• In the lungs, HCO 3 - reenters RBC and re-combines with H+ to form the CO 2 (through a couple
intermediates) that diffuse out into the alveolus, and can be expelled through the lungs.

BOHR EFFECT VS HALDANE EFFECT

Bohr effect: CO 2 and H+ affect the affinity of Hb for O 2
• As pO 2 is increased, the O 2 content bound to Hb slowly
increases until Hb gets saturated (O 2 content starts to plateau).
• The amount of O 2 that has been delivered in the tissue by Hb
can be determined by subtracting the O 2 content from a place
of low pO 2 , (e.g. thigh tissue) from a place of high pO 2 (e.g. lungs)
• The Bohr effect (right shifted green curve) says that increased
CO 2 and H+ (e.g. in muscle tissue) makes O 2 delivery higher
than it would be just from low pO2 there.

Haldane effect: O 2 affects the affinity of Hb for CO 2 / H+

• As you increase pO 2 , the content of CO 2 increases. (Note: Not S shaped like O 2 b/c there’s no
cooperative binding.)
• Can determine the amount of CO 2 delivered in the same
way as O 2 before, by subtracting the CO 2 content at two
different pCO 2 ’s
• Haldane effect says that with increased O 2 (like in the lungs),
the affinity of Hb for CO 2 and H+ is decreased, so more CO 2
content will be delivered there than it would from just the high
pO 2 there.

BLOOD TYPES
• Embedded in the cell membranes of red blood cells are all kinds of proteins and molecules —
two of which are very important for determining blood type: A and B glycolipids.
• Some people have both A and B glycolipids (AB blood type), others have just A (A type) or B (B
type), and others have none of these glycolipids (type O).
• Recall: antibodies of the immune system tag specific foreign bodies (like bacteria) for
destruction, but they’re careful not to make antibodies for its own helpful molecules.
• For this reason, a person with type AB blood does not have
A or B antibodies. Meanwhile, a person with type A blood
does not have A antibodies, but will have B antibodies.
• Those with B type blood have A antibodies, but no B ones.
• A person with type O blood has both A and B antibodies,
because their body doesn’t recognize either type of glycolipid.
• If a person with type A blood receives a transfusion from
AB blood, that person’s antibodies would bind to this
transfused blood and his body would start to destroy it,
causing a huge amount of inflammation.
• The chart to the right shows which blood types can donate
to which. O is universal donor; AB is the universal recipient.
ORGAN SYSTEMS 46

HOW WE MAKE BLOOD CLOTS

• Blood vessels are made of endothelial cells (each with a nucleus). What happens if a blood vessel
breaks?
• Part 1 — Platelet plug: when/where there’s a break, platelets come together to coagulate & block
hole.
• Platelets are tiny pieces of cells - with no nucleus - floating around in your blood all the time
• How do they know to clump up at the break and not elsewhere in the blood? The
environment in the blood vessel is different than the environment outside of the blood vessel.
• Outside of the blood vessel there is collagen, which chemically interacts with platelets and
causes them to stick together to plug the hole.
• Part 2 — Fibrin enters to strengthen platelet plug; forms mesh of protein that holds platelets
together.
• Fibrin strands are made of subunits that naturally like to polymerize, or stick together.
• How does fibrin not polymerize while floating around in blood? Because we don’t exactly
have fibrin floating around, but fibrinogen (basically fibrin, with an extra bit that keeps it
from sticking).
• Fibrin is turned into fibrinogen at the site of break, thanks to a whole cascade of coagulation
factors that starts with tissue factors (e.g. factor III — like collagen, which are only found outside
blood vessel), and ends with activated thrombin (aka factor II) coming into site of break to
catalyze fibrinogen —> fibrin.
• Note: a lot more thrombin is activated that there is/was tissue factor, because of the cascade
Details on coagulation cascade:
• Thrombin is itself activated from its inactive form prothrombin.
• Intrinsic pathway: XII —> XI —> IX + VIII —> X + V —> II (thrombin) —> I (fibrin)
• Note: This is not XII becoming XI, becoming IX… Instead, activated XII catalyzes the
conversion of XI from its inactive form into its active form, and active form of XI catalyzes IX
into its active form, etc…
• Factor X is the very important enzyme that activates thrombin
• As you move down the intrinsic pathway, the amount of each enzyme present increases, thus
increasing the active forms of each until you end up with a ton of thrombin (and thus lots of
activated fibrin)
• Extrinsic pathway: III (tissue factor) —> VII —> X + V —> II (thrombin) —> I (fibrin)
• The extrinsic pathway is the original spark that sets off the cascade, while the intrinsic pathway
is the workhouse that gets most of the coagulation done. How?
• Tissue factor III sets off a little bit of VII, which activates a little X, which then activates a little
bit of thrombin. Thrombin is then what really gets the workhorse going by activating many
other enzymes
[Think of thrombin activating 5 odd numbers starting with 5: 5 7 9 11 13 … but actually it activates 8, not 9.
almost.]
• What is factor XIII? Well, factor I activates fibrinogen —> fibrin so the fibrin can form
strands, but then factor XIII comes in to connect the fibrin strands together (cross-links
them) so they actually form a tight mesh.
• Negative feedback loops (governed by thrombin) prevent the enzyme activation pathways from
spiraling out of control such that you become one walking blood clot.
• Thrombin helps create plasmin from plasminogen, which works directly on on the mesh of
fibrin to break the cross-links apart. Helpful, but doesn’t prevent the rest of the enzyme
pathways from continual activation.
ORGAN SYSTEMS 47
• Thrombin also stimulates production of antithrombin, which decreases the amount of
thrombin produced from prothrombin, and impedes the production of activated X from
inactive X.
• If these pathways aren’t working you can’t clot very well and have haemophilia, aka you bleed a
lot. There are three different types of haemophilia, associated with 3 different factor deficiencies
• A — VIII • B — IX • C — XI

Plasmin breaks down fibrin and fibrinogen, which serves to limit clot formation.
The intrinsic pathway is initiated by components which are already ‘in’ the blood.
Factor XII is associated with the intrinsic pathway, and catalyzes the formation of factor XI, which catalyzes the
formation of IX, which catalyzes the formation of X.
Factor X is common to both pathways, but is not ‘upstream’ so to speak.
The extrinsic pathway proceeds in the presence of tissue factor (TF) which is released in response to tissue injury or
insult.
Endothelial cell insult is the principal component which activates and drives the extrinsic pathway of the
coagulation cascade.

RED BLOOD CELLS AND PLATELETS

• Red blood cells last ~120 hours, which is about 4 days. Platelets last even less time, only 1-2
days..
So your body constantly needs to produce more of these — which it does in the bone marrow.
ORGAN SYSTEMS 48
• Erythropoiesis: Red blood cells are made from a precursor cell which has a nucleus (RBCs don’t).
The precursor divides many times, and eventually some of the daughter cells turn into
erythrocytes / RBCs
• Platelets are fragments of cells that bud off from a huge cell called a megakaryocyte. So platelets
are basically bits of cytoplasm surrounded by a membrane. A megokaryocyte can yield many
platelets.
• What does your body do with old RBCs and platelets it doesn’t want? Breaks them down via the
spleen.
• When blood (coming from the heart) passes through the spleen, a spleen cell called a monocyte
(which is basically a macrophage) will recognize and engulf any old red blood cells, chew them
up, and recycle anything important (such as iron, and some amino acids).
• Most of the old RBC and platelet breakdown happens in the spleen, but some also happens in
the liver, through a similar process.
• How does the body know how many new RBCs and platelets to make?
• Low oxygen levels stimulates the release of a hormone called erythropoietin (aka EPO)
in/from the kidney, which tells the bone marrow to produce more RBCs via erythropoiesis.
• Some athletes take EPO so their body makes more RBCs and they get more oxygen to their
muscle.
• If you need more platelets, your body releases the hormone thrombopoietin, which signals the
megokaryocytes to make more.

BLOOD CELLS LINEAGES

• In the blood vessels, you have about 10 different kinds of blood cells, from RBCs to T-cels, to B-
cells, to platelets, and more… where do they all come from? Bone marrow! Specifically from the
heads of long bones and from different flat bones (like the sternum) throughout the body.
• All blood cells have a single precursor: a pluripotent hematopoietic stem cell
• This pluripotent cell gives rise to two different lineages: myeloid and lymphoid
• Myeloid lineage yields red blood cells
and megakaryocytes (from which platelets
are made), as well as mast cells (which
release histamines in allergic reactions)
• The myeloid lineage also yields monocytes,
which then become macrophages (part of
the immune system) when they settle in
the tissues.
• This monocyte lineage also yields three
other types of cells: neutrophils (most
common immune cell), eosinophils,
and basophils.
• Lymphoid lineage yields B-cells (which
make antibodies), T-cells, and
“natural killer” cells.
• Dendritic cells can come from either
lymphoid or myeloid (monocyte) lineages.

————————————————Respiratory System—————————————
———
ORGAN SYSTEMS 49
THE LUNGS:
• Whether you breathe in through your nose or mouth, it will follow a path to the back of your
throat to the Adam’s apple, or the voice box. Air passes through the voice box into the trachea.
• From the trachea, air goes into the right and left lungs.
• The right lung has three lobes (upper, middle, lower) and the left lung has two lobes.
• The left lung also has a cardiac notch, where the heart sits.
• Around the lungs are the ribs and rib muscles. Below the lungs and the heart is the diaphragm
muscle.
• Within each lung are many branches (basically an upside down tree), which we call the bronchial
tree.
• If we zoom in on a little branch, we would see a bunch of sacs called the alveoli. The air you
inhales runs into the alveoli, takes a U-turn, and you exhale it back out. Before you exhale, your
lungs give up O 2 and take away CO 2 from tiny blood vessels that run next to to the alveoli.
• Note: the conducting zone is simply a series of tubes through which gases travel, while the
respiratory zone directly participates in gas exchange.
INHALING AND EXHALING:
• Whether you breathe in through your nose or mouth, it will follow a path to the back of your
throat to the Adam’s apple, or the voice box. Air passes through the voice box into the trachea.
• Recall, the more frequently collisions are happening between air molecules, the higher the
pressure is.
• For the general atmosphere, P = 760 mmHg.
• When you inhale:
• Volume of the lungs increases, which causes pressure of molecules inside the lungs to
decrease (bc there are fewer collisions). P = ~757 mmHg now, which some call “negative,”
by comparison to 760.
• Air molecules move into the lungs, causing pressure to increase back up to 760 mmHg.
• When you exhale:
• Volume of the lungs decreases, which cause pressures to increase because now there are
more molecules than before (763 mmHg) for the same initial volume.
• This pressure causes air molecules to leave until you have about the same amount as before,
and
• pressure decreases back to 760 mmHg.

HOW DOES LUNG VOLUME CHANGE?

• In the middle of the chest is a large bone called the sternum (aka breast bone); 7/12 pairs of ribs attach to
the sternum. Between the ribs are intercostal muscles.
• When you start to inhale:
• Your intercostal muscles contract and your ribs move outwards.
• At the same time, your diaphragm contracts and goes from being curved upwards to flattened
out.
• As these muscles contract, your lungs and heart will physically be drawn downwards and out.
• The expansion of your lungs is really all your alveoli expanding (you have ~500 million of them);
they’re pulled outwards as your muscles move down and out.
• Note that the muscles do not physically pull open the alveoli; their enlargement is caused
indirectly through a decrease in pressure and influx of air.
• Alveoli are covered in elastin, a protein that helps them stretch open.
• The energy for contraction / inhalation comes from chemical energy, ATP.
• When you exhale, your muscles relax.
ORGAN SYSTEMS 50
• The alveoli then recoil (the elastin molecules “snap back” into their original size).. which is
the driving force behind brining lungs back open to normal size.
• The energy for relaxation / exhalation comes from elastic potential energy.

HENRY’S LAW AND THE SOLUBILITY OF O2 AND CO2

• Look at the interface between a gas and a liquid, H 2 O — what happens at that surface layer?
• Total pressure is 1 atm = 760 mmHg, but if we’re just looking at green molecule,s which make up
about 50% of the air, we say its partial pressure = 760mmHg(.50) = 380mmHg
• If the number of green molecules increases, that’s basically saying the partial pressure
increases.
• As partial pressure rises, more of those green molecule will enter the water. So partial
pressure tells you about likelihood that a molecule will enter the solvent.
• Meanwhile, the constant K H tells you the likelihood of a solute leaving the liquid layer. It
takes into account solute, solvent, and temperature.
• The concentration of a solute dissolved in solvent can be determined by the equation: C = P solv /
KH.
• This is Henry’s law. It basically says there’s a relationship between partial pressure and
concentration.
• Now let’s look at two cups of water placed in two different atmospheres: One is made of 21% O 2 ,
the other is made of 21% CO 2 , both at 25º C.
• The concentration of O 2 that dissolves in the surface layer of water is much lower (0.27
mmol/L) than the concentration of CO 2 that dissolves (7.24 mmol / L).
• We can even rearrange Henry’s law to K H = P solv / C and calculate that the K H of O 2 is 769
L•atm / mol, while the K H of CO 2 is lower: 29 L•atm / mol.
• Henry’s law tells us that the partial pressure is a measure of what’s going into the water, while
the constant is a measure of what’s going out — So it what’s going in on both sides is equivalent,
the difference is in what’s leaving.
• With O 2 , there was low concentration, so O 2 was constantly leaving the water.
• Not much CO 2 went out of the water though; it’s concentration was higher. Recall,
CO 2 + H 2 O—> H 2 CO 3 (reversible) —> HCO 3 - + H+ (reversible)
• We can directly compare K H values, and say 769 / 29 = 26, so CO 2 is about 26 times more
soluble than O 2 in water
• In our lungs, which are about 37º C, and have a solvent of blood instead of water, CO 2 is about 22
times more soluble.
FICK’S LAW OF DIFFUSION
• Consider a bunch of molecules trying to diffuse over a short distance (like from one wall to
another) over time… how can you maximize the number that diffuse across? Some ideas:
• Less thick wall
• Smaller molecular weight (MW) molecules (We know from Graham’s law that smaller molecules
move faster)
• Increase partial pressure P 1 of molecules
• Increase surface area for molecules to diffuse across
• Fick’s law: V = [(P 1 – P 2 ) x A x D] / T
• V is rate of particles moving (amount like moles, or volume)
• P 1 is pressure on first wall, while P 2 is the pressure on the second wall. Of course, if the
pressure of P 2 is < P 1 , more molecules will want to diffuse from wall 1 to wall 2.
• A is surface area, the higher it is the more molecules that can get across.
ORGAN SYSTEMS 51
• D is diffusion constant, which is basically a ratio of solubility (from Henry’s law) by
molecular weight; D = K H / √(MW)
• T is thickness of the wall.
• This formula can also be written as [V/A] = [(P 1 – P 2 )/T] x D, or [flux] = [gradient] x D.
• Flux can be defined as the “net rate” of particles moving through an area.
• Gradient is the change in pressure (or in particles in a volume)
over a distance.

OXYGEN MOVEMENT FROM ALVEOLI TO CAPILLARIES

• Recall, after oxygen enters through your mouth/nose and
eventually gets to either your left or right lungs, it will
enter the alveoli. What happens then? ————————>
• The O 2 molecules leaves the alveolus lumen and enters a layer of fluid lining before passing
through into the epithelial cells of the alveolus.
• After leaving the epithelial cells, O 2 encounters the basement membrane of the alveolus (which
provides support), a thicker layer of connective tissue (more structural support), and then a 2nd
basement membrane.
• After passing through the basement membrane of the capillary, O 2 goes through the endothelial
cells of the capillary wall and finally enters the lumen, where it can bind to a red blood cell (at 1
of 4 spots).
• Note: all these layers are basically liquid, and are made of mostly water… so O 2 goes from gas
phase and must diffuse across lots of liquid before reaching the capillary.
• Fick’s law can be used here to figure out the amount of O 2 diffusing over time.
• P1 of this equation can be found from the alveolar gas equation, which takes into account the
percent of O 2 in the air they’re breathing, atmospheric pressure, P H20 , and more.
• Area can be affected by how effectively a person’s alveoli is
working; if half don't work then not as much O 2 can get across.
• Thickness is also very important — if the amount of fluid in the
layer increases (such as with infection), then the O 2 that can get
across will be lower
• Diffusion constant will stay the same, though.
• Basically, if a person is not getting enough oxygen, there could be many factors affecting the
problem.

THE RESPIRATORY CENTER

• The respiratory center of the brain is in the brain stem. There are two clustered areas in the
respiratory center, with neurons that communicate between them.
• Respiratory gathers information from different places and executes commands (such as how fast
and how deep you breathe) based on that info
• Central and Peripheral chemoreceptors send info on different chemicals to the respiratory
center.
• Central chemoreceptors are adjacent to the respiratory center. They gather info on CO 2
levels, pH (but not O 2 levels) and send it to the respiratory center for processing.
• Peripheral chemoreceptors (outside the brain) detect O 2 levels as well as CO 2 and pH. These
include CN 9 (glossopharngeal) nerve from the carotid body chemoreceptor, and CN 10 (vagus
nerve) from the aortic body — which send their info through nerves into the brain.
• Mechanoreceptors send information about pressure to the respiratory center.
ORGAN SYSTEMS 52
• Mechanoreceptors are found all over, in the lungs, nose, GI tract, etc; and they send their
information through a bunch of different pathways.
• Those in the lungs and GI hitch a ride on the vagus nerve, while the one in the nose
connects to the respiratory center via CN 5 (trigeminal nerve).
• Ex: If you inhale some pollen, that will trigger the mechanoreceptor in your lung, which will
send info through CN 5 to trigger a response from the respiratory center.
• Ex: Lungs have smoke receptors, stretch receptors, and more.
• Hypothalamus also sends information to the respiratory center — things like fear which may
trigger a change in breathing.
• The cerebrum — which controls all voluntary actions including things like yelling, or singing,
where you would need to control your breath — also sends info to the respiratory center.
• What does the respiratory center do with all this information? It executes changes in breathing
by controlling different muscles through motor nerves in the spinal cord:
Motor nerves Muscles
• C1 – C3 • accessory muscles
• C3 – C5 • diaphragm
• T1 – T11 • intercostal muscles
• T6 – L1 • abdominal muscles

THERMOREGULATION IN THE LUNGS

• Humans lose heat by sweating and also by, like furry animals, taking in cool air and expelling hot
air.
• When we inhale cool air, it enters into the lungs and alveoli, and will equilibrate with the
temperature of the blood that's passing by the capillaries.
• The air we exhale will thus be about our internal body temperature, 98.6 ºF.
• This coincides well with oxygen — because we’ll need to breathe more heavily to
thermoregulate from the heat of exercising, but we also need more oxygen, which breathing
heavily will allow us to get!

CONSIDER:
• Two ‘broad’ categories must be considered which may affect hemoglobin saturation: 1. Is there
enough oxygen present to saturate the hemoglobin, and 2. physiological factors which affect Hb’s
oxygen affinity.
• An increase in temperature, pCO2, 2,3-BPG concentration, or a decrease in pH will decrease
O2 affinity.
• If the pO2 in the afferent capillary is low (the capillary coming TO the alveoli), concentration
gradients will favor greater diffusion of oxygen into the vessel, thereby increasing the amount
of oxygen available to bind.
• Factors affecting gas diffusion into the capillaries include wall thickness, wall surface area,
partial pressure difference, and the ventilation-perfusion ratio.
• The longer blood ‘hangs around’ in the alveolar capillaries, the longer the hemoglobin has to
recruit oxygen. If blood is flowing too quickly for ventilation to match it, the hemoglobin
saturation will decrease.
• Many respiratory diseases affect pulmonary function by altering the ability of alveoli to
participate in gas exchange. What physical change would most greatly reduce the degree to
which a particular alveolus is ventilated?
ORGAN SYSTEMS 53
• Ventilation would be decreased in any setting which does not allow adequate airflow,
including obstruction and structural/mechanical changes to the lung which prevent alveolar
filling.
• Increased pressure within an alveolus would prevent airflow into the alveolar space.
• Gas pressure is increased with increasing temperature and decreasing container volume.
• Increased elastic recoil of the alveolar wall would increase the inward force of the wall on the
gas as the wall tried to collapse, which would increase the pressure of gases within an
alveolus, which would hinder airflow into the space. This would most greatly reduce
ventilation of an alveolus.

————————————————Lymphatic System—————————————
———
WHAT IS THE LYMPHATIC SYSTEM:
• High pressure in blood vessels forces fluid out through the endothelial cells (particularly in
capillaries).
• Big particles like red blood cells cannot get out, but other fluid (water, small proteins) then
accumulates extracellularly around the capillaries.
• The lymphatic system is just another plumbing system — made of vessels that sort of start in the
middle of nowhere and collect the accumulated fluid, and then bring it back into the blood.
• Unlike blood vessels, the lymphatic system is not a closed loop. It starts at the lymph region,
where fluid is collected, and then ends where it reenters the blood vessel to deposit said fluid.
• Shortly after the lymph region, after some fluid has left the vessels, the capillary vessel is left
with a higher concentration of red blood cells and solutes than the extracellular space with the
lymph fluid.
• Consequently, some fluid actually flows back into the capillaries.
• This is because of this concentration gradient (aka this increase in osmotic pressure pushing
fluid into the vessels), as well as the fact that the overall hydrostatic pressure in capillaries is
lower here compared to earlier.
• Overall, though, more fluid still goes out than comes in — so the net result is lymph squeezed
out.
• Why don’t these cells just tighten up connections to prevent things from getting out? Well, the
cells around the blood vessel need the nutrients (glucose, etc.) and they get that from the lymph.
The lymphatic system also has important immune system and circulatory (for fats/proteins)
functions.
• Lymph vessels are all over your body, and are similar to capillaries / blood vessels in that
different branches come together to eventually dump all the lymph back into circulation.

HOW LYMPHATIC VESSELS MOVE FLUID:

• How can lymphatic vessels pump all the fluid up your body in one direction? How do they pump
it back into the high pressure system? Two answers:
• (1) Location of re-entery — The lymph vessel re-enters the blood at the very end of the
venous system, which has about the lowest pressure of anywhere in your body. (120 mmHg
in arteries out of your heart, ~5 mmHg where lymphatic vessels reenter.)
• (2) One-way valves — Within the lymph vessels, valve structures prevent fluid from moving
in the opposite direction.
• But how does motion begin?
ORGAN SYSTEMS 54
• a) Smooth muscle at the beginning of the lymph system — small contraction of this pushes
fluid on
• b) Skeletal muscle throughout the body — the natural movement / contraction of our
muscles throughout the day is bound to affect some nearby lymph vessels, helps push fluid on
its way.
• Lymph vessel starts at what looks like closed ends, but they’re very porous — these ends sort of
act like valves themselves, allowing fluid to enter, but (when pressure builds up), these ends
prevent fluid from going out.
• Lymph re-enters the circulatory system at subclavian veins, which are right near the superior
vena cava.

LYMPHATIC SYSTEM’S ROLE IN IMMUNITY:

• Infection is when your body gets attacked by a foreign invader, e.g. bacteria or virus.
• Infections aren’t usually in the blood itself, but in the tissues around it (proof: infections stay
localized; if it was in your blood it would go all over the body)
• Local immune cells called macrophages fight the bacteria present in that tissue area, but the body
also pulls in more powerful T-cells and B-cells that react to the specific invader. Problem: These
immune cells aren’t just sitting around everywhere.
• In order for them to specialize, a special environment is required that can’t occur in the
tissues where any bacteria may enter. So how do we get B and T-cells to see the bacteria and
react to them? Lymphatic system!
• Any bacteria present in the tissue, as well as some macrophages that may have gobbled up the
bacteria are swept into the lymphatic vessel along with fluid. It takes them to the lymph node,
where B and T-cells are stored. There, those immune cells will basically ready themselves to fight
the specific bacteria.
• The lymph vessel also continues on after the nodes — so a side effect of the lymph system is that
it basically filters the fluid / blood in the body. If bacteria were to flow through the lymphatic
system and then deposit bacteria at the subclavian veins, it could infect the blood and get all over
the body.
• Lymph nodes are very small, and not considered organs. There are about 600 of them in the
body, and some are so close to the skin you can feel them (particularly those between the thigh
and abdomen, and along your clavicle / neck).
• Any lymph coming out of any tissue in your body will pass through at least one lymph node
before depositing back into the blood.

LIPID AND PROTEIN TRANSPORT IN THE LYMPHATIC SYSTEM:

• We know lymphatic system aids in fluid collection and deposit, as well as in immunity. A third
function is in the transport of important molecules from digestions . . .
• Consider the small intestine, which carries food (glucose, fats, etc) that the body needs for
energy.
• Glucose diffuses into the cells lining the small intestine, and then is pumped out, where it can
then diffuse into the capillaries.
• Fatty acid chains are pumped into the cells of the small intestine’s wall, where they are
packaged and exit as chylomicrons — those are too big to diffuse into capillaries.
• The lymphatic vessels in the small intestine, called lacteal, allow chylomicrons to diffuse in, travel
through the lymphatic system, and be deposited back into the circulatory system.
• A little further away from the small intestine, you may have other cells proteins, waste products,
etc. that have difficulty entering the capillaries. But the body needs them in blood circulation so it
ORGAN SYSTEMS 55
can deposit the hormones (or whatever) where needed, deposit waste products in the liver /
kidneys, etc.
• So these peptides and waste products and other necessary molecules that are too big to enter
the capillaries will be picked up by the lymphatic system!
• They, too, will eventually be deposited back into the circulatory system at the subclavian
vein.
• Lymph from the lower body, the left arm, and the left side of the head drains into the circulation
via the largest lymph vessel, the thoracic duct. Lymph from the right arm drains into circulation
via the right lymphatic duct. These ducts then enter systemic circulation at the junction of the left
(or right) subclavian vein and the jugular vein.

WHAT IS ACTUALLY IN LYMPH:

• Note: lymph is only called lymph once it enters the lymphatic system; before that its just
extracellular fluid — the makeup is basically the same, though.
• We know that lymph comes from blood vessels originally; it’s the fluid squeezed out between the
cells in the capillaries. But blood has a lot of different molecules in it (~45% red blood cells,
water, proteins of varying sizes, etc.)
• Lymph has 0% red blood cells, and only about 1/2 – 1/3 the amount of protein as blood does
(you might think the percentage is more, but water diffuses out much more easily than proteins,
thus diluting any proteins present in lymph.)
• Note: this 1/2 - 1/3 ratio is just an average — really, concentrations differ throughout
different branches of the lymph system. Ex: liver makes a lot of proteins, so the lyphatic
vessels around it will have a much higher concentration of protein than elsewhere in the
system. Similarly, the concentration of fats in the lacteal (small intestine area) part of the
lymphatic system is going to be much higher there than elsewhere.
• Smaller proteins also have an easier time getting out of the blood vessels and into lymph. The
ratio of small protein (albumin, e.g.) to big protein (like immunoglobin) is greater in the lymph
that in the blood, even if you have more albumin molecules in the blood.
• Why is it important there be less protein in the lymph? Recall, some fluid goes back into the
blood vessel after it exits in capillaries, instead of being absorbed by the lymph. This is because
of a higher osmotic pressure pulling fluid back in because there’s more protein in the blood than
in the lymph.
• About 3L of net lymph is produced in a day! (much more is initially squeezed out, then reenters.)
————————————————Immune System——————————————
——
INNATE / NONSPECIFIC IMMUNITY:
• Immune system has two lines of (nonspecific or innate) defense:
• first: Keep pathogens out — skin (and oils on the skin), mucous membranes, acidic stomach
acid
• second: If pathogens enter, kill them to prevent widespread infection. — inflammatory
response (brings blood and fighter cells to site of infection), phagocytes, white blood cells.
• Phagocytes are a class of cell that can eat up other things, most namely pathogens.
• It has receptors that respond to foreign things. Once the pathogen binds to these receptors, it
is engulfed by the the phagocyte and enters the cell in a vesicle called a phagosome.
• Then other vesicles that contain things that can destroy phagosomes (such as lysosome,
reactive oxygen species) then merge with the phagosome and break up the pathogen.
ORGAN SYSTEMS 56
• Some of those constituent molecules of the consumed pathogen are then taken and attached to
other proteins, in phagocytes its the major histocompatability complex type II, and presented
onto the membrane surface of the phagocyte.
• These antigens are crucial to our immune system, because they allow specific immune cells to
know what is in the body and to come up with a specific response to that threat. Thus many
phagocytes are also called antigen presenting cells.
There are many types of white blood cells, aka leukocytes, some of which are also phagocytes:
• Neutrophils (most common; fast and abundant) — phagocytic cells that are also classified as
granulocytes because they contain granules in their cytoplasm. These granules are very toxic to
bacteria and fungi, and cause them to stop proliferating or die on contact
• Macrophages
• Mast Cells — important for wound healing & defense against pathogens via inflammatory
response.
• Found in mucous membranes and connective tissues
• When activated, they release cytokines and granules that contain chemical molecules to
create an inflammatory cascade. Mediators, such as histamine, cause blood vessels to dilate,
increasing blood flow and cell trafficking to the area of infection.
• Cytokines released during this process act as a messenger service, alerting other immune
cells, like neutrophils and macrophages, to make their way to the area of infection, or to be on
alert for circulating threats.
• Eosinophils — granulocytes that target multicellular parasites. They secrete a range of highly
toxic proteins and free radicals that kill bacteria and parasites. Can also phagocytose.
• use of toxic proteins & free radicals also causes tissue damage during allergic reactions, so
activation and toxin release by eosinophils is highly regulated to prevent unnecessary
damage.
• found in many locations, including the thymus, lower gastrointestinal tract, ovaries, uterus,
spleen, and lymph nodes.
• Basophils — also granulocytes that attack multicellular parasites. They release histamine like
mast cells. The use of histamine makes basophils and mast cells key players in mounting an
allergic response.
• Natural Killer cells (NK cells) — do not directly attack pathogens, but instead destroy infected
host cells in order to stop the spread of an infection. Infected or compromised host cells can
signal natural kill cells for destruction through the expression of specific receptors and antigen
presentation.
• Dendritic cells — antigen-presenting cells that are located in tissues, and can contact external
environments through the skin, the inner mucosal lining of the nose, lungs, stomach, and
intestines.
• Since dendritic cells are located in tissues that are common points for initial infection, they
identify threats & act as messengers for the rest of the immune system via antigen
presentation.
• These are most effective at eliciting adaptive immune response.

THE COMPLEMENT SYSTEM:

• Also called the complement cascade, this is a mechanism that complements other aspects of the
immune response. Typically, the complement system acts as a part of the innate immune system,
but it can work with the adaptive immune system if necessary.
ORGAN SYSTEMS 57
• The complement system is made of a variety of proteins that, when inactive, circulate in the
blood. When activated, these proteins come together to initiate the complement cascade, which
starts the following steps:
1. Opsonization: A process in which foreign particles are marked for phagocytosis. All of the
pathways require an antigen to signal that there is a threat present. Opsonization tags infected
cells and identifies circulating pathogens expressing the same antigens.
2. Chemotaxis: The attraction and movement of macrophages to a chemical signal. Chemotaxis
uses cytokines and chemokines to attract macrophages and neutrophils to the site of infection,
ensuring that pathogens in the area will be destroyed. By bringing immune cells to an area
with identified pathogens, it improves the likelihood that the threats will be destroyed and
infection will be treated.
3. Cell Lysis: The breaking down or destruction of the membrane of a cell. The proteins of the
complement system puncture the membranes of foreign cells, destroying the integrity of the
pathogen. Destroying the membrane of foreign cells or pathogens weakens their ability to
proliferate, and helps to stop the spread of infection.
4. Agglutination: Agglutination uses antibodies to cluster and bind pathogens together. By
bringing as many pathogens together in the same area, the cells of the immune system can
mount an attack and weaken the infection. Other innate immune system cells continue to
circulate throughout the body in order to track down any other pathogens that have not been
clustered and bound for destruction.

ADAPTIVE IMMUNE RESPONSE: HUMORAL VS. CELL-MEDIATED:

• Unlike the innate immune system, which attacks only based on the identification of general
threats, adaptive immunity is activated by exposure to pathogens, and uses an immunological
memory to learn about the threat and enhance the immune response accordingly.
• The adaptive immune response (which uses B and T cells) is much slower to respond to
threats and infections than the innate immune response, which is primed and ready to fight
at all times.
• Lymphocytes (another type of leukocyte) can be divided into B lymphocytes and T lymphocytes.
• B-cells are produced in bone marrow. T-cells also start off in the bone marrow, but mature and
become what they are in the thymus.
• B-lymphocytes participate in the humoral response; while T-cells participate in cell-mediated
response (include helper T-cells).
• “Humoral” refers to the bodily fluids where these free-floating serum antibodies bind to
pathogens (before they infiltrate cells) and assist with elimination.
ORGAN SYSTEMS 58
• Someone who has never been exposed to a specific disease can gain humoral immunity
through administration of antibodies from someone who has been exposed, and survived the
same disease.
• “Cell-mediated” refers to the fact that the response is carried out by cytotoxic cells. Much like
humoral immunity, someone who has not been exposed to a specific disease can gain cell-
mediated immunity through the administration of T cells from someone that has been
exposed, and survived the same disease.

B-CELLS
• B-cells have many protein complexes on their surface (up to 10,000 of them!) called membrane
bound antibodies. (antibodies are also called immunoglobulins).
• Each B-cell has one type of membrane bound antibodies on it. There is a variable portion of
the antibody structure that is different between B-cells. There’s 1010 combinations of variable
portions!
• During development, potential self-responding combinations, for your own cells, are weeded
out.
• How do all these combinations arise if they come from the same B-cells with the same DNA? In
the development of the B-cells (hematopoesis), there’s a lot of intentional reshuffling of DNA that
codes for the different variable parts.
• These different combinations practically ensure that some B-cell will bind to a foreign
pathogen, even if it’s never been seen before. The part of the bacteria / pathogen it binds to is
the epitope.
• As soon as one of these epitopes are bound, the B-cell becomes activated (though in order to
really become activated, helper T-cells are needed), and starts cloning himself, repeatedly!
• When the specific B-cell divides over and over, the daughter cells start to differentiate. They
become:
• Memory cells — these cells stick around a long time, with the perfect variable receptor on them
(these are in higher quantities than the original B-cell, so if this pathogen ever re-enters, there
are more specific B-cells to recognize it.)
• Effector cells — These turn into antibody factories; they start spitting out tons and tons of the
variable proteins that can uniquely bind to the infecting pathogens. When these antibodies bind,
they:
ORGAN SYSTEMS 59
• (a) Cause opsonization: tag pathogens for pick up, make it easier for phagocytes to identify /
engulf
• (b) Might make it harder for the pathogen to function — viruses, e.g., won’t be able to enter a
host cell as easily with a big antibody hanging off of it.
• (c) Can join pathogens together — on each antibody is two identical heavy chains and two
identical light chains, with a specific variable portion on each one. Each of these branches can
bind to the epitome, so one branch may bind to one virus, and another to a second virus,
effectively joining them (which makes it harder for the viruses to infect, and easier for the
phagocytes to identify.
• The T H cells act to activate other immune cells, while the T C cells assist with the elimination of
pathogens and infected host cells.

SOME VOCABULARY:
• Self — particles, such as proteins and other molecules, that are a part of, or made by, your body.
They can be found circulating in your blood or attached to different tissues.
• Something that is self should not be targeted and destroyed by the immune system.
• The non-reactivity of the immune system to self particles is called tolerance.
• Non-self — particles that are not made by your body, and are recognized as potentially harmful
(aka foreign bodies). Non-self particles can be bacteria, viruses, parasites, pollen, dust, and toxic
chemicals.
• The non-self particles and foreign bodies that are infectious or pathogenic, like bacteria,
viruses, and parasites, make proteins called antigens that allow the human body to know that
they intend to cause damage.
• Antigens — anything that causes an immune response. Can be entire pathogens, like bacteria,
viruses, fungi, and parasites; or smaller proteins that pathogens express.
• Antigens are like a name tag for each pathogen that announce the pathogens’ presence to
your immune system. Some pathogens are general, whereas others are very specific.
• A general antigen would announce “I’m dangerous”, whereas a specific antigen would
announce “I’m a bacteria that will cause an infection in your gastrointestinal tract” or “I’m the
influenza virus”.
• Cytokines — molecules that are used for cell signaling, or cell-to-cell communication. Cytokines
are similar to chemokines, wherein they can be used to communicate with neighboring or distant
cells about initiating an immune response.
• Cytokines are also used to trigger cell trafficking, or movement, to a specific area of the body.
• Chemokines are a type of cytokines that are released by infected cells. Infected host cells
release chemokines in order to initiate an immune response, and to warn neighboring cells of
the threat.

PROFESSIONAL ANTIGEN PRESENTING CELLS (APC) AND MHC II COMPLEXES:

• Recall, that when a phagocyte engulfs a pathogen, they take some of digested pieces of it and
attach it to the major histocompatability complex type II, then present this onto the phagocyte’s
membrane.
• A very similar process happens in B-cells, which have certain variable ends on membrane-bound
antibodies that are specific to the epitomes of certain pathogens.
• After a specific pathogen binds to a specific B-cell, it gets engulfed, which starts the activation
process. The B-cell then proliferates itself and activates (usually with helper T-cells) into
memory cells and plasma / effector cells that produce lots of antibodies
ORGAN SYSTEMS 60
• The B-cell will also take pieces of the broken down pathogen, attach them to MHC II proteins,
and present them on their membrane.
• Cells that use MHC II to present bits of pathogen are called professional antigen presenting cells,
this includes phagocytes and B-cells.

HELPER T CELLS:
• Adaptive immune system has humoral response (pathogens floating around) & cell-mediated
response
• B-cells are humoral response; T-cells are involved in cell mediated response
• T-cells mature in the thymus. We’ll focus on two types of T-cells: helper and cytotoxic
• When activated, helper T-cells sound an alarm to generate antibodies, which go on to disable
a specific pathogen (that is still floating around, not in cells)
• Cytotoxic T-cells attack cells that have been infiltrated (or are abnormal in some way, like
cancer cells) and kill them to prevent spread of the pathogen / cancer.
• Once an antigen is presented on a macrophage or a B-cell, the helper T-cell recognizes it.
• Let’s say we have a dendritic cell (phagocyte) and it’s already consumed a pathogen and put an
antigen from it on an MHC II complex on its membrane.
• The helper T-cell has a T-cell receptor on it that bonds to the MHC II + antigen complex. Just
like the B-cell, this T-cell receptor has a variable portion, so different T-cells are specific to
certain MHC II complexes and certain parts of the pathogen.
• Once the T-cell identifies and bonds its receptor to the MHC II complex, it is activated.
• Note: Dendritic cells are actually the best at activating helper T-cells, especially naive helper T-
cells (means they’re non-memory, non-effector and have never been activated nor had anything
bound to it).
• When a helper T-cell is activated, it divides into many many copies, and starts to differentiate
into:
• (1) memory T-cells: Like memory B-cells, these stay around for many years in case the
pathogen returns. They have the same receptor as their parent, but last much longer.
• (2) effector T-cells: These release cytokines. There are many types of cytokines (which are
peptides), but they all essentially raise the alarm of the immune system. When cytokines
enter other immune system cells, it makes them multiply or strengthen their immune
response.
• This is a central role, tells both activated cytotoxic T-cells to get in gear, and activated B-
cells.
• The effector T-cells also activate the B-cells (for the same species of virus) so they start
proliferating and differentiating. The variable portion of the T-cell connects to the same
specific virus as the B-cell that engulfed the pathogen; the combination of antigen + MHC
II is the same.
• That combination is usually what activates the B cell and allows it to divide and
differentiate.
• Why do we have this double system? A fail safe mechanism… The likelihood of both the T-cell
and B-cell having the same variable receptor + MHC II for a specific pathogen is very small; this
prevents lymphocytes from accidentally mutating a receptor / trying to kill one of your own
cells.

CYTOTOXIC T CELLS:
• Recall, antigen presenting cells (like various phagocytes, B-cells) present pieces of a pathogen
they’ve consumed from the humoral space just floating around on their membrane with MHC II.
ORGAN SYSTEMS 61
• All nucleated cells in the human body have another major histocompatibility complex type I, or
MHC I
• even cells with MHC II also have this
• Because it’s on pretty much every cell (except RBCs), any cell in the human body that has
wacky stuff going on (cancerous cells, or ones that have been taken over by a virus), will take
parts of those proteins (from the cancer cell, virus, etc.) and present them on MHC I.
• Helper T-cells (with the correct variable portion) bond to MHC II complexes, get activated, divide
and differentiated, and effect a specialized immune response to them.
• Cytotoxic T-cells bond with MHC I complexes (also with a specific variable portion), get
activated, and differentiates and divide. Like the other T-cells, these differentiate into
• memory: stick around in case this mutation / cancer / pathogen shows up again
• effector: go on to kill any infected / mutated cells with that specific MHC I complex they
recognize
• effector cytotoxic T-cells work by exocytosing perforin proteins that make holes in the
membrane of the infected cell, or releasing granzymes that induce mechanisms for cell
death.

REVIEW OF B CELLS, CD4+ T CELLS, CD48+ T CELLS:

• B-cells — each one has uniquely specific membrane bound antibodies (bc of unique variable
portion)
• For activation, the B-cell needs binding of a pathogen /antigen on to its antibody and helper
T-cell stimulation. (helper T-cells come in because B-cell consumes the pathogen and
presents a piece of it on an MHC II complex, which the helper T-cell recognizes)
• Once activated, the B-cell starts dividing and differentiating into memory cells (so there’s
more of this variable receptor / a faster response if this pathogen were to return), and
effector B-cells (which basically turn into antibody making machines — these are commonly
called plasma cells).
• The antibodies made from these plasma cells then go around and kill or impede growth of
those specific pathogens floating around, tag them for pickup from macrophages, etc.
• T-cells — two main types. All have T-cell receptors, and either CD4 receptors or CD8 receptors.
• Unlike antibodies, which can bind to pathogens directly, T-cell receptors can only recognize
antigens that are bound to MHC I or MHC II membrane surface receptor molecules.
• The CD4 receptor helps bind the MHC II complexes; so most CD4+ T cells are helper T cells.
Likewise, CD8+ T-cells bind to MHC I complexes, so most CD8+ T-cells are cytotoxic.
• Recall, every nucleated cell can present antigens on MHC I complexes, the CD8 protein
recognizes that and kills infected / “bad” cells.
• And CD4 proteins bind to MHC II complexes that have bits of pathogens on them.
• When these T-cells get activated, they divide and differentiate into effector and memory cells
• effector [CD4] helper T-cells can activate B-cells, and also releases cytokines — alarm
bells that tell other immune cells to get in gear.
• effector [CD8] cytotoxic T-cells kills cells with the specific MHC I complex on them
• memory CD4 and CD8 T-cells stick around in case that specific pathogen / cancerous
mutation comes up again.

CLONAL SELECTION: How are the B and T cells prepared to fight infection?
(1) They are made, and are very specific.
• B-cells divide and form millions of descendants in the bone marrow.
ORGAN SYSTEMS 62
• Unlike other parts of the body, each daughter cell that grows up is different from its parents
and all of the other daughter cells, because each daughter cell has a different / unique
receptor (which eventually becomes their antibody). This is because in the process of being
made, there’s a shuffling of DNA that codes for this variable receptor.
• T-cells divide and form millions of descendants in the thymus, which has 2 lobes and is located
behind the sternum. Similar to B-cells, they have a unique receptor. Each daughter T-cell also has
a unique receptor that identifies a unique antigen.
• So we end up with many many genetically different T-cells and B-cells that are responsive to
many things that may or may not even exist, because the creation of the variable receptor piece
is sort of random. After this, the B- and T-cells go to the lymph nodes.
• In the lymph nodes, the B and T cells are essentially just waiting for that specific pathogen, which
they can identify, to enter the body.
(2) They recognize a specific invader
• Let’s say a part of tissue gets infected. Dendritic cells engulf and digest them, and present the
antigen from it on their membrane with MHC II. They, along with some of the bacteria, get swept
into the lymph system and eventually end up in the lymph nodes.
• In the lymph nodes, only the specific T-cells, which can recognize the very specific pathogen
on the dendritic cell (or other antigen presenting cells), will bind to the antigen and become
activated.
• B-cells react directly to the specific bacteria, not to antigen presenting cells, by binding with
their antibody.
• None of the other B and T-cells do anything about the infection because they can’t bind to
these specific pathogens that were brought into the lymph node.
• (3) After binding their antigen, the B and T cells jump into action, replicating like crazy,
differentiating into effector / memory cells, etc. and do their thing.
• This process is called clonal selection (because the B and T cells select specific antigens and then
clone themselves to respond.
SELF VS. NON-SELF IMMUNITY:
• How does your immune system know not to attack itself? How does it distinguish foreigners?
• This answer is not always obvious. Think back to the B-cell and its receptor antibodies, which
bind to foreign pathogens (specific receptors for specific pathogens — those are generated at
random).
• The fact that the variable receptors are created at random means they might create an
antibody that reacts to something important in your own body.
• There’s no way to keep the B-cell from creating antibodies that would react to yourself, so we
need to figure out the self-antibodies are and kill them. (This is applicable for both T and B cells,
of course.)
• In the bone marrow is where B cells get their unique (randomized) receptor. How can we figure
out if a B-cell has an antibody that reacts to self (e.g. say it reacts to insulin)? Keep around
various proteins your body uses in the bone marrow that the body uses while these B-cells are
being vetted.
• Your body can then respond and kill any B-cell that binds to anything while still in the bone
marrow. [ex: you’ll have a little bit of insulin, hemoglobin, etc. floating around in the bone
marrow and one B-cell with a randomized variable receptor might recognize and binds to
that insulin. As a result, that B-cell dies.]
• A similar process happens for T-cells in the thymus.
• In order to make sure T cells will perform properly once they have matured and have been
released from the thymus, they undergo two selection processes:
ORGAN SYSTEMS 63
• Positive selection ensures MHC restriction by testing the ability of MHCI and MHCII to
distinguish between self and nonself proteins. In order to pass the positive selection process,
cells must be capable of binding only self-MHC molecules. If these cells bind nonself
molecules instead of self-MHC molecules, they fail the positive selection process and are
eliminated by apoptosis.
• Negative selection tests for self tolerance. Negative selection tests the binding capabilities of
CD4 and CD8 specifically. The ideal example of self tolerance is when a T cell will only bind to
self-MHC molecules presenting a foreign antigen. If a T cell binds, via CD4 or CD8, a self-MHC
molecule that isn’t presenting an antigen, or a self-MHC molecule that presenting a self-
antigen, it will fail negative selection and be eliminated by apoptosis.
• After positive and negative selection, we are left with three types of mature T cells: Helper T cells
(T H ), Cytotoxic T cells (T C ), and T regulatory cells (T reg )
• Helper T cells express CD4, and help with the activation of T C , B cells, and other immune cells.
• Cytotoxic T cells express CD8, and are responsible for removing pathogens and infected host
cells.
• T regulatory cells express CD4 and another receptor, called CD25. T regulatory cells help
distinguish between self & nonself molecules, and by doing so, reduce risk of autoimmune
diseases.
• The B-cells and T-cells that have been vetted can go on to a lymph node or somewhere where it
waits to recognize pathogens.
• Sometimes, a B cell that reacts to self will escape, though. (Maybe you don’t have all the possible
proteins in your bone marrow / thymus, maybe the body made a mistake, whatever).
• When this happens, that B-cell will find the protein it was made to react with (which is a part
of your own system), bind to it, ingest it, and present a piece of it on an MHC II complex. It
then needs a T-cell with the same receptor to come along that will recognize the same piece
in order to activate.
• Without that T-cell, nothing will really happen. So even if a B cell escapes, unless a T-cell with
the same specific receptor has also escaped (which is even more unlikely, of course), there’s
not an issue.
Ways it can go wrong:
• What if bacteria got into the bone marrow? The B-cell will bind to it and be killed as if it
responded to self — thus it wont’ get out into the lymph system to trigger immune response to
that bacteria.
• Not too much of an issue, because even if you have bacterium in the bone marrow for a
couple weeks or a month, it will eventually go away and your bone marrow can make those
specific antibodied B-cells again. (and hopefully you already had some B-cells for that
pathogen in your lymph nodes).
• When the process goes wrong, you get an autoimmune disease, where the body attacks itself.
• Ex: Myasthenia Gravis:
• Muscle fibers have receptors on them that receive neural stimulation to activate/contract the
fiber.
• In myasthenia gravis, you develop antibodies against that muscle receptor. When those
antibodies bind, it either stops the muscle fiber from functioning or destroys the receptor. So
it’s harder for muscles to contract and be stimulated. You slowly become paralyzed.

HOW WHITE BLOOD CELLS MOVE AROUND:

• Neutrophils circulate in the blood, but only do their work in the tissues at the site of an infection.
ORGAN SYSTEMS 64
• How do they know where to squeeze out of the blood vessels into tissues?
• Macrophages at the site of infection will gobble up bacteria and release chemical signals that
tell endothelial cells of a nearby blood vessel that there’s an infection there.
• As a result, the endothelial cells express proteins that stick to the neutrophils. And then,
because they’re stuck, the neutrophils squeeze through endothelial cells in an active process.
In the tissue, they phagocytose the bacteria and then die. (When they die neutrophils become
pus.)
• Immune cells only ever cross from the blood into the tissue; it’s impossible for them to go the
other way. To enter circulation (such as for macrophages to present antigens to T and B cells),
they must enter the lymphatic vessel and go to the lymph nodes. In the lymph node is antigen
presentation, which causes B and T cells to activate and go to the side of the infection. How do
they get there?
• The activated T cells enter the thoracic duct (final, fat lymphatic vessel) and eventually drain
back into the blood. Once in circulation, those cells act similarly to neutrophils; they can see from
endothelial proteins where the infection is, and then squeeze out between cells to fight bacteria
in the tissue.
• B cells don’t really need to be in the tissue, though, so they mostly hang out in the lymph nodes.
Their job is to release antibodies that can float around the body themselves and go to the
infection site on their own.

BLOOD CELLS LINEAGES

• In the blood vessels, you have about 10 different kinds of blood cells, from RBCs to T-cels, to B-
cells, to platelets, and more… where do they all come from? Bone marrow! Specifically from the
heads of long bones and from different flat bones (like the sternum) throughout the body.
• All blood cells have a single precursor: a pluripotent hematopoietic stem cell
• This pluripotent cell gives rise to two different lineages: myeloid and lymphoid
• Myeloid lineage yields red blood cells and megakaryocytes (from which platelets are made), as
well as mast cells (which release histamines in allergic reactions)
• The myeloid lineage also yields monocytes,
which then become macrophages (part of the
immune system) when they settle in the tissues.
• This monocyte lineage also yields three
other types of cells: neutrophils (most
common immune cell), eosinophils,
and basophils.
• Lymphoid lineage yields B-cells (which
make antibodies), T-cells, and
“natural killer” cells.
• Dendritic cells can come from either
lymphoid or myeloid (monocyte) lineages.
—————————————————Renal System———————————————
——
KIDNEY FUNCTION AND ANATOMY
• Humans have 2 kidneys, each about the size of a fist, that sit around the midsection
(closer to the back than the front of the body).
• Kidneys receive blood from the heart (over a liter per minute!), filter it and reabsorb
what is needed, then produce urine with the waste products to expel from the body.
ORGAN SYSTEMS 65
• Kidneys can hold about 22% of your whole body’s blood supply!
• Each kidney has an oxygenated blood vessel (renal artery) and a renal vein.
• The artery holds onto everything in the blood, from nutrients (Na+ ions, AA,
glucose, etc.) to oxygen, to waste products (urea, toxins, extra electrolytes like
Na+ that we don’t need, etc). — Note: if you have too much of a nutrient, it becomes waste
product.
• The vein then takes filtered blood, which still has the nutrients and some (but less) oxygen, away.
• Kidneys are critically important in maintaining homeostasis by regulating pH level (via H+ ions),
blood pressure (via Na+ and Cl- ions), as well as osmolarity and expulsion of waste. It also makes
hormones!
• How is it that the kidneys do this? Each kidney has two capillary beds:
• The Vasa Recta delivers O 2 to kidney tissue
• The Peritubular Capillaries recollect nutrients
to filter and then return via the veins.
• Two main functions of the kidney: filtration (gets
rid of waste products) and collection of those waste
products into the urine.
• The nephron is the functional unit of a kidney
— it’s responsible for both functions.
• The nephron is situated in both renal cortex
(the outside area / shell of the kidney) and the
renal medulla (middle area).. It sort of dances
between the cortex and medulla and where it
is determines what role it’s playing: reabsorption
of nutrients or collection of waste.
• The nephron part that’s situated in the renal medulla is called the renal calyx (plural: calyces). This is
the first part where urine is present.
• The renal pelvis is a central area where all the calyces collect together.
• Urine exits the kidney through the ureter off the renal pelvis and sends it into the bladder.
• For any organ with “tubes” (artery, vein, and ureter in this case), the tubes are collectively known
as the hilum.

THE KIDNEY AND THE NEPHRON — OVERVIEW OF THE FILTRATION PROCESS

• Each kidney contains around a million nephrons!
• The blood enters the kidney through the afferent arterial, goes into a windy place called the
glomerulus, and leaves through the efferent arterial.
• Kidneys have two arteries, in contrast to other capillary systems where blood enters by an artery
and leaves by a vein. This maintains necessary pressure.
• The glomerulus is surrounded by a structure called the Bowman’s
capsule, which has many cells called podacytes.
• When blood enters the glomerulus, about a fifth of it goes into the
Bowmans’ space. This fluid is the filtrate, & contains things that are
ORGAN SYSTEMS 66
easily dissolved (ex: Na+, glucose, amino acids, etc.). Things that do
not dissolve easily (ex: RBCs) aren’t filtered into Bowman’s space.
• Bowman’s capsule is sort of the beginning of the nephron. From there, the filtrate enters the
proximal tubule (this has a convoluted part, then becomes straight), where important nutrients
are reabsorbed.
[ATP is used to pump out Na+, which helps bring in other things.]
• Close to the cells that line the proximal tubule is another capillary system that pumps blood that
doesn’t go into the filtrate (and a little water from the filtrate) back to the body.
• After the proximal tubule, the blood enters the Loop of Henle. This section makes up most of the
nephron, and extends into both the renal cortex and the renal medulla.
• One function of the loop of Henle is to make the renal medulla space salty, or hypertonic, by
actively pumping out salts (Na+, K+, Cl-, etc). It uses ATP to do this.
• The ascending part of the Loop is only permeable to salts, whereas the descending part is
only permeable to water.
• The descending part is thus where H 2 O molecules diffuse out; that’s where/how a lot of our
water that is initially filtered out in the Bowman’s space is gained back. (This explains why
the loop of Henle is so long, to allow enough H 2 O to diffuse out… see countercurrent mult.
section for more)
• After the Loop of Henle, our blood reaches the distal convoluted tubule, which actually loops
around close to the Bowman’s capsule again. This is where more nutrients (& a bit more water)
are reabsorbed.
• After going through the distal tubule, our filtrate has been processed. A lot of the water has been
taken out / reabsorbed (so the filtrate is more concentrated), and we’ve reabsorbed the
nutrients we don’t want to lose. It’s now mainly waste products and water we don’t need any
more.
• This processed filtrate is then dumped into collecting ducts, which go back down to the
medulla.
• Anti-diuretic hormones dictate how porous the collecting duct is.. if it’s more porous then we
lose more water from the filtrate into the medulla (b/c of concentration gradient). This
makes the filtrate even more concentrated.
• Eventually, the collecting ducts dump this concentrated filtrate into the ureter, where it exits the
kidney.
• Main substances excreted in urine are:
• Metabolic waste products (e.g. urea, creatinine),
• Electrolytes —inorganic compounds (eg. sodium, potassium, calcium, chloride, and
bicarbonate) that your body uses to control the fluid content / levels inside your body fluids.
• Water
• Urine production is obligatory, it happens regardless of what is going on with your body because
of the need to remove various solutes in order to keep internal conditions stable and relatively
constant (homeostasis). This ensures that the body’s physiological processes continue operating
effectively.

GLOMERULAR FILTRATION IN THE NEPHRON — DETAILS

• The first step in making urine is for the glomerulus to separate the liquid part of your blood, from your
blood cells and turn it into filtrate, and then let the rest of the blood go on.
• Filtrate contains all sorts of ion and nutrients, basically anything that can be dissolved in water.
Things that cannot be dissolved in water, such as red blood cells, do not leave the capillary.
ORGAN SYSTEMS 67
• Blood that is about to be filtered enters the glomerulus, which is basically a tuft of blood capillaries.
• The glomerulus is nestled inside a cup-like sac located at the end of each nephron, called the
Bowman’s capsule, or the glomerular capsule.
• So, how does the Glomerulus capillary actually determine what is filtered and how much is filtered
into Bowman’s capsule? Capillary walls are made up of three layers of filtration:
• Endothelium - this has relatively large pores (aka fenestrations, 70-100 nm in diameter), which
solutes, plasma proteins and fluid can pass through, but not big things like red blood cells.
• Basement membrane - this membrane is also made up of three layers, and is fused to the
endothelial layer. Its job is to prevent plasma proteins from being filtered out of the bloodstream.
• Epithelium (Tubular cells) - this layer consists of
specialized cells called podocytes, which are attached
to the basement membrane by foot processes (pedicels)
• Podocytes wrap around the capillaries, but leave
slits between them, known as filtration slits.
• A thin diaphragm between the slits acts as a final
filtration barrier before the fluid enters the
glomerular space to the Bowman’s capsule.
• Together, the glomerulus and Bowman’s capsule filtering
unit are known as a renal corpuscle.
• In addition to the unique glomerular capillary bed, the
kidneys have other specialized capillaries called peritubular capillaries — tiny blood vessels that run
parallel to and surround the proximal and distal tubules of the nephron, as well as around the loop of
Henle, where they are known as the vasa recta.
• The vasa recta is important for countercurrent exchange, the process that concentrates urine.
ORGAN SYSTEMS 68

CHANGING GLOMERULAR FILTRATION RATE

• Recall that the glomerulus is sandwiched between two arterioles - afferent arterioles deliver blood to
the glomerulus, while efferent arterioles carry it away.
• This is unlike most capillary beds, which are are sandwiched between arterioles and venules rather
than two arterioles.. In those, the hydrostatic pressure usually drops as blood travels through the
capillary bed into the venules and veins.
• The constriction of efferent arterioles as blood exits the glomerulus provides resistance to blood flow,
preventing a pressure drop, which could not be achieved if blood were to flow into venules, which do
not really constrict. The two arterioles change in size to increase or decrease blood pressure in the
glomerulus.
• In addition, efferent arterioles are smaller in diameter than afferent arterioles… This means
pressurized blood enters the glomerulus through a relatively wide tube, but is forced to exit through
a narrower tube
• If diameter of efferent arteriole is bigger, filtration rate is lower. If diameter of efferent arteriole
is smaller, filtration is higher!
• These unique features (plus the heart supplying the kidneys with > 1L blood per min), maintain a
high glomerular capillary pressure filtration function, regardless of fluctuations in blood flow.
• Example: the sympathetic nervous system can stimulate the efferent arteriole to constrict even
during exercise when blood flow to the kidney is reduced.
• Example: In renal artery stenosis, we have a very narrow/stenosed renal artery, there is less blood
that runs across our capillaries and is filtered away.. there’s going to be some blood / nutrients
backed up, which is bad.
• Glomerular Filtration Rate = rate at which kidneys filter blood
• The main driving force for the filtering process, or outward pressure, is the blood pressure as it enters
the glomerulus. This is counteracted to some extent by inward pressure due to the hydrostatic pressure
of the fluid within the urinary space, and the pressure generated by the proteins left in the capillaries
that tend to pull water back into the circulatory system (colloidal osmotic pressure).
• The net filtration pressure is the outward pressure minus the inward pressure.

Regulation of glomerular filtration rate: It’s normal for your blood pressure to fluctuate throughout the
day, but this has no effect on the glomerular filtration rate.. how?
• Renal autoregulation — the kidney itself can adjust the dilation or constriction of the afferent
arterioles, which counteracts changes in blood pressure. This intrinsic mechanism works over a large
range of blood pressure, but can malfunction if you have kidney disease.
• Neural (nervous system) control and hormonal control — these extrinsic mechanisms can override
renal autoregulation and decrease the glomerular filtration rate when necessary.
• Ex: If you have a large drop in blood pressure, which can happen if you lose a lot of blood, your
nervous system will stimulate contraction of the afferent arteriole, reducing urine production. If
further measures are needed your nervous system can also activate the renin-angiotensin-
aldosterone system, a hormone system that regulates blood pressure and fluid balance.
ORGAN SYSTEMS 69
• Hormonal control — The atrial natriuretic peptide hormone can increase your glomerular filtration
rate. This hormone is produced in your heart and is secreted when your plasma volume increases,
which increases urine production.
• Glomerular filtration rate (GFR) can be estimated by measuring creatinine!
• Creatinine is a waste product made in muscle when it is metabolized to
generate energy.
• Creatinine is not reabsorbed or secreted, but is then exclusively filtered
through the kidneys. Its rate of excretion from your blood is directly
related to how efficiently your kidneys are filtering!
• By measuring the amount of creatinine in a blood sample, and combining this with other
information (e.g. age, ethnicity, gender, height, weight), the GFR can be estimated, which gives
doctors a good idea of how well your kidneys are working.

TUBULAR REABSORPTION IN THE NEPHRON

• If the fluid that filters through the glomerulus and Bowman’s capsule (glomerular filtrate) flowed
straight to your bladder and then out your body, you would lose more than 10-times the entire volume
of your extracellular body fluids (plasma and interstitial fluid) every day.
• Fortunately, tubular reabsorption mechanisms in the
nephrons move solutes and water out of the filtrate
and back into your bloodstream. [It’s called
reabsorption because the first time these nutrients/
solutes were absorbed was into the bloodstream
from the digestive tract after a meal.]
• Recall, nephrons are divided into five segments, with
different segments responsible for reabsorbing
different substances —————————————>
• Reabsorption is a two-step process:
(1) Passive or active movement of water & dissolved solutes from the fluid inside the tubule through
the tubule wall into the space outside.
(2) Movement of water and these substances through the capillary walls back into your bloodstream,
again, either by passive or active transport.
• The walls of the nephron are made of a single layer of cuboidal epithelial cells; their ultrastructure
changes depending on the function of the segment they are in.
• Ex: The surface of the cells facing the lumen of the proximal convoluted
tubule are covered in microvilli (tiny finger-like structures); called a
brush border. This border (along with the extensive length of the
proximal tubule) dramatically increases the surface area available for
reabsorption of substances into the blood. (~80% of the glomerular
filtrate is reabsorbed in this segment.)
• Cuboidal epithelial cells are also densely packed with mitochondria (the
cell’s energy generators), which ensure enough energy is available to fuel
the active transport systems needed for efficient reabsorption.

• Recall, sodium is the major positively charged electrolyte in extracellular body fluid.
ORGAN SYSTEMS 70
• The amount of sodium in fluid influences its volume, which in turn determines blood volume and
blood pressure.
• Most of the solute reabsorbed in the proximal tubule is in the form of sodium bicarbonate and
sodium chloride, and about 70% of the sodium reabsorption occurs here.
• Sodium reabsorption is tightly coupled to passive water reabsorption, meaning when sodium
moves, water follows.
• Reabsorption of Na+ in the early proximal convoluted tubule: The most essential substances in the
filtrate are reabsorbed in the first half of the proximal convoluted tubule (early proximal tubule). These
include glucose, amino acids, phosphate, lactate and citrate, which “piggy-back” on Na+ co-
transporters that move sodium down its electrochemical gradient into tubule epithelial cells.
• For this to continue, the sodium gradient must be maintained, which means sodium cannot be
allowed to build up inside the epithelial cells of the proximal tubule wall. This is achieved using:
• Sodium/potassium ATPase, a sodium pump (active transporter)— moves 3 Na+ ions out of the
cell for reabsorption, and 2 K+ ions in. This is located on the opposite side of the epithelial cell.
• Sodium/proton exchanger — enables reabsorption of bicarbonate. Glucose, AAs and other
substances passively diffuse out of the epithelial cells and are then reabsorbed by the blood
capillaries. By the time the filtrate has reached the mid part of the proximal tubule, 100% of the
filtered glucose and amino acids have been reabsorbed, as well as large amounts of sodium,
bicarbonate, phosphate, lactate, and citrate ions.
• Reabsorption of Na+ in the late proximal convoluted tubule: The fluid entering the late proximal tubule
has been depleted of the essential substances, and chloride ions have been left behind in the tubule.
Due to extensive reabsorption of water in the early section of tubule, the concentration of chloride ions
is high and its ions are highly concentrated, and it is now their turn for reabsorption.
Chloride is transported into the tubule epithelial cells through the following processes:
• Chloride/formate anion exchangers driven by the high concentration of chloride in the filtrate.
Chloride diffuses out of the cell through channels in the cell wall, then on into the bloodstream.
• Passive movement through spaces between epithelial cells of the tubule wall, aka tight
junctions.
• This is another important route for reabsorption of small solutes such as NaCl and H 2 O.
Sodium continues to be reabsorbed in this part of the tubule via sodium/proton exchangers, and
actively transported through the tubule wall to the bloodstream by the sodium/potassium
ATPase.
• After proximal convoluted tubule, ~15% of phosphate is reabsorbed in the proximal straight tubule.
• Reabsorption of Na+ in the loop of Henle: The filtrate then enters the loop of Henle (descending and
ascending limbs), which is responsible for concentrating or diluting the tubular fluid using a process
called countercurrent multiplication.
• The distal convoluted tubule and collecting ducts are then largely responsible for reabsorbing water
as required to produce urine at a concentration that maintains body fluid homeostasis.
• Reabsorption of Na+ in the thick ascending limb: A further 25% of the Na+ and K+ is reabsorbed
through walls of the thick ascending limb of the loop of Henle via the three-ion cotransporter
(sodium/potassium/chloride); Na+/K+ ATPase again maintains the Na+ concentration gradient.
• Sodium is actively pumped out, while potassium and chloride diffuse through channels in the
tubule wall and into the bloodstream. Recall, the walls of the thick ascending limb are
impermeable to water, so none is reabsorbed here.
ORGAN SYSTEMS 71
• Reabsorption of Na+ in the distal tubule and collecting duct: The tubular fluid now enters the distal
tubule and collecting duct, or terminal nephron. The early distal tubule reabsorbs a further 5% of
the sodium, and the late distal tubule and collecting duct fine tune reabsorption of the last little bit
(around 3%), determining exactly how much sodium will be excreted.
• These segments of the nephron have slightly different transporters, as well as the
sodium/potassium ATPase that drives reabsorption of calcium and chloride.
• Sodium reabsorption in the late distal tubule and collecting duct is regulated by hormones,
which stimulate or inhibit sodium reabsorption as necessary.

• Other ions: Calcium reabsorption throughout the nephron is largely similar to sodium reabsorption
with over 99% being reabsorbed, while phosphate reabsorption is similar to that of glucose in that it
primarily occurs within the proximal tubule. Reabsorption of magnesium differs in that the majority of
the reabsorption occurs in the ascending limb of the loop of Henle.

• Consider: The importance of the kidneys in maintaining body fluid composition is clear when we look
at what the impact on the body when our kidneys start to fail. Retention of waste products causes
disturbances in multiple organ systems. Loss of water and electrolyte homeostasis lead to elevated
extracellular body fluid volume, which may produce edema and hypertension, reduced phosphate
excretion, loss of bone calcium, and symptoms of lethargy, nausea, diarrhoea and vomiting.
• Diabetes insipidus is a rare disorder that causes you to feel very thirsty (despite drinking a lot),
and to produce large amounts of urine. It is usually caused by a malfunction in the production of
antidiuretic hormone (ADH), a hormone that prevents the production of dilute urine (i.e.,
retains water in the body). This can happen for a number of different reasons, including damage to
the pituitary (e.g., caused by a tumor, surgery, or infection) that disrupts the normal production,
storage and release of ADH. However, it may also occur due to a defect in the tubules themselves
that prevents them from responding to ADH, or during pregnancy, when a placental enzyme
destroys ADH in the mother.

COUNTER CURRENT MULTIPLICATION IN THE KIDNEY

• Countercurrent multiplication in the kidneys is the process of using energy to generate an osmotic
gradient that enables you to reabsorb water from the tubular fluid and produce concentrated urine.
ORGAN SYSTEMS 72
• The kidneys contain two types of nephrons, superficial cortical nephrons (70-80%) and
juxtamedullary nephrons (20-30%).
• These names refer to the location of the glomerular capsule, which is either in the outer cortex of
the kidney, or near the corticomedullary border.
• Loop of Henle of cortical nephrons penetrates only as far as the outer medulla of the kidney, but
that of the juxtamedullary nephrons penetrate deep within the inner medulla, so the latter is largely
responsible for countercurrent multiplication. (although both types regulate solute / water levels)

Overview of Countercurrent Multiplication

• Blood comes into to a nephron through the afferent arteriole, circles around the glomerulus, and exits
through the efferent arteriole. In circling around the glomerulus, a ton of fluid filters out of the blood
and into Bowman’s capsule.. this fluid is then filtered to become urine.
• After the fluid enters the Bowman’s capsule, it flows into the proximal convoluted tubule, where ions
(Na+, Cl-, etc) and other builders of macromolecules (AAs, glucose) are reabsorbed, along with water.
• Proximal convoluted tubule reabsorbs about 65% (most, by far) of the nutrients from the filtrate.
• From the proximal convoluted tubule, the filtrate flows into the loop of Henle, which has two limbs
going in opposite directions — the descending limb and the ascending limb.
• This portion of the nephron extends into the renal medulla of the kidney, which is very salty
• Descending limb is only permeable to H 2 O.
• Ascending limb is the exact opposite; it’s
impermeable to water but allows
reabsorption of ions such as Cl-, K+, Na+
• These characteristics lead to counter-current
multiplication, a process by which actively
reabsorbing ions in the ascending limb
makes the medulla salty (b/c it doesn’t allow
reabsorption of H 2 O, and this saltiness of the
interstitium allows H 2 O to be reabsorbed
passively in the descending limb.
• The amount of water passively absorbed is
multiplied by the saltiness of the medulla,
which occurs as a result of actively pumping
ions out of the ascending limb.
• After the ascending loop of Henle, the filtrate enters the distal convoluted tubule (DCT), which is
responsible for the reabsorption of other ions / important nutrients.
• Note the “scientific kiss” that occurs here, where the DCT comes back towards the glomerulus.
This produces the juxtaglomerular apparatus, responsible for controlling blood pressure.
• After leaving the distal convoluted tubule, this more concentrated filtrate gathers in the collecting duct.
• Note that there are many DCTs which feed into a single collecting duct.
• The collecting duct also descends into the renal medulla, and allows for further reabsorption of
H 2 O and urea. Urea is one of the main waste products we pee away, but sometimes kidneys like to
hold onto it (by reabsorption) to increase the osmolarity in the medulla to help drive water
reabsorption in the loop of Henle. From here, it goes into urea recycling.
• From the collecting duct, this filtrate (now urine!) enters renal calyces and is sent off to be peed out.
ORGAN SYSTEMS 73
• After reabsorption, the efferent arteriole collects, via small peritubular capillaries (purple) across the
nephron, all the nutrients that have been reabsorbed! These capillaries then feed into the renal vein.
Details of Countercurrent Multiplication in the Loop of Henle
• The 3 segments of the loop of Henle have different characteristics that enable countercurrent
mult:
• Thin descending limb — passively permeable to both water & small solutes (ions, urea, etc.).
• Water and solutes move down their concentration gradients until their concentrations
within the descending tubule and the interstitial space have equilibrated.
• As such, water moves out and solutes to move in. This means the tubular fluid becomes
steadily more concentrated or hyperosmotic (compared to blood) as it travels down.
• Thin ascending limb — passively permeable to small solutes, but impermeable to water,
which means water cannot escape from this part of the loop.
• As a result, solutes move out of the tubular fluid, but water is retained and the tubular
fluid becomes steadily more dilute or hyposmotic as it moves up the ascending limb of the
tubule.
• Thick ascending limb (sometimes called “diluting segment” actively reabsorbs Na+, K+ and
Cl+.
• This segment is also impermeable to water, which again means H 2 O cannot leave.
• Countercurrent multiplication moves sodium chloride from the tubular fluid into the interstitial
space deep within the kidneys. Although it’s really a continual process, the way countercurrent
multiplication process builds up an osmotic gradient in the interstitial fluid can be thought of in
two steps:
1. The single effect. The single effect is driven by active transport of sodium chloride out of the
tubular fluid in the thick ascending limb into the interstitial fluid, which becomes
hyperosmotic.
— As a result, water moves passively down its concentration gradient out of the tubular fluid
in the descending limb into the interstitial space, until it reaches equilibrium.
2. Fluid flow. As urine is continually being produced, new tubular fluid enters the descending
limb, which pushes the fluid at higher osmolarity down the tube. An osmotic gradient begins
to develop.
• As the fluid continues to move through the loop of Henle, these two steps are repeated over and
over, causing the osmotic gradient to steadily multiply until it reaches a steady state. The length
of the loop of Henle determines the size of the gradient - the longer the loop, the greater the
osmotic gradient.
• Although the loops of Henle are essential for concentrating urine, they don’t
work alone. The specialized blood capillary network (the vasa recta) that
surrounds the loop is equally important for countercurrent exchange:
• The vasa recta returns absorbed water to the circulatory system.
• Consists of long, hairpin-shaped capillaries that run parallel to the loop.
• These hairpin turns slow the rate of blood flow, so any solutes that are
reabsorbed into bloodstream have time to diffuse back into interstitial
fluid, maintaining the hyperosmotic medulla for H 2 O reabsorption.
• The concentration of urine is controlled by ADH, which can increase water
permeability in the late distal tubule and collecting ducts. This increases
active transport of NaCl in the thick ascending limb, and enhances
countercurrent mult. and urea recycling, thus increasing H 2 O reabsorption.
ORGAN SYSTEMS 74
• Urea recycling in the inner medulla also contributes to the
osmotic gradient generated by the loop of Henle. ADH
increases water permeability, but not urea permeability, in
the cortical and outer medullary collecting ducts, causing
urea to concentrate in the tubular fluid in this segment.
• In the inner medullary collecting ducts, ADH increases
both water and urea permeability, which allows urea to
flow passively down its concentration gradient into the
interstitial fluid, also adding to the osmotic gradient that
helps drive water reabsorption.
SECONDARY ACTIVE TRANSPORT IN THE NEPHRON
• The proximal tubule has a brush border, with the glomerular filtrate entering the lumen of the
nephron. This lumen/tube is surrounded by cells.
• note: membrane of cell side facing the lumen is apical, while that facing the capillary is
basolateral.
• Adjacent to proximal tubule is the peritubular capillary, where reabsorbed nutrients re-enter the blood.
• On the basolateral side of the proximal convoluted tubule is a sodium/potassium pump! Sends 3 Na+
out (using ATP) and takes in 2 K+.
• This active pumping out of Na+ means we’ll have a lower Na+ concentration inside the cells of the
tubule wall than inside the lumen. Na+ wants to leave the lumen, then, to go into the cell.
• A co-transporter symporter on the apical membrane takes advantage of this concentration gradient.
As Na+ leaves the lumen to enter the cell(s) of tubule wall, moving down its concentration gradient,
a glucose molecule is simultaneously transported up its concentration gradient without using ATP.
• This same process happens in the loop of Henle with other ions… the basolateral cell wall of the
ascending limb of the loop has a Na+/K+ pump, which reduces Na+ concentration in the cell(s) of the
tube’s wall. Na+ then wants to move from the lumen to those cells, down its concentration gradient,
and with it (via the Na+/K+/Cl– cotransporter) takes another ion up its concentration gradient.
• Use of cotransporters after Na+ has already been pumped out is called secondary active transport.
• In the distal convoluted tubule, Na+ is again pumped out via a Na+/K+ pump in the basolateral cell wall
of the tubule, lowering Na+ concentration in the cell(s) of DCT’s wall. In this case, it drives
reabsorption of Ca2+ through an antiporter. (The apical membrane of the cells of the tubule wall is
porous to Ca2+)
• Recall that the peritubular capillaries run parallel to these tubules.. Thanks to the Na+/K+ pump, the
concentration of Na+ in the capillary blood is higher than in the cell, so Na+ will want to go back in.
When Na+ moves in, the Ca2+ is simultaneously moved up its gradient (in opposite direction).

URINATION
• After we concentrate urine in our nephrons, it flows through the collecting duct to the renal calyx at the
tip of the medulla. Several renal calyces come together to make the renal pelvis, and from there our
urine flows out of the ureter into the bladder.
• Ureters attach to the back of the bladder. They have valves that prevent backflow of urine up the
ureter towards the kidneys.
• The ureters spray urine into the bladder with the ureter jet, one at a time (recall ultrasound video)
ORGAN SYSTEMS 75
• Looking at the bladder from the side, the anterior (front) has a sort of point and both interior and
posterior sides funnel down.
• The bladder is lined with transitional epithelium, which is structurally somewhere in between the flat
squaemous epithelium and taller columnar epithelium. These types of cell allows the bladder to
expand!
• The bladder then funnels into the urethra, controlled (at the top of the urethra / bottom of the bladdar)
by the internal urethral sphincter (IUS). This sphincter is involuntary & thus made of smooth
muscle.
• In women, after the IUS, we have the external urethra sphincter (EUS), a membranous part
surrounding the urethra. This is in our control (unlike IUS) and thus it’s made of skeletal muscle. This
is the muscle we learn to control in potty training. After the EUS, the urethra is fairly short (much
shorter than in men), and it leads to the outside world.
• In men, after the IUS there is the prostatic urethra (named because it passes through the prostate,
which circumscribes the urethra), and then the EUS. After the EUS, the urine will travel through a
urethra section called the spongey urethra, which is in the penis. After this, the urine leaves the world.
• Note: If our ureter valves (which are normally one-way and prevent backflow) malfunction, we can get
what’s called stasis, where the urine basically sits in the ureter. This can be a problem, and even cause
infection, if there’s any bacteria there, which is not unlikely seeing as our urethra is connected to the
outside world. [Women are much more susceptible to these UTIs bc their urethra is so much shorter.]
—————————————Renal Regulation of Blood Pressure——————————
———
OVERVIEW OF THE RAAS SYSTEM AND RENIN PRODUCTION
• RAAS = Renin Angiotensin Aldosterone System. It begins with a set of cells that releases messengers.
• The key cell is the juxtaglomerular cells, which are in the blood vessels of the kidney. They’re
made of smooth muscle, and release renin: an endocrine peptide hormone that helps raise blood
pressure.
• Recall that in the kidney, the afferent arteriole leads in to the glomerulus, and the efferent
arteriole leaves. In between these arterioles, the distal convoluted tubule crosses over. ———>
• The distal convoluted tubules are partly made of some special macula densa cells.
• The arterioles are made of the inner layer (aka the tunica intima) of endothelial cells,
then a layer of smooth muscle cells (tunica media).
• On the afferent arteriole side (well, both sides, but mostly afferent), the tunica media also
has clusters of juxtaglomerular cells - also called granular cells because they all have little
granules in them. After this layer is the tunica externa layer, which is home to many nerve
endings for a nearby sympathetic nerve (will be important later)
• In the arterioles are also mesangial cells, which are mostly there for structural support.
• Together, this is all called the juxtaglomerular apparatus, whose goal is to release renin.
• The granules of the JG cells are filled with renin. When released, renin enters afferent arteriole,
goes through the glomerulus, and exits through the efferent arteriole. But how / why is renin
released?
• Triggers for JG cells to release renin include:
• (1) Low blood pressure
• JG cells directly sense low blood pressure in the afferent arteriole
 ORGAN SYSTEMS 76
• (2) Sympathetic (fight or flight) nerve cell stimulation
• Major stressor events cause this nerve cell to fire on the afferent arteriole, which in turn causes
the release of renin from JG cells
• (3) Low Na+ concentration in the distal convoluted tubule, sensed by macula densa cells.
• Macula densa cells sense concentration of sodium ion in glomerular filtrate.
• Macula densa cells (which form the lining of the distal convoluted tubule) are part of the juxtaglomerular
apparatus, which regulates blood pressure.

• A component of blood pressure is blood volume: higher blood volume means higher blood pressure.
• A decrease in sodium ion in the distal convoluted tubule implies low blood pressure.
• Macula densa cells send local, short-range signals to juxtaglomerular cells via release
of prostaglandins.
• Prostaglandins are molecules that send short-range signals between cells; unlike hormones,
they are not produced by specific organs, but rather throughout the body.
• Renin is released in response to signals that represent low mean arterial pressure.
• The sympathetic nervous system innervates the juxtaglomerular apparatus and can signal in response
to low blood pressure.
• Macula densa cells detect low blood pressure by sensing sodium concentration in the glomerular
filtrate, not in the blood plasma.
• Renin is not released in response to detection of low plasma electrolyte levels by macula densa
cells.
•

• If BP is low, not a lot of blood is moving through the glomerulus, so not a lot of fluid is moving
through the nephron, and thus a lot of salt is being reabsorbed. Macula Densa cells “taste” the
fluid going by and sense that there’s not much salt in it (bc blood pressure is low), so they
signal JG cells to release renin through paracrine (short-ish distance) prostaglandins.

ANGIOTENSINOGEN —> ANGIOTENSIN 1 —> ANGIOTENSIN 2 —> INCREASED BLOOD

PRESSURE
• In addition to the kidney, with its juxtaglomerular apparatus (and sympathetic nerves), the liver is also
involved in raising blood pressure.
• Liver cells release angiotensinogen, a large (~450 AA) hormone precursor, or inactive hormone.
• When angiotensinogen meets up with renin in blood vessels (all over body), renin cleaves that long
AA chain into just about 10 AA, effectively converting angiotensinogen into its active form:
angiotensin 1
• Angiotensin 1 now floats through capillaries, tiny blood vessels that are so small they’re basically just
made of a layer of endothelial cells. In these endothelial cells is ACE: Angiotensin Converting
Enzyme.
• ACE cuts another 2 amino acids off angiotensin 1 making it into the 8 AA hormone, angiotensin
2.
• Note: It used to be thought that ACE was only present in the lung capillaries, but is now widely
recognized that ACE is in a lot of different vessels / organs, including the kidneys.
ORGAN SYSTEMS 77
• Angiotensin 2 ultimately raises blood pressure through four different cell types:
(1) Vasoconstriction — causes smooth muscle cells of blood vessels to constrict and increase
resistance
• Angiotensin = “blood vessel” “tension”
• Recall, blood pressure can be measured with ∆P = Q x R ———> P A - P V = (SV x HR) x R, so it
makes sense that if you increase resistance, arteriole blood pressure will also be increased (because
venous blood pressure doesn’t really change).
— note: SV = stroke volume = mL of blood pumped out of the heart with each beat
(2) Increases Na+ reabsorption in the kidneys — by reabsorbing Na+, the kidneys also end up
absorbing and retaining more water with it.
• When your blood has this increased Na+ and increased water, it will cause the stroke volume to go
up and, as we saw above in P A - P V = (SV x HR) x R, by increasing stroke volume (SV), blood
pressure will be increased
(3) Causes pituitary gland to secrete antidiuretic hormone — ADH also accomplishes (1), making
blood vessels constrict. And it sort of accomplishes (2), making kidneys retain H 2 O instead of Na+.
[Water retention also makes SV increase, and thus pressure.]
(4) Causes adrenal gland (on top of kidney) to secrete aldosterone, which also accomplishes (2) -
increases reabsorption of Na+ in the kidneys (and thus increases SV).
• What’s the difference between salt and water reabsorption?
• When Na+ is reabsorbed, the medulla gets salty, so H 2 O absorption will follow… as long as the
tube is permeable to H 2 O. [Where
• If the tube is impermeable to H 2 O, though, obviously this will not work. Instead, the tube uses a
bunch of special channels to allow H 2 O through.
• The area of the nephron where angiotensin 2 and aldosterone affect reabsorption is permeable to
water, so causing Na+ reabsorption works to retain water, too.
• But the area where ADH affects the nephron is impermeable to water, so it must directly cause
H 2 O reabsorption through channels.

DETAILS OF ALDOSTERONE FUNCTION IN RAISING BP:

• Aldosterone is released by the adrenal gland, which has two parts: cortex (outer) and medulla (inner).
• Adrenal cortex cells are provided nutrients / oxygen by small capillaries, and they’re filled
with cholesterol. The cholesterol is very useful in making the hormone aldosterone.
• Triggers for adrenal cortex to make aldosterone:
(1) Angiotensin 2
(2) Increase in K+ concentration
• Aldosterone affects the late distal convoluted tubules and the collecting ducts of nephrons.
• These tubules are lined with principal cells, which are adjacent to the peritubular
capillary. (the side of peripheral cells facing the capillary is the basolateral surface; that
facing the lumen is the apical surface)
• There are lots of K+ ions inside the principal cell, and lots of Na+ in the blood flowing through the
capillaries. These two ions are exchanged through the sodium-potassium pump on the basolateral
surface — 3 Na+ ions move out of the cell as 2 K+ ions are pumped in.
• Aldosterone works by:
ORGAN SYSTEMS 78
1. Making the sodium-potassium pump in the basolateral surface of the tubule / duct work harder.
2. Opening potassium channels on the apical surface, so K+ flows out of the principal cells into the
fluid (soon to be urine) flowing through the tubule. This increases drive to get K+ into the cell.
3. Opening Na+ channels, moving Na+ into the principal cell from the urine, which again makes
the Na+/K+ pump work even harder to pump Na+ out of the principal cells (where concentration
is increasing) into the capillaries. When Na+ enters the capillaries, water follows.
• TL:DR — Aldosterone works on the principal cell and causes blood to lose K+ and gain Na+ (and
thus gain water)… this leads to increased stroke volume and thus increased blood pressure

ALDOSTERONE ALSO REMOVES ACID FROM THE BLOOD:

• Aldosterone also works on α-intercalated cells, whose main job is to get rid of protons (and thus
acid).
• Alpha intercalated cells are in the collecting duct; they secrete hydronium ion (acid) and absorb
bicarbonate.
[The ß-intercalated cell, by contrast, tries to hold onto acid.]
• The α-intercalated cell is also bordered by a peritubular capillary on the basolateral side.
• Recall: all cells make CO 2 and H 2 O through glycolysis, and are then turned into H+ and HCO 3 - by
carbonic anhydrase.
• Let’s say the blood is getting a bit too acidic and H+ starts building up. What happens?
• In the α-intercalated cell’s basolateral side, there is a channel that allows HCO 3 - to travel from the
cell into the capillary and simultaneously brings a Cl- into the cell. In the blood, the HCO 3 -
combines with H+ to make CO 2 and H 2 O.
• In the α-intercalated cell, that Cl- that entered when HCO 3 - left can leave the cell through a
channel on the basolateral side.
• But we’re still left with the H+ from the initial rxn with carbonic anhydrase… For every H+ we
remove from the blood, we have one in the cell, and these start to build up.
How do we get rid of the acid from α-intercalated cells? 4 main transporters
• On the apical side, there’s an active transporter (requires ATP) that will send the H+ from the α-
intercalated cell into the urine, and it can just be peed out. Aldosterone makes this transporter work
super well.
• A second transporter on the apical side can send out H+ without using energy; instead it uses the Na+
concentration gradient. Aldosterone also makes this transporter work super well.
• Recall that cells have a lot of K+, but not a lot of Na+. (Most of the Na+ is in the blood.) The
entrance of Na+ down its gradient fuels the movement of H+ against its gradient.
• A third type of transporter on the apical side also requires energy (is “active” transporter) to allow H+
out. As H+ leaves the cell, K+ is driven back in, against its gradient (which is why energy is required).
• In α-intercalated cells, there are also (like all cells) sodium-potassium pumps on the basolateral side
that bring 2 K+ in and force our 3 Na+; this also takes energy.
• TL;DR — Acid is removed from the blood by bringing in HCO 3 - from α-intercalated cells to
neutralize it, but that leaves H+ (from the same rxn) in the α-intercalated cells. H+ is then removed
from those cells by several transporters, two of which are driven by aldosterone.
ORGAN SYSTEMS 79
ANTI-DIURETIC HORMONE (ADH) SECRETION:
• ADH is sometimes called vasopressin.
• Consider the pituitary/hypothalamus structure: There is the hypothalamus (at the top), the
infundibulum in the middle, and then the two lobes of the pituitary: anterior and posterior.
• On this structure is also a little nodule called the optic chiasm, above which sits the supraoptic
nucleus (recall that a nucleus is a collection of cell bodies / somas).
• The nerve cells in the supraoptic nucleus start there and travel all the way down to the posterior
pituitary; this is how the hypothalamus and pituitary are connected.
• There are lots of tiny capillaries and venules in the posterior pituitary, as well.
• ADH is a peptide hormone made in the nerve cells of the supraoptic nerve cells.
• When there’s a trigger, these nerve cells fire off ADH and signal the capillaries to release ADH
hormone into the body.
• What are the triggers for ADH release?
• *High blood concentration (aka high osmolarity, meaning level of solutes in the blood) — this is
most important trigger
• Body likes to stay in the 280 - 300 mOsm/L range. If it gets above 300, it’s a little salty / too
osmotic and ADH is triggered to be released (by osmoreceptors in unknown locations)
• Low blood volume
• This is sensed by nerve endings in the walls of the vena cava blood vessels and the right atrium
(because, recall, the venous system is very large volume.. If the cells of those walls sense that
they are less stretched, they know blood volume is low and they trigger ADH release.
• Low Blood Pressure
• This is sensed by arteriole baroreceptors in the aortic arch and the carotid sinuses on both sides.
• Angiotensin 2 also triggers release of ADH.

ANTI-DIURETIC HORMONE (ADH) EFFECTS ON INCREASING BLOOD PRESSURE:

• ADH signals all arteriole vessels of the body, with their smooth muscle, to constrict. This increases
resistance, which in turn increases blood pressure. P A - P V = (SV x HR) x R
• It also causes the kidneys to retain / reabsorb water by affecting the collecting duct, specifically, which
causes stroke volume to increase.
• As you go deeper in the medulla (from bowman’s capsule down the loop of Henle), there is an
increasing gradient of mOsm concentration. It gets salty
• In the collecting duct cells, there are little vesicles called aquaporins, which do not allow water to
go through, except through their aquaporin channels.
• Note, though, that they are not close to the wall, so H 2 O cannot enter the collecting ducts.
• ADH will float through the blood (which flows in opposite direction to the urine in the
collecting duct that the capillary is next to), and signals the collecting duct cells to merge
aquaporin vesicles with the apical wall of the cell, so channels allow water in and out.
• After opening the aquaporin channels, lots of H 2 O flows into the cell and then basically straight into
the adjacent peritubular capillary, significantly increasing blood volume and thus stroke volume, and
thus blood pressure.
ORGAN SYSTEMS 80

ALDOSTERONE AND ADH:

• Aldosterone: uses an osmole to pull H 2 O into the blood
• The tubules it affects are water permeable. It pulls Na+ into the capillary and sends in K+ through
an active transport pump.
• Recall, Na+ is not able to cross membranes; which means it is a big contributor to tonicity; it can’t
leave the blood vessel. By comparison, K+ can slightly cross membranes, but net tonicity still
increases. This increase in tonicity pulls in water.
• Increases osmolarity and also increases volume.
• Because they both increase proportionally, we don’t think of osmolarity really being affect.
• ADH: uses channels to pull H 2 O into the blood
• The tubules it affects are not water permeable, so it opens aquaporin channels that allow H 2 O
across.
• Increases volume, but not osmols, so overall osmolarity (fraction of osmole / vol.) decreases.
• Given this information and the changes the hormones make, think about a situation where you want to
• increase volume but maintain osmolarity: increase ADH
• increase volume, regardless of osmolarity: increase aldosterone and ADH
• decrease osmolarity, regardless of volume: ADH
• decrease osmolarity, maintain volume: increase ADH, decrease aldosterone

——————————————Gastrointestinal System——————————————
——
OVERVIEW OF THE GASTROINTESTINAL TRACT
• Mouth: chewing + hydrolysis (enzymatic breakdown) = bolus.
• Esophagus: propela bolus
• Stomach: churning (like chewing, but more dimensions) + hydrolysis + storage = chyme.
• Small Intestine: hydrolysis + absorption
• Large intestine (colon): absorption (not of nutrients, but ions, water, vitamin K, etc.)
• Rectum: storage of processed food until we expel it
• Anus: expulsion
MOUTH (ORAL / BUCCAL CAVITY)
• Goal of the mouth is to convert food into bolus, which we do in two steps:
(1) Chewing (mastication) — accomplished by teeth and the tongue.
• The tongue is made of extrinsic and intrinsic muscles.
• Extrinsic tongue muscles cause elevation, depression, protrusion, retraction
• Intrinsic tongue muscles (only inside the tongue) shorten & widen (run A/P), and lengthen &
narrow (R/L)
(2) Breakdown of food particles by hydrolysis. The enzymes in our mouth that do this come from
glands.
ORGAN SYSTEMS 81
• Glands release: Serous content (for enzymes) - breakdown / cut food by hydrolysis, and
mucinous (musin) content - wet the food to make it easier to form bolus)
• Parotid glands (mainly serous) release about 25% of saliva content
• Submandibular (also mainly serous) - 70% of saliva
• Sublingual gland (mainly releases mucin) - 5% of saliva
• Von Ebner’s gland (mainly at the tip of the tongue, also serous) - less than 5% of saliva
• Von Ebner’s gland is important in that is releases lingual lipase, which breaks down triglycerides into
free fatty acids, diglycerides, and monoglycerides.
• The other three glands (parotid, submandibular, and sublingual) release α-amylase, which breaks
down starch into smaller carbs
• Note that the amount of hydrolysis and breakdown that occurs in the mouth is very insufficient for
digestion; it’s basically just so we can taste things (e.g. enjoy the sugars in our soda)
• The mouth normally is at a pH of ~7, but if we eat a lot of sugar (which, recall, has a lot of hydroxyl
groups), it can actually lower the pH of your mouth to as low as 5.5! This acidity will start to break
down your teeth.

TEETH
• mandible = lower jaw; maxilla = upper jaw. There is
symmetry both on the left/right sides, as well as
between the mandible and maxilla.
• The textbook picture to the right – with 4 central incisors,
4 lateral incisors, 8 premolar, and 12 molar teeth –is
actually only what 28% of people’s teeth look like.
• Why? Your 3rd molars are your wisdom teeth, and
most people (72%) have them removed.
• Wisdom teeth are often removed because teeth come up
through little holes in your gums (aka gingiva). In most
people, the hole for the 3rd molar is very small — too
small for the 3rd molar to get through. So the tooth ends up twisting and trying to “erupt” through the
gingiva in a such bad way that it can cause inflammation and tearing.

ESOPHAGUS
• There are sphincters — circular localizations of muscle — at the very top and very bottom of the
esophagus. These keep food moving in one direction.
• The upper esophageal sphincter only opens when we tell it to, and is thus made of skeletal muscle.
• The lower esophageal sphincter doesn’t really look like a sphincter, because it’s not a ring of muscle
that opens and closes when we want. Instead it’s really the diaphragm — a sheet of muscle that lines
the connection between the thoracic cavity (lungs, heart, etc), and the abdominal cavity, and helps our
lungs expand to breathe.
• This diaphragm forms a ring around the base of the esophagus and holds it in place.
• Over time, humans can get a hernia where the esophagus moves up through the diaphragm (aka
lower esophageal sphincter) and causes acid reflux.
ORGAN SYSTEMS 82
• The esophagus works as a passageway for food, and doesn’t do much except peristalsis — the
wavelike propulsion of food. Contraction of the muscle above + simultaneous relaxation of muscle
below.
• Esophageal tract is not made of 100% skeletal or 100% smooth muscle; instead it’s split into thirds.
• top-third: all skeletal muscle, which is completely in our control
• middle-third: combination of skeletal and smooth
• last-third: all smooth muscle, 100% not in our control.

STOMACH
• Stomach is primarily responsible for 3 steps:
• (1) receives bolus of food
• (2) churns the bolus / food to break down the food even more
• (3) hydrolysis (enzyme assisted breakdown) of the bolus
• These steps end with making chyme, which just sort of sits there for a little bit (the stomach also
stores food, up to 4 L at a time!) before moving on to the small intestine.
• The stomach is lined with many infoldings of the gastric wall that help to increase surface area. The
folds are lined with cells that secrete enzymes. Three main types of cells:
• Parietal cells — release HCl
• Chief cells — release pepsinogen (inactive form of pepsin. HCl turns pepsinogen into pepsin)
• Pepsin break down proteins by cleaving peptide bonds; thus, peptin is the only type of molecule
broken down in the stomach.
• Note: with just these two secretions, HCl and pepsin, your stomach would basically eat itself!
This is what is happening when we get gastric ulcers.
• Mucous cells — make mucous to line the stomach wall and protect it from pepsin and HCl.

SMALL INTESTINE
• The small intestine has three different parts to it:
• (1) Duodenum — receives chyme from the stomach. Most of the digestion occurs here.
• (2) Jejunum — most absorption happens here
• (3) Ileum — absorbs important things like vitamins
• The Duodenum is very busy with four key processes:
• Receives chyme and HCl from the stomach
• Liver and gallbladder send bile to the duodenum
• Pancreas also delivers some important enzymes
• The duodenum itself has brush border enzymes, which are important for absorption and for
enzymatic activity.
• The brush border is basically in-foldings on the wall of the duodenum (bumps face in), called villi.
• Within each villus is even more in-foldings, microscopic projections of tiny bumps called
microvilli
ORGAN SYSTEMS 83
• All these increase surface area for absorption and digestions, because the projections have
enzymes.
Digestion (in the duodenum):
• Protein is broken down by several enzymes in the small intestine into constituent amino acids
• Peptidase is found on the brush border.
• The pancreas sends trypsinogen and chymotrypsinogen, which an enzyme called
enteropeptidase turn into their active forms of trypsin and chymotrypsin.
• Carbohydrates are broken down by: amylase (sent by the pancreas) and lactidase (can only break apart
lactose — this is found on the brush border).
• When you get a stomach bug, it can inflame the duodenum and actually knock off some of the
lactidase enzymes. Thus, you may be temporarily lactose intolerant.
• Eventually you’re left with just monosacharides.
• Nucleotides are broken down by nucleosidases on the brush border, which cleaves base–pentose bond.
• Fat is broken down by lipase, which is released by the pancreas and cleaves triglycerides into the
glycerol backbone and 3 fatty acids.
• Bile released by the liver / gall bladder to organize the fatty acids.
Absorption (mostly in the jejunum)
• After digestion, we have all out monomers (AA, monosaccharides, nucleobases, fatty acids, etc.)
• Amino acids are funneled into intestinal cells with primary active transport (uses ATP) —>
eventually enters a blood capillary.
• Sugar monosaccharides are funneled into and eventually out of the intestinal cells with secondary
active transport — This is when an ion like Na+ flows down its concentration gradient into the cell
from the lumen (or out of the cell into the capillary), which allows the monosaccharide to also enter (or
exit)
• The P-pentose and nitrogenous base also enter/exit the cell with primary active transport and
eventually end up in the blood capillary.
• Because of their nonpolar tail, fatty acids can just diffuse across the membrane into the enterocyte
(intestinal cell). There, they are organized into chylomicrons, which are too big to go to the blood
capillary. Instead, chylomicrons are absorbed into the lymphatic capillary (aka lacteal), where they are
further digested into smaller bits and can then get into the veins and eventually the blood capillaries.

LIVER
• The liver is responsible for for main things:
• (1) Metabolism — involves catabolism and anabolism
• (2) Storage
• Carbs are stored as glycogen, while fats can be stored as lipoprotein and triglycerides.
• Proteins are also seen in the liver, but aren’t really stored.. instead they’re turned into molecules
like albumin and sent off into the bloodstream until they need to be retrieved back to the liver
• (3) Detoxification — achieved mainly by cytochrome P450. Unlike other enzymes, they can take
many different kinds of substrates and react with them.
ORGAN SYSTEMS 84
• This detoxification process causes a problem when we take medications, it decreases the drug
efficacy.
• (4) Bile production — needed for fat absorption
• Uniquely, the liver has two separate blood supplies going to it, and one that leaves it. These three
vessels make up the portal triad.
• The portal vein supplies the liver with nutrient rich blood (The nutrients come from food
absorbed in the intestinal track, which go through circulation to end up in the portal vein.)
• The proper hepatic artery supplies the liver with arteriole, oxygen-rich blood.
• The hepatic vein carries away nutrient- & oxygen-poor blood. This blood then travels to the
heart to be oxygenated, goes past intestines to gain nutrients, then re-enters liver through portal
vein.
• The other output from the liver is bile, which leaves through the common hepatic duct.

Hepatic lobule
• The portal triad is important to identify in surgery, and is easy to identify when we look at pieces of the
liver called hepatic lobules.
• In the hepatic lobule, there are many lot of liver cells, or hepatocytes, and around them three distinct
branches that make up the portal triad. There’s actually bunches of portal triads surrounding
hepatocytes — this leads to 6 distinct sides of the hepatic lobule.
• The portal vein is how we get nutrient rich blood to enter the hepatic lobule (portal vein branches
are called sinusoids), where hepatocytes then break those nutrients down for storage or whatever is
needed. The proper hepatic artery brings in oxygen to the hepatic lobule.
• Once those have been extracted, we need to send the blood out to be oxygenated and get nutrients
again.. so the blood collects in the center of the hepatic lobule, into the central vein, which then
becomes the hepatic vein. (which sends blood back to the heart —> intestines, etc)

Biliary tree
• Bile is composed of bile pigments (make the color and aren’t really important for function) and bile
salts (very important, help us emulsify fat into miscelles, which can then be absorbed in the ileum).
• Bile that’s made in the liver travels through the common hepatic duct into the cystic duct, which
then leads it to be (temporarily) stored in the gall bladder, a blind pouch..
• The singular purpose of the gall bladder is to store the bile.
• The hormone that causes bile to be released from the gall bladder is cholecystokinin (CCK); it causes
the gall bladder to contract, and in doing so all the bile is squeezed back through the cystic duct and
then into the common bile duct.
• The common bile duct travels to the duodenum of the small intestine and releases its bile there. In the
duodenum, fats are emulsified.
• Note, though, that fat is not absorbed in the duodenum. Instead, the bile salts with the emulsified
fat travel along to the ileum (last part of the small intestine) for absorption.
• What happens to bile salts after they’re absorbed in the ileum? They circulate back to the liver to
repeat the process.

EXOCRINE PANCREAS
ORGAN SYSTEMS 85
• The pancreas sits below and behind the stomach, and sort of hugs the duodenum of the small intestine.
• Some say it’s in a completely different section of the body, not in the peritoneum (abdominal
cavity with the stomach, intestine, etc.), but is instead is in the retroperitoneum (along with some
big blood vessels)
• The pancreas releases powerful enzymes that digest lots of macromolecules — things we eat
as well as some that make up parts of our body. It also is unique in that it’s un-encapsulated;
it’s just a slurry of cells (which makes it difficult especially for surgeons operating nearby).
• Many consider the pancreas to be the “lion” of the abdomen because of it’s importance and power.
• There are two main components to the pancreas:
• Exocrine pancreas takes salts and enzymes and releases them in the duodenum.
• Endocrine pancreas releases hormones.
• The exocrine pancreas releases four main things:
• (1) Bicarbonate — neutralizes gastric acid (HCl with chyme from the stomach)
• (2) Amylase — breaks down starch into monosaccharides.
• (3) Lipase — breaks down triglycerides into free FAs, monoglycerides, diglycerides, and glycerol.
• (4) Proteolytic enzymes — includes trypsinogen and chymotrypsinogen.
• Trypsinogen is turned into its active form trypsin by anteropeptidase enzyme in the
duodenum. Chymotryspinogen is then turned into its active form chymotrypsin by trypsin!
• What happens when the bonds of trypsinogen are broken while its still in the pancreas? — e.g.
if you get hit in the abdomen really hard and trypsinogen ends up turning into trypsin? Well,
because the pancreas is un-encapsulated, that trypsin would just travel around and digest all
sorts of proteins (in membranes, in our food, in other organs, etc)… not good.
• The endocrine pancreas is more famous — it releases hormones rather than enzymes and salts. Those
hormones enter the blood stream and move all over the body.
• The endocrine pancreas is composed of many islet cells that sit in “islands.”
• Three main types of islet cells (all are present to some extent in each island):
(1) α-islet cells: release glucagon [breaks down many macromolecules, e.g. glycogen —>
glucose]
(2) ß-islet cells: release insulin [builds up / stores macromolecules, e.g. glucose ——>
glycogen.
• It’s also the hormone responsible for diabetes, aka “eye nerve & kidney disease, which is
caused by too much glucose in the body bc insulin isn’t working.
• Type I diabetes: no insulin
• Type II diabetes: insulin receptors are broken
(3) ∂-islet cells: release somatostatin [stops the effect of other hormones in the GI tract]

COLON, RECTUM, AND ANUS

• After food is absorbed in the small intestine, it travels to the large intestine (which is bigger in
diameter, but actually much shorter).
• At the end of the small intestine / beginning of the large intestine is the ileocecal valve.
ORGAN SYSTEMS 86
• The first main part of the large intestine is the cecum (with appendix “tail” hanging off). It then goes
up through the ascending colon, then goes across through the transverse colon, and then down the
descending colon. The last part of the large intestine is the sigmoid colon (has an S shape to it).
• The large intestine is most responsible for absorbing:
• Water
• If we absorb too little water, the output of our body would be a little watery. This is diarrhea.
• If we absorb too much water, we’ll get constipated.
• The disease cholera attacks certain proteins / receptors in the intestinal lining that cause you to
lose tremendous amounts of fluid and eventually lead to death by dehydration. If, however, you
can keep a person very hydrated throughout the whole disease manifestation, they’ll end up
passing the bacteria and be okay.
• Inorganic Ions — includes Na+, K+
• Like other organs (the small intestine and, more notably, the kidney), Na+ and K+ are absorbed
with transport mechanisms. The kidney is much more important for inorganic ion absorption
than the large intestine, so even if you have to have a colonectomy, you’ll be okay.
• The large intestine is also home to lots of micro-organisms that assist in digestion of things like
carbohydrates, making byproducts of methane (CH 4 ) and dihydrogen sulfide (H 2 S)
• After the sigmoid colon is the rectum, whose main function is storage. It holds onto stool until it’s an
appropriate time to go to the bathroom.
• The anus comes next, and is composed of two sphincters:
• Internal anal sphincter is made of smooth muscle that is involuntary.
• External anal sphincter is made of skeletal muscle; it’s under our control.
• When it’s time to release stool, the internal anal sphincter will relax and the stool will move
forward to push on our external anal sphincter, so we know it’s time to go. But we can wait until
we get to a bathroom b/c the external sphincter is under own own control.

CONTROL OF THE GI TRACT

• The GI tract has sort of its own brain! It’s called the enteric nervous system, because it can act on its
own without having to send neuronal signals to the brain or spinal cord to regulate its action.
• ex: When we consume a meal, we initiate the gastrocolic reflex. The presence of food in your
stomach is signal 1 — tells your colon it’s time to make way for food that’s coming down; so it
pushes the food/stool that’s currently in there out.
• The GI tract is also under hormonal control. Important hormones include:
• Gastrin: released from mucosal cells when we notice there’s food in the stomach. It’s initially
released into bloodstream, then comes back into stomach to stimulate secretion of digestive juices.
• Gastrin causes secretion of HCl from the stomach’s parietal cells and pepsinogen from chief cells.
Gastrin also increases stomach motility (churning power of the stomach to produce chyme).
• Gastrin is checked by low pH (~3) — this decreases gastrin release.
• When chyme is delivered to the duodenum, it causes release of secretin hormone into the bloodstream.
• Secretin first goes to the pancreas and cause the release of bicarbonate rich solution (involves
pancreatic enzymes and bicarbonate, which will neutralize the acid of chyme.
ORGAN SYSTEMS 87
• Secretin also goes back to the stomach to inhibit stomach motility and acid / pepsinogen release (it
counters gastrin)
• Because of the acidic chyme, we also see the release of cholosystokinin (CCK) from our intestinal
mucousa into our bloodstream where it travels to:
(1) The pancreas, to stimulate release of pancreatic enzymes, such as lipase.
(2) The gall bladder, to cause it to contract, sending bile back into the cystic duct and down and
out of the common bile duct into the duodenum. There it helps emulsify fat
(3) Cholosystokinin also goes into the stomach and decreases stomach motility to slow the
release of chyme.
• Note: It’s not just chyme as a whole that requires CCK to be released, it’s the fat in our chyme that
specifically causes the release of CCK.
• Similarly, it’s not a macromolecule that causes secretin to be released, but the HCl that comes in
along with chyme.
• The pancreas also is a big player of hormones, causes glycogen build up and break down.

————————————————Muscular System———————————————
———
HTTP://OERPUB.GITHUB.IO/EPUBJS-DEMO-BOOK/CONTENT/M46447.XHTML

MYOSIN AND ACTIN

• Myosins comprise a family of ATP-dependent motor proteins. They’re known for their role in muscle
contraction and their involvement in a wide range of other motility processes.
• Myosin 2 (has two heads) is an ATPase involved in actin-based motility (muscle contraction)
• Contraction of muscle:.
(1) Myosin is bound to the actin filament. ATP then binds to myosin “head” & myosin releases
actin.
(2) ATP hydrolyzes (—> ADP + Pi + energy). This “cocks” the myosin protein to high energy
conformation (“loads the spring”)
(3) Phosphate group is released from myosin, which releases the energy of the cocked position and
causes it to push on the actin filament, it “releases the
spring” as a power stroke that creates mechanical energy.
(4) ADP released, and myosin is still bound to the actin…
so we’re where we were in step 1, but one stroke further
along the actin filament. Chemical energy (ATP) has turned into mechanical energy.
• This action contracts the muscle cell, and through the synchronous process in many muscle cells,
contracts the entire muscle.

TROPOMYOSIN AND TROPONIN AND THEIR ROLE IN REGULATING MUSCLE CONTRACTION:

• When the myosin releases the actin after ATP binds, why wouldn’t the actin just go back to where it
was before, because of the tension? How does myosin keep pulling it along when it’s not on the actin
filament 100% of the time?
• You have many myosins working on one actin filament at once! So when one pair of heads is off
the actin, others might be in the process of pulling it; they all work together.
ORGAN SYSTEMS 88
• How do we stop this movement of myosin along actin when we don’t want to contract our muscle?
— Tropomyosin and Troponin!
• Tropomyosin protein coils around the actin, and it’s attached by the protein complex troponin.
• When a muscle is contracting, tropomyosin keeps the myosin from crawling up the actin.
• Blocks the myosin from being able to attach to the actin in its usual place OR if myosin is already
bound, tropomyosin keeps it from moving and walking up the actin.
• The only way to make the troponin unblock myosin is for the troponin to change its shape; this only
happens with a high concentration of calcium ions in the cell.
• Ca2+ binds to troponin and changes its conformation enough that the tropomyosin is moved out of
the way and myosin can bind and walk up the actin. [contraction]
• If Ca2+ concentration gets low, the troponin will go back to standard conformation and that makes
the tropomyosin block the myosin again, so contraction does not happen. [relaxation]

SARCOPLASMIC RETICULUM:
• How does the nervous system tell the cells to make its Ca2+ concentration high and contract muscle, or
make the Ca2+ concentration low and relax muscle? The sarcoplasmic reticulum
• The membrane of the muscle cell is the sarcolemma, and in it is a fold called the T-tubule.
• Inside of the muscle cell is an organelle called the sarcoplasmic reticulum, whose function is
purely storage. ATP-fueled channels on the SR pump in lot of Ca2+, so in a resting muscle, you
have a very high concentration of Ca2+ concentration within the SR.
• A protein complex connects the T-tubule to the sarcoplasmic reticulum.
• When a muscle is contracting, the SR will release the Ca2+ into the cell (where actin/myosin/etc.
are)
• How does the sarcoplasmic reticulum know when to release the Ca2+? Motor neuron synapse!
• A motor neuron synapses on the muscle cell. Recall that for a neuron to be synapsed, it sends an action
potential down its axon. Na+ voltage gated channel open and depolarizes membrane in one place,
which causes Na+ voltage gated channels to open up further along and depolarize the membrane there .
. . etc. Eventually at the axon terminal, Ca2+ gates are opened and Ca2+ floods into the axon terminal
body. The Ca2+ binds to vesicles that are holding neurotransmitters, the vesicles bind to the membrane
of the neuron, and neurotransmitters are released into the synaptic cleft.
• In motor neurons, the neurotransmitter released is acetylcholine.
• Acetylcholine binds to receptors on the muscle cell, which opens gated channels that allow Na+ inside
the muscle cell, which causes membrane depolarization and action potential in that cell!
• The action potential travels along the membrane as subsequent channels are opened, and eventually
reaches the T-tubule.
• When the action potential gets far enough down the T-tubule, the protein complex triggers all
the Ca2+ ions to be dumped from the sarcoplasmic reticulum into the cell.
• Of course, this Ca2+ in the cell then binds to troponin, which changes conformation to release
tropomyosin, and myosin can start “walking” along the actin filament to contract the muscle cell.
• Once the signal goes away, the “door” releasing Ca2+ closes & SR gains back all Ca2+ in just 30
millisec!
ORGAN SYSTEMS 89
ANATOMY OF A MUSCLE CELL:
• Tendons on either side of the muscle anchor it to bone. The tendon is just a type of connective tissue,
and it’s somewhat continuous with the connective tissue that forms the outer layer of the muscle, the
epimysium. The epimysium protects the muscles.
• A second layer of connective tissue, called the perimysium, is right under this protective layer. The
perimysium covers subunits of muscle, including the fascicle (aka fassiculus).
• Within each fasicle there’s another layer of connective tissue called the endomysium, which covers
individual muscle cells (aka myofibers)
• The myofiber has bumps on the outside, which are where nuclei sit — on the periphery of the cell.
• The cytoplasm of the myofiber is called the sarcoplasm. (myo = muscle; sarco = flesh)
• Within the myofiber is a further division called a myofibril — this is where contraction actually
occurs.
• If you look at a myofiber under the microscope, you’ll see striations (another name for skeletal
muscle is “striated skeletal muscle”). These striations are the z-lines, or z-disks, and the space
between two z-lines is called the sarcomere — it’s the most basic unit of muscle contraction.
• Actin filaments are anchored to the z-line, and myosin
is attached to the actin. (Myosin is anchored in the
sarcomere by the protein titin.
• The sarcomere has 2 different parts: A-bands & I-bands.
• The part that’s myosin and actin is the A-band.
• The part that is solely actin is the I-band.
• In contraction, it’s the actin filaments that move. So the
Z-lines move closer together, towards the center of the
sarcomere, and the I band is shortened but the A-band
remains the same length.

THREE TYPES OF MUSCLE:

• There are three types of muscle — smooth, skeletal, & cardiac — which are involved in basically all
movement of the body.
• Skeletal muscle: most are attached to tendon and bone, but not all are (e.g. external oblique muscles
are not attached to a tendon, or the “tendon” is just a sheet of fibrous tissue called aponeurosis).
• Skeletal muscles are voluntary, and are the fastest type of muscle
• They’re also straight, and have many nuclei that show up as bumps (they’re on the periphery rather
than in the middle) on the cell.
• Cardiac muscle is in the heart; this is only where you can find these special cells. — involuntary
• Cardiac muscles are branched (which makes them easy to spot), and have 1-2 nuclei, also in the
middle of the cell.
• Smooth muscle: largely found in the walls of hollow organs (e.g. stomach, bowels, etc) & blood
vessels
• Involuntary; slowest muscle
• Often described as “spindle-shaped;” smooth muscle cells have just one nucleus in the middle
ORGAN SYSTEMS 90
• Ex: Involuntary processes like vasodilation take a lot longer than than the active, voluntary process of
using skeletal muscles to jump, e.g.
• Skeletal and cardiac muscle is striated; smooth muscle is not.
A general rule of thumb is that smooth muscle is often found in hollow organs, like stomach and intestine.
(esophagus etc) + helps dilate blood vessels.
MOTOR NEURONS:
• Upper motor neurons (in the brain) send a signal to lower motor neurons (in the PNS).
• UMNs tell the LMNs when to start and when to stop contracting. LMNs directly signal muscle
cells.
• The soma is the body of the lower motor neuron. Dendrites of the LMN receive signals from the
UMN; then the LMN then sends out the signal through the axon.
• If you have a lower motor neuron injury, your muscle(s) experience weakness because they can’t
contract like they’re supposed to. If you have an upper motor neuron injury, you would also experience
weakness in the muscle(s), but this time because your muscle never receives the signal to contract.
• The key thing we look for with UMN injury, though, is not a weakness due to muscles not
receiving start signal; it’s a constant spasticity because the muscles don’t receive the stop signal.
• To make sure that signals aren’t dissipated and instead stay in the axon going down, some neurons are
insulated with a fatty myelin sheath. Action potential jumps down those axons along nodes of Ranvier.
• In the CNS, myelin is produced by oligodendrocytes. In the PNS, it’s produced by Schwann cells.
NEUROMUSCULAR JUNCTION, MOTOR END-PLATE:
• The neuromuscular junction is where motor neurons talk to muscle cells.
• Involves the axon terminal and the receiving muscle cell. In the receiving portion of the muscle cell
there are many folds, which increase the surface area available for Na+ and Ca2+ channels.
• The axon terminal receives action potential in the opening of Na+ channels so sodium floods into the
cell and depolarizes the membrane. At the same time (and only in the terminal), Ca2+ channels open so
Ca2+ floods into the axon terminal body.
• The Ca2+ then binds to vesicles that are holding neurotransmitter, acetylcholine the vesicles bind to
the membrane of the neuron, and lots of acetylcholine is released into the synaptic cleft.
• On the receiving muscle cell are nicotinic acetyl-choline receptors; when ACh binds, it opens the Na+
channels so Na+ floods the cell and depolarizes. After the cell is sufficiently depolarized, the
sarcoplasmic reticulum is triggered to open it’s floodgate and send lots of Ca2+ into the cell.
• Note: In cardiac muscle, intracellular Ca2+ is a trigger for the release of even more calcium from the
SR. This mechanism doesn’t occur in skeletal muscle, though.
• Gap junctions connect adjacent muscle cells, and allow for “synergy” between muscle fibers — when
one muscle cell contracts, many groups of muscle cells are triggered to contract.

TYPE 1 AND TYPE 2 MUSCLE FIBERS:

• Golden rule: mitochondria are more prevalent in type 1 muscle than type 2
• Color: Type 1 muscle fibers are red, because their increased mitochondria means they produce more
energy from oxygen (in oxidative phosphorylation) than type 2 fibers, which are white.
• Contraction Speed: Because type 1 muscle fibers rely on mitochondria, they have a very involved
energy making process (glycolysis, krebs, electron transport, etc.) & thus have slower contraction
speed
 ORGAN SYSTEMS 91
• Conduction Velocity: This is also slow in type 1 (“slow twitch”), compared to type 2’s fast twitch.
• Activity: Type 1 fibers (bc mitochondria) undergo aerobic respiration. Type 2 use anaerobic
respiration.
• Duration of contraction: Type 1 fibers, bc they can make a lot of ATP, will have a long duration
contraction. Type 2 can’t make as much ATP, so they have shorter duration contractions.
• Long duration contractions are used in places like your back or thigh muscles, which are used to
stand for long periods of time and to walk at an even pace.
• Short duration fibers are found in places like the arms, so you can quickly shake someone’s hand;
or in the fingers used to flick something — if you do those things all day long you’ll get very tired!
• Fatigue: Because type 1 muscle fibers have a lot of energy, they are resistant to fatigue. In contrast,
type 2 muscle fibers don’t have as much mitochondria or energy so they are easily fatigued.
• Power: Type 2 fibers generate more instantaneous force than type 1 fibers. Type 1 fibers have more
energy overall, though, and more fibers contracting for longer durations, so type 1 is more powerful.
• Storage: Both fast twitch (type 2) and slow twitch (type 1) use ATP to contract, but they use different
mechanisms to produce it. ATP is a very reactive molecule — if we have it we expect it to be used
right away… So type 2 muscle fibers, with their faster contractions, use ATP as the main energy
storage, in addition to creatine phosphate. In type 1 muscle fibers, triglycerides are the main energy
storage.
Type 1 Type 2

color red white

contraction speed slow fast

conduction velocity slow twitch fast twitch
activity aerobic respiration anaerobic respiration
duration long short
fatigue resistant to fatigue easily fatigued
power strong power less power
storage triglycerides ATP and creatine

CALCIUM PUTS MYOSIN TO WORK:

• Let’s zoom into the heart wall. You see cardiac cells, with branches and 1-2 nuclei. Inside that heart
cell, there are many proteins, most notably actin fibers and - in the middle of that actin - myosin.
• The z-lines (or z-disks) are pulled towards each other when muscle cell contracts.
• Binding sites for myosin are cover up with tropomyosin, bound to the actin fiber by
troponin (which is really a protein complex, with subunits C, I, and T).
• When troponin-C binds Ca2+, it moves the whole complex out of the way and myosin
can then bind to the actin.
• TL;DR — myosin likes when Ca2+ is around because then it can do work
• How do we increase inotropy, i.e. increase muscle contraction
• (1) Increase Ca2+ in the cell
• (2) Get troponin-C to be more sensitive, and bind Ca2+ more easily
ORGAN SYSTEMS 92

MUSCLE INNERVATION:
• Voluntary contractions are those of the skeletal muscle.
• These are controlled by me, so I use the cerebral cortex or the spinal cord.
• Involuntary contractions include those of cardiac and smooth muscles. We don’t need to think about
when to beat our heart, or when to vasoconstrict our capillaries in our hand when it’s cold.
• These are beyond me, so I use the brainstem or ganglia beside the spinal cord.
• The brainstem is responsible for involuntary contractions through sympathetic or parasympathetic
mechanisms. The sympathetic ganglia (i.e. cell body/soma of neurons) that sit outside the brain and
spinal cord) are also involved in involuntary contractions.

AUTONOMIC VS. SOMATIC, DIVISIONS OF THE PERIPHERAL NERVOUS SYSTEM:

• The autonomic system is under involuntary control; the somatic is under voluntary control
• Somatic nervous systems use acetylcholine as neurotransmitters.
• There are two subdivisions to the autonomic nervous system: sympathetic and parasympathetic.
• Sympathetic = “fight or flight” response
• The pre-ganglionic nerves of the SNS use acetylcholine still, but the post-ganglionic nerves use
epinephrine (aka adrenaline) as an endocrine hormone, with norepinephrine as neurotransmitters
• Parasympathetic = “rest and digest” response
• Also uses acetylcholine.

THERMOREGULATION:
• When the skin perceives that it’s hot outside (or wherever you are), it will send a neuronal signal to the
hypothalamus in the brain.
• The anterior (front) part of the hypothalamus responds to hot temperatures.
• The posterior (back) part of the hypothalamus responds to cold temperatures.
• The brain then sends a signal back to smooth muscles (which line our blood vessels) and skeletal
muscles (particularly in our core) as needed to help us maintain our core body temperature.
• In a hot environment, smooth muscle relaxes and vasodilates the arterioles. This allows the blood
flow to the skin to increase which allows us to dissapate heat.
• In a cold environment, smooth muscle will contract and vasoconstrict the arterioles. This shrinks
the heat filled blood vessels away from the skin so less heat is lost.
• Our skeletal muscles (particularly those in the core) shiver when we’re cold. This is because when
skeletal muscle contracts, ATP —> ADP + energy.. so our body shivers to increase this exothermic
reaction and release energy into the cells as heat.

————————————————Skeletal System————————————————
——
SKELETAL STRUCTURE AND FUNCTION:
• Arthropods have exoskeletons. Humans, and all vertebrates, have endoskeletons!
ORGAN SYSTEMS 93
• Our skeleton provides a variety of functions:
• Supports / structures the body, and provides a framework for movement
• Protects vital organs
• Performs a variety of physiological functions (most notably, storage of Ca2+ and hematopoiesis,
or the production of cellular components of our blood — RBCs, WBCs, and platelets).
• The axial skeletal is our skull, ribcage, and vertebral column — down the midline of our body.
• The appendicular skeleton is everything else — limbs, hip / pelvic area, metatarsals, etc.
Another classification of our skeletal system is between flat bones and long bones.
• Flat bones = skull, rubs, and bones in the pelvis
• Made of an inner spongey / cancellous bone, and an outer shell of compact bone
• Protect organs and serve as site of hematopoiesis.
• Long Bones = humerus, femur
• The long middle portion of long bones is the diaphysis; the ends are called epiphysis.
• In between the diaphysis and epiphysis (or where they connect) is the metaphysis, which
is where the growth plate is found.
• Long bones are also made of same inner spongey bone, and an outer shell of compact bone
• These provide the framework for movement, and also serve as a site of hematopoiesis.
• There are two types of bone marrow: red and yellow.
• Red bone marrow serves as site of hematopoiesis. (red = blood) — found in flat bones and in the
epiphysis of long bones
• Yellow bone marrow is the site of fat storage — found in diaphyses of long bones.

MICROSCOPIC STRUCTURE OF BONE — THE HAVERSIAN SYSTEM:

• The innermost part of a bone is made of spongey bone, which is filled with cavities called trabeculae.
• Surface area of spongey bone is 10x that of outer compact bone. Its purpose is to make bone light.
• Compact bone has fewer gaps and spaces than spongey bone, but what really makes it different is that
it has a specific type of organization made of osteon functional units (aka the Haversian system).
• Each osteon looks sort of like a cylinder, and it has multiple concentric layers of bone (sheets) that
wrap around to form the osteon. Each of these layers is called a lamellae.
• In the center of the lamellae layers is the Haversian canal, or central canal. Blood and lymph
vessels, as well as nerves, travel through this canal.
• In between the sheets of lamellae are tiny channels
called canaliculli. They branch out from the central
canal to empty spaces called lacunae. Each lacunae is
just an empty space for osteocytes, or bone cells.
• The osteocytes have long cellular processes that
branch through the canalliculi to contact other
osteocytes via gap junctions, which allow the cells
to communicate and exchange nutrients / signals.
ORGAN SYSTEMS 94
• Volkmann’s canals run perpendicular to the Haversian
canals, and they connect osteons to one another.
They also carry their own set of small blood vessels.
• The outermost superficial layer of bone is called
the periosteum.

CELLULAR STRUCTURE OF BONE:

• Bone is mostly made up of the bone matrix, and then the cells that help to form this bony matrix.
• The bone matrix consists of two principal building blocks:
• Osteoid forms the organic portion of the matrix
• Hydroxyapatite forms the inorganic portion of the matrix
• Osteoid consists of a soft but highly ordered structure of proteins and type 1 collagen fibers.
Together, this gives bone its tensile strength.
• Tensile strength refers to how much an object can be stretched before breaking. This is different
from compressive strength, which is how much the object can be compressed before breaking.
• Hydroxyapatite is made of calcium phosphate crystals. These make up the mineral content of bones,
and give them their rigid strength and density.
• There are four different types of cells we should know in bone:
• (1) Osteoprogenitor
• These cells are basically an immature version, or the precursor to, osteoblasts. They differentiate
into osteoblasts under certain growth factors
• (2) Osteoblasts
• These are responsible for synthesizing collagen and proteins (specifically, osteocalcin and
osteopontin, which together make up osteoid, the organic part of bone matrix).
• Osteoblasts also synthesize alkalaine phosphatase, which is responsible for forming
hydroxyapatite.
• Once osteoblasts have synthesized enough collagen, proteins, and alkaline phosphatase to form the
organic and inorganic portions of the bony matrix around them, they mature into the osteocyte.
• (3) Osteocytes
• The spaces osteocytes occupy are called lacunae (“lakes” of empty space in bone)
• They have little branched projections that reach out to communicate with other osteocytes or
osteoblasts, which give them a star-like appearance.
• (4) Oxteoclasts
• Derived from monocytes
• These are responsible for bone resorption; they break bone back down (using an enzyme called
tartrate resistant acid phosphotase).
• Bone is constantly being remodeled — it’s built up with osteoblasts (using alkaline phosphatase), and
broken down by osteoclasts (using tartrate resistant phosphotase).
• As osteoclasts are resorbing bone, they start to form empty spaces. Recall, empty spaces are lacunae;
osteoclasts form a special type of lacunae called Howship’s lacunae.
ORGAN SYSTEMS 95
SKELETAL ENDOCRINE CONTROL:
• One of the main functions that bone performs is storage of calcium.
• Calcium homeostasis (the flow of calcium between the bloodstream and bone) is under endocrine
hormone control. These hormones alter the ratio of osteoclast activity to osteoblast activity.
• As osteoclast activity increases (more bone resorption / break down) relative to osteoblast activity,
there’s an increase in the liberation of calcium and phosphate into the bloodstream from bone.
• The opposite happens with an increase in osteoblast activity - Ca2+ & PO 4 3– levels in blood
decrease.
• Main hormones responsible for maintaining calcium homeostasis are: parathyroid (PTH), calcitonin,
and calcitriol (which is basically the active form of vitamin D).
• These hormones help to regulate the amount of calcium absorbed from the gut or reabsorbed from
the kidneys. They also help regulate osteoblast / osteoclast activity in bone.
• Calcitonin decreases the amount of calcium and phosphate in the blood. (calcitonin tones down blood)
• Parathyroid hormone (PTH) and calcitrol both increase calcium in the blood; but PTH decreases
phosphate levels, while calcitrol increases them.
• General themes of calcium homeostasis:
(1) Each time calcium increases in the blood, you have a concurrent increase in phosphate. Same
thing if Ca2+ decreases, phosphate will decrease.
(2) If calcium + phosphate increases in the blood, it decreases in bone; and vice versa.

PTH increase Calcitonin increase Calcitriol increase

osteoblast activity decreases increases decreases

osteoclast activity increases decreases increases

intestinal / renal increases decreases increases

Ca2+ absorption

• Why does the concentration of free Ca2+ in the blood matter so much? Why the elaborate system?
• Too much free Ca2+ ions in the blood leads to hyper-excitable cell membranes. Can cause lethargy,
fatigue, and memory loss.
• Too little calcium in the blood leads to muscle cramps and convulsions.

CARTILAGE:
• Cartilage is, at the most basic level, an extracellular connective tissue found throughout the body. It’s
created by cells called chondrocytes, which derive from the same precursor cells as bone
(fibroblasts).
• Chondrocytes secrete collagen (fibrous protein) and elastin (elastic protein)
• These two proteins give cartilage strength and flexibility.
• Cartilage is not innervated (no nerve cells) and it’s avascular (doesn’t have arteries, veins, or blood
vessels). Instead, cartilage receives its nutrition and immune protection from the surrounding fluid.
• There are three main types of cartilage in the body:
ORGAN SYSTEMS 96
(1) Hyalin (articular) cartilage — found in the larynx, trachea, all the joints (where the surfaces of
bones are articulating each other).
• Its main purpose is to reduce friction and absorb shock.
(2) Elastic cartilage — found in the shape of the outer ear and in the epiglottis (which protects your
airway when you’re swallowing food.)
• Its main purpose is to provide shape and support
(3) Fibrous cartilage — found in the intervertebral discs of the spine, and where the two halves of
your
pelvic bone come together to form a joint (pubic symphysis)
• Main purpose is to provide rigidity and absorb the shock transmitted between these joints.

LIGAMENTS, TENDONS, AND JOINTS:

• Ligaments and tendons are types of extra strong and dense connective tissue
• Ligaments connect bone to bone; tendons connect muscle to bone.
• A joint is the point where one bone meets up with another — there are different joint types in the body:
• Synarthroses joints — immovable; where two bones are fused together (ex: in the skull)
• Antiarthroses joints — both stiff, but slightly moveable (ex: vertebral joints)
• Synovial joints (aka diarthroses) — includes ball and sockets joints (ex: shoulders and hips) which
have many degrees of motion, and hinge joints (ex: elbow or knee) which have one plane of
movement.
• These are lubricated by synovial fluid, contained within synovial capsule that surrounds the joint.
• The surfaces of bones that meet up in a joint are lined by a special kind of smooth cartilage: articular
(aka hyalin) cartilage. Like all cartilage, it’s avascular and not innervated — so it has a hard time
getting the nutrients it needs to heal and recover if it were to become damaged by overuse or infection.
• Overuse of joints over time can lead to inflammation, which causes arthritis. (This can cause
permanent destruction of articular cartilage, which leads to the pain and stiffness).
• Ossification is the process in which cartilage is transformed into bone. Bone grows in three stages:
first, tissue forms a mesh of collagen fibers, then the body creates a polysaccharide that acts like
cement to hold the tissues together. Finally, calcium crystals salts are deposited to form bone.

———————————————Integumentary System——————————————
———
SKIN OVERVIEW
• The integumentary system comprises the skin and appendages. The appendages include nails,
hair, and sweat glands.
• The skin is the largest organ of your body, weighing approximately 21 pounds.
• The skin has several functions: it serves as an impermeable surface to the outside, serves as a
structural barrier, serves as an immunological barrier against pathogens such as viruses, can
perceive stimuli from the environment via receptors, conducts sensation, and cools the body via
sweating (thermoregulation) by evaporative cooling

WHAT IS SKIN? (Epidermis)

• There are three distinct layers to the skin. In order from outermost to innermost, the order is:
epidermis, dermis, and hypodermis (subcutaneous tissue).
ORGAN SYSTEMS 97
• The epidermis is composed of five strata (latyers). The stratum basale is the most inferior strata
of the epidermis and is composed of keratinocytes, which secrete cytokeratin, giving skin its
toughness to protect skin. The stratum basale also is known for rapid cell division, and where
we get our skin color. The cells that give skin color are called melanocytes. The melanocytes
secrete melanin, which causes skin color.
• The amount of melanin determines the darkness of skin.
• The layer on top of the stratum basale is called the stratum spinosum, or the spiny layer. It is
composed of desmosomes, which permit water loss. This layer also includes Langerhans cells,
which are part of the immune system.
• Above the stratum spinosum is called the stratum granulosum. This is composed of granules
called keratohyalin granules. These granules hold proteins which help handle keratin. They
move cytokeratin around the cells. These cells also release lamellar bodies, which secrete lipids
that give skin its water-tight capability.
• The layer above is the stratum lucidum, or the clear layer. This layer is composed of dead
keratinocytes, which are clear. These cells have lost their nuclei and organelles.
• The outermost layer is the stratum corneum, composed of stacked layers of dead keratinocytes.
15-20 layers of these cells which randomly and continuously slough off.

WHAT LIES BENEATH THE EPIDERMIS (Dermis and Hypodermis)

• The dermis is composed of two strata and sits below the epidermis. The bottomost layer of the
epidermis is the stratum basale. Immediately underneath that is the first layer of the dermis, or
the papillary dermis. Underneath that is the bottomost layer of the dermis is the reticular
dermis.
• While the epidermis is composed of epithelial tissue, the dermis and hypodermis is composed of
connective tissue. Connective tissue contains proteins like actin, collagen, and structural
proteins. Its primary purpose is to hold things together.
• In the papillary dermis, there is thin, loose connective tissue. In the reticular dermis, there is
thicker and denser connective tissue to anchor things down.
• The thin connective tissue of the papillary dermis allows for movement of structures like blood
vessels and diffusion of oxygen. This layer must be flexible to allow for this.
• The papillary dermis also contains nerve endings.
• The reticular dermis contains thick dense tissue for anchoring structures down. This layer also
anchors glands, which extend outward toward the epidermis, and also anchors follicles form
which hairs protrude. The hair follicle is anchored within the reticular dermis.
ORGAN SYSTEMS 98
• The reticular dermis also contains an arrector pili muscle, which allows for hair to stand on end
when you are cold.
• The hypodermis is the bottommost layer of skin. It is also known as subcutaneous fat. This layer
is composed of many layers of fat. Fat is used to absorb shock and insulates tissue.

WHERE DO OUR HAIR AND NAILS COME FROM?

• Nails and hair are part of our appendages, the second component of the integument. The nail
root is attached to the epidermis. Cells emerge from the stratum basale and other layers of the
epidermis and extend to form the nail.
• The nail is therefore considered a part of the epidermis. It is made up of keratin packed into dead
cells. This is what keeps the nail strong. The fingernails grow 4x faster than the toenails.
• The hair is another appendage. Hair grows from the dermis, the middle layer between the
epidermis and the hypodermis. The dermis has two layers (papillary and reticular layer).
• The follicle originates in the reticular dermis, and the shaft of the hair emerges outwards through
the other layers.
• The hair also is composed of keratin. There is a band of muscle in the papillary dermis called the
arrector pili muscle, a smooth muscle which causes hair to stand on end when it contracts. This
is what causes goosebumps as well.
• Hair standing on end creates a bed of warm, insulating air to protect polar bears from the cold. In
humans, the hair is not long enough so this phenomenon does not occur, so the hair can be
considered a vestigial structure.
WHAT’S IN SWEAT? (HOLOCRINE, APOCRINE, MEROCRINE GLANDS)
• There are three kinds of glands in the reticular dermis. Ducts lead out from the reticular dermis to
aid in secretions.
• There are three kinds of glands in the reticular dermis: the holocrine gland, apocrine gland,
and merocrine gland.
• The holocrine gland disintegrates an entire cell to release sebum. These glands are also known as
sebaceous gland.
• Apocrine glands release secretions form the apex (top) of the cell. These glands release proteins,
lipids, and steroids.
• The merocrine glands release watery sweat via exocytosis.
ORGAN SYSTEMS 99
• Holocrine glands are found on the face, chest on the back. Apocrine glands are concentrated in
the armpits, groin, and around the nipples.
• Apocrine sweat glands release secretions right into the hair follicle, in contrast to the other
glands.
• Merocrine glands are concentrated in the palms and soles.
• Sebum from the holocrine gland is used to lubricate the skin and to slow bacterial growth.
• Apocrine glands do not start to release secretions until puberty starts. These glands are
implicated in emotional sweating.
• Merocrine glands are considered the most important, as they hope to cool down during
evaporative cooling, and allow the disposal of salts and nitrogenous wastes. Lysozyme and
antibodies are also released by the merocrine glands.

WHY DOES SWEATING COOL YOU DOWN?

• Sweat is mostly composed of water. A rephrasing of the titular question is: why does water
sitting on the surface of the skin cool us down?
• When the body temperature rises, the temperature of our epidermis also rises. This epidermis is
in contact with water, therefore heat is transferred from the skin to the water molecules of sweat
sitting on the skin.
• When the water of the sweat has enough energy, it evaporates. This cools down the entire
system of water and skin, as only the highest energy molecules of water are those that evaporate.
Therefore, the departure of high energy water molecules decreases the total kinetic energy of the
system, and therefore the temperature.
OVERVIEW OF SENSATION AND MEISSNER’S CORPUSCLE
• Our skin helps us perceive the environment and plays a role in sensation. Mechanoreceptors
and other receptors generate signals in respond to stimuli to help us perceive the environment.
This sensation takes place via afferent nerve fibers which take a stimulus and create a signal for
processing in our CNS. Efferent nerve fibers are used to communicate from the CNS to muscle
fibers.
• A-delta fibers are afferent fibers which perceive pain and temperature. A-beta fibers perceive
everything, and include mechanoreceptors.
• The structure of the mechanoreceptor determine the function, and the function will help us
determine the location of the receptor.
• The Meissner’s corpuscle is a type of mechanoreceptor, located in the papillary dermis for
perception of external stimuli. In the corpuscle are layers of disks composed of many nuclei.
ORGAN SYSTEMS 100
These disks are known as epithelial or laminar disks. When a force perturbs a disk, the disks are
nudged past each other. Sodium ions then enter an afferent fiber, causing an action potential and
sensation.
• Meissner’s corpuscle is used to perceive light touch in glaborous skin, or non-hairy skin. For
example, this mechanoreceptor would perceive the feeling of putting on a smooth cotton T-shirt.
• In Messiner’s corpuscle, a constantly changing stimulus is needed to perceive the stimulus.
Therefore, after the cotton T-shirt is on our skin and no longer moving, it will not be felt and
Meissner’s corpuscle will not be activated.

PACNIAN’S CORPUSCLE AND MERKEL’S DISK

• Pacnian’s corpuscle is another mechanoreceptor. It is also known as the onion-layered
corpuscle or the lamellar corpuscular.
• When a significant force touches one of the lamella, or one of the concentric rings of the
corpuscle, an action potential in an efferent nerve cell is activated.
• This type of corpuscle responds to a deep touch in hairy and non-hairy skin. For example, a poke
or push would activate this corpuscle.
• This type of mechanoreceptor also requires a constantly changing stimulus. It is located in the
hypodermis.

• Merkel’s disk is a single disk. It is a specialized keratinocyte which holds many vesicles. These
vesicles hold many neuropeptides, and the disk is attached to a receptor.
• When the disk is stimulated, the peptides are released and stimulate a receptor, causing sodium
to enter the disk.
• This stimulates an afferent neuron. It is located in the stratum basale or the papillary dermis.
• It responds to light touch that is sustained. The stimulus does not need to change for us to notice
it.
RUFFINI’S ENDING AND HAIR FOLLICLE RECEPTOR
• Ruffini’s ending is another corpuscle. It is called Ruffini’s ending or Ruffini’s corpuscle. This
mechanoreceptor has no disks or rings, but rather a afferent nerve fiber. It is a A-beta fiber which
branches into the corpuscle.
• There are many afferent branch receptors in the corpuscle, as well as collagen, a structural fiber.
When the skin is stretched, a force is generated which hits the Ruffini corpuscle. This causes the
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collagen to be perturbed. Because this collagen shifts, ion channels within the A-beta fiber opens
causing an action potential to be generated.
• This type of mechanoreceptor responds to sustained touch and is located deep within the skin in
the dermis, specifically the reticular dermis.
• The last mechanoreceptor discussed is the hair follicle receptor. When a stimulus touches a
hair, there is a nerve fiber that surrounds the follicle.
• The impetus for this action potential is due to the deflection of the hair (a light touch on hairy
skin). This type of receptor is located in the reticular dermis. A constantly changing stimulus is
needed, else collagen will fill in the receptor.
PAIN AND TEMPERATURE
• The perception of pain is called nociception while the perception of heat is called
thermoception. We sense pain and temperature using a specialized receptor.
• To sense temperature, we rely on the TrpV1 receptor, which is also sensitive to pain. TrpV1 is a
receptor located in the cell membrane. When there is a change in temperature, a conformational
change occurs in this protein.
• When heat or pain are applied, this conformational change occurs. Each cell with TrpV1 receptor
has nerve fibers which send signals to the brain.
• Pain, such as poking, causes cells to break up and release molecules, which bind to TrpV1
receptors, causing the same conformational change a change in temperature causes, sending a
signal to the brain.
• There are three types of nerve fibers: fast, medium, and slow. Fast nerve fibers are fat and
contain a lot of myelin, allowing the signal to travel quickly. The large diameter of the nerve
fiber also causes less resistance. These types of fibers are also known as A-beta fibers.
• Medium nerve fibers are smaller in diameter and have less myelin, causing a slower signal.
These are known as A-delta fibers.
• Slow nerve fibers are very small in diameter and are unmyelinated. Signals through these fibers
are sent to the brain slowly. They are also known as c fibers.
• When we touch a stove, all fibers would act. A-beta fibers will act fast causing us to recoil our
hand, A-delta fibers will carry the sensation of pain, and c-fibers will cause a lingering sense of
pain hours after we have touched the stove.
• Similarly, when we eat spicy foods containing capsaicin, the capsaicin binds to nerve fibers,
causing the signaling pathway as a change in temperature.
THERMOREGULATION BY MUSCLES
• We shiver and use our muscles to maintain our body temperature, a process called
thermoregulation. When we perceive it is hot, our brain senses it is hot in the hypothalamus.
• The hypothalamus is split into the anterior and posterior hypothalamus, each of which
responding to different temperature.
• When it is hot, we use the front (anterior) hypothalamus (mnemonic – think Front=Fire). If it is
cold, we use the posterior part of our hypothalamus.
• Smooth muscle lines our arterioles, while skeletal muscle works on our biceps, etc.
• When blood cells move around in arterioles, they carry energy. When it is hot, we aim to
dissipate this energy/heat. Vasodilation therefore occurs when it is hot to dilate the arterioles of
the skin. This allows more blood flow to flow near the skin, allowing us to cool off by diverting
blood flow to our skin.
• Skeletal muscles do nothing when it is hot.
• Vasoconstriction occurs when it is cold, causing arterioles near the skin to become narrower to
retain more heat carried by the blood. Skeletal muscle contract when it is cold and take ATP to
make ADP and energy. This is an exothermic reaction, which can be used to heat up in cold
ORGAN SYSTEMS 102
environments (shivering).

Reproductive System:
•

A secondary spermatocyte is formed after completion of meiosis I; it has 46 chromatids and 23

chromosomes.

Reproductive System:
Ejaculatory duct is not one of the first structure to conduct sperm during ejaculation
Vas Deferens is not one of the first structure to conduct sperm during ejaculation
Ampulla of vas deferens is the expansion of the vas deferens closer to ejaculatory duct.
Epididymis, vas deferens, ampulla of vas deferens, ejaculatory duct, urethra is the correct order.
Prostatic cancer may lead to inhibition of secretions of prostate that are essential for sperm activation
Bulbourethral glands produce pre ejaculatory fluid that aids in lubrication, thus its obstruction does not interfer
with sperm production, maturation or activation (acronym: think of an imaginary BULBO lubricant brand)
During spermiogenesis, maturation of the sperm, unnecessary cytoplasm is shed off.
The pliable tissues are not responsible for secretion of seminal fluid
Corpus spongiosum remains pliable during an erection.
During an erection the corpus spongiosum remains pliable, corpora cavernosa becomes firm, and the pliable
tissues maintain the urethra open.
Clitoris is very distant from cervix
Fimbriae is connected with ovaries, thus distant from cervix
Fornix is immediately adjacent to cervical canal, thus likely to be infected.

Oxytocin is responsible for labor contractions and kept at low levels during pregnancy
Levels of estrogen are kept high during pregnancy
Progesterone secretion has to be kept high during pregnancy. Progesterone is initially secreted by
corpus luteum, so early degeneration of corpus luteum may lead to misscarriage.

The ovaries hold the corpus luteum that secrete estrogen earlier in the pregnancy and the placenta
is responsible for estrogen production later in the pregnancy
Low estrogen/progesterone = menses

Estrogen levels peak twice during the uterine cycle, and changes do not consistently correlate with changes in the
endometrium.
Luteinizing hormone levels peak prior to thickening of the endometrium.
Follicle-stimulating hormone levels peak prior to thickening of the endometrium.
Progesterone is a progestational hormone whose peak is correlated with thickening of the endometrium.

Estrogen levels must rise before ovulation

Follicle stimulating hormone levels must rise before ovulation
Luteinizing hormone levels must rise before ovulation.
Progesterone levels rise after ovulation already occurred.
ORGAN SYSTEMS 103

Order of Sperm Leaving: straight tubules, rete testis, efferent ductules, epididymis ductus, vas
deferens, ejaculatory duct, prostatic urethra, membranous urethra

Second polar body is haploid

Hint #2
Secondary oocyte is halpoid
Hint #3
Spermatid is haploid
Hint #4
Primary spermatocyte, primary oocyte, and zygote are examples of diploid cells

Sertoli cells' tight junction create the blood testis barrier prevent antibodies from binding to sperm
Credits: reddit.com/u/magstarr

Other:
Stratified layers of epithelial cells line tissues and glands that require layers of protection.
Simple, single layer epithelia allow for the passage of small particles.
Simple cuboidal epithelial cells line secretory ducts.
The lining of lymphatic vessels is composed of simple squamous epithelium.
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