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stuffxthree-blog · 11 years ago

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Getting High On Life

Biology concepts – bacteria, climate, respiratory, birds, arthropods, astrobiology, clouds

Carl Sagan wasn’t just the host of the original Cosmoson TV.

He solved the riddles of Venus’ high temperature, the seasons

on Mars, and the color of Titan. He also wrote one of my

favorite speculative fiction novels, Contact. The movie is

good; the book is better.

The astrophysicist Carl Sagan said, “There are naive questions, tedious questions, ill-phrased questions, questions put after inadequate self-criticism. But every question is a cry to understand the world. There is no such thing as a dumb question.” A cry to understand the world – so keep asking the questions, even if they seem silly.

Today’s question might seem a little naive – Is there any life that could escape Earth?But I assure you, there’s more to it than you might think – and no, the answer isn’t an astronaut. Let’s put it another way - is there any living organism that could get high enough on its own to leave our atmosphere?

Well, I guess the first prerequisite for escaping our atmosphere would be an organism that could get really, really high. Some birds can fly at absurd altitudes.

The Ruppell’s Griffon Vulture (Gyps rueppellii) has the highest recorded flight. On November 29, 1975, a Ruppell’s vulture was sucked into the jet engine of a plane flying at 39,700 ft (12.1 km, Mt. Everest is 9.0 km) over the Ivory Coast in Africa. A unfortunate flight plan for the bird, but amazingly the plane landed safely after ingesting a bird with a 10-foot wingspan.

These two pictures are not at the same scale. The Ruppell’s

vulture on the left has a wing span of about 10 ft (3 m),

while the bar headed goose on the right (see the bars?) has

a span of about half that. They should not box one another,

it’s be a slaughter. But still, these are both much bigger than

most birds. Is their longer wing span part of their success at

high altitudes? Songbirds rarely fly above 2000 feet.

We don’t know how often the vultures venture that high, but the bar headed goose (Anser indicus) makes a habit of flying over Mt. Everest. This is a migratory bird that flies over the Himalayas twice a year, sustaining 8-hr flights at more than 28,000-29,000+ feet (8.8 km).

The real question is why birds would fly so high. As you ascend, the air becomes thinner; fewer molecules make the atmosphere less dense. Since bird flight is basically supported by the air, thinner air makes flying much more difficult.

Difficult flying means that more energy is required. Birds live right on the edge of oxygen debt all the time; flying is tough at any altitude. But high in the air, it becomes even harder and requires more energy. And what’s needed to make energy in the form of ATP – oxygen (see this post) – the very thing there is less of at high altitude.

The bar headed goose and his compatriot avians breaks some rules in order to become a high flier. Birds in general are better at oxygenating their muscles, because they can exchange oxygen for carbon dioxide on both their inhalation and their exhalation (this will be the focus of s series soon). But that isn’t all.

Birds can also pant better than mammals. Panting is way to get more oxygen to the muscles, but it comes at a cost - it brings blood vessel constriction in the brain (an attempt to prevent oxidative damage). This makes for poor control, focus and decision making. But birds can pant much longer and harder without constricting brain vessels, so they don’t make stupid decisions - birds aren't bird brained.

Bar headed geese go even further (a 2013 study). The blood vessels in their muscles penetrate deeper and are more extensive. This can supercharge their muscles with oxygen so they can make more ATP and flap more energetically. Finally, the hemoglobin (oxygen-carrying molecule) of bar headed goose red blood cells is slightly different than that of other birds. It grabs onto oxygen molecules easier and quicker, so it does a better job of transporting the maximum amount of oxygen to the muscles.

We humans may not want to flap at high altitudes, but we could learn a lot from the bar headed goose about maximizing oxygen utilization. That’s where we get most of our best ideas – we steal them from nature’s rule breakers.

Many species of spiders, mites, and small caterpillars use

kiting as a means of dispersal. Remember that these are

newborns, and are usually of the smaller species, so these

fellows are awfully small. That makes it possible for a breeze

to catch the silk they spin straight up into the air and carry

them off to new neighborhoods. This is thought to be one of

the primary ways arthropods colonize newly formed islands.

But we shouldn’t restrict our discussion to birds, there may be other things that get high (pun intended). The winds can help out. Some small arthropods disperse themselves as youngsters by ballooningwith silk. Spiderlings (newly hatched spiders) risk being eaten by siblings if they hang around after hatching, and too many spiders in one area makes it hard to find food, so they get as high as they can and then shoot out a strand of silk.

The wind picks up the youngsters and deposits them somewhere else. However, the wind sometimes doesn’t want to let them go. They've been know to travel into the jet stream, and have been noted living in weather balloons at more than 16,000 ft (4.9 km).

Bees too have been found on the slopes of Mt. Everest (5.6 km). A 2014 study says bees could theoretically fly at almost 30,000 ft.; they could look down at Mt. Everest if they chose to. The researchers reduced the density of air and the oxygen concentration to match what would be found on top of the world and the bees flew just fine. They compensated not by beating their wings faster, but by widening and lengthening their stroke. Pretty good for an organism that many mistakenly believe shouldn’t be able to fly at all. But just because they could fly at that altitude, doesn’t mean that they do.

For one thing, bees and other arthropods go dormant when temperatures dip into the 40’s ˚F (7-10˚C) they become immobile and if they stay that way, they die. Not a good candidate for escaping Earth, where the temperature approaches -40˚C as you travel through the clouds.

These are the major types of clouds and their average altitudes.

They carry dust, water, chemicals, and apparently a whole lot of

bacteria and fungi. The 2013 paper says the bacteria act as seeds

for cloud formation and can therefore affect the weather.

Powerful beings.

The clouds are up there, could they harbor life? They contain water; life needs water. There are several types of clouds and they sit at various altitudes based on type, topping out at about 13 km (8 mi). The highest clouds are at about the same altitude that the griffon vulture has been known to fly (see picture).

Do all clouds have a living lining? You betcha. A 2013 study has shown that the clouds are actually their own biological environment. Bacteria, some from the ground, some from the ocean, and perhaps some from the air, are living and dividing up in the clouds. The study sampled air at 10,000 feet and found that air over water, had more marine organisms, while air over land had more soil organisms. They also found that hurricane air had many more organisms, so they hypothesize that strong winds pull up more organisms into the upper atmosphere.

But wait you say, the vulture was at 39,000 feet, and these bacteria were only at 10,000 ft. Well, let’s go higher. A 2009 study from Indiashowed that microbes were living as high as 25 miles (41 km) in the stratosphere. This shames the vulture and he makes him feel inadequate. What’s more, the 2009 study found three strains of bacteria in the clouds that are not found on the surface of the Earth!

Meteorites are one way that life might travel from planet to

planet. The organisms would have to survive the jolt that

speeds them to escape speed (bacteria can), and they have to

survive the temperatures of reentry. Interestingly, studies

show that even though the surface of a meteor entering the

atmosphere is several thousand degrees, it feels like a warm

summer day just a few centimeters deeper.

Bacteria are particularly well suited for life in the atmosphere. There are bacteria that can withstand intense radiation, can live in extreme cold temperatures, and can live nearly without water. These sound like good candidates for something that could escape Earth altogether.

A 2012 draft genome of one of these bacteria, Janibacter hoylei, confirms that it is different from any organism found previously on Earth. These bugs might be living their entire existences in the upper reaches of the atmosphere.

But we could look at this from the other direction as well. Could J. hoylei have come from space and is just living in the clouds because it liked the first place it saw when it got here? Astrobiologists are excited to study these high altitude bacteria in terms of whether they could seed other planets or whether life could come here from other places.

The hiccup in all our hypothetical space entering organisms is something called escape speed. In order to leave Earth’s gravitational pull, an object on the ground must travel at 11.2 km/sec. The escape speed decreases as you travel away from the center of mass, but even at 9000 km, an object must travel at 7.1 km/sec. A bullet fired from a rifle travels at about 1.7 km/sec, so you get the idea. It ain’t easy to leave Earth behind, even if you happen to be rugged enough to survive space (as some bacteria and lichens can, see this post and this post).

The Earth’s magnetic field protects life on the planet from many

types of deadly radiation. Near the poles, the earth’s magnetic field

lines bend to pass through the center of the planet. It is here at the

poles that the radiation can interact with the field lines in a position

for us to see. These are the Northern and Southern Lights.

One theory holds that bacteria living in the high atmosphere could be affected by the magnetic field lines of the Earth and sort of ride along a magnetic railway. Tom Dehel, an electrical engineer for the FAA, proposed in 2006 that electromagnetic fluxes, like the solar flares and fields that produce the auroras in the northern and southern hemispheres, could provide charged bacteria with enough energy that they could escape Earth’s gravitational pull. Not one scientist I could find has signed on to this idea. But still, there are no silly hypotheses, they’re all just a cry for the truth.

Next week, another question with a more fascinating answer than you would expect - why is it so hard to catch or swat a fly?

Pawar SP, Dhotre DP, Shetty SA, Chowdhury SP, Chaudhari BL, & Shouche YS (2012). Genome sequence of Janibacter hoylei MTCC8307, isolated from the stratospheric air. Journal of bacteriology, 194 (23), 6629-30 PMID: 23144385

Dillon ME, & Dudley R (2014). Surpassing Mt. Everest: extreme flight performance of alpine bumble-bees. Biology letters, 10 (2) PMID: 24501268

Hawkes LA, Balachandran S, Batbayar N, Butler PJ, Chua B, Douglas DC, Frappell PB, Hou Y, Milsom WK, Newman SH, Prosser DJ, Sathiyaselvam P, Scott GR, Takekawa JY, Natsagdorj T, Wikelski M, Witt MJ, Yan B, & Bishop CM (2013). The paradox of extreme high-altitude migration in bar-headed geese Anser indicus. Proceedings. Biological sciences / The Royal Society, 280 (1750) PMID: 23118436

#zoology #genome #escape speed #clouds #bird #astrobiology #arthropod

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stuffxthree-blog · 11 years ago

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Biology Position available

I was asked by the Adella Ramirez, the chairperson fo the science department at Waller High School to post the following: Waller High School in Waller ISD, Waller Texas is in need of an AP and duel credit Biology teacher due to a late resignation (our teacher left to go to a private school). The schedule is quite favorable. Contact info:

Brian Merrell (Principal)

Waller High School

20950 Field Store Road

Waller, TX 77484

ph 936-372-3654

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stuffxthree-blog · 11 years ago

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Fall Leaves And Orange Flamingos

Biology concepts – pigment, carotenoids, flamingos, cyanobacteria, bacteriophage, trophic cascade effect, spirulina, alga

These are the two species of Old World flamingos, the greater

(upper left) and the lesser (bottom right). Their ranges are

included, pointed out by the convenient arrows. Even though

the pictures don’t show it because I couldn’t get them to stand

next to one another, the greater is twice the height of the lesser,

hence the names. Notice the color variation as well. However,

color isn’t based on species.

There are two species of flamingos in Asia and Africa, the greater and lesser flamingos. There are also four New World flamingo species, but let’s focus on the two Old World species for today – the answer to our question holds for the New Worlders as well. Why are flamingos pink? Well, they aren’t always pink. And the reason they can be pink isn’t simple, but it’s something to which we can all relate.

The greater flamingo(Phoenicopterus roseus) is much larger than the lesser flamingo (Phoenicopterus minor) –- that makes sense. Greater flamingos average about 140 cm (55 in) tall, but they only weigh about 3 kg (6.6 lb). They're mostly legs, and there isn’t a lot of meat on those legs. If given a choice at the next flamingo fry, choose a breast over a drumstick.

The lesser flamingo weighs in at only 2 kg (4.4 lb) on average and are half as tall as the greater flamingo. But they make up for this in numbers. There are over 1.5-2.5 million lesser flamingos in East Africa, maybe twice as many as the greater flamingos, even though the larger species has a much broader range.

Flamingos are freaky birds. Their knees seem to bend backwards, but it's just an illusion since those backward bending joints are really their ankles. They tend to stand on one leg, and the reasons for this are not completely known. Some birds do it for camouflage, since on one leg they look more like branches. This probably doesn’t work for flamingos – since they’re pink!

A 2010 study showed that flamingos stand on one leg much more often when they are in water, so they hypothesized that they do it to reduce the amount of body heat that is lost to the water. Also, the scientists saw that the flamingos stood on one leg in the water for less total time as the temperature increased. This was definitive proof for leg position as a method of thermoregulation.

Other theories state that flamingos might stand on one leg because it takes a lot of energy to pump blood down and then back up those long legs Birds live on the edge of starvation everyday; by pulling up one leg at a time, they can reduce the distance and therefore the energy needed for moving blood. Or, they may do it to reduce the fungal and parasite loads on each leg – that last explanation is weak, I think.

All species of flamingos feed by turning their heads upside down.

In this way, they can scoop in some water and filter out their

food. Evolution is funny, they could have just evolved scooping

lower jaws, but for some reason they have scooping upper jaws

and therefore turn their heads over. Remember that evolution is

a point to point exercise in mutation and possiblebenefit; it

doesn’t move toward simple or toward logical.

Flamingos also have those funky looking beaks, but they’re functional because they eat with their heads turned upside down. As a result, it’s their lower jaw that is fixed and their upper jaw swings free. They don’t use their jaw to chew their food; they don’t really have teeth.

Instead, flamingos are filter feeders. This isn’t unheard of, there are other birds that filter their food to keep only things within a certain size range and then swallow them whole, but they are the biggest of the filter feeding birds. When their two jaws come together, they form a sort of comb assembly on the sides, the wider the distance between the comb’s “teeth,” the bigger the objects that can fit through.

Old studies shows that they use the “teeth” (actually called lamellae) to exclude things that are too big, and then to filter out things that are too small, like excess water. The tongue sits in a deep groove and pulls in and pushes out water and those things it doesn’t eat. This pumping occurs up to 20 times per second in lesser flamingos and 6-8 times/second in greater flamingos (see this video and watch for water squirting out). Different bill shapes and different spaces and lamellae sizes are specific to each species, and each eats according to its filter.

The popular answer for why flamingos are pink is because of their diet. All that stuff we talked about above is related to that answer, but you can now sense that it’s a little more complicated. The greater and lesser flamingos have different filters because they eat different things. Yet they both end up pink.

Here are the major source of nutrition for the Old World flamingos.

On the top left are the brine shrimp that make up the majority of

the diet of greater flamingos. On the bottom is A. fusiformis, the

major calorie provider for the lesser species. On the top right are

spirulina tablets from a health food market, made from dried

Arthospira organisms. Notice that none are pink, yet the flamingos

are pink. Just how do they pick up color from their food?

In the picture to the left you see the foods of the greater and lesser flamingos. Greater flamingos have a tongue/jaw filter that excludes all but the tiny brine shrimp and those things smaller (larvae of aquatic beetles and flies), so this is what they eat. The filter assembly of the lesser flamingo is much narrower, it only lets tiny cyanobacteria (lower image) into their gullet.

Cyanobacteria are sometimes called, perhaps incorrectly, blue-green or red algae. Alga has no clear-cut definition; some consider anything with chlorophyll and no protective cells over their gametes to be an alga, but others exclude all prokaryotes from the classification. I think the term cyanobacteria (Cyanophyta) is much more accurate.

The cyanobacteria that lesser flamingos eat used to be called Spirulina, but are now classified as species of Arthospira. A. fusiformis is the main dietary source of nutrition for lesser flamingos (of course greater flamingos eat them too; their filters let them in and keep them in), but there is also A. maximus. Together, they make up the spirulina that is popular in health food markets today.

We said above that the answer to today’s questions was that flamingos are pink or orangish based on the food they eat. But their food isn’t pink or orangish!! Look at the picture, spirulina is green. The explanation is related to something you see every year, and is something we have talked about before. It’s just like how the leaves turn colors in Autumn.

The green leaves in summer have red and other pigments, but they’re masked by so much chlorophyll (see this post). In fall, the leaves stop making chlorophyll, so the other colors shine through. The spirulina and brine shrimp have red and yellow pigments, but again there is so much green that the other colors are masked.

Here are two lobsters. Actually, it’s one lobster and one dinner.

The only difference is boiling water. The carotenoids in the shell

of the live version are bound to proteins and this changes their

light absorbing and reflecting properties (color). The hot water

denatures the proteins and frees up the carotenoids to be the

color they always dreamed of being.

When digested, the chlorophyll breaks down or is eliminated. But some other pigments, especially the carotenoids, stick around and get deposited in the tissues and feathers, now you can see them because the chlorophyll isn’t there to mask them. Why do the brine shrimp that the greater flamingos eat turn them pink? Because they feed on cyanobacteria that contain carotenoids. Their carotenoids are released when the flamingos digest the shrimp.

There's another reason for the different colors of food and flamingo. The pigments are sometimes complexed to proteins, and this can make them look brownish, bluish, gray, or green – like the many species of brine shrimp, aquatic beetles, and larval flies. This is very similar to lobsters and shrimp. They're bluish or grey when scooting around in the water, but turn red/pink when they are cooked.

Carotenoids come in many varieties; their chemistries run the gamut from alcohols to esters to plain hydrocarbons. We see them in carrots (alpha and beta carotenes - orange) and tomatoes (lycopene - red) for example. Spirulina has many carotenoids, but the one there in highest concentration is called astaxanthin (pink, as in salmon meat). The percentage of different carotenoids and the total amount of them in the diet determines the color of the feathers and skin. This is why some flamingos can be bright orange, while others are very light pink.

These are just a few of the dozens of carotenoids found in nature.

The longer the carbon chain, the lighter the color, from red to

yellow. This is just a basic generality, different side chains and

rings can alter the color well. And just to let you know, carotene

was named for carrots, not the other way around.

On the other hand, if there is little carotenoid in their diet, the feathers will be white. The pigment is lost over time, so the pigment trapped there when they were produced will fade. But flamingos molt, so that new, pink feathers replace old whitening ones. That is, if they eat their carotenoids. In zoos, their diet is often supplemented with canthaxanthin that keeps them a presentable pink. The exception – babies always start out grey.

For lesser flamingos, their food is sometimes their doom. A 2006 study found that blooms of toxic cyanobacteria produce two different toxins (microcystin and anatoxin) and have been responsible for several die offs in lesser flamingo population over the last 20 years. They have also found that in some instances, the spirulina they eat will also produce toxin, but they don’t know if it is enough to kill them. Microcystin from an algae bloom is the same toxin that shut down the Toledo water system earlier this week.

What may be worse, a bacteriophage(a virus that infects bacteria, see this post) has been increasing in the alkaline lakes where the spirulina grows according to a 2014 study. It infects and kills the A. fusiformis. The kill off of the cyanobacteria leads to a trophic cascade effect; the average adult needs 70 grams of A. fusiformis a day to survive, and that is dry weight, not saturated with water. Lose the base of the food chain and everything else loses too.

Lake Natron is VERY salty, and it contains lots of other minerals.

Natron is a combination of salt and minerals that the Egyptians

used to mummify the bodies of those who could afford it. Not

everyone got to be mummified; if that were the case, we would

have many undead walking around, placing curses on

successful tomb hunters. The minerals are so concentrated that

dead animals that fall in end up mummified and calcified. They

look like gargoyles on a French cathedral.

One last interesting point. While the lesser flamingos can live and eat in several alkaline lakes of eastern Africa, they all fly to one particular lake when it’s time to mate – like a Club Med for pink birds. Lake Natron in Tanzania is their destination. This lake is highly alkaline, hot (nearly 130 ˚F), and just chock full of minerals. The flamingos handle it just fine, but many other birds die from crashing into the highly reflective waters. The carcasses then calcify (basically, turn to stone), and wash up as little gargoyles. Even with all this deadly water, there are two species of fish that live in those waters – I wonder if the stonefish is one of them.

Next week, another question to investigate - can living anything short of an astronaut make it to space?

Anderson MJ, & Williams SA (2010). Why do flamingos stand on one leg? Zoo biology, 29 (3), 365-74 PMID: 19637281

Peduzzi P, Gruber M, Gruber M, Schagerl M. (2014). The virus's tooth: cyanophages affect an African flamingo population in a bottom-up cascade. ISME J. , 8 (6), 1346-1351

Kotut K, Ballot A, & Krienitz L (2006). Toxic cyanobacteria and their toxins in standing waters of Kenya: implications for water resource use. Journal of water and health, 4 (2), 233-45 PMID: 16813016

#zoology #pigment #ornithology #food chain #flamingo #exception #cyanobacteria #carotenoids #bacteriophage

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stuffxthree-blog · 11 years ago

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Does Life Come In XXXS?

Biology concepts – characteristics of life, archaea, bacteria, mycoplasma, synthetic biology, symbiosis, parasitism, nanobacteria, genome

As part of this blog, we have talked about some pretty small life. Wolffia globosa is the smallest flowering plant, only 0.6 mm long. We also talked about archaea, a different kingdom than bacteria, but still on the smallish side of life. The tardigrade is the toughest animal, but is also one of the smallest, at 100 µm (0.00394 inch).

The organism on the top is T. dieteri, and arthropod, just

as is any crab or spider. The size is deceiving. The pictures

on the bottom are to scale and are copepods, also

arthropods. The organism on the top is a parasite of the

organisms on the bottom. The small blue line? That would

be the scaled size of T. dieteri. So…. it’s SMALL.

The question for today is – is there a minimum size for life? Candidates might include bacteria or archaea; heck there’s an arthropod, Tantulacus dieteri, that's only 85 µm long! As long as we can keep finding smaller and smaller cells, we know that the minimum size for life is that small or smaller. So we keep looking – you’d be surprised how important it is to keep looking for smaller life.

Here’s one thing we should be able to agree on, viruses don’t get to play in our game. Viruses are very small, but they're not life! We’ve talked about this before - the seven characteristics of life (see this post). Viruses need a host in order to replicate, they don’t manage homeostasis, and they aren’t cells, so they aren’t life.

So how small has actual life become? Let’s assume that since tardigrades and T. dieteri are over 50 µm, huge when compared to some bacteria, our current minimum for life is probably a bacterium or archaea.

Let’s go straight to the genus of smallest bacteria we know about – the mycoplasma (from mykes = fungus, and plasma = formed). They were first described in 1898, but the observer didn’t have a clue what he was looking at; hence the fungal part of the name.

Mycoplasma don’t have the traditional cell wall of many bacteria, so they look different and this might be why they were mistaken for fungi. Whatever the scientists thought of them, they were confusing enough to be roundly ignored for 50 years. Rediscovered in the 1950’s-1960’s, this time they were thought to be L-forms of bacteria. L-forms are organisms that for some reason have lost their cell wall.

There are stable forms of L-bacteria; they can live divide and live on without their cell wall. There are also unstable L-forms as well; those that may revert to walled bacteria at any moment. Are mycoplasma simply bacteria that have lost a cell wall? Nope. They didn’t have a cell wall to lose. They have no cell wall genes, so if they had a cell wall, it was millions of years ago, before they became their own genus.

The difference between some free living cells. You can

probably see the E. coli in bright green, but you may have

to squint to see the mycoplasma above it. It’s pink. Really,

it’s there. Compare these sizes to those of the arthropods

above. 1 mm is equal to 1000 µm.

Mycoplasma is really, really, SMALLLLLLL.

Mycoplasma are generally described in the range of 0.2-0.8 µm in diameter. But this is a little misleading, because they are often not spherical. Even without a cell wall, they can take interesting three-dimensional forms and maintain them. Mycoplasmapneumoniae, which causes a form of …..….. anyone?…….. right, pneumonia, is pear shaped, so its 0.25 µm diameter is actually the measurement on its short side.

So mycoplasma are small, but they still have to play by the rules. They contain DNA and salts and proteins and ribosomes and other things that take up room. A single ribosome is about 50 nm in diameter (0.05 µm or 0.00000005 m), so there must be a certain volume required for the cell to function – a minimum size for life.

Which of the mycoplasma species is the smallest? Mycoplasma genitalium is considered to be the smallest mycoplasma known, and the smallest form of free-living organism - my gosh – you can fit about 400 M. pneumoniae inside one E. coli! As such, it is the current minimum size for life that we have. M. genitalium is 200 nm (0.2 µm) x 600 nm (0.6 µm), so they’re pretty dawg on small. Let’s put it this way, there are 25,400,000 nm in one inch – mucho small.

It is important to note that M. genitalium is free living, but does need some help. It uses cholesterol in its membrane but doesn’t make it itself. It picks it up from the cells that it lives near……wait for it….. your genital epithelium.

One of the human diseases that is becoming more

convincingly associated with M. genitalium is pelvic

inflammatory disease (PID). Resulting when many

different sexually transmitted diseases go untreated,

PID can cause permanent damage to the reproductive

organs of women. It is important to get treatment early.

The inflammation of PID may be associated with the

fallopian tubes or ovary, and will cause a chronic pain

in the lower abdomen, bleeding and pain on urination.

M. genitalium is a cause of non-gonococcal urethritis (inflammation of the urethra). A late 2013 review states that 1-3% of the general population is infected with M. genitalium, more than with gonorrhea. It is linked to pelvic inflammatory disease, and the review cites studies showing that people infected with this mycoplasma are more at risk for HIV and have more dual infections. It’s a sexually transmitted organism, just another reason for proper restraint. But even though it's helped out by your genital epithelium, it can live on its own and divide outside a host, so it's considered a free-living organism.

The idea of free-living is important because M. genitalium also has a very small genome (amount of DNA in one cell, including the list of all its genes). M. genitalium has about 580 kbp of DNA where kbp = kilobase pairs. Remember that DNA is doubled stranded (usually) so each base is paired with another. Knowing this, we count them as a unit. In all, M. genitalium has just 520 or so genes; it can make about that many proteins.

Genome size could be another way of determining the minimum size of life - what's the minimum number of genes or number of base pairs of DNA for an organism to still meet all seven characteristics of life? As of summer 2014, no organism smaller in size than M. genitalium has been described, but there have been some other organisms discovered with smaller genomes.

Nanoarchaeum equitanswas thought to have the smallest gene for a while, with only 491 kbp of DNA. It is an archaea that lives on the edge of hydrothermal vents at the bottom of the ocean. But it is an obligate symbiont with another archaea; it can’t survive without its partner, so can you say it has the minimal genome? It relies on another organism’s DNA.

On the left is the leafhopper in which N. deltocepahlinicola makes

his home. Well inside its cells that is. The leafhopper survives on

phloem and xylem; high in carbs but little protein. The bacterium

makes the amino acids the leafhopper can’t in exchange for energy

in the form of ATP. On the right is a colored photomicrograph of

the abdomen. The red is one type of endosymbiont bacteria,

the green is N. deltocephalinicola.

This is also true of Carsonella ruddii (159 kbp, 182 genes) and Nasuia deltocephalinicola. They are bacteria that must live inside insect cells, like those of grasshoppers. N. deltocephalinicola has the smallest known genome (112 kbp, 137 genes), but it doesn’t even make ATP, it steals it from the arthropod cells. This could hardly be considered free living, and so it can’t be considered the minimal genome for life. And even at that, their cell sizes are still bigger than M. genitalium.

So why is it important to find the minimal size and minimal genome for life? So we can use the information. J. Craig Venter (of the human genome project) wanted to develop a synthetic form of life (synthetic biology); a bacterium that could be developed to provide hydrogen for energy or eat waste to reduce pollution. Others say we need to know so that we can better recognize life on other planets, or life that may have come here from other planets (astrobiology).

Being J. Craig Venter, develop a synthetic form of life is exactly what he and his research institute did. It’s interesting that Venter was one of the scientists that first sequenced the entire M. genitalium genome in 1995. Some 15 years later, Venter’s JCVI-syn1.0 (2010) was the first synthetic life, housing 1000 kbp and 500 or so genes. The genome was based on that of another mycoplasma, M. mycoides. They modified the genome, and introduced it into a cell membrane that had been evacuated of all its constituents. The resulting cell was capable of growing, dividing, you know…. living.

If M. genitalium represents our current estimate for the minimum size of life, it’s only because we’re thinking of life as we know it. Perhaps we have already found life that is smaller, and the minimum size is actually much smaller than M. genitalium.

This is a photomicrograph of a meteorite from Mars. The

small spheres (like the ones the arrows point to, are

supposedly nanobacteria. Proof of life on Mars,

contamination from Earth nanobacteria, or just mineral

spheres that look a little like incredibly tiny bacteria?

The answer is C.

Something termed a nanobe and something else called a nanobacterium were described 20-30 years ago. Nanobes were first found in the rocks that came up during oil drilling in Australia, while nanobacteria were also found in surface rocks. The size of both (about 1/20 size of M. genitalium) negates their use of ribosomes and DNA. They stain for DNA, but this may be artifact, the artificial result of other things picking up the stain.

But nanobes/nanobacteria have their proponents. Some scientists say that since no DNA has been exhibited, they are a completely different form of life, so size restriction (big enough to hold ribosomes) doesn’t apply. Nanobacteria are also claimed to be important in human disease, as these structures are found in many calcifications of diseased tissues.

On the other hand, nanobacteria are probably just mineral formations. A 2013 study showed that they form spontaneously from many different biological fluid samples, and their appearance in diseased tissues is more a sign of disease than a cause of it. We’ll just have to keep looking for something smaller.

Next week, another question tackled and dissected - think pink.

Manhart LE (2013). Mycoplasma genitalium: An emergent sexually transmitted disease? Infectious disease clinics of North America, 27 (4), 779-92 PMID: 24275270

Wu CY, Young L, Young D, Martel J, & Young JD (2013). Bions: a family of biomimetic mineralo-organic complexes derived from biological fluids. PloS one, 8 (9) PMID: 24086546

Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang RY, Algire MA, Benders GA, Montague MG, Ma L, Moodie MM, Merryman C, Vashee S, Krishnakumar R, Assad-Garcia N, Andrews-Pfannkoch C, Denisova EA, Young L, Qi ZQ, Segall-Shapiro TH, Calvey CH, Parmar PP, Hutchison CA 3rd, Smith HO, & Venter JC (2010). Creation of a bacterial cell controlled by a chemically synthesized genome. Science (New York, N.Y.), 329 (5987), 52-6 PMID: 20488990

#synthetic biology #size #mycoplasma #genome #exception #bacteria #archaea

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stuffxthree-blog · 11 years ago

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Let's Get Loud

Biology concepts – vocalizations, mechanical sounds, sonar, decibels, stridulation

Today it seems that truth is more complex than ever.

van Goethe was a German statesman and a very successful

writer. He wrote novels, scientific treatises, lyric poems, as

well as dramas. Born in 1749, one might say that his quote

was true for his day; it was a simpler time. But think how

simple our time will seem to those who live a hundred

years from now – unless we’ve found our way back

to the Stone Age.

I have worked for years in science, and I’m supposed to be a big boy and realize that things are complicated. But I still get frustrated when I can’t get a simple answer. It seems nothing's simple, every answer has a caveat – heck, I make a blog of the exceptions to answers!

This week’s question is no exception – What living thing makes the loudest sound? Notice I said living thing, because I didn’t want to exclude anyone from the contest. Who knows, maybe some bacterium living in Wyoming makes a heck of a racket, it’s just that nobody is around to hear it. Or maybe a redwood falling down is the loudest. See, nothing’s ever simple.

This leads us to a second question – one which we have to answer first. What’s a sound? We are surrounded by air, and air has mass and density – it’s stuff. You can push stuff around. When you push the air, it moves away, which creates a wave, because the air you move then moves the air next to it, and so on.

A sound wave is generated when a force creates a vibration, and that vibration moves air, and that vibration is then propagated through the air. The air moves in the same direction the vibration was moving, and this makes it a longitudinal wave (see animation below).

A sound wave is a longitudinal wave, where the source moves

in the same direction as the wave. There is a compression of

the medium (air or water) and then a rarefaction with fewer

molecules as the compression moves on. The wavelength is

the distance between compressions and the frequency (how

high or low the sound is) is 1/wavelength.

So now we have a sound wave, but do we have a sound? It’s like the old question, if a tree falls and nobody’s there to hear it, does it make a sound? If you define a sound as a sound wave, then yes it does. Does that mean that every sound wave is a sound? There are sounds waves that dogs hear and we don’t because the frequency is too high – are they sound? There are waves that are too low or too soft for anything to hear, are they still sounds?

If you define sound as something your brain recognizes, then a sound doesn’t occur until the sound wave is transduced (changed in form) by a your ear to an electrical chemical impulse and that impulse is interpreted by the auditory cortex of your brain. See, nothing has a simple answer.

So, does a lonely falling tree make a sound? Scott McFarland of the University of Oregon installed microphones all over Crater Lake National Park 100 miles southeast of Eugene. In the remotest parts of the preservation land, he has heard everything from buzzing mosquito wings to, yes, falling trees. Unfortunately, he has also heard human intrusion.

Even from the most isolated areas, about 20% of every recording included airplane noise. He also heard cars, people, and detonations. It seems that no place is really naturally quiet anymore. But there were those falling trees -does that mean they do make a sound? Nope, it was a sound wave captured by recording equipment, transduced to digital information, stored, changed back to a sound wave by a speaker, and then to a neural impulse by our inner ear. It still isn’t interpreted as a sound until it reaches a brain, any brain. If a rabbit or bull moose is nearby, their ears would transduce the sound wave and they would “hear” something, even if they don’t think to themselves, “Hey, a tree just fell.” So again, it’s not so simple, maybe something with a functioning ear is in range.

The old tree falls in a forest question started out as a philosophical

question. It was meant as a thought experiment to students to

discuss the nature of what is real versus what is observable. However,

when it existed as a philosophical question, no mention of sound was

made, but was concerned with whether the tree existed at all if no one

was there to perceive it. It wasn’t until 1883 that the sound reference

was made, and then it was posed as more of a scientific question,

as we approach it in today’s post.

The human hearing sense is pretty sensitive. The pressure needed to generate a sound wave that a human could hear is about one billionth the value of atmospheric pressure. But this sound wave would be just barely audible (depending on the frequency), so it would be soft.

This brings us to a very short discussion of what it means to be loud or soft. We often measure loudness in decibels (db). A decibel is one tenth (deci) of a bel (named for Alexander Graham Bell), which is a unit of power or intensity.

Every 10 db increase represents a 10 fold change in intensity, so the scale is logarithmic. In acoustics(from Greek akoustos = hearing, and ic= pertaining to) this means that decibel is a measure of sound pressure, compared to a reference pressure (20 micropascals – we’ll get back to this).

Howler monkeys are the largest of the New World monkeys. But in

one way they are like old world primates. Howlers are the only new

world monkeys with color vision in both males and females. They all

see like we see, so they can discriminate different shades of green, red,

and blue. In most new world monkeys, the color receptor gene is on

the X chromosome, so females may get two types and be color vision

function, but all males get only one, and see only black and white.

A fairly recent gene duplication in howlers have given it color

vision again.

Examples of things that are loud (high sound pressure) would be a jet taking off 25 meters away (150 db), a clap of very nearby thunder (120 db), or a Harley Davidson 25 feet away (70 db). Note the distances; sound waves dissipate in power as they travel, the transference of energy along the wave goes in all directions and is not 100% efficient. This is why you can’t hear your brother playing with your Rock’em Sock’em Robots when you’re down the hall.

So who’s the loudest? The howler monkey (genus Alouatta, 15 species) has a great claim to being the loudest living thing. Used for communication over tremendous distances, the howl of this primate reaches 128 db from several feet away (hear it here). Howlers have an enlarged hyoid bone that is U-shaped. This creates an air sac on their throat that they can use to make their howl resonate.

The howl is really more of a growl for males but is higher pitched for females, and they can be heard more than 3.5 miles away. The question is why do they do it. A 2014 study concluded that the black howler monkey (Alouatta pigra) use their calls for several reasons, but most relate to defense.

The lesser water boatman (Micronecta scholtzi) is only 2 mm

long, but packs a big auditory punch. It’s a freshwater (aquatic

rather than marine) insect. Many marine animals have loud

calls, but here is an example of one that lives in slow moving

streams and ponds. You can hear it when standing on the bank.

This means the sound is so loud it can traverse the water/air

boundary, which usually stops most sounds.

They howl most often in defense of feeding areas. The volume of the howl makes the monkey seem bigger than he/she is. They also use it to defend infants or mates from males that are not part of the group. It calls attention and help comes a runnin’.

If we look at smaller land animals, some of them are loud too. Cicadas can produce stridulations (see this post) that reach 100 db from a foot away. But the king of the small animals would be the lesser water boatman.

This small freshwater insect (Micronecta scholtzi) can put out a stridulation of 105 db, even though it’s entire body is only 2 mm (0.078 in) long! A 2011 paper in PLoS One broke down the song of the male into three different parts, each with its own peak intensity. The loudest part could be heard from a riverside, even though the insect is underwater. By comparing peak db to size, the male outcalls every other organism we will discuss.

But it’s only the male that calls so loud. Why? Because he’s looking for a mate, and it’s his penis rubbing against his abdomen that makes the stridulation. This sort of eliminates the females from participating in the contest.

But back to the bigger animals. Bats are extremely loud, but their calls are of such high frequency that we can't hear them. Parrots can call to each other in the range of 100 db, but we can go bigger. In fact, the biggest animal may have the biggest voice as well.

The blue whale is the heaviest animal to yet live on Earth.

Being this large, it still has two natural enemies – man, who

hunted it to near extinction, and the orca. Orcas coordinate

their attacks on the blue behemoths, often trying to separate

babies from their mothers. Nearly 25% of sighted blue whales

have scars from either orcas or monumentally stupid octopus.

The blue whale(Balaenoptera musculus) is the largest living animal and the heaviest animal ever to live on Earth (yet). The whale’s song can reach 188 db! Some of the frequencies are too low for us to hear, but the higher pitched (higher energy) sounds can be detected 800 km (497 miles) way (hear it here).

Interestingly, a 2009 study shows that blue whale songs are getting lower in frequency. Since the whaling ban of 1966, male blue whale songs have been using lower and lower tones. The authors suggest several reasons for this. Males may not need to call out so loudly to find females because the ban has resulted in higher numbers of whales. But it is also possible that more man made noise in the ocean is forcing them to use lower frequencies.

The sperm whale is right there too. It doesn’t really vocalize, but it makes clicks to echolocate each other and prey. The clicks are made by forcing air through two lips (folds of tissue) in front of their blowhole. These clicks come in several varieties, but the “usual” click can reach 230 db. This makes them the kings of sound, if you don’t limit your choices to sounds made with the mouth.

Sounds in water are louder than in air, because the density is higher and the transmission is more efficient. So decibels in water are relative to 1 millipascal instead of the 20 micropascals in air. If you want to compare directly, you need to subtract 61.5 db from the water sounds. This still makes the sperm whale clicks 170 db and the blue whale song about 127 db, just about the howler monkey level. So the sperm whale wins our contest.

The different pistol or mantis shrimp are not very large, but

they have second largest sound to size ratio in the natural

world. Only one claw is the pistol. The right image is an

enlargement of the claw. S= socket, pl = plunger, D= dactyl,

p = propus. The muscles of the dactyl close it so fast, that the

water displaced in the socket by the plunger shoots out at

100 km/hr. This produces the cavitation bubble.

But for interesting and functional loud noise, I like to go with the pistol shrimp (family Alpheidae, hundreds of species). A special engineering twist allows them to cock one pincher like a gun. When they release it, the sound wave travels so forcefully and fast that the water around it turns to vapor and a cavitation bubble is produced (see video). The temperature in the immediate vicinity reaches 4000˚C and prey within 1.8 meters is stunned or killed! The sound, from several inches away, is 218 db (before subtracting the 61.5 db to match air measurements) when the bubble collapses.

A 2006 study describes that the hoods of the carapace (shell) that partially cover the eyes of the pistol shrimp are to protect themselves from their own explosive snap. The study suggests the hoods evolved first, and that allowed for the development of stronger and stronger snaps. If this continues, the pistol shrimp may start taking humans out!

Next week, another question about the extremes of life.

Van Belle S, Estrada A, & Garber PA (2014). The function of loud calls in black howler monkeys (Alouatta pigra): Food, mate, or infant defense? American journal of primatology PMID: 24865565

Sueur J, Mackie D, & Windmill JF (2011). So small, so loud: extremely high sound pressure level from a pygmy aquatic insect (Corixidae, Micronectinae). PloS one, 6 (6) PMID: 21698252

McDonald, M., Hildebrand, J., & Mesnick, S. (2009). Worldwide decline in tonal frequencies of blue whale songs Endangered Species Research, 9, 13-21 DOI: 10.3354/esr00217

Anker A, Ahyong ST, Noël PY, & Palmer AR (2006). Morphological phylogeny of alpheid shrimps: parallel preadaptation and the origin of a key morphological innovation, the snapping claw. Evolution; international journal of organic evolution, 60 (12), 2507-28 PMID: 17263113

#zoology #vocalization #stridulation #sperm whale #sound #pistol shrimp #howler monkey #hearing #exception #blue whale

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stuffxthree-blog · 11 years ago

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East To West And Back Again

Biological concepts – carbohydrates, heliotropism, monoecious, dioecious

I’m trying to think of a situation where quantity is better than

quality. Perhaps some could argue that since quality is subjective,

one person’s quality would be another person’s attempt for

quantity. In friends and experiences, I go with quality. You can

travel to every place on Earth, but if you don’t come back

changed, there was no quality. You can have many

acquaintances, but you really need only one true friend.

When it comes to the number of economically important plants, the Americas have not got many to show off. But what the two continents lack in number they make up for in quality. We have talked before about the biology of corn from North America and how it has been important for the development of molecular medicine.

Potatoes, cocoa beans, peanuts, and vanilla are also from the New World and deserve posts of their own. We’ll hear about vanilla later this summer. But one plant from the Americas has been important for food, oil, and decoration – the sunflower.

If we are going to talk about sunflowers, one question immediately comes to mind. Do sunflowers really turn to follow the sun? The answer is more complicated than it would first seem, and the answer is just part of the amazing biology of this plant.

First things first – the sunflower (genus Helianthus, about 50 species), as named in Carolus Linnaeus in 1752, does not refer to their tendency to follow the sun. Instead, he called them sunflowers because, ”Who could see this plant….without admiring the handsome flower modeled after the sun’s shape.”

Analysis of nearly fossilized human waste from the caves of Arizona (4000 BCE) show that sunflowers were an important part of the Native American diet. Sunflowers were tough, so they could grow in the Great Plains and other environments that got little rain and lots of sun. They could also grow in temperate environments. Basically, all of North America was there home.

The buffalo would trample huge swathes of land in their migrations, and the torn up ground was perfect for germination of the sunflower seeds. Slowly, this rapacious weed became a cultivated crop. Hybrids were grown, crossing prairie species with forest species and such. In modern science, the sunflower has been used extensively to study genetics of hybrids, much of this work being done at Indiana University in Bloomington, IN – my alma mater, thank you very much.

Number two - the sunflower isn’t a flower, it’s an inflorescence. This is a scientific word for a group of flowers bunched together on the same stem. We talked long ago about the Philodendron selloum inflorescence that controls it’s own temperature and gets hot to attract pollinating beetles.

Sunflowers actually have two types of flowers, the rays and the

discs. The ray florets have a longer petal, they are yellow because

bees see yellow best. The rays are fertile, and have very small

stamens and pistils that provide pollen and ovules. The disc florets,

when male, may have a sterility gene, and this makes sunflowers

very good for studying hybridizations. They also have a naturally

occurring restorer gene, so that they can again make

functional pollen.

In the sunflower, there are two types of flowers, the ray florets around the edge that every one thinks are the only flower petals, and the disc florets, which everyone assumes are the seeds. The ray florets are sterile and therefore for show only; they attract the pollinators.

The ray florets are usually bright yellow, but the disc florets are different colors in different species. They can be yellow, maroon, or even red. The red varieties all stem from a single mutation, but that isn’t the weird part. The disc florets start out male, and produce stamens and pollen, but then turn female as they mature, with the stigma pushing its way up through the middle.

This makes the flowers “perfect” and the sunflower monecious, meaning that have both male and female structures on one plant, but it also makes them smart, as the different timing reduces the chances of self-pollination (pollen and stigma aren’t around at the same time). For more discussion of monoecious(meaning “one house – male and female flowers on same plant, maybe even as the same flower as with the sunflower) and dioeciousplants (male and female flowers on separate plants), see this post.

But even in this, the sunflower can be an exception. The florets mature from the outside discs to the inside discs over time. So while the inner ones may still be male, the outer ones may have become female. In times when pollinators are more rare, if a disc floret remains unpollinated, its stigma may bend down enough to touch the pollen of the still male florets more towards the center of the inflorescence! This is rare, but does occur in species that are annuals.

An achene is a type of fruit that has a hard shell and the seed is

inside. Strawberries are accessory fruits, where the accessory

organs from many achenes join together. The achenes are the

little pieces on the outside. The papery husk (exocarp) of the

sunflower achene is made from the ovary wall and protects

the seed until it is ready to germinate, like being stuck in dry,

hard, cold ground, or in the belly of a bird.

And third, the disc florets each produce a single fruit (achene), which we call (incorrectly by the way) a sunflower seed. Inside the achene shell is the sunflower seed that we eat. A single sunflower inflorescence can have as many as two thousand disc florets, so that’s a lot of fruit. In species that have more than one inflorescence, each inflorescence will have many fewer than two thousand. Flowers are energetically very costly to produce. Incidentally, almost all the wild varieties have more than one inflorescence, the domesticated versions are bred to have one.

Now for the answer to today’s question – do sunflowers follow the sun? Well, yes and no. Young sunflower plants, including the very small, juvenile flowers, have the capacity to grow very quickly. This means lots of cell growth, and the need for lots of sunlight (to produce ATP and carbohydrates by photosynthesis).

The ability to follow the source of sunlight, called heliotropism (helio = sun, and tropic = loving) requires lots of cell growth. The flower stalks don’t turn so much as they grow in a different direction. As long as the cell growth is rapid enough and the stalk is small enough to respond to changes in cell size, the plant can appear to turn.

Heliotropism is seen in many plants; they need the sun for their

very lives, so it isn’t surprising that their biology would evolve to

maximize sun exposure. The reason the cartoon uses grass – that’s

the plant in which heliotropism was first studied. What scientist

discovered this marvel of nature? Charles Darwin.

The sunlight causes destruction of a plant hormone group called auxins, so they build up in the cells of the shady side. Auxins like indole acetic acid (IAA) promote cell growth and division, so there is much more growth (longer cells and more cells) on the shady side. The uneven growth pattern makes one side longer than the other and forces the stalk to turn (see picture).

So, immature flowers will face east in the morning and west in the afternoon. But that is only part of the answer. By morning, they’re facing east again. How does thathappen? A current review (2014) suggests that there may be a diurnal rhythm of several plant hormones, or a natural easterly face that is altered by light signaling. The actual mechanism for the daily turning waits to be identified.

But even this is only half the story. As the stalk gets larger and the heavy inflorescence matures, there can’t be enough cell division or hormone action for the plant to move this massive flower. The mature flowers face east all the time. But why east? Maybe they just can’t bring themselves to move one morning, and since they start out facing east, they stay that way when they give up.

Maybe, but I would imagine there’s a more biologically reason than surrender. The 2014 review cites a study that hypothesizes that facing east protects pollen from the mature florets from sun damage. Final answer, sunflowers follow the sun until it’s time to make little sunflowers, then they settle down and face the rising sun.

So young sunflowers turn with the sun, but how about another question – Why? It’s an inflorescence, not the most efficient photosynthesizer (more about this soon), so why would that structure turn to keep facing the sun? It seems like it would keep the flower in one place and turn the leaves to the sun. Hmmmm.

Now that we’ve answered the question of the day and raised another, let’s talk about the sunflower and world history. But for some unfortunate biology, you might eat sunflower roots like French fries.

The Jerusalem artichoke tuber (top) looks a little like ginger root,

but it is sweeter and not so fibrous. See the text for why you almost

grew up eating McDonald’s sunchoke fries instead of potato fries.

One species of sunflower, Helioanthus tuberosus, has an edible tuber root that is often called a Jerusalem artichoke. Since the sunflower is from North America, you know that the Jerusalem part of the name is wrong. And it’s not an artichoke either. How it got its name

Around 1600, the Jerusalem artichoke became a popular foodstuff. Easily grown and propagated, the sunflower tuber was a great source of carbohydrates and protein. It was easy to prepare, lasted a long time in storage, and didn’t taste like dirt or wood. Cultivation of the Jerusalem artichoke took off, and it became the primary food for many poor people and a delicacy for the rich.

The South American potato filled the same role, so who would win out as the food of the day? The Jerusalem artichoke (also called a sunchoke) had one big drawback, and it lost the battle. The potato won out, and 250 years later the great potato famine changed the immigration/emigration and ethnic patterns of the world.

What was this thing that cost H. tuberosus the war? It gives you gas. Among the many carbohydrate molecules produced by the Jerusalem artichoke is inulin. This polymer of six carbon sugars is one of those sugars that humans can’t digest, like cellulose. But our gut bacteria can.

Inulin is a branched chain of six carbon sugars. They come in several

varieties and together are called fructans. The “n” means there can be

any number of these units in the chain. They are a good source of

natural fructose, and chicory (right) is the most commercial source of f

ructans. Chicory has been used as a coffee substitute, a salad green

(endive and radicchio are types of chicory) and even in brewing beer.

In breaking down inulin, bacteria produce fructose monomers. They use these monomers as an energy source, and in doing so, produce carbon dioxide. In Central Europe, where the potato vs. Jerusalem artichoke battle was taking place, about 30-40% of the population have a genetic predilection for poor fructose absorption. This means more fructose stays in the gut….more bacteria food. This means much more carbon dioxide and …. flatulence.

In U.S. finer restaurants and gastropubs, the sunchoke is making a comeback, mostly because Americans can usually absorb fructose just fine. And the fructose helps diabetics too. Many diabetics use the high fructose:glucose ration to even out their glycemic indices.

What’s more, a 2014 study found that mice fed a high fructose diet over time do develop type II diabetes and/or fatty liver. Preceding the disease development, many specific genes change their expression patterns. If their diet was supplemented with extract from Jerusalem artichoke, many of the genes showed normal expression, and the diseases did not develop. Not bad for a sun chasing flower.

Next week, another question to investigate - what/who makes the loudest noise in life?

Vandenbrink JP, Brown EA, Harmer SL, & Blackman BK (2014). Turning heads: The biology of solar tracking in sunflower. Plant science : an international journal of experimental plant biology, 224C, 20-26 PMID: 24908502

Chang WC, Jia H, Aw W, Saito K, Hasegawa S, & Kato H (2014). Beneficial effects of soluble dietary Jerusalem artichoke (Helianthus tuberosus) in the prevention of the onset of type 2 diabetes and non-alcoholic fatty liver disease in high-fructose diet-fed rats. The British journal of nutrition, 1-9 PMID: 24968200

#sunflower #plant #monoecious #heliotropism #exception #dioecious #carbon dioxide #carbohydrate #botany #auxin #achene

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stuffxthree-blog · 11 years ago

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What’s So Repelling About Repellents?

Biology concepts – thermosensing, repellent, odor receptors, gustatory receptors, semiochemcials

Science explains our world, and then technology and engineering

build a model of that for our use. The better we know how our

universe works, the better we can make use of it. In the 1985

film Real Genius, this difference is stated when the scientist

students ask what a 6 megawatt laser might be for, one student

says, “Let the engineers figure out a use for it.” In this case, they

used it to fill a house with popcorn.

Science exists to describe our universe in terms of rules and mechanisms; what is and how it comes to be. Knowing that something exists is only half the equation. Science seeks to explain how something exists in terms of the rules of the universe. Observation is good, but it only shows us the question – mechanisms of action and interactions show us the answers.

As an example – we know that certain naturally occurring oils and well as some man made chemicals keep mosquitoes from feeding on us. This is the observation. But the question is – how do mosquito repellents work? The answer is more interesting and more complicated than you would initially think. Repellents rarely repel.

Investigating how chemicals keep us from getting bitten will teach us about how the living systems work, will give us a better understanding of our universe, and then give us better insect repellents. Don’t think that’s important? Consider the hundreds of millions of people who are infected every year (several million die) with mosquito-borne diseases (malaria, encephalitis, dengue fever, yellow fever, filiariasis). So yes, we need more repellents.

Mosquito borne diseases can be unpleasant at best. Top left is

filariasis, a worm is transmitted via mosquito and it clogs up

your lymphatic vessels, so that body parts swell from excess

fluid. Top right – malaria can result in so much red blood cell

lysis that your spleen (the guy who cleans them up) can

rupture. Bottom left – Dengue fever is often called breakbone

fever, the pain is not something an image can express. But the

hemorrhagic form of the disease can produce some bleeding

in weird places. Oh, and it can kill you too. Bottom right –

yellow fever is caused by a virus transmitted by mosquito. Your

liver breaks down and causes your whole body to turn yellow

and you bleed into your skin.

We should start with the repellents for which we have good ideas of their mechanism of action. But there aren’t any. We have some hypotheses and working ideas of the modes of action of mosquito repellents, but nothing is definitive yet. Let’s look at two of them and see if we can find some common pathways.

Citronella oil

Citronella is a combination of many different natural oils produced in lemongrass plants (Cymbopogon nardus and Cymbopogon winteratu). As a natural oil and a flavoring in Asian cooking, one would think that citronella oil would be considered just about the safest insect repellent this side of a slap with an open palm.

But no, Canada says that one small component of citronella oil called methyleugenol, can increase the likelihood of tumor formation in rats. Of course this was when methyleugenol was distilled from the oil, given by itself in large doses, and introduced directly into the stomach. But Canada is still in the process of banning citronella oil as an insect repellent. Of course, you can still eat thai food in Canada, which is often flavored with lemongrass.

The EU, on the other hand, said that the repelling function of citronella oil hadn’t been proven and it was deemed illegal to use in the EU in 2006. Oh, you could eat it, and use it soap or perfumes, you just couldn’t use it to keep mosquitoes away. They reconsidered in 2014 and some restricted uses of citronella oil as a repellent are now allowed.

Citronella oil comes from the lemongrass plant (Cymbopogon

nardus or Cymbopogon winteratu). There are two major species

for acquiring the oil, and the oil from each is a little different in

the percentage of each chemical. Lemon grass is also used in

cooking, the woody stalks are used with extra long cook times.

The torches that burn citronella oil work pretty well, but you

have to stay in the volatilized cloud of oil for them to be efficient.

Despite these issues, the U.S. Environmental Protection Agency (EPA) says citronella is safe and effective as an insect repellent. One weird side issue – you can take all the lemongrass you want from the US to Canada, where its oil is under attack, but you can’t bring any lemongrass from Canada to the US, where it is considered safe. Hmmmm.

Citronella oil probably works in a couple of ways. It's strong and sweet smelling, so it covers up and dilutes the odors that mosquitoes use to find you. If they’re detecting all the citronella in the air, then they aren’t smelling you. But research also shows that citronella oil activates TRPA1 ion channels. In us, they detect cold and noxious chemicals and are interpreted as pain. It is very possible that the detected signals in mosquitoes just come through as something unpleasant and to be avoided.

In this way, citronella would be an actual repellent. It repels on contact as well, as the taste is thought to activate bitter taste receptors and contact greatly reduces feeding time.

But citronella only seems to work when you are in the cloud produced by burning the candles or torches, or within the area of the spray. And if you’re using an oil or cream with citronella, it should really be reapplied every 30-45 minutes - not the most user-friendly method for discouraging pests.

DEET

World War II in the Pacific was an insect nightmare for the US Army. In response to the plethora of insect-borne disease that ran through the allied forces, defense scientists starting looking for better insect repellents. In 1946, their efforts produced N,N-Diethyl-meta-toluamide, or DEET.

Just how they came up with DEET is a mystery to me, it must have been a massive exercise in trial and error. Why? Because we know less about how DEET works than we do about citronella oil. And that’s with the benefit of 40 years of research. They didn’t have a clue how it worked or even what systems it was targeting when developed in the 40’s.

Guess which hand has been treated with DEET. The

mosquitoes come very close to the hand that was treated,

but don’t land on it. This argues that DEET is less repelling,

than it is disguising. On the right, the structure of DEET is

similar to several human semiochemicals, it fits into the lock

and key system of several odor receptors and activates or

inhibits them.

Originally it was believed that DEET disrupted the mosquito’s ability to detect semiochemicals(octenol) produced by mammals, especially humans, so mosquitoes couldn’t find a mammalian host to feed on. Then they played around with the idea that it blocked detection of CO2.

More recent studies have been more rigorous, but haven’t helped solve the puzzle. A 2008 study suggested that DEET was actually repellent; the mosquitoes didn’t like the smell and would avoid it. But other studies have shown different mechanisms of action.

A study in the journal Nature in 2011 found that mosquito odor receptors could be confused by DEET. The receptors for octenol were less responsive in the presence of DEET, but other receptors more more responsive. The conclusion of the study was that odorants from humans could be detected, but their pattern was confused, so the mosquito didn’t recognize the target as a target. It’s as if we disappear from the mosquitoes radar when we wear DEET.

A 2010 study showed similar results. DEET activated certain odor receptors but not others when given alone, but the opposite effects were seen when DEET was given in the presence of things from human sweat that would normally attract a mosquito. Once again, the signals were confused. This is really more of a chemical disguise for us, not a repellent. Next time your kids go outside, you should insist that they apply their mosquito confusant.

However, a 2013 study in the Journal of Vector Ecology found that heat and moisture were critical elements for recognition of targets by female mosquitoes, and that DEET messed not with odor, but with detection of heat and/or moisture. Different from the other studies, but still more of a masking than a repellent.

Something a little disturbing. Mosquitoes can learn to ignore

DEET. Most mosquitoes will be confused by DEET and never

find you. But if they do and then are repelled by the taste, they

learn from that and the second taste is not repellent. Hopefully

they just don’t find you a second time.

There was an interesting study from 2013that showed that if you mutate or knock out Orco, one of the co-receptors (a protein that works with many different odor receptors so that they can function properly), then two things happened. One, DEET didn’t have any effect on the mosquitoes, and two, mosquitoes that normally preferred humans greatly would then settle for any mammal.

Weird - Orco is needed for both DEET to work and for mosquitoes to find humans more attractive. I haven’t figured that one out yet. The researchers showed that DEET only maintained an effect on the Orco mutant mosquitoes when they landed on a DEET covered surface, and then they didn’t like it at all.

This suggested that DEET might have more than one mechanism, confusion in the air and repellent taste on contact. Older studies supported this idea, as a couple of studies in 2005 and 2006 showed that contact with DEET would reduce feeding behavior in mosquitoes and one in 2010 showed that fruit fly bitter taste receptors are activated by DEET.

So, we have studies that say DEET is a confusant rather than a repellent, others that say it is a true obnoxious smell that they can’t stand, and yet others that say DEET is confusing to the smell and repellent to the taste. But there are more. Other studies suggest that DEET actually inhibits the smelling of anything, while others say that it inhibits an important protein called cytochrome p450.

Used commercially since the 1950’s, DEET has been the gold standard for efficiency for many years. Although it has to be used at fairly high concentrations, it can keep mosquitoes away for 4-6 hours at concentrations where citronella oil might work for less than an hour. At 100% concentration, DEET is active for more than 12 hours. What’s more, if you combine DEET with 5% vanillin, it works two hours longer!

A lime with cloves stuck in it as a mosquito repellent – really?

Well, lime is kind of like citronella oil, and clove has eugenol,

which acts on TRPV1 ion channels. But how many would you

have to have, or do you wear them like earrings? Penny royal

contains menthol and mosquitoes stay away from it. But it

also has toxins that will kill you.

As good as DEET is, people still question whether it’s safe. The EPA in a 2014 review said that DEET is safe for human use and poses no identifiable risks for human health, even in children. But this doesn’t keep people from suspecting chemical usage of carrying negative effects.

On the other hand, DEET dissolves plastic, foam rubber, spandex, gore-tex, and nylon. I can see where this might make people leery about slathering it on their skin for hours at a time. And a few people are allergic to DEET, so the best current repellent isn’t without some negatives.

One last point – a newer repellent called picaridinis almost as effective as DEET and doesn’t eat your back packing equipment and clothes. The interesting point is that picaridin is a synthetic version of piperine, the spicy chemical in black peppercorns. Add to this that menthol is also a fairly decent mosquito repellent, and we have some good arguments that TRP receptors might be involved in repelling activity – as with citronella oil. Piperine is a TRPV1 agonist, and menthol activates TRPM8 and TRPV1. All our talk about spicy food and heat/cold receptors has an impact even in the spread of malaria and other deadly diseases!

Next week, another question to answer - do sunflowers really turn with the sun?

DeGennaro M, McBride CS, Seeholzer L, Nakagawa T, Dennis EJ, Goldman C, Jasinskiene N, James AA, & Vosshall LB (2013). orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET. Nature, 498 (7455), 487-91 PMID: 23719379

Stanczyk NM, Brookfield JF, Field LM, & Logan JG (2013). Aedes aegypti mosquitoes exhibit decreased repellency by DEET following previous exposure. PloS one, 8 (2) PMID: 23437043

Klun JA, Kramer M, & Debboun M (2013). Four simple stimuli that induce host-seeking and blood-feeding behaviors in two mosquito species, with a clue to DEET's mode of action. Journal of vector ecology : journal of the Society for Vector Ecology, 38 (1), 143-53 PMID: 23701619

#zoology #TRPV1 #TRPA1 #thermosensing #taste #smell #repellents #odor receptors #insect #gustatory receptors #exception #DEET #citronella oil #animal

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stuffxthree-blog · 11 years ago

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How Do Mosquitoes Find You?

Biology concepts – semiochemicals, hematophagy, proboscis, thermosensing, TRPA1

Sure, mosquitoes suck blood and pass along malaria

that kill more humans than any other infectious disease.

But would it be good to get rid of them. They provide

food for birds – one scientist suggests that elimination

of Arctic mosquitoes could reduce northern bird

populations by 50%. And mosquitoes pollinate flowers

too, like blueberries and cranberries. See, they’re

not all bad.

We can start our summer series of biology questions by continuing our discussion of taste and thermosensing. It seems that some people are bitten by mosquitoes if they peak out the front door, while other people can sit outside next to tall grass or ponds for hours with suffering a single bite. Unfortunately, I happen to be in the former category.

How do mosquitoes find some people and not others? Are some people just tastier than others?

First let’s get some common misconceptions and basic information out of the way. Do mosquitoes bite you (or any other animal)? No, they have no teeth, so they don’t bite in the traditional sense. What they do have is an elongated set of mouthparts called a proboscis. The sheath on the outside retracts as the longer parts inside pierce the skin like a hypodermic needle. Only this is a flexible hypodermic needle, small enough to go around individual cells and look for a small vein or venule.

On the left is a drawing of the mosquito proboscis parts. Most sit

in a groove of the labium, which retracts as the rest is injected

into the skin. The maxillae and mandibles are like our upper and

lower jaws. They are the sharp parts. The hypopharynx is what

delivers the anticoagulant saliva. On the right is the parts put

together. The fuzzy part is the labium and the sharp tips are

from the maxillae.

Take a look at these videos taken from a 2012 PLoS One study of a mosquito biting a mouse. The squarish objects are skin cells, and the red streaks are blood vessels. The second video in the sequence shows what happens when the proboscis finds a vessel and starts to suck out the blood. Makes you respect the mosquito a bit more – these are some determined females.

Of course it’s only the females that feed on blood. This suggests that feeding on blood is related to having babies. And it is – just not in a “gotta get the baby some food” sort of way. Most mosquito species require a blood meal in order to develop viable eggs. Females get energy from drinking nectar (full of carbohydrates), but they need protein to produce yolk for the eggs. They get the protein from feeding on blood. If the female doesn’t feed on blood, the eggs will be produced, but they won’t be able to hatch and become larva.

But here is one of our exceptions – some mosquitoes have gotten around the need for blood meals. All 92 species of mosquito in the genus Toxorhynchites (elephant mosquito) don’t need to feed on blood. Instead, their larvae feed on the larva of other mosquitoes, and the gather the proteins they need to lay viable eggs from their larval meals. They store the amino acids in their larval and pupal bodies, until they become adults and need them to lay eggs of their own.

Compare the sizes of the elephant mosquito (left) and

A. aegypti. I’m very glad that the females of the

Toxorhynchites genus don’t suck blood. They could drain

people dry! Even though their size is small, species like the

one on the right can consume 300 ml a day from every

caribou in a herd when they are swarming.

This suggests that the elephant mosquitoes could be used to combat disease spreading mosquitoes, like the Aedes aegypti mosquitoes that spread dengue fever, yellow fever and the current disease of interest, chikungunya fever. And the elephant mosquito has been used as a natural biocontrol agent. What's weird is that A. aegypti females actually help the situation.

A. aegypti, and many other mosquitoes that lay eggs in water, have larvae that eat bacteria. So they want to lay eggs where there are a lot of bacteria. Well, the eating of larvae by Toxorhynchitesspecies leaves lots of little pieces of mosquito larva in the water, and this provides bacteria with a lot of food. A June 2014 study showed that A. aegypti females actually prefer to lay eggs in water that contain predators for their larva, because it increases the bacterial numbers so much. Thos that survive have lots of bacteria to feed on. It’s a calculated behavior – risk being eaten or risk starving.

So some mosquitoes will go a long way and risk death in order to get a good meal for their potential offspring. They’re looking for mammals usually, but even here there are exceptions. Some mosquito species, like Culiseta melanura, feed almost exclusively on bird blood – they say it tastes like chicken.

The picture represents the transmission cycle for

eastern equine encephalitis virus (EEEV). It can’t be

transmitted from mammals to other animals, so they are

called dead-end hosts. But it can produce disease in

them. Humans most often will present with a limiting or

subclinical disease, but horses have a hard time with it.

The major source is in birds, and the transmission from

bird to bird is by mosquitoes that rarely bite humans. The

way into dead-end hosts is by a mosquito that normally

bites mammals occasionally biting a bird, or the rare

occasion that a bird specific mosquito will bit a mammal.

But just because they feed mostly from birds doesn’t mean they aren’t important disease transmission. They are – for horses. Eastern equine encephalitis virus is passed from bird to bird by C. melanura, so the birds, especially cardinals, are a reservoir of virus. Then, when another species of mosquito that is less particular about its host species bite a bird then bites a horse or person, the disease can be spread. There are even cases where a C. melanura will occasionally feed on a human and spread the disease directly.

With this background, we still need to answer our question of the day – how do mosquitoes find a blood meal. Believe it or not, your socks help answer the question. For many years it was assumed that mosquitoes followed the heat of warm-blooded animals in order to find a meal, but this was an assumption that was not tested rigorously.

Then it was discovered that carbon dioxide (CO2) is a strong cue for mosquitoes seeking sustenance. CO2 means respiration, and respiration possibly means mammals. The mosquitoes have taste receptors in their antennae and mouths that will sense changes in CO2 and they will follow the path of more carbon dioxide right to your nose and mouth (see this post).

Large people and pregnant women tend to exhale more CO2, so they will be more attractive to mosquitoes. But there are large individuals who never get bothered by mosquitoes. Maybe there’s more to it.

Semiochemicals are part of the answer. Semio- comes from the Greek meaning signal, like in semaphore flags. So semiochemicals are molecules emitted by organisms for communication. Pheromones are the most famous of the semiochemicals – and we know that these are used in many animals, from helping to guide ants to follow the path of their predecessors, to influencing mate choices in many animals.

Semiochemicals might be attractants or repellants. In some cases, they can be both. Take human body odor – it contains dozens of semiochemicals, people find body odor repulsive, but mosquitoes enjoy it like the smell of fresh apple pie. Of course, body odor is only offensive nowadays; before the advent of deodorant, daily or three times daily baths and showers, perfume, aftershave, and of course Axe products – everybody smelled like that guy that lives under the bridge.

On the top of this image is a general idea of semiochemicals.

If they work on members of the same species (like mating

signals), then they are called pheromones. If they work on

other species, they are called alleochemicals. Each can be

either attractive or repellant. On the bottom is a homemade

mosquito trap. You might be able to see that it has been

baited with old shoes and grimy socks.

Bacteria feed on the sweat, sugars and proteins that mammals exude, and they give even more semiochemicals. This can make you more or less attractive to mosquitoes. In general, people with many types of bacteria on their skin are less attractive, while those with mostly a few attractive species will get bitten more often. Having a high number of bacteria is a turn off too, probably because that would expose the mosquitoes to more possible pathogens as well. Is it possible to be so disgustingly colonized that even mosquitoes won’t land on you?

Mosquitoes are attracted to several different semiochemicals, including octenol, CO2, and nonanal. On mosquito antennae, especially the female antennae, there are receptors in the sensilla (see this post) for at least 27 different chemicals in human sweat.

Studies have shown that old socks are a good experimental attractant for mosquitoes. Instead of using an arm or other body part, scientists will compare the attractive ability of someone’s old sweat socks to individual chemicals or mixtures of chemicals. Of course, whose socks you use matters as well. Some people are classified as high attractors (HA) and some as low attractors (LA), so studies often include comparisons of chemicals or mixtures to both HA and LA socks.

But there are other considerations as well. People with blood type O secrete different semiochemicals and are more attractive to many species of mosquitoes. Go ahead, try to change your blood type so you’re less attractive to mosquitoes.

Different species may aim for different body parts. Some seem to prefer feet and ankles, but this may be because they are closer to the ground. If convection currents created by the body heat rising suck the mosquitoes in from below, then it is really the fact that they are following their noses and not going after feet particularly. A small 1998 study showed that mosquitoes that went after feet and ankles preferentially did not do so when the volunteers lied on their backs and raised their feet high in to the air. But, what we have stumbled across in this discussion is body heat.

This is part of a complex figure from a 2011 scientific paper.

In addition to the pretty colors used, the message is that these

researchers identified TRPA1 ion channels on the proboscis

of a species of mosquito. They don’t just sense heat with

their antennae, but also their sucking parts. I wonder if the

interior parts also have TRPA1 to help them find a vessel

when the proboscis is inserted into the tissue.

But what was old is new again…. Scientists are again looking at heat as an attractant for mosquitoes. As compared to HA or LA socks, heat isn’t a strong attractor, but warm socks attract more mosquitoes than cold socks. On the other hand, a 2010 study says that heat and moisture is a greater attractor than heat alone, so it would seem that people working outside in the heat would be the perfect attractors for mosquitoes.

Since heat does seem to be an attractor, it would follow that female mosquitoes would have a receptor for heat. Voila, a new study shows that mosquitoes have sensilla on their antennae and palps that house TRPA1 ion channels. A 2011 study even showed that one malaria-carrying mosquito has TRPA1 receptors on its proboscis. We have talked before about how many mammals use this receptor to sense noxious cold as well as chemicals that cause irritation or pain.

On the left is a species of tick. You wouldn’t believe how big they

can get when feeding on blood. Look it up – I dare you. On the

right is a bedbug. The bedbug is not that closely related to the

tick, since the tick is an arachnid. Count the legs on each – spiders

(arachnids) have eight legs, insects have six. Both these animals

feed on blood, but no one has identified a heat sensor in them.

But in birds, reptiles and insects, TRPA1 is a heat sensor. The 2009 studyshowed that the TRPA1 were expressed on the female antennae only. But that isn’t to say that only female mosquitoes have TRPA1. A 2013 study indicates that A. gambiae mosquito larvae have functioning TRPA1 so that they can sense water temperature and stay in the most comfortable water.

So mosquitoes (most female mosquitoes) are finding suitable hosts for blood meals by using their senses of taste, smell, sight, and infrared detection. There are other vampire insects as well, ticks, bedbugs, etc. I wonder if they are using heat sensing too. These have yet to be reported on.

Next week, a related question – just how and why do mosquito repellants work?

Maekawa E, Aonuma H, Nelson B, Yoshimura A, Tokunaga F, Fukumoto S, & Kanuka H (2011). The role of proboscis of the malaria vector mosquito Anopheles stephensi in host-seeking behavior. Parasites & vectors, 4 PMID: 21272298

Albeny-Simões D, Murrell EG, Elliot SL, Andrade MR, Lima E, Juliano SA, & Vilela EF (2014). Attracted to the enemy: Aedes aegypti prefers oviposition sites with predator-killed conspecifics. Oecologia, 175 (2), 481-92 PMID: 24590205

Olanga EA, Okal MN, Mbadi PA, Kokwaro ED, & Mukabana WR (2010). Attraction of Anopheles gambiae to odour baits augmented with heat and moisture. Malaria journal, 9 PMID: 20051143

Liu C, & Zwiebel LJ (2013). Molecular characterization of larval peripheral thermosensory responses of the malaria vector mosquito Anopheles gambiae. PloS one, 8 (8) PMID: 23940815

#zoology #TRPA1 #thermosensing #semiochemicals #protein #proboscis #pheromone #hematophagy #exception #animal

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stuffxthree-blog · 11 years ago

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They Can See The Blood Running Through You

Biology concepts- thermosensors, TRPV1, hematophagy, taste sense, alternate splicing, echolocation

All three species of vampire bat live in Central to South

America, the common vampire bat (Desmodus rotundus),

the hairy-legged vampire bat (Diphylla ecaudata), and

the white-winged vampire bat (Diaemus youngi).

Any idea what the picture to the left shows? A hint – this may be the most sophisticated piece of machinery ever devised by nature. Together with the organism to which it’s attached, this piece of evolutionary engineering is capable of almost everything a billion dollar jet can do.

It’s the nose of the common vampire bat (Desmodus rotundus). These bats belong to the family Phyllostomidae, one of three families of leaf-nosed bats (Rhinolophidae and Megadermatidae being the other two families). One of the exceptional skills mediated by this nose makes use of the same receptor that makes our mouths burn when we eat chili peppers. Vampire bats can detect the hot blood in your veins from far away!

It’s the noseleaves of the vampire bat that are so amazing, but maybe we should include the rest of the bat head as well. The ears, teeth, mouth, and eyes all work with the nose to give this bat some jet fighter skills.

Leaf nosed bats come in some very odd varieties. The picture on the below and right will give you some idea of the shapes and sizes possible. The question is – what’s the reason for these bizarre growths and why isn’t one odd shape enough? The answer will best be found if we know what their function is, because in biology – form follows function (except for proteins, see this post).

Here are some different leaf nosed bats. Top middle is the Ridley’s leaf

nose bat; bottom left is the Honduran white bat. Top right is the

Commerson’s leaf nose bat and the middle bottom is the greater

spear-nosed bat. The bottom right image is of the cleaf nosed bat of

Vietnam, a more newly discovered variety. It was first described in

2008, but it took 4 years to determine if it was a new species or just

a variant of another species.

Two basic needs of the bat are to find food and find its way. Whether it's a fruit bat, an insectivorous bat, or a vampire bat, a bat must be able to negotiate obstacles within its environment and find a source of nutrition.

To accomplish these tasks, especially given that most bats are nocturnal, they use echolocation. They send out a high-pitched sound, and it bounces off objects and returns to their ears. This is very much like the radar used in airplanes. But this isn’t all they use. Bats can see just about as well as humans; the phrase “blind as a bat” might as well be “blind as a Bob.”

We said most bats are nocturnal. This is Livingstone’s fruit bat

or Comoro flying fox. It is a fruit eating bat of the Comoros

Islands in the western Indian Ocean (just northwest of Madagascar)

and is at least partially diurnal. Other bats may be seen during

the day, but it almost always because they have been disturbed

in their hiding place or they were disturbed in their

feeding the night before.

Bats can also smell their way to food, especially fruit bats. But to answer the question about the noseleaves we have to return to echolocation. Vampire bat sounds emitted for echolocation come through their nose, not their mouth! According to a 2010 study, the leaves aren’t used to gather the returning sound, but to focus the outgoing sound so that the “pictures” formed by the returning echos will be most accurate.

Different shapes help to increase the difference in the reflectivity of objects in the area of focus as opposed to those in the periphery. This allows the various species to hone in what they need to discern and dismiss those things that are uninteresting. Different backgrounds and different needs require different nose leaf shapes.

This answers the question about the wild shapes of noses, but it brings up another question. If vampire bats find their food by echolocation, sight, and smell, then why do they have heat sensors?

To answer this new question, consider the sizes of the vampire bat and its intended prey. The bat weighs about 2.5 oz (71 g), but it needs blood for food (mammalian blood for common vampire bats, bird blood for hairy legged and white-winged species). In fact, vampire bats are the only mammals that completely depend on hematophagy (blood meals). Because of this, they often feed on animals that are over 1000x their size.

Pigs are a favorite source of blood for vampire bats. Here, a

sleeping pig has been bitten on the snout. Why the snout – read

on. Notice the bat can hold its weight with its wings, and that

there seems to be more blood than you would expect from

such a small bite. Again, read on to know why.

To get to the blood of say a cow or horse, vampire bats would have to have teeth so large that they couldn’t lift themselves for flight. No, they have to be very careful about where they bite a victim; somewhere that will bring enough blood to feed on, but won’t cause the huge animal to kill them. Vampire bat teeth are so sharp that prey animals rarely feel the bite, and since the bats are nocturnal, the victims are most often asleep at the time and stay asleep during the feed.

The bats need to locate a place on the sleeping animals where blood vessels are near the surface. This is where the heat sensing comes into play. Vessels close to the surface will give off the most heat to the environment, and vampire bats can “see” these vessels from up to 20 cm away!

The vessels in question need to be covered with less hair, so the bat almost always goes for the lower leg or snout. They will land on the ground, and walk or run up to the prey from behind the animal to make the bite. Vampire bats wings are much stronger than most other bats, so they have an easier time moving along the ground, supporting some of their weight on their wings.

On the left you can see the incisors of the vampire bat. The cheek

teeth and canines are used to shave off any hair from the site, but

the incisors do the cutting. The lack enamel, so they are always

razor sharp. On the right, the tongue is being used to take in the

blood. The tongue is deeply grooved, so the anticoagulant saliva

runs down into the wound and more blood can easily be lapped up.

Their teeth then cut a 5 mm x 5 mm gouge in the victim and they lap up the blood that comes out. It isn’t too common, but vampire bats do feed on humans. This leads us to another amazing skill. Instinct tells the vampire that a good feeding once will probably mean a good feeding again – if they can find the same animal. So how do they find the same animal several night is a row? They hear them.

A 2006 study showed that vampire bats do tend to feed on the same individual (be it human or cow) for several nights in a row. They can distinguish their previous victim by the sounds of their breathing! Every animal has a unique breathing pattern and sound profile, and the vampire bat can distinguish between individuals to find the one that matched a previous good meal. Imagine if we could find our favorite meal again by listening for the clinking of the right pans!

Returning to a good feeding spot each night, the vampire bat searches for a surface vessel to drink about 1-2 teaspoons of blood (4-5 ml). This isn’t enough to harm the animals, and is what allows them to go back several nights in a row.

Rabies can be spread by bats, and they don’t have to bite you.

When a bat bites an infected animal, it takes in the virus. The

virus grows in the animal and gets distributed to the saliva as

well. Startled bats sometimes spit, and if this gets into your

eyes, mouth, nose, or an open wound, you could contract the

infection. It’s rare overall, but rabies kills about 60,000

people a year.

This doesn’t mean that feeding by vampire bats is without negative consequences. One, the idea of being fed on gives me the heebie jeebies. Two, the vampire bat is a common vector for rabies virus. And three, in the cattle of Latin America, repeated feeding by vampire bats is associated with reduced milk production in dairy cattle and reduced mass gain in beef cattle. So if you wake to find a vampire bat licking your ankle, best to shoo him away and try to breathe differently tomorrow night.

How do vampire bats locate that ankle vessel they need to feed on? Back we go to that amazing nose. The heat sensors of bats are called pit organs, just like in the pit vipers we talked about last week. There are three to four of these organs in the noseleaves of the bat, and a couple across the upper lip as well.

As opposed to the pit vipers, vampire bats have adapted a heat sensor, not a cold sensor to use as their infrared detector for blood vessels. TRPV1, the same receptor that is used for the capsaicin burn and heat regulation in mammals, is present in very high numbers in the neurons of the pit organs.

But this is no ordinary TRPV1. Mammals can’t detect heat from 20 cm away with a regular TRPV1 – this is a modified TRPV1. A 2011 study found that this version of the protein is missing the last three amino acids on the carboxy terminus (the end produced last). This small change increases the sensitivity of the receptor from 43˚C all the way down to 30˚C, so that small differences in heat can be noted from almost a foot away.

One more amazing fact - the bats have regular TRPV1 too. The two version of the protein come from the same gene and the normal one is used throughout the bat’s body for all the things we use TRPV1 for: heat regulation, reproduction, cancer inhibition, etc. Only in the neurons of the pit organs is the mRNA altered after it is transcribed from the gene (alternately spliced) to make the slightly shorter, more sensitive protein.

Here is a cartoon of how blood clots. On the bottom flow chart,

the first anti-co line is where desmolaris and draculin work.

The third line is where desmoteplase acts.

Now our bat friend has located a victim, found a surface vessel and taken a bite to let the blood flow. There’s yet another problem. Mammalian blood clots to prevent loss. The bats must either keep biting, which might wake their prey, or have a way to keep the blood flowing.

Their mouths have specialized salivary glands that make anticoagulants so no clot is formed. There is one anticoagulant that someone with a sense of humor named draculin. It acts to prevent blood clot formation. We have mentioned a second anticoagulant before, called desmoteplase. One of our Halloween posts talked about how it may be good for people that have had strokes. It dissolves any clots that may form.

A 2014 clinical trial is showing that desmoteplase is better than the tissue plasminogen activator clot busters now being used (rtPA), since they have a half-life of four hours (as opposed to 5 minutes for rtPA) and it’s breakdown products aren’t as toxic to nerves and the blood brain barrier as compared to rtPA.

A newer anticoagulant is called desmolaris. A 2013 study showed that it works on yet another part of the clotting system to prevent clot formation. And this isn’t all of them. A 2014 protein survey suggests that there may be dozens more anticoagulant proteins in vampire bat saliva.

Which flying machine is more complex and cool?

Lets add up the vampire bat’s technologies and compare them to an F16. The bat can fly and turn better. The bat has radar and infrared heat detection. It has high powered listening devices that can discriminate between two individuals. Finally, it has biological weapons that allow it to do its work without alarming the target.

All that in a “machine” that can fit into the palm of your hand. Defense aeronautical engineers must feel so embarrassed.

Next week, let’s take it just a bit further. Female mosquitoes aren’t just looking for you, they’re tasting and feeling for you. They use CO2 gradients as well as my prodigious heat to find me on a warm picnicking evening.

Vanderelst D, De Mey F, Peremans H, Geipel I, Kalko E, & Firzlaff U (2010). What noseleaves do for FM bats depends on their degree of sensorial specialization. PloS one, 5 (8) PMID: 20808438

Patel R, Ispoglou S, & Apostolakis S (2014). Desmoteplase as a potential treatment for cerebral ischaemia. Expert opinion on investigational drugs, 23 (6), 865-73 PMID: 24766516

Ma D, Mizurini DM, Assumpção TC, Li Y, Qi Y, Kotsyfakis M, Ribeiro JM, Monteiro RQ, & Francischetti IM (2013). Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo. Blood, 122 (25), 4094-106 PMID: 24159172

Gröger U, & Wiegrebe L (2006). Classification of human breathing sounds by the common vampire bat, Desmodus rotundus. BMC biology, 4 PMID: 16780579

Gracheva EO, Cordero-Morales JF, González-Carcacía JA, Ingolia NT, Manno C, Aranguren CI, Weissman JS, & Julius D (2011). Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature, 476 (7358), 88-91 PMID: 21814281

For more information or classroom activities, see:

Leaf-nosed bats –

http://animaldiversity.ummz.umich.edu/accounts/Phyllostomidae/

http://animals.jrank.org/pages/2868/American-Leaf-Nosed-Bats-Phyllostomidae.html

http://sandwalk.blogspot.com/2012/02/ugliness-of-leaf-nosed-bat.html

http://www.speciesconservation.org/case-studies-projects/ridleys-leaf-nosed-bat-ridleys-round-leafed-bat/3049

http://animals.jrank.org/pages/2860/Old-World-Leaf-Nosed-Bats-Hipposideridae.html

http://animaldiversity.ummz.umich.edu/accounts/Hipposideridae/

http://www.inaturalist.org/taxa/71378-Hipposideridae

http://www.ehow.com/about_6579902_leaf_nosed-bat.html

http://animaldiversity.ummz.umich.edu/accounts/Rhinolophidae/

http://kids.nationalgeographic.com/animals/vampire-bat.html

http://animaldiversity.ummz.umich.edu/accounts/Desmodus_rotundus/

Echolocation –

http://www.teachengineering.org/view_activity.php?url=collection/cub_/activities/cub_soundandlight/cub_soundandlight_lesson4_activity1.xml

http://www.exploresound.org/home/teachers-parents/

http://skramar.wikispaces.com/III.+Classroom+Activity

http://kindernature.storycounty.com/display.aspx?DocID=20097271336

http://www.unco.edu/nhs/physics/faculty/adams/Research/USB/Index_PS.htm

http://www.scholastic.com/teachers/lesson-plan/bat-cave-7-science-activities

https://www.youtube.com/watch?v=Hr-Y2Tt8gFE

http://channel.nationalgeographic.com/channel/brain-games/videos/echolocation/

http://www.bbc.co.uk/learningzone/clips/bats-catch-fish-using-echolocation/10517.html

https://www.youtube.com/watch?v=p08Y0oRAX3g

http://www.scientificamerican.com/article/how-do-bats-echolocate-an/

http://askabiologist.asu.edu/echolocation

http://nelson.beckman.illinois.edu/courses/neuroethol/models/bat_echolocation/bat_echolocation.html

Alternate splicing –

http://highered.mcgraw-hill.com/sites/9834092339/student_view0/chapter16/animation_-_exon_shuffling.html

https://www.youtube.com/watch?v=FVuAwBGw_pQ

http://www.dnalc.org/view/16938-3D-Animation-of-RNA-Splicing.html

http://www.dnalc.org/view/16940-Alternative-RNA-Splicing.html

http://bcs.whfreeman.com/thelifewire/content/chp14/1402001.html

http://www.hartnell.edu/tutorials/biology/splicing.html

http://www.eurasnet.info/education/alternate-splicing/what-is-alternate-splicing

http://www.premierbiosoft.com/tech_notes/gene-splicing.html

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&ved=0CGoQFjAI&url=http%3A%2F%2Fwww.bioscience-explained.org%2FENvol4_1%2Fpdf%2Fspliceeng.pdf&ei=QfuYU-KCLsKayASduIDwCA&usg=AFQjCNGbbnWnBAbaDG1g-bbiPEOI0rRm0g&sig2=EUOIonqIgKKSeR4ogUEyfA&bvm=bv.68911936,d.aWw

http://www.nobelprize.org/educational/medicine/dna/a/splicing/splicing_alternative.html

Anticoagulants -

http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/TheImpactofCongenitalHeartDefects/Anticoagulation_UCM_307110_Article.jsp

http://www.nlm.nih.gov/medlineplus/bloodthinners.html

http://www.healthline.com/health/anticoagulant-and-antiplatelet-drugs

http://www.strokeassociation.org/STROKEORG/LifeAfterStroke/HealthyLivingAfterStroke/ManagingMedicines/Anti-Clotting-Agents-Explained_UCM_310452_Article.jsp

https://www.youtube.com/watch?v=cy3a__OOa2M

https://www.youtube.com/watch?v=9QVTHDM90io

http://www.hopkinsmedicine.org/hematology/coagulation.swf

http://www.allaboutbleeding.com/hcp/understanding-coagulation.aspx

#zoology #vampire bat #TRPV1 #pit organ #hematophagy #heat sensing #exception #echolocation #animal #alternate splicing

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stuffxthree-blog · 11 years ago

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Sneaking Up On A Snake

Biology concepts – thermosensor, sight-hunters, snake hearing, mutation, TRPA1, pit vipers

We have been talking about taste sense for many weeks. I

remember a 1975 movie called, A Boy And His Dog, starring a

very young Don Johnson. It was a post-apocalyptic story of a

guy, his dog, and cannibalism. The best line of the movie? “Well,

she might not have had good taste, but she sure tasted good.”

Of course, this isn’t the kind of tastes we have been talking about.

We’ve come a long way since we started talking about taste sense. We have learned about how TRPV1 capsaicin receptors sense pain and heat. We have also learned that TRPV1 capsaicin receptors have cousins that sense cold - TRPM8 and TRPA1. They may generate pain, and they certainly help to warm us when we are cold.

We have even learned that in rare cases, the cold receptors can be heat sensors, like in chickens and insects where TRPA1 sense hot instead of cold. And this leads us to today’s exception. It’s time to talk about how these relatives of taste receptors help animals to become better hunters and to better sense their environment. Today let’s focus on snakes.

Snakes have a number of ways to catch prey (see this post). Some lie in wait, blending in with the jungle or background until a moving potential dinner catches their eye and moves across their path. Vision is their primary way of finding dinner. As a consequence, most sight-hunting snakes are diurnal (active in daylight).

Here is the southern black racer. You can see it has big eyes with

round pupils so lots of light can enter – it’s a sight hunter. Many

grow to be 5 ft. (1.5 m) long, so they can look intimidating. But

they are not venomous and will usually exit the seen if disturbed.

The non-venomous Southern black racer (Coluber constrictor priapus) is a sight-hunting snake of North and Central America. It’s called a racer because it is quick, reaching 4 mph (1.8 kph) in a very short time. Even though it is a constrictor, it typically doesn’t coil around the lizard, mole, or bird (I said they were quick) that it catches. It prefers to crush them into the ground to suffocate them. Sometimes nature can be a little rough around the edges.

Other snakes use the combination of scent and taste that we talked about a while back. The Jacobson organ (more scientifically called the vomeronasal organ, VNO) in their mouth can sense the molecules that the tongue pulls in from the air. Like it or not, every organism has molecules floating off of them continuously. Snakes' VNO can pick these up. See this post for more on the VNO.

Some snakes “hear” their prey coming. True, snakes don’t have an outer ear opening or the small bones that convert sound waves into mechanical waves in our middle ear (see this post for an explanation). But they do have a cochlea, the organ for sensing the vibrations and converting them to a nerve signal. Many snakes can sense the vibrations that their prey generate when they move through the environment using this cochlea and their lower jaw.

Similar to something called bone conduction hearing in animals with ears like ours, vibrations that travel through the bone can also cause movement in the hairs of the cochlea. As we discussed previously, the bending of the sensory hairs of the cochlea are transduced to chemico-electrical signals that travel to the hearing centers of the brain.

This is from a scientific paper showing the bone hearing of a python.

The red is the lower jawbone. The bark blue is the quadrate bone

and the green is the equivalent to our stapes bone of the middle

ear. The light blue is the inner ear space and the purple is where

the cochlea is housed. Vibrations go from red, to blue, to green to

light blue, to purple. You can see how sound waves would find it

tough to get to the cochlea.

A 2008 study showed that many snakes rest their jaw bones against the ground. The vibrations caused by moving animals are transferred from the ground to the bone, and from the bone to the buried cochlea. The sensation in the brain is a lot like muffled knocks, not unlike the bass that is turned up too loud in peoples’ cars.

This was followed by a 2012 study that showed pythons have very sensitive vibratory hearing, but poor sound pressure hearing. Almost all their hearing input comes from the vibrations they sense in the ground or tree, or whatever they happen to be lying on. So be on tip toes, that snake may hear you coming.

But how does any of this relate to a receptor for painful cold and controls mammalian breathing rate? Well, another way some snakes find their prey is by sensing the heat they give off – even from a few meters away.

Pit vipers are a subfamily of the Viperdae family, called Crotalinae.There are two types of vipers; all of them have hinged fangs, the ones that are folded up into the upper jaw when the mouth is closed, but protrude for striking as the mouth is opened. Pit vipers differ from true vipers in that they have pits (duh!); more about these below. True vipers live exclusively in Africa and tropical Europe and Asia.

In America, where I live, there are a lot of pit vipers. Cottonmouths, rattlesnakes (all 30 species), water moccasins, copperheads – these are all pit vipers. From southern Canada to Argentina, and from Eastern Europe to parts of Asia, pit vipers are not rare. Eyelash vipers (Bothriechis schlegelii) of South America are arboreal (live in the trees). They have bright coloring, but sit still and wait for their prey to happen by. They strike from above, so they scare the heck out of jungle hikers.

On the left is the eyelash viper. You can see it doesn’t mean business

because its hinged fangs aren’t extended. In the middle is the two-striped

forest pit viper. It is protecting it’s young, so the fangs are extended. On

the right is a sidewinder rattlesnake. Sidewinders are amazing and will

get their own post soon.

The amazing thing is that there aren’t any pit vipers or true vipers in Australia. The land of a million weird and painful deaths has nothing to offer in the way of hinged fang venomous snakes. I’m sure there’s a movement to import some.

But it’s specific part of the pit viper that we are interested in today – namely the pit. The pit organ is located between the eye and the nostril, on each side of the snake’s head. It is a hollow pit, so the actual business end of the pit organ is inside the snake’s skull.

The pit is lined with epithelium, but it also has a membrane that is stretched across the base. As a consequence of the location membrane, there are air pockets on each side of the membrane. The trigeminal nerve innervates the membrane and there are thermosensors in the cells of the membrane.

So, the pit organ is a thermosensor that helps them locate prey animals (or predators). But wait you say. Sure, pit vipers may use a thermosensitive ion channel to sense the heat given off by passing prey animals. But we just said they use a COLD sensing ion channel, TRPA1. What gives?

The pit on a pit viper is located between the nostril and the eye.

It would be easy to mistake the pit for the nostril. The cartoon

shows the pit anatomy. The air chamber helps cool the air

quickly and stops the TRPA1 receptors from firing again. This

is so the snake won’t get a residual image of something warm,

when the target may have moved in the interim period.

The explanation is two fold. 1) We said a couple of weeks ago that TRPA1 might sense painful cold on its own, or may work with other TRP’s to respond to very cold temperature. But whichever way it works, it is very similar to TRPV1 for heat sensing and TRPM8 for cold sensing. 2) Remember that in birds, lizards, and many insects, TRPA1 actually senses heat, not cold.

So maybe it’s not so terribly bizarre that pit vipers use TRPA1 to sense their prey. But before they touch it??? We eat chili peppers and we react to the capsaicin in our mouths and noses. We go out on a summer day, and the heat activates our TRPV receptors in skin and other tissues. We eat something cold (or menthol) and we feel the cold sensations it touches or tissues. But snakes feel the heat of their prey before they eat, from a distance away! There must be more at work.

And there is. The TRPA1 ion channels in the pit organs of pit vipers have a mutated version of TRPA1. Here’s how things work according to a 2010 study that identified TRPA1 as the heat sensor. The pit is a hole with a membrane stretched toward the back. Consequently, there is an air chamber on both sides of the membrane. The membrane is highly vasculature and has the sensitive nerve endings with the TRPA1 channels.

The TRPA1 receptors are always firing, but at a low rate. Neutrally warm objects don’t change the firing rate, but warmer objects (as little as 0.001 ˚C warmer than background) will increase the firing rate. The receptor is mutated according to a 2011 study, with 11 amino acids of the pit TRPA1 divergent on only pit-containing snakes. These changes make the receptor so sensitive that it can react to infrared light signals (heat) from several feet away. That would be like our mouth burning over a chili pepper that we walked past in the supermarket.

Since the sensors are spread across the entire membrane, the effect on locating the source is sort of like vision or a pinhole camera. Light passes through the pupil and diverges before it hits the retina. This provides for a larger spread of the “image” across the membrane and allows for precise two-dimensional map of the target. The difference in heat between the target and the background gives a “picture” of the object that is warm.

The Taylor’s Cantil viper will play dead and then strike, but this

brings up an important point. DON’T get near a pit viper, even if

you are sure it’s dead. The pit is wired directly to the brain and

muscles. A dead snake, even one with a severed head, can still

strike as long as there is any residual neural electrical flow. People

die every year from snake bites from dead snakes.

The picture generated is also a little like hearing, since the heat will reach one pit earlier or more strongly. By comparing the timing and the strength of the signals from each pit, the distance and direction to the target can be detected by the brain (see this post for localization of sound waves).

Because the heat “picture” pit vipers pick up is based on the difference between the temperature of target and background, most pit vipers hunt when coolest, so temperature gradient between environment and prey is greatest. Prey will stick out the most.

Snakes can also use the pit more conventionally, as a thermosensor for its whole body. The basal rate of firing will tell the snake when to move to shade if it’s too warm or move to sun if it’s too cold. This is how it regulates its body temperature.

Pythons and boas can also have heat-sensing pits, but they are

5-10 times less sensitive because of their differing anatomy.

The amazing thing is that they evolved the same special power

independently from pit vipers, although they both use mutated

versions of TRPA1. The nostril has a black arrow and the pits

have red arrows.

The exception to today’s exception: some non-pit vipers have pits. In terms of evolution, pits evolved once in pit vipers, but they have sprung up several times in boas and pythons. These pits are less sophisticated (no membrane or air chambers), are less sensitive, and are located in different places.

Boas and pythons with pits have 3-4 simple pits in their upper lips. They don’t have the suspended membrane for sensing temperature, the TRPA1 sensors are housed within the epidermal cells at the back of the pit.

Next week – vampire bats and mosquitoes get into the mutated thermosensor act as well.

Christensen CB, Christensen-Dalsgaard J, Brandt C, & Madsen PT (2012). Hearing with an atympanic ear: good vibration and poor sound-pressure detection in the royal python, Python regius. The Journal of experimental biology, 215 (Pt 2), 331-42 PMID: 22189777

Gracheva EO, Ingolia NT, Kelly YM, Cordero-Morales JF, Hollopeter G, Chesler AT, Sánchez EE, Perez JC, Weissman JS, & Julius D (2010). Molecular basis of infrared detection by snakes. Nature, 464 (7291), 1006-11 PMID: 20228791

Geng J, Liang D, Jiang K, & Zhang P (2011). Molecular evolution of the infrared sensory gene TRPA1 in snakes and implications for functional studies. PloS one, 6 (12) PMID: 22163322

For more information or classroom activities, see:

Pit vipers –

http://www.kidzone.ws/lw/snakes/facts11.htm

http://animals.howstuffworks.com/snakes/pit-viper-info.htm

http://animals.pawnation.com/pit-viper-snake-4957.html

http://www.newton.dep.anl.gov/natbltn/600-699/nb681.htm

http://www.biologyofthepitvipers.com/

http://news.nationalgeographic.com/news/2011/07/110713-new-species-pit-viper-china-snakes-animals-science/

https://www.youtube.com/watch?v=lySW2-eYilg

https://www.youtube.com/watch?v=f_G4Q1NAqoA

http://www.nature.com/news/2010/100314/full/news.2010.122.html

http://www.mapoflife.org/topics/topic_312_infrared-detection-in-snakes/

http://www.nsf.gov/news/special_reports/science_nation/infraredsnakes.jsp

http://www.phschool.com/science/science_news/articles/snake_pits.html

Bone conduction hearing –

http://www.healthyhearing.com/content/articles/Research/Hearing/26145-Do-snakes-have-ears

http://what-did-you-say.org/2012/07/08/out-in-the-wild-hissy-bone-conduction-hearing-could-prevent-a-bite/

http://jeb.biologists.org/content/215/2/ii.full

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

http://www.hearinglosseducation.com/treatments/direct-bone-conduction

http://electronics.howstuffworks.com/gadgets/audio-music/bone-conducting-headphones.htm

http://www.oticonmedical.com/Medical/YourTreatment/About%20bone%20conduction/How%20does%20it%20work.aspx#.U5dGWIVf13I

http://www.britannica.com/EBchecked/topic/72920/bone-conduction

VNO (Jacobson organ) -

http://chemistry.about.com/cs/medical/a/aa051601a.htm

http://www.neuro.fsu.edu/~mmered/vomer/snake.htm

http://reptilis.net/smell.html

http://chemse.oxfordjournals.org/content/26/4/433.full

http://www.sciencedirect.com/science/article/pii/S187972961100010X

http://www.catbehaviorassociates.com/what-is-the-vomeronasal-organ/

#vomeronasal organ #TRPA1 #snake #pit viper #mutation #jacobson organ #exception #animal

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stuffxthree-blog · 11 years ago

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What Cold Really Looks Like

Biology concepts – TRPA1, cold sensing, oxygen sensing, proteasome function, hypoxia, normoxia, hyperoxia, phototransduction, optogenetics, methyl anthranilate

Last week we learned that the TRPA1 ion channel causes you pain when you are too cold and helps you to avoid the cell damage that cold can produce. Even if that’s all it did, it would be pretty amazing, but there’s much more. It turns out that TRPA1 can do some amazing things - like keeping the right amount of oxygen in your cells.

Prolyl hydroxylase domain enzymes (PHD1, 2, and 3) are the primary mammalian sensors for oxygen in the blood and tissues when oxygen levels are normal (normoxia) or low (hypoxia). Oxygen binding to the PHD acts as an "on" switch for the binding of another molecule to PHD, a molecule called 2-oxoglutarate (2-OG). 2-OG can only bind to PHD if O2is already bound.

On the left is a cartoon that shows how ubiquitin and PHD proteins

help mediate the destruction of unneeded damaged proteins. On the

right is the proteasome, the structure which recognizes the proteins

targeted for destruction and carries out the cutting that

releases amino acids.

The function of 2-OG bound to a PHD is to trigger the destruction of another type of protein, called hypoxia inducible factors (HIFs). They do this by modifying some of the amino acids of the HIF so that cell thinks the HIF is old or defective. Old and defective proteins are recycled for their parts by a big complex of proteins called a proteasome.

When there is sufficient oxygen in the blood and tissues, the PHD is bound by O2 and 2-OG, so the HIFs are degraded. But when there is hypoxia – little O2 and 2-OG are bound to the PHD – and there is no destruction of HIFs.

If they aren’t targeted for the proteasome, HIFs are free to do their job. They turn on genes that work to increase oxygen in the blood and tissues, including making more red blood cells, using more iron for heme, stimulating the production of new blood vessels, and triggering cells to use glycolysis instead of the citric acid cycle because glycolysis doesn’t need O2(here’s a review).

When oxygen levels in blood and tissue return to normal, more O2 will be free to bind to the PHDs and the HIFS will then be degraded. Their effects on genes will be turned off as their concentration decreases.

Oxygen sensing in the cells is important at all stages of life. At one

time it was believed that very premature infants, with less than

mature lungs, would benefit from a high oxygen environment.

What it actually did was make them blind due to oxygen mediated

damaged to the retina.

This is all well and good for normoxic or hypoxic situations, but how would it help in times of too much oxygen (hyperoxia)? And believe me, too much oxygen is a very bad thing. Short bursts of high oxygen can be disorientating, with central nervous symptoms that affect breathing and may cause myopia.

Prolonged exposure to high levels of O2 (or short exposures to very high levels) can cause cell destruction, collapse of lung alveoli, retinal detachment, and seizures. Scuba divers, firemen, and anyone else using oxygen tanks must be aware of the dangers of either running out of oxygen or breathing in too much.

This is where TRPA1 ion channels enter the picture. A 2008 study showed that TRPA1 can be activated by O2. In hyperoxic situations, there is too much oxygen to be bound up by the available PHDs, so some is left to interact with TRPA1 channels in the membranes of the vagus and sensory neurons, as well as in tissue cells. The O2 can open the TRPA1 channel directly and lead to firing of the neuron.

The more O2 there is, there more activation of TRPA1, and this is good. In hyperoxic situations, the body constricts many blood vessels to limit the excess oxygen getting into the tissues. Hyperoxia also ramps up the cells’ protective mechanisms against reactive oxygen species damage.

What we don’t know is which responses to hyperoxia are controlled by the TRPA1 channel activity. A 2011 study goes onto show that the PHDs lose their inhibitory function on TRPA1 in both hyperoxia and hypoxia. This is a similar conundrum to the one we saw last week - where TRPA1 senses cold, but responds to many of the “hot” agonists of TRPV1. Here, the same sensor is stimulating different responses to too much ortoo little oxygen.

Some situations with low oxygen tension can create big problems.

On the left is pneumonia; the filling of the alveoli with edema fluid

limits the amount of oxygen that can get to the bloodstream. In the

middle is Payne Stewart; at altitude, his plane lost cabin pressure,

everyone on board basically went to sleep, and the plane flew in a

straight line until it ran out of fuel and crashed. On the right is a diver

who specializes in going as deep as possible on one breath. Many

participants drown.

The same channel that senses really cold temperatures in your skin and tells you that this bad by stimulating pain also helps you keep a normal amount of oxygen in your tissues – a system that has little or nothing to do with pain. Weird enough for you? Well it gets weirder.

It seems that your TRPA1 cold sensing channels are important for tanning in the summer! A 2013 study shows that a process called phototransduction uses G-protein coupled receptors to stimulate TRPA1 in melanocyte and keratinocyte membranes and results in an influx of calcium. This destabilizes the membranes and facilitates the transfer of melanosomes from melanocytes into the surrounding keratinocytes, as we have talked about before.

Phototransduction in general is where light energy is changed (transduced) into another form of energy. The best example is in the retina of the eye, where rods and cones turn visual light into neural signals that are then processed in the brain as images – that’s how you see. In the skin, the energy of the UV light is turned into chemical energy (flow of ions in and out of channels) to stimulate cellular activity.

The retina is the most obvious example of phototransduction. Light

energy is converted to chemical energy and information. Light

strikes the retina, and excites the rods and cones. On the level of

the membrane, the light (hv) set in motion a series of reactions that

results in the opening or closing of ion channels, including

the TRPA1 channel.

A second 2013 study from the same group says that retinol (hear the word retina in there? As in the retina of your eye?) is the photoactive chemical that starts the G-protein couple receptor cascade that then results in TRPA1 activation and melanin synthesis in melanocytes.

A new photosensitive protein called optovin has been identified in zebrafish. It mediates TRPA1 activation via a sensitive part of the TRPA1. Optovin allows for optical control of TRPA1-expressing neurons, meaning - optovin absorbs light, generates singlet oxygen radicals and these interact with the the oxygen-sensitive cysteine residues on TRPA1 and activates the receptor. Sound familiar? This is similar to the binding of oxygen that helps the body recognize and respond to hyperoxia.

In an effort to take advantage of this great system, the research field of optogenetics has been born. Let’s say you want to study what happens when a set of neurons fires. Introduce optovin and TRPA1 (or a similar system, like opsin or retinal) into the appropriate neural pathway and then you can fire them at will just by shining a light on them. Imagine, shine a laser pointer on a mouse and instantly he starts to jump, or drool, or tell a joke.

Optogenetics was the method of the year in 2010! On the left

is how it works, using phototransduction molecules to stimulate

responses in target cells. On the left is how it works in a live rat.

The light is positioned so that it can illuminate the altered

neurons so that processes can be turned on and off with light.

One last exception for the day – one that will lead to some amazing stories for next week. In mammals and many other animals, TRPA1 senses noxious cold (in addition to the amazing things we just talked about), but in some species it acts completely the opposite.

In mosquitoes, TRPA1 senses heat instead of cold. A 2013 study shows that larval A. gambiae (the mosquitoes that carry malaria) rely on TRPA1. If you decrease the amount of TRPA1, the mosquito larvae don’t exhibit thermal locomotive behaviors that would normally keep them in the preferred temperature of water. This might be important for killing mosquito larvae in water; if you can use antagonists to TRPA1 to move them away from their optimum temperature, they’ll die as babies and never become bloodsuckers.

In fruit flies, TRPA1 is also important for circadian (daily) locomotor activity patterns (2013 study). Instead of having a light/dark drive their activity, the temperature fluctuations between day and night can also serve to entrain circadian cycles. There are activity cells in fly brain for morning, daytime, and evening activity levels. TRPA1 isn’t expressed in morning neurons, so it’s activation by heat is what increases activity in day and evening.

TRPA1 gene function (painless in fruit flies) controls many

circadian behaviors. Depending on the amount of firing, it

tells the fly what time of day it is, and this time controls

which behaviors will be favored.

Another 2013 study shows that TRPA1 is used as thermoregulatory control of circadian rhythm in drosophila. Loss of TRPA1 altered behaviors and changed the expression of an important circadian rhythm protein called Per in the pacemaker cells.

In this one regard, birds are a lot like mosquitoes and flies. Chickens for example, have TRPA1 channels that induce pain due to high heat, just like their TRPV1 channels (which, you remember, don’t react to capsaicin).

A 2014 study showed that chicken TRPA1 is a heat and noxious chemical sensor – it acts opposite to the TRPA1 in humans, even though we are both homeotherms (maintain a body temperature within a small range). Chicken TRPA1 is almost always co-expressed with TRPV1, so they double up on heat but might have less cold sensing – why? - cold can still be damaging to cells so they need to know to avoid it.

The weird TRPA1 of birds lends itself to a bizarre use for us. Methyl anthranilate (MA) is a non-lethal bird repellent, and the same 2014 study shows that it works by activating bird TRPA1 pain sensors. MA doesn’t activate TRPA1 in other species, like humans; three amino acids critical for its MA activity are different in bird and mammal TRPA1.

Since MA doesn’t work on human TRPA1, it can be sprayed on crops to keep birds away – it’s a chemical scarecrow - if it only had a brain! It can also be sprayed on surfaces to keep birds from congregating. MA works as a repellent by stimulating the trigeminal nerves via TRPA1 in the bird’s beak, eyes and throat.

Grapples (pronounced grape – ple) are apples soaked in

methyl anthranilate (MA) so they taste like grapes. MA is

sensed as hot in birds by TRPA1 but does not activate

the human TRPA1. We taste it as grape flavor and smell.

For me – if you want to taste grapes, eat grapes!

Very similar to MA is dimethyl anthranilate (diMA). It also activates bird TRPA1 and can be used as a repellent, but we use it for flavoring grape Kool Aid. Too bad Jim Jones wasn’t leading a flock of chickens – they’d all still be alive.

Both MA and diMA are naturally occurring in concord grapes, strawberries, other fruits, and are especially important for flavor of apples. Maybe that’s why they make grapples – grape-flavored apples. Actually, grapples are apples soaked in MA, not a genetic hybrid. DiMA is also released from musk glands of foxes, and is produced in rotting flesh – does spoiling meat taste like apples or grapes to you?

Next week – odd changes in TRPA1 and TRPV1 turn animals into better hunters.

Bellono, N., & Oancea, E. (2013). UV light phototransduction depolarizes human melanocytes Channels, 7 (4) DOI: 10.4161/chan.25322

Bellono NW, Kammel LG, Zimmerman AL, & Oancea E (2013). UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes. Proceedings of the National Academy of Sciences of the United States of America, 110 (6), 2383-8 PMID: 23345429

Saito S, Banzawa N, Fukuta N, Saito CT, Takahashi K, Imagawa T, Ohta T, & Tominaga M (2014). Heat and noxious chemical sensor, chicken TRPA1, as a target of bird repellents and identification of its structural determinants by multispecies functional comparison. Molecular biology and evolution, 31 (3), 708-22 PMID: 24398321

For more information or classroom activities, see:

Oxygen sensing –

http://www.nature.com/scitable/content/oxygen-sensing-by-hif-hydroxylases-57249

http://www.cell.com/developmental-cell/abstract/S1534-5807%2813%2900353-5\

http://www.cell.com/cell-metabolism/abstract/S1550-4131%2808%2900318-5

http://www.uchicago.edu/research/center/center_for_systems_biology_of_oxygen_sensing/

http://proteopedia.org/wiki/index.php/Molecular_Playground/Prolyl_Hydroxylase_Domain_%28PHD%29_Enzyme

http://www.sdbonline.org/sites/fly/genebrief/hph_fatiga.htm

http://www.dailymotion.com/video/xqzjjn_oxygen-animation_news

Proteasome –

http://www.hhmi.org/biointeractive/proteasome

http://www.hhmi.org/biointeractive/proteasome-and-protein-regulation

http://dehistology.blogspot.com/2011/06/proteasomes.html

http://sites.sinauer.com/cooper5e/animation0802.html

http://biology-animations.blogspot.com/2011/10/ubiquitin-proteasome-system.html

http://www.cellsignal.com/common/content/content.jsp?id=pathways-ubiquitin

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Proteasome.html

https://www.princeton.edu/~achaney/tmve/wiki100k/docs/Proteasome.html

Phototransduction –

http://sites.sinauer.com/neuroscience5e/animations11.02.html

https://www.youtube.com/watch?v=KosDT4z6NBc

https://www.youtube.com/watch?v=AuLR0kzfwBU

http://visiongroup.psychology.dal.ca/kevin/kevinteaching.html

http://www.biochemj.org/csb/frame.htm

http://bcs.whfreeman.com/thelifewire/content/chp45/4502002.html

http://www.authorstream.com/Presentation/abhijitgg25-1967051-retina-phototransduction/

https://www.khanacademy.org/science/health-and-medicine/nervous-system-and-sensory-infor/sight-2014-03-27T18:45:34.237Z/v/phototransduction-cascade

http://absolutelyoptical.com/linchpin-of-skin-response-to-uva-light-discovered/

http://www.uniprot.org/citations/23345429

Optogenetics –

http://www.stanford.edu/group/dlab/optogenetics/

http://www.scientificamerican.com/article/optogenetics-controlling/

http://optogenetics.weebly.com/what-is-it.html

http://www.wiringthebrain.com/2013/09/why-optogenetics-deserves-hype.html

http://www.npr.org/blogs/health/2013/12/26/256881128/experimental-tool-uses-light-to-tweak-the-living-brain

https://www.youtube.com/watch?v=I64X7vHSHOE

http://research.jax.org/grs/optogenetics.html

http://www.nytimes.com/2014/04/22/science/mind-control-in-a-flash-of-light.html?_r=0

https://www.youtube.com/watch?v=QA67v4vSg00

http://i-biology.net/2011/02/10/optogenetics-the-brain-watch-this-video/

https://www.youtube.com/watch?v=qydCa9R6lSU

Methyl anthranilate –

http://www.flockfighters.com/products_MA.html

http://scienceblogs.com/moleculeoftheday/2008/12/15/methyl-anthranilate-mm-grapey/

http://web1.caryacademy.org/facultywebs/gray_rushin/StudentProjects/CompoundWebSites/2003/methylanthranilate/index.htm

http://www.basenotes.net/threads/377014-dimethyl-anthranilate-vs-methyl-anthranilate

http://www.quora.com/History-of-Science/How-was-methyl-anthranilate-discovered

http://absurdapple.typepad.com/absurdappleblog/2008/02/grapple-with-th.html

http://www.odditycentral.com/pics/grapple-the-unique-apple-that-tastes-like-concord-grapes.html

#zoology #thermosensing #thermoregulation #phototransduction #optogenetics #methylanthranilate #exception #animal

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stuffxthree-blog · 11 years ago

Text

Sometimes, Cold Hurts

Biology concepts – nature of science, TRPA1, thermoregulation, noxious sensor, chemical sensor, mutation, protein domains

"As we acquire more knowledge, things do not become more comprehensible, but more mysterious."

Albert Schweitser was an organist without compare. He toured

the world playing different organs for concerts. Some of these

organs were huge, this one has five keyboards and dozens of

different knobs and buttons. The money from his concerts

went directly to building his hospital complex in Africa

(bottom). At its height, there were over 70 different buildings.

All care was, and is, free.

These are the words of Albert Schweitzer, physician, theologian, philanthropist, and organist. Yep – he played a mean organ. Albert was born in the Alsace part of France in 1875, and was raised in a household of ministers and musicians. He turned out to be both - but so much more.

Schweitzer became a minister, but toured the world's great churches giving organ concerts for big bucks. He used the money to put himself through medical school and establish a hospital in French Equatorial Africa in the 1910’s. He expanded his hospital to over 70 buildings and treated up to 500 patients at a time, always funding his efforts with his organ concert money and the money he made from writing books.

He was awarded the Nobel Peace Prize in 1952. His quote above is true, whether he was speaking of the secrets of life in the spiritual or scientific sense. I personally phrase Schweitzer’s sentiment a little differently. The more we know, the less we know we know. Scientific knowledge is meant to do two opposite things – one, answer questions, and two, create questions. Every decent answer we think we find should bring to mind many more questions.

This naturally occurs when science works at its best, but the hardest part is knowing if we have an answer. If we aren’t sure about the answer, we have to keep looking. Of course we always keep looking, but some answers come to be so well supported that it is not the answer we question but the details of the answer – like evolution or fundamental forces.

But if the answers are tentative or not well supported, then how good are the questions that spring from them? Can our questions only be as good as our previous answers? This I where we're lucky, because bad questions can lead to good answers, if we keep our minds open to what we see and don’t find just we are expecting to find.

How does this apply to our discussion of thermoregulation and heat/cool sensing? Well, what happens when you find a thermosensor that you can’t get a good answer as to what it does? Makes it hard to design new questions doesn’t it?

The left image is of Thomas Hunt Morgan, an American researcher

who set out to disprove Darwin’s theory of evolution using fruit

flies. He chose them because they were cheap and bred quickly –

a new generation came along every 10 days. He started

inspecting them for mutations, and then bred the mutants to

normal flies. The proportion of mutant offspring was EXACTLY

as Darwin predicted. On the right are two images of different

mutants, often these are induced using radioactivity. On the

bottom, you can see a leg growing where an antenna ought to be.

The sensor ion channel that I speak of is the TRPA1. Studies assign it a role in pain sensation – just like TRPV1 for heat. But what stimulates it to generate a pain signal?

TRPA1 was first described in drosophila melongaster (fruit flies). Historically, fruit flies have made great models because they eat cheap and reproduce quickly. You can read about the history of their use in genetics in a great book called The Violinist’s Thumbby Same Keene.

The scientists would induce mutations in flies (and their subsequent offspring) by giving them radiation or chemicals. They wouldn’t have any idea which flies were mutated, or what the mutations were, it was just a shotgun method. They would then study the flies, looking for abnormal anatomy, abnormal behavior, or abnormal responses to stimuli. In some cases, the mutations were spontaneous, not caused by radiation or the chemicals, but finding them was done the same way, and the ionizing radiation or mutagenic chemicals just made the mutation rate much higher. When they found a fly with a change, then they would go to work and identify the mutation.

One mutation they noticed was that some flies wouldn’t avoid things that should have been painful. Before they knew what gene was involved, they decided to call it painless. Comparing it to known genes, they found it was the drosophila homolog to a mammalian TRP called TRPA1 or ANKTM1. TRPV’s and TRPM8 were already known, and they all have ankyrin repeats, so I don’t know why TRPA1 got the “A” for ankyrin.

Ankyrin is just one of thousands of known protein domains, meaning short sequences of amino acids that are known to have specific functions. Ankyrin is often found to mediate protein folding and protein-protein interactions, even though its own folding is a little out of the ordinary. Most proteins with ankyrin domains have about 4-6 repeats of the 33 amino acid sequence, but the parasite Giardia lamblia has a protein with 34 repeats.

This is a computer generated image based on ankyrin repeat

morphology. The different repeats are good for building a protein

interaction domain. The interesting thing is that although

most ankyrin repeats have this shape, they bind different

protein structures and induce different functions. Where's

the specificity? Good question - could win you a Nobel Prize.

As for the “1” in TRPA1, all I can say is that they must be anticipating the discovery of more TRPs of this type, although right now it stands alone. It’s kind of weird though, you don’t call a dad “Sr.” if there is no “Jr.” so why is there a TRPA1 if there are no other TRPA’s?

So, flies with broken painless(TRPA1) genes didn’t respond to pain; therefore, TRPA1 must be a gene that codes for a protein that confers a pain signal. This meshed well with the information from mammals showing that TRPA1 stimulated pain signals from some chemicals. But was this all?

This is where the controversy began and still continues. Some studies find that TRPA1 is a noxious chemical receptor, some say it's a noxious cold receptor. Some experiments show it to be both, a receptor for pain from cold and a receptor for pain from chemicals. And then there are those that show it to be a heat receptor! More on those studies in a couple of weeks – they’re cool… I mean hot!

Even within mammals, the results can sometimes be very different. Old studies suggested that TRPA1 was a noxious cold sensor (below 15˚C) in humans, but newer research (2013) shows that while TRPA1 does sense cold in rats and mice, it isn’t affected by cold in humans or monkeys. Many of the older reports suggesting that TRPA1 is a noxious cold sensor were based on studies in mice, so maybe they do act differently in humans.

The other possibility is that they don’t sense intense cold directly, but work with other TRPs to respond with pain when cold is sensed. A 2014 study showed that TRPA1 modulates TRPV1 activity. The two are often co-expressed on the same neurons, and they are also activated by many of the same chemicals. This study shows sensitization of TRPV1 by activation of TRPA1 – so maybe this is why your hands burn when you go out in to the cold for a long time.

Here is a cartoon comparison of TRPV1 and TRPA1. The parts

that go through the membrane (transmembrane domains)

look very similar, but you can see many differences

in the intracellular tails of each. Remember that TRPV1 and

TRPA1 bind many of the same chemical agonists, but look at

the difference in the ankyrin repeats and the other domains

of the tails, as well as the cytoplasmic sides of the TM

domains. These are where specificity occurs.

An earlier study (2012) also showed that activity from TRPV1-4 receptors could modulate the activity of TRPA1. Gentle warm temperatures could desensitize TRPA1 and therefore keep pain from being felt. Could this be one of the ways that warm compresses work against pain?

So, if TRPA1 modulates TRPV1 and vice versa for pain sensation, maybe TRPA1 works with TRPM8 to induce noxious cold pain. There have been papers that suggest TRPM8 does sense cold temperatures below 15˚C and when those cells are lost, mice have no aversion to painfully cold stimuli. It is probable that TRPA1 works with TRPM8 and TRPV1 to elicit pain to cold temperatures.

Maybe we could get some insights into the cold sensing of TRPA1 if we could find out if it participates in warming the body when it is cold. TRPV1 is a heat sensor and initiates cooling programs. TRPM8 sense cool and starts to warm the body – so what about TRPA1?

Well, it looks like we get no help there at all. Even in the species that are most likely to have noxious cold sensation via TRPA1 (rats and mice), the channel doesn’t look to be calling for warming responses. In fact, a 2014 study suggests that when TRPA1 ion channels are knocked out in mice, cold temperatures induced physiologic changes just as if the TRPA1 was there – TRPA1 was not a participant in inducing warming activities.

This cartoon gives you an idea of how TRPA1 can work with

other TRPs in order to increase pain or bring pain when other

signals alone might not. This example is with injury and

inflammation. Some things trigger TRPV1 but the activation

of TRPV1 can influence TRPA1 activity. This would sensitize

for more pain. Perhaps this is how pain is generated from

intense cold, even if TRPA1 doesn’t respond to cold on its

own. TRPM8 does respond to cold, so maybe it or TRPV1

are the triggers needed for TRPA1 to bring pain from cold.

In the same set up, blocking TRPM8 channels did result in a hypothermia (mouse bodies did not initiate a warming response to cold temperatures). So, the authors concluded that while TRPA1 does cause pain in response to cold, it doesn’t start or participate in a program to warm the mice.

Oh well, like we said at the beginning of the post, the more we know, the less we seem to know for sure. I think TRPA1 is probably involved in cold pain, even if it doesn’t sense it directly. But I can’t wait to see what they find out next.

What we do know is that TRPA1 is intimately involved with pain. Migraine headaches probably have a TRPA1 component. A 2013 paper summarized the evidence by saying that many migraine triggers are now known to be TRPA1 activators. Many of the endogenous stress activators of TRPA1, like oxidative damage, electrophilic stress, etc. also act to induce pain. Finally, many of the drugs and analgesics that work on migraines are being identified as TRPA1 antagonists.

Since it’s evident that TRPA1 doesn’t work in thermoregulation (see above), maybe we can use antagonists of TRPA1 as pain drugs without worrying about the hyperthermias and hypothermias associated with TRPV1 antagonists and TRPM8 antagonists. And wouldn’t you know it, a new antagonist for TRPA1 has just been discovered in a weird place.

Meet the Peruvian green velvet tarantula. It does have a

green hue on its legs and it is soft and velvety. But it isn’t

from Peru. It actually lives in northern Chile, south of the

Peruvian border. Its venom contains a TRPA1 antagonist,

but the problem is that even though it is not likely to bite

the hand that feeds it, it will fling urticating hairs at the

drop of a hat. This is important, as we discussed here.

The Peruvian green velvet tarantula (Thrixopelma puriens) has a peptide in its venom that is the first identified peptide (protein) TRPA1 antagonist. What’s it doing in venom? One of the purposes of venom is to cause pain – pain is a great teacher – enough pain and you won’t attack that spider again. But here is a potential pain killer in the venom, maybe the green velvet tarantula is trying to kill its prey, but doesn’t want to cause undue stress to its victim. Is that how evolution works?

One last tidbit about TRPA1 – it could save your life in the middle of the night. If you block mouse nasal activity of TRPA1, they won’t wake up in response to formalin, acrolein, or other noxious stimuli that should generate an avoidance response. Would a house fire be something you need to wake up from – you bet. Another recent study found that TRPA1 sensors in upper airway cells are important for sensing smoke from wood fires. Don’t hate the TRPA1 because it gives you pain – enjoy the pain – it’s keeping you safe.

Next week – prepare to throw TRPA1 a party; it’s saving your life in many more ways.

de Oliveira, C., Garami, A., Lehto, S., Pakai, E., Tekus, V., Pohoczky, K., Youngblood, B., Wang, W., Kort, M., Kym, P., Pinter, E., Gavva, N., & Romanovsky, A. (2014). Transient Receptor Potential Channel Ankyrin-1 Is Not a Cold Sensor for Autonomic Thermoregulation in Rodents Journal of Neuroscience, 34 (13), 4445-4452 DOI: 10.1523/JNEUROSCI.5387-13.2014

Spahn V, Stein C, & Zöllner C (2014). Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1. Molecular pharmacology, 85 (2), 335-44 PMID: 24275229

Benemei S, Fusi C, Trevisan G, & Geppetti P (2014). The TRPA1 channel in migraine mechanism and treatment. British journal of pharmacology, 171 (10), 2552-67 PMID: 24206166

Gui J, Liu B, Cao G, Lipchik AM, Perez M, Dekan Z, Mobli M, Daly NL, Alewood PF, Parker LL, King GF, Zhou Y, Jordt SE, & Nitabach MN (2014). A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by binding to the S1-S4 gating domain. Current biology : CB, 24 (5), 473-83 PMID: 24530065

For more information or classroom activities, see:

Albert Schweitzer –

http://www.nobelprize.org/nobel_prizes/peace/laureates/1952/schweitzer-bio.html

http://home.pcisys.net/~jnf/

http://www.lucidcafe.com/library/96jan/schweitzer.html

http://www.chapman.edu/research-and-institutions/schweitzer-institute/

http://life.time.com/history/albert-schweitzer-in-africa-behind-the-picture/

http://www.schweitzersymposium.com/en/home

http://people.bu.edu/wwildman/bce/schweitzer.htm

Protein domains/motifs –

http://www.fasebj.org/content/9/8/597.abstract

http://www.ebi.ac.uk/training/online/course/introduction-protein-classification-ebi/protein-classification/what-are-protein-domains

http://www.proteinstructures.com/Structure/Structure/protein-domains.html

http://www.cellsignal.com/common/content/content.jsp?id=protein-domains

http://igem.org/Videos/Protein_Coding_Regions_and_Domains

http://vimeo.com/45046587

https://www.youtube.com/watch?v=9yPbWR0aaLU

http://www.proteinstructures.com/Structure/Structure/protein-motifs.html

http://www.genome.jp/tools/motif/

http://bioweb.uwlax.edu/genweb/molecular/Seq_Anal/Protein_Motifs/protein_motifs.htm

http://www.ebi.ac.uk/training/online/course/biomacromolecular-structures-introduction-ebi-reso/proteins/structural-motifs

Pervian green velvet tarantula –

http://www.nytimes.com/2014/02/18/science/the-peruvian-green-velvet-tarantulas-gift.html?_r=0

http://www.cell.com/current-biology/abstract/S0960-9822%2814%2900014-1

http://www.yalealumnimagazine.com/articles/3891

#zoology #TRPA1 #thermosensing #thermoregulation #protein domains #nature of science #fruit fly #exception #animal

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stuffxthree-blog · 11 years ago

Text

Cold Receptors Come In From The Cold

Biology concepts – thermosensing, cool sensing, allergy, cross-reactivity, cold allergy, sperm maturation, acrosome reaction, opiate withdrawal

You can be allergic to things that touch your skin – like poison ivy,

things injected, like bee venom, things eaten – like foods, or things

inhaled – like perfumes. But now we need to add something else

to this list – cold? On the right you see a common way to test for

allergy. Anything that produces a wheal and flare reaction

(blanched and raised surrounded by red) is considered positive.

But what if they’re just allergic to the metal needle?

Allergies can result when your immune system, specifically your mast cells, have an exaggerated response to something that should be innocuous. We have talked about the different kinds of immune hypersensitivity reactions before, but in general, allergy (or atopy, from Greek for out of place) occurs when your body produces a type of antibody (IgE) that recognizes foreign substances and causes your mast cells to release histamine.

Histamine release can lead to itching, watery eyes, runny nose, and even hives (urticaria, from Latin for nettle, see the post on nettle toxins). The IgE is good for helping you learn to avoid poisons and such, but what if your body makes and IgE to something that isn’t dangerous, like peanuts or latex?

Sometimes it isn’t even a case of building an antibody to something that is normally not deemed foreign. Sometimes a peanut molecule just looks enough like some other antigen that an IgE is tricked into binding to the peanut molecule or the banana molecule.

The fruit-latex syndrome is a good example of this. In many cases of people being allergic to latex (Hevea brasiliensis), they also have an allergy to avocados, kiwi fruit, bananas, or chestnuts. The IgE that recognizes the latex hevein protein cross reacts with a beta-glucanase enzyme protein from the fruits.

In the cases of cross-reacting antibodies, there are antibodies to innocuous antigens, your body reacts to them just like they were something dangerous. Histamine release results from IgEs grouping around an allergen and then attaching to a mast cell. If you have encountered this allergen before and have ramped up the number of IgEs that recognize this antigen, the mechanisms can lead to anaphylaxis. This life threatening condition is marked by inflammation that can cut off airways and a lowering of blood pressure that could kill the brain.

Spina bifida patients often develop latex and tropical fruit allergies.

Spina bifida is an incomplete closing of the spinal cord in the fetus

and can lead to severe difficulties in leg movement. It can range from

undetectable to very evident, like in the right image above. Lots of

treatment means lots of chances to develop latex hypersensitivity,

and almost 2/3 of spina bifida patients develop a latex allergy. A 2011

studysays that they first develop allergy to latex, and then this cross-

reacts with the fruit. So patients without latex allergy don’t have

to avoid the fruits.

People allergic to nuts or bee stings are forced to carry around injectors of epinephrine just in case their allergies are triggered. The epinephrine constricts blood vessels, increases the heart rate and the amount of blood moved, so your blood pressure won’t drop too far if you take it soon enough. It also dilates the airways and stops inflammation so you can keep breathing. These are all good things.

Like we said, this is how allergies can and sometimes dowork. But there are exceptions. Did you know that you can be allergic to cold weather? Yes, I hear you out there, chuckling that you’ve been allergic to shoveling snow for years. But what I’m talking about is a physical allergy – hives, breathing problems, itching, and cough – just because your skin and airways are exposed to cold air.

No – you can’t make an antibody to an environmental condition like cold – at least not as far as I know. But remember that TRPM8 is a cool sensor, stimulated by cold temperatures. What if your body skipped the antibody part and the cold temperature itself stimulated mast cell degranulation (release of histamine granules)? Maybe it does, but whether the cold acts via TRPM8 is another question.

Mast cells (in red) degranulate in response to allergens.

The allergen (1) is recognized and bound by the

appropriate IgE antibodies (2). The end of the antibody

opposite the allergen binding site has a receptor on the

mast cell surface (3). Crosslinking of more than one

surface recpeotr with Ab causes degranulation and

release of inflammatory mediators, like histamine (4)

from the granules usually stored in the cytoplasm (5).

There are only a couple of studies that have looked at TRPM8 and cold-induced urticaria. In 2010, a study using rat mast cells showed that they do express YRPM8 ion channels and that they do release histamine when exposed to cold or methanol (a TRPM8 agonist). The histamine release could be blocked, even at cold temperatures, by treating the cells with a TRPM8 antagonist. Pretty convincing, eh?

But the very next year, another study said it was unlikely that TRPM8 was responsible for cold-induced urticaria. This study used human mast cells and mice. Although they did find TRPM8 channels on the mouse mast cells, they didn’t release histamine in the presence of cold in their experimental model. And the researchers didn’t even find TRPM8 expressed on the human cells. This is a bit unusual, since mice are usually a great model for human physiology.

In mast cells from mice with no TRPM8 channels (TRPM8 knockout mice), the mast cell response to cold was normal, so this study concluded that TRPM8 is not involved in cold urticaria. Confusing, but a good opportunity to cheer the relentlessness of science. Study will continue until something is repeatable and can’t be proved wrong. Maybe it will be you – curing cold allergy might not make you rich, but cold-triggered asthma follows a similar stimulation – and solving that little problem will get you a Nobel Prize and a big fat check.

How about another exception? One important difference between TRPV1 warm/hot sensor and TRPM8 cool/cold sensor is that TRPV1 is often located on pain neurons, while TRPM8 is located on other types of neurons and other cell types. TRPM8 activation is not associated with pain sensation directly, since they don’t help depolarize pain neurons. But there is an exception – your teeth.

The left cartoon shows the dentinal pores and how they have

odontoblast processes in them. If the dentin is expose by

receding gums or by decay, the pores are then exposed. On

the right, different stimuli can cause the fluid in the pores to

move, which then puts strain or stretch on the processes, this

causes shifts in ions and that can cause the neurons to fire. These

neurons only carry one message – pain.

Inside the middle of each tooth is the pulp (in the pulp chamber), made up of a few layers of cells that can make more tooth material (odontoblasts), some blood vessels, and a set of nerves. Odontoblastsmake a product called dentin, which is hard, but not as hard as enamel. The enamel on your teeth is not very thick, most of the structure is dentin. As you age, insults to the tooth (like decay), can stimulate the laying down of additional layers of dentin inside the pulp chamber.

The dentin has minute pores that travel out from the middle to the base of the enamel layer. If decay or some other stimulus reaches the pore, processes (like fingers) of the odontoblasts in the pores can react to the stimuli. These then signal the neurons in the pulp. However, the pulp has onlypain sensing neurons. So every stimulus that reaches the pulp will be interpreted as pain.

The odontoblasts have TRPV1 channels, TRPM8 channels and TRPA1 channels (we will talk more about these next week). The hydrodynamic theory of tooth pain says that the changes in temperature that reach the odontoblast processes result in pressure changes and this puts mechanical stress (stretch or shear) on the membranes. These then trigger the channels and the signal is passed to the pain neuron.

A 2013 PLoS study says this is partially true. Their results seem to indicate that very cold and very hot stimuli do produce mechanical pressure on the membrane, so TRPV1 and TRPA1 are responsible for mechano-sensitive pain. But they suggest that in the case of TRPM8, cool/cold temperatures trigger the odontoblasts and neuron. The neuron only has one thing to say - pain – so when triggered by TRPM8 signals in the neighboring odontoblast, it responds the only way it knows how. Too bad, but it has spawned a million dollar industry in toothpastes for people with sensitive teeth.

This is a cartoon of the head of a sea urchin sperm, but many

of the concepts apply in humans as well. See all the red

arrows? Those represent the places where calcium flux is

important in maturation and function. And what do TRPV1

and TRPM8 move the best – calcium. The acrosome reaction

actually dissolved the membrane around the acrosome so that

it can more easily enter the ova. This has to be done at a proper

time; TRPM8 activation prevents it from happening too early.

Here’s another TRPM8 function that we will touch on only briefly. We talked about TRPV1 being important in sperm maturation and in entry into the egg. Well, it looks like TRPM8 is involved as well, only in the opposite direction. TRPM8 signaling, according to a 2011 study, TRPM8 activation preventssperm maturation. This is also important, you need the capacitation and the acrosome reaction to occur at the proper point because they shorten the sperm survival time.

TRPM8 signaling prevents the acrosome reaction, but when the egg is near, a chemical called CRISP4 is released from the egg or parts near there. CRISP4 is a TRPM8 inhibitor. When TRPM8 is inhibited, now TRPV1 can be stimulated to trigger the acrosome reaction.

The interesting part here is that up to the point of CRISP4 release, something is constantly stimulating TRPM8 activity in the sperm cell. I really doubt that there's a cold stimulus way up inside the uterus, so just what is activating TRPM8? We know about lots of endogenous activators of TRPV1, but there has only been one study saying that TRPM8 might have a body-produced agonist, a type of lipid called lysophopholipids. But I think we are missing a bunch of other agonists – maybe you could look for those someday.

OK, here’s the last weird function for TRPM8 today. Would you believe it works in morphine action and withdrawal (when addicted)? Opiates like morphine are analgesic andcold antinociceptive. You take morphine and you don’t sense cold – of course, you won’t sense much of anything else either. For cold, we know how it acts. Opiates cause the internalization of TRPM8 channels on neurons. If there are no exposed channels, they can’t be triggered to allow ions into the neuron.

It goes even further; this isn’t some byproduct or side effect. Menthol is known to create analgesia (one of the reasons they use it in cigarettes). But according to a 2013 paper, if you give naloxone (an opiate blocker) at the same time as menthol – no analgesia. TRPM8 internalization is required for morphine to work.

The term, “cold turkey” is fairly old, first appearing in print

around 1910. It means “without preparation,” but just where

it came from is a matter of question. It might refer to the fact

that cold turkey after Thanksgiving doesn’t need preparation.

It might also be related to “talk turkey, which means to get

down to business. But the way that drug addicts feel cold,

sweat, are pale and have goose bumps – the visual aspect is

not wasted. By the way – who would smoke a cold turkey?

This is important when you are trying to kick a morphine habit. As you stop taking the opiates, TRPM8 quickly relocates to the membrane of the cell and is very easily activated. This causes a cold hypersensitivity and hyperalgesia. People going through withdrawal feel cold because their TRPM8 channels are firing. This is one explanation for calling it, “going cold turkey.” It is uncomfortable and painful, and is one of the main reasons that patients fail detox.

The naloxone that is used to treat morphine addiction binds to the opioid receptor, but doesn’t produce the analgesia. It also allows the TRPM8 to remain externalized, so they don’t have the rebound feeling of cold and pain. Pretty impressive – and now you know how it works.

Next week – TRPM8 is for cold, then there’s the cold that hurts. That is a different receptor, called TRPA1. It makes cold hurt, abut it also saves you from the cold.

Gibbs GM, Orta G, Reddy T, Koppers AJ, Martínez-López P, de la Vega-Beltràn JL, Lo JC, Veldhuis N, Jamsai D, McIntyre P, Darszon A, & O'Bryan MK (2011). Cysteine-rich secretory protein 4 is an inhibitor of transient receptor potential M8 with a role in establishing sperm function. Proceedings of the National Academy of Sciences of the United States of America, 108 (17), 7034-9 PMID: 21482758

Shapovalov G, Gkika D, Devilliers M, Kondratskyi A, Gordienko D, Busserolles J, Bokhobza A, Eschalier A, Skryma R, & Prevarskaya N (2013). Opiates modulate thermosensation by internalizing cold receptor TRPM8. Cell reports, 4 (3), 504-15 PMID: 23911290

Medic N, Desai A, Komarow H, Burch LH, Bandara G, Beaven MA, Metcalfe DD, & Gilfillan AM (2011). Examination of the role of TRPM8 in human mast cell activation and its relevance to the etiology of cold-induced urticaria. Cell calcium, 50 (5), 473-80 PMID: 21906810 Cho Y, Jang Y, Yang YD, Lee CH, Lee Y, & Oh U (2010). TRPM8 mediates cold and menthol allergies associated with mast cell activation. Cell calcium, 48 (4), 202-8 PMID: 20934218

For more information or classroom activities, see:

Cold allergy –

http://www.accuweather.com/en/weather-news/allergic-to-cold-adapting-to-l/19934125

http://www.coldurticaria.info/

http://www.nbcnews.com/health/health-news/allergic-cold-gene-detectives-find-new-clues-f1C6435965

http://www.mayoclinic.org/diseases-conditions/cold-urticaria/basics/definition/con-20034524

http://usatoday30.usatoday.com/news/health/medical/health/medical/coldflu/story/2012-01-23/Allergic-to-cold-Its-a-real-condition-experts-say/52759906/1

http://www.drgreene.com/qa-articles/cold-allergies/

Hydrodynamic theory of tooth pain –

http://www.dentalcare.com/en-US/dental-education/continuing-education/ce200/ce200.aspx?ModuleName=coursecontent&PartID=1&SectionID=-1

http://www.wisegeek.com/in-dentistry-what-is-the-hydrodynamic-theory.htm

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=14&sqi=2&ved=0CIwBEBYwDQ&url=http%3A%2F%2Fwww.mbfys.ru.nl%2Fstaff%2Fj.vangisbergen%2Fendnote%2Fendnotepdfs%2Fcolleges%2FTANDARTSEN%2FPLAATJES%2520EN%2520FILES%2Foral%2520neurophysiol%2520JUNGE%2Fhydrodynamic_theory_LECT06.doc&ei=W05IU7zCHaLCyQGTiYDQBQ&usg=AFQjCNEtK2R_BX3DAJj03Ep0_pPGB2ulwg&sig2=_F9lV6O4KCaixwoAnLugLw

http://www.drbui.com/artdentinhypersensitivity.html

http://www.juniordentist.com/theories-of-pain-transmission-through-dentin.html

Sperm maturation –

http://embryo.asu.edu/pages/sperm-capacitation

http://www.pbs.org/wgbh/nova/education/activities/2811_baby.html

http://www.keytoconceive.com/sperm-capacitation.php

http://www.glowm.com/section_view/heading/Sperm%20Transport%20and%20Capacitation/item/315

http://www.youtube.com/watch?v=rrFsTdfe2qw

http://www.wisegeek.org/what-is-sperm-capacitation.htm

http://www.youtube.com/watch?v=-J9deipbdSI

http://community.babycenter.com/post/a36676870/capacitation

http://education-portal.com/academy/lesson/acrosome-reaction-function-definition.html#lesson

http://www.youtube.com/watch?v=5-g8dLcERlM

http://www.youtube.com/watch?v=-jLyzWrSTOA

http://www.stanford.edu/group/Urchin/acrosome.htm

http://www.embryology.ch/anglais/dbefruchtung/akrosom02.html

http://worms.zoology.wisc.edu/urchins/SUfert_acrosome.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181525/

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/reprod/fert/fert.html

Drug withdrawal –

http://en.ria.ru/infographics/20100524/159134332.html

http://emedicine.medscape.com/article/819502-overview

http://www.addictionsandrecovery.org/withdrawal.htm

http://www.nlm.nih.gov/medlineplus/ency/article/000949.htm

http://www.hindawi.com/journals/tswj/2012/940613/

http://derekwmeyer.blogspot.com/2012/05/physical-component-of-opiate-withdrawal.html

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=16&ved=0CH8QFjAFOAo&url=http%3A%2F%2Fwww.drneurosci.com%2Fcurrentissues%2Fthephysiologicalbasisofdrugaddiction.pdf&ei=81JIU8akN-reyAHNi4GgCA&usg=AFQjCNFpwBNfSjgwuPQ02N4fRj7wKeaQdA&sig2=gihQYdc3hBHJak9mxCBh2g&bvm=bv.64542518,d.aWc

http://www.eperc.mcw.edu/EPERC/FastFactsIndex/ff_095.htm

#zoology #TRPV1 #TRPM8 #thermoregulation #sperm maturation #opiate withdrawal #hydrodynamic theory of tooth pain #exception #animal #allergy

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stuffxthree-blog · 11 years ago

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The Cold Cure All

Biology concepts – thermoregulation, TRPM8, TRPV1, heat sensing, cool sensing, vasoconstriction, nasal resistance, viral cold

The common cold. The red nose is from irritation from

tissue and inflammation. The medicines are to treat the

symptoms. Colds are caused by viruses, and we don’t

really have treatments for viruses. What I don’t

understand is the thermometer; adults with colds very

rarely have fever. Kids usually run a fever, but not adults.

So either this is the oldest looking child or he is worried

about something other than a cold.

It sucks when you have a cold – or does it blow? Your nose is stuffed, it’s hard to breathe, you have a cough that won’t stop and seems to do you no good. You’re chilled, but don’t know if you want to feel warmer. Is there anything you can do? One popular treatment might just be a lie.

I have noticed two things that seem to help the stuffiness I feel with a cold. One is exercise – it always seems to open up my nasal passages and make it easier to breathe. The rush of endorphins doesn’t hurt either – I may not be getting better, but I don’t mind the cold as much with a good dose of endogenous opiates running through my veins.

For me, a second short-term nose opener is going outside into the cold weather to shovel snow or chop wood. Why would being cold help a stuffed nose? Ponder that question for a second while I vent on a common misconception. Why do we say we catch a cold? It’s a viral infection, does temperature have anything to do with it at all?

Sure, more people have colds in the winter – but you know from this blog that correlation does not imply causation. Having a cold in winter doesn’t mean that the winter weather had anything to do with catching cold.

Your mother always told you to wear your coat outside or you’d catch your death of cold. Your basketball coach did a hat check after practice to make sure you didn’t leave for home with wet hair on an uncovered head. Were there reasons for this?

Underneath all that winter gear is Randy Parker, Ralphie’s

little brother from A Christmas Story. His mother, in her

time-honored wisdom, didn’t want him to a catch cold by

being cold. The problem was that wrapping him up just

kept the cold from stimulating his metabolism and his

immune system over time. Plus, he found it hard to go

through doorways; he couldn’t put his arms down!

In a word, no. That isn’t to say that there is no effect from cold weather, but it's minimal. A cold is caused by a great many viruses. These viruses are transmitted from person to person via respiratory droplets and on surfaces. The closer people pack together, the more likely the virus will be transmitted from one person to another.

When are people most often closer to other people? The winter – people spend more time inside, heating systems recycle the air; it’s the season for sharing. The cold weather encourages people to stay inside, where they are more likely to receive a viral gift from someone else.

So the cold does play a role, including a slight decrease in immune function due to changes in blood flow, and the fact that cold air holds less moisture, so your mucosal membranes dry out and are a bit more susceptible to being invaded by a virus. But cold is by no means the main culprit, so I propose a letter writing campaign to rename the cold – maybe you could catch a crowd, or a doorknob, or maybe we could just call it Dennis.

O.K., now that thatissue is resolved, back to the question of how cool air and exercise can help you breathe better when you have a “cold.” The key is a concept called nasal resistance.

Nasal resistance is the main way to slow air entering the

lungs. Being slower and higher pressure keeps the lungs

from overinflating or collapsing. The nasal vestibule (1)

squeezes together as you inhale, the smaller space prevents

too much air from entering. Inside is the vestibule is the

valve (3), the narrowest region. The turbinates (5-8, superior,

middle, and inferior) can expand slightly to decrease the

nasal volume. There are small muscles (alae nasi) in the

vestibule which can contract to decrease resistance as well.

Paralysis of these muscles leads to collapse of the naostrils.

Basically, the more stuff in the way of the air, the higher

the resistance.

Nasal resistance is an important way to keep our lungs from popping or collapsing. If the resistance to air entering the lungs is too high, the lungs will collapse like a balloon with a hole in it. If the resistance is too low, you could overinflate and pop them – also like a balloon. The nose, believe it or not, is responsible for about 50% of the resistance to air entering the lungs (see picture).

Having a cold increases mucous production (trying to catch viral particles before they reach your cells). A cold virus infection also puffs up the nasal tissues due to immune inflammation reactions. These responses increase nasal resistance and decrease airflow. It is much harder to get the same volume of air into your lungs through your nose. This observation won’t win me the Nobel Prize; we’ve all experienced it.

Exercise reduces nasal resistance through stimulation of the sympathetic nervous system. Hard physical work is a lot like the fight or flight response. Your body vasoconstricts vessels in the periphery so that more blood can go to the big muscles. You also need more oxygen, so the alae nasi muscles in your nose relax and the airways get bigger. Both of these actions decrease nasal resistance and increase airflow to the lungs. During a cold this is helpful since your ventilatory spaces are clogged with snot.

On the other hand, my sojourns into the brutal winter are against the literature. Cold air is supposed to increase nasal resistance. Cold air is bad for the lungs – it saps heat from the rest of the body. Therefore, the nose anatomy functions to warm the air. When cold air enters and triggers the TRPM8 cool sensors (there’s our first reference to the topic we have been discussing), the alae nasi muscles contract and the blood vessels in the nasal mucosa dilate. This swells the internal nasal tissues, increasing the surface area and thereby transferring more heat to the air before it reaches the lungs.

Rebreathing is a good way to reduce nasal resistance. Just

hold your breath for a while or breathe into a paper bag.

Increased CO2 in blood brings vasoconstriction, so tissues will

shrink and breathing will be easier. The same goes for changing

from a supine (lying) position to standing or sitting. The change

in filling of sinus vessels and nasal vessels will shrink tissues as

well and you will breathe easier for while.

This should increase the nasal resistance, which will be high anyway due to all the mucous production going on. The cold air should make it harder to breathe, but for me it clears my nose when I have a cold. Where’s the disconnect? In fact, what I have always attributed to the cold air is probably a result of what I was doing, not where I was doing it.

I go out in the cold to chop wood or shovel snow - I have a tendency to attack my work, so these activities become exercise. Upon reflection, I now realize that it was once again exercise that was reducing my nasal resistance and allowing me to breathe more normally, not the act of going out into the cold. I’m caught in my own correlation-causation trap; there were other factors that I had failed to take into account. I had too many variables in my experiment! I never considered going out into the snow and not working hard.

Now let’s consider another cold and cough treatment, Vicks VapoRub. The active ingredients in this concoction are menthol and camphor. We have talked recently about how menthol is a TRPM8 agonist (so mints make everything seem colder), and that camphor is an agonist for both TRPM8 and TRPV1, so it can induce feelings of warmth or cool, depending on the concentration and placement.

You rub the Vicks on your chest when you have a cold. The camphor stimulates TRPV1 and makes your trunk feel warm. The menthol vapors rise and your breathe some in, they make your nose less stuffy. Or so it seems.

Here is a late 1950’s ad for Vick’s VapoRub. Which child would

you rather have? A simple greasy rub on the chest and all the

problems are solved. If you can read the headline, it seems that

atom tracing shows that the vapors get into the lungs. One – is

there anything more 1950’s than talking about atoms? Two – we

now know that Vicks works in the nose, not the lungs.

The commercials for Vicks VapoRub show the menthol/camphor fumes entering the nose, and the cold sufferer then relaxing and breathing more easily - convincing stuff, visually. It does seem that it's easier to breathe. But it’s all a trick our brains are playing on us. Remember that TRPM8 senses cool/cold temperature differences.

When you breathe in quickly and deeply, the rushing air is colder than the air that was just hanging out in your nose. This triggers the TRPM8 sensor, and your brain interprets it as a lot of air rushing up your nose and to your lungs – decoding the signal means that you are breathing well and deeply.

Now switch to the situation where you have a cold and can’t bring in air through your nose. The menthol/camphor of the Vicks VapoRub penetrates your nose and stimulates the TRPM8 channels there. Your brain interprets this data just as if cool air was rushing over the TRPM8 channels. It concludes that you are breathing well. You think you are breathing easier, but no actual change has occurred in nasal resistance! A 2008 study showed this to be the case. Bad brain! We can’t fool Mother Nature, but apparently she fools us all the time.

One thing that is true about the VapoRub is that it can calm a cough. Menthol, in particular, is excellent in its anti-tussive capability. Tussiveis from the Latin tussis, meaning a cough, although I’ve never heard anyone say, “I have a very bad tussis today.” Likewise, does this mean that when you are coughing, you are really tussing? Do you need to “tuss up” that ten dollars you owe me? (Yes, I am aware of the snickering from those of you of the Cornish persuasion - look it up.)

Developed in 1865, Lofthouse was looking to help fisherman

with their seasonal colds. The lozenge contains menthol and

eucalyptus, just like Halls, but much earlier. The fisherman

liked them so much they called them their friend. Hence the

name; they’re still sold today. Menthol drops can calm a cough,

but menthol is also slightly analgesic, so some throat pain can

be reduced by them as well.

Nevertheless, recent studies have shown that menthol, through its activation of TRPM8, does have a calming effect on a cough. We knew this was so, Halls mentho-lyptus (for menthol and eucalyptus – another TRPM8 agonist) drops have been around since 1930’s, with other brands like Smith Brothers and Pines having predated Halls by some 80 years. But the 2012 study showed that menthol’s action on cough was through TRPM8 action.

A 2013 study went further. It assessed the anti-tussive action of menthol in guinea pigs and showed that the effect on TRPM8 was only effective when it was in vapor form and when it was applied to the nasal passages. Menthol on trachea or throat TRPM8 had no effect on cough. So – when you use Halls cough drops, it's the vapors from the dissolving drops that go up your nose and help stop the cough – don’t chew on them and swallow! You put them in your mouth, but they don’t act there. But don’t stuff them up your nose either – did I need to say that?

We have considered TRPM8 in thermoregulation, nasal resistance, and cough. Next week, let’s show some funky functions for cold receptors – like how they can stop cancer or how they screw up opiate addiction withdrawal.

Lindemann J, Tsakiropoulou E, Scheithauer MO, Konstantinidis I, & Wiesmiller KM (2008). Impact of menthol inhalation on nasal mucosal temperature and nasal patency. American journal of rhinology, 22 (4), 402-5 PMID: 18702906

Buday T, Brozmanova M, Biringerova Z, Gavliakova S, Poliacek I, Calkovsky V, Shetthalli MV, & Plevkova J (2012). Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels. Cough (London, England), 8 (1) PMID: 23199233

Plevkova J, Kollarik M, Poliacek I, Brozmanova M, Surdenikova L, Tatar M, Mori N, & Canning BJ (2013). The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol. Journal of applied physiology (Bethesda, Md. : 1985), 115 (2), 268-74 PMID: 23640596

For more information or classroom activities, see:

Cold viruses –

http://www.brainpop.com/educators/community/bp-jr-topic/colds-and-flu/

http://www.discoveryeducation.com/teachers/free-lesson-plans/allergies-v-viruses.cfm

http://www.developingteachers.com/etgplans/etg1.htm

https://www.google.com/#q=cold+virus+classroom+activity

http://www.theguardian.com/teacher-network/teacher-blog/2012/dec/23/colds-viruses-resources-lessons

http://www.everydayhealth.com/cold-flu/exercise-for-common-cold.aspx

http://www.teachengineering.org/view_lesson.php?url=collection/duk_/lessons/duk_virus_mary_less/duk_virus_mary_less.xml

http://www.ncsta.org/reflector/archives/summer07/activity.html

http://www.eduplace.com/rdg/gen_act/survival/survive.html

http://www.scholastic.com/browse/article.jsp?id=3751431

http://health.howstuffworks.com/diseases-conditions/cold-flu/cold-causes.htm

http://www.mayoclinic.org/diseases-conditions/common-cold/basics/definition/con-20019062

http://www.cdc.gov/getsmart/antibiotic-use/uri/colds.html

http://kidshealth.org/parent/infections/common/cold.html

http://www.wired.com/2012/03/ff_antivirals/

http://www.webmd.com/cold-and-flu/cold-guide/understanding-common-cold-basics

http://www.commoncold.org/

nasal resistance –

http://emedicine.medscape.com/article/874822-overview

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&sqi=2&ved=0CDEQFjAB&url=http%3A%2F%2Fotolaryngology.wdfiles.com%2Flocal--files%2Frhinology%2FNasal%2520resistance%2520%25E2%2580%2593%2520Ent%2520Scholar.pdf&ei=7FdBU_LlFoOZ2QXn1IHgCQ&usg=AFQjCNE0ZdBvXvkoPyXGZ23QL7vY809V6A&sig2=kR4-w2ncfzB8HKK3vWezfg

http://www.drtbalu.com/nasal_resis.html

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=6&sqi=2&ved=0CFQQFjAF&url=http%3A%2F%2Fwww.researchgate.net%2Fpublication%2F7367287_Nasal_obstruction_and_its_impact_on_sleep-related_breathing_disorders%2Ffile%2Fd912f50b9db2c55ce8.pdf&ei=7FdBU_LlFoOZ2QXn1IHgCQ&usg=AFQjCNHZpXTK7gmaFTJCJD8D6feYbH_sNw&sig2=beqT9entOz6HfWYWcJKPow

http://www.specialistmedicalrandwick.com.au/the-chest-and-sleep-centre/nasal-resistance-testing/

http://oto.sagepub.com/content/143/2_suppl/P164.2.full.pdf+html

menthol and cough –

http://www.webmd.com/cold-and-flu/cold-guide/cough-syrup-cough-medicine

http://www.wisegeek.org/what-are-the-benefits-of-menthol-cough-drops.htm

https://www.zocdoc.com/answers/4547/do-cough-drops-work#.

http://askville.amazon.com/limit-cough-drops-period-time/AnswerViewer.do?requestId=16427900

http://www.aedrops.com/how-does-menthol-relieve-throat-irritation/

#virus #tussis #TRPM8 #thermoregulation #nasal resistance #menthol #exception #cough #cold #camphor

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stuffxthree-blog · 11 years ago

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Cold Keeps You Warm

Biology concepts – thermoregulation, TRPM8, vasoconstriction, brown adipose tissue, agonists/antagonists

Pep-O Mint was the first Lifesaver flavor, invented

in 1912. This was followed quickly by the Lifesaver

car in 1918. Built on a Dodge truck chassis, the

important word was dodge, since the car didn’t have

a windshield and the driver had to stick his head out

the side window to see ahead.

Let’s do a demonstration. Borrow a peppermint lifesaver from a friend (well, not borrow really - you’re not going to give it back). Place it between your teeth, so you can close your lips around it and suck air in through the hole (this will be the control for our experiment).

Now put the candy in your mouth like normal and suck on it for a minute or two – don’t chew it up. Swallow to get the saliva out of your mouth and take out the candy. Now take in a long slow breath of air. How does it feel? Did the room get colder in the last two minutes?

If you are like most people, the air feels colder in your mouth now that you've eaten menthol (peppermint). Just like capsaicin can make hot things seem hotter via TRPV1, the cold sensing channel we talked about last week, TRPM8, can make room temperature air seem colder.

The TRPM8 cold sensing ion channel is important for keeping our body temperature in a normal range. Just like TRPV1 senses when we are too warm and initiates cooling mechanisms, TRPM8 tells us we are cold and institutes procedures to make us warmer. One way is to stimulate vasoconstriction, so less heat is lost from the blood through our skin. I’m sure you have noticed that your skin is paler when you are out in the cold. This is from vasoconstriction limiting the amount of blood moving into the surface vessels.

When your core temperature varies from your skin

temperature by too much, TRPM8 will institute

heat conserving and/or generating mechanisms.

For heat conservation, more of the blood (left

cartoon) that goes the skin can be shunted through

the capillaries before it gets to the surface. This

helps reduce the amount of heat loss via radiation

of the heat in the blood. On the right is the effect of

the arrector pili muscles. When cold, they contract

and raise the hairs, trap air, and therefore trap body

heat against the skin so less heat is loss. The

contraction also mounds up the skin – goosebumps.

TRPM8 can also stimulate shivering and the burning of fat to generate warmth. Through the sensations and reactions of TRPV1 and TRPM8, animals learn to maintain a more or less constant body temperature, seeking out temperatures that are good for physiology and avoiding temperatures that would change their core temperature by too much. This was shown in a series of studies described in a 2013 paper, where mice without temperature sensing receptors TRPV1 and/or TRPM8 would not avoid hot or cold temperatures and were prone to hyperthermia and or hypothermia.

So how does the TRPM8 channel sense cold? We saw that with TRPV1 the heat induced a conformation change that caused the channel to open and calcium to flow in and start a neural action potential. Could cold induce a conformation change as well? Maybe. What was seen in a 2011 study was that TRPM8 neurons started firing when the temperature dropped to 28.4˚C (83 ˚F). As the temperature dropped, the neurons would fire more and more strongly, so it could act as a thermostat.

When the temperature dropped severely (to 10˚C) the core temperature changed little, but skin temperature dropped considerably. The TRPM8 thermostat was targeted to keeping the organs and brain warm, not the skin. It accomplishes this by diverting heat via the blood away from the skin. A 2012 study showed that TRPM8 antagonists brought a systemic hypothermia, but repeated use of the antagonist reduced the magnitude of the temperature drop – so unlike most TRPV1antagonists (that bring bad hyperthermia), TRPM8 antagonists might be helpful in medicine.

We don’t yet know how cold activates TRPM8. In

warmth, the channel is closed. With cooler

temperature or menthol (M), the channel is open,

but we don’t know if cold achieves this by a

conformation change. If really cold, the regulatory

proteins break away and the channel can’t work.

So TRPM8 is active in a range of temperatures.

But this still doesn’t answer the questions as to how TRPM8 can detect cool temperatures. It may or may not be a conformation change, but what does occur is an alteration in the apparenttemperature threshold of the neuron. The cold temperature should inhibit firing (cold slows metabolism and chemical activity), but here it increases the metabolism and biochemical activities. TRPM8 makes the neuron seem warmer so that the firing is easier, and this transfers information that the area is in fact colder! That’s an exception.

However it manages the feat, TRPM8 is important for keeping mammals warm. It might even help you lose weight. Chronic cold stimulates TRPM8 all the time, and this ramps up your heat production. A 2012 study showed that for mice, chronic cold could actually prevent them from becoming obese.

Heat production takes energy, and burning more energy helps you lose weight. But there is an important balancing act at work here. Our fat also protects us against losing too much heat in the cold. Look at whales, they have a layer of blubber all over their body to insulate them from the cold water. It has been shown that people with an even layer of fat all over their body make good cold weather swimmers, like Lynne Cox, who swam from her perfectly good boat to the shores of Antarctica and across the Bering Strait in 4˚C (40˚F) water.

On the other hand, bactrian camels keep their fat limited to two humps (one for dromedaries) in order to prevent against having too much insulation in their desert environment. Camels need to be able to dissipate lots of heat. And no, the humps aren’t for storing water! Remember we said that one of the great things about fat is that you can store lots of energy in a small space precisely because can be stored without water.

In brown adipose tissue, there are ATP synthase

proteins (for making ATP) and uncoupling proteins

(for generating heat) in the inner mitochondrial

membrane. When cold, the number of UCP proteins is

increased, as is the number of mitochondria. About

65% of the energy of the proto gradient formed by the

respiratory chain can be converted to ATP by the ATP

synthase. But using the UCP to allow protons back in

means that 100% of the energy is changed to

heat, no ATP is made.

It seems that TRPM8 can stimulate the burning of fat to produce heat. We talked about this before with capsaicin as well. Brown adipose tissue has more mitochondria and more of a protein called UCP1 (uncoupling protein). UCP separates mitochondrial energy burning from ATP production; all the energy goes to making heat.

A 2014 study showed that chronic cold makes brown fat AND white fat upregulate UCP and generate more mitochondria. It makes white fat more like brown fat and this means that more fat is burned. In mice, this chronic cold is enough to keep them from becoming obese, even on a high glucose diet. So if you want to stay skinny, turn your thermostat way down all year round.

The study that showed that chronic cold kept mice from getting fat wasn’t as cruel as it may sound. They didn’t keep the mice at cold temperature all the time, they used a chemical that could mimic the cold and make the TRPM8 channels fire all the time. What did they use? Menthol.

This is a good place to point out the similar exception for TRPV1 and TRPM8. They are both proteins that can be activated by both environmental factors and by chemicals. We saw that TRPV1 is activated by capsaicin and other chemicals. The opening of the channel and firing of the neurons in response to these chemicals was interpreted exactly the same as if the neurons were exposed to damaging heat.

There are many agonists for TRPM8, similar to TRPV1.

In fact, some things that activate TRPM8 also activate

TRPV1. An interesting one is the synthetic agonist called

icilin. It is thousands of time more active on TRPM8 than

cool temperatures. However, it binds to TRPM8 in a

completely different way as compared to menthol and

cool temperatures.

With TRPM8, menthol (in mints) and some other chemicals open the ion channels just as cool/cold temperatures would, and our brains trick us into thinking the mouth or skin is colder than it really is. That’s what is behind our lifesaver trick at the beginning of the post. The air wasn’t any colder; your brain makes you think it was.

Menthol is a terpene alkaloid contained in plants of the genus Mentha (mint, from the Greek mintha). This genus includes 25 species of aromatic herbs, such as peppermint, spearmint, and pennyroyals. Most mints can be and are used in making foods and drinks, but the pennyroyals also contain toxic compounds that will induce liver failure and kill you.

At low concentrations in the mouth or on skin, menthol produces a pleasant cooling sensation, but higher concentrations produce burning, irritation and pain (this has to do with how it activates TRPV1, TRPV3, TRPM8, and TRPA1, depending on the concentration).

In the oral cavity, a small amount of menthol actually desensitizes TRPV1 activation by heat and capsaicin, so chili peppers might not seem so spicy. Biochemical evidence shows that menthol sparks a release of glutamate from neurons. But an increase in glutamate neurotransmitter can actually stop the type C nociceptive neurons from firing (an inhibitory neurotransmitter in this case).

Pennyroyal is a member of the mentha genus (left). It, like

many plants (right image is orange mint), has been used in

medicine. It can be ground and drunk with water to settle a

sick tummy or to induce perspiration. However, pennyroyal

has to be used carefully. In addition to menthol, it contains a

chemical called pulegone. Too much pulegone and here

come the seizures, organ failure and death. Don’t confuse

the two mints.

At this same time, menthol (or other TRPM8 agonists) will sensitize TRPM8 receptors, the combination of these two results means that sucking in air after a wintergreen or peppermint candy will make the air seem colder, but might also make a hot cup of coffee seem cold as well.

I think the only way to resolve these ideas is to start a controlled experiment. What do you predict would happen if you froze a chili pepper and then took a bite? How about eating peppermint laced with capsaicin, or a strong peppermint flavored tea that has been heated to near boiling? Who will win out, TRPM8 or TRPV1?

It may not be so easy to figure out. The agonists and antagonists of the TRPs can have effects on multiple receptors and the effects can be different at different concentrations. Menthol sensitizes TRPM8, but if the temperature is above 37˚ C (98˚ F) it actually makes TRPV3, a heat sensor, more active (2006).

Camphor comes from some species of laurel trees (left), as well as

from some herbs of the mint family, like camphor basil (right).

Dried rosemary leaves are up to 20% camphor. Camphor has

been used for many things, including as a flavoring in asian

sweets, an analgesic, an insect repellent, and a rust proofing

agent. I find it hard to rectify those uses with one another.

Take oil of wintergreen in BenGay for example. We showed that it was a TRPV1 agonist, so it could induce analgesia by counter irritation. But it is also a TRPM8 agonist. In the oral cavity at lower concentrations than used in BenGay, it activates TRPM8 and desensitizes TRPV1. The lifesaver trick will work with peppermint, spearmint, and wintergreen flavors; they all activate TRPM8.

And then there’s camphor. Like menthol, camphor is terpenoid chemical. Camphor can make things seem cool (by activating and sensitizing TRPM8), but it’s more complicated. It actually potentiates both heat and cold sensations. A 2013 study shows that it can sensitize or potentiate TRPV1 (painful hot) and TRPM8 (non-painful cool). Camphor can even activate the noxious cold sensor TRPA1 that we will talk about in a couple of posts. This means that it can be analgesic or painful, warming and cooling.

It becomes even more confusing when you realize that camphor activates TRPM8, just like menthol, but can inhibit the activation of TRPM8 by menthol. Weird, right? Well, consider this – Vick's VapoRub contains menthol and camphor as its active ingredients. Next week, we'll investigate how they can work together to open your nose and make you feel both warm and fuzzy while they cool and invigorate you at the same time.

Pogorzala LA, Mishra SK, & Hoon MA (2013). The cellular code for mammalian thermosensation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (13), 5533-41 PMID: 23536068

Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, Vencato J, De Stefani D, Silvestrin V, Rizzuto R, Bassetto F, De Caro R, & Vettor R (2014). Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Molecular and cellular endocrinology, 383 (1-2), 137-46 PMID: 24342393

Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y, Jin R, Ma L, Wang P, Zhu Z, Li L, Zhong J, Liu D, Nilius B, & Zhu Z (2012). Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. Journal of molecular cell biology, 4 (2), 88-96 PMID: 22241835

Selescu T, Ciobanu AC, Dobre C, Reid G, & Babes A (2013). Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin. Chemical senses, 38 (7), 563-75 PMID: 23828908

For more information or classroom activities, see:

Thermoregulation –

http://beyondcoldwaterbootcamp.com/en/thermo-regulation

http://www.unm.edu/~lkravitz/Article%20folder/thermoregulation.html

http://dwb.unl.edu/teacher/nsf/c01/c01links/www.science.mcmaster.ca/biology/4s03/thermoregulation.html

https://worldofbiology.wikispaces.com/biol+2+classroom+presentations

http://www.pbslearningmedia.org/resource/lsps07.sci.life.reg.heatexchange/blood-flow-and-thermoregulation/

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=5&ved=0CDwQFjAE&url=http%3A%2F%2Fbio.classes.ucsc.edu%2Fbio131%2FThometz%2520Website%2F9%2520-%2520Thermoregulation%2520Lab%25202012.pdf&ei=zSIzU6SuFqPEyQGZ4oD4CA&usg=AFQjCNERS9ye-sPF7qZM-dJHUsFPQ031Tw&sig2=xLwl_fcQ3rIxKcZiLictmw

http://www.life.umd.edu/classroom/bsci338m/Lectures/Temperature.html

https://www.khanacademy.org/science/mcat/organ-systems/muscular-system/v/thermoregulation-by-muscles

https://www.youtube.com/watch?v=kg7QdpOug2Y

http://www.nsta.org/publications/news/story.aspx?id=53687

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=16&ved=0CEgQFjAFOAo&url=http%3A%2F%2Fwww.tarleton.edu%2F~jblevins%2Fexercise%2520physiology%2FSpring%252009%2Fpowers7_ppt_Chap12%2520%255BRead-Only%255D%2520%255BCompatibility%2520Mode%255D.pdf&ei=HSMzU-ToHaSHygGerwE&usg=AFQjCNHxnlMTdNoOKd1p9lJrSyv6yew6Jg&sig2=fsvfEpvq9j0LTxOVaSYQwQ

http://www.studyblue.com/notes/note/n/ch-40-hwpdf/file/9213703

http://vce-unit1and2biology.wikispaces.com/thermoregulation

http://en.wikioffuture.org/Dissertation_Research:_Olfactory_Modulation_of_Thermoregulation_and_Flight_in_Moths

http://hyperphysics.phy-astr.gsu.edu/hbase/thermo/heatreg.html

https://www.youtube.com/watch?v=TSUCdLkI474

http://people.seas.harvard.edu/~jones/cscie129/pages/health/thermreg.htm

https://www.stanford.edu/group/stanfordbirds/text/essays/Temperature_Regulation.html

https://www.mdc-berlin.de/26954638/de/research/research_teams/temperature_detection_and_thermoregulation/Research?cntx=40550329

#zoology #TRPV1. TRPM8 #thermoregulation #obesity #menthol #exception #camphor #brown adipose tissue #animal

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stuffxthree-blog · 11 years ago

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Everybody Wants To Be Cool

Biology concepts – TRPM8 cold sensor, menthol, evolution, cold pleasure

The old ads for menthol cigarettes are fascinating, from a biology point of view. The “cool” and the “refreshing” aspects were reflected by using spring and summer outdoor pictures, most often with lots of cool water. At the end of today’s post, we see why this was so. We also see an African American, since menthol cigarettes were targeted much more strongly urban African Americans. They were newer smokers and in typically hotter environments, so the coldness and soothing abilities of the menthol were great selling points.

In 1924, Lloyd “Spud” Hughes patented the menthol cigarette. Not a big deal in the beginning, Hughes sold his patent to a cigarette manufacturer who marketed them as Spud cigarettes in 1927. They became the fifth largest seller, although there still wasn’t much in the way of profit. Kool cigarettes came along in 1933 and advertised the menthol casket nails as “soothing to the throat” and claimed they were actually medicinal.

The menthol cooled the feel of the smoke in the mouth and throat (much more next week on hos menthol feels cool). Menthol made it feel as though you weren’t sucking hot smoke into your lungs. And menthol deadened the discomfort that cigarettes could generate by irritating the lining of the throat and lungs.

These days, almost 90% of cigarettes contain some menthol, even if they don’t advertise themselves as menthol cigarettes. Why? The “cool” factor lends itself to novice smokers, while the throat analgesia appeals to the seasoned addict. But that may not be the main reason. A study from 2004 showed that menthol slows the metabolism of nicotine.

Slowing the metabolism of nicotine, menthol results in nicotine staying in the system longer and at greater concentrations - just perfect for developing a physical addiction. This, combined with the ability to comfortably smoke more cigarettes because of the slight throat numbing and apparent cooling of hot smoke would encourage more consumption, more addiction, and therefore more profit.

There is now (2013-2014) a push by the US Food and Drug Administration to ban or regulate menthol cigarettes. Did you know that menthol addition to shampoo is federally regulated but its addition to cigarettes is not? Let’s look at some of the reasons a change is being considered.

The tobacco plant has supplied cells that are used to show the danger of menthol cigarettes. I just love that. But tobacco has been involved in science in other ways as well. New efforts are underway to have genetically modified tobacco produce medicines or biodisel. And the tobacco mosaic disease actually led to the discovery of viruses and the coining of the word “virus.” This same virus was instrumental in establishing the fields of virology, plant virology and all of molecular biology.

A 2013 series of experiments showed that menthol-containing cigarette smoke is more toxic to cells than non-mentholated cigarette smoke. Menthol alone had no toxic effect on the cells, so it is the combination of menthol and cigarette smoke that kills cells at a higher rate. In the most delicious irony imaginable, the two cell types that the researchers used to monitor cell death after smoke exposure were human lung cells and tobacco plant cells!!!

Additional recent evidence suggests that menthol interacts with the nicotine receptor in the brain. Brody and his co-workers showed that menthol cigarette smoke up regulates the number of nicotine receptors in the brain more than regular cigarette smoke. This might explain why it is harder for menthol cigarette smokers to quit smoking and why more of them fail in their efforts to quit.

Another 2013 study showed that menthol decreased the activity of the nicotine receptor, so that more nicotine was necessary to reach the same level of activation. Once again, this would contribute to a physical addiction. Just a bit of information if you are considering taking up the habit - the “cool” factor and refreshing cold of mentholated smoke just may contribute to your death.

So sensing cool or cold has its place in biology and in society. Chili peppers are sensed as burning hot because they just happen to bind to and activate the TRPV1 heat sensing ion channel – it’s the biological joke being played on us that we have talked about before. TRPV1 a receptor that reacts to both environmental (temperature, pH) conditions and food substances.

On the other end of the scale is the sense of cold. Do organisms sense cold like they sense heat? Isn’t cold just a lack of heat, so that a feeling of cold is just a lack of activation of TRPV receptors? Nope. There are receptors specifically designed to sense cool or cold. Are there exceptions in cold sensing like there were for heat? You should know that answer by now.

Melastatin was the first TRPM protein discovered. The name comes from melanin (the pigment in skin and hair cells) and statin, which means to stop. It was important because it could stop the invasion of tumors of melanin producing cells. We call this maliganant melanoma, one of the deadliest cancers. Tumors with more melastatin were less aggressive and invasive, while those with little melastatin killed patients much sooner.

We learned recently that there are six different TRPV cation channels, and at least four of them are important for sensing different ranges of temperatures. In some cases, like with TRPV1, noxious heat (or capsaicin) results in a sensation of pain and burning, and the body’s mechanisms for cooling are turned on.

Another TRP family member, TRPM8, turns out to be the receptor channel that senses cool temperatures, from about 28˚C (82 ˚F) down to about 10˚C (50 ˚F) or even lower. The M stands for melastatin, a name for the first TRPM, before they knew it was a family of proteins. Now there are eight known members of the TRPM subfamily of TRP ion channels.

TRPM5 is particularly interesting for our recent discussion of taste, since it works to change the mechanical energy of taste particles + taste receptors into an electrical signal that is sent to the brain. Once again, we see the close relationship between the ion channels, like TRPV1 for capsaicin, and the taste sense. Maybe cold and TRPM8 also influence taste. We shall see.

Less is known about TRPM8 as compared to TRPV1 although they were discovered about the same time (early 2000’s). The pain associated with capsaicin and noxious heat aspects of TRPV1 made it sexier to study. I think we will see that TRPM8 and TRPA1 can be quite interesting in their own right.

Here’s a quick overview of the thermosensing by TRPs. We will talk about it more next week. The TRPVs are generally for warm temperatures, while TRPM8 is for cool temp.s. TRPA1 will be our focus in a few weeks; it senses painful cold. But notice, the garlic and wasabi pictured with TYRPA1 also activate TRPV1, and the camphor shown for TRPV1 also activates TRPM8 (next week). These are related and complex systems.

First of all, TRPM8 is involved in thermoregulation, just as is TRPV1. In humans and other mammals (the naked mole rat excepted), when TRPV1 is activated, the body automatically thinks it is too hot and initiates cooling mechanisms. With TRPM8, the effect is the opposite. Stimulation of this ion channel tells the body that it is too cold, and mechanisms are initiated to increase the core temperature. We will talk about how TRPM8 helps to regulate body temperature next week.

The big question is why it’s important to sense cold as well as heat. For some reason, we sense cool/cold with some distinct proteins and heat with different proteins. Remember, evolution doesn’t follow a plan to make things complex, functional and efficient. Sometimes the functions occur at separate times and come from different pathways; there is no evolutionary goal or roadmap to a destination. It’s all chance.

A 2013 review has an interesting hypothesis as to why sensing cold/cold is so important, aside from just alerting us to the chance we might freeze to death. Based on mouse study results from as early as the 1970’s, and on the answers that human subjects give, it seems that coolness is an evolutionary plus. No- I don’t mean that The Fonz from Happy Days was an evolutionary leap into the future, I mean that cool sensations somehow help us survive and propagate.

We typically heat food because it increases aroma, increases taste, and reduces the work in digestion. These are all important for getting us the nutrients and the calories we need. Taste, as we said several weeks ago, is nature’s way of getting us to eat those things we need and avoid those foods that might harm us.

So why would cool foods or sensations be helpful? Cooling would decrease aroma and taste, so it must be something other than taste. The obvious reason for drinking something cold would be that it cools off our body – but it doesn’t work that way. As soon as you drink a cold drink, your body reacts to the cold by constricting the blood vessels near the cold surface so that heat is not lost. TRPM8 also invokes heating mechanisms after it is activated by the cold water or soda. So in truth, cold drinks don’t cool you off.

On the left is a mint julep, famous in Kentucky and the Deep South during the hot summers. It contains Kentucky bourbon, which is why it is brownish. On the right is the mojito, also good on hot days, but uses rum, so it is popular in the Caribbean and Florida, where the rum is. The connection? They both use mint (menthol) to increase the coolness and refreshing characteristics of the drinks. TRPM8 hard at work to make your Saturday evening a success.

Yet they still feel refreshing on a hot day – what gives? Refreshing may be the key word here. People use many words that together make up “refreshing.” They say that cold drinks revive them, restore their energy, arouse them, reduce stress. All these feelings would promote survival behaviors in a hot environment. But we might also drink a cold drink on a cold day and deem it pleasant. In this case, pleasant can be equated to useful – and useful means promoting survival.

The 1970’s experiments showed that mice would lick a cold piece of metal when they were thirsty, showing that cold helps satisfy thirst. The more amazing thing was that the mice would lick the cold metal even if they could drink all they wanted. This meant that cold drinks were a reward; they activate a pleasure center in the brain. Many studies and experiments have shown these results to be true for humans as well.

So a cold drink on a cold day might be seen as unpleasant, while a cold drink on a hot day is very pleasant (useful). But more important, a cold drink on a cold day when you are thirsty is seen as pleasant and satisfying. It’s our brain helping us to garner the things we need; if cold water is all that’s available to a cold caveman, he better want to drink it. It works the same on skin, cold applied to the skin on a hot day – such as jumping into the pool on a warm day is seen as pleasant, even if it doesn’t cool the body all that much (see above). But the same cannonball on New Years day with the Polar Bear Club, is completely unpleasant.

Comedian and late night talk show host Jimmy Fallon took the Polar Bear Plunge in Chicago this past New Years. Basically, 3000 people jump into a 34˚F (1˚C) Lake Michigan to support Special Olympics. Some do it for the charity, some for the thrill, some because they are unbalanced. For those with a heart condition, it can kill you.

The brain is an amazing organ, it works with our body to get us what we need, and tricks us into doing it – that’s basically what pleasurable things are, evolutionary tricks. But remember – too much of a good thing can be bad in an environment where we can manipulate nature. Unfortunately, evolution doesn’t look into the future, it only worries about what keeps us alive at this moment. This explains the danger of menthol in cigarettes – we find it pleasant even if it is bad for us in the long run.

We will talk more about the TRPM8 next week, about how menthol seems to cool you down, how TRPM8 is a lot like TRPV1, and how it may save your life.

Eccles R, Du-Plessis L, Dommels Y, & Wilkinson JE (2013). Cold pleasure. Why we like ice drinks, ice-lollies and ice cream. Appetite, 71, 357-60 PMID: 24060271

Noriyasu A, Konishi T, Mochizuki S, Sakurai K, Tanaike Y, Matsuyama K, Uezu K, & Kawano T (2013). Menthol-enhanced cytotoxicity of cigarette smoke demonstrated in two bioassay models. Tobacco induced diseases, 11 (1) PMID: 24001273

Brody AL, Mukhin AG, La Charite J, Ta K, Farahi J, Sugar CA, Mamoun MS, Vellios E, Archie M, Kozman M, Phuong J, Arlorio F, & Mandelkern MA (2013). Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 16 (5), 957-66 PMID: 23171716

Ashoor A, Nordman JC, Veltri D, Yang KH, Al Kury L, Shuba Y, Mahgoub M, Howarth FC, Sadek B, Shehu A, Kabbani N, & Oz M (2013). Menthol binding and inhibition of α7-nicotinic acetylcholine receptors. PloS one, 8 (7) PMID: 23935840

For more information or classroom activities, see: Menthol in cigarettes – http://smokefree.gov/menthol-cigarettes http://www.cancer.org/cancer/news/expertvoices/post/2013/08/28/menthol-cigarettes-whats-the-big-deal.aspx http://www.npr.org/2014/01/01/258671720/fda-weighs-restrictions-possible-ban-on-menthol-cigarettes http://www.huffingtonpost.com/2013/11/22/latino-smokers-menthol-cigarettes_n_4326094.html http://www.forbes.com/sites/robwaters/2013/11/20/menthol-an-unequal-opportunity-killer-why-hasnt-the-fda-banned-it/ http://www.webmd.com/smoking-cessation/news/20110323/are-menthol-cigarettes-riskier-than-non-mentholhttp://www.theguardian.com/society/2013/oct/08/menthol-cigarettes-to-be-banned-eu http://www.fool.com/investing/general/2013/12/14/judgement-day-for-menthol-cigarettes-is-getting-cl.aspx

http://www.dw.de/european-parliament-approves-stricter-tobacco-regulations/a-17458107 In lieu of additional web sources, I suggest investigating the National Center for Biotechnology Information site (http://www.ncbi.nlm.nih.gov/) from the National library of Medicine. This site has many resources, from looking at the amino acid or nucleotide sequences from any protein or gene you can imagine (GenBank, http://www.ncbi.nlm.nih.gov/genbank/) to scientific journal articles that may or may not be available to you. Look at PubMed Central (PMC, http://www.ncbi.nlm.nih.gov/pmc/) where all articles are available free to the public.

#zoology #TRPV1. TRPM8 #thermoregulation #exception #cool sensing #animal

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stuffxthree-blog · 11 years ago

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Capsaicin Receptors – Matters Of Life And Death

Biology concepts – cochlear amplification, capsaicin, tinnitus, neural plasticity, long term depression, sperm capacitation, acrosome reaction, apoptosis, reactive oxygen species, cancer

On the left are the Red Hot Chili Peppers. I am most interested in the

member on the right – Flea. Acknowledged as the second best rock

bassist of all time (right behind John Entwhistle), he gathers as much

or more attention for his name choice and his seeming inability to

wear a shirt. On the right is Donnie Thornberry, of the Wild

Thornberrys. He was a feral child raised by animals in Africa. His

character is voiced by Flea – ahhh, it’s starting to make sense.

I have never been a fan of the Red Hot Chili Peppers (sometimes known as RHCP). The music is nails on a chalkboard to me, and their bassist is named for a plague-carrying arthropod. But in the interest of fair play, I looked deeper. In late 2013, lead singer Anthony Kiedis and “Flea” produced a film intended to honor the life of jazz pianist Joe Albany. Add to this that Kiedis acted in an ABC After School Special when he was a teenager, and I now see that the Chili Peppers are more than just bad music.

I use this story to introduce today’s topic - there is so much more to the capsaicin in chili peppers than just heat and pain. We learned last week how capsaicin and other TRPV1 agonists can combat obesity and damage from stroke, but these abilities were related to the TRPV1 function in thermoregulation. Today let’s look at some functions that are so far outside normal TRPV1/capsaicin function that they can be considered exceptional – like jazz piano from the RHCP.

Hearing

We have explained the mechanism of hair cell action in hearing before. The inner hair cells are bent by the sound wave in the cochlea and converted to a neural impulse to be detected as sound. The outer hair cellswork to amplify the wave so that the sound is louder and can register a signal in the inner hair cells.

Scientists know that TRPV1 is expressed on the inner and outer hair cells, and works in the cochlear amplification system particularly. However, we don’t know its exact function(s) there. On the down side, we know that TRPV1 must work in a narrow range, because drugs and agonists that excite TRPV1 can lead to hearing problems.

Acoustic injury (acute or chronic loud noise), gentimicin (an antibiotic), and cisplatin (a cancer drug) can all cause hearing damage. A 2009 study of gentimicin damage to the cochlea showed that it increased TRPV1 expression in the outer hair cells. A 2008 study of cisplatin showed that its damage to the hair cells could be suppressed if you decreased TRPV1 activity.

Most often people think of tinnitus as a ringing in the

ears, but it doesn’t have to be. It can be clicking, buzzing,

hissing, or roaring sounds as well. If you hear voices –

well, that’s something completely different. Also, tinnitus

is usually characterized as a neural transduction issue,

often from damage to the hair cells, so only you hear it.

But there are problems in blood vessels, muscles, or

bones (TMJ) near the ear that produce soucnds other

can hear. This is called objective tinnitus.

A 2013 study indicates that TRPV1 is important for the uptake of the drugs into the hair cells, and then they do their damage. An older study shows that even without drugs to be taken up, increased TRPV1 expression is the cause of acoustic injury tinnitus (ringing) and hearing loss. Another paper showed that capsaicin itself blocks the action potential in the outer hair cells and dampens the cochlear amplification system. Why anyone would stick a chili pepper in his ear is beyond me.

So we see that a little TRPV1 activity is good, but too much is bad. This is not to say that eating a lot of peppers will harm your hearing; dietary capsaicin never gets to your cochlea unless you’re a horribly messy eater. We will return to this idea with TRPV1 and capsaicin; it can be an angel or a devil.

Memory and learning

Neural plasticity (the ability to change neural connections, building some, losing others) is important in learning and memory. We have discussed long-term potentiation (LTP) in terms of memory, where a reinforcement of action potentials between two neurons or in a pathway lead to a strong connection and a new item learned or remembered.

The flip side is long-term depression (LTD). This mechanism is what allows you to weaken and lose connections between neurons that aren’t being reinforced. You can’t learn something as well unless you keep reinventing the connections, including losing some. However, don’t get the idea that you have to forget some thing in order to remember something new, it is much more complicated than that.

This is a good carton because it helps me point out a

dichotomy. Many people say that your brain is a muscle,

if you don’t exercise it, you will lose it. This is like the

atrophy of your muscles if you don’t use them. But we are

reading in this post that losing some neural connections

is important for learning. Long term depression is similar

to not using your brain. Those connections that are not

reinforced are lost – but here it is a good thing,

a necessary thing.

TRPV1 acts in LTD. Without TRPV1 activity, all connections could continue to be strengthened, and a ceiling level of excitability would be reached. Then you wouldhave trouble adding new information.

TRPV1 acts at the level of the hippocampus (important for memory) through an endocannabinoid called anandamide. We already know that anandamide is a TRPV1 agonist. A 2008 study indicated that there was no LTD activity in mice that had no TRPV1 channels. This study found that TRPV1 was “necessary and sufficient” for LTD, meaning that it was needed and only it was needed for the effect.

Another 2008 study points out how this is important for us. Stress brings too much LTD and not enough LTP. When you’re stressed it’s harder to learn new things and easier to lose established knowledge. Amazingly, TRPV1 agonists like capsaicin can regulate this in stress. Stress + TRPV1 agonists led to reduced LTD and improved LTP. It seems that capsaicin and other TRPV1 agonists regulate synaptic plasticity in both directions, keeping us on balance and always learning.

Reproduction

Put simply, without capsaicin channels none of us are here to read this great stuff. TRPV1 activity, through various agonists, is important for sperm motility and fertilization of the egg. The sperm meets the egg and here we go - is that the whole picture? Nope. It takes a lot to arrange their introduction, and some of it involves TRPV1 channels.

You ever wonder why the testicles are kept outside the trunk of the body? It’s to keep the sperm cool – heat kills sperm. TRPV1 receptors sense high heat and institutes local reactions to cool the sperm. A 2008 study showed that TRPV1 knockout mice had much higher levels of sperm death in the testicle when the temperature was raised. It didn’t make the mice sterile, but it was close.

On left is a cartoon of sperm capacitation, making it ready tofertilize travel to the egg. The loss of the cholesterol coat isimportant for increasing motility and for finishing the signals that point out whee the egg is. The acrosome is also prepared here, but there are more acrosome changes in the right image showing the

acrosome reaction. Here, the spem head becomes a weapon, dissolving the outer layers of the egg and stabbing it for entry.

So TRPV1 is important for sperm even before they start their journey. The first thing that happens after the sperm enters the female reproductive tract is that they undergo a process called capacitation. These changes make the sperm ready to bind to the egg. TRPV1 and its agonist anandamide (same as in LTD) are important late in capacitation. They prepare the sperm for transfer of the DNA to the egg.

TRPV1 and endocannabinoid receptors are also responsible for the increase in sperm motility after capacitation. The sperm swim toward the egg, but how do they know where she is? There are many signals, including osmolarity differences, hormones, temperature changes, pH changes, and liquid currents. We have seen that several of these (pH, temp., hormones, osmosis) are sensed by TRPV1 channels.

It’s been shown that TRPV1 on the sperm post-acrosomal and head regions are important for sperm motility. A 2013 study showed that inhibiting TRPV1 slowed down fish sperm. And in a 2013 study of infertile men, the motility of the sperm in men with low levels of anandamide was decreased.

Strangely, even though capacitated sperm are thermotactic (swim toward higher temperatures), this is one time where it DOESN’T involve TRPV1/capsaicin receptors. It still involves calcium, but the flux is through a different receptor system.

Once the sperm finds the egg, it undergoes the acrosome reaction. This makes it possible for the sperm - only one mind you - to enter the egg. A 2009 study indicated that anandamide and TRPV1 are crucial for the acrosome reaction as well.

From inside the male, to inside the female, to inside the egg, capsaicin receptors are crucial for making tiny humans. It doesn’t get more important than that. What I don’t know is if eating peppers affects any of this. Would a habanero make you more fertile or less?

The PSA test (prostate specific antigen) can be used

for monitoring treatment of prostate disease as well

as for diagnosis of prostate cancer in conjunction with

other tests. The tests measure s aprotein produced by

the prostate that is often elevated in those with prostate

cancer. PSA can be free or bound to a protein. You want

the free:bound ratio to be high, and low ratio is more

indicitive of cancer. However, there are noncancerous

reasons for an elevated PSA, so don’t go nuts if your

levels ar higher than normal (score of 4 ng/ml).

Cancer

In cancer we see the dual nature of TRPV1 again. In some cases it prevents or stops cancer, while in others, capsaicin might contribute to cancer.

Prostate cancer has been studied a lot with respect to TRPV1. Capsaicin, in particular, has an effect on prostatic cancer cells. It kills the cells and reduces tumor size in mice. However, in humans, little work as been done. One epidemiology study found that Nigerians that eat more peppers have a lower rate and later onset of prostate cancer.

In addition, a single study followed a man whose prostate cancer returned after several disease free years. His PSA value(prostate specific antigen, a sign of cancerous growth) started to double weekly, so he started taking 2 ml habanero sauce once or twice week. His PSA value increases slowed by half. He stopped and they sped up. He started daily habanero sauce and the PSA dropped. Sounds like a treatment to me.

The mechanisms of capsaicin action on prostate cancer cells has been determined in in vitro work. They are both TRPV1 dependent and TRPV1 independent. (studies) Capsaicin increases ROS, induces apoptosis, destabilizes membranes, throws off ion balances…basically everything capsaicin stopswhen used for protective hypothermia (from last week).

It isn’t just prostate cancer where capsaicin may help. In a mouse model of lung cancer, giving capsaicin prevent the lung tumors from forming by increasing apoptosis in the cancerous cells. Whether this is TRPV1 dependent or independent was not discussed.

But there is a darker side to capsaicin and TRPV1 in prostate cancer. The agonists have a small window of effectiveness. Low levels actually promote cancer growth, but higher levels cause cell cycle arrest and apoptosis. In one study, 10 µM capsaicin actually created prostate tumors in mice.

Where do you come down on the question of whether

peppers are good for you or not? Do they cause cancer

or prevent it? Do they cause pain or prevent it? I think

that as with most things, moderation is the key. Too

much of anything is bad for you, except maybe this blog.

One thing I do know; we have sharp canines for a reason -

we were meant to eat meat. This statement is why

she has that look on her face.

The bad news continues... maybe. Several studies have linked capsaicin to stomach, oral cavity, and gall bladder cancer. One epidemiologic study showed that US counties with higher Mexican American, Cajun, and Creole populations have higher rates of these cancers, and it just so happens that these are the folks that eat more chili peppers. Some skin cancers are also associated with capsaicin. This is a bit disconcerting considering the number of topical capsaicin pain creams on the market.

In squamous cell skin cancer, capsaicin can sometimes stunt the growth of tumors via apoptosis, but the mechanism seems to be TRPV1 independent, since a TRPV1 antagonist brings the same effect. The take home message is that TRPV1/capsaicin effects may be diet, individual, cancer specific. This will make it hard to develop therapeutics.

Next week - now its time to start talking about cool receptors. Like how the cigarette companies use "cool" to sell smokes.

Lee JH, Park C, Kim SJ, Kim HJ, Oh GS, Shen A, So HS, & Park R (2013). Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability. Experimental & molecular medicine, 45 PMID: 23470714

Amoako AA, Marczylo TH, Marczylo EL, Elson J, Willets JM, Taylor AH, & Konje JC (2013). Anandamide modulates human sperm motility: implications for men with asthenozoospermia and oligoasthenoteratozoospermia. Human reproduction (Oxford, England), 28 (8), 2058-66 PMID: 23697839

Gonzales CB, Kirma NB, De La Chapa JJ, Chen R, Henry MA, Luo S, & Hargreaves KM (2014). Vanilloids induce oral cancer apoptosis independent of TRPV1. Oral oncology PMID: 24434067

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, & Devaki T (2013). Capsaicin provokes apoptosis and restricts benzo(a)pyrene induced lung tumorigenesis in Swiss albino mice. International immunopharmacology, 17 (2), 254-9 PMID: 23747734

For more information or classroom activities, see:

Cochlear amplification –

http://www.slideshare.net/lynnroyer/hair-cell-function-and-purpose

https://www.bcm.edu/healthcare/care-centers/otolaryngology/patient-information/how-ear-works/inner-outer-hair-cells

http://neuroscience.uth.tmc.edu/s2/chapter12.html

http://www.d.umn.edu/~jfitzake/Lectures/UndergradPharmacy/SensoryPhysiology/Audition/OHCFunction.html

http://147.162.36.50/cochlea/cochleapages/theory/hcells/hcells.htm

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=5&ved=0CFQQFjAE&url=http%3A%2F%2Fwww.bcs.rochester.edu%2Fcourses%2Fcrsinf%2F221%2FARCHIVES%2FS11%2FCochlear_Amplifier.pdf&ei=YYoXU4X4NYS0ygHQ6oD4CA&usg=AFQjCNFHqR7wKBFlhBt1pSD9KRyFyt74Vg&sig2=G0wcwNIEzpSuSt5ZMkotlA&bvm=bv.62286460,d.aWc

http://medicalxpress.com/news/2012-12-cochlear-amplification-optical-technique.html

http://www.neurophys.wisc.edu/auditory/johc.html

http://science.howstuffworks.com/life/human-biology/hearing5.htm

Tinnitus –

http://www.dangerousdecibels.org/education/resources/dangerous-decibels-dvd/

http://www.ata.org/for-patients/student-zone

https://faculty.washington.edu/chudler/chhearing.html

http://faculty.washington.edu/chudler/hearing.html

http://www.ata.org/

http://www.webmd.com/a-to-z-guides/understanding-tinnitus-basics

http://www.mayoclinic.org/diseases-conditions/tinnitus/basics/definition/con-20021487

http://www.nlm.nih.gov/medlineplus/tinnitus.html

http://www.medicinenet.com/tinnitus_ringing_in_the_ears/article.htm

Sperm capacitation –

http://embryo.asu.edu/pages/sperm-capacitation

http://www.pbs.org/wgbh/nova/education/activities/2811_baby.html

http://www.keytoconceive.com/sperm-capacitation.php

http://www.glowm.com/section_view/heading/Sperm%20Transport%20and%20Capacitation/item/315

http://www.youtube.com/watch?v=rrFsTdfe2qw

http://www.wisegeek.org/what-is-sperm-capacitation.htm

http://www.youtube.com/watch?v=-J9deipbdSI

http://community.babycenter.com/post/a36676870/capacitation

Acrosome reaction –

http://education-portal.com/academy/lesson/acrosome-reaction-function-definition.html#lesson

http://www.youtube.com/watch?v=5-g8dLcERlM

http://www.youtube.com/watch?v=-jLyzWrSTOA

http://www.stanford.edu/group/Urchin/acrosome.htm

http://www.embryology.ch/anglais/dbefruchtung/akrosom02.html

http://worms.zoology.wisc.edu/urchins/SUfert_acrosome.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181525/

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/reprod/fert/fert.html

#zoology #TRPV1 #tinnitus #sperm motility #fertilization #exception #cochlear amplification #capsaicin #capacitation #cancer #apoptosis #animal #acrosome reaction

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