Monday, August 06, 2012

Tit Bits of the week

Welcome back all,

    As i look at the calendar, after a chillax weekend and lazying around i was thinking of what do i write about this monday. Nothing had caught my attention that needs to be blogged. Ofcourse that doesnt mean microbiology was celebrating a holiday last week. It just means that i didn't get a paper that had caught me up so much that i wanted to write about it. Anyways, there still was some headlines of microbes floating around that i thought i will make a note of here. And maybe i will stumble upon something that i can talk about.

Photo 1: Curiosity rover (Image taken from here)
    Oh and by the way, the NASA project curiosity has successfully landed. What's interesting about it for a microbiologist? The "Curiosity" vehicle is meticulously designed and equipped to look for signatures of life. And maybe we find some microbes sitting on another planet and minding its own business there. And if things turn out so, we could be more serious of some "Astromicrobiology / Cosmomicrobiology" (Too complicated words). Thats interesting to me cause we probably would be talking more microbiology in the context of some panspermia theories. (Read more here).

    You must have heard about the German patient story, who controlled his HIV status with a stem cell transplant (Link). Following this a landmark paper by Wilen CB etal (Link) showed that by chopping of specific genes using a zinc finger nuclease, we could probably engineer some resistance to cells against HIV. The same whole issue of transplanting stem cells has come up again. Two men with HIV infections no more  show retropositivity in their blood cells following bone marrow transplantation (Link). This whole issue is now interesting to me. What we can do is catch hold of a donor who has stem cells resistant to HIV probably get it to replicate in laboratory and pack as vials and give transplants to HIV patients. Boom!! (Am just speculating the future possibilities. If someone finds himself such a possible donor, he better patent his cells!!!). I have a better feel of this issue. IF we could possibly find a commercial method to engineer the cells from patient himself and then transplant him back (Read Wlien CB paper i mentioned above) we are really a step nearer to shutting down the HIV menace. Interesting enough.

Fig 1: Endonuclease domain of influenza
     Influenza virus have been in news for a long time now. But this is bit different. The influenza virus is in itself a outlier of the fact that unlike other RNA viruses, they replicate in nucleus. An explanation is so. Influenza being a negative sense RNA genome. For this it first needs to produce a positive sense mRNA in order to produce necessary enzymes. The feasibility to do this exists in nucleus. In the host nucleus, the virus carries out its primary transcription through a special mechanism known as "Cap snatching". The host mRNA is stolen and broken down into small fragments of 10-20 bases length. This is done with the help of an endonuclease. This activity is embedded in the viral RdRp (RNA-dependent RNA polymerase). The generated fragments is used a a primer to kick start building new cRNA from which all required materials can be built. (For more information click here). This is pure elegancy which is not completely understood. The researchers elucidated the 3D structure of the polymerase and observe interactions by several different small molecule inhibitors that can attack its active site. As Stephen Cusack says "Based on this detailed structural information we can now design new synthetic chemicals which bind even more tightly to the endonuclease active site and thus will potentially be more potent inhibitors of influenza virus replication" and "We can even try to build in anti-drug resistance by making sure the inhibitors only contact those amino acids that the virus cannot mutate since they are essential for the normal activity of the polymerase. The figure 1 (shown above  right, shows secondary structure of the endonuclease domain of the influenza virus polymerase; ß-sheets in yellow and α-helices in blue. The active site lysine 134 and the amino acid side chains that ligand the two metal ions (represented as green spheres) in the active site are indicated. (Source).) Read paper here and here.

     Every disease that we know of has a multifactorial etiology. Often if not always, a part is played by microbes that we interact with daily. Diseases that have been thought to be completely innate are now found to been triggered at least in part by microbes. Multiple sclerosis and many other auto immune disorder has been speculated to be due to gut microbiome. Mind you, I'm not specifying a organism but a collection of microbes- "The Microbiome". Read more here. The idea is that immune system is trained and kept at healthy conditions most often by our normal flora. Change in flora and change in immune response. This at times have even lead me to ask a question. Is our immune system deciding which microbe should stay or microbe is deciding what immune system should stay. Thats why our body should interact well with the filthy microbiome out there in environment, to stay healthy. (Read my previous post Microbiophobia). Why am i talking about all this? for 2 reasons. 1st awareness and 2nd, to break the news.

Photo 2: Gestational Diabetes (Source)

   The news that am talking about above is that of a relation between pregnancy, diabetes and gastro-microbiome. Gestational diabetes is not so uncommon phenomenon. This is attributed to a resistance to insulin, which increases in all mothers during pregnancy. of this about 2-5% develop a temporary diabetes. In majority of scenraio's there is no external symptoms and is detected only by screening. Only rarely do the classic symptoms of diabetes appear, e.g excessive thirst, frequent urination and tiredness. The fetus probably has a parasitic role in gestation period. The physiological reprogramming of sensitivity to insulin in mothers is thought to be placenta mediated. The fetus can then gain the extra glucose not taken up by mother. (Am not sure if this is the case. But thats how i see it.

Fig 2: Potential mechanisms for insulin resistance in skeletal muscle during late pregnancy in human gestational diabetes  (Source: Linda etal; Link)

      Apologies for such a long digression to tell you a single line news. And the news is "Pregnancy alters microbiota of gut". There are some important findings that i latched onto. First is the diversity of gut bacteria declined between the first and third trimesters, but the abundance of certain types, such as the Proteobacteria and Actinobacteria, increased. This according to me should be co related to the known fact that in early pregnancy, insulin secretion increases, while insulin sensitivity is unchanged, decreased, or may even increase. In late gestation, maternal adipose tissue decline, while postprandial FFA levels increase and insulin-mediated glucose disposal worsens. This correlates with the findings of the study, that third-trimester microbiota resembles that of people at risk of diabetes. David Relman commented “That is pretty suggestive that the microbiome is at least contributing to the change, or maybe driving it”. Ley makes a statement “The body might be using the microbes as a tool" and "You alter the microbiota, and they give you the changes in metabolism that you want”. If she hadn't said it, that would be exactly the same statement that i would have made here. (Source). For more information on link between diabetes and microbes go here and here.

     As i said already, am not discussing a paper in full today. So, Signing off for now. Be sure to check my post in my other blog on luminescence and its application in laboratory science.
Rebecca M. DuBois etal (2012). Structural and Biochemical Basis for Development of Influenza Virus Inhibitors Targeting the PA Endonuclease PLoS pathogens

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