Applied Bimatics - An Informatics & eHealth Blog

I am a clinician with a passion for informatics. This blog is about my eHealth journey exploring interoperability in Electronic Medical Records (EMR/EHR), Patient Safety, Pharmacovigilance, Data Analytics, Clinical Research and Bioinformatics in a clinical context. Comparing Canadian, Indian and Middle Eastern healthcare systems and services. Join our open facebook group here: https://www.facebook.com/groups/clinical.bioinformaticians/


Testing Webservices

Debugging
Debugging (Photo credit: mikemol)
Last night I added 2 more webservices to DermKnowledgeBASE. Debugging webservices is a nightmare. (At least it was, until the wee hours of the morning). It always returns SoapFault exception mentioning that "looks like we got no XML document". After several wasted hours of hard work I found the way to use the instruction here. The best answer is rather cryptic. So I have included the code I used to display the request and response so that debugging becomes much easier.



Change the wsdl path and the function call. Hope this saves some time for someone!

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The great anti-ageing mantra


Matrix metalloproteinases (MMPs) are important in dermatology as they are involved in remodelling extracellular matrix (ECM). It is a big family of enzymes, all having a common domain structure with a pro-peptide region, catalytic domain, hinge region and the haemopexin-like C-terminal domain.  They are involved in a variety of biological functions. MMP1 is involved in the premature ageing in smokers.[1] Inhibition of certain MMPs have anti-ageing effect while inhibition of others promote hyperproliferative disorders and scars. However because of the structural similarities, rational design of specific inhibitors are very difficult. Most of the rationally designed MMP inhibitors like  marimastat (BB-2516) and  cipemastat (Ro 32-3555) have performed poorly in clinical studies.

This is a Graph showing the mutual activation ...
This is a Graph showing the mutual activation of matrix metallo-proteinases. (Photo credit: Wikipedia)
This paper [2] proposes a new approach wherein regulatory sites hidden and scattered over different locations on the protein’s surface are targeted instead of the catalytic site using specially designed branched amphiphilic molecules. They have demonstrated that MMP family possess a unique set of such sites making it possible to target specific MMPs without affecting others. If this technology can be successfully developed it may have several applications including many dermatological uses.

References:

1. Lahmann, Christine et al. "Matrix metalloproteinase-1 and skin ageing in smokers." The Lancet 357.9260 (2001): 935-936.

2. Udi, Yael et al. "Unraveling hidden regulatory sites in structurally homologous metalloproteases." Journal of Molecular Biology (2013).


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Rational Peptide Design


A hexapeptide mimic of the N-terminal end of SNAP-25 which competes with this protein for a position in the SNARE complex is being used as a cosmetic peptide to eliminate facial lines resulting from muscular activity. However industry standard for the same indication is Botulinum Neurotoxin A that can enter the neuron by SV2 mediated endocytosis. It is not known whether the hexapeptide mimic actually enters the neuron in sufficient concentration to give the proposed effect. Read the clinical implications of the story here.

One of the earliest studies on this Acetyl Hexapeptide - 3 gives a ‘rational’ explanation for this limitation. Let me quote from the article:[1]

Gp41 coiled coil hexamer 1aik topview
Gp41 coiled coil hexamer 1aik topview (Photo credit: Wikipedia)
Sequence and structure analysis of the N-terminal of SNAP-25 revealed the sequence EMQRR that display a high propensity to acquire an alpha-helical Structure along with a pronounced coiled-coil probability. AGADIR, a programme that estimates helical propensity of peptides, predicted a remarkable 12 % probability for this small peptide. These properties suggest that a peptide patterned after this sequence may modulate Calcium dependent  exocytosis, Similar to those peptides derived from the C-terminal of SNAP-25.

I have the following questions about the rational explanation:

1. How can a hexapeptide have coiled-coil probability? (A minimum of 20 amino acids are needed for a coiled coil)[2]
2. Is 12% probability remarkable?
3. How is a N-terminal mimic be similar to a C-terminal mimic?

Is this an attempt to suggest that the structural peculiarities mediate an HIV virus like receptor mediated endocytosis. If only we knew the truth. If only....

References:


1. Blanes‐Mira, C et al. "A synthetic hexapeptide (Argireline) with antiwrinkle activity." International journal of cosmetic science 24.5 (2002): 303-310.

2. Rose, A. "Genome-Wide Identification of Arabidopsis Coiled-Coil Proteins and ..." 2004. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC389916/>


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About Me

As a Dermatologist and Informatician my research mainly involves application of bioinformatics techniques and tools in dermatological conditions. However my research interests are varied and I have publications in areas ranging from artificial intelligence, sequence analysis, systems biology, ontology development, microarray analysis, immunology, computational biology and clinical dermatology. I am also interested in eHealth, Health Informatics and Health Policy.

Address

Bell Raj Eapen
Hamilton, ON
Canada