HAPPY FATHER’S DAY!


 

 

SOME QUOTES FOR TODAY:

 

One night a father overheard his son pray: Dear God, Make me the kind of man my Daddy is. Later that night, the Father prayed, Dear God, Make me the kind of man my son wants me to be.

 

Sherman made the terrible discovery that men make about their fathers sooner or later… that the man before him was not an aging father but a boy, a boy much like himself, a boy who grew up and had a child of his own and, as best he could, out of a sense of duty and, perhaps love, adopted a role called Being a Father so that his child would have something mythical and infinitely important: a Protector, who would keep a lid on all the chaotic and catastrophic possibilities of life.
Tom Wolfe
The Bonfire of the Vanities

 

There are fathers who do not love their children, but there is no grandfather who does not adore his grandson.
Victor Hugo 

 

“I won’t lie to you, fatherhood isn’t easy like motherhood”

Dan Castellaneta

 

By the time a man realizes that maybe his father was right,
he usually has a son who thinks he’s wrong.
Charles Wadsworth 

 

“A father is a banker provided by nature.”
– French Proverb

 

The child had every toy his father wanted.”
– Robert C. Whitten

 

LEONTINE: An only son, Sir, might expect more indulgence
CROAKER: An only father, Sir, might expect more obedience
– Oliver Goldsmith 1728-1774 from The Good Natured Man

 

It is admirable for a man to take his son fishing, but there is a special place in heaven for the father who takes his daughter shopping.
John Sinor

 

We think our fathers fools, so wise we grow.
Our wiser sons, no doubt will think us so.
– Alexander Pope

 

 

When I was a boy of 14, my father was so ignorant I could hardly stand to have the old man around. But when I got to be 21, I was astonished at how much the old man had learned in seven years.

 

The father is always a Republican toward his son, and his mother’s always a democrat.
– Robert Frost

 

There are three stages of a man’s life: He believes in Santa Claus, he doesn’t believe in Santa Claus, he is Santa Claus.

 

Life was a lot simpler when what we honored was father and mother rather than all major credit cards.
– Robert Orben

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Q: About the production of NADH in the Krebs Cycle


 

Cycle_de_krebs numerado

In this representation of Krebs Cycle, each reaction is marked with a number.  The reactions where NAD+ is reduced to NADH.H+ are those marked with the numbers:

 

a)     1,3 and 4

 

b)     3,4 and 5

 

c)      3,4 and 6

 

d)     3,4 and 8

 

e)     5,6 and 7

 

f)       4,5 and 6

Biochemistry of the Complement System


 

 

The binding of the antibody and the antigen is not enough sometimes to give an effective protection against the invader agent; that is why it is necessary the complementary action of other components of the immunological system able to neutralize or promote the neutralization of the foreign agent.  

 

Complement system is a set of proteins that form a biochemical cascade which participates in the immunological mechanisms of the body. This system, several times, act complementary (and as result) of the antigen-antibody interaction, but some times can even act independently of the action of antibodies.

 

The proteins that form this system are mainly proteolytic enzymes in form of  zymogens, that when the mechanism is initiated, are activated and trigger defense mechanisms that include a wide range of actions,  from the activation of  phagocytosis to the lysis of foreign cells. Other complement proteins act as cofactors while others act as inhibitors.

 

Most of the proteins that form the complement system are synthesized in the liver. Complement proteins form approximately 5 % -10 % of plasma globulins. They are components of the acute phase response and their concentration in blood is increased during infections, injuries, and traumas. Most of these proteins are named with a C letter and a number that was assigned in the order that they were discovered.

 

The functions of the complement system include:

 

1. – Cell lysis

2. – Stimulation of phagocytosis through opsonization.

3. – Attraction of phagocytic cells through chemotaxis

4. – Contribution to the inflammatory and allergic reactions, by stimulating degranulation and release of intracellular enzymes, histamine, etc.

5. – Facilitation of immune complex elimination.

 

Activation of the complement system can happens through any of the following mechanisms:

 

1. – Classic complement pathway.

2. – Alternative pathway

3. – Mannose-binding Lectine pathway.

 

In the classic activation pathway, the antigen-antibody interaction provokes allosteric changes in the immunoglobulin that exposes, in the constant region 2 the heavy chains (HC2), a binding site for C1q, a protein of the complement system.  The binding (and subsequent activation) of C1q to the constant region of the heavy chains activates two other proteins of the complement system: C1s and C1r.  C1s is a serine protease which acts on C4; when C4 is activated, C4 acts on C2.  The active fragments of C4 and C2 form the complex C3 convertase, which hydrolyzes C3. (C1q can be activated also by mycoplasms, bacterial endotoxins, RNA virus, and some membranes, in the absence of antibodies)

 

When C3 is activated the signal is highly amplified, since C3 is the most abundant protein of the complement system, and it can experiment also self-activation.  The C3 b derived from C3 binds to glycoproteins in the cell surface. Since macrophages and neutrophils have C3b receptors, they recognize the cells covered with C3b and phagocyte them.

 

Another part of C3b binds to C5 forming a complex that is hydrolyzed by C3 convertase (aka C3/C5 convertase).This hydrolysis produce C5a, which attracts neutrophils, and C5b. C5b form a complex in the cellular membrane with C6, C7 and C8. This complex guide the polymerization of around 15 molecules of C9, to form a pore that goes through the membrane lipid bilayer of the foreign cell,  allowing the passage of ions and small molecules, and provoking the cell lysis.  This complement complex is called the Complement Membrane Attack Complex (MAC).

 

The following video shows a version of this process:

 

 

The alternative pathway occurs in the absence of the antigen:antibody complex.  Usually, a certain quantity of C3 is spontaneously hydrolyzed releasing 3a and 3b. In normal conditions, 3b is inactivated, but in the presence of bacteria, or invader particles or molecules (virus, fungus, bacteria, parasites, snake’s venoms, or Ig A)  3b can bind to the bacteria membrane and interact with other plasma protein, Factor B, forming a C3bB complex. This complex, when hydrolyzed by another protein (Factor D) releases Ba and becomes a C3bBb complex, with C3/C5 convertase activity. This complex triggers ulterior changes that provoke the formation of the Membrane Attack complex and the invader cell lysis. (Some proteins,  Factor H and factor I inhibit C3 convertase, while properdin stabilizes C3 convertase active conformation)

 

 

A third form of complement activation is the Mannose-binding Lectine pathway. In this pathway, the Mannose-Binding Lectine (MBL), a serum protein that is able to link to mannose and other monosaccharides in the glycolipids and glycoproteins of the surface of the invader cells, form a complex with two serine proteases zymogens (Mannose-binding lectin Associated Serine Proteases)  MASP-I and MASP-II. When the MBL binds to the oligosaccharides on the bacteria, virus and fungus surface, the serine proteases result activated and hydrolyze C4 and C2 proteins, triggering the complement cascade.

 

 

It does not matter which activation mechanism is used, the three of them converge in the formation of a complex with C3 convertase activity, formation of C3b and the progression of the cascade that culminates with the foreign cell lysis.

 

 

Even when different textbooks differ in some specific details, the fact is that the complement system main functions include:

 

1.- Opsonization (marking foreign cells for phagocytosis; e.g. C3b)

2.- Chemotaxis (attraction of neutrophils to the invader agent; e.g. C5a)

3.- Lysis of invader cells (Ex C5, C6, C7, C8, and C9)

4.- Contributing to the inflammatory and allergic response,  by stimulating cell degranulation and release of enzymes, histamine, and other substances (Effects of C3a, C4a, C5a)

5.- Promoting the elimination of immune complexes (Ex. C3b )

 

This video summarizes the mechanism of action of the complement system (some small  details are different; do not care about that and pay attention to the big picture):

 

 

 Complement system dysfunction is related to some diseases, like acquired or congenital deficit of individual complement components. In these diseases, the patient shows an increased susceptibility to Neisseria or pyogenic infections.

There is also an important association between the deficiency of complement factors and immunological diseases of the type of Systemic Lupus Erythematosus, and other collagen and vascular diseases, as well as with some cases of chronic nephritis, angioedema, etc.

 

Additional information can be found in the following links:

 

Complement System

 Complement Membrane Attack Complex

 Moore, E.:

Complement Deficiencies.

When the immune system has  inadequate levels of Complement proteins

 

Gupta, R.; Agraharkar, M.:

Complement Related Disorders

 Chaganti, K.R. et al:

Complement Deficiencies

 Glovski, M. et al:

Complement determinations in human disease

Q: About a patient receiving Cholestyramine (LM-12)


 

 

Cholestyramine is used to reduce serum cholesterol because of its ability to interfere with the enterohepatic circulation of bile salts in the feces. When this drug is prescribed to a patient, which of the following compounds will be found in high concentrations in feces?

 

a) Doxycholate

 

b) Palmitate

 

c) Glucuronate

 

d) Bilirrubin

 

e) Squalen

 

f) estercobilinogen

Immunoglobulins: structure and functions.


 

Angel of the West (This sculpture represents an IgG molecule)

 

Immunoglobulins are glycoproteins that function as antibodies. In fact, the terms antibodies and immunoglobulins are usually used indistinctly: immunoglobulins highlight structure and antibody highlights function. Immunoglobulins can be found attached to the B-cell membranes, in secretions or circulating in blood.

 

Immunoglobulins are produced as a response to the detection of foreign molecules in our body. These foreign substances that trigger the production of antibodies are called antigens.

 

Circulating immunoglobulins are included in the plasma protein fraction of the gamma globulins.

 

Plasma Electrophoresis

 

 

 

 

 

 There are different types of immunoglobulins: IgG, IgM, IgA, IgD and IgE. All of them have in common that their basic unit is formed by two pairs of peptide chains: a pair of Light chains or L chains (approximately 220 amino acids each) and a pair of Heavy chains or H chains (around 440 amino acids each).

 

These four chains in the basic structure are linked through disulfide bridges between cystein residues in the backbone of the peptide chains. Each Light chain is linked to one Heavy chain and each Heavy chain is associated to a Light chain and to the other Heavy chain.

 

The following graphic shows the Heavy chains in blue, the Light chains in green and the disulfide linkages between the chains in red (there are additional intrachain disulfide bridges that are not shown in this graphic)

 

 

Observe also in the graphic that in the L chains can be distinguished two regions or domains: VL and CL, while in the H chains, 4 regions or domains can be found:  VH, CH1, CH2 and CH3. Each of these regions is composed by 70 to 110 amino acids.

 

The V regions are Variable regions: the amino acid sequence in these regions (the NH2- terminal regions of L and H chains) is highly variable, and within them, in the L and in the C chains, there are hyper variable regions (CDRs of Complementarity-determining regions) that form the specific antigen binding site complementary to the specific antigen.

 

 

This video shows the structure of a typical immunoglobulin IgG:

 

 

As you have seen, there are two binding sites for antigens in each (LH)2 unit. When a (LH)2 unit is hydrolyzed with papain, three fragments are released: two Fab and one Fc fragment.

 

 

The Fab fragments contain the structure that is able to bind to the antigen (Fab = Fragment antigen-binding), while the Fc fragment (c means crystallizable) is not able to bind to the antigen, but contain a complement binding site, that is exposed when the interaction between the Fab fragment and the antigen occurs. This binding occurs through non covalent interactions (Van der Waals forces, Hydrogen bonds, hydrophobic interactions) and triggers conformational changes similar to those observed in the enzyme-substrate inducing fit mechanism. This allosteric effect exposes sites in the constant regions of the heavy chains, related to the binding and activation of complement proteins.

 

This complement system is formed by eleven different proteins that are sequentially activated for associating to the cell membrane to cause lysis and death of the invading bacterial cell.

 

 

Another important role of the complement system is to generate proteins called opsonins, which stimulate phagocytosis by neutrophils and macrophages.

 

(More detailed information about the complement system can be found here)

 

In addition to the activation of the complement system, the constant regions of the Heavy chains define the ability of the (LH)2 basic structure to associate to others (LH)2 units and determine the kind of immunoglobulin.

 

There are four kind of Heavy chains:  g (Gamma),  a (Alpha), d (Delta),  e (Epsilon) and m (Mu).

Gamma chains are similar in their constant regions that are different to the other kind of heavy chain constant regions. The same is valid for each of the different kinds of Heavy chains.

 

Immunoglobulins that contain Gamma chains are called IgG.  IgG molecules are formed by one (LH)2 unit. These are the most abundant immunoglobulins in sera (600-1800 mg/dL). They promote phagocytosis in plasma and activate the complement system. IgG are the only kind of antibodies that can cross the placenta.

 

Observe in the following diagram of an IgG molecule, the two Heavy chains (in red and blue) and the two Light chains (in green and yellow).

 

 

In this diagram can be observed the variable and constant regions of the IgG and the interchain and intrachain disulfide linkages in the structure.

 

 

Immunoglobulins containing alpha chains are called IgA. IgA is found mainly in mucosal secretions, tears, colostrum and milk. These are the initial defense in mucosas against pathogen agents. They appear usually as dimmers of (LH)2 units

 

IgM contain mu heavy chains. IgM antibodies are expressed in the surface of B-cells and are found primarily in plasma. They are the first antibodies produced in significant quantities against an antigen. They promote phagocytosis and activate the complement system. They appear usually as pentamers of (LH)2 units

 

 

Ig E contains Heavy chains type epsilon. IgE, a (LH)2 monomer, plays an important role in allergic reactions and increase in worm infestations.

 

The role of IgD (immunoglobulins with delta heavy chains) is not very well known. This kind if IgG is found in the surface of the B-cells that have not been exposed to antigens. IgD structure correspond also to a (LH)2 monomer,

 

There are also different classes of L chains:  the Lambda (l) and Kappa (k) class. Each immunoglobulin molecule has either lambda or kappa chains, but not both.

Lambda chain are similar in their constant regions, Kappa chains are similar between them in those regions.

 

In summary, immunoglobulins are proteins that function as antibodies. The basic structure of immunoglobulins is a unit formed by two light chains and two heavy chains. These units contain variable domains and constant domains. The variable domains of the L and H chains are responsible of the binding to the antigens, while the constant regions of the H chains are responsible for the activation of the complement system and the ability of some of these (LH)2 units to form polymers.

Q: About an adult patient with jaundice


 

While attending a 21 years old male black patient who complains of abdominal pain, you observe a pale light yellow color of the skin and sclerotics. You suspect that the patient has jaundice; urine dipstick test is negative for bilirrubin but positive for urobilinogen.

 

When laboratory reports of blood tests arrive, they show the following results:

 

– Hematocrite: 28% (reference range from 41% to 53%)

 

– Hemoglobin: 8 g/dL (13.5-17.5 g/dL)

 

– Alanin aminotransferase (ALT) : 12 U/L (reference range 8-20 U/L)

 

– Aspartate aminotransferase (AST): 18 U/L (reference range 8-20 U/L)

 

– Alkaline Phosphatase (ALP): 80 U/L (reference range: 44-147 U/L)

 

– Total Bilirrubin: 3.5 mg/dL (normal = 0.1 to 1 mg/dL)

 

– Direct bilirrubin 0.2 mg/dL (normal from 0 to 0.3 mg/dL).

 

 

Which of the following options are compatible with the results shown above?

 

a)     jaundice of prehepatic cause

 

b)     jaundice of hepatic cause  because of deficiency in the intake of bilirrubin

 

c)      jaundice of hepatic cause because of deficiency in the conjugation of bilirrubin

 

d)     jaundice of hepatic cause because of deficiency in the excretion of bilirrubin from the hepatocyte.

 

e)     jaundice of posthepatic cause (extrahepatic biliary obstruction)

Q: About Fructose 2,6 Bisphosphate (CM-24)


 

 

 

Which of the following sentences explain better the role of fructose  2,6-bisphosphate in glycolysis?

 

a) It antagonizes phosphofructokinase-1

 

b) It is an intermediate of glycolysis

 

c) It activates covalently  aldolase

 

d) It inhibits allosterically hexokinase

 

e) It allosterically activates phosphofructokinase-1