* c u r i o s i t a s *

Reprogrammed iPS-cells are not safe from self immune-attack.

2011-06-28T03:25:00.000-07:00

The transition of Stem Cells (SC) from emergence to utter-prominence on the therapeutic-horizon has been phenomenal. While the promise of cell-based therapeutics has been there, applications of pluripotent SC’s for treatment of human patients have largely been under a cloud of controversy and doubt. While there are several, few doubts are glaring. One among those is the possible immunological-rejection of SC’s by the patient (since they are derived from other humans, grafted SC’s are viewed as allografts or non-self by the immune system). There were few attempts to overcome this impediment, not necessarily with the right moral-code, though (read Hwang et al., Science).

This virtual blind-end was resuscitated recently by the work of Yamanaka et al. and others, who found out a way to, well, at least theoretically, get around the immunological-rejection problem.

They made pluripotent cells from adult human skin, and named them induced-pluripotent-stem-cells (iPSCs). To cut a very-long story short, Yamanaka’s group dumped the original (and vastly controversial) method of pluripotent stem-cell derivation from human-embryos, and generated pluripotent cells from adult skin cells instead, by a method of cellular reprogramming (de-differentiation) [1]. Everybody rejoiced. This was no mean achievement, in terms of both the science behind it and the effort. This was the holy-grail of cell-based therapeutics, good news for both patients and the therapeutic-industry. This study was hailed, since it was reasoned that, at least theoretically, iPSCs by virtue of their origin from the patient’s own cells, would be recognized as ‘self’ and hence would not be mauled by the patient’s immune system, and hence could be a safe bet for cell-based therapies like cell-transfers, organ-grafts etc. This was followed by a series of iPS-cell derivations, from mice as well as humans [2,3,4].

Schematic representation of derivation of pluripotent iPS-cells derived from self-cells upon de-differentiation, and are capable of differentiation into all types of cells under in-vitro conditions or upon transplantation for therapeutic purposes. Since they are formed from self-cells, they were thought to be resistant to immunological attack, a belief proved wrong in this study.

All was fine, until this ‘letter’ in Nature spoiled the party. It was shown by a group from University of California (UC), San Diego (SD), that the underlying assumption that iPSCs would be immunologically tolerated was incorrect [5]. They showed that iPSCs, notwithstanding the reason of immune-tolerance, were actually actively repelled by the body’s defenses. Immunologist Yang Xu of UCSD and his colleagues tested what happened to several kinds of pluripotent cells when they were transplanted into genetically matched mice. Inbred mouse strains are the genetic equivalent of identical twins, and they can serve as organ donors for each other without any immune suppression. The researchers used two popular inbred strains, called B6 and 129, for their experiments.

Results:

When the researchers implanted ES cells from a B6 mouse embryo into a B6 mouse, it formed a typical growth, called a teratoma, which is a mixture of differentiating cell types (Teratoma formation is a standard test of pluripotency for ES and iPS cells). ES cells from a 129 mouse, on the other hand, were unable to form teratomas in B6 mice because the animals’ immune systems attacked the cells, which they recognized as foreign.

The researchers then implanted iPS cells made from B6 mouse cells into B6 mice. To their surprise, many of the cells failed to form teratomas at all-similar to what the researchers saw when they transplanted ES cells from one mouse strain to another.

The teratomas that did grow were soon attacked by the recipient’s immune system and were rejected, which is the same as that triggered by organ transplant between individuals.

The immune reaction was less severe when the researchers used iPS cells made with a newer technique. The new method ensures that the added genes that trigger reprogramming turn off after they’ve done their job. But the reaction didn’t go away completely. The researchers showed that the iPS cell teratomas expressed high levels of certain genes that could trigger immune cells to attack. That is probably due to incomplete reprogramming that leaves some genes misexpressed, Xu says.

Discussion: what next.

> The results add to a series of findings that iPS cells differ in subtle but potentially important ways from ES cells [writeup here].

> The team used two different methods to make the iPS cells, and they showed slightly different propensities to trigger immune rejection, so it may be that reprogramming methods can be fine-tuned to avoid the problem altogether.

References:

[1] Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

[2] Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

[3] Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

[4] Park, I.-H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).

[5] Tongbiao Zhao, Zhen-Ning Zhang, Zhili Rong & Yang Xu. Immunogenicity of induced pluripotent stem cells. Nature, doi:10.1038/nature10135

Evidence of a Pluripotent Human Embryonic Stem Cell Line Derived from a Cloned Blastocyst. Woo Suk Hwang et al. Science 2004: 303; 1669-1674

Algae could help clean-up nuclear-accident sites

2011-04-06T02:52:00.000-07:00

The 'Mushroom-cloud' formed due to a nuclear explosion (image adapted from)

The dark images and darker consequences of several nuclear disasters like the Chernobyl (April 26, 1986), Kyshtym (September 29, 1957), Three-Mile island (March 28, 1979) and the very-ongoing Japan’s Fukushima Nuclear accident constantly remind us of the Frankensteinian possibilities of nuclear-capability. With world governments heralding nuclear energy as a panacea for all energy needs, there has been a spurt in the proliferation of nuclear technology, capability and of course, nuclear reactors. And as the world clamours for a debate on 'responsible' nuclear usage and simultaneously goes 'nuclear' at a tumbling speed we remain naked under the threatening shroud of a looming nuclear disaster.

While we recklessly roll towards reactors, our capabilities at cleaning-up a nuclear-spillage or tidying-up post radioactive-leakage remains abysmally poor. Our technology to efficiently dispose off radioactive garbage is juvenile at best, and Nature, again, seems to show the way.

from Manhattan to Moniliferum

A recent paper [1] by Minna krejci's group, a materials scientist at Northwestern University in Evanston Illinois, claims that the common freshwater alga Closterium moniliferum might hold the key to an efficient nuclear-clean-up-act, after humans have messed up! Members of the desmid order, they are unicellular eukaryotic fresh-water alga popularly known for their distinctive crescent shapes measuring ~260 micron in length.

Clostridium moniliferum (source)

These crescent-shaped C. moniliferum have an unusual ability to remove strontium from water, depositing it in crystals that form in subcellular structures known as vacuoles — an ability that could include the radioactive isotope strontium-90. The unicellular desmid green algae are ubiquitous in fresh water habitats and robust in lab in-vitro cultures, and as such are particularly suitable as a model system for Sr/Ba biomineralization [2].

Why is Strontium harmful?

Strontium lies exactly below calcium in the periodic table, and shares similar chemical properties and atomic size with calcium, so biological processes can't easily separate the two elements. That makes strontium-90, which has a half-life of about 30 years [3] a particularly dangerous radio-isotope: it can infiltrate body fluids like milk, and body tissues like bone marrow, bones, blood and others, where the harmful radiation that it emits can eventually lead to metastasis and cancer. It must be recalled that it was primarily Strontium-90 which caused havoc during the Chernobyl disaster of 1986. Unfortunately, reactor waste and accidental spills can contain up to ten billion times more of the harmless calcium than the dangerous strontium, making it extremely difficult to selectively clean up the strontium without also having to dispose of the harmless calcium.

other methods, which are largely inefficient:

And, in the case of 90Sr, even the most advanced ion-exchange materials find it challenging to efficiently separate out Ca2+, Sr2+, and Ba2+ owing to their chemical similarity [4]. While phytoremediation approaches utilizing the accumulation of environmental contaminants by green plants are becoming increasingly popular, the effectiveness of such approaches for Sr-90 sequestration are drastically reduced in the presence of Ca2+, due to the indiscriminate transport of Ca2+, Sr2+, and Ba2+ exhibited by most organisms [5].

Why is this alga (Clostridium moniliferum) significant?

This humble fresh-water alga has no particular interest in strontium: it mostly cares for barium. But as strontium happens to be midway between calcium and barium in atomic-size and other properties, so any of it that happens to be around gets crystallized as well. Calcium, as it turns out, even being far more abundant than either of the other two elements, is different enough to barium that it gets left behind, and doesn’t crystallize. The result is a crystal that is chiefly composed of barium, but is heavily enriched in strontium and has no calcium.

BaSO4 crystals in C. moniliferum. a) Confocal microscopy image showing the lobes of the two chloroplasts (red); cell membrane in green. b) DIC image of BaSO4 crystals (arrow) in the terminal vacuole. c) SEM image of rhombic (arrowhead) and hexagonal (arrow) crystals that remain after cells have been ashed.

[image from paper (1)]

How do they do that?

The mechanism of barium or strontium entry into the organism is not well studied, but it is known that sulphate-rich vacuoles of the alga greatly aid formation of the crystals. Since, barium and strontium have relatively low solubility in sulphate solutions; they easily precipitate out to form crystals of BaSO4 in the sulphate rich small terminal vacuoles at the tips of the crescent-shaped cells. Do the crystals serve any physiological function? It’s not known yet.

The possibilities

> Now that it’s known that the organism actively hunts for barium, it is perhaps possible to enhance the uptake of strontium by tailoring the amount of barium in the algae's environment.
> It would then be possible to ‘seed’ a spill of radioactive material, with barium to encourage the algae to grab the strontium of the nuclear waste.
> It might also be possible to improve the process by tinkering with sulphate levels in the environment, thereby changing the amount of sulphate in the vacuoles, but indeed it would depend on an understanding of how cells might respond to altered conditions.

Then what?

Once isolated by the algae, the strontium could be kept in high-level nuclear waste repositories, while the rest of the waste could go to a less expensive lower-level repository, saving space and money. In any case, the hundreds of millions of litres of stored strontium containing nuclear waste in the United States alone.

questions and curiosities

> It’s not yet tested how well the algae survive in the presence of radioactivity. But, since the process begins quickly, wherein cells precipitate crystals within 30 minutes to an hour; and of course, one can culture as much of the algae as one wants, so even if viability is compromised, they would probably live long enough to start removing strontium!
> There could be concerns regarding passing up of Sr-90 along the food-chain [which could possibly be circumvented by restricting algal-growth within a specific area devoid of its natural predators].

Overall, this definitely appears to be a good idea to start with. Additionally, organismal-sources to sink-off other radioisotopes like plutonium, cobalt, cesium, iodine, etc. needs to be found out to come up with a robust radioactive-clean up regimen.

References

[1] Selective Sequestration of Strontium in Desmid Green Algae by Biogenic Co-precipitation with Barite. Minna R. Krejci, Lydia Finney, Stefan Vogt, and Derk Joester. DOI: 10.1002/cssc.201000448

[2] A. J. Brook, The Biology of Desmids, University of California Press, Berkeley,1981.

[3] M. Eisenbud, T. F. Gesell, Environmental Radioactivity from Natural, Industrial, and Military Sources, Academic Press, San Diego, 1997.

[4] M. Manos, N. Ding, M. Kanatzidis, Proc. Natl. Acad. Sci. USA 2008, 105, 3696; A. Braun et al., Application of Ion Exchange Processes for the Treatment of Radioactive Waste and Management of Spent Ion Exchangers, International Atomic Energy Agency, Vienna, 2002.

[5] S. Singh, S. Eapen, V. Thorat, C. P. Kaushik, K. Raj, S. F. D’Souza, Ecotoxicol. Environ. Saf. 2008, 69, 306– 311.
[6] Nature news article

Circadian-Clocks tick without DNA

2011-02-12T08:11:00.000-08:00

Intricate machinary of a clock. Is there a master-tuner? [image]

This idea would forever change the way we would look at Circadain-Rythms, simply because it trashed a dogma - one that required DNA to run biological-clocks!

Circadian Rythms: All forms of life undergo circadian (roughly 24-hour) fluctuations in energy availability that are tied to alternating cycles of light and darkness. These self-sustained rhythms could be biochemical, physiological, or behavioural processes. Our biological clocks organize such internal energetic cycles through 'transcription–translation feedback loops'.

What is known: There are specific "clock-genes" that comprise of a 'forward limb' involving a set of transcriptional activators that induce the transcription of a set of repressors which comprise the 'negative limb' and duly feeds back to inhibit the forward limb [1]. This modulatory cycle repeats itself every 24 hours. Energy-cycles show transcription-dependent circadian periodicity; such cycles include the alternating oxygenic and nitrogen-fixing phases of photosynthesis, and the glycolytic and oxidative cycles in eukaryotes.

BIG Questions:

1.Is the nucleus [actually the DNA contained in it] necessary for clock-maintainance in mammals?

Actually, several classical model organisms that are genetically tractable (for example, yeast and C. elegans) have not been found to express any known ‘clock genes’, but do exhibit circadian rhythms [2,3].

2.Are the transcriptional [DNA-based] and nontranscriptional [non-DNA based] cycles interrelated?

Experiments:

** How do you check for the necessity [or not] of DNA in a given life process? Easy, check for the process in a cell type that lacks a nucleus.

Neill and Reddy did exactly that! They established human red blood cells (RBCs, enucleated-mammalian cells) as an appropriate model system to test if they might have a rythmic-clock operating. Crucially, these cells lack both a nucleus and the energy-producing mitochondria.

RBC's : non-nucleated and just perfect! [image]

These cells therefore function mainly as oxygen shuttles, utilizing haemoglobin. Interestingly, RBCs possess the evolutionarily conserved enzymes of the peroxiredoxin family [4], which control intarcellular peroxide leves and react to rising intracellular reactive oxygen species (ROS) levels by forming oligomers. Importantly, they had been previously showed to exhibit circadian-periodicity in hepatic-cells [5]

1] Do Peroxiredoxins exhibit circadian redox rhythms in RBC's?

O’Neill and Reddy monitored the monomer–dimer transition of peroxiredoxin proteins in RBCs from three human volunteers. The oligomerization-pattern was self-sustained over several cycles within an approximate 24-hour period.

Next, they had to prove that RBC's should show the property of 'Entrainment', i.e to be a useful timing mechanism, oscillations (of oscillators) should be tuneable by external cues so that they can be reset when misaligned. Here, they used Temperature as a cue. And indeed, Peroxiredoxin oxidation cycles were synchronized in response to temperature cycles.

* To rule out the presence of contaminating nucleated cells [WBC etc.], inhibitors of translation (Cycloheximide) and transcription (a-Amanitin) were added, which could not perturb the peroxiredoxin oxidation rhythm, proving that this clock could run efficiently in the absence of transcription and was totally independant of DNA.

As it turns out, in RBC's, Haemoglobin [Hb] is a major source of Peroxides via autooxidation [Heme structure, here on Wiki]. So, did Hb also show periodicity? Yes, it did! They used intrinsic front-face fluorescence as a real-time assay of rhythmicity [6] and indicated reversible low amplitude oxidation of haemoglobin in RBCs.

* Now, what drives the rhythmic cycles of oligomerization for peroxiredoxin? Are they related to othe Biochemical cycles on RBCs'?

Given that red blood cells are dependant on glycolysis for ATP synthesis, and this contributes significantly to the NADH flux in RBCs'. Could ATP and NADPH oscillate with cycle? Yes, Indeed! The researchers reported weak oscillations in the levels of ATP (and also NADPH)!

2] Could they be related to Nuclear events? Is there a connection between the nucleus's interior and exterior?

Experiments:

they assayed mouse embryonic fibroblasts [MEF] from Cry1/Cry2 double-knockout mice, which lack cyclical expression of known clock genes/proteins [7]. Rhythms in peroxiredoxin oxidation were altered relative to those seen in wild-type MEFs. Therefore, in nucleated cells, peroxiredoxin rhythms are influenced by the transcription–translation feedback loop.

* Could the reverse be true? That is, if levels of Peroredoxin in cells fall, could it effect levels of transcription?

Indeed, as knockdown of PRX2 and PRX4 in human U2OS-cells resulted in a long-period phenotype, whereas si-RNAs directed against PRX3 and PRX5 depressed the amplitude of circadian oscillations!
Therefore, in nucleated cells, there is likely to be an intricate interplay between transcription-dependent processes and non-nuclear events, which seem to be reciprocally regulating each other.

Take Home message:

Circadian Rythms are NOT maintained exclusively by the Nucleus, but are also influenced by events occuring in the cytosol, AND adequate modulation is brought about by an essential interplay interplay of both processes.

References

* This paper

O’Neill, J. S. & Reddy, A. B. Circadian clocks in human red blood cells. Nature doi:10.1038/nature09702

** the other paper [in the same issue of Nature by same group]
O’Neill, J. S. et al. Circadian rhythms persist without transcription in a eukaryote.Nature doi:10.1038/nature09654

1. Reddy, A. B. & O’Neill, J. S. Healthy clocks, healthy body, healthy mind. Trends Cell Biol. 20, 36–44 (2009).

2. Eelderink-Chen, Z. et al. A circadian clock in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 107, 2043–2047 (2010).

3. Kippert, F., Saunders, D. S. & Blaxter, M. L. Caenorhabditis elegans has a circadian clock. Curr. Biol. 12, R47–R49 (2002).

4. Hall, A., Karplus, P. A. & Poole, L. B. Typical 2-Cys peroxiredoxins–structures, mechanisms and functions. FEBS J. 276, 2469–2477 (2009).

5. Reddy, A. B. et al. Circadian orchestration of the hepatic proteome. Curr. Biol. 16, 1107–1115 (2006).

6. Kennett, E. C. et al. Investigation of methaemoglobin reduction by extracellular NADH in mammalian erythrocytes. Int. J.Biochem.Cell Biol.37,1438–1445(2005).

7. Yagita, K., Tamanini, F., van der Horst, G. T. J.&Okamura, H. Molecular mechanisms of the biological clock in cultured fibroblasts. Science 292, 278–281 (2001).

* c u r i o s i t a s *: Lazy Sperms Check Inbreeding

2011-01-24T06:51:00.000-08:00

* c u r i o s i t a s *: Lazy Sperms Check Inbreeding

Lazy Sperms Check Inbreeding

2011-01-20T08:07:00.000-08:00

Inbreeding (mating between relatives) is costly, primarily as a consequence of the expression of deleterious recessive alleles[1,2] from a overtly constricted gene-pool.

Some instances of adverse effects of inbreeding: The dwindling numbers of cheetahs has been attributed to a genetic bottleneck caused by heavy inbreeding [3], and in humans, appearance of several harmful traits (eg. Haemophilia in european royal families, 'reproductive wastage' in a population of Dammam, Saudi Arabia [4], Ellis-van Creveld disease in Amish settlements [5], decreased fertility rates in Hutterites [6] etc.) has been attributed to unabated consanguineous relationships.

Researchers have long suspected that polyandry - females taking multiple mates - evolved in some species as a strategy to reduce breeding with relatives, and therefore as a means to reduce the negative fitness consequences of mating with genetically related males.

Evidence suggests that the genetic relatedness (or genetic similarity) between mating partners is associated with competitive fertilization success [7]. In externally fertilizing fishes, it has been shown that the ovarian fluid (OF) released by the females with their eggs during spawning affects sperm swimming velocity [8], and this effect is influenced by the identity (genotype) of the interacting male and female [9]. Furthermore, there is ample evidence that sperm kinematic parameters are important determinants of sperm competition success [10].

Clelia Gasparini and Andrea Pilastro from the University of Padova, Italy, investigated female preference for unrelated mates in the guppy (Poecilia reticulata), an internally fertilizing species of fish, in which the females mate multiply.

Their aim was to experimentally demonstrate whether the selection bias which would determine mechanisms reducing fertilizations by genetically related mates was operating at the gametic (sperm and ova) level.

Guppies (source)

Reasons why Guppies were used as a model system:

1. ideal model to study post-copulatory mechanisms of inbreeding avoidance [11].

2. inbreeding has deleterious fitness consequences in this species [12].

3. males can undermine female choice by means of gonopodial thrusting [13], a coercive mating tactic that allows males to forcibly inseminate females.

4. Paternity analysis in natural populations has revealed a paternity skew towards unrelated males [14], suggesting that mechanisms reducing fertilizations by genetically related mates do operate in this species.

Experiments:

a. Paired sperm competition test in which sperms were artificially inseminated two unrelated females. The difference in paternity success across females in relation to the difference in genetic relatedness among mates was later analysed.

b. Determination of whether insemination from related males would result in a reduced brood size, via differential fertilization success or embryo viability, by comparing brood size of females that were artificially inseminated with the sperm from either a brother or an unrelated male.

c. Finally, exploration of physiological mechanisms by which females mediate inbreeding avoidance.

Critical Observations:

To confirm that polyandrous female guppies do give an edge to sperm from non-related males, Andrea Pilastro and Clelia Gasparini at the University of Padova in Italy performed artificial insemination of 28 virgin females with sperm from either an unrelated or related male.

* Related males fertilized 10 percent fewer eggs than unrelated males.

To then investigate the source of the advantage [expt. 'c'], the team looked at the interaction between sperm and OF.

In an in vitro computer assisted sperm analysis (commonly called CASA) measurement aimed at measuring critical kinematic parameters of sperm movement.
* A male guppy's sperm-velocity is 5-10 percent slower in the OF of his sister than that of an unrelated female.

In other words, it demonstrates that genetic relatedness influences the effect of OF on sperm performance by increasing the swimming velocity of sperm from unrelated males in the guppy.

This throws up an important point, that there now exists an interesting coincidence between the effect measured in sperm velocity and that consequently found in paternity.

Future work / Possibilites:
How the guppies' genetics influence OF-sperm interaction is still unknown, but Pilastro suspects the involvement of signaling peptides/receptors etc. present on the sperm-surface.

Although it might be beyond the scope of this investigation, but an 'In-vitro-fertilization' expt. (in the absense of 'OF') could have ruled out inherent inequalities in fertilization-capabilites of sperms from brothers and non-relative donors.

Although this may not be the only explanation for biased paternity, but it's an interesting paper since it has shown experimental evidence for this kind of selection for the first time. Indeed, it could also be a common mode of sexual selection among other species as well.

References

The paper: Clelia Gasparini and Andrea Pilastro, 2010. Cryptic female preference for genetically unrelated males is mediated by ovarian fluid in the guppy. Proceedings of the Royal Society. doi:10.1098/rspb.2010.2369

1. Thornhill, N.W. 1993 The natural history of inbreeding and outbreeding: theoretical and empirical perspectives. Chicago, IL: Chicago University Press.

2. Charlesworth, B. & Charlesworth, D. 1999 The genetic basis of inbreeding depression. Genet. Res. 74, 329–340

3. M Menotti-Raymond and S J O'Brien, 1993. Dating the genetic bottleneck of the African cheetah. Proc Natl Acad Sci, 90(8): 3172–3176.

4. Al-Abdulkareem, A. and Ballal, S. 1998. Consanguineous Marriages in an Urban Area of Saudi Arabia: Rates and Adverse Health Effects on Offspring. Journal of Community Health, Vol. 23, No. 1, pp 75-83.

5. Dorsten, L., Hotchkiss, L., and King, T. 1999. The Effect of Inbreeding on Early Childhood Mortality: Twelve Generations of an Amish Settlement. Demography. Vol. 36. No. 2. pp. 263-271.

6. Ober, C., Hyslop, T., and Hauck, W. 1999. Inbreeding Effects on Fertility in Humans: Evidence For Reproductive Compensation. American Journal of Human Genetics. Vol. 64. pp 225-231.
7. Olsson, M., Shine, R., Madsen, T., Gullberg, A. & Tegelstrom, H. 1996 Sperm selection by females. Nature, 383, 585–585.

8. Urbach, D., Folstad, I. & Rudolfsen, G. 2005 Effects of ovarian fluid on sperm velocity in Arctic charr (Salvelinus alpinus). Behav. Ecol. Sociobiol. 57, 438–444.
9. Rosengrave, P., Gemmell,N. J.,Metcalf, V.,McBride, K.& Montgomerie, R. 2008 A mechanism for cryptic female choice in chinook salmon. Behav. Ecol. 19, 1179–1185.
10. Gage,M. J. G., Macfarlane, C. P., Yeates, S.,Ward, R. G., Searle, J. B. & Parker, G. A. 2004 Spermatozoal traits and sperm competition in Atlantic salmon: relative sperm velocity is the primary determinant of fertilization success. Current Biology. 14, 44–47.

11. Magurran, A. E. 2005 Evolutionary ecology: the Trinidadian guppy. Oxford, UK: Oxford University Press.

12. Zajitschek, S. R. K., Lindholm, A. K., Evans, J. P. & Brooks, R. C. 2009 Experimental evidence that high levels of inbreeding depress sperm competitiveness. J. Evolutionary Biology. 22, 1338–1345.

13. Pilastro, A. & Bisazza, A. 1999 Insemination efficiency of two alternative male mating tactics in the guppy (Poecilia reticulata). Proc. R. Soc. Lond. B 266, 1887–1891.

14. Johnson, A. M., Chappell, G., Price, A. C., Rodd, F. H., Olendorf, R. & Hughes, K. A. 2010 Inbreeding depression and inbreeding avoidance in a natural population of guppies (Poecilia reticulata). Ethology 116, 448–457.

* Slow sperm prevent inbreeding [story in 'The Scientist'] here.

* Insightful discussion on 'Inbreeding In Humans' [here].

Arsenic-aliens? Arsenated-DNA? or simply Arsenic-Adaptation?

2010-12-05T01:14:00.000-08:00

GFAJ-1 bacteria

Even at the risk of sounding deliriously dreamy, I'd say that the impact of the present discovery is such that humans could well be witnessing the emergence of alternative life-forms on earth. In fact, existing (but yet-undiscovered) life-forms could well push us enough to gape at the limits of endurance and stunning adaptations of Life. High-dreaming, Science fiction writers now only have to thank NASA for vindicating their way-off-the-scale 'absurd'-imaginations; which of course now seems inane and possible. What was earlier sci-fi is now routine, what was earlier a 'distant-possibility' is now 'present' and possible. This report raises the possibility that we could indeed well be staring right in the face of creatures which might not care for Carbon.

In other words, there is a heightened likelihood of life-on-earth that uses elements other than what is normally 'prescribed'. The protagonist of this bizarre scientific-discovery (a bacterium) does exactly that - it substitutes Arsenic (As) for Phosphorus (P) in major bio-molecules to sustain its growth.

But why the chest-thumps? why the brouhaha? Because, the knowledge of the occurrence of exchange of major bio-elements raises a brazen possibility which could have profound evolutionary and geochemical significance. In fact, it is the first time in the history of biology that there's been anything found that can swap a major element for another in the basic structure. Ha, SETI just got a shot in the arm!

Are we talking to 'them' yet?!

Important: please visit the "Critique" section at the end of the post for a more nuanced understanding of some of the pitfalls of the paper, discussed in detail by a trained and practicing microbiologist.

Some background: Life on earth depends largely on six major nutrient elements - Carbon [C], Hydrogen [H], Nitrogen [N], oxygen [O], Sulfur [S], and Phosphorus [P], which make up the bulk of the cellular macromolecules - proteins, lipids and DNA. NO element has ever been shown to replace any of the 6-mentioned elements as core-constituents, efficiently and effectively, Never! This is what makes the discovery very special. It goes on to show just that!

Having said that, let me also mention that As-loving bacteria have been known for some time, and indeed, a previous study by the same group, also published in 'Science', showed that bacteria (some species of cyanobacteria and others taken from the same source [Mono-Lake, Calif.]) could effectively photosynthesize by extracting electrons from arsenite by oxidation, in order to help convert CO2 to biomass [source]. Undoubtedly, a rigorous scan of extremophiles in our lava-spewing volcanoes, hot-water springs, oceans etc. might throw up other interesting life forms. Indeed, a recent study in PNAS showed that there were hitherto unknown ultrasmall, nanoscale organisms (500 nm in diameter) residing in extreme conditions in a copper mine sludge that is as acidic as battery acid. They called the organisms ARMAN (archaeal Richmond Mine acidophilic nanoorganisms).

Rationale: 'As' is considered to be a chemical-analog of 'P', as it lies directly below P on the periodic table. There are tremendous physico-chemical similarities between their common salts AsO43- and PO43-, but owing to the relative instability of As-salts which get very easily hydrolyzed, they are not incorporated into biological processes [read metabolism], and are actually poisonous.
The question these guys asked was: Would organisms incorporate AsO43- into their system, if theres just no PO43- around? As it turned out, they actually did! Read on.

The bacterium: Samples of the rod-shaped GFAJ-1 bacteria, belonging to the salt-loving Halomonadaceae family of proteobacteria (identified by 16S rRNA sequence phylogeny), were recovered from the toxic, hypersaline and alkaline waters of Mono Lake, California, where the dissolved arsenic concentrations reached upto 200 μM on average, making it one of the highest natural concentrations of As in the world.

methodology: The investigators used lake sediments as inocula into an aerobic defined artificial medium at pH 9.8 containing 10 mM glucose, vitamins, trace metals but no added PO43- nor any additional complex organic supplements (e.g. yeast extract, peptone) with a regimen of increasing AsO43- additions spanning the range 100 μM to 5mM. Currently this isolate, strain GFAJ-1 is maintained aerobically with 40 mM AsO43-, 10 mM glucose and no added PO43- (+As/-P condition).

Stoichiometry and elemental distribution in the cell: Investigators used radiolabeled [73-AsO4-3-] to obtain more specific information about the intracellular distribution of arsenic. Wolfe-Simon and colleagues learned that about one-tenth of the arsenic absorbed by the bacteria ended up in their nucleic acids, but more than three quarters of the 73-AsO4-3- into the protein fraction, with a small fraction going into lipids.
This meant that the bacteria indeed could use As as a substitute, and was not merely using [and reusing] the scarce P-pool.

Data produced by mass-spectrometry methods known as ICP-MS and NanoSIMS, showing the distribution of various chemical elements within GFAJ-1 cells, revealed a clear difference between cells grown with As [which were loaded with As] and those grown with P [had very little phosphorus]. In cells grown with phosphorus, the opposite was true.

To confirm that the As was actually being incorporated into DNA, folks used gel purification of DNA to isolate and concentrate DNA from GFAJ-1 cells.
NanoSIMS measurement of these concentrated DNA extractions showed that arsenic was indeed present in their DNA.

Clinching evidence came from Micro extended X-ray absorption fine structure spectroscopy (µEXAFS) experiments, which showed that As bonded to O and C in the same way P bonds to O.
In other words: GFAJ-1 probably can substitute As for P in its DNA and all the while continue its life happily with children, as if nothing happened!

Now that we revere the DNA molecule as the 'ladder-of-life', and P [phosphate] as the backbone of this fantastic ladder [the basic DNA structure is here]; this study hits at the very-bottom of all dogmas and beliefs, by hinting that there could be alternatives to the elements. It reinforces what SETI-believers and star-wars worshippers have long been ranting about; that life can exist under a much wider range of environments than hitherto believed. GFAJ-1 are proof of life’s amazing ability to adapt to even the most difficult conditions.

But really, are we looking at Arsenated-DNA yet? Life forms that operate beyond the realms of the mandatory 6-elements? Maybe [or not]!

Questions that remain:
*Does all the phosphate get replaced by arsenates in the backbone of DNA? Then [by virute of its
inherent instability], every bond in that chain would hydrolyze in minutes.

*Alternatively, if there is an arsenate-for-Phosphate structure, it has to be seriously stabilized by some as-yet-unknown mechanism. We dont know that yet.

*None of the measurements clearly proves that Arsenate is doing what phosphate normally would, in the DNA [although presently its difficult to come up with an alternative explanation].

*Does GFAJ-1 actively employ its arsenic-incorporating ability in its natural state, in the lake; or is it some very bizarre thing, which happens only under controlled laboratory-conditions.

*And, are there other As-using forms waiting to be discovered? Maybe even forms which have done away with DNA?

Applications?
*These bacteria might one day help to clean up arsenic-contaminated drinking water

*Or, clean up and bio-remediation after an oil spill [read the disastrous effects of Oil-spill in an earlier post].

*The field of custom-engineering microbes is a hot area of alternative energy. A synthetic organism that works by different chemicals entirely might actually just as important as the new arsenic-eating GFAJ-1 bacterium.

But a point to ponder is that GFeAJ-1 does NOT preferentially use As over P, hence all its usage would have to be limited to P-free environs.

Critique: following links lead to an expert's critique (Dr. Rosemary (Rosie) J. Redfield, a microbiologist at University of British Columbia) of the claims made in the paper, posted in her blog. She's torn the paper apart on issues of microbial-assays, but (admittedly) is not an expert on the biophysical aspects of the paper.

* Here is a very insightful paper [Science, 1987, Vol. 235, 1173-1178], with valuable references which discuss why Nature chose Phosphates as a fundamental building block [and not Arsenate, Citrate or Silicate].

References:

** A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus [here]
Felisa Wolfe-Simon1, Jodi Switzer Blum, Thomas R. Kulp, Gwyneth W. Gordon, Shelley E.

Hoeft, Jennifer Pett-Ridge, John F. Stolz, Samuel M. Webb, Peter K. Weber, Paul C. W. Davies,

Ariel D. Anbar and Ronald S. Oremland.
Science, DOI: 10.1126/science.1197258, published Online 2 December 2010.

** "Microbe gets toxic response"

** Arsenic-eating microbe may redefine chemistry of life [Nature news, here]

** Arsenic eating bacteria opens new possibilities for alien life [here]

** Arsenic-based bacteria point to new life forms [here]

A cure for Alzheimer's: from Mice to Men?

2010-11-29T04:49:00.000-08:00

Faces of Alzheimer's (Source)

A recent scientific-report is scorching news headlines, for very obvious reasons. This study claims, for the first time, that boosting levels of a single 'master regulator' of brain signaling, (EphB2) one effectively resolves symptoms of the dreaded Alzheimer's disease (AD), at least for now, in mice. Although achieving similar results in humans might still be a long way off, yet findings of the study have raised hope of an entirely new approach to tackling this debilitating disease in humans.

Alzheimer's diesease: (AD)—also called senile dementia of the Alzheimer type, primary degenerative dementia of the Alzheimer's type, or simply Alzheimer's—is the most common form of dementia. As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss and the general withdrawal of the sufferer as their senses decline. This degenerative disease was first described by the German psychiatrist and neuropathologist Alois Alzheimer, in 1906.

I dont have recent data, but in 2006 alone, there were 26.6 million sufferers worldwide. And, AD is predicted to affect 1 in 85 people globally by 2050. The disease course is generally characterised with progressive patterns of cognitive and functional impairments.

Mechanism: AD has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid. Beta-amyloid is a fragment from a larger transmembrane protein called amyloid precursor protein (APP). APP is critical to neuron growth, survival and post-injury repair. In AD, APP gets divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile/amyloid plaques.

AD is also caused due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.

About EphB2 (wiki): Members of the Eph family of receptor tyrosine kinases control many aspects of cellular interactions during development, including axon guidance in neurons. Hence, EphB2 acts both as a receptor and an enzyme in a Neuron. EphB2 also regulates postnatal synaptic function in the mammalian CNS. A number of Eph receptors and their ligands (Ephrins) continue to be expressed following the period of primary CNS innervation. It is considered rather important for dendritic maturation and critical for synaptic functions. Incidentally, brain levels of EphB2 are decreased in AD.

Outline of the study: Scientists at the Gladstone Institute of Neurological Disease (GIND) in San Francisco used a genetically engineered mouse model of AD, which simulates the disease (AD) and has abnormally low levels of EphB2 in memory centers of the brain. As it turned out during the course of the study, improving EphB2 levels in these mice by gene therapy completely fixed their memory problems.

mice used for the study [hAPP-mice]: Human amyloid precursor protein (hAPP) transgenic mice with high brain levels of amyloid-beta oligomers have reduced hippocampal levels of tyrosine-phosphorylated NMDA receptors (a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function in neurons) and key components of NMDA-receptor-dependent signalling pathways. Very significantly, Hippocampal-levels of the receptor tyrosine kinase EphB2 are depleted in both AD patients and hAPP mice, which makes it an apt model-system choice.

Crucial Experiments / Observations: Investigators used gene therapy to experimentally alter EphB2 levels in memory centers of mice.
Reducing EphB2 levels using sh-RNA in normal healthy mice disrupted neurotransmission, impaired synaptic plasticity and reduced synaptic strength. Overall, it gave them memory problems similar to those seen in AD. This finding suggests that the reduced EphB2 levels in AD brains directly contribute to the memory problems that characterize the AD-condition.
Having achieved this, the cricitcal question of course now, was to assess whether normalizing EphB2 levels could fix memory problems caused by amyloid proteins.
To determine if increasing EphB2 expression in the dentate gyrus of hAPP mice reverses memory deficits, folks used a lentivirus expressing EphB2 (gene therapy method). Indeed, increasing dentate gyrus EphB2 levels reversed LTP deficits in two independent cohorts of hAPP mice. Dumping EphB2 proteins rescued synaptic functions and ameliorated cognitive (Spatial learning and memory) deficits in hAPP mice.

This study shows that EphB2 depletion contributes to amyloid-b-induced neuronal deficits and cognitive dysfunction. It pointedly shows that EphB2 impairment is necessary and sufficient to elicit impaired Long term Potentiation (LTP) and memory. Importantly, they showed that increasing neuronal EphB2 levels in hAPP mice reversed these deficits.

Of course, this work immediately doesn't provide medical advice, diagnosis or treatment for humans but could certainly pave the way for follow-up studies and eventual possible remedies for scores of human patients.
This study also stirs the already-sizzling debate of whether there could be potential "Master-Genes" in our system. Of course, with a growing acceptance for Network-models of signaling, one has to still work out the various possible targets and nodes (sensitive check points of control, where subsets of the signaling module meet) for a better understanding of the signaling pathway leading to AD.

References:

* Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature, November 2010; DOI: 10.1038/nature09635. Moustapha Cissé, Brian Halabisky, Julie Harris, Nino Devidze, Dena B. Dubal, Binggui Sun, Anna Orr, Gregor Lotz, Daniel H. Kim, Patricia Hamto, Kaitlyn Ho, Gui-Qiu Yu and Lennart Mucke.

* The Receptor Tyrosine Kinase EphB2 Regulates NMDA-Dependent Synaptic Function. Neuron, Vol. 32, 1041–1056, December 20, 2001. Jeffrey T. Henderson, John Georgiou, Zhenping Jia, Jennifer Robertson, Sabine Elowe, John C. Roder,and Tony Pawson.

* Gene Therapy Prevents Memory Problems in Mice With Alzheimer's Disease [Source]

* An Alzheimer's cure? Boosting levels of a 'master regulator' of brain signaling could resolve symptoms [Source]

Rethinking Genomic Structures

2010-11-22T06:07:00.000-08:00

Oikopleura dioica (source)

In a fascinating find, investigators described the genomic sequence of a tiny, transparent, mucus-covered marine animal, as the "alien-genome". Reason? It simply shatters a lot of our etched-in-stone scientific notions about eukaryotic genome architecture.
The genome of Oikopleura dioica breaks all the organizational rules previously thought to be critical for animal genomes - turning on its head a long held scientific-belief, that common architectural features of genomes observed across all animal kingdoms, are maintained by natural selection.

This study goes on to show that genome arrangement could actually be rather plastic!
The belief: Decades of arduous scientific work has shown that there exists a remarkable similarity in genome organization between species as distant and diverse as humans and sea sponges. These common multiple genomic features includes the order of genes, intron-exon organization, transposon diversity and developmental gene repertoire. This enormous amount of data somehow (mis)-led many of us to infer that a designated, non-flexible animal genome architecture is necessary to preserve form and function and is actively maintained by natural selection.
As it turns out, the genome of this tunicate, Oikopleura shatters this long-held belief!
About the animal: Tunicates are viewed as the closest living relatives of vertebrates, were probably simplified from more complex chordate ancestors.
Larvacean tunicates represent the second most abundant component of marine zooplankton and filter small particles by their gelatinous house which it secretes from a terminally differentiated oikplastic epithelium. Oikopleura dioica is the most cosmopolitan larvacean, has a very short life cycle (4 days at 20°C) and can be reared in the laboratory for hundreds of generations. Unique among tunicates, it has separate sexes. In fact, Oikopleura dioica is a favorite model-system for genetic, genomic and embryological studies.
The effort: Over 50 collaborating researchers at the Sars International Centre for Marine Molecular Biology at the University of Bergen in Norway, together with colleagues at Genoscope, a national sequencing center in France, sequenced and analyzed the Oikopleura genome, with high coverage shotgun reads (14X) using males.
Experiments/Observations:

At only 70 million base pairs (Mb), it turned out to be the smallest known animal genome. Remarkably, with 18,020 predicted genes, almost as much as a human's, but tucked into a DNA sequence 40 times shorter, makes the Oikopleura genome unusually compact. Although, two exceptions to global compaction are particularly interesting, as they may illustrate where excessive reduction could be harmful. First, a small population of Oikopleura developmentally regulated transcription factor genes have relatively large introns and intergenic spaces, and second, genes on the Y chromosome (since sex is genetically defined in Oikopleura), all expressed in the testis during spermatogenesis, have giant introns.
Moreover, while animals from sea anemones to primates have conserved the physical location of certain genes near each other, Oikopleura's genes appeared to have been randomly located, almost shuffled. Yet, Oikopleura has many of the same essential phenotypic features as other tunicates with traditional genome architecture.
Another significant peculiarity was the locations of introns - another structural feature conserved across several phyla - was gone, yet newer introns (5 to 6) had emerged all over the genome, sharing sequence-similarity to neighbours. This perhaps adds another dimension to the old scientific debate - where do introns originate?
Additionally, the Oikopleura genome leacked genes involved in immunity. In fact, many conserved immunity genes failed detection, supporting a minimized immune system consistent with the short Oikopleura life history.
Reason: Experts suggest that Oikopleura, is a rapidly evolving animal, with constant mutations in its nuclear and mitochondrial genomes. This speedy evolution is likely due to the fact that the animal spends most its life just below the ocean surface, bombarded by UV rays and other mutagens. Evolution of this rate, might have resulted this distinctively different genomic-architecture, unparalled in the animal kingdom.

Overall, this work suggests that multiple genome organization features, have dramatically changed in the Oikopleura lineage. And despite an unprecedented genome revolution, the Oikopleura lineage preserved essential morphological features, even maintaining the chordate body plan to the adult stage.

It also throws up interesting questions..

-How does Oikopleura deal with this immense radiation induced DNA-damage? Does it have a unique DNA-recombination-repair mechanism?

-Fundamentally, why do larger animals (like us) need larger genomes?

References:

* Plasticity of Animal Genome Architecture Unmasked by Rapid Evolution of a Pelagic Tunicate.
Science, published online 18 November 2010, doi:10.1126/science.1194167.

* Thomson group, working on Oikopleura.

* Who needs structure, anyway?

Tumbled-Thinkers of the world - Unite [and Rejoice]!

2010-10-12T05:49:00.000-07:00

the "tumbled-thinker"

It's that time of the year, when the air's chilly and festive, the Hot-n'-Serious Nobels' have just left us dreamy-eyed, soaked in sweat and a wide anticipatory grin lies plastered across our face...it's time for some serious-fun and serious-thought...its time to celebrate the intelligently-whacky Ig-Nobel-awards.

...following words (and the story thereon), are from the Ig-nobel site on Improbable-research

------

Why We Do It

Our goal is to make people laugh, then make them think. We also hope to spur people's curiosity, and to raise the question: How do you decide what's important and what's not, and what's real and what's not — in science and everywhere else?

"The most exciting phrase to hear in science, the one that heralds new discoveries, is not 'Eureka!' but, 'That's funny..." —Isaac Asimov

"Once you eliminate the impossible, whatever remains, no matter how improbable, must be the truth." —Sherlock Holmes

--------
The 2010 Ig Nobel Prize Winners
The 2010 Ig Nobel Prizes were awarded on Thursday night, September 30, at the 20th First Annual Ig Nobel Prize Ceremony, at Harvard's Sanders Theatre.

ENGINEERING PRIZE: Karina Acevedo-Whitehouse and Agnes Rocha-Gosselin of the Zoological Society of London, UK, and Diane Gendron of Instituto Politecnico Nacional, Baja California Sur, Mexico, for perfecting a method to collect whale snot, using a remote-control helicopter.
REFERENCE: "A Novel Non-Invasive Tool for Disease Surveillance of Free-Ranging Whales and Its Relevance to Conservation Programs," Karina Acevedo-Whitehouse, Agnes Rocha-Gosselin and Diane Gendron, Animal Conservation, vol. 13, no. 2, April 2010, pp. 217-25.

MEDICINE PRIZE: Simon Rietveld of the University of Amsterdam, The Netherlands, and Ilja van Beest of Tilburg University, The Netherlands, for discovering that symptoms of asthma can be treated with a roller-coaster ride.
REFERENCE: "Rollercoaster Asthma: When Positive Emotional Stress Interferes with Dyspnea Perception," Simon Rietveld and Ilja van Beest, Behaviour Research and Therapy, vol. 45, 2006, pp. 977–87.

TRANSPORTATION PLANNING PRIZE: Toshiyuki Nakagaki, Atsushi Tero, Seiji Takagi, Tetsu Saigusa, Kentaro Ito, Kenji Yumiki, Ryo Kobayashi of Japan, and Dan Bebber, Mark Fricker of the UK, for using slime mold to determine the optimal routes for railroad tracks.
REFERENCE: "Rules for Biologically Inspired Adaptive Network Design," Atsushi Tero, Seiji Takagi, Tetsu Saigusa, Kentaro Ito, Dan P. Bebber, Mark D. Fricker, Kenji Yumiki, Ryo Kobayashi, Toshiyuki Nakagaki, Science, Vol. 327. no. 5964, January 22, 2010, pp. 439-42.
[NOTE: THE FOLLOWING ARE CO-WINNERS BOTH THIS YEAR AND IN 2008 when they were awarded an Ig Nobel Prize for demonstrating that slime molds can solve puzzles: Toshiyuki Nakagaki, Ryo Kobayashi, Atsushi Tero]

PHYSICS PRIZE: Lianne Parkin, Sheila Williams, and Patricia Priest of the University of Otago, New Zealand, for demonstrating that, on icy footpaths in wintertime, people slip and fall less often if they wear socks on the outside of their shoes.
REFERENCE: "Preventing Winter Falls: A Randomised Controlled Trial of a Novel Intervention," Lianne Parkin, Sheila Williams, and Patricia Priest, New Zealand Medical Journal. vol. 122, no, 1298, July 3, 2009, pp. 31-8.

PEACE PRIZE: Richard Stephens, John Atkins, and Andrew Kingston of Keele University, UK, for confirming the widely held belief that swearing relieves pain.
REFERENCE: "Swearing as a Response to Pain," Richard Stephens, John Atkins, and Andrew Kingston, Neuroreport, vol. 20 , no. 12, 2009, pp. 1056-60.

PUBLIC HEALTH PRIZE: Manuel Barbeito, Charles Mathews, and Larry Taylor of the Industrial Health and Safety Office, Fort Detrick, Maryland, USA, for determining by experiment that microbes cling to bearded scientists.
REFERENCE: "Microbiological Laboratory Hazard of Bearded Men," Manuel S. Barbeito, Charles T. Mathews, and Larry A. Taylor, Applied Microbiology, vol. 15, no. 4, July 1967, pp. 899–906.

ECONOMICS PRIZE: The executives and directors of Goldman Sachs, AIG, Lehman Brothers, Bear Stearns, Merrill Lynch, and Magnetar for creating and promoting new ways to invest money — ways that maximize financial gain and minimize financial risk for the world economy, or for a portion thereof.

CHEMISTRY PRIZE: Eric Adams of MIT, Scott Socolofsky of Texas A&M University, Stephen Masutani of the University of Hawaii, and BP [British Petroleum], for disproving the old belief that oil and water don't mix.
REFERENCE: "Review of Deep Oil Spill Modeling Activity Supported by the Deep Spill JIP and Offshore Operator’s Committee. Final Report," Eric Adams and Scott Socolofsky, 2005.

MANAGEMENT PRIZE: Alessandro Pluchino, Andrea Rapisarda, and Cesare Garofalo of the University of Catania, Italy, for demonstrating mathematically that organizations would become more efficient if they promoted people at random.
REFERENCE: “The Peter Principle Revisited: A Computational Study,” Alessandro Pluchino, Andrea Rapisarda, and Cesare Garofalo, Physica A, vol. 389, no. 3, February 2010, pp. 467-72.

BIOLOGY PRIZE: Libiao Zhang, Min Tan, Guangjian Zhu, Jianping Ye, Tiyu Hong, Shanyi Zhou, and Shuyi Zhang of China, and Gareth Jones of the University of Bristol, UK, for scientifically documenting fellatio in fruit bats.
REFERENCE: "Fellatio by Fruit Bats Prolongs Copulation Time," Min Tan, Gareth Jones, Guangjian Zhu, Jianping Ye, Tiyu Hong, Shanyi Zhou, Shuyi Zhang and Libiao Zhang, PLoS ONE, vol. 4, no. 10, e7595.

****

* c u r i o s i t a s *: Science of Symbiosis in the Solar-Salamander.

2010-08-26T01:46:00.000-07:00

Science of Symbiosis in the Solar-Salamander.

2010-08-26T01:45:00.000-07:00

spotted salamander (source)

Be forewarned!...Another long-held scientific-dogma could be in the pipeline for complete annihilation! gulp further, and faster...[sorry for sounding like the eager foreword of a naive novella]...but this story IS as seductive as it can get...

For long, scientists heve believed, with good reason though, that the vertebrate system owing to it's highly specialized and robust adaptive-immune system rejects anything that is not 'self'. It translates into the following - It is impossible for a symbiont to live and propagate 'inside' a healthy vertebrate body, without retaliation from the host's immune system! Period!

(A) Individual eggs within a salamander egg-mass, with tiny green alga Oophila, which provides the greenish appearance.

..Not any more, says Ryan Kerney of Dalhousie University in Halifax, Nova Scotia, Canada (Ryan is here). And the basis for this new-found boom in Ryan's voice comes from his close observations of a clutch of spotted-salamander (Ambystoma maculatum) eggs, which are green in appearance. He watched and watched and noticed something really extraordinary in those otherwise mundane and oft-studied eggs.

He realized for the first time, that the salamander eggs have a intracellular-guest - the single-celled alga, Oophila amblystomatis! Actually, these alga are generally called "salamander algae", and are a species of single-celled alga. The Latin specific name actually translates into "loves salamander eggs". And, it is these alga which give the characterisitc emerald-green colour to the salamander embryos as well as the jelly capsule that encases them.

Interestingly, it had been earlier known that the algae enjoy a symbiotic relationship with the spotted salamander, which lays its eggs in bodies of water. However, the symbiosis was thought to occur between the salamander embryo and algae living 'outside' it — a relationship hinging on the embryo producing nitrogen-rich waste that is useful to algae, and the algae reciprocating with increasing the oxygen content of the water in the immediate vicinity of the respiring embryos...but this new observation totally destroys the paradigm of symbiosis without cohabitation...hmm...so far so good....

(B) Detail of a single image. Head and gills of the dark, developing embryo are visible and the tiny green dots are the endosymbiont algae (source for A and B).

Ryan goes on to suggest, that the green alga could be directly providing the products of photosynthesis — oxygen and carbohydrate — to the salamander cells that encapsulate them, thus making them energy-sufficient! This is indirectly-evidenced by Transmission Electron Microscopy (TEM) images which show several mitochrondria (which are the 'powerhouses' of animal cells, converting oxygen and a metabolic product of glucose into ATP, a molecule that cells use to store chemical energy) bordering the algal symbiont in the salamander cells. So salamander mitochondria gathered around an algal cell might be there to take advantage of the oxygen and carbohydrate generated by photosynthesis in that particular cell.

An earlier study by Lynda Goff, a molecular marine biologist and a host-parasite-interaction specialist, at the UC, Santa Cruz, who worked on this pair of organisms about 30 years ago, had successfully demonstrated, among other things, that embryos lacking algae in their surrounding jelly are slow to hatch also saw a logarithmic increase in algal cells as the embryo developed, and in those that did contain algae, the community was not static.

The question however remains as to how are the algal-cells present in the embryos evade self-destruction? Ryan says the it could be that either the salamander cells have turned their internal immune system off, or the algae have somehow bypassed it.

Another interesting question could be to probe the mode of entry of the algae inside the embryos?
A naturally happening likely moment is when the embryos' nervous systems begin to form. A time-lapse video made by Roger Hangarter at Indiana University in Bloomington reveals a fluorescent green flash next to each embryo at that point in its development. The flare is a bloom of algae, which is probably drawn to a release of nitrogen-rich waste from the embryo. Ryan postulates that if waste is released, then there must also be a way in — and the large number of algae in the bloom increases the chances that some will make it in...fair logic!

One of Ryan's most curious discoveries is of the presence of algae in the oviducts of adult female spotted salamanders, where the embryo-encompassing jelly sacs form — a finding that points to the possibility that symbiotic algae could be passed from mother to the offspring's jelly sacs during reproduction. Therefore is this a maternal-gift? This in turn raises another possibility - that whether algae could be getting into the germ [sex] cells. That would really challenge the dogma [of vertebrate cells disposing of foreign biological material].

Now, is this smacking of Epigenetics? Inheritance that is modulated not by DNA, and in this specific case, not even by intracellular molecular factors, but at an organismal level? Big Question.

The salamander happens to be an interesting animal - most of its cells retain a degree of pluripotency. That is, the animal has the capability to regrow its lost limbs when it loses them (remember the common Gecko which lets off its tail when threatened and usually regrows it)...does this mean that such animals have different modes of 'self' and 'non-self'-recognition?

The answer probably is very easy.....we have absolutely No-Idea at this point!

Food for Thought? Yes. Yes.

References

* Green Eggs and Jam: Adaptations That Help Spotted Salamanders Reproduce (here).

* Green eggs power solar salamanders (here).

* Salamander's egg surprise (here)

* A solar salamander (here)

* Henrey Orr (1888). Note on the development of amphibians, chiefly concerning the central nervous system; with additional observations on the hypophysis, mouth, and the appendages and skeleton of the head Quarterly Journal of Microscopical Science

* Gilbert, P. (1944). The Alga-Egg Relationship in Ambystoma Maculatum, A Case of Symbiosis Ecology, 25 (3)

Mysterious cell component Nucleolinus (re)-discovered!

2010-08-13T02:25:00.000-07:00

DIC image of Nucleolinus within the surf-calm, spisula (right) oocyte.

Surprise, Surprise! In the ripe age of satellite imagery and femto-scale probes, when folks are busy tweezing protein surfaces, these guys have (re)-discovered a cell-organelle. Perhaps, it's akin to the discovery of a new continent in the age of the terrace-pervading 'google-earth'.

Folks from the Marine Biological Laboratory's (MBL) Josephine Bay Paul Center, at the University of Illinois present their discoveries regarding the "Nucleolinus" in a paper in the Proceedings of the National Academy of Sciences (PNAS).
Although the nucleolinus, a cellular structure observed in the nucleus of many cells, including invertebrate egg cells and some mammalian cells, was discovered (and forgotten) more than 150 years ago, and other scientists had proposed its involvement in cell division, difficulties in visualizing the nucleolinus inside most cells had kept further studies at bay.
The scientists went on to develop a ribo-probe - NLi-1 for the RNA molecule present exclusively in the nucleolinus compartment in the oocytes of the surf clam, Spisula solidissima (the unfortunate clam is a valued delicacy in some cultures!). This breakthrough development of a marker for the elusive organelle would now serve the purpose of a beacon, and make future studies into its relevance and consequence in cells easier.
Other in situ observations in the oocytes revealed that the nucleolinus (and NLI-1) were inseparably associated with the developing spindle and centrosomes, and therefore could be related to cell-division.

Laser microsurgery that targeted the nucleolinus resulted in failed meiotic cell division in parthenogenetically activated oocytes and failed mitosis in fertilized oocytes, hence acribing a definitive role to the Nucleolinus in cell-division.

This investigation could clarify recent studies indicating an important role for the nucleolus in cell division. Possibly it was the shy Nucleolinus, all the way!

Curiously, the paper's bibliography cites references from as further back as 1857! (We, Indians were busy fighting the 1st war of independence against imperialist marauders then...)..

References:

* Alliegro, M.A., Henry, J.J., Alliegro, M.C. Rediscovery of the Nucleolinus, a Dynamic RNA-Rich Organelle Associated with the Nucleolus, Spindle, and Centrosomes. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1008469107

*Alliegro MC, Alliegro MA, Palazzo RE (2006) Centrosome-associated RNA in surf clam
oocytes. Proc Natl Acad Sci USA 103:9034–9038.

* Scientists Confirm Role for Mysterious Cell Component -- The Nucleolinus.

investigating the Science of Death in Living Colour.

2010-07-26T04:29:00.000-07:00

Pictured is an optical micrograph of cells 24 hours after initiation of apoptosis. The image combines coherent anti-Stokes Raman scattering (CARS) microscopy and two-photon excited fluorescence (TPEF) to show spatial distributions of major biomolecules such as proteins (red), RNA (green), DNA (blue) and lipids (grey) during apoptosis. Here, proteins abandon the nucleolus, accumulating in a highly irregular distribution in the nucleoplasm, and genomic DNA condenses and partially segregates from the proteins. (from the cover page of PNAS, July 20.)

Arguably, the most celebrated phenomenon studied by biologists, the science of programmed cell-death or Apoptosis, is essential to normal development, healthy immune system function, cancer prevention and a plethora of other functions. The pace of investigation in this already deadly field would now surely hotten up with the monitoring of Real-Time Dynamics of apoptotic cells in Living Color.
New science featured on the cover of the current issue of PNAS, University at Buffalo (UB) scientists have developed a biophotonic imaging approach capable of monitoring in real-time, the transformations that cellular macromolecules undergo during programmed cell death.
To develop the know-how of efficiently capturing transient and high-resolution cellular images of the phenomenon, an interdisciplinary UB team of biologists, chemists and physicists, led by Paras N. Prasad, executive director of the UB Institute for Lasers, Photonics and Biophotonics, utilized an advanced biophotonic approach that combines three techniques: a nonlinear, optical imaging system CARS (Coherent anti-Stokes Raman scattering), TPEF (two-photon excited fluorescence), which images living tissue and cells at deep penetration and Fluorescence Recovery after Photobleaching (FRAP), to measure dynamics of proteins.
This approach allows one to to monitor in a single scan, four different types of images, characterizing the distribution of proteins, DNA, RNA and lipids, the 4 major macromolecules, in the cell. The resulting composite image integrates in one picture the information on all four types of biomolecules, with each type of molecule represented by a different color: proteins in red, RNA in green, DNA in blue and lipids in grey, as shown on the PNAS cover. This kind of Multiplex imaging provided new information on the rate at which proteins diffuse through the cell nucleus, the UB scientists say.
Researchers noted that before apoptosis was induced, the distribution of proteins in the cell was relatively uniform, but once apoptosis develops, nuclear structures disintegrate, the proteins become irregularly distributed and their diffusion rate slows down.
This ability of dynamic mapping of molecular transformations could potentially help realize the promise of customized molecular medicine, in which chemotherapy, for example, can be precisely targeted to cellular changes exhibited by individual patients. It can also be a valuable drug development tool for screening new compounds. With the increased understanding of cellular events at the molecular level, where one can clearly visualise the changing dynamics of DNA, RNA and lipids during the cell's disintegration, one could specifically use it for monitoring how specific cancer drugs affect individual cells.
The advancement in Biophotonic-tools to effectively investigate, and perhaps use it for predictive and therapeutic purposes has opened up the field of customized bio-medicine. Moreover, this could be employed towards the study of new fundamental cellular investigations and structural reorganization throughout the mitotic cell cycle.

reference:

* Biophotonic probing of macromolecular transformations during apoptosis.

Proceedings of the National Academy of Sciences, 2010; 107 (29)

* http://www.sciencedaily.com/

* Wikipedia for basic information on Apoptosis, (Bio)-Photonics, Cancer, Immune regulations etc.

scary thing is...can get away with Temper-Issues in some cultures, not in some others!

2010-07-21T02:41:00.000-07:00

Anger is “an emotional state that varies in intensity from mild irritation to intense fury and rage,” according to Charles Spielberger, PhD, a psychologist who specializes in the study of anger. Like other emotions, it is accompanied by physiological and biological changes; when you get angry, your heart rate and blood pressure go up, as do the levels of adrenaline, and noradrenaline.

Getting angry might help you get your way if you're negotiating with European Americans, but watch out – in negotiations with East Asians, getting angry may actually hurt your cause. That's the conclusion of a new study on how people from different ethnic groups react to anger in their negotiations.
Most scientific research on negotiations, done on western populations have shown that anger is a good strategy – it gets you larger concessions than other emotions, like happiness, or no emotions. Recent work done by Hajo Adam, of INSEAD in France, who coauthored with William Maddux of INSEAD and Aiwa Shirako of the University of California - Berkeley, noticed differences in emotions in people working from different ethnicities. They noticed that sometimes people get angry, and react differently to a given situation. He thought this differential-response to a particular emotion could be due to intercultural differences.
The experiment used volunteers at the University of California - Berkeley. Half were Americans of European ethnicity and half were Asian or Asian American.
Each student took part in a negotiation on a computer and were told that they were negotiating with another human participant, when actually they were negotiating with a computer program. The student was supposed to be selling an electronic gadget, and making deals on sale-issues like warranty period and price. In some negotiations, the computer said it was angry about the negotiation; in others, it did not mention emotion.
European Americans made larger concessions to an angry opponent than to a non-emotional opponent. Asians and Asian Americans, however, made smaller concessions if their opponent was angry rather than non-emotional.
A subsequent experiment suggested that this may happen because of cultural norms about whether it's appropriate to get mad.

This experiment started with telling the participants whether or not expressing anger was acceptable during the study. Asians and Asian Americans made greater concessions to an angry opponent if they were told that expressing anger was acceptable. European Americans were less likely to make concessions if they were told that anger was unacceptable.
When anger expressions are perceived as inappropriate, "People tend to react negatively. They no longer want to concede," says Adam. "They may even want to shut down and potentially penalize the counterpart for acting inappropriately." "I think what's important is that one person expressing emotions really affects another person's feelings, thoughts, and behavior," says Adam. "And these
reactions to emotional displays can critically depend on a person's cultural background."

Do different genders follow the same ethnic-vulnerability pattern? We don't know yet.

-----------------------------------------------

Credits-

* Association for Psychological Science, 2010, July 20. Getting angry can help negotiations in some cultures, hurt it in others.

* ScienceDaily

* Image- http://www.instablogsimages.com/images/2009/06/22/12-angry-men_xVKci_6648.jpg

* Research review on anger in psychotherapy. Journal of Clinical Psychology, 1999, Volume 55 Issue 3, Pages 353 - 363

the Science, nonsense and consequence of the BP Oil-spill.

2010-07-07T05:53:00.000-07:00

The notorious BP (British Petroleum-the MNC petrochem. giant) oil spill (also referred to as the Deepwater Horizon oil spill, the Gulf of Mexico oil spill, the BP oil disaster or the Macondo blowout) is a massive ongoing oil spill in the Gulf of Mexico that is one of the largest offshore spills in the history of our planet with hundreds of millions of gallons spilled to date. It stems from a sea floor oil gusher that resulted from the April 20, 2010 Deepwater Horizon drilling rig explosion which killed 11 platform workers and injured 17 others.

Volume of the spill
scientists estimate that the well is spewing out 35,000 to 60,000 barrels of crude-oil per day and possibly even more. The previous best estimates fell in the range of 20,000 to 40,000 barrels per day. The resulting oil slick covers at least 2,500 square miles (6,500 km2) of pristine marine-area threatening hundreds of miles of beaches, wetlands and estuaries along the northern Gulf coast. Moreover, changes in weather as well as the Gulf of Mexico's Loop Current, which brings water from the gulf around Florida and up the Atlantic Coast. This could affect the outcome, with a possible speed of 100 miles (160 km) a day.

Wheres the fluid headed?
The National Oceanic and Atmospheric Administration (NOAA) of the US currently tracks wind and tidal data in the gulf, which offers an initial, course-grained look at the likely path of the oil. Now a team of computer scientists from Texas, North Carolina, and Indiana are looking to offer a finer picture of where the oil is likely to pile up, particularly as it ravages through the web of channels in the wetlands off the Louisiana coast [more here].

Among the biggest questions of the Deepwater Horizon spill is how much oil remains underwater and where's it heading. Now marine scientists are using SONAR to track undersea oil plumes though they are'nt sure whether the technique would succeed.

Slick-model simulations by scientists have suggested that it's "anyones' guess" when the oil would reach the deep waters of the Atlantic! Depending on the behavior of local eddy-currents, it could take anywhere from 70 days to 6 months.

The HUGE ecological-cost of the irresponsible Spill.

The question is the following: Does our irrepressible greed have the right to kill, murder and plunder all, everything? Will we stop at nothing? O.K, now some facts.

The fragile marine ecosystem in the gulf of Mexico area and in-line of the spill flow is now hugely threatened. The future of the flora/fauna of the area remains bleak as there's a real and present threat of a total ecosystem-washout with the BP and US-govt. agencies being unable to stem the flow of the oil and/or neutralize the effects of the viciously-viscous, dead, thick-fluid.
Among the many affected species are the Sea-Turtles (including the Ridley and the Mississippi. Loggerhead turtles) which incubate their eggs in the sands of the northern Gulf of Mexico. Incidentally, the gender of the turtle embryos gets determined by the temperature of the nest, in a time-frame of aprrox. 50-days. Scientists and volunteers are now planning a may-day evacuation of the eggs to cleaner areas to resurrect whatever is left.

A total of 21 whale and dolphin species that routinely inhabit the northern Gulf are protected under the Marine Mammal Protection Act. The greatest threat is if whales get oil in the filtering structure in their mouths, which could lead to starvation and death. Also, when marine mammals come to the surface to breathe they may inhale hydrocarbon vapors that could potentially result in lung injuries.

Manatees (above in pic.) are beginning to spread out along their full range of summer habitat in the Gulf, making them particularly vulnerable to the gushing oil-contaminated waters.

Apart from the glamorous marine mega-fauna and oil spill poster animals, there are numerous others which are on the brink of total-annihilation.

Nesting and migrating shorebirds such as plovers, sandpipers and oystercatchers which nest on beaches and barrier islands are especially vulnerable to oil washing ashore onto their nesting-grounds, and so are birds which dive in the water in search of fish etc.

The brown pelican (other dramatic pictures of affected animals is here) has not had an easy time of it. The gangling birds were only removed from the endangered species list last year, and they are already facing a very-serious threat.
The humble Fish, Shellfish and Crabs get the rough deal as the fragile delta estuary ecosystem , which is also the breeding ground for a lot of fish, shellfish and crabs, gets drwoned under a thick layer of sticky oil. Also the North Atlantic Bluefin Tuna, Gulf-Sturgeon, Marsh-Rice Rat, Shrimps, Oysters, Planktons, Pancake-Batfish are all forced to face a grim situation as the assault of Man's greed mounts!

Sargassum, a floating seaweed, plays an important role in the marine ecosystem, harboring fish larvae, young turtles, and other marine life. Increasing evidence suggests that the Gulf of Mexico is the source for sargassum habitats in the Atlantic Ocean; and the oil spill could as well, spell the end-of-line for this benevolent fragile-weed.

Dispersants-Toxicity issues, and effect on natural oil-scavengers:

Dispersants, which include molecules called surfactants, work much like dish detergent, helping clean up oil spills by breaking oil blobs into tiny droplets. Microbes in the ocean can then gobble up the droplets more easily. The BP crews have applied more than 37,850 liters of the chemical to the gulf each day over the past month, a small portion of it in the deep ocean; and concerns over the toxic effects of the dispersants have been growing. In lab tests, toxicologists have found that concentrations of Corexit, BP's dispersant of choice, can kill shrimp or fish. The other effect, of course, is that the chemical may undermine the cleanup efforts of its own microbial allies. A few dozen microbes (like Alcanivorax borkumensis) eat oil in the ocean, but they do it in different ways. Over time, the surfactants in dispersants like Corexit might affect the ability of Alcanivorax and other surfactant-makers like it to eat oil.

May we all rest in peace! (the logo in the background is of BP).

References:

Science-magazine

http://news.sciencemag.org/oilspill/ : has well-researched articles devoted exclusively to the oil-spill. This write-up acknowledges some of the data from it's articles.

http://en.wikipedia.org/wiki/Deepwater_Horizon_oil_spill

The oil-soaked images are by photographer Charlie Riedel on a beach on Louisiana's East Grand Terre Island. They are from the following URL :

http://www.boston.com/bigpicture/2010/06/caught_in_the_oil.html

genetic variations, the key to elixir of life?

2010-07-01T23:31:00.000-07:00

Mortality is in the genes!

Whether you're going to celebrate your birth-centenary breathing well, or stop at 85, panting heavily depends, at least partially on your genetic signature - says a new study conducted by a team led by Thomas Perls, a professor of medicine at the Boston University School of Medicine in Massachusetts.
They have shown that a cluster of 150 variations in DNA sequence can be used to predict — with 77% accuracy — whether a person has the genetic wherewithal to live to 100 years old; this after rigorous trekking through the genomes of more than 1,000 centenarians, scoring about 300,000 sequence variations for possible links to exceptionally long lifespans.

The scientific information that emerged was that a complex mix of genetic variants, potentially affecting everything from endocrine-system mediated bone metabolism to stress responses and brain-cell function was associated with its regulation. Some of the discovered variants could play a potential role in staving off debilitating age-related diseases, such as Alzheimer's and the notoriously-ubiquitous cardiovascular diseases.
This complexity of regulation of life-span involving several systems, seems perfectly logical as the search for single 'messiah'-genes with big effects on longevity, has not proven fruitful.
For long, and with good reason, longevity was known to be primarily a matter of environment and genetics is thought to contribute to only about 25-30% of the variation in survival to 85 years of age. As it turns out, in order to live beyond the 85's, you can as well, hold your folks responsible!

A vital-key to longer life-span may be postponing age-related illnesses, and 90% of centenarians remain disability-free into their early 90s, says Perls. They categorized 90% of the centenarians into 19 groups based on the pattern of genetic variations they had, which correlated with patterns in the frequency and age of onset of debilitating diseases such as dementia and high blood pressure. Of course, the science here, does not address instances where larger and more diverse populations, are involved, but if true, the researchers suggest that the key factor for achieving extreme longevity is not a lack of genetic variants that predispose a person to disease, but rather the enrichment of longevity-associated variants that perhaps resist and overcome disease-associated risks.

A potential for misuse, of course is with greedy corporate Pharma/genetic testing -giants who could peddle the information for changes/corrections in the genetic make-up of an individual as an elixir of life.....and the sunny side could be that people can get a screening done before buying life-insurance!

Refs

* Nature News and Views

* Genetic Signatures of Exceptional Longevity in Humans
Science DOI: 10.1126/science.1190532

pitching in for "itch"!

2010-06-10T04:34:00.000-07:00

Earthen sculpture of a bust of a wild-eyed man scratching his back by Robert Arneson, titled Pablo Ruiz with Itch

Itch (Latin: pruritus) is an unpleasant sensation that causes the desire or reflex to scratch the affected area; and the stimuli that causes it is termed Pruritic stimuli. Chronic itch represents a significant clinical problem resulting from renal diseases and liver diseases, as well as several serious skin
diseases such as atopic dermatitis.
Itch has resisted several attempts to classify it as any one type of sensory experience. Research has shown that though itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response patterns are totally different; while pain creates a withdrawal reflex, itch invariably leads to a scratch reflex. The controversy over their apparent similarity persisted because until now nobody could show that both acted through different neuronal-pathways.
The group headed by Zhou-Feng Chen at the Pain-Center in the Washington University School of Medicine, in a 2007 Nature paper, described the gastrin-releasing peptide receptor (GRPR) and implied it in mediating itch sensation in the dorsal spinal cord. GRPR mutant mice showed comparable thermal, mechanical, inflammatory and neuropathic pain responses relative to wild-type mice. In contrast, induction of scratching behaviour was significantly reduced in GRPR mutant mice in response to pruritogenic stimuli. It was significantly indicative that Gastrin-releasing peptide receptor (GRPR) is an itch-specific gene in the spinal cord. Moreover, direct spinal cerebrospinal fluid injection of a GRPR antagonist significantly inhibited scratching behaviour in three independent itch models.

a. scratching behaviour induced by intradermal injection of compound 48/80; b. PAR2 agonist SLIGRL-NH2; c. chloroquine.

As it turns out, the group has with sufficient evidence, recently shown that Itch and Pain are two different sensations propagated by different pathways, and the mechanism of itch-relief by scratching. But more about in in another post.

Reference

A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord
Yan-Gang Sun and Zhou-Feng Chen.
Nature, Vol 448,9 August 2007.

How would you look when you grow Old?

2010-06-05T01:40:00.000-07:00

....or if you were of Caribbean, East or West-Asian or Caucasian descent? Or how would you appear if the Italian painter of the early renaissance, Sandro Botticelli, decided to paint your face? Or would you like it, if you were to suddenly turn the tide of time to visit your childhood, or change into an Ape-(wo)man (and be proud of our common-collective-lineage)!...All this and a few more could be done at the Face Transformer hosted by the Perception lab at the Univ. of St Andrews.

To give you an idea:

Arguably the most famous and discussed picture in the world; the "Afghan Girl", later identified as Sharbat Gula, snapped by Steve Mc-Curry of the NGC on a trip to picture the refugee camps of war-torn Afghanistan.

The face-transformer reveals what she'd have looked like if she'd be of Caribbean descent (and not mid-eastern), a child, or Botticelli's muse, or when she'd be past her prime.

There is also an infant mode, and a feminiser, Modigliani's impression and a cartoon-scape but it all goes downhill from here.. Fun tool to play with, regardless.

Thanks:

http://phineasgage.wordpress.com/

http://perception.st-and.ac.uk/

"Gene Doping" - Risks behind the dehumanization of sport.

2010-06-01T01:29:00.000-07:00

When High-glamour sporting medals and eye-popping multi-million-dollar contracts are at stake, athletes and coaches have been known to resort to drastic measures to strike gold. But as the metabolic-steroid era evolves amidst increased testing, policing and public hectoring, what other performance booster shall enter the ring? Friends, welcome the newest chip of the block - Gene-Doping!
Science is increasingly becoming humanity’s partner and handmaiden in the effort to enhance oneself, many forms of which are becoming more feasible, sought-after, and even justifiable in the quest for healthier, happier, and longer lives. Science has just added genetic manipulation to our enhancement tool kit.
Recently, the successful development of 'gene therapy' has provided the concepts, tools and opportunity for genetic modification of functions that affect normal human traits, which have been to some success, applied to alleviate diesease conditions. Frighteningly, Gene-therapy might now be also used for non-therapeutic purposes like gene-based "enhancement" of athletic performance.
Indeed, some therapies that are being developed to help people with degenerative diseases and genetic defects live longer and more high-functioning lives might also be used to boost healthy bodies. These include treatments that regenerate muscle, increase its strength, and provides respite from ageing and
degeneration.

But Gene-thearpy is truly and factually in it's infancy, and results that have been tested in cell-lines or mouse-models are yet to be successfully and safely tested in human or at least non-human primate models (monkeys etc.), for adequate translation into humans; which as is understood would take its own time before a judgment could be pronounced.

For example, enhanced muscle function from the insulin like growth factor (IGF-1) or follistatin transgenes has already been demonstrated, and the celebrated lipid-modulator PPAR-delta has been known to enhance endurance performance in mice that overexpress the gene but studies in humans remain scarce, and there's no reason to believe that mice and humans would behave the same way!
In the age of internet, not surprisingly, these scientific studies are known in sport communities and are coming temptingly close to human doping.

A 'dw-world' news-report implicates a German athletic coach in attempting to obtain a gene-transfer vector that induces expression of the erythropoietin gene.

A Chinese genetics lab reportedly offered gene-juicings before the 2008 Olympic Games in Beijing.
Gnawing close at the doping-heels, the World Anti-Doping Agency (WADA), put gene therapy on its list of no-no's back in 2004. Even as the race to discover new competitive edges gathers momentum, so does the race to detect them. Gene overexpression would likely produce broad metabolic, genetic, and proteomic changes which could be then tagged as a signature and used as a marker. New-age, high-throughput sequencing techniques, as are currently used to scan for developmental disorders and other genetic red flags, will likely be able to catch such changes too.
Although advertisements promoting products that promise to enhance athletic performance have pervaded the internet, recently it has become home for advertisements that claim to “alter muscle genes…by activating your genetic machinery”(-here), or that state “your genetic limitations are a thing of the past!” (-here) or “Finally, every bodybuilder can be genetically gifted!” (-here).

Gene-therapy and in this case -Doping could, at least in fantastic-theory could help us conjure images of a potential horror scenario of a hybrid-athlete with the speed of a cheetah, a jump of a kangaroo and the strength of a gorilla painted by Australian scientist Robin Parisotto in his book Blood Sports, which is a funny, frightening yet enlightening history of drugs in sport.

The point of concern is that these treatments have so far only been able to produce “faster or stronger mice.” But that doesn’t mean somebody getting an Olympic medal, or scoring a goal at the World Cup Soccer, 2010, isn’t a rat.

References:

* Science, Vol 327, 5 Feb, 2010, Gene Doping and Sport, .

* J. Appl. Physiol. 96, 1097, 2004, Viral expression of insulin-like growth factor-I enhances muscle
hypertrophy in resistance-trained rats.

* Cell, 134, 405, 2008, AMPK and PPARdelta agonists are exercise mimetics.

* Sci. Transl. Med. 1, 6ra15, 2009.

http://en.wikipedia.org/wiki/Gene_doping

http://www.scientificamerican.com/blog/post.cfm?id=athlete-alert-is-genetic-juicing-se-2010-02-04
http://www.genedoping.com/docs/Gene%20Doping.pdf
http://www.exrx.net/Steroids.html

A mouse model for OCD, OCD, OCD, OCD.......

2010-05-29T06:08:00.000-07:00

What is it? -- Obsessive-compulsive disorder (OCD) is associated with repetitive functions, such as handwashing, counting and organizing things over and over again. Whereas an unaffected person might lock a door and know it is locked, a person with OCD is never sure and goes back to check over and over. OCD as a condition can interfere with normal life and those with severe OCD can’t hold down jobs. The causes of OCD and therefore the treatments remain unknown and/or very poorly tested.

By switching off a single gene in mice, Howard Hughes Medical Institute (HHMI) researchers have created rodents that behave anxiously and fixate on grooming.

The genetically altered mice, which behave much like people with obsessive-compulsive disorder, could help scientists design new therapies for this debilitating condition. A physiscain-scientist, Shahin Rafii of Weill Cornell Medical College in New York City and his colleagues Francis Lee and Sergey Shmelkov came across a gene called slitrk5, which is turned on in blood stem, leukemic, and vascular cells, they found, but it's activity is highest in the brain.

To see if they could find out more about slitrk5’s function, the researchers took the 'knockout'-approach and developed mice that completely lacked the gene. When the mice reached about three months of age, people began to notice that they seemed extremely anxious. They spent less time in open spaces or in high places and preferred corners or enclosed places more than mice typically do, and were extremely anxious and 'jumpy'.

Sore wounds and bald patches on the animals’ faces, were a sure giveaway of the animals’ intense and persistent preoccupation with self-grooming. The mice groomed themselves longer and more frequently than normal mice -- to the point that they lost fur and developed sores. The behavior recalls that of people with trichotillomania, a disease related to OCD in which people obsessively tug on their hair to the point that they pull it out.

Interestingly, Rafii and his colleagues found that treating the afflicted mice with Prozac (fluoxetine), which is a drug commonly prescribed to alleviate the symptoms of OCD in patients, ameliorated the excessive grooming.

Rafii’s team then collaborated with Lee and Adilia Hormigo of Weill Cornell, experts in molecular neuropsychiatry, on experiments that revealed patterns of activity in the animals’ brains that were strikingly similar to those in people with OCD. The orbitofrontal cortex, which sits in the front of the brain, behind the eyes, and contributes to decision-making, was unusually active in the mice. Functional imaging studies have shown that this area is hyperactive in patients with OCD, too. Notably, the earlier existing models of OCD didnt demonstrate the same kind of overactivation.

In addition, Rafii and his team found that in mice without slitrk5, a region deep in the brain called the striatum is smaller, forms less complex neural structures, and harbors fewer glutamate receptors than in normal mice. As a result, information does not appear to transmit well between the cortex and the striatum.

Predictably, Rafii now wants to know whether humans with OCD have mutations in the slitrk5 gene. His team has already begun searching for such mutations in the DNA of affected patients. If the search is successfull, we might have a proper understanding and optimistically, a possible cure of the dreaded condition.

Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice.
Nature Medicine, Volume: 16, Pages: 598–602, 2010.

some amazing Agricultural-Innovations!!

2010-05-03T10:57:00.000-07:00

While leafing through few socio-scientific reports on recent developments/innovations in the agricultural sector, I came across a strange phenomenon, which probably is a reflection of the consumerist, mall-culture times.
While the majority of the print-media dealt with glamorous events like creation of pest, diesease/stress resistant plant-transgenics or high-yeilding hybrid-technology, the recently high-beat Organic-farming, or rant about the recent promises of agri-giants like Monsanto et.al.......very few actually dealt with crux issues surrounding fast shrinking farm lands, acute labour shortage, decreasing income per acre of cultivation, and economic frustration which are just some of the key factors hurting a farmer's confidence in continuing farming.
The reports dealt even less with actual farmer-needs or the issues surrounding farmland-hardware-innovation which would be efficient, cost-effective and would save labour-effort and time for the average farmer in India who does'nt own vast tracts of land and/or the resources to attend to them.

As it turned out, I stumbled upon few reports of farmers themselves finding inexpensive and smart-cures for their woes, and splendid ones at that! Below are a few instances.....you might appreciate the sheer out-of-box thinking or just plain common-sense.....

Bicycle inspired plougher and weeder

The report is here

A tilting cart offers relief to animals and workers in the field

entire report is here

Converted Enfield performs field operations

The entire report is here:

...............................................................................................................................................

The growing concern over "Water-Footprint"

2010-04-01T00:05:00.000-07:00

Alongside the now-famous Carbon-footprint is the concern over its lesser known but equally woeful sibling "Water-Footprint".

Water-Footprint is an indicator of water use that includes both direct and indirect water usage by a consumer or producer.The water footprint of an individual, community or business is defined as the total volume of freshwater that is used to produce the goods and services consumed by the individual or community or produced by the business.

History 

The water footprint concept was introduced in 2002 by A.Y. Hoekstra from UNESCO-IHE as an alternative indicator of water use (Report as pdf)*.

The Colours of water-footprint 

A water footprint consists of three components: the blue, green and grey water footprint.

The blue water footprint is the volume of freshwater that evaporated from the global blue water resources (surface water and ground water) to produce the goods and services consumed by the individual or community.

The green water footprint is the volume of water evaporated from the global green water resources (rainwater stored in the soil as soil moisture).

The grey water footprint is the volume of polluted water that associates with the production of all goods and services for the individual or community.

The global average Water Footprint is 1240 m³ water/person/year.

It is approximated that:

900 lit produce 1kg of maize

1350 lit produce 1kg of wheat

16000 lit produce 1kg of beef etc. (available on www.waterfootprint.org)

Criticism

The parameters used for calculating water-footprint have come under scrutiny and may not be adequately argumentative. For example the 140 litres required for production of one cup of coffee might be of no harm to water resources as its cultivation occurs mainly in humid areas. Nevertheless, the figures suggest the sum of water quantities as an environmental concern, which may not be supported by research.

Further Reading/Information

http://en.wikipedia.org/wiki/Water_footprint

http://www.waterfootprint.org

* Hoekstra, A.Y. (2003) (ed) Virtual water trade: Proceedings of the International Expert Meeting on Virtual Water Trade, IHE Delft, the Netherlands

princetonwaterwatch.wordpress.com

Secret of Sperm-motility revealed!!

2010-02-04T13:02:00.000-08:00

image of sperm (from "google-images" )

The "Sperm" happens to be the ONLY naturally motile cell of the body. But, the exact mechanism of it's movement has always remained a mystery.

Yuriy Kirichok and his team from UCSD have identified the mechanism that triggers sperm's race to the egg, reports a study in Cell.

Rationale and hypothesis:

Not many people think about electricity when they talk about sperm cells and this is the first time someone actually recorded the cellular process in a human sperm. By measuring the electrical current passing through the sperm cell membrane, the researchers identified a channel that releases a flood of protons from a sperm cell, initiating its trip up the fallopian tubes and on to the egg.

While inside the testes, sperm remain immobile. But upon ejaculation, when sperm enter the vagina, their intracellular pH rises, prompting their initial movement from the vagina to the fallopian tubes.

Observations:

At rest, sperm cells are full of protons (acidified environment). Upon activation, the proton channel [voltage-sensor-only (Hv1) channel], pokes a hole in the sperm plasma membrane and the protons that have accumulated blow out (alkalinazation) and the sperm becomes activated.

Hv1 is confined to the principal piece of the sperm flagellum, where it is expressed at unusually high density. Robust flagellar Hv1-dependent proton conductance is activated by:
* membrane depolarization,
* an alkaline extracellular environment,
* endocannabinoid anandamide, naturally present in male and female reproductive tracts,
* and removal of extracellular zinc, a potent Hv1 blocker.

Methodology:

* used human sperm-cells.
* These guys have used the newly-improved, age-old technique of Patch-Clamp, to measure minute electrophysiological changes happening on the sperm-membrane during the different phases of it's motility.

Potential uses:

possibilities for male contraception and enhancing male fertility, which of course, as of now, seems to be a far cry. Even if it were feasible to develop a compound to block the Hv1 channel, the resulting contraceptive would likely be a unisex or female based contraception, not a male one since the entire physiological changes are driven by the female tract.

Snippet: Marijuana smokers may have fertility problems, Kirichok said, because the drug hyper-activates the
channel and burns out the sperm prematurely.

*************************************************************

Acid Extrusion from Human Spermatozoa Is Mediated by Flagellar Voltage-Gated Proton Channel

Polina V. Lishko, Inna L. Botchkina, Andriy Fedorenko, and Yuriy Kirichok.

Cell 140, 327–337, February 5, 2010.

how to keep Ovaries Female? Ask "FOXL2".

2009-12-15T01:06:00.000-08:00

The eternal oppositesYin & Yang

The celebrated Male-ness transcription factor SRY, encoded by the Y-chromosome is needed for the differentiation of the indifferent gonads into Testis.

In this study, Mathias Trier, from EMBL demonstrates that in the mouse, a single factor, the forkhead transcriptional regulator, FOXL2, is required to prevent transdifferentiation of an ovary to a testis in the adult animal.

In one of their earlier studies in 2004, when they knocked out the gene in mice, females began to form ovaries, but later in development, the ovaries degenerated.

In the The current study the investigators let the mice develop ovaries normally, and then knocked down the gene once the animals reached adulthood.

Rationale behind the attempt:

1. Foxl2 is known to behave differently during development and adulthood. It regulates other genes important to organ differentiation.

2. During development, another gene, Wnt4, is expressed which is thought to be the major signal that suppresses the male program of development. After the female gonads develop, Wnt4 shuts off.

Contrarily, Foxl2's expression throughout the life of a female suggests that it is continually needed in female

physiology.

Critical Observations:

Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific

genes including the critical SRY target gene Sox9.

Granulosa and Theca cells got reprogrammed into Sertoli- and Leydig- cell lineages

Testosterone levels were comparable to those of normal XY male littermates.

Change from ovarian cells to testicular cells didn't affect the outward physical appearance of the mice, i.e. the secondary sexual characters didnt undergo a change.

The overarching take-home-message from the work is that a fully differentiated adult organ has the potential - under conducive circumstances - to undergo radical remodeling, and undergo trans-differentiation.

And, FOXL2 and SOX9, which are gatekeepers of male- and female-ness oppose each other’s action

to ensure together the establishment and maintenance of the different female and male supporting cell types respectively.

But really, how do efficient epigenetic-changes happen in the cell in a span less than 48 hours, is a question not answered in this study.

Some questions which remain:

* Would the same phenomenon be possible in the Male as well? That is, the testis changing into an ovary.

* Female being the pre-differentiation default-sex , it is surprising that one' would need a factor to maintain "female-ness" throughout life?

* Moreover does SRY or its target genes, maintain "male-ness" in the adult male?

* And what is the role of FOXL2 in the Male?

* To change the epigenetics, phenotype, function and overall the total "identity" of a cell to another, by just 1 factor is a bit of a concern.
The most pertinent question, therefore perhaps is the following: Why did mother-nature evolve such a "dangerous" strategy, whereby tinkering with just 1 gene, changes everything? To put it this way, what is the relevance of having a "master-player" and make a system increasingly vulnerable?

References:

Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation.

Cell 139, 1130–1142, December 11, 2009

N. Henriette Uhlenhaut, Susanne Jakob, Katrin Anlag, Tobias Eisenberger, Ryohei Sekido, Jana Kress, Anna-Corina Treier, Claudia Klugmann, Christian Klasen, Nadine I. Holter, Dieter Riethmacher, Gu¨ nther Schu¨ tz, Austin J. Cooney, Robin Lovell-Badge, and Mathias Treier1

http://www.the-scientist.com/blog/display/56212/

The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance.
Development, 131, 933-942 (2004)
Dirk Schmidt, Catherine E. Ovitt, Katrin Anlag, Sandra Fehsenfeld, Lars Gredsted, Anna-Corina Treier and Mathias Treier.

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Salute the SPERM

2009-11-27T12:50:00.000-08:00

a group of sperms with a distinct Head and Tail

How are we made? How do we end up having millions of cells when we have only started with 2 of them (actually 1, after they have fused)?

Imagine this: we are totally non-existent until one among the father's millions-of sperms would have located and fused with the mother's egg (oocyte as it is called). Imagine also that the sperm and the egg are totally powerless to make us, all alone by themselves - i.e to make us, it's inevitable that they beat all odds and meet each other!

And what's even more incredible is that once they have met successfully, the destiny is sealed- they must forgo their individual entities and must now function as a whole, a new entity, which is both similar and different to each other. In other words, they must die as individuals, to make us!

The sperm is the only motile cell of the body. The only cell, which can, by virtue of its huge reserves of energy and a peculiar structure (it has a 'head' and a huge tail stcuk to its behind), undergoes a swift biochemical change (Capacitation, which I'll explain later), beats its tail frantically to generate a forward propulsive force and moves extremely rapidly in order to meet its paramour, the oocyte. The sperm, has a haploid (x) number of chromosomes (so does the oocyte), in order to give rise to a normal (2x) number upon fusion.

During Spermatogenesis, the spermatogonia (2x) undergo meiosis to form mature spermatids (x), which in the female tract, undergo this fantastic biochemical-switch called Capacitiation (which is actually a cumulative term for 2 separate events - Hyperactivation and Acrosome reaction) and is characterised with a distinct, almost-violent, whiplash movement of the tail (resembling the letter '8').

Interestingly, a huge-Calcium ion influx into the sperm, aided by the sudden high-fluidity of the it's cell-membrane is necessary and sufficient to bringing about capacitation. It has been shown experiments with Ca-channel blockers, ionophores etc, that sperm-capacitation could be blocked.

It is also evidenced by various groups, that the Capacitation-event is a result of distinct tyrosine-residue phosphorylation of several important proteins (as it turns out ser-thr phosp. play a relatively-smaller role in it). Obviously, protein kinases, mainly of the EGF-R family and also RTK and TK's of the NR type are the major culprits for bringing our this phenomenon! Inhibition of tyr. residue phosphorylation-events by suitable inhibitors have shown the dependancy of the event on crucial catalytic-activity of the kinases. Interestingly, only some Phosphatases have been shown to play a critical role in the event. As it turns out, the sperm has a super-compact DNA (Histones are replaced by Protamines, which are more basic-proteins and therefore package the DNA even more tightly). Hence, only proteomic and not genomic actions, decide the fate of this motile-cell!!