· SIMPLE SQUAMOUS--lung alveoli,blood vessels,descending limb of loop of henle,parietal layer of bowman's membrane..
·
SIMPLE
CUBOIDAL-->duct of many glands,germinal layer of ovary,thyroid follicles
·
SIMPLE
COLOUMNAR--gallbladder,stomach,small intestine..most of large intestine
·
SIMPLE COLOUMNAR
CILIATED--uterus and uterine tube,ependyma of spinal cord,small bronchi and
bronchiole
·
PSEUDOSTRATIFIED
CILIATED COLOUMNAR--trachea,bronchi,nasopharynx
·
STRATIFIED SQUAMOUS
NONKERATINIZED-lining of
mouth,tongue,tonsil,pharynx,esophagus,epiglottis,cornea,vagina and
KERATINIZED--skin
·
TRANSITONAL
EPITHELIUM-major and minor calyx,pelvis renal,ureter,bladder,proximal part of
urethra..
·
STRATIFIED
CUBOIDAL--pancreas,sweat gland,salivary gland
·
EPIPHYSIS
1. Pressure epiphysis : which transmits weight from one bone
to another. Eg: Head of femur, Condyles of tibia, Lower end radius.
2. Traction epiphysis or apophysis : situated at the point
of attachment of
muscles or tendons. Eg : Trochanters of femur, Tubercles of
Humerus, Mastoid process
3. Atavistic epiphysis : which represents a part of the
skeleton which has lost its
original function. Eg: Coracoid process of scapula, Post.
tubercle of talus, Ostrigonum
4. Aberrant Epiphysis : Not always present. Eg: Head of 1st
MC, Base of Other MC.
PRIMARY EPIPHYSIS
1. Vertebral body: Calve
2. Carpal scaphoid: Preiser
3. Lunate, adult: Kienbock
4. Patella: Kohler
5. Talus: Mouchet
6. Tarsal scaphoid: Kohler
7. Medial Cuneiform: Buscke
8. Femoral trochanter: Monde Felix
9. Patella: Sinding-Larsen
10. Tibial head: Ritter
11. Tibial tubercle: Osgood-Schlatter
12. Os calcis: Sever
13. Metatarsal head: Freiberg
SECONDARY EPIPHYSIS
1. Vertebral epiphysis: Scheuermann’s
2. Sternal end clavicle: Friedrich
3. Humeral head: Hass
4. Humeral capitellum: Panner
5. Radial head: Brailsford
6. Distal ulna: Burns
7. Metacarpal heads: Mauclaire
8. Iliac crest: Buchman
9. Pubic symphysis: Van Neck
10. Ischiopubic region: Oldberg
11. Femoral head: Legg-Calve - Perthes
·
There are differences in the way that intermediate
filaments interact with microtubules and microfilaments within the
cytoplasm; however, their ropelike arrangement is well suited to providing
mechanical stability to the cell and resisting stretch, allowing the cell to
respond to tension.
The different
types of intermediate filaments all have a similar structural pattern:
nonhelical head and tail segments with a helical arrangement in the center of
the intermediate filament structure.
Intermediate
filaments that are “intermediate” in diameter (8 to 10 nm) between thin and
thick filaments are of five different types. Type I and type II are the
acidic and basic keratins (cytokeratins) respectively and are found
specifically in epithelial cells. Type III intermediate filaments are
composed of vimentin, desmin, and glial fibrillary acidic protein (GFAP).
Vimentin is found in cells of mesenchymal origin, desmin in muscle cells, and
glial fibrillary acidic protein in astrocytes. Type IV intermediate
filaments are neurofilament proteins found in neurons. Type V
intermediate filaments include the nuclear lamins A, B, and C and are
associated with nuclear lamina of all cells.
Movement is
generated by motor proteins such as myosin, dynein, and kinesin. There is a good
mnemonic device for remembering the direction of movement directed by kinesin
and dynein. Kinesin kicks the molecules out; dynein drags them in; also, the
plus end of the microtubule is oriented toward the plasma membrane, so minus
end toward nucleus. This works for fibroblasts as well as neurons.
Nucleation of
microtubules is conducted by centrosomes.
Microtubule-associated proteins (MAPs)
stabilize or destabilize microtubules. Microtubules function in organellar
transport (e.g., axonal transport).
COP-I (COat Protein-I) coats vesicles involved in retrograde
transport from Golgi→RER. COP-II
is the coat protein for vesicles transported in an anterograde direction
from the RER→Golgi
·
The integrins are transmembrane heterodimers that
act as membrane receptors for extracellular matrix components.
The best examples
are the fibronectin
receptor and the laminin receptor. The receptor structure
includes an intracytosolic portion that binds to the actin cytoskeleton through
the attachment proteins talin or ALPHA-actinin. The extracellular portion has
specificity for extracellular matrix molecules.
Fibronectin is an
adhesive glycoprotein that is important for cell attachment. It is important
for modulation of cell migration in the adult and during development. Neural crest
and other cells appear to be guided along fibronectin-coated pathways in the
embryo.
Fibronectin is
found in three forms:
- a plasma form that is involved in blood clotting;
- a cell surface form, which binds to the cell surface transiently;
- a matrix form, which is fibrillar in arrangement.
Fibronectin
contains a cell-binding domain (RGD sequence), a collagen-binding domain, and a
heparin-binding domain. Type IV collagen is responsible for providing support.
Collagen fibrils are connected
to other extracellular matrix molecules by the FACIT (fibril-associated
collagens with interrupted triple helices = collagen 9-13) collagens.
Type I collagen is found in dentin.
·
The primary function of entactin (nidogen) is to cross-link laminin to type IV collagen. The basal lamina
is formed by interactions between type IV collagen, laminin, entactin, and the
proteoglycan perlecan.
·
In Ehlers-Danlos disorder type IV there is
improperly formed type III collagen, which is responsible for the elasticity of
the intestinal and aortic walls. In this form of the disorder there are errors
in the transcription of type III collagen mRNA or in translation of this mRNA.
Hyperextensible
skin occurs in Ehlers-Danlos
type VI disorder in which problems with the hydroxylation of the
amino acid lysine and subsequent cross-linking result in enhanced elasticity.
Type VII
Ehlers-Danlos disorder involves a specific deficiency in an amino
terminal procollagen peptidase. This results from a genetic mutation that
alters the propeptide sequence in such a way that the molecular orientation and
cross-linking are adversely affected. The result is hypermobility of synovial
joints. Increased degradation of proteoglycans occurs in osteoarthritis.
·
The cell cortex is an area of the cell immediately
underneath the plasma membrane and is rich in actin, which is required for cytokinesis.
This region is important in maintaining the mechanical strength of the
cytoplasm of the cell. It is also essential for cellular functions that require
surface motility. These functions include phagocytosis, cytokinesis, and cell
locomotion. Although movement of vesicles along filaments is regulated by minimyosins (myosin I), movement of
vesicles and organelles is predominantly a function of microtubules under the
influence of the unidirectional motors kinesin
and dynein. The movements of cilia and flagella are driven by dynein and
chromosomal movements occur through microtubular kinetics.
·
Endothelial cells synthesize a number of antithrombogenic
factors including plasminogen activator and prostacyclin. Prostacyclin functions
through cyclic AMP to inhibit thromboxane production by platelets.
Endothelial cells
synthesize the basal
lamina including types IV, V, and VIII collagens, fibronectin, and
laminin. Secretion of A and B blood group antigens also occurs in endothelial cells.
Angiotensin
converting enzyme on the endothelial cell surface converts angiotensin I to
angiotensin II (a potent vasoconstrictor), but also serves as an inactivation
enzyme (bradykininase) for bradykinin, a vasodilator.
The endothelium
produces nitric oxide, also known as endothelium–derived relaxing factor
(EDRF), and endothelin, the most potent vasoconstrictor in the body.
Endothelial cells
also synthesize plasminogen inhibitor, a coagulant and von Willebrand factor
(factor VIII) which is found in Weibel-Palade granules in endothelial cells of
vessels larger than capillaries. A deficiency of factor VIII leads to decreased
platelet aggregation and hemophilia.
·
The sebaceous glands are holocrine (i.e., they
shed the cell along with the secretory product). Sebum is a lipid product
released into a duct that terminates in a hair follicle. The photomicrograph
represents a microscopic section obtained from thin skin. The presence of
sebaceous glands identifies the section as thin skin. Sebaceous glands and hair
follicles are not found in thick skin. Another difference between thick and
thin skin is the virtual absence of the stratum lucidum in thin skin.
The sweat glands
are of two different types: merocrine glands and apocrine glands.
The merocrine glands
release their secretion through exocytosis with conservation of membrane.
In the anal,
areolar, and axillary regions, the sweat glands are of the apocrine type and
empty into the hair follicles. In apocrine glands, the apical part of the cell
is released with the secretion.
·
The epididymis functions in the storage, maturation, and phagocytosis of sperm
and residual bodies. In addition, the epididymis is involved in the
absorption of testicular fluid and the secretion of glycoproteins. These
glycoproteins may be involved in the inhibition of capacitation. The epithelium
of the epididymis is pseudostratified with stereocilia (modified microvilli for
absorption), and the wall contains extensive connective tissue.
·
The glomerular filtration barrier is a physical
and charge barrier that exhibits selectivity based on molecular size and
charge.
The barrier is
formed by three components:
(1)
glomerular capillary endothelial cells,
(2) glomerular basement membrane: The
presence of collagen type IV in the lamina densa of the basement membrane
presents a physical barrier to the passage of large proteins from the blood to
the urinary space. Glycosaminoglycans, particularly heparan sulfate, produce a
polyanionic charge that binds cationic molecules
(3) podocyte layer. Filtration slits
are found between adjacent podocyte foot processes and provide a gap of
approximately 50 micron. The foot processes are coated with a glycoprotein
called podocalyxin, which is rich
in sialic acid and provides mutual repulsion to maintain the structure of the
filtration slits. It also possesses a large polyanionic charge for repulsion of
large anionic proteins.
·
GOLGI ORGAN:
cis: hydroxylated
and phosphorylated protein
Medial: Glycosylation site
Trans: sorting
2 diseases: I cell disease
(mucolipoidosis II, def of NAG phosphotransferases) & hyperproinsulinemia(
s/s similar to NIDDM )
The discoid stacks
(CGN, cis, medial, trans, and TGN as
one moves from the RER-side to the secretory vesicle-side) of the Golgi
apparatus are involved in packaging and routing proteins for export or delivery
to other organelles, including lysosomes and peroxisomes.
Secretory granules
leave the TGN to dock with the plasma
membrane. In that process, v-SNARE on the vesicle docks with t-SNARE on
the cell membrane and requires Rab
GTPase-activity, linking to tethering proteins, and eventually to a
receptor protein in the cell membrane.
·
Four most common disorders of peroxisomes are:
.Zellweger (cerebrohepatorenal) syndrome ( EMPTY PEROXISOMES
IN EM)
.Neonatal adrenoleukodystrophy
.Infantile Refsum disease
.Hyperpipecolatemia
·
Liver Zones:
Zone I:
periportal zone–most sensitive to toxic injury, affected first by viral
hepatitis
Zone II:
intermediate zone
Zone III:
pericentral vein zone, contains P-450 system, affected first by ischemia,
alcoholic hepatitis
·
PTH stimulation of osteoblasts
releases macrophage colony-stimulating factor (M-CSF)
and RANK-L. M-CSF stimulates
differentiation of monocytes into osteoclasts. RANK-L is found in both membrane
and soluble forms and binds to RANK (receptor for activation of nuclear factor
kappa B) on osteoclasts and osteoclast precursors stimulating osteoclastic
activation/ ruffled border formation. Osteoprotegerin (OPG) is a decoy
receptor for RANK-L, binds RANK-L, and leads to inhibition of osteoclastic
activity. Those molecules create the link between osteoblasts and osteoclasts
known as the ARF
(activation-resorption-formation) cycle in which activation of
osteoclasts is inextricably linked to osteoblasts. This has been one of the
problems in treating osteoporosis in which osteoclastic activity dominates
osteoblastic activity.
Osteoprotegerin inhibits osteoclastic activity.
·
The polyanionic
charge of the membrane is produced by the sugar side chains on the glycoproteins and glycolipids.
Glycoproteins often terminate in sialic acid side chains, which impart a
negative (polyanionic) charge to the membrane. Similarly, the glycolipids (also
called glycosphingolipids), particularly the gangliosides, terminate in sialic
acid residues with a strong negative charge.
·
Freeze fracture
is a procedure in which the tissue is rapidly
frozen and fractured with a knife. The fracture plane occurs through
the hydrophobic central plane of
membranes, which is the plane of least
resistance to the cleavage force. The two faces are essentially the
two interior faces of the membrane. They are described as the extracellular
face (E face) and the protoplasmic
face (P face). The cytoplasm is the
backing for the P face, which in general contains numerous intramembranous
particles (mostly protein). The E face is backed by the extracellular space and
in general contains a paucity of intramembranous particles compared with the P
face.
·
In its anion exchanger role, band 3 protein exchanges bicarbonate ion for chloride ion.
Bicarbonate is transported by band 3 out of the RBC in exchange for chloride,
permitting the highly efficient transport of CO2 to the lungs as bicarbonate.
In the absence of band 3 protein, the bicarbonate buffering of the blood is
reduced, leading to acidosis or lowering of blood pH. The result is reduced
capacity to carry CO2. In addition to its functional, bidirectional anion
exchanger role, band 3 plays a key membrane
structural role, since the cytoplasmic domain of the protein
interacts with spectrin through an ankyrin bridge. Spectrin exists as dimers
and trimers; the trimers are bound together by actin, thus providing a
connection to the cytoskeleton maintaining the shape and stability of the RBC.
The result of a null mutation in band 3 is the formation of erythrocytes that
are small and round instead of biconcave (spherocytosis).
·
Asymmetry of the
lipid bilayer is established during membrane synthesis in the
endoplasmic reticulum before reaching the Golgi apparatus
·
Desmin is found
in striated and most smooth muscle, except vascular smooth muscle.
Glial fibrillary acidic protein, GFAP, is specific for
astrocytes, not microglia or oligodendrocytes.
·
The stability, arrangement, and functions of
actin filaments depend on the actin-binding proteins. The fundamental structure
of the actin molecule is the same no matter what the function or arrangement in
a cell. Actin-binding proteins have a
variety of functions: (1) tropomyosin
strengthens actin filaments, (2) fibrin and villin
are actin-bundling proteins, (3) filamin and
gelsolin regulate transformation from the sol to the gel state, (4)
members of the myosin II family are
responsible for sliding filaments, (5) myosin I
(minimyosin) is responsible for movement of vesicles on filaments, and
(6) spectrin cross-links the sides of actin
filaments to the plasma membrane.
·
Nucleation of
microtubules is conducted by centrosomes.
·
Batten’s disease,
neuronal ceroid lipofuscinoses, in which there is a build-up of
lipofuscin because of the absence of specific lysosomal enzymes.
The child has shown a failure to thrive, is
microcephalic, exhibits myoclonic jerks, delayed psychomotor development,
visual disturbance and seizures. Analysis of fibroblasts from the skin by
electron microscopy confirms the presence of fingerprint inclusion bodies.
Elevated levels of dolichol are found in the urine.
Dolichol is normally associated with N-linked glycosylation in the rough
endoplasmic reticulum (RER) an en
bloc method in which dolichol is added to the protein. O-linked glycosylation occurs in the Golgi, by a mechanism involving oligosaccharide
(glycosyl) transferases rather than en bloc with dolichol. N-linked oligosaccharides are the most common
oligosaccharides found in glycoproteins
and contain sugar residues linked to the NH2 amide
nitrogen of asparagine. O-linked
oligosaccharides have sugar residues linked to hydroxyl
groups on the side chains of serine and threonine. The diversity in
oligosaccharides is produced by selective removal of glucose and mannose from
the core oligosaccharide. This trimming process begins in the RER before
reaching the Golgi, where the final mannose-residue trimming occurs. Sulfation and
protein sorting are carried out in the Golgi apparatus, but do not involve
dolichol.
·
Zellweger
syndrome, in which peroxisomes are empty.
A boy is born with epicanthal folds, a high forehead,
hypoplastic supraorbital ridges, and upslanting palpebral fissures. He shows
growth retardation following birth, he feels like a rag doll when held, and he
exhibits neonatal seizures. He also has a ventricular septal defect, glaucoma,
cataracts, elevated iron and copper levels in his blood, and hepatomegaly. A
liver biopsy is prepared for electron microscopy and shows the presence of
empty peroxisomes. The pathologist describes them as peroxisome “ghosts.”
Peroxisomes are
the sole site of plasmalogen synthesis. Plasmalogen is a group of
glycerol-based phospholipids in which the aliphatic side chains are not
attached by ester linkages. They have a widespread distribution with highest
concentrations in the brain, spinal cord, liver, and kidney. Energy production,
exocytosis, detoxification, and the synthesis of lysosomal enzymes would not be
affected in that disease. In Zellweger syndrome, peroxisomes are empty
because of the failure of the signal system that sorts protein to the
peroxisome. Because the peroxisome lacks a genome (DNA) or synthetic
machinery (ribosomes), it must import all proteins. The defect appears to be in
the peroxisomal membrane (peroxins),
but errors or absence of the peroxisomal signal sequence would result in the
same symptoms. Peroxisomes have only a single
membrane around them and contain catalase. Peroxisomes carry out
oxidation reactions to protect the cell. Those oxidation reactions remove
hydrogen atoms from molecules like alcohol and phenols to form hydrogen
peroxide. In the peroxidative reaction, catalase breaks down hydrogen peroxide
to water and oxygen. Most of the alcohol humans consume is broken down by
the ADH (alcohol dehydrogenase) and MEOS (microsomal ethanol-oxidizing
system, that is, P450 cytochrome) pathways in the hepatocyte (liver cell)
cytoplasm; the remaining small percentage is broken down by oxidation in the
peroxisomes of hepatocytes using catalase.
·
Cytochalasins
are potent inhibitors of cell motility and
other cellular events that depend on actin assembly: cytokinesis, which is
conducted by the actin-containing contractile ring; phagocytosis;
and formation of lamellipodia. Cytochalasins bind to the plus end of actin
filaments and prevent further polymerization. The movement of chromosomes in
anaphase of the cell cycle depends on disassembly of microtubules at the
kinetochore in anaphase A and addition at the plus end of the polar
microtubules in anaphase B.
·
Chloroquine
neutralizes acidic compartments such as the secretory vesicles.
Chloroquine treatment inhibits the conversion of proinsulin to insulin,
resulting in decreased formation of insulin
within secretory vesicles.
·
Leigh’s Disease
(Subacute Necrotizing Encephalomyelopathy), a generalized (systemic)
form of Cytochrome C oxidase (COX) Deficiency,
characterized by progressive degeneration of the brain and dysfunction of the
heart, kidneys, muscles, and liver. Symptoms include loss
of acquired motor skills and loss of appetite, vomiting, irritability, and/or
seizure activity. As Leigh’s Disease progresses, symptoms include
generalized weakness; loss of muscle tone (hypotonia); and/or episodes of
lactic acidosis with lactate higher in the CSF than the blood.
·
Within the ER
there are protein chaperones and mechanisms to prevent aberrant
protein folding and to catalyze isomerization of correct covalent bonds.
Frequently, changes in the extracellular environment result in aberrant protein
folding in the ER as occurs in Alzheimer disease.
·
Signal hypothesis
& function of the signal recognition particle (SRP):
The SRP prevents
degradation of newly synthesized peptides because translocation across the
ER membrane protects the nascent peptide from proteases. The signal hypothesis
is the basis of the targeting of transmembrane, lysosomal, and exportable
proteins across the ER membrane. It is the key event in the segregation
of noncytosolic proteins in the ER cisternae. The result of SRP activity is
attachment of ribosomes translating the secretory protein to the ER membrane
and the translocation of the protein across the ER membrane. The SRP binds to
the N terminus of the signal peptide as the peptide emerges from the ribosome
and induces an immediate delay in translation until the ribosome interacts with
a docking protein, also known as an SRP receptor, in the ER membrane. In the
function of the RER, a presequence on the 3’-end of the AUG initiation codon is
translated as an N-(amino)-terminal presequence [amino-terminal signal leader
(prepeptide) sequence] that recognizes the ER membrane and leads to the
translocation of the peptide across the ER membrane. This recognition is
accomplished through the SRP, which cycles between the ER membrane and the
cytosol. After the SRP-bound ribosome attaches to the ER membrane via the
docking protein, translation continues with displacement of the SRP for
subsequent recycling and translocation of the peptide across the ER membrane.
Enzymatic cleavage (answer e) of the signal sequence releases the newly synthesized
peptide.
·
Inclusion
(I)–cell disease: There is an absence or deficiency of
N-acetylglucosamine phosphotransferase and an absence
of mannose-6-phosphate (M6P) on the lysosomal enzymes. The failure to
add M6P in the cis-Golgi results in inappropriate vesicular segregation by M6P
receptors in the trans–Golgi network (TGN). The default pathway is transport to
the cell membrane and secretion from the cell by exocytosis for proteins
lacking M6P. Lysosomal enzymes are secreted into the bloodstream, and undigested substrates build up within the cells.
There is no missorting back to the Golgi.
Peroxisomal
enzymes, which are sorted by the presence of three specific amino acids located
at the C-terminus: Ser–Lys–Leu–COO−, are not affected.
KDEL is the signal used for retrieval of proteins
from the Golgi back to the endoplasmic reticulum.
SNAREs
[soluble-N-ethylemalemide sensitive factor (NSF) attachment protein receptors]
are the receptors for SNAPs [soluble-N-ethylemalemide sensitive factor (NSF)
attachment proteins] and bind vesicles to membranes. Trafficking to other
structures, such as the nucleus and mitochondria, is regulated by nuclear
localization signals (NLSs) or an N-terminal signal peptide, respectively.
·
The TCOF1 gene
encodes treacle. Expression of treacle is
critical during early embryonic development in structures that form bones and other facial structures. Treacle is
active in the nucleolus. The nucleolus is
the site of ribosomal protein transcription and treacle regulates ribosomal DNA
transcription and therefore ribosomal RNA (rRNA) synthesis. The nucleolus is a
highly organized, heterogeneous structure within the nucleus, with distinct
regions visible by electron microscopy: (1) fibrillar centers, which
represent the nucleolar organizer regions where DNA is not being actively
transcribed; (2) dense fibrillar components (pars fibrosa) where RNA
molecules are being transcribed; and (3) a granular component (pars
granulosa) where ribosomal subunits undergo maturation. The nucleolar
organizer contains clusters of rRNA genes (DNA). The size and number of
nucleoli differ with the metabolic activity of cells.
·
Meiosis
is the mechanism used by the reproductive organs to generate gametes—cells with
the haploid number of chromosomes. DNA synthesis occurs before meiotic prophase
I begins and is followed by a G2 phase. Cells then enter meiotic prophase I.
During meiotic prophase I, maternal
and paternal chromosomes are precisely paired, and recombination occurs in each
pair of homologous chromosomes. The first meiotic prophase consists of five
substages: leptotene, zygotene, pachytene,
diplotene, and diakinesis. During metaphase
I, there is random segregation of maternal and paternal chromosomes.
Homologous chromosomes are aligned on the metaphase plate of the meiotic
spindle in metaphase I. The second meiotic division is responsible for the
reduction in the chromosome content of the cell by 50%. In meiotic division II,
metaphase consists of daughter chromatids of single homologous chromosomes
aligned on a metaphase plate (metaphase II).
Condensation of the chromatids occurs in leptotene. In zygotene, the
synaptonemal complex begins to form, which initiates the close association
between chromosomes known as synapsis. The bivalent is formed between the two sets
of homologous chromosomes (one set maternal and one set paternal equals a pair
of maternal chromatids and a pair of paternal chromatids). The four chromatids
form a tetrad (bivalent). Pachytene begins as soon as the synapsis is complete
and includes the period of crossover. The fully formed synaptonemal complex is
present during the pachytene stage. At each point where crossover has occurred
between two chromatids of the homologous chromosomes, an attachment point known
as a chiasma forms. The formation of
chiasmata and desynapsing (separation of the axes of the synaptonemal complex)
occurs in the diplotene stage. Diakinesis is an intermediate phase between
diplotene and metaphase of the first meiotic division.
·
In Hutchinson-Gilford
progerial syndrome (HGPS) an abnormal protein, progerin, is generated and has a “dominant negative”
effect on the function of lamins. The lamins are intermediate
filament proteins that regulate the nuclear envelope, maintain its stability,
and are phosphorylated (prometaphase) and dephosphorylated (telophase) during
the cell cycle. In HGPS the results are dramatic abnormalities in the
architecture of the nucleus, changes in nuclear shape, loss of heterochromatin
(unable to attach to lamins), and an altered distribution of nuclear proteins.
·
Triple A syndrome
is an autosomal recessive neuroendocrinological disease caused by
mutations in a gene that encodes the nucleoporin ALADIN, a component of
the nuclear pore complex labeled with the arrows in the electron micrograph.
The immediate effect of mutations in the nucleoporins is decreased import of
macromolecules from the cytoplasm. Patients with triple A syndrome have adrenocorticotrophic (ACTH)-resistant adrenal failure,
achalasia (abnormal esophageal motility most often due to inability of the
esophageal sphincter to relax), and alacramia (reduced ability to
produce tears). They also demonstrate neurological symptoms affecting the
cranial nerves, autonomic nervous system (Horner’s syndrome and orthostatic
hypotension).
·
Microvillous
inclusion disease (MID) which results in the absence of microvilli
in the small intestinal absorptive cell (enterocyte) brush border (apical
structure labeled between the arrows in the photomicrograph). MID is associated
with an inability to absorb even simple nutrients; the disease presents
as refractory diarrhea in the newborn period with chronic dependency
on total parenteral nutrition. In MID, microvilli are found as inclusions
in the apical enterocyte.(Microvilli increase
surface area for specialized uptake of molecules by pinocytosis,
receptor-mediated endocytosis, and phagocytosis. The microvilli also contain
the brush border enzymes such as lactase and alkaline phosphatase.)
·
Alterations in
connexin density or distribution may be differentially affected
during the development of hypertrophy, thereby increasing the risk of reentrant or nonsustained ventricular tachycardia
seen in African-American males.
·
Distal tubule cells
of the kidney and striated duct cells of the submandibular glands
possess prominent basal infoldings
that are observed at the light microscopic level as basal striations. Basal
folds are modifications of the basal region of the cell. These deep infoldings
of the basal plasma membrane increase surface area and compartmentalize numerous
mitochondria that provide energy for ionic and water transport.
·
Nexin, the radial
spokes, and the basal body all play a role in restricting the
sliding motion and converting it to the bending of the axoneme in relation to
the basal body. Dynein is a
high-molecular-weight ATPase. When dynein is activated, it produces the sliding
motion of the microtubules as it walks along the adjacent doublet. The basal body anchors the microtubules and also
plays an essential role in converting the sliding of the outer microtubules
into the bending of the cilium. The basal bodies resist the sliding movement
generated by dynein activation. Nexin
links the outer microtubular doublets, creating a strap-like arrangement of
paired microtubules around the central microtubule doublet. The radial spokes hold the microtubule doublets in
place, and sliding is limited lengthwise. The radial spokes are rigid and do
not slide against nexin.
·
The centriole
consists of nine microtubule triplets
arranged together by linking proteins to form a cartwheel arrangement.
Microtubules are found in different structural patterns within the cell. The basal body is a centriole-like structure
associated with the ciliary axoneme. It too has a nine-triplet arrangement of
microtubules. Cytoplasmic microtubules are found in the singlet form and
undergo constant association and dissociation of tubulin at their plus ends and
minus ends, respectively. Flagella
have the same “9+2” arrangement as cilia, but are limited to one per cell and
in adult humans are found only in sperm. The axoneme
has the classic “9+2” arrangement of microtubules. Stereocilia are
large, modified microvilli, found in the epididymis and on hair cells in the
organ of Corti, therefore, they are not composed of microtubules.
·
Growth in the length
of long bones after birth (postnatally) occurs through cell proliferation of chondroblasts (immature chandrocytes)
in the secondary ossification centers of the epiphyses. The primary
ossification centers “close” soon after birth.
Growth in the width of the long bone occurs by
the addition of osteoblasts from the periosteum
and deposition of a periosteal collar
The action
of osteoblasts is to deposit bone matrix and secrete alkaline phosphatase; they
do not proliferate in either the primary or the secondary ossification centers.
·
Type II autosomal
dominant osteopetrosis (type II ADO), also known as Albers-Schönberg disease with a characteristic
radiological image of “sandwich vertebrae.”
The targets in this disease are the osteoclasts which are indicated in the
micrographs. Osteoclast function is altered in osteopetrosis. Osteoclasts
function by release of lytic enzymes and protons (derived from carbonic acid)
into the calcified matrix beneath the ruffled border and not through a grinding
action. The bone compartment around the ruffled border of the osteoclast is,
therefore, analogous to a secondary lysosome in function, albeit extracellular.
Osteoclasts use protons derived from carbonic acid, catalyzed by carbonic
anydrase, in similar fashion to parietal cells of the stomach.
·
Downregulation of the anti-angiogenic peptides, angiostatin and endostain, would
enhance tumor growth. Angiostatin is a
cleavage product of plasminogen; endostatin
is a cleavage product of type XVIII collagen.
The
angiopoietins (Ang) 1 and 2 bind their receptor, Tie2, a receptor tyrosine
kinase which regulates endothelial cell proliterative status. Ang 1 binds Tie2 leading
to periendothelial cell recruitment and
therefore vascular maturation.
Ang 2 is found in organs of the female reproductive tract and blocks Ang 1
effects when VEGF is absent. The result is regression of the blood vessel. Ang
2 in the presence of VEGF leads to loosening of the surrounding cells
permitting multiplication of endothelial cells and angiogenesis.
·
In multiple
sclerosis (MS), a demyelinating disease in which both CD4+ and CD8+-T cells as well as
autoantibodies are targeted to oligodendrocytes. MS is twice as prevalent in
women as in men and demyelination is most commonly found in the anterior corpus callosum.
·
Xenotransplantation
induces hyperacute graft rejection since human preformed antibodies recognize [alpha]Gal(1–3)[beta]Gal terminal
carbohydrates present on animal endothelial cells in the graft. Interestingly,
Old World monkeys and humans do not express that xenoantigen on their
endothelial cells.
·
Passage from the blood to the lymphoid
compartment involves specific homing receptors on lymphocytes, which are
complementary to addressins on the postcapillary high
endothelial venules (HEVs) and explains the specificity of
lymphocyte homing. The cells that line the HEVs permit the selective passage of
lymphocytes by diapedesis through the intercellular junctions. Lymphocytes have
specific homing receptors on their cell surfaces that provide entry for mucosal
(versus lymph node) seeding. High endothelial venules (HEVs) provide a
mechanism for lymphocytes to leave the bloodstream and enter specific areas of
the lymph nodes. HEVs are also found in Peyer’s patches and during inflammation
of tissues (e.g., the synovium in rheumatoid arthritis). Under normal
conditions, HEVs are found in the T-dependent areas, that is, the deep cortex
(paracortex) of the lymph nodes and the interfollicular regions of the Peyer’s
patches. T cells home to T-dependent areas of the lymph nodes, spleen, and
Peyer’s patches. The circulation and recirculation of lymphocytes is a constant
process that allows lymphocytes to continuously monitor the presence of
antigen. The circulation process also allows augmentation of the immune response
to infection.
·
Type II
dentinogenesis imperfecta, an autosomal dominant disorder caused by
mutation in the DSPP gene. The result is
defective dentin, discoloration of the translucent teeth (blue-gray or
yellow-brown color). Those teeth are weaker than normal, making them prone to
rapid decay, wear, breakage, and loss. Type II dentinogenesis imperfecta occurs
about 1 in 6000–8000 births. Type I
occurs in conjunction with osteogenesis imperfecta with
mutations in type I collagen; children
with type I have typical blue sclerae with defects in bone and dentin.
·
Glycation results in the production of advanced glycation end-products (AGE), which
alters the properties of the glomerular basement membrane. The cellular
receptor for AGE is called RAGE and
is a multiligand member of the immunoglobulin superfamily of cell surface
molecules. In addition, to its role in diabetes, RAGE interacts with molecular
pathways that regulate homeostasis, development,
and inflammation and plays a role in pathological conditions such as
Alzheimer’s disease and diabetes mellitus. Binding of a ligand to RAGE
activates key cell signaling pathways, such as p21
(ras), MAP kinases, and NFkappa-B (NFκB), thereby reprogramming
cellular characteristics. The interactions and terminology are further
complicated by the presence of ENRAGE
(extracellular newly identified RAGE-binding protein) that interacts with
cellular RAGE on endothelial cells, macrophages, lymphocytes, and other cells
to activate proinflammatory mediators. Interactions between AGE, RAGE, and
ENRAGE may explain many diabetic complications including delayed wound healing.
AGE derivatization is probably nonspecific and involves not only basal
lamina-specific molecules, but also a vast array of extracellular and
intracellular proteins (transcription factors, structural proteins, and
membrane transporters). Hence, cellular coordination/communication becomes
slowly but progressively hampered in the kidney and other organs.
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