Penicillin

A great old government film touting the discovery and promise of Penicillin:

Penicillins are a group of drugs naturally produced by penicillium molds. The antibiotic activity of penicillium was first observed by Alexander Fleming in 1928. He recognized the value of what he was seeing, but was unable to isolate the molecule that mediated the activity and therefore could not perform appropriate trials. It was not until Howard Florey and a team of researchers including Ernst Boris Chain and others from the Sir William Dunn School of Pathology, University of Oxford managed to isolate and purify the substance that its great promise became evident. (later Fleming, Florey and Chain shared the Nobel Prize in Medicine for their work)

A number of naturally occurring penicillins exist, each characterized by a beta-lactam ring joined to a variable R-group. These drugs may be effective in the treatment of certain, susceptible (mostly) gram positive bacteria. The mechanism of action is the inhibition of peptidoglycan crosslinks in the bacterial cell wall, such that organisms cannot produce new cell wall and wind up shedding the wall during division. Without the cell wall, the bacteria is highly susceptible to immunological mechanisms and is readily killed.

Unfortunately, many otherwise susceptible bacteria produce an enzyme (penicillinase / beta-lactamase) that cleaves the beta lactam ring structure leaving it ineffective. This single enzyme can be easily passed from one bacteria to another via a sex pilus or transformation rendering them non-susceptible to the antibiotic.

 

This enzyme breaks the β-lactam ring and deactivates it’s antibacterial properties. Because beta-lactam is central to the activity of penicillins, cephamycins, and carbapenems, all of these antibiotics can be rendered ineffective by organisms possessing this enzyme.

To counter this beta-lactamase activity, Clavulanic Acid can be used as an inhibitor of this enzyme. Clavulanic acid acts as a competitive ‘suicide inhibitor’, covalently bonding to the active site of the β-lactamase and irreversibly inactivating it. Compounds of the drug (Penicillin) and the enzyme inhibitor (Clavulanic Acid) are available as Amoxicillin under a number of brand names.

 

The Haemopoietic Stem Cell

Reblogged from All About Blood:

The Discovery of Haemopoietic Stem Cell

 

Blood was regarded as an important tissue, but till the mid 1800s it was not known how blood cells were made. Three discoveries lead to the modern concept of haemopoietic stem cell.

1. Neumann and Bizzozero separately, in 1868, proposed that the bone marrow was the site of blood production throughout the postnatal life.
2. Improvement in staining techniques lead to the discovery of a spectrum of cells in the bone marrow.  

Read more… 892 more words

An excellent post looking at hematopoietic stem cells and the work done with them over the years. And even a bit of a FACS cheat sheet at the end.

 

Dark Night of the Scarecrow : after 30 years of nightmares

Have you ever been haunted by an old movie existing in the shadows of your mind? Something you shouldn’t have seen? Perhaps hiding behind the couch when your parents thought you were in bed sleeping? 

I can think of several films I saw that way when I was young. Films that gained special power because my memory was incomplete and my mind filled in the gaps with things a lot scarier than the film itself. 

I was too afraid to keep watching that night and left scared out of my wits early on to stew in my own imaginings.

It must have been thirty years ago, and I never even knew what the movie was until just recently, when Netflix found it for me: Dark Night of the Scarecrow, Directed by Frank De Felitta in 1981, starring more familiar faces than you’d believe.

The film opens introducing us to Bubba, a man from the mold of Lenny from ‘Of Mice and Men’, a big man with a small mind. Not five minutes in, Bubba is (wrongly) accused of doing harm to a young girl who he plays with regularly.

The good old boys in town form up a quick posse to bring street justice to the man that they have already decided was a menace to their town. Soon, they corner the simpleminded man as he hides in plain sight as a scarecrow near his house.

 From then on, everything goes so predictably, Bubba could have written it:

 The men learn of Bubba’s innocence with their guns hot in their hands, there’s a trial but the men get off (they appear to have benefitted from a ‘stand your ground’ law that strongly favors the survivors of an interaction. But as the trial ends, they are cursed by Bubba’s old crone of a mother. One by one, over the next several days, the men see the scarecrow in their fields, panic and get themselves killed in ways that are arguably accidental.

There are some moments of tension once in a while, but this is not the kind of movie that will make you jump. Ever. I would not say that it’s a very good film, but it’s not terrible either. And Bubba will haunt your children’s dreams for years if you let they get a glimpse.

A la the ‘They’re Coming to get you Barbara’ movie review site (may it rest in peace), I’d give it two severed thumbs up.

 

Wrapped in Plastic

 

B Cell Activation (The Basics)

B cells, along with T cells, are lymphocytes that bear antigen receptors that have been randomized for their binding specificity during development (see my earlier post). On the B Cell, the antigen receptor is aptly named: B Cell Receptor, or more commonly, BCR.

Like the T cell Receptor (TCR) on T Cells, the BCR is a transmembrane protein expressed on the plasma membrane, where it can bind by antigen. Unlike the TCR, B Cells are not ‘presented’ antigen by other cells in the context of an MHC molecule. Instead, B Cells ‘see’ antigens in their native state – imagine these as soluble toxins or cell-surface antigens on bacteria of viruses.

APC : T Cell Interaction   vs  Native Antigen : B Cell

Another difference between T Cell and B Cell activation is that T Cells become activated, but do not change their expression of their antigen receptor. B Cells, on the other hand, may react in one of several different ways.  In general terms, this means differentiation into either Memory Cells or Plasma Cells.

Memory B Cells proliferate, but retain their membrane-bound receptors. This makes sense because the purpose of these cells is to lie in wait until antigen is seen again, so they need their receptors to ‘see’ it.

Plasma cells lose their membrane-bound receptors, but continue to express the same molecule in a soluble form called Antibody. In fact, they grow in size and fill with ER and Golgi Apparatus to handle the extreme output of protein that they begin producing (~2000 molecules / sec according  to  Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002. ).

Antibody comes in a number of varieties, but all share a similar core structure as the one pictured to the right. It consists to two heavy chains and two light chains, creating two unique binding sites for antigen.

Events following B Cell Activation

Once cells become activated, they may either immediately become short-lived plasma cells (SLPCs) that secrete antibody identical to the BCR for a short time and then die off, or they may enter into Germinal Center (GC) Reactions. In the GC, B cells get T Cell help and compete for antigen in a poorly understood manner whilst undergoing hypermutation of the BCR’s antigen-binding site.  This results in BCR / Antibodies with higher affinity (greater binding ability) for antigen that may then differentiate into either Long-Lived Plasma Cells (LLPCs) of memory cells. These several differentiation paths can be seen in the illustration below.

 

To Summarize:

1. B Cells are activated as a result of crosslinking BCRs by native antigen

2. B cells do require help from T Cells to enter germinal center reactions and produce LLPCs and memory cells (although getting help was not discussed here)

3. B cells become activated and either start producing antibody right away as SLPCs or enter genrminal center reactions.

4. Once in a germinal center, B cells undergo hypermutation of the antigen-binding section of  their BCR/Antibody.

5. Following the GC reaction, B cells bearing high-affinity BCR/antibody will differentiate into LLPCs or memory cells.

 

I will tell you three things …

Without enzymes this is useless:

The Owls are not what they seem.

There’s a lot of this singer in the bars of Twin Peaks:

 

It’s that time again: Jeopardy and Cookies

The Microbiology Game Board

Tomorrow (Thursday) is review day for the final exams in both my General Biology and Microbiology classes.

Maybe later I’ll post a few hints to help your team win.

Maybe.