Right handedness, and genes for hairiness

Plus, how the bee microbiome uses cyanide from dietary toxins to fend off parasites, and links between mitochondrial DNA in the blood and personality type...
01 March 2023
Presented by Chris Smith
Production by Chris Smith.


A monkey doing a tube test to judge hand dominance


Why are 90% of humans right handed and where did we get this from; genes for how - and where - hair grows; the intriguing timing behind how sunflowers flower; how the microbiome of the bee weaponises dietary toxins to deal with parasites, and a connection emerges between personality type and mitochondria...

In this episode


00:34 - Genes linked to hair loss and hairiness

Studying mammals that have lost hair over evolutionary time reveals the genes linked to how hair works...

Genes linked to hair loss and hairiness
Nathan Clark, University of Utah

To a subject that goes over most people’s heads, but literally, rather than in an intellectual way: I’m talking about hair, and why we have it, or not; where we have it, and what sort of hair we have across different parts of the body. It’s so consistent that it must be genetically determined. But, hitherto, only a relatively small number of genes have been linked to hairiness. Now, the University of Utah’s Nathan Clark has hit on a method that’s found many more. As he explains to Chris Smith, his team reasoned that many different mammalian species have independently evolved to lose their hair. So if you look for genes that are consistently linked to this happening, it’s highly likely they’ve got a role to play in how hair works…

Nathan - We were looking at all of mammals and one of the most special traits that mammals shares that we have hair, right? But if you look at the diversity of mammals, you quickly realise there are many species that have actually lost most of that hair and they are more closely related to other species that continue to have hair. So we were interested in understanding which genes are responsible for mammals losing hair. And so we asked ourselves, did those species lose their hair through the same type of genetic mechanism? Did we all lose our hair because of changes in the same genes?

Chris - I suppose the subtlety here that one must appreciate is that when you look across the animal kingdom and you find these animals that don't have hair, they have hairier ancestors. So it's not like they're all related from one hair free ancestor, they've all independently lost hair across evolutionary time.

Nathan - Yeah. And, and what allows us to study those species altogether is the fact that us mammals, we share a large proportion of our genes. And so when we produce hair, it's through action of the same genes. So similarly, when species lose their hair, it could also be through the changes to those specific genes as well.

Chris - So if we can find what genes have been mutated to make non-hirsute humans <laugh>, we can solve baldness?

Nathan - Well, perhaps. That that could help us find gene regions to pay attention to if we want to try to start restimulating hair growth. But I have to say that was not our goal in this paper.

Chris - Indeed. But how did you do it?

Nathan - For that I must give a lot of credit to someone. I work with Dr. Amanda Kowalczyk, who came up with this method to study the genomes of these species that have hair and that don't, and she found a way to understand which gene regions are changing more rapidly or they're mutating more rapidly in the hairless species compared to the ones who maintain a full coat of body hair. And when she did that, independently across these different hairless species like the elephants and the rhinoceros and the dolphins what quickly rose to the top were a set of genes called keratins, which we already know are important for the formation of hair. Something that was exciting to come out of that is that Dr. Kowalczyk found there were other genes that we don't know very much about at all, that were also very high on that list. So that immediately suggest to us that those genes are also responsible for the creation of hair.

Chris - When you say "genes that are changing very rapidly," what does that mean?

Nathan - So normally when a gene is important to an organism, over long periods of time, the gene will resist change. So over time those genes appear to change not at all, or at least very slowly because they're so important. However, when a species no longer needs a particular function like hair, those genes will be allowed to deteriorate. There will no longer be kind of mechanisms to remove those mutations.

Chris - How did you do this then? Did you consider many, many species in parallel and look at those same genes and ask which ones are changing a lot and then realise that they are the hairy ones or rather the non hairy ones?

Nathan - Exactly. We group the species together into the hairy ones and the reduced hair or hairless species. And we have ways of kind of measuring the rate of change, you know, the numbers of changes that occur in a particular gene, say per million years. And we were able to do just a simple statistical test to ask whether any particular gene was evolving more rapidly in the hairless species compared to the hairy ones. And that produced this list that we studied.

Chris - And how many genes have you now got that are linked in some way to being hairy or not?

Nathan - Well, it depends on where you draw the threshold for confidence, but I would say, you know, around 100 genes.

Chris - When you look at those genes and you look at what we already knew or suspected was involved in hairiness or being hairless, how many of them are new hits?

Nathan - I think new hits we would have around 20 to 30. But those we need to still follow up and validate or kind of prove that they really are contributing to hairlessness.

Chris - So at the moment you can link them but you don't know what they do. Is that a reasonable summary?

Nathan - That's a perfect summary. For right now, this is the first step in a process of discovery where we can exploit this interesting difference, but evolutionarily between hairless and hairy species. And so the remaining steps are to experimentally go and determine and validate that.

Chris - What do they look like they might do? You must have looked at them and got some kind of initial instinctive reaction to what they look like they might be doing. You mentioned the keratins, obviously they're the hairy proteins, so it's, it's obvious that some of those may change, but what about the others?

Nathan - There's a particular group that scored very highly. We found about four micro RNA genes, which are genes that don't encode instructions to make a protein, but instead they kind of bind to and interact with messages within the nucleus in the cell to turn genes down to kind of change how much protein is being made by other genes. So you can think of them as kind of master dials or regulators and switches. Some of these nothing was known about them whatsoever. So it seems like they're kind of, some of these new genes are master controllers that act in skin and hair development.

Chris - It sort of strikes me that what you now have is almost a shopping list of places to go and look at that have some kind of intriguing, but as yet undetermined link to how hairy a body part is. So this is quite exciting. You've now got plenty of work and plenty of avenues to pursue.

Nathan - For sure. We've definitely been already contacting a couple of groups that study kind of hair follicle and hair formation within models like mice. And more and more people keep suggesting we go talk to companies that are interested in hair stimulation and hair growth and you know, perhaps that's an avenue like a partnership we could find later.

Chris - But flipping that round, there are some agents - some drugs - which, as a side effect, do promote hirsutism. So perhaps what you could do is to say, "well, we'll look at those things and see if they do have some kind of impact on some of these genes."

Nathan - That's a great idea. Yeah. Looking for any kinds of perturbations we can make and experimentally find changes.

A handshake drawn on a chalkboard.

08:26 - Are other animals right handed like humans?

Is mankind unique in so strongly favouring the right hand over the left, or are other close human relatives the same?

Are other animals right handed like humans?
Kai Caspar, University of Duisburg-Essen

Something that has baffled biologists for decades is the powerful preponderance among the human race - and even our cave-dwelling ancestors tens of thousands of years ago - to prefer to use our right hands in the majority of cases. But are we alone in doing this, or do any of our close evolutionary relatives show signs of a hand bias too? Speaking with Chris Smith, Kai Caspar…

Kai - We wanted to learn how handedness evolved within the primates, right? Because we as humans have quite distinct handedness patterns and no one really knows how those emerged. And so by looking at different primate species, we hope that we could get hints on how the specific handedness of our species came from.

Chris - When we look at the human race, it's not just that a few people are handed, it's really, really skewed, isn't it? Like 90% of the population are right-handed. So how does that compare with our next nearest relatives in evolutionary terms? Mm-Hmm. <Affirmative>, what, what does it look like in that perspective?

Kai - It's actually very different. So as you said, we have as humans for quite a long time, this extreme right handedness propensity; it's present in all of our different populations. So you might look at hunter gatherers at urbanised societies, and even our closest living relatives to chimpanzees and bonobos. If you look at those, we have only about 50% right-handers. The right handers are still the largest fraction, very few left-handers and quite a number of ambiguously handed individuals that do not have a strong hand preference whatsoever. This is something that appears rather alien to us humans, but is rather common in many of the non-human primates.

Chris - How did you come up with this conclusion? How did you actually gather the data and then produce this very comprehensive look at our close relatives when you were doing this work?

Kai - We were trying to find a test. So a certain task that a lot of different species of apes and monkeys could do to have a standard surveying literature. We came across this so-called tube task, which is very simple. You just have small tube that you fill with some food incentive that the primates like. And then you will see of course that the animal will grasp the tube of one hand while the other one will retrieve the food. And if you observe it, you can do statistics and find out whether there is a significant bias towards right or left-handedness at the individual level. And when you test a number of individuals, of course you can do this for the population and by going through various zoos, we compiled quite a nice sample of different species and could then use these data to really open the phylogenetic perspective onto this. So we go through the primate family tree and see, well, species A has a certain hand preference pattern, species B has another one. And within this compilation we can also place humans of course, and view humans within this evolutionary framework.

Chris - You present the data as a big sort of graph where you've got a line representing how handed the population is and then other boxes for how big their brain is and so on it. It's a very nice way of displaying it, but it does show humans are way out there on their own with the vast majority of the population skewed one way and everybody else in all these different species, it seems to be roughly down the middle. So this argues then that whatever happened to us happened after we split away from all these other groups.

Kai - Yes, this is one of the main conclusions of the paper that we, humans are really unique, not so much in the strength of hand preference. This means if we are looking at an individual, be it an individual human or individual monkey. So if a human is a right-hander or lefthander, we are very consistent in using this one hand. The same might be true for various monkeys and also some apes, but what is really unusual is this population level bias that if we look at humans, we have this over-representation of right-handers. This really seems to be unique, has to be something that is unique to our lineage that led to the emergence of these hand preference patterns.

Chris - When you ask researchers over the years, why do you think that there is this hand preference, they, they kind of wave their hands about a bit and excuse the pun, and they say it's because the left side of the human brain is dominant, that's where language is. Well that to me just sort of kicks the can down the road because it then makes the question, well why is language on that side of the brain? Why should that hemisphere be dominant? What do you think based now on what you can see from across the animal spectrum and there isn't this relationship, what do you personally think is going on that that means we have this population level bias towards being right hand dominant 90% of the time.

Kai - So honestly I don't know. And what makes this study important is that we challenge many of the ideas prevailing in the research community, right? For instance, that the lifestyle of a species, whether it lives in trees or it lives on the ground, has something to say about these hand preference patterns. So that whether it uses tools or not, there's quite an influential hypothesis that claims that tool use is the main driver of hand preferences. But we looked at different tool using species and others that do not habitually use tools. And we found no differences whatsoever. But what our data do not allow us to do is come up with an alternative hypothesis. So I think you can criticise all the different approaches that have been proposed in the past, but we still miss the key to find out what really drove the evolution of this righthandedness in our species.

Chris - Often when we want to know the answer to why we do a certain thing or look a certain way or a certain thing works a certain way, we look to evolution because we can see how incrementally it's happened or it gives us clues. This lifestyle factor goes with this behavior, which is what you were just saying about things like tree living or ground living, isn't it? Yeah. So if we can't delve into the primate history to find the answer, if we look outside primates, if we look at other animals mm-hmm. <Affirmative>, now I know that's outside the scope of what you were considering here, but are there any animals that have the same population level handedness bias that we do that might give us clues as to why we are like this?

Kai - There are certainly non primate animals, also non primate mammals that have strong hand preferences and also significant population level hand preferences. So ground living kangaroos, there is strong bias in these animals towards right handedness, curiously. And it has been hypothesised that, again, terrestrial lifestyle has led to this and walking on two legs. And we also have evidence from certain groups of birds parrots for instance, that they have very strong limb preferences. Of course we're not talking about hands here but about feet. But yes, in principle maybe these animal groups that are more distant from us might give us some hints in the future.


16:02 - Why sunflowers are extraordinary timekeepers

For sunflowers, timekeeping plays a huge role in how they develop and how they reproduce...

Why sunflowers are extraordinary timekeepers
Stacey Harmer, UC Davis

Sunflowers have an interesting pattern of development and flowering. They’re actually flowers inside flowers: the outer yellow petals surround a dense bed of inner, smaller flowers or florets where the pollen-bearing and female parts are located. Those inner florets develop in a sequential, spiral pattern from the centre out; but as soon as flowering begins, things change abruptly, and this occurs in concentric circles starting from the outermost florets and working inwards in a sequence of rings towards the centre. And there’s a very good reason why the flowers employ these different timing tactics, as Chris Smith hears from Stacey Harmer…

Stacey - If you look very early in development when you see this big sunflower disc. Every small floret in the middle of that disc is an individual flower that's gonna go on to make a seed. And if you look early in development, you see these beautiful spiral patterns across the disc. And that's something that people have been, you know, noted and been interested in for many, many years. But you look at them in the middle of flowering, you'll see that that spiral pattern has become a ring-like pattern. And that is because those individual florets are undergoing development in a day by day basis. And so on one day for example, you'll have an outer ring of dozens of florets changing the, the shape of the flowers as they're releasing pollen. And then the next day, the next most internal ring of florets undergoes that developmental transition. And so we just wanted to understand how could it be that you went from a spiral pattern of development to this ring-like pattern?

Chris - When you say a spiral pattern, I'm envisaging something a bit like a corkscrew. Is that what you mean?

Stacey - Almost true. It's spirals going in opposite directions. If you look at a pine cone, for example, if you look at the bottom of a pine cone and you can see the arrangement of the different scales going in two opposite directions. Yeah, I I can't think of a good non-biological analogy!

Chris - <Laugh>, so that's a hard question you can't answer! But is the question then how the flower has the transition from a spiral pattern of development that's clearly temporal to this concentric ring pattern that's also temporal, but, but there's a different spacial organization to it, how that occurs and why that occurs during the flowering process?

Stacey - You actually said that beautifully. That was exactly the question that we had and we decided that time lapse photography was our biggest tool. First we had plants in growth chambers so we could control the environment precisely and we had them in constant temperature. And then we had them in light dark cycles to mimic a long summer day, 16 hours of light, eight hours of darkness. And so we set up little cameras and just took photographs of the discs as they were undergoing development over time. And we could indeed see these beautiful rhythmic patterns. And, and the thing that was most remarkable about this is that if you looked within a ring as, as you described it, one of these concentric rings on the head, all of those florets were developing together. You could see the florets swelling up a little bit later. You could see the anthers emerging. Those are the, the organs that release pollen. And even though the florets had been specified early in development, days apart, they were developing at this point just completely in lockstep with each other so that they could release their pollen altogether.

Chris - So were they talking to each other to do that or is it pre-specified? And they're very good at counting, so they're keeping time and they're all individual entities, but they all know very well what time it is. So they know when it's their moment and that's why they're all in lockstep?

Stacey - Exactly right. But they, it's, it turns out we, we could do our, our imaging in different environmental conditions if we put them into constant darkness. We saw very much the same pattern going from the outside to the inside of the flower. And so that says that there's an internal timer as you suggested. However, if we put them into constant light conditions, then development was totally disrupted and we could, we did some experiments where we manipulated the timing that they saw light and we found that if they were exposed to light when they expected darkness, that caused a stop in the developmental process. But if they got the light during the daytime when they expected to see it, development continued just fine. So this kind of experiment allowed us to conclude that the development was controlled both by their internal circadian timers and also it was very sensitive to light signaling pathways.

Chris - Why do they do this?

Stacey - Sunflowers are members of the daisy family and that is one of the most successful plants that there are. And people believe that they're so successful because they have this composite flower, this false flower where you have many, many florets all undergoing development at the same time as you might expect, people have shown that the more florets are developing together, the more interested bees are in the flowers. And so we believe that having all of these flutes developing at the same time and in, in fact in a quite short span of time in the morning, makes them just irresistible to pollinating insects like bees.

Chris - Well I'm glad you brought up the question of pollen because I wanted to ask that on a sort of practical basis that are there male and female flowers then, or do the individual entities, the florets, are they some of them male, some female? How does this work?

Stacey - Right. This is another fascinating thing about these plants. The flowers are alternately male and then female. If you look at the a developing sunflower head, you know midway through the flowering process you'll see that there's a ring of florets on the outside that are female. They've released their, their stigma, which is what received pollen. And then if you go in a little bit, you'll see there's a ring of florets that are male that are releasing pollen. If you waited 24 hours and looked again, you would see that the florets that had been releasing pollen are now exerting their stigma. So they're now in a female stage of development. So an individual floret is male on day one and it's female on day two.

Chris - And do they manage to avoid self pollination so you don't end up with the floret pollinating the one next door to it by accident? Cause obviously you want a remote flower with potentially a, a few different genes doing your pollination, not you yourself.

Stacey - You're exactly right. Yes. And that's the, that's we think believe why this mechanism exists is to promote cross pollination that it's very clever. If you look at a a sunflower, you have those long ray pedals and bees will typically land on the pedals and then walk in towards the disc where the, the florets are. On the way, they walk over female flowers towards male flowers where they collect pollen and then they'll go off to a different plant, a different flower and repeat the process. And so that means that they take the pollen from plant number one and you know, track it over the female florets of plant number two on their way to collect more pollen.

A honeybee

23:54 - Bee microbiome fights parasites with cyanide

The bee microbiome can weaponise dietary toxins to defend against parasites…

Bee microbiome fights parasites with cyanide
Erick Motta, University of Texas at Austin

Our guts are crammed with microbes; in fact some say that we’re passengers in our own bodies, outnumbered in cellular terms by our own microbiomes. We know that these microorganisms are crucial for good health. They access and liberate micronutrients in our food that we can’t; they suppress the growth of pathogens; they’re involved with the regulation of the immune system, and even talk to the nervous system. In recent years we’ve also realised that they may even be detoxifying our diet and breaking down potential poisons before they can be absorbed. And other animals are no different, including the humble honeybee. Speaking with Chris Smith, Erick Motta, at the University of Texas at Austin, has been studying how the bee microbiome can make use of and even weaponise potential dietary toxins, like the cyanide-containing amygdalin bees pick up in almond pollen, to fight off parasites…

Erick - I work with good microbes and I use honeybees as a model to investigate how they can play a role. Basically break down components from the diet, which sometimes can be toxic to animals. And this seems to be the case for some specific plant toxins that we may get from our diet.

Chris - Are honeybees particularly vulnerable to this effect?

Erick - Yeah, so that's the great question here because we don't really know what happens once they metabolize these kinds of toxins. I have studied one specific toxin that honeybees they may face in the environment. The name is amygdalin. So this is a plant toxin found in almonds. Amygdalin by itself is not toxic, but when it's broken down, when it's metabolised, then it can release a specific toxic molecules that can provide a detrimental effect to the animal.

Chris - It's a precursor to making cyanide, isn't it, amygdalin that the almonds make? Yes. What what did you do then to investigate how this is and isn't produced in the gut?

Erick - We use honeybees without microbes in the gut. So to investigate whether or not the bee was playing a role in this degradation, we had these two main groups of bees, one group, the bees, they basically didn't have any microbes in the gut. And the other group, we allowed them to acquire these microbes by interacting with all the bees from the hive because that's how they acquired these microbes by social interaction. We exposed them to this plant toxin to see how it would be metabolised in the gut. And we found that whenever the microbes were there we wouldn't detect intermediates: byproducts from amygdalin degradation as we would see in bees with the microbes.

Chris - Does that tell you then that the bees do some of the breaking down and the microbes do the rest of the breaking down and they get rid of those potentially toxic intermediates? The microbes are doing that job and without the microbes, the bees would effectively be poisoned by those accumulating degradation products?

Erick - Yeah, so it's kind of going to this direction but we don't really know how much those byproducts they can be toxic. So right now the what we know it's that the microbes, they can fully metabolise amygdalin and it can release hydrogen cyanide, which is this toxic molecule. But based on the exposure levels, how much they are basically consuming from amygdalin, this doesn't seem to give a detrimental effect to this. So we believe that there may be another component going on here, which means that those toxic molecules being released, they may help these actually fight specific parasites because other studies they have shown that amygdalin exposure whenever bees, they are fed on amygdalin, actually they don't have much parasites proliferating in their guts.

Chris - But in the absence of the microbes, if the bees break it down to an intermediate, what happens to that intermediate? Does that build up and does that poison the bee? Yeah, so it does need the microbes to get rid of it. Is that the case?

Erick - Yeah, so whenever they don't have the microbes, some specific intermediates, they're gonna accumulate, but we don't know how toxic they are. And probably it's gonna be a matter of concentration. So if it gets accumulated in the gut, that may bring some detrimental effect to bees. But this deserve further investigation.

Chris - It's intriguing this though, isn't it, because the bees are basically using microbes to break down something that might be toxic, save them from a, a potentially toxic effect of an intermediate and in the process weaponise it to get rid of another nasty!

Erick - Yeah, that's true. Yeah. So sometimes it's hard to predict the consequences of metabolising the toxin because the byproducts may be even more toxic or may be not toxic. So it's just a matter of like what's being produced and the concentration that it's being produced in the gut. So in this case, what do we know is that both the host and the microbes, they play a role integrating amygdalin and this leads to the production of hydrogen cyanide. Initially we thought this would be bad for the bees, but it seems that based on the levels that they can be exposed when they're pollinating almond trees, it's not the case because they still keep going there and actually honeybees, they are the exclusive pollinator for almond trees. So the thing here is why this is happening and we believe there are like potential benefits to this especially in parasite prevention, but this needs to be proven yet.


29:33 - Mitochondrial DNA linked to Personality type

A connection has emerged between human personality traits and mitochondrial DNA in the bloodstream...

Mitochondrial DNA linked to Personality type
Luigi Ferrucci, US National Institute of Ageing

Psychologists have known for many years that some sorts of personality type are associated with certain health outcomes. But these are associations and it could be that lifestyle factors common to the psychology and the disease are what link the two. But, speaking with Chris Smith, Luigi Ferrucci, who directs the US National Institute of Ageing, has made a surprising discovery: a connection between personality type and mitochondrial DNA in the bloodstream…

Luigi - Some people are more resistant to stress than others. And our question was why, what is the mechanism by which, you know, aptitude and personality mediate the effect on health.

Chris - And what did you measure to find out?

Luigi - One of the things that we have recently discovered, not us, but the entire world is that the mitochondria, which are the source of energy in the cell also the hub for many of the environmental stress, you know, and that makes sense because you know where the energy is is probably the best way to kind of shift energy from one function to another and under stress that become extremely important. So we hypothesised that people with certain personality will have different characteristic of mitochondria and these different characteristic of mitochondria will mediate the relationship between personality and health outcome. And in this case we look for mortality because mortality and survival are very, very solid and strong health outcomes. There is a biomarker of mitochondria that you can measure in the blood. When you do a genome sequencing in the blood, there are many, many, many molecule of mitochondrial DNA, and the amount of mitochondrial DNA is an indicator of mitochondrial volume and mitochondrial health. So we hypothesised that lower mitochondrial DNA copy number in the blood will be associated with different personalities.

Chris - Who did you look at though? You've mentioned what the possible association is, but you haven't said in whom. So who are you looking at?

Luigi - So when you look this association study, the problem is that we're never sure that this result is by chance. So in order to make sure that the result was strong, we measure this both personality and mitochondrial DNA copy number in two different populations. One is the Baltimore longitudinal study of aging and one is the Sardinia study, a study of aging in Sardinia. So we wanted to measure the same thing in two population that are an ocean apart.

Chris - So you've got from these study participants, you've got their personality type. Yes. And you've got blood samples and you are now asking are there any associations between what's going on in terms of the number of mitochondria in the blood and Yeah, well-documented psychological tests that put people into different categories of, of what their personality is?

Luigi - Personality is measured with a highly standardised questionnaire and divide people and measures different aspect of personality. And there is a very strong and wide literature suggesting of this personality trait. Neuroticism is associated with adverse health outcome, higher risk of cardiovascular disease and higher risk of cancer. And in fact what we found is that neuroticism were strongly associated with lower level of mitochondrial DNA copy number. It was amazing that the result were exactly the same in these two very, very independent and very, very different populations.

Chris - Is this one snapshot in time? Because obviously what we don't know is whether this is a chicken or egg thing. Is it cause or effect?

Luigi - That's a very good question, but has also a simple answer. Personality does not change over time. So even if we were doing longitudinal studies, because the predictor does not change over time, we will not find anything different on what we have found in the cross-sectional study.

Chris - How do you explain this then?

Luigi - We were sceptical. We do know from the literature that there is an association between neuroticism and mortality. Can we do an analysis to see whether this association is mediated by mitochondrial DNA copy number? So we did something that statistically can help you understand whether three variables one after the other are related. So that personality affect the DNA copy number and through this effect affects mortality. So that if you adjust the analysis or mitochondrial DNA copy number, the association between neuroticism and the mortality basically fade - disappear - because it's all explained by DNA copy number. And that's exactly what we found there was a very, very strong mediation.

Chris - So what do you think is going on? Why is there this connection?

Luigi - Well the my answer is hypothetical. We don't have any proof or what is the mechanism right now, but our hypothesis is that the stress affect mitochondria and the mitochondria become dysfunctional and the mitochondria that become dysfunctional tend to be eliminated by the mechanism that's called mitophagy because otherwise they will create damage to the cell. And because of that we find that people that are more sensitive to stress tend to have lower mitochondria. As I mentioned, this is something that you know, is, is an hypothesis that drive our interpretation of this study, but will have to be demonstrated using possibly animal models.


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