Value-based decision making: lessons learnt from a crayfish

We are always at cross roads while making decisions—it can be something trivial as whether to do groceries or to go to the parlor; or, something more important as whether to take a shorter, riskier route or to take a longer but safer route to reach a destination. Like us, other animals also have to assess situations and make decisions constantly. For example, a deer might have to decide whether to feed near a fresh grassy patch where there is a risk of getting eaten by tiger or to move to safer, but distant grounds with drier grass. Thus, animals are often faced with trade off between foraging decisions and risk of predation. A recent study says that crayfish, cousins of lobsters are also faced with such decisions.

Researchers in the Psychology Department of University of Maryland found that when crayfish were simultaneously offered two contrasting choices between finding food and moving away from a potential threat, they responded after weighing in the costs-benefits of the two situations. Furthermore, this study also outlines possible neuronal mechanisms underlying such behavioral choices. Crayfish and other invertebrates are excellent model organisms to examine neurons associated with foraging and antipredaoty behaviors, because of their simplistic neural networks compared to vertebrates.

Juvenile crayfish show two kinds of antipredatory behaviors in response to a moving shadow (which is considered a ‘predator’ in this study): they either freeze or tail-flip, propelling themselves away from the shadow. Tail-flips are mediated by excitation of a pair of neurons called Medial Giant interneuron (MG). Researches found that while slow-moving shadows elicited a tail-flip response, faster shadows caused crayfish to freeze. Tail-flipping facilitated the animals to move away from shadows, but this also took them away from food source. The authors also varied the concentration of the food—high concentration being a more favorable food source than lower concentration. They found that crayfish froze more often in presence of a favorable food source; however a slow-moving shadow (i.e. threat from a predator) evoked a tail-flipping response regardless of an attractive food source. This suggests that crayfish make value-based decisions that are ultimately adaptive, and these behaviors are mediated thru identifiable neural circuits.

A complete version of the article appears in the recent issue of Proceedings of the Royal Society B doi:10.1098/rspb.2010.1000
http://rspb.royalsocietypublishing.org/content/early/2010/06/12/rspb.2010.1000.short?rss=1

This article was contributed by Ms. Divya Bellur Uma, University of Maryland, Dept. of Psychology, Maryland

Prions go the Darwinian way … in cell cultures!

Well… looks like prions also have the propensity to evolve and undergo the natural selection process, just like us living beings. A recent report in the Science journal (Vol. 327. no. 5967, pp. 869 - 872) features new findings that suggests these lifeless-like molecules to adopt a darwinian evolution approach under special conditions in cell cultures. What makes it interesting is that they have shown prions, which are devoid of any nucleic acid material, can selectively amplify and mutate as per the requirement of the environment.

Prions are infectious proteins composed of β-sheet conformers. These β-sheet or PrP Sc conformers are derived from misfolding of the prion protein PrP. These β-sheet rich conformers are responsible for number of diseases like scrapie in Sheep, bovine spongiform encephalopathy (BSE) also known as mad cow disease in cattle and Creutzfeldt–Jakob disease (CJD) and kuru in humans.

Prions are characterized by the incubation time and neuropathology they elicit in a particular host and hence occur in distinct strains. The protein-only hypothesis assumes that each strain is associated with different conformer of PrP Sc. Cell-free conversion experiments and protein misfolding cyclic amplification (PMCA) have shown that conformational templating is possible at protein level.

Prion strain identity is thought to be encoded by PrP Sc conformations. Here the authors determine the cell culture properties of prions using cell panel assays. They show that when prions were transferred from brain to cultured cells, prions strain changed and was more cell adapted. However, when prions were returned from cells to brain, they became brain adapted again. The cell adapted strain outcompeted their brain counterparts in cell culture and brain adapted strain outcompeted when they were returned to brain. Experiments conducted with inhibitor swainsonine showed that when prions were grown in presence of inhibitor the resistant strain outgrew the sensitive strain and viseversa when grown in absence of the inhibitor. The authors suggest a quasispecies concept and Darwainian evolution for prions. They show that pions are subjected to mutations and to selective amplification depending on the different environments. The authors also suggest that drug resisstance would be less in drugs targeting PrP than drugs inhibiting PrP Sc.

This article was contributed by Dr. Shailaja Divekar, Georgetown University Medical Center, Washington DC

Is miR-143 gene a new hope for prostate cancer diagnosis and treatment?

A recent finding by a team of scientists from the IRCM (Institut de Recherche en Cancérologie de Montpellier), France has shown that a new type of miRNA molecule - miR-143, plays a very important role in prostate cancer by curbing the growth of cancer cells through the process of interfering with the ERK5 signaling.

So what is microRNA and why are they a new face in the therapeutics for the Biotech and Pharma? A microRNA (miRNA or µRNA) is a single-stranded RNA molecule of 21-23 nucleotides in length, which regulates a gene expression after the process of transcription. This entirely new class of molecules is beginning to generate a lot of interest due to its potential applications in cure of many diseases as well its basic importance in a cell's genetic machinery. Together with siRNA, these two classes of RNA molecules comprise the current system of RNA interference technology.

Coming to the actual findings by the scientists, the investigation was based on an earlier observation by the scientists that treatment of the prostate cancer cells correlated with an increased expression of the miR-143 gene. Continuing their work, they observed that the expression of miR-143 correlated inversely with the histopathological grades in human prostate cancer.

So how does the miR-143 actually contribute its role in arresting the growth of prostate cancer? The ERK5 gene (Extracellular-signal-regulated kinase 5) - a member of the mitogen-activated protein kinase (MAPK) family of genes, is known to have an important role in the proliferation and differentiation processes of the cells (EMBO reports 7, 8, 782–786 (2006)). This gene was shown to harbor a putative consensus site at the 3'UTR end. A detailed set of mechanistic studies showed that miR-143 exerts its tumor abrogating activity by directly interfering with the activity of ERk5 gene. Finally, the scientists showed successfully that, rescue of the miR-143 expression decreased the progression of tumors using a mouse model. Taken together, these mechanistic studies showed that ERK5 is one of the possible target genes for the miR-143 to act upon.

The significance of these findings is important from different perspectives. First, a mechanistic link between the miR-143 and ERk5 is demonstrated thus paving way more studies to understand the complexities of miRNA based controls in cancer progression. The role of miRNA themselves are only beginning to be understood, Results like these are likely to spur further investigations into the tole of miRNA in other cancers. Finally, the study shows a direct possible application of this findings in the molecular diagnosis and treatment of prostate cancers. Given their varying levels at different stages of prostate cancer, they could well be candidate biomarker for prostate cancer. Also, the rescue effect of the miR-143 shows its possible role in the development of new strategies for therapeutics.

A complete version of this article appears in the recent issue of PLoS ONE 4(10): e7542 .

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Sequerome Science News

Stem cells from Human Cord Blood…

Consider this future scenario… your doctor advises you for a regenerative transplant and asks you to contact your Cord Blood Bank (something that was stored from the umbilical cord when you were born). Seems a leap of faith, but possibly not! Recently a team of researchers led by Dr. Ulrich Martin from the Hanover Medical School, Germany have not only shown the possibility of inducing pluripotent stem cells from human cord blood but also its advantages over using normal adult cells (of somatic origin). Their article appears in the recent issue of the journal “Cell Stem Cell” - Volume 5, Issue 4, 434-441, 2 October 2009.

Pluripotent stem cells are stem cells that have the ability to become any type of cell in the body. Recent research has shown the possibility of generating such stem cells from regular human adult cells by inducing certain genes. The disadvantage and challenge in this method rises from the risk of these adult cells to acquire mutations and eventually lose their cellular identity or even become tumors.

The authors of the paper have shown the possibility of generating induced pluripotent stem cells (iPSCs) from human Cord Blood, an easily available source. These cells show the characteristics that are typical of human embryonic stem cells without actually having to obtain them by involving the embroyo at all. Due to this nature of these cells, they can be made to become any type of cell in the human body including the functional cardiomyocytes. Since they can be sourced from the individual's own cord blood (collected and stored at birth), they can be routinely harvested without any donor risk. This method can be of immediate relevance and great advantage for pediatric patients who are born with genetic diseases or congenital malformations.

Watermelons in your Car’s gas tank!

Well… if the recent findings are any indicator, your car could be getting its bioethanol from ‘reject’ watermelons in the near future. The fact is, one in every 5 watermelons is rejected and of no use to the growers as a source of revenue. Scientists have recently found a way to convert these rejects into “biofuel”.

Watermelons consist of simple sugars that allow for more efficient conversion to ethanol, as compared to corn that contain complex sugars, and hence have to be broken down using enzymatic degradation. Further, watermelons consist of nutrients like lycopene and L-citrulline. Processing of watermelons to produce lycopene and L-citrulline, yields a waste stream of watermelon juice. The rationale behind the investigation was based on the fact that watermelon juice contains 7- 10% (weight/volume) directly fermentable sugars, and 15-35 μmol/ml of free amino acids. Thus its potential as feedstock, diluent, and nitrogen supplement was investigated in fermentations to produce bioethanol.

The study showed that whole watermelon juice as well as watermelon, with the lycopene-containing chromoplasts removed, could be fermented to produce significant amount of ethanol. Lycopene containing chloroplast could be easily solubilised after fermentation, suggesting two uses for wasted watermelons. The first was as a biofuel and the second was for harvesting nutrients like Lycopene and L-citrulline. Further, the watermelon juice in the form of waste stream could be used as a as diluent, sugar supplement, and nitrogen supplement in the fermentation of molasses. It also served as nitrogen source for yeast in the fermentation process making it a useful diluent in fermenting other sugars. The results clearly demonstrated multiple uses for the water melon juice, from this study.

Speaking of the economics of the production, the authors say that the current unmarketable watermelons – 8.4 t/ha (tones/hectare), left in the field at harvest, would produce about 220 L/ha (liters/hectare) of ethanol for on-farm use. This could also act as an additional revenue stream for the grower. The authors have also discussed the application and feasibility of this technology on the farms and given an approximate estimate of the production rate of ethanol from the 20% of the watermelon yield.

The article appears in the recent issue of Biotechnology for Biofuels – 2009, 2:18 and is available for free download.

This article was contributed by Dr. Shailaja Divekar, Georgetown University Medical Center, Washington DC

Epigenetic engineering of ribosomal RNA genes: TIP5 knockdown offers promise for Biopharmaceutical industry

Ribosomal RNA (rRNA) genes code for a major component of ribosomes, a major component in the cell for making proteins. One of the major challenges for the biopharmaceutical manufacturing industry is the selection of mammalian high-producer cell lines. The production of rRNA genes is mainly regulated by the NoRC (Nucleolar remodelling complex) which in turn regulates the cell's full production capacity.

A recent finding by researchers from Switzerland shows that knocking down the TIP5 subunit of NoRC significantly increases the production of recombinant proteins through decrease in number of silent rRNA genes. In their words "... this is the first time that an engineered decrease in the number of silent rRNA genes could be correlated with enhanced production of rRNA and ribosomes and consequently with higher productivity of mammalian cells.". They further state "Epigenetic engineering of ribosomal RNA genes offers new possibilities for improving biopharmaceutical manufacturing and provides novel insights into the complex regulatory network which governs the translation machinery in normal cellular processes as well as in pathological conditions like cancer.".

In a series of experiments, the scientists took an approach to knockdown the expression of TIP5 (TTF-1-interacting protein 5), which is an important component of NoRC. Using the RNA interference technology, the expression of TIP5 was knocked down and followed by examining the levels of rRNA production and ribosome synthesis. To be further sure, a separate experiment showed that enhancement of rRNA transcription rate was not enough to enhance heterlogous protein production.

The results point to a new strategy that could improve biopharmaceutical production of important protein therapeutics. They also provide new possible insights into the complex regulatory networks that govern the translation machinery in a cell.

Their findings appear in the recent issue of PLoS ONE: 4(8): e6653. doi:10.1371/journal.pone.0006653

Role of Vitamin D as an important promoter of T cell regulation in patients with Multiple sclerosis

The human immune system has a specialized sub-population of T-cells called the regulatory T-cells that play an important role in preventing us from autoimmune diseases like Multiple sclerosis. A recent clinical study by scientists show that Vitamin D has a positive role on the Treg cells and shift the Th1/Th2 balance towards Th2. In other words their findings suggest that Vitamin D could be an important promoter of T-cell regulation in vivo in patients with Multiple sclerosis and possible even other autoimmune diseases. Their findings appear in the recent issue of PLoS One 4(8): e6635. doi:10.1371/journal.pone.0006635