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IBS summary
- Embryology
Pre-embryonic (weeks 1-3): After first fertilisation the fertilised egg
replicates to form a new blastomere, these two cells are surrounded
by a zona pellucida
...
Following this we see differentiation within the
cell mass of the morula where some differentiate into the
trophoblast which is the outer covering of the blastocyst the other
cells form the inner cell mass, there also exists the blastocyst cavity
in the centre of the blastocyst
...
After this the inner cell mass then splits into the
ectoderm, which forms the skin brain and nervous system, and
endoderm, which forms the lining of the gut and other internal organs and is surrounded by the
trophoblast, within the endoderm is the yolk sac which contains the nutrients needed for the
continued replication of the cells
...
In the 3rd week of development there are several
noticeable features that develop within the ectoderm of the embryo
...
Between these two membranes a
groove appears which is the primitive streak
...
It helps
in the embryonic induction of other cells to become what they are
meant to be by releasing chemical signals
...

It is eventually replaced by vertebrae and in adults the only remnants
seen is the nucleus pulposus in the spinal cord
...
This plate folds dorsally creating the neural
groove and fold
...
There are also peripheral
cells that break free known as the neural crest which
forms the peripheral nervous system, as well as
differentiating into various cells such as
neuroendocrine cells, melanocytes in addition to
being able to differentiate into the facial
mesenchyme cells
...
Usually the fluid is drained by the aqueduct of sylvius however if there is a blockage
then hydrocephalus occurs as fluid builds up in the brain
...
Microcephally occurs if there is no
cerebral cortex or it is too small
...

- Membrane Transport
Important to regulate intracellular ion concentrations and their uptake along with nutrients and the
excretion of waste products
...

Passive transport: diffusion down a concentration or electrochemical gradient without the use of
energy or a carrier
...
Membranes are most permeable to small,
lipophilic molecules when there is a high electrochemical gradient
...
Channels are
faster than transporters but transporters can be regulated
...
Despite sodium ions being a lot smaller than potassium ions the
potassium ions can fit through much better due
to the selectivity filter
...
To get through the ions must be
dehydrated as hydrated ions are too large and
this requires energy
...

Transporters: these also exhibit selectivity but transport less than 1000 molecules per second so are
slow
...
An example of a
uniporter is the glucose transporters ‘Glut’ which only transport glucose and are expressed by most
cell types
...

Glut 1 is found on the surface of erythrocytes and carries glucose into the red blood cells along a
concentration gradient but as Glut 1 transporters work both ways it is important that glucose is not
lost back out of the cell and so once within the erythrocyte the glucose is converted to glucose 6
phosphate which maintains the glucose concentration gradient
...

Sodium Potassium Pump: found on all cells and uses 30% of most cells available energy as it
hydrolyses ATP in order to transport 3 Na+ ions out of the cell in exchange for transporting 2 K+ ions

inside
...
The pump
works as follows:
1
...

2
...
The pump then binds to two extracellular potassium ions which stimulates the phosphate to
detach from the pump which reverses the conformational change and moves the two
potassium ions into the cell
...
There are symporters such as sodium glucose co
transport which moves glucose into the cell with sodium along the sodium electrochemical gradient,
alternatively there are antiporters such as the sodium calcium ion antiporter which moves calcium
out as Na+ moves in
...
To move
one glucose molecule into the endothelial cells requires 2 sodium ions to diffuse in
...
It happens more to move
glucose into the cell by this method due to the cooperative binding and the higher concentration of
sodium outside so glucose is more likely to bind outside
...
This method is important as the glucose cannot diffuse directly into
the blood stream due to the existence of the tight junctions preventing paracellular transmission of
the glucose
...

- Amino Acids
Glycine
Alanine
Valine
Leucine
Isoleucine
Proline

Aliphatic (hydrophobic)

Phenylalanine
Tryptophan
Tyrosine

Aromatic

Glutamate
Aspartate

Acidic (Negative)

Glutamine
Asparagine

Amides

Serine
Threonine

Alcohols (nucleophilic)

Methionine (Hydrophobic)
Cysteine (Nucleophilic)
Histidine
Lysine
Arginine

Sulphur containing

Basic (Positive)

Amino acids have two weakly ionising groups, the amine group and the acid group so is amphipathic,
this also means that there is two pKa values of the amino acid
...
At pHs below the pKa value
for each group the undissociated form is predominant and at pHs above the dissociated form is the
most common
...
The
charge that can form on these groups are important in their influence on protein structure and
function
...

- Proteins
There are 4 levels of protein structure:
Primary – linear sequence of amino acids
Secondary – folding of the sequence of amino acids either into an alpha helix or beta pleated sheet
stabilised by hydrogen bonds between the carbonyl oxygen and the hydrogen of the proteins, in an
alpha helix the amide hydrogen is bound to the hydrogen of the residue 4 places ahead
...
Myoglobin
is a globular protein and a compact monomer, which is 75% alpha helical and contains a haem
group
...

Extracellular proteins are stabilised by disulphide bridges between the highly reacitive and available
sulph-hydro group on the cysteine amino acids, the bridge is very stable apart from in reducing
conditions
...


- Cell components




Mitochondria – site of respiration
Ribosomes – site of protein synthesis by translation
Nucleus – storage of DNA and site of transcription


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Cytosol – site of metabolic reactions within the cell
Smooth endoplasmic reticulum – Lipid metabolism, detoxification and calcium ion storage
Rough endoplasmic reticulum – synthesis of extracellular proteins
Golgi apparatus – modification of proteins
Endosomes – control uptake from the cells surface
Lysosomes – contain enzymes and are important in digestion
Peroxisomes – carry out oxidation and the synthesis of myelin

Due to the large amounts of organelles and other molecules within the cells of the body diffusion is
an unreliable method to transport substances throughout the cell and so the cytoskeleton is
important
...





Tubulin microtubules: the thickest of all the cytoskeletal filaments 25nm, there are 2
isoforms of the protein alpha and beta
...
The microtubules are important for the movement of organelles and
vesicles as well as in cell division where they provide the origin of spindle fibres
...
The tubules radiate away from the microfilament
organising centres by the nucleus and align with mitochondria
...
There are six isoforms of the microfilament
which all require ATP for their assembly, unlike microtubules
...
The actin fibres are helical in their
arrangement and are often located in the cell cortex
...
The filaments are formed from alpha
helical monomers that then coil together which form a coiled coil dimer of two of the
monomer filaments
...
There are many different forms: attached to the
nucleus are lamins, which form the nuclear lamina and
aid in the breaking down and reformation of the nuclear
envelope during mitosis; keratins, neurofilaments and
vimentins in different cell types
...
There
are different types of intermediate filament depending
on the cell type they are found within:
o Epithelial cells – keratin
o Mesenchymal – vimentin
o Myocardial – Desmin

The cell adhesion molecules are very important in organising the
cytoskeletons components, actin binds to Adherens junctions and
intermediate filaments bind to desmosomes and
hemidesmosomes
...

External signals can influence the positon of the dynamic equilibrium of the two forms of the
microfilaments
...

In order to transport proteins; such as transcriptional factors, structural proteins, and ribosomal
proteins; into and out of the nucleus an import sequence of basic amino acids is attached to the
protein which interacts with importids which allow proteins through
...

Proteins encoded in the mitochondria are also synthesised completely in the cytosol and are
transferred into the mitochondria which means they must cross two membranes, the import
sequences of mitochondrial proteins are amphipathic helices at the N-terminus
...






First the precursor mitochondrial protein’s signal sequence is recognised by receptors on the
surface of the mitochondria and the sequence binds to the receptor in the TOM complex
The TOM complex carries out the insertion of the protein into the mitochondria with the
help of the TIM23 complex which translocates the protein into the matrix of the
mitochondria
Once inside signal peptidase cleaves the signal and leaves the mature mitochondrial protein

This cleavage makes the import irreversible which is important as if the protein leaves the
mitochondria if the mitochondria bursts due to a fault it may be as a result of a damaged protein
which we would not want being incorporated into healthy mitochondria
...
Proteins destined for the extracellular
surface are synthesised in the ribosomes on the rough endoplasmic reticulum and then transported
by golgi apparatus to the surface or to lysosomes by vesicular transport, for this reason cells with a
large secretory role have a large amount of rough endoplasmic reticulum
...
The signals on
secretory proteins are 15-20 hydrophobic amino acids which are located at the N terminus
...
The polypeptide chains being formed by the ribosomes anchor the
ribosomes to the surface of the endoplasmic reticulum
...
This occurs by Sar-1 GDP being altered to a Sar-1
GTP protein by a protein on the
surface of the endoplasmic reticulum,
and causes a conformational change,
allowing it to bind to the surface of the
endoplasmic reticulum
...
Eventually it joins the vesicular tubular cluster which is moved along microfilaments by
motor proteins to join the cis Golgi network
...


Within the Golgi apparatus N linked oligosaccharide side chains
are modified, O-linked glycosylation occurs where a
carbohydrate molecule is attached to an oxygen on an amino
acid residue which will become hydrated so it becomes slippery,
mannose-6-phosphate modification also occurs and within the
Trans-Golgi network the final destination is decided
...
Regulated
pathways only release the protein in secretory granules when a
signal is provided, lysosomes are supplied by late endosomes
...
The negative
charges within the structure of HbS cause the haemoglobin molecules to repel one another and
instead of the normal conformation they form long strands which causes erythrocytes to have a
sickle shape instead of the normal biconcave disk, this change in shape means that it cannot fit
through blood vessels effectively and can cause blockages, or the cells burst and the haemoglobin is
metabolised by the liver which results in the high bilirubin levels
...
Upon storage more sickle cells appear because HbS only polymerises when it is
deoxygenated
...

Because being heterozygous for SCD is asymptomatic and gives people protection against malaria
SCD is common as it gives heterozygotes a selective advantage
...
The abnormal structure leads to defective mineralisation
and fragile bones, to test for OI electrophoresis can be carried out which identifies the slower
moving cross linked chains
...

- Enzymes within the body:



Accelerate metabolic reactions
Enable the regulation of the rates of reactions and the pathways taken

- Enzymes in biomedicine:


Can be used in diagnosis as when cells are damaged we can identify the cellular enzymes
that are within the plasma and determine which cells are damged, we can also identify
which tissue the drug comes from because of the existence of isoenzymes which are
different forms of the enzyme depending on the tissue they reside within
...


- Transcription
1
...
RNA polymerase binds to the primer site on the gene
3
...

4
...
Pre-mRNA undergoes splicing which removes introns from the pre mRNA
6
...
The mature mRNA leaves the nucleus through nuclear pores in order for it to reach the
ribosomes for translation
Within transcription enzymes modify the end and start of the m-RNA by adding a modified
guanosine triphosphate at the start of the sequence and a poly A tail, a repeating sequence of
adenine nucleotides, at the end to add stability to the structure
...
Intron loops out of the pre-mRNA as snRNPs, (small nuclear ribonucleoprotein particles)
formed from snRNA and proteins, attach to the mRNA to form a splicesome
2
...

2
...

4
...

6
...


Methionine binds at the P site of the large subunit of the ribosome
mRNA is pulled through the ribosome until a start codon is read by the small subunit
the anticodon of the methionine-tRNA complex then binds to the AUG sequence
the complimentary tRNA molecule then joins at the A site of the ribosome
peptide bonds form between the two amino acids
the tRNA molecules move along until they leave and this continues until a stop signal is read
as there is no anticodon on any tRNA molecule complimentary to the stop codon a release
factor binds instead
8
...
the ribosomal subunits then separate and the release factor is released and the mRNA
disintegrates





RNA is transcribed (read) and translated in a 5’ to 3’ direction!
RNA is read in groups of three bases (Triplets)
On each strand of DNA there are 3 reading frames and 6 on a double stranded helix
Codons code for amino acids





The genetic code is universal and degenerate
There is only one start codon and that is AUG for methionine
UAA, UGA and UAG are stop codons and do not code for amino acids

An open reading frame is a string of sense codons (those which code for an amino acid) that starts
with an ATG group and is ended by a stop codon
...


N–

Amino acid chain

Start of chain

–C
End of chain

During translation amino acids are joined together by peptide bonds which are formed in a
condensation reaction between the amine group of one amino acid and the carbonyl group of
another
...

- mRNA
Uses the nucleotides U,A,C,G
...
The
cap of the mRNA is a modified
GTP molecule which allows
the ribosome to recognise it
and bind to it
...
Within prokaryotes there is no introns in the pre-mRNA and so
there is no need for splicing however introns must be removed from eukaryotic pre-mRNA as it is
not CO-Linear
...

Large subunit 60S:
- 28S rRNA
- 5
...


- tRNA
Transfer RNA carries amino acids to the ribosomes during translation when they become assembled
into polypeptide chains
...
At the opposite pole the anticodon is located which
reads the codon on the mRNA so the amino acid is placed in the correct location
...
One aminoacyl-tRNA synthetases is used for each
amino acid even if the anticodon differs, so 20 exist
...
The amino acid docks to the active
site of aminoacyl-tRNA synthetase
as well at ATP which binds
2
...
Following this tRNA is able to bind
to the enzyme and AMP is released,
whilst in the complex the tRNA
binds to the amino acid forming a
fully charged tRNA molecule which
can then be released
...
The nucleotides are joined together by a condensation
reaction which creates a phosphodiester bond
...

1
...
DNA helicase unwinds the double helix into its two separate strands which are kept separate
by single strand binding proteins which is important as the hydrogen bonds wish to reform
between the two DNA strands
...
RNA primase adds ribonucleoside triphosphates to synthesise an RNA primer at the 3’ end of
DNA and moving from 3’ to 5’ creating the primer in a 5’ to 3’ direction
4
...

5
...
Before completion another exonuclease removes the RNA primers and polymerase fills the
gap with DNA and removes any extra nucleotides
7
...
Gyrase is used again to relax the coils that arise after the replication
9
...


In eukaryotes there are multiple locations of replication and so replication is faster than in
prokaryotes where there is only one location of replication so it is slower, 1000 bases per second
and 100 bases per second respectively
...

- Bases
There are two types of nucleotide bases; purines, the larger bases, and
pyramidines which have a smaller structure
...
The pyramidine bases are cytosine and thymine and the purine
bases are adenine and guanine, base pairing exists between specific bases
...

Bases are linked to the deoxyribose sugar by an N-glycosidic bond and the
sugar then bonds to the phosphate group by a phosphodiester bond
- Asexual reproduction
This occurs within prokaryotes that have no nucleus so their DNA is contained
in one circular ring of DNA floating within their cytoplasm and during reproduction the circle
replicates each moves to the opposite side of the cell and then the cell splits forming two genetically
identical cells
...
Within these cells the reproduction is split up into cell cycles, at each phase of the cell cycle a
different process is occurring
...

- Mitosis
There are 4 stages of mitosis
 Prophase – the chromosomes condense and are visible within the nucleus whilst mitotic
spindles move to opposite sides of the cell
 Metaphase – the chromosomes line up down the middle of the cell whilst the nuclear
envelope breaks down and the mitotic spindle fibres extend
...

 Anaphase – the sister chromatids are separated from one another and pulled to opposite
sides of the cell by spindle fibres
 Teleophase – two new nuclear envelopes form and within them the DNA relaxes as nucleoli
reappear
Following the separation of the sister chromatids, cytokinesis occurs as a furrow in the membrane
appears and the actin filaments form a contractile ring to separate the two new cells and then the
new plasma membrane is formed
...
Meiosis is also useful in the re-assortment of genes by
independent segregation and due to crossing over at chiasmata
...
Each of these chromosomes replicates their DNA and
sometimes during this there is crossing over of DNA at chiasmata between homologous
pairs (but non-sister), creating recombinant DNA
...
Following this meiosis II
occurs which separates the sister chromatids and creates
gametes with 23 single chromosomes in
...

 The eggs do not fully go through meiosis though and their development is stopped in the
early stages of the first meiotic division and remain as a Primary Oocyte
...

 Secondary oocyte undergoes meiosis II to produce two haploid cells however it is arrested
at metaphase until fertilisation occurs
All polar bodies are lost from the body
In males all products of meiosis go to become sperm and the process starts by many mitotic
divisions to make more germ cells
...
This can occur in both the first or second meiotic division and results in an embryo with
3 chromosomes for the gene
...


There are several different outcomes from chromosomal non-disjunction of the sex chromosomes:
 Turners syndrome 45 chromosomes X0: sufferers have only one X chromosome and no
other chromosome and are always female but have a short stature, webbed neck and are
always infertile due to gonadal dysgenesis as germ cells are lost
 Klinefelter’s syndrome 47 chromosomes XXY: sufferers have more of a feminine look to
them with larger breasts and wider hips with less muscle and smaller penis and testicles and
are infertile, majority have normal IQ
 47 XXX: outwardly normal female with some patients being infertile
 47XYY: tall or very tall male which are relatively infertile
- Non-disjunction within the autosome
Downs syndrome is the result of an extra chromosome 21 which results in sufferers having 47
chromosomes and can either be 47XY +21 or 47XX +21, this results from non-disjunction during
meiosis of the gametes that made the child or it can also occur rarely (<1%) in early mitotic division
...
The risk of downs syndrome
dramatically increases with maternal age
...

Those with chromosome 21 trisomy are intellectually disadvantaged unlike those with sex
chromosome trisomy
...

There is also the possibility of triploidy where the patient has 69 chromosomes 23 x 3 where there is
some brief survival but they usually die within a few days of birth
...
It is possible for there to be deletion of a small
segment of chromosome which results in monosomy for the genes on that section which can result
in a variety of syndromes
...
If they are 46XX from the father then it results in a hydatidiform mole, and if from the
mother it is ovarian teratoma
...
DNA wound
around 8 histones (H2A, H2B, H3 and H4) is known as a nucleosome, which occurs every 200 base
pairs and forms a beads on a string appearance
...
New histones are attached to the lagging
strand and the leading strand retains the old histone proteins
...

Epigenetics: how genes are read and expressed by the cell without changes to the DNA
...
It is done by
applying trypsin to the DNA strand whilst the cell is in metaphase and then staining it, the banding
pattern is identical for the chromosomes however there are differences in the size of
heterochromatic blocks in the centre of the chromosome differ, satellite regions which are
euchromatic regions at the ends of the chromosomes vary in size as well as Y chromosomes varying
...
850 is taken around
prophase and prometaphase and the 400 resolution is in metaphase
...
There is
also the probability of triploidy which is people having more chromosomes which will always cause
problems
...
In flies males have double expression of the X-chromosome, however in mammals females
have one of their X-chromosomes ‘shut down’ so they have the same expression as males
...
The inactive
X chromosome appears as a densely staining ‘Barr body’ in the nucleus of the cell
...
Within these introns there are
repeat elements, which are most commonly LINE&SINE families which make up roughly ¼ of our
genome and can be used in DNA fingerprinting
...
The gene
regulatory sequences are GAATG which bind gene-specific transcriptional activators
...

Transcriptional factors have sequences on that gene
regulatory proteins bind to that then loop the DNA to
allow the regulatory proteins to attach onto the RNA
polymerase and activate it or inhibit it
...
g dominant otosclerosis, Huntington
disease and Achondroplasia
o Genetic surprises occur when both parents are ‘normal’ wheras the child expresses
symptoms of a dominant condition, there are 3 possible explanations:
1
...
New mutation in the sperm or egg causing the disorder
3
...
g cystic fibrosis, phenylketonuria, Albinism
o There are also genetic surprises with autosomal recessive conditions such as
albinism where both parents are homozygotic for the disorder yet the child is
‘normal’
...

Eumelanins
Tyrosine

Dopa

Black/brown

Dopa Quinone

Pheomelanins
Yellow

A deficiency of Tyrosine is the most common cause of albinism in Caucasians,
however deficiencies of the other enzymes can cause the same result
...

Sex linked recessive: gene causing a condition is located on the X chromosome but is
recessive and so will not be shown in the phenotype if there is another gene present
...
g
...

o In haemophilia A the sufferer has a deficiency in factor VIII which is encoded on the
X chromosome

- Determining gender
The Y chromosome contains the SRY gene which codes for a protein that carries out a cascade of
reactions which results into a male phenotype, without a Y chromosome or a mutation in this gene
or androgen insensitivity the individual has female phenotype
...
Such an inborn error occurs
within phenylketonuria:
Dietary protein
Phenylalanine
PHENYLKETONURIA – Phenyl ketones found in the
urine + alternate products
Dietary protein

Tyrosine
Homogentisic acid
ALKAPTONURIA –

Homogentisic acid found in
urine

Fumarate +
Acetoacetic acid
Phenylketonuria can be restricted by modifying the diet to reduce protein intake particularly
Phenylalanine as it can lead to mental retardation, however if it is identified early by a heel prick test
then the baby can be on low Phe diet and reduce the mental damage
...
From the generation of these alleles the distribution is down to
genetic drift or population bottlenecks, as well as changing selection pressures
...
Many viruses carry oncogenes however there
are also non-virally induced cancers that are the result of oncogenes
...


- Biological membranes
The membranes of cells are made up
of phospholipid bilayers that contain
many other molecules such as
proteins, lipids and cholesterol
molecules
...

More than 50% of the cell membrane
is made up of phospholipids
...
There are also 2 fatty acids attached to the 1st and 2nd carbons of the glycerol molecule
...
The
arrangement of the phospholipids into these micelles or phospholipid bilayers is due to them being
more energetically favourable
...

There are 4 major phospholipids in mammalian plasma membranes:
 Phosphatidylethanolamine
 Phosphatidylserine
Phosphoglycerides which are derived from glycerol, only
 Phosphatidylcholine
vary in the group attached to the phosphate
 Sphingomyelin --------------------- Sphingolipid, derived from sphingosine

The fluid nature of the membrane is important:





Allows lipids and proteins to diffuse in the 2D space to move into more complicated
structures and interact with one another
Allows other membranes to fuse together, important in exocytosis and phagocytosis
Enables cells to change shape
Ensures the daughter cells have the same amount of membrane

Fatty acids are synthesised within the cytosol and get transferred to the endoplasmic reticulum by
fatty acid binding proteins that enable the FA to be transported through the cytosol without forming
micelles, it is on the outer cytosolic leaflet ER that the fatty acids get embedded and where glycerol,
phosphate and the choline or other groups get added, it is only on the outside as the cytosol
contains the necessary enzymes
...
The endoplasmic reticulum membrane then buds off and travels to the cell
membrane where it then joins with the membrane however now what was the inner leaflet of the
ER is now the outer leaflet of the cell
...

The fluidity of the membrane can be altered depending on the composition of the membrane
...
Bacteria and yeast use this to their advantage and in cold
conditions they synthesise more unsaturated phospholipids so their membranes stay fluid at lower
temperatures
...

- Glycolipids
These are molecules based on sphingosine with a sugar attached, these sugar residues are only
found on the extracellular leaflet
...


- Integral and Peripheral proteins
Proteins also have hydrophilic and hydrophobic sections and so can lie within the membrane as
either integral or peripheral proteins
...

Translocators on the surface of the endoplasmic reticulum identify this signal and allow the cotranslational translocation of the protein into the lumen of the endoplasmic reticulum
...

Single pass membrane proteins are synthesised by ribosomes and are directed to the translocator
proteins on the surface of the endoplasmic reticulum where they pass through and the start transfer
sequence is cleaved by signal peptidase however following this, some way through the protein is a
stop transfer sequence which ceases the translocation and the protein is ejected laterally from the
translocator protein to be an integral single pass protein
...
Then there is a stop signal within the protein that ceases the translocation and
leaves a multi-pass membrane spanning protein
...

Glycosylation occurs in the lumen of the ER and Golgi apparatus as the sugar residues are localised
to the outside of the cell membrane
...

- Nuclear pore complex
The nucleus has a double membrane and so uses nuclear pores to span this double membrane and
allow for the bidirectional transport of molecules between the cytoplasm and nucleoplasm
...
They are the largest protein complex in the cell and are
made up of more 400 individual protein molecules and around 30 nucleoporins
...
This is possible due to the many pathways of cell communication
and the ability of our cells to adhere to one another and to the extracellular matrix
...
There are many communication
pathways:








Contact dependent: cells have surface signal molecules that are found within the cell
membrane and can bind to receptors on the surface of other cells an enable cell to cell
communication
...

Paracrine: the signalling cell can release a signal into the immediate area of the cell which
can alert cells that are nearby, this method is highly localised
Synaptic: the signalling cell body can be a long distance from the receptor cell as the axon
can be meters long, an electrical action potential travels along the axon and stimulates
release of a neurotransmitter to the target cell
...

Endocrine: signalling cells release a hormone into the bloodstream so the signal can reach
anywhere in the body as long as the target cell has a complimentary receptor on its surface
...
However it is possible for the endocrine
cells to be able to secrete more than one hormone and the receptor cells can have more
than one receptor on its surface
...
Thyroid hormones and steroid hormones can enter the cell
this way
...

Upon reaching the target cell in the blood stream
steroid and thyroid hormones are released from
their carrier molecules, and they diffuse through the
plasma membrane into the cytosol and then diffuses
through the nuclear membrane where the hormone
binds to a receptor and forms a hormone receptor
complex that then binds to the promoter region
upstream of the target gene which stimulates
transcription and then translation so more of the
protein is produced
...

- Extracellular receptors
these are hydrophilic substances that cannot pass through the plasma membrane so the receptor is
expressed on the outside of the cell
...

Signals that bind to extracellular receptors affect intracellular signal transduction pathways by
binding to the receptor which triggers intra cellular signalling proteins that can travel to the target
proteins to carry out a variety of functions by stimulating the target proteins to: alter metabolism,
alter gene expression or alter cell shape or movement etc
...
The fast route involves altering the protein function within the
cytosol which alters the cytoplasmic machinery and so then the cells behaviour, it is also possible for
the extracellular action to cause the transcription of certain genes and their translation and
expression which results in altered cell behaviour but in a slower manner
...
This phosphorylation normally activates the target however sometimes it may inactivate
...

In order for protein kinase A to alter the metabolism it must go through a series of reactions:





PKA catalyses the phosphorylation of phosphorylase kinase by transferring the phosphate
from ATP to the enzyme which then makes phosphorylase kinase active
Phosphorylase kinase in turn activates glycogen phosphorylase by adding the phosphate
from an ATP molecule to it
Activated glycogen phosphorylase converts glycogen into glucose

This is a very important function of adrenaline as it releases glucose from muscle cells by binding to
the G-protein coupled receptors on the muscle cell surface giving them the glucose needed for the
muscles to fight or flee
...

- Modifying gene expression
The activated PKA is able to enter the nucleus through the nuclear pores and once inside the
nucleoplasm it phosphorylates CREB which activates it
...

- WNT
This is a paracrine molecule which can act locally over a range of 1-5 cell diameters which is
important in embryonic development
...
However, when a Wnt signal molecule
binds to a surface receptor of a cell the destruction complex is not formed and so beta catenin
accumulates within the cell and can enter the nucleus where it is able to bind to another factor
forming a complex which binds to the promotor region of the target gene which, through
transcription and translation, leads to cell proliferation
...

Cell proliferation
Cells proliferate for many reasons including embryogenesis, wound repair, maintenance of tissues as
well as adaptation to stimuli
...

In healthy cells, there are control mechanisms to regulate cell proliferation as well as cell death
control
...
There
are a number of receptors and monitors that help decide the path a cell should take:




Growth factor receptors, upon binding of a growth factor to a receptor, 2 receptors dimerise
which brings the intracellular tyrosine kinase groups of the receptor protein together which
Trans-phosphorylate one another, thus activating one another
...

Monitors of genome integrity





TGF-β receptors
Integrins
Monitors of cell metabolism

In order to intervene in cancer there are several antibodies that intervene in the tyrosine kinase
receptor action, such as kinase inhibitors and antibodies that can attack the receptors and ligands
...
There is a similar check part
way through S phase and all replication will cease
if a mutation is found
...
The final check
point is before anaphase and if the chromatids are
not properly arranged on the spindle fibres
...
If G1 is lost then inappropriate
proliferation occurs and the others result in a loss
of the integrity of the genome and an increased
rate of mutation
...

Mutations occur in different places along the DNA strand and thus have different severities on the
genome
...

Mutations within the coding region or exon are more easily detectible by the cell and are lethal
mutations that can kill the individual if expressed
...

The cyclins control cyclin dependent kinases to
regulate their action as CDK’s are at a constant
level within the cell so it is the level of cyclin
within the cell that controls the rate of action
...

Cyclin D’s are needed to start the cell cycle and
their concentration within the cell is directly
altered by growth factors which are constantly informing the cell of its environment, the type of
growth factor is dependent on the location of the cell: smooth muscle cells and fibroblasts have
receptors from platelet derived growth factor whilst epithelial cells only have receptors for
epidermal growth factor
...
Following cyclin D activating the cell cycle the cycle is autonomous and no longer
relies on external factors, instead they detect internal stimuli such as mutations of the DNA
...
p27kip1 is produced in the resting phase of the cell
cycle and inhibits CDK1 and CDK2 by binding to the cyclins, however when growth factors reach the
cell they stimulate P13K which is a transporter which moves p27kip1 out of the nucleus and into the
cytoplasm which prevents it from inhibiting the action of CDK1 and CDK2
...

TGF-β is capable of increasing the level of INK4 and thus further inhibiting the action of cyclin D and
CDK4, thus preventing G1 to occur and keeping the cells in G0
...

Rb is a tumour suppressor gene that becomes more and more phosphorylated as the cell cycle
continues, with it being unphosphorylated in G0, weakly phosphorylated in G1 and
Hyperphosphorylated after passing the R point then dephosphorylated at the end of mitosis
...
A lack of this gene results in retinoblastoma
...

P53 monitors the integrity of the genome within the cell and controls apoptosis of the faulty cells
...
If any abnormalities are detected then it increases p21cip1 action, stopping CDK1 and
CDK2 action, thus preventing the cell cycle from occurring, allowing repair to occur to the genome
...
If there is a bi-mutation in the P53 gene
then it no longer works and allows cells to divide with a mutation in them, this makes mutations in
the P53 gene common in many cancers
...
Also if the cell loses adhesion to the extracellular
matrix then it also goes through apoptosis
...

- Apoptosis the controlled death of a cell in contrast to necrosis which is uncontrolled bursting which
damages surrounding cells by releasing lysosomal hydrolases
...
No one cleavage has been proven to be more important than
another but a typical one is the cleavage of iCAD (a Dnase enzyme) which activates it and cleaves
DNA at exposed nucleosomes which results in the DNA ladder effect in apoptotic cells
...
Tumour necrosis factors bind to trimer receptors
on the surface of the cell, such receptors are TNF1, Fas and TRAIL
...

Intrinsic apoptosis is regulated within the cell and is activated when the cell identifies a fault, upon
identifying the fault the cell increases the membranes permeability through involved mitochondrial
outer membrane permeabilization (MOMP)
...
The signal stimulates BAX to oligomerise and
insert into the mitochondrial membrane which allows MOMP to occur
...
The APAF-1 itself oligomerises and recruits and
activates procaspase 9 in the apoptosome
...

At the end of apoptosis the cell ends up as apoptotic bodies that are engulfed by macrophages
B-cell lymphoma is a slow growing B-cell tumour that is the result of overexpression of BCL-2 gene
which results in large amounts of the BCL-2 protein in the membrane of mitochondria which
prevents MOMD and results in a build-up of cytochrome C within the mitochondria that cannot
leave to bind to APAF-1 for apoptosome production
...

Burkitt’s lymphoma is a very rapidly growing childhood cancer linked with chronic infection by
malarial parasites which increases the patient’s vulnerability to Epstein Barr virus which increases BLymphocyte (a white blood cell) proliferation
...
The translation is of the immunoglobin gene from chromosome 2,14
or 22 with that of the myc gene, it is the immunoglobulin enhancer sequence that causes the
overexpression
...

Epithelia are classified by 3 characteristics:




Number of cell layers: one=simple, one but cross over=pseudostratified, multiple=stratified
Shapes of cell: flattened=squamous, cube shaped=cuboidal,
column like=columnar
Specialisations: presence of keratin=Keratinised, presence of
villi=microvilli (to increase surface area), presence of
cilia=ciliated (to allow movement in lumen)

(In stratified epithelia the shape is that of the outermost layer of cells)





- Skin

All epithelial cells have a free apical membrane
...

Skin is important in
keeping out bacteria and
retaining water thanks to
the epithelial cells and the
tight junctions
...

Langerhans cells that
reside in the epidermis,
particularly in the spinous
layer, provide immune
support
...

In the dermis there are many somatic and autonomic nerve endings which provide sensation from
the skin, in conjunction with merkel cells, Pacinian corpuscles (deep touch) and Meissner’s
corpuscles (light touch) /the concentration of these nerve endings depends on the location on the
body
...
Within the dermis there are many
collagen strands in the extracellular matrix which provides strength and support
...


Focal adhesions and hemi-desmosomes are only
located on the basal surface of epithelial cells as
they adhere the epithelial cell to the basal
lamina
...

Tight junctions have a barrier and fence function,
keeping substances from passing between the
epithelial cells so they can diffuse through the
basal lamina and to stop the movement of
proteins between the basolateral and apical
membrane
Adherens junctions and desmosomes are involved in cell-cell adhesion, whilst gap junctions are
important in communication between the epithelial cells, and contain many connexions, protein
channels which align from one cell to the other and facilitate this communication
...

Desmosome composition
Desmosomes are composed of desmosomal
cadherins which extend into the extracellular
space, the cadherins are Desmocollins
(DSC1,DSC2,DSC3) and Desmogleins
(DSG1,DSG2,DSG3,DSG4) they are all single
pass membrane proteins whose
intreacellular domains interact with
plakogobin and plakophillin
...
More superficially the DSG3 and
DSC3 genes are turned off and more deep
the DSG1 and DSC1 genes are turned off
...


All the junctions are vital in preserving the integrity of the tissue
...

- Extracellular matrix
This is an intricate network of macro molecules located underneath the basement membrane (a thin
sheet of specialised ECM composed mainly of collagen IV and laminin a heterotrimer), within this
connective tissue the macromolecules are largely secreted by fibroblasts
...

- Epidermis
This is a kind of epithelial tissue which is 10-20 cells thick which prevents microbial invasion and the
loss of water
...
K1 and K10 keratin
expressed here
Stratum corneum composed of 10-30 layers of corneocytes which are anucleated and
terminally differentiated keratinocytes
...


Pemphigus this is an acquired auto immune disease that results in a blistering of the skin thanks to a
defect in cell-cell adhesion, there are 2 types:




Pemphigus foliaceus is a fault in the interaction between DSG1 proteins causing problems in
the adhesion of the epidermal cells in the upper layers
...

Pemphigus vulgaris is a fault in the interaction between DSG3 proteins which results in
blistering in the lower levels where there is a high concentration of the DSG3 proteins,
leading to a severely compromised epidermis which can affect the mucous membranes and
almost always leads to death by infection or water loss if left untreated
...
Those that survive childhood are at an increased risk of
squamous cell carcinoma
...
Water is important as it is the solvent for all solutes of the body
but we must regulate the total body water in order to prevent damage to our cells and to maintain
osmotic and chemical gradients for physiological function and the transport of nutrients and ions for
cell communication
...

Water is able to move into and out of cells through Aquaporins: these are channels within the
membrane of cells which allow the passive transport of water without allowing ions to pass through,
even hydrated ones as they are too large
...

The endothelial cells of the blood vessels allow the flow of water and ions but not proteins
to leave and enter the plasma
...
despite this
they all have the same osmolarity so are osmotically stable
...

Osmotic pressure – the applied pressure that prevents the net flow of water, the higher difference in
the solute concentration, the higher the osmotic pressure

Osmolarity(mOsm/L) – osmoles/Litre of solution (1M = 1 osmole per litre)
Osmolality(mOsm/kg) – osmoles/Kg of solvent
100mM glucose = 100mOsmoles of glucose
100mM NaCl = 200mOsmoles NaCl
This is because glucose does not dissociate in solution In contrast to NaCl which dissociates into Na+
and Cl- so we multiply by the number of particles
...

However due to the retention of the anions, there is a higher concentration of solutes in the cell
than outside so the osmolarity is greater than the outside
...


Isosmotic=solution with equal solute regardless of permeability of the membrane to the solute
Hyperosmotic=solution with osmolarity greater than another solution regardless of permeability of
the membrane to the solute
Hyposmotic=solution with an osmolarity less than another solution regardless of permeability of the
membrane to the solute
Tonicity describes the concentration of non-permeable solute in relation to other cells
...

HYPEROSMOTIC=HIGHER SOLUTE CONCENTRATION
HYPERTONIC=HIGHER NON-SOLUBLE SOLUTE CONCENTRATION
In addition to the chemical gradients there is also the electrical charge on the cells, at rest the
positive and negative charges are largely equal between the two compartments however there is a
resting potential of -70mV with the inside of the cell being more negative than the outside due to
there being a minor difference in the ion concentrations – a small change in the number of ions
creates a large potential difference across the membrane but the bulk concentration of ions is not
affected
...
As most membranes are permeable to potassium ions it is the main contributor to the
membrane potential, potassium ions move out of the cell along the concentration gradient as there
is a lower concentration of K+ outside of the cell than on the inside, however this increases the
negative charge on the inside of the cell so K+ ions diffuse back into the cell along the
electrochemical gradient, maintaining the resting potential
...
If the pump is not present then there is an imbalance of the ions and problems with
water retention and nervous transmission can arise, the gradient is also important in transporting
other substances such as glucose
...

The membrane potential takes into account all the ions potentials and the permeability
of the membrane to each ion
...


Ion Eion
(mV)
+ +61
Na
K+ -90
Cl- -53
Ca2+ +120





Hypokalaemia: low concentration of potassium extracellularly and so there is a larger efflux
of potassium ions than normal, creating a more negative membrane potential which means
that the cells are less excitable
Hyperkalaemia: high extracellular concentration of potassium so K+ ions diffuse into the cell
more readily and results in a less negative membrane potential, increasing the cells
excitability
...
Chemical name (IUPAC)
2
...
Brand name, specific to a company’s method of processing or the composition
The rate at which drugs bind to receptors is proportional to the concentration of the drug, however
the rate at which the drug detaches is unique to the chemical
...
of Drug + ratio of K-/K+

K=rate constant

By knowing what percentage of receptors drugs are bound to at what concentration helps us know
the correct concentration to administer the drug at
...

p EC50 = -log10(EC50)

drugs with larger p EC50 are more potent
...
However if the antagonist is
irreversible then the presence of the antagonist
decreases the maximal response
...


Efficacy: the degree to which an agonist produces a response when binding to a given proportion of
receptors
...

Affinity: the probability of the drug occupying a receptor at a given time
Selectivity: degree to which a drug acts on a given site relative to other sites
Potency: the measure of drug activity expressed in terms of the amount required to produce an
effect of given intensity, so they create a greater response at lower concentrations
...


There are a variety of different receptors that drugs can bind to:






Receptors within the cytosol that move into the nucleus, such as those that growth factors
bind to
...


When prescribing drugs, we need to achieve maximum effectiveness at minimum risk to the patient
whilst ensuring no wastage of resources and ensuring patient’s wishes are respected at all times
...
g antacids, bulk laxatives, osmotic
laxatives, GA – tend to need high concentrations
Specific actions
o Chemically sensitive proteins react to the drug
o The drugs aim to restore normal function in diseased cells
o Receptors that already exist on the cell react to the drug binding,
o Can be used in lower concentrations
o Chemical composition is important in ensuring that chemical bonds can form
between the drug and receptor and to be sure there is no electrochemical repulsion

Routes of administration of drugs:





Topical – administered directly to where it is needed, local effect and slow method
Enteral – desired effect is systemic as the drug is administered by the digestive tract and
carried to the site, slow method of drug administration
Parenteral – systemic effect as drug is administered not to the direct site and not through
the digestive tract, this is a fast method and IV IM AC and IP all deliver the drug fast
Percutaneous – ‘by way of the skin’ such as inhalation, sublingual

Despite the different routes of administration all drugs have to cross a membrane to reach their
point of action
...

The level at which a drug is ionised at a certain pH determines the solubility of the drug to pass
through the membrane
...
Small lipophilic drugs are able to cross
membranes easily and so it is useful for drugs that need to cross the blood brain barrier
...
Certain drugs and substances can also affect the motility of the gut and increased
motility decreases the absorption rate
...
It is also important that drugs are not metabolised before they reach
the systemic circulation, there are many barriers to the drug:





Digestive enzymes in the gut lumen
Monoamine oxidases, Cytochrome P450s and many other enzymes are found in the gut wall
that are a barrier to drugs and foreign bodies as they can metabolise them
MAO and peptidases also exist within the lungs and can metabolise drugs inhaled
There are many different enzymes within the liver that can metabolise drugs if taken
intravenously before they get digested

All of these affect the bioavailability of the drug which is the percentage of the drug taken into the
body that is available intravenously, fatter people have lower availability as more of the drug is
taken into body water
...

Once within the blood the distribution depends on the blood flow, the lipid solubility of the drug and
any barriers to diffusion, tissue binding and plasma protein binding
...

Pharmacokinetics and pharmacodynamics all play a role in the clinical effect from a certain dose
...
More polar drugs cannot leave the plasma so leave
in the urine
...

Phase I metabolism: metabolite made more reactive
Phase II metabolism: conjugation of metabolite making the drug more water soluble
Some drugs such as prodrugs require metabolism to activate themselves
...
The liver can also adapt to
alcohol, if there is high alcohol uptake over an extended period of time then the liver producers
more enzymes to metabolise alcohol which increases the resistance to alcohol
...

Before drugs are excreted through the renal system in urination, they must undergo glomerular
filtration, tubular reabsorption and excretion
...
The half-life of a drug is the time taken for
half the original concentration of the drug to exist within the body or the plasma
...
Over 95% of the drug is removed after 5 halflives
...

Parasympathetic nerves use nicotinic cholinergic synapses at the ganglion and muscarinic cholinergic
synapses at the effector
...
ACh is made from acetate and choline by choline
acetyltransferase and is broken down by acetylcholinesterase
...

Muscarinic agonists are examples of parasympathomimetics as they all cause activation of the
parasympathetic nervous system
...
They are also useful during operations to
reduce secretions
...

β receptor agonists are useful in combatting cardiogenic shock, anaphylactic shock and asthma
α receptor antagonists combat hypertension and benign prostatic hyperplasia
β receptor antagonists combat angina hypertension anxiety chronic heart failure and cardiac
arrhythmias

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