The third eye

The pineal gland held fascination since Descartes’ nefarious claim that it is the seat of the soul. There is no evidence of that; he said it might be where the soul resides because he thought the pineal gland was the only solitaire structure in the brain so it must be special. By ‘solitaire’ I mean that all other brain structures come in doublets: 2 amygdalae, 2 hippocampi, 2 thalami, 2 hemispheres etc. He was wrong about that as well, in that there are some other singletons in the brain besides the pineal, like the anterior or posterior commissure, the cerebellar vermis, some deep brainstem and medullary structures etc.

Descartes’ dualism was the only escape route the mystics at the time had from of the demanding of evidence by the budding natural philosophers later known as scientists. So when some scientists noted that some lizards have a third eye on top of their head, the mystics and, later, the conspiracy theorists went nuts. Here, see, if the soul seat is linked with the third eye, the awakening of this eye in people would surely result in heightened awareness, closeness to the Divinity, oneness with Universe and other similar rubbish that can be otherwise easily and reliably achieved by a good dollop of magic mushrooms. Cheaper, too.

Back to the lizards. Yes, you read right: some lizards and frogs have a third eye. This eye is not exactly like the other two, but it has cells sensitive to light, even if they are not perceiving light in the same way the retinal cells from the lateral eyes are. It is located on the top of the skull, so sometimes is called the parietal organ (because it’s in-between the parietal skull bones, see pic).

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Dorsal view of the head of the adult Carolina anole (Anolis carolinensis) clearly showing the parietal eye (small gray/clear oval) at the top of its head. Photo by TheAlphaWolf. Courtesy of Wikipedia. License: CC BY-SA 3.0

It is believed to be a vestigial organ, meaning that primitive vertebrates might have had it as a matter of course but it disappeared in the more recently evolved animals. Importantly, birds and mammals don’t have it. Not at all, not a bit, not atrophied, not able to be “awakened” no matter what your favorite “lemme see your chakras” guru says. Go on, touch your top of the skull and see if you have some peeking soft tissue there. And no, the soft tissue that babies are born with right there on the top of the skull is not a third eye; it’s a fontanelle that allows for the rapid expansion of the brain during the first year of life.

The parietal organ’s anatomical connection to the pineal gland is not surprising at all for scientists because the pineal’s role in every single animal that has it is the regulation of some circadian rhythms by the production of melatonin. In humans, the eyes send the information to the pineal that is day or night and the pineal adjusts the melatonin production accordingly, i.e. less melatonin produced during the day and more during the night. The lizards’ third eye’s main role is to provide information to the pineal about the ambient light for thermoregulatory purposes.

After this long introduction, here is the point: almost twenty years ago Xiong et al. (1998) looked at how this third eye perceives light. In the human eye, light hitting the rods and cones in the retina (reception) launches a biochemical cascade (transduction) that results in seeing (coding of the stimulus in the brain). Briefly, transduction goes thusly: the photon(s) causes a special protein sensitive to light (e.g. rhodopsin) in the photoreceptor cells in the retina to split into its components (photobleaching), one of these components changes its conformation, then activates a G-protein (transducin), which then activates the enzyme phosphodiesterase (PDE), which then destroys a nucleotide called cyclic guanosine monophosphate (cGMP), which results in the closing of the cell’s ion channels, which leads to less neurotransmitter GABA released, which causes the nearby cells (bipolar cells) to release another neurotransmitter (glutamate), which increases the firing rate of another set of cells (ganglion cells) and from there to the brain we go. Phew, visual transduction IS difficult. And this is the brief version.

It turns out that the third eye retina doesn’t have all the types of cells that the normal eyes have. Specifically, it misses the bipolar, horizontal and amacrine cells, having only ganglion and photoreception cells. So how goes the phototransduction in the third eye’s retina, if at all?

Xiong et al. (1998) isolated photoreceptor cells from the third eyes of the lizard Uta stansburiana. And then they did a bunch of electrophysiological recording on those cells under different illumination and chemical conditions.

They found that the phototransduction in the third eye is different from the lateral eyes in that when they expected to see hyperpolarization of the cell, they observed depolarization instead. Also, when they expected the PDE to break down cGMP they found that PDE is inhibited thereby increasing the amount of cGMP  The fact that G-protein can inhibit PDE was totally unexpected and showed a novel way of cellular signaling. Moreover, they speculate that their results can make sense only if not one, but two G-proteins with opposite actions work in tandem.

A probably dumb technical question though: the human rhodopsin takes about 30 minutes to restore itself from photobleaching. Xiong et al. (1998) let the cells adapt to dark for 10 minutes before recordings. So I wonder if the results would have been slightly different if they allowed the cell more time to adapt? But I’m not an expert in retina science, you’ve seen how difficult it is, right? Maybe the lizard proteins are different or rhodopsin adaptation time has little or nothing to do with their experiments? After all, later research has shown that the third eye has its own unique opsins, like the green-sensitive parietopsin discovered by Su et al. (2006).

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REFERENCE:  Xiong WH, Solessio EC, & Yau KW (Sep 1998). An unusual cGMP pathway underlying depolarizing light response of the vertebrate parietal-eye photoreceptor. Nature Neuroscience, 1(5): 359-365. PMID: 10196524, DOI: 10.1038/1570. ARTICLE

Tags: whole-cell electrophysiological recordings, perforated-patch electrophysiological recording, phototransduction, rhodopsin, photoreceptor, retina, G-protein, phosphodiesterase (PDE), cyclic guanosine monophosphate (cGMP), adenylyl cyclase,  3-isobutyl-1-methyl-xanthine (IBMX), parietal eye, third eye, lizard, opsin, G-protein, Uta stansburiana

By Neuronicus, 30 March 2017

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The FIRSTS: Melatonin (1958)

By the late 18th and beginning of 19th century, some scientists were busily investigating how animals get their colors and how do they change colour in response to the environment. They identified several types of chromatophores, i.e. cells that contain pigments. Biological pigments are called melanins (don’t confuse them with melatonin). One of these cells is the melanophore which contains black pigments, called this way in the very typical scientist unimaginative style because “melas” in Greek means black or dark and “phoros” means carrier.

A couple of these scientists, McCord & Allen (1917), thought that the pineal gland from the brain might contain some substance that might interact with the melanophores. How did they get this idea is unclear from their paper; seems like a logical outcome of their contemporaries’ discussions and experiments, though they do not explain it in detail. They hint of other experiments where various glands have been fed to amphibians and then noticed their color change. So McCord & Allen obtained cow brains, extracted the pineal glands and fed them to tadpoles. Within 30 to 60 minutes, depending on the concentration, the tadpoles fed with pineal extract changed color from dark to light (see picture).

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Excerpt from McCord & Allen (1917, doi: 10.1002/jez.1400230108) showing the change in tadpole skin appearance after application of bovine pineal gland extract.

Fast forward now to 1958 when an MD PhD called Aaron B. Lerner with an interest in dermatology thought that whatever was responsible for the skin color changes in the McCord & Allen (1917) paper might be useful in treating skin diseases. But first he had to extract the substance from the pineal glands and he and his colleagues had better tools for this task than the mere alcohol and acetone of his brethren of 40 years ago.

Lerner et al. (1958) made full use of the then-recently discovered paper chromatography and some standard biochemistry techniques for the time like Soxhlet extraction and fluorescence spectroscopy and discovered a substance that can lighten frog skin color and can inhibit the melanocyte stimulating hormone (MSH). “It is suggested that this substance be called melatonin” (p. 2587). Lerner and his colleagues also isolated the MSH and cryoglobulin.

Changing skin color is one of melatonin’s minor roles; its main function is to regulate circadian rhythms like sleep and awake cycles in animals (it has an oxidative stress protection in plants). Melatonin, in animals, is produced by the pineal gland only, more during the night, less during the day. Pineal gets information about the day/night cycles from the eyes. In some countries melatonin is sold as an over the counter soporific, i.e. sleeping pill.

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REFERENCES:

1) McCord CP & Allen FP (Jan 1917). Evidences associating pineal gland function with alterations in pigmentation. Journal of Experimental Zoology, Part A, 23 (1):  207–224, DOI: 10.1002/jez.1400230108 ARTICLE 

2) Lerner AB, Case JD, Takahashi Y, Lee TH, & Mori W (May 1958). Isolation of Melatonin, the Pineal Gland Factor that Lightens Melanocytes. Journal of the American Chemical Society, 80 (10), p. 2587–2587, DOI: 10.1021/ja01543a060 ARTICLE (although JACS gives access only to the first page of a paper, the fact that this article is only half a page makes their endeavour useless in this case)

By Neuronicus, 18 March 2017

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Vanity and passion fruit

Ultraviolet irradiation exposure from our sun accelerates the skin aging, process called photoaging. It can even cause skin cancers. There has been some considerable research on how our beloved sun does that.

For example, one way the UV radiation leads to skin damage is by promoting the production of free radicals as reactive oxygen species (ROS), which do many bad things, like direct DNA damage. Another bad thing done by ROS is the upregulation of the mitogen-activated protein kinase (MAPK) signaling pathway which activates all sorts of transcription factors which, in turn, produce proteins that lead to collagen degradation and voilà, aged skin. I know I lost some of you at the MAPK point; you can think of MAPK as a massive proteinaceous hub, a multi-button console with many inputs and outputs. A very sensitive and incredibly complex hub that controls nearly all important aspects of cell function, with many feedback loops, so if you mess with it, cell Armageddon may be happening. Or nothing at all. It’s that complex.

But I digress. What MAPK is doing is less relevant for the paper I am introducing to you today than the fact that we have physiological markers for skin aging due to UV. Bravo et al. (2017) cultured human skin cells in a Petri dish, treated them with various concentrations of an extract of passion fruit (Passiflora tarminiana) and then bombarded them with UV (the B type, 280–315 nm). The authors made the extract themselves, is not something you just buy (yet).

The UV produced the expected damage, translated as increased matrix mettoproteinase-1 (MMP-1), collagenase, and ROS production and decreased procollagen. Pretreatment with passion fruit extract significantly mitigated these UV effects in a dose-dependant manner. The concentration of their concoction that worked best was 10 μg/mL. Then the authors did some more chemistry to figure out what in their concoction is responsible, or at least probably responsible, for the observed wonderful effects. The authors believe the procyianidins and flavonoids are the culprits because 1) they have been proven to be strong antioxidants before and 2) this plant has them in very high amounts.

Good news then for the antiaging cosmetics industry. Perhaps even for dermatologists and their patients.

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Reference: Bravo K, Duque L, Ferreres F, Moreno DA, & Osorio E. (EPUB ahead of print: 3 Feb 2017). Passiflora tarminiana fruits reduce UVB-induced photoaging in human skin fibroblasts. Journal of Photochemistry and Photobiology, 168: 78-88. PMID: 28189068, DOI: 10.1016/j.jphotobiol.2017.01.023. ARTICLE

By Neuronicus, 13 February 2017

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The FIRSTS: The Name of Myelin (1854)

One reason why I don’t post more often is that I have such a hard time deciding what to cover (Hint: send me stuff YOU find awesome). Most of the cool and new stuff is already covered by big platforms with full-time employees and I try to stay away of the media-grabbers. Mostly. Some papers I find so cool that it doesn’t matter that professional science journalists have already covered them and I too jump on the wagon with my meager contribution. Anyway, here is a glimpse on how my train of thought goes on inspiration-less days.

Inner monologue: Check the usual journals’ current issues. Nothing catches my eye. Maybe I’ll feature a historical. Open Wikipedia front page and see what happened today throughout history. Aha, apparently Babinski died in 1932. He’s the one who described the Babinski’s sign. Normally, when the sole of the foot is stroked, the big toe flexes inwards, towards the sole. If it extends upwards, then that’s a sure sign of neurological damage, the Babinski’s sign. But healthy infants can have that sign too not because they have neurological damage, but because their corticospinal neurons are not fully myelinated. Myelin, who discovered that? Probably Schwann. Quick search on PubMed. Too many. Restrict to ‘history”. I hate the search function on PubMed, it brings either to many or no hits, no matter the parameters. Ah, look, Virchow. Interesting. Aha. Find the original reference. Aha. Springer charges 40 bucks for a paper published in 1854?! The hell with that! I’m not even going to check if I have institutional access. Get the pdf from other sources. It’s in German. Bummer. Go to Highwire. Find recent history of myelin. Mielinization? Myelination? Myelinification? All have hits… Get “Fundamental Neuroscience” off of the shelf and check… aha, myelination. Ok. Look at the pretty diagram with the saltatory conduction! Enough! Go back to Virchow. Does it have pictures, maybe I can navigate the legend? Nope. Check if any German speaking friends are online. Nope, they’re probably asleep, which is what I should be doing. Drat. Refine Highwire search. Evrika! “Hystory of Myelin” by Boullerne, 2016. Got the author manuscript. Hurray. Read. Write.

Myelinated fibers, a.k.a. white matter has been observed and described by various anatomists, as early as the 16th century, Boullerne (2016) informs us. But the name of myelin was given only in 1854 by Rudolph Virchow, a physician with a rich academic and public life. Although Virchow introduced the term to distinguish between bone marrow and the medullary substance, paradoxically, he managed to muddy waters even more because he did not restrict the usage of the term mylein to … well, myelin. He used it also to refer to substances in blood cells and egg’s yolk and spleen and, frankly, from the quotes provided in the paper, I cannot make heads or tails of what Virchow thought myelin was. The word myelin comes form the Greek myelos or muelos, which means marrow.

Boullerne (2016) obviously did a lot of research, as the 53-page account is full of quotes from original references. Being such a scholar on the history of myelin I have no choice but to believe her when she says: “In 1868, the neurologist Jean-Martin Charcot (1825-1893) used myelin (myéline) in what can be considered its first correct attribution.”

So even if Virchow coined the term, he was using it incorrectly! Nevertheless, in 1858 he correctly identified the main role of myelin: electrical insulation of the axon. Genial insight for the time.

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I love historical reviews of sciency stuff. This one is a ‘must-have’ for any biologist or neuroscientist. Chemists and physicists, too, don’t shy away; the paper has something for you too, like myelin’s biochemistry or its birefringence properties.

Reference: Boullerne, AI (Sep 2016, Epub 8 Jun 2016). The history of myelin. Experimental Neurology, 283(Pt B): 431-45. doi: 10.1016/j.expneurol.2016.06.005. ARTICLE

Original Reference: Virchow R. (Dec 1854). Ueber das ausgebreitete Vorkommen einer dem Nervenmark analogen Substanz in den thierischen Geweben. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, 6(4): 562–572. doi:10.1007/BF02116709. ARTICLE

P.S. I don’t think is right that Springer can retain the copyright for the Virchow paper and charge $39.95 for it. I don’t think they have the copyright for it anyway, despite their claims, because the paper is 162 years old. I am aware of no German or American copyright law that extends for so long. So, if you need it for academic purposes, write to me and thou shall have it.

By Neuronicus, 29 October 2016

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The FIRSTS: The rise and fall of Pokemon (2001-2005?)

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Few people know that Pokemon refers not only to a game, but also to a gene. An oncogene, to be precise, with a rather strange story.

An oncogene is a gene that promotes cancer (from oncology). Conventionally, a gene name is written in lowercase italicized letters (pokemon), whereas the protein the gene makes is not italicized (POKEMON, Pokemon, or pokemon, depending on the species). Maeda et al. (2005) first established in a Petri dish that the Pokemon is required for the growth of malignant tumors. Then, through a series of classic molecular biology experiments, the scientists found out how exactly Pokemon acts to accomplish this (by suppressing the expression of anti-cancer genes). Next, they engineered mice with pokemon overexpressed and saw that the mice with a lot of Pokemon “developed aggressive tumours” (p. 282). Then the authors checked how is this gene behaving in human cancers and found out that “Pokemon is expressed at very high levels in a subset of human lymphomas” (p. 284).

And here is how the gene got its name, according to Pier Paolo Pandolfi, the leader of the research group. Bear with me because it’s complicated. [*Takes deep breath*]: PO in POK stands for POZ domain (poxvirus and zinc finger) and K in POK stands for Krüppel (zinc finger transcription factor) whereas EMON stands for erythroid myeloid ontogenic factor. POK-EMON. Simple, eh? Phew…

Truth be told, Pandolfi first named the gene pokemon at a conference in 2001 (Simonite, 2005). Then the name has been used by researchers at various scientific meetings and poster presentations.

But when the Maeda et al. paper was published in Nature in 2005 which discovered the mechanism through which the gene promotes cancer, a lot of people, scientists and journalists alike, in an attempt at humour, flooded the internet with eye-catching titles along the lines of “Pokemon causes cancer”, “Pokemon kills you” and the like. I mean, even the researchers themselves in the abstract of the paper state: “Pokemon is aberrantly overexpressed in human cancers”. In response, The Pokémon Company threatened to sue for trademark copyright infringement because they didn’t want the game to be associated with cancer, like the gene is, even if the researches said the name is an acronym (maybe they meant backronym?). In the end, the researchers changed the name of the pokemon gene to the far less enticing zbtb7.

As the question mark in the title of the post suggests, the pokeman gene may not be entirely dead yet because there are stubborn scientists that still use the name pokemon and not zbtb7. I hope they have the cash to take on Nintendo if they decide to sue after all.

Too bad the zbtb7 (a.k.a. pokemon) gene was not a beneficial gene… Because another group of researchers named their new-found gene in 2008 pikachurin and so far, Nintendo din not make any waves… That is, probably, because Pikachurin is a protein in the eye retina that is required for proper vision by speeding the electric signals. Zip zip zip Pikachurin goes…

References:

  1. Maeda T, Hobbs RM, Merghoub T, Guernah I, Zelent A, Cordon-Cardo C, Teruya-Feldstein J, & Pandolfi PP (20 Jan 2005). Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature, 433(7023):278-85. PMID: 15662416, DOI: 10.1038/nature03203. ARTICLE | FULLTEXT PDF at Univ. Barcelona
  2. Simonite T (15 Dec 2005). Pokémon blocks gene name. Nature, 438(7070):897. PMID: 16355177, DOI: 10.1038/438897a. ARTICLE 

By Neuronicus, 18 July 2016

Eating high-fat dairy may lower your risk of being overweight

84 - CopyMany people buy low-fat dairy, like 2% milk, in the hopes that ingesting less fat means that they will be less fattier.

Contrary to this popular belief, a new study found that consumption of high-fat dairy lowers the risk of weight gain by 8% in middle-aged and elderly women.

Rautiainen et al. (2016) studied 18 438 women over 45 years old who did not have cancer, diabetes or cardiovascular diseases. They collected data on the women’s weight, eating habits, smoking, alcohol use, physical activity, medical history, hormone use, and vitamin intake for  8 to 17 years. “Total dairy product intake was calculated by summing intake of low-fat dairy products (skim and low-fat milk, sherbet, yogurt, and cottage and ricotta cheeses) and high-fat dairy products (whole milk, cream, sour cream, ice cream, cream cheese, other cheese, and butter)” (p. 980).

At the beginning of the study, all women included in the analyses were normal weight.

Over the course of the study, all women gained some weight, probably as a result of normal aging.

Women who ate more dairy gained less weight than women who didn’t. This finding is due to the high-fat dairy intake; in other words, women who ate high-fat dairy gained less weight compared to the women who consumed low-fat dairy. Skimmed milk seemed to be the worst for weight gain compared to low-fat yogurt.

I did not notice any speculation as to why this may be the case, so I’ll offer one: maybe the people who eat high-fat dairy get more calories from the same amount of food so maybe they eat less overall.

Reference: Rautiainen S, Wang L, Lee IM, Manson JE, Buring JE, & Sesso HD (Apr 2016, Epub 24 Feb 2016). Dairy consumption in association with weight change and risk of becoming overweight or obese in middle-aged and older women: a prospective cohort study. The American Journal of Clinical Nutrition, 103(4): 979-988. doi: 10.3945/ajcn.115.118406. Article | FREE FULLTEXT PDF | SuppData

By Neuronicus, 7 April 2016

Pic of the day: The most prevalent infection

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Reference: Flegr J, Prandota J, Sovickova M, Israili ZH (2014). Toxoplasmosis – A Global Threat. Correlation of Latent Toxoplasmosis with Specific Disease Burden in a Set of 88 Countries. PLoS ONE, 9(3): e90203. doi:10.1371/journal.pone.0090203. Article | FREE fulltext PDF

By Neuronicus, 22 March 2016

Now, isn’t that sweet?

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When I opened one of my social media pages today, I saw a message from a friend of mine which was urging people to not believe everything they read, particularly when it comes to issues like safety and health. Instead, one should go directly at the original research articles on a particular issue. In case the reader is not familiar with the scientific jargon, the message was accompanied by one of the many very useful links to blogs that teach a non-scientist how to cleverly read a scientific paper without any specific science training.

Needless to say, I had to spread the message, as I believe in it wholeheartedly. All good and well, but what happens when you encounter two research papers with drastically opposite views on the same topic? What do you do then? Who do you believe?

So I thought pertinent to tell you my short experience with one of these issues and see if we can find a way out of this conundrum. A few days ago, the British Chancellor of the Exchequer (the rough equivalent of a Secretary of the Treasury or Minister of Finance in other countries) announced the introduction of a new tax on sugary drinks: the more sugar a company puts in its drinks, the more taxes it would pay. In his speech announcing the law, Mr. George Osborne was saying that the reason for this law is that there is a positive association between sugar consumption and obesity, meaning the more sugar you eat, the fatter you get. Naturally, he did not cite any studies (he would be a really odd politician if he did so).

Therefore, I started looking for these studies. As a scientist, but not a specialist in nutrition, the first thing I did was searching for reviews on the association between sugar consumption and obesity on peer-reviewed databases (like the Nature journals, the US NIH Library of Medicine, and the Stanford Search Engine). My next step would have been skimming a handful of reviews and then look at their references and select some dozens or so of research papers and read those. But I didn’t get that far and here is why.

At first glance (that is, skimming about a hundred abstracts or so), it seems there are overwhelmingly more papers out there that say there is a positive correlation between sugar intake and obesity in both children and adults. But, when looking at reviews, there are plenty of reviews on both sides of the issue! Usually, the reviews tend to reflect the compounded data, that’s what they are for and that’s why is a good idea to start with a review on a subject, if one knows nothing about it. So this dissociation between research data and reviews seemed suspicious. Among the reviews in question, the ones that seemed more systematic than others are this one and this one, with obvious opposite conclusions.

And then, instead of going for the original research and leave the reviews alone, I did something I am trying like hell not to do: I looked the authors and their affiliations up. Those who follow my blog might have noticed that very rarely do I mention where the research has taken place and, except in the Reference section, I almost never mention the name of the journal where the research was published in the main body of the text. And I do this quite intentionally as I am trying – and urge the readers to do the same thing – to not judge the book by the cover. That is, not forming a priori expectations based on the fame/prestige (or lack thereof) of the institution or journal in which the research was conducted and published, respectively. Judge the work by its value, not by its authors; and this paid off many times during my career, as I have seen crappy-crappity-crap papers published in Nature or Science, bloopers of cosmic proportions coming from NASA (see arsenic-DNA incorporation), or really big names screwing up big time. On the other hand, I have seen some quite interesting work, admittedly rare, done in Thailand, Morocco or other countries not known for their expensive research facilities.

But even in research the old dictum “follow the money” is, unfortunately, valid. Because a quick search showed that most of the nay-sayers (i.e. sugar does not cause weight gain) were 1) from USA and 2) had been funded by the food and beverage industry. Luckily for everybody, enter the scene: Canada. Leave it for the Canadians to set things straight. In other words, a true rara avis poked its head amidst this controversy: a meta-review. Lo and behold – a review of reviews! Massougbodji et al. (2014) found all sorts of things, from the lack of consensus on the strength of the evidence on causality to the quality of these reviews. But the one finding that was interesting to me was:

“reviews funded by the industry were less likely to conclude that there was a strong association between sugar-sweetened beverages consumption and obesity/weight gain” (p. 1103).

In conclusion, I would add a morsel of advice to my friend’s message: in addition to looking up the original research on a topic, also look where the money funding that research is coming from. Money with no strings attached usually comes only from governments. Usually is the word, there may be exceptions, I am sure I am not well-versed in the behind-the-scenes money politics. But if you see Marlboro paying for “research” that says smoking is not causing lung cancer or the American Beverage Association funding studies to establish daily intake limits for high-fructose corn syrup, for sure you should cock an eyebrow before reading further.

Reference: Massougbodji J, Le Bodo Y, Fratu R, & De Wals P (2014). Reviews examining sugar-sweetened beverages and body weight: correlates of their quality and conclusions. The American Journal of Clinical Nutrition, 99:1096–1104. doi: 10.3945/ajcn.113.063776. Article | FREE PDF

By Neuronicus, 20 March 2016

Inhaling a bitter tasting solution may help with asthma (don’t try this at home, yet)

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Asthma is an inflammatory disease of the lungs’ airways. The airway smooth muscle (ASM) expresses a large number of G protein-coupled receptors (GPCRs). The GPCRs are proteins bound to the cell membrane that sense what happens outside the cell and thus signal the cell to engage in appropriate responses. There are many, many types of GPCRs (in the upper hundreds) all over the body. Furthermore, alternative splicing (that is reshuffling parts of the gene that codes for a protein in such a way that you can get several different proteins from the same gene) may produce new types.

In an a effort to characterize the GPCRs in the ASM in the hope of finding an asthma pharmacological target, Einstein et al. (2008) found many more types of these receptors than previously thought, produced mainly by alternative splicing. In a subsequent study, the same group found out that some of these GPCRs are the same GPCRs that are expressed by your tongue in order to taste bitterness (Desphande et al., 2010)! The researchers were not expecting this.

Moreover, the bitter receptors (called TAS2Rs) in the lungs are fully functional, that is they respond to bitter substances like quinine. The response is, surprisingly, that of relaxation of the airways. It’s surprising because the role of bitter receptors in the tongue is to signal avoidance of bitter foods, because they usually contain toxins. So Desphande et al. (2010) (and anyone else in their shoes) would have expected a similar role for the bitter receptors in the lungs: that is, upon smelling something bitter the airways would close to prevent further poisoning. The data proved this expectation to be wrong.

The work so far has been done in isolated human cells. If quinine relaxes the ASM in an Petri dish, would it do so also when the ASM is still attached to its owner? So the researchers gave some bitter inhalants to some mice who had asthma and this treatment DECREASED the airway obstruction in a dose-dependent manner.

Asthma hits 300 million people worldwide and more than a quarter million die of it per year. So this research sparks great hopes for a new treatment direction.

References:

  1. Einstein R, Jordan H, Zhou W, Brenner M, Moses EG, & Liggett SB (1 Apr 2008, Epub 24 Mar 2008). Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors. Proceedings of the National Academy of Sciences of the United States of America, 105(13):5230-5. doi: 10.1073/pnas.0801319105. Article | FREE PDF
  1. Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS, & Liggett SB. (Nov 2010, Epub 24 Oct 2010). Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nature Medicine, 16(11):1299-304. doi: 10.1038/nm.2237. Article | FREE PDF 

By Neuronicus, 10 March 2016