Monday, March 31, 2014

Assignment #2

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960759/
Am J Clin Exp Immunol. 2014; 3(1): 30–36. Published online Feb 27, 2014.

Tissue plasminogen activator and inflammation: from phenotype to signaling mechanisms
Tissue plasminogen activator (t-PA) is a serine protease that acts as cytokine to activate receptor-mediated signaling events. tPA has been shown to modulate inflammatory responses in tissue injury. What this means is that tPA could be used to target the autoimmune and inflammatory disease which could be huge in the medical world as tPA is already used for myocardial infarction, pulmonary embolism, stroke, thrombosis and frostbite. The picture shown below shows the mechanism of tPA in modulating inflammation. "A: tPA binds to LRP-1 and induces activation of NF-κB. B: tPA promotes the aggregation of annexin A2 and integrin CD11b, leading to activation of ILK, phosphorylation and degradation of IκB, and eventually activation of NF-κB. C: tPA forms complex with LRP-1, PAI-1, and Mac-1, which results in the increased macrophage migration." 
An external file that holds a picture, illustration, etc.
Object name is ajcei0003-0030-f1.jpg

http://www.rcsb.org/pdb/explore/explore.do?structureId=1TPM
This article from the Protein Data Bank articulates that the amino acid sequence of the first domain of tPA has eight residues that are highly conserved in the type 1 finger domains of human fibronectin. The overall fold of the t-PA finger domain similarity to that of the seventh type 1 repeat of human fibronectin with the side-chains of conserved residues lying in similar conformations is rather striking. One significant difference between the two molecules is that hydrophobic residues cover the exposed surface of the principal beta-sheet region in the t-PA finger domain. One idea is that one face of this region may interact with parts of the complete t-PA protein. A construct of 50 residues from this finger domain of tPA was expressed and its solution structure was determined by two-dimensional nmr-spec.

http://www.nejm.org/doi/full/10.1056/NEJMct1007370
Wechsler, Lawrence R. Intravenous Thrombolytic Therapy for Acute Ischemic Stroke. New England Journal of Medicine 364:2138-2146, 2011.
This feature starts off with a case vignette that includes a therapeutic recommendation for an 81-year-old man that was diagnosed with acute ischemic stroke. He was recommended immediate initiation of intravenous thrombolytic therapy as the CT scan of his brain showed no hemorrhage and no early ischemic changes. The estimated direct medical costs of stroke in the United States were $25 billion in 2007. This article then talks about the clinical problem of strokes, pathophysiology and effect of therapy, clinical evidence, clinical use, adverse effects, areas of uncertainty, guidelines and recommendations for tPA and treatment of ischemic stroke. The cost of rt-PA was estimated to be $2,750 and more expensive than standard care for ischemic stroke in the short term, owing to the cost of the drug and the need for additional resources. However, the drug and treatment is associated with lower costs in the long term, since it reduces the risk of subsequent disability. So although tPA might be an expensive drug, it is cost effective and worthwhile generally, especially when treating cases such as acute Ischemic stroke.



Although Wikipedia is not always seen as a credible site, they do a brief synopsis of many articles describing tPA. tPA is known as a clot buster and helps the body breakdown clots such as embolic and thrombatic illnesses such as myocardial infarction, pulmonary embolism, stroke, thrombosis and frostbite. For stroke where it is most often used, it can dissolve the blood clots in the brain and decrease the chances of death or disability if used within 4.5 hours after the onset of stroke symptoms. They are now working on a version that will only work at the site of the clot so as not to allow hemorrhaging elsewhere for the patient so it is safer to use. How tPA works is that it cleaves the zymogen plaminogen at its Arg561-Val562 peptide bond, into the serine protease plamin which causes hyperfibrinolysis (a thinner blood or breakdown of the clot). tPA also plays a role in tissue remodeling and cell migration.
This picture was just from wikipedia but shows where tPA acts.
http://upload.wikimedia.org/wikipedia/commons/0/0e/Fibrinolysis.png




Monday, March 3, 2014

Assignment #1 "exploring images"

The USA protein flag.


Sticks and tpa.
Minty cool.

Bloody shadow.

Cluster buster.

One extra:
Icy cool.



tPA proteint: Tissue Plasminogen Activator: 10.2210/pdb1tpm/pdb