This week in research

Good to see people back,

        Last week i signed of with just a few news. Subsequently there was lot of microbiology that came up. I should have written blog late last week cause so many paper caught my attention. And an announcement. I recently launched my website- "Microboids" (A rather funny name, but will do it for me). I have brought all my digital materials under this one hood. If you haven't checked it out yet, have a look at it. (Oh no, this is not any advertisement, but kind of self promotion!!).

Photo 1: Caenorhabditis briggsae
(Source)

       So, let see what is been making the news. The first catchy material for me, has to do with Caenorhabditis briggsae nematode. They are model animals for studying evolution of animal, their development and behavior. The study by Clark KA etal published in PloS, has found some selfish DNA in the mitochondrion, affecting the life span of the organism. Denver (co-author) said, "Selfish DNA is not supposed to be found in animals. But it could turn out to be fairly important as a new genetic model to study the type of mitochondrial decay that is associated with human aging." (Source). Need to excurse a bit here. I don't understand the use of "Selfish DNA" quite well here. As per wikipedia "Selfish DNA refers to those sequences of DNA which, in their purest form, have two distinct properties: The DNA sequence spreads by forming additional copies of itself within the genome; and it makes no specific contribution to the reproductive success of its host organism". I thought the transposons and retrotransposons are selfish DNA. They are present in abundance in human genome (Reference here and here). The interesting point is that this study is expected to shed some light into the process of aging.

      I have another equally interesting news form nematode, which has a different story to tell. The story is form another PLoS journal- PLoS pathogens by Robbie Rae etal. Its a fact that the life span of an organism is increased when its reproductive system is removed (I really didn't know that till i had read this paper. I guess sex reduces life span!!!). The mechanism is largely unknown. By using Pristionchus pacificus (a species related to C. elegans), the genetic expression pattern (Using Microarray technique) which may show reasons for increased longevity was studied. They propose that the resistance is due to expression of genes involved in insulin signaling, nuclear pore complexes, ribosomal translation and lipid production. This is the first study to show a significant link between reproductive system, lifespan and innate immunity.

Photo 2: N Fujii

     Rarely i have come across a week, where a paper hasn't been published on HIV. This leaves me wondering. If i had to write a review on HIV and publish it as a book, the very next day of print, it would be declared as outdated. HIV mode of entry to cell requires the use of a CD4 receptor and a co-receptor which is either CXCR4 or CCR5 as per standard models. (I mean to say there are other entry mechanisms which we have realized to operate). CCR5 blockers such as Maraviroc is available, but CXCR4 antagonists are not in market. In 2005, Nobutaka Fujii (Photo Shown to right) proposed a cyclic penta-peptide to be used as an antagonist for CXCR4. The Figure 1 below illustrates the pentapeptide.

Fig 1: Pentapeptide against CXCR4 (Source)

       The new paper by Demmer etal, came up with a better peptide simply by shifting the arginine side chain they could improve the pharmacological properties. I haven't got my hands on to this article in full. I just  could have a look at this image (Shown below).

Fig 2: Frozen Peptoid Boosts CXCR4 Affinity and Anti-HIV Activity (Source)

     I have two reviews in addition to all this that is worth a careful reading. The first is in PLoS pathogens by Zeldovich VB and Bakardjiev titled "Host Defense and Tolerance: Unique Challenges in the Placenta". This review focusses on how the immunity has to deal with a paradox situation laying down the armor of immunity for the sake of growing fetus (Link). The 2nd review is by Christophe Vanpouille etal titled "Microbicides: still a long road to success." (Link).

    I have an interesting short story to talk about here, Though not related to medical field in any way this was so interesting when i first heard about it. But then i came across this video (below) that explains everything i want to tell.

Video 1: Cordyceps: attack of the killer fungi (From Youtube)

   Inspired by zombie above i thought i will make a brief mention of the human zombie protein. I mean prions. For a background information on prion disorders please refer to my previous posts here.

   I want to give an additional set of background information here. The first question that is asked in the field of prion biology is "Are they genetic or environmental". I must admit, they are the only kind that is both. They can be genetic (Such as FFI or Familial Fatal Insomnia and many subtypes of CJD) or acquired as infection (Classical example is kuru). You can read some of the details in my notes section here. The infection is thought to be acquired mainly by ingestion (Not always). So from GIT or through blood somehow the proteins set a journey to the central nervous system. Meantime, they are known to colonize lymph nodes. It is now well agreed that that the prions migrate from lymph nodes to Peripheral nervous system and then subsequently to Central nervous system

Fig 3: The spread of prions throughout the body
(Source)

    Extraneural prion accumulation is thought to occur primarily within stromal cells within follicular dendritic cells (FDCs). B cell-derived tumor necrosis factor (TNF) and Lymphotoxins are believed to keep the FDC in game. The receptor for these include a LTβR and TNFR1. 

     The tumor necrosis factor α receptor (TNFR1) on suitable stimulation activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH2-kinase (JNK)/ activator protein 1 (AP1) cascade. The LTβR decides the regulation of inflammatory response actions.

     Quoting from the journal "A number of studies have implicated FDCs in the germinal centers of secondary lymphoid organs as the primary reservoirs of prions prior to neuroinvasion, Yet the ability of TNFR1 null cells to accumulate prions with a minimal loss of infectivity compared to wild type presents an apparent paradox, since FDC maintenance depends on TNFR1 signaling". So that was the question this paper tried to answer. And the answer they found was interesting. The TNFR1 was not important at all in this context. The main player was LTβR signaling. It also coincides with entry of prions into lymphoid organs through High endothelial venules (HEV) and replicate in presence of mature dendritic cells.

Tracy O’Connor, Nathalie Frei, Jana Sponarova, Petra Schwarz, Mathias Heikenwalder, & Adriano Aguzzi (2012). Lymphotoxin, but Not TNF, Is Required for Prion Invasion of Lymph Nodes PLoS pathogens

Demmer, O., Frank, A. O., Hagn, F., Schottelius, M., Marinelli, L., Cosconati, S., Brack-Werner, R., Kremb, S., Wester, H.-J. and Kessler, H. (2012). A Conformationally Frozen Peptoid Boosts CXCR4 Affinity and Anti-HIV Activity Angewandte Chemie International Edition DOI: 10.1002/anie.201202090