This month, new hearing tests to spot those likely to struggle with speech in noisy environments, how your DNA is at risk from hacking on a public database, plants with three parents, researchers recreate endometriosis in mice and show that cannabis might be an effective treatment, and the nerve fibres that make us like a cuddle.
In this episode
00:36 - Struggling to hear in noisy places?
Struggling to hear in noisy places?
Daniel Polley, Harvard Medical School
Do you find that speech is much harder to follow in noisy places? Does background din make what other people are saying trickier to understand? The good news is that you’re not alone: lots of people struggle, and it’s often because, as we age, we lose hearing acuity. By the time we’re 40, we can have as few as half the number of fibres in our auditory nerves that we had when we were 4. But traditional hearing tests are notoriously poor at picking this up. Luckily, “here’s” someone who can help! Speaking with Chris Smith, Harvard's Daniel Polley...
Daniel - My name is Daniel Polley. I am the director of the Lauer Tinnitus Research Center and I think we have discovered a new type of test for a very common but hidden hearing complaint. The problem which many of us, especially if we've reached the ripe age of say 35 or older, confront, is going to a crowded location like a bar, restaurant, or a pub in the UK, and we are listening to our conversational partner across the table and they're speaking loudly enough, but somehow our hearing keeps getting pulled into the conversation from the people next to you. You're having a hard time separating the voice of the person talking to you from the voice of the people you're trying to have fade into the background.
Chris - And what is the issue that's causing that to happen?
Daniel - Well, that's really the key question because many people that complain of this will go to their hearing specialist. The hearing specialist will do their standard set of tests and that type of test is useful for identifying a hearing loss. But it doesn't really help in identifying this hidden hearing complaint of being unable to follow conversations in noisy backgrounds.
Chris - And what fraction of people, when they experience this symptom, will go and have those tests and then be sent away saying, nope, your hearing's absolutely fine?
Daniel - Right? So the dark matter in the universe or all the people that have this complaint, but don't go to a hearing specialist because maybe they figure it's not worth the bother. But we have looked into the database at our clinical care center and we find that about 10% of people come in with a hearing complaint but are told that their hearing is normal.
Chris - So what can we do about it then? In terms of what have you managed to discover here, that means we're in a position to better inform people about the status of their hearing?
Daniel - So one way was to kind of ask how the first stations in the brain that process sound, how well they are capturing a signal that we nerdy scientists called frequency modulation. If you think of, for example the sound of an ambulance siren - wee ooh wee ooh - and the more sensitive you are to that little warble, the better able you are to understand speech and background noise. And for us that was a huge hint because we could try to zoom in and capture the way that the earliest stages of the brain were encoding these little warbles.
Chris - How can you make that appraisal when you can't necessarily drill a hole in someone's head and make those measurements? What sort of proxy markers are there for that sort of encoding that are sensitive enough that you can use them?
Daniel - The ear is tiny. It is intricate. It is locked into the densest bone in the body. It is really trying to hide from us. It's really inaccessible. So what we can do is put an electrode in the ear canal so that we can measure electrical signals from the ear canal generated by the early stages of processing. Then we can play those types of sounds, those warbles, and we can analyze with what fidelity do the electrical signals lock into those subtle changes in frequency.
Chris - And is there any way of then standardizing this: so you make those measurements, how do you then relate that to whether the person really does or doesn't have good hearing or struggles to hear in noisy environments? Do just ask them or do you play them other sounds to mask what you're presenting to them? How do you then work out how useful that is as a guide?
Daniel - That's one measurement, and then we need to relate it to how much they struggle with a challenge that resembles listening to your conversational partner across the table at the pub. So for that, we test their hearing when we challenge them with kind of a listening task that simulates listening in a crowded restaurant. They will have a conversational partner, we call him Fred, and Fred will read off a series of numbers, and meanwhile two people next to Fred that are spatially separated a little bit will read off numbers at the same time. And so the listeners task is to repeat back the numbers that Fred said and we'll see if they get confused by the numbers that the people next to Fred are saying. For instance, if they will latch into the wrong stream and repeat the wrong set of numbers.
Chris - And how do you tell how hard they're working at the same time? Because that was part and parcel of what we were saying, that actually the brain has to do a lot of heavy lifting here to disentangle this extraneous noise that's coming in. So how do you get at that?
Daniel - I'm glad you asked because we added another type of measure that's very different and it relates to what many of us know as effort. If we're listening for an hour, let's say half an hour, an hour, to that person in the crowded restaurant, we start to get a bit worn down. It actually requires a lot of effort to martial all of these cognitive resources like attention and prediction, memory - maybe you're trying to look at the mouth to integrate the visual signals with the auditory signals. And we cannot directly measure cognitive assets because there is no electrode for that, but what we can do is measure the pupil. That may seem strange, but when we're using more effort to solve a problem, our pupils get a little bit wider and so while they're doing that task of listening to Fred while trying to suppress the sound of Fred's neighbours, we're looking at changes in the diameter of their pupil. The people that are having to burn more cognitive fuel to use more effort to understand, their pupils are getting wider than people are having an easier time of it.
Chris - And then what do you put all of this information together? The sensitivity to the ambulance frequency modulation type sound, with the ability to understand and correctly remember what Fred has said, and then your pupil size, you integrate all of that together and this is the predictor.
Daniel - Exactly right. Knowing these three pieces of information we could predict with 80% accuracy how well you do in this type of listening challenge. What we don't know is can, on an individual basis, we bring you in and say, you know, this is, this is the issue with you - yes or no. So in that sense, a further development is needed to sort of refine the sensitivity in the selectivity of the test.
07:36 - Has someone stolen your genome?
Has someone stolen your genome?
Michael Edge, University of California Davis
A common trend at the moment is to get your DNA sequenced; often you learn how much Neanderthal is in you, that you’ve got Irish, Welsh and Cossack ancestry, and some of these resources also let you know about things like disease risk genes. Some people go further and upload their genome to a range of online platforms that use the sequence data to do things like reunite you with your long lost relatives. But, as UC Davis researcher Michael Edge explains to Chris Smith, many of these platforms are vulnerable to some simple exploits, so there’s a very danger that you could end up with your genome getting hacked and stolen…
Michael - What some of these websites do is they allow people to upload their own genetic data, so people will get their genetic data from someplace like '23 and Me' or ancestry.com and then they're allowed to upload that information to one of these other websites like GEDmatch, family tree DNA, MyHeritage. And one reason those have been really interesting is that law enforcement police have wanted to upload genetic information they have from a crime scene and use that information to find people who they're interested in. So one very high profile case was there was this serial killer in California called "The Golden State Killer", and about two years ago he was caught using this kind of method. So somebody uploaded genetic information to GEDmatch, was able to find some second and third cousins and then ultimately track him down. And what we were interested in is if somebody uploaded the right kind of information to these datasets, could they actually compromise the privacy of a lot of different people who are in those datasets? So could you actually figure out genetic information of the people who are in the databases by just uploading particularly well-chosen datasets?
Chris - Well, give me an example then of a way in which something could happen that would concern you...
Michael - Well, one reason could be insurance. In the United States, people are protected in terms of their health insurance by an act called GINA. But that doesn't apply to all kinds of insurance. So you could imagine people being interested in this information and maybe using it to discriminate against certain people. Or you could imagine somebody maybe stealing part of somebody's genome, learning part of their genome, and then using that to construct a fake relative and then gain their trust. So maybe if I know part of your genome, I can build a genome that looks like it's your long lost second cousin or something, and then try to connect with you on one of these services. And maybe that gives me an "in" for some kind of phishing scam or something like that.
Chris - So what question did you ask of the system? How did you approach this in the first place?
Michael - We kind of had two broad ideas for how somebody could attack this dataset. One idea was maybe they can just take advantage of the fact that all of our genomes are like a mosaic built from pieces of our ancestors' genomes. And what that means is that we all share little pieces of genome with each other. If I upload my genome, and I'm shown all the places where I match somebody in the dataset, then I know something about all those people's genomes where I match them. And I'll match my close relatives and, depending on how short of a piece of genome the database is willing to show me, I might match people who I'm not even particularly closely related to. So that's one kind of attack: it's just by looking at sort of tiles of my genome that match other people's genomes and in particular not just my genome, but many people's genomes that I could download from the internet, and looking at where all of them match with other people, can I figure out other people's genetic information? And then the other broad method we thought about was attacking the algorithm that these websites use - in particular GEDmatch uses - to identify matching segments. And we found that there's a way you could trick the algorithm into basically showing you somebody's genotype at a site that you care about.
Chris - Have you put these vulnerabilities to the owners of these sites?
Michael - Yes, we did. So three months before we published anything, we went and talked to representatives of all these different companies, told them basically what we were planning to do, and gave them a sense of what our results were going to be roughly.
Chris - And what did they say?
Michael - Many of them assured us that they didn't think that these problems would really affect their website in one way or another in different cases - that was either convincing or not. We know a bit about what GEDmatch has done, but in the other cases we don't know whether they've done much.
Chris - Given that you've put this out in the public domain, one would hope that they would tighten up, but is there a way of tightening up without destroying the raison d'etre behind the whole initiative?
Michael - Yeah, that's a good question. And we think there are lots of ways. So we suggested a bunch in our paper and two pretty easy ones for them to do would be first to only show either long matching segments, or just not show the location of segments at all. So some companies follow this model and that protects them from one of the major types of attack that we propose. And the other method is using more up to date methods for finding segments that match between two people. There's an older class of methods that's vulnerable to a type of hacking that we talk about. Most of the companies have assured us that they use a newer method that wouldn't be vulnerable in the same way, but GEDmatch we think is still using the older method. And then a third thing that would be very effective but is a bit harder - because it requires cooperation - is these sites that allow uploads could actually start only accepting uploads that are tagged with a digital signature that ensures that they're from a trusted source. So that would mean that I, as just an independent person, couldn't go and make a text file that's formatted the way 23 and me does it, and then upload it to one of these places. That I think is a big hole that all of them have now.
Chris - Do you think this really is a big risk though? Because if someone was that hell bent on discovering, say my DNA, they really wouldn't struggle to track me down, shake my hand a few times, make friends with me at work, invent some story to gain a sample from me, which they could do without me even realizing they'd done it. So is there much to be gained really from going to all this trouble of hacking one of these sites?
Michael - Yeah, so I think if you have a specific target you're interested in, you're right - and actually the laws on that in the United States are pretty loose in terms of being able to follow somebody around and use found DNA. The difference with these kinds of methods that we're talking about in this paper is you'd get all this information at the same time. So rather than having to track one individual down or a set of individuals down, you'd get some information from potentially everybody in one of these databases. GEDmatch, for example, has over a million people in it.
Chris - What would you say then is the bottom line here? What's the advice you give to people then - just don't upload your DNA?
Michael - I wouldn't say that. I mean, people come to this with a lot of different concerns and a lot of different interests, so I wouldn't say don't do it, but I would say to be very careful when you do it and to realize what you're sharing. This is information that's not just one's own information. It's about one's relatives, even very distant relatives, even unborn relatives. And once it's out there, you can't retract it in the way that, you know, if my credit card information gets stolen, if I have to, it's a pain, but I can change it. And that's not true with our DNA, right!
15:34 - Plants with 3 parents
Plants with 3 parents
Rita Gross-Hardt, University of Bremen
When we reproduce, a single sperm is permitted to fertilise a single egg, bringing together two half-sets of chromosomes to produce a cell containing the full 23 pairs. And if anything goes wrong with this process - such as two sperm fertilising the same egg and contributing too many chromosomes - the result is usually lethal. But plants, on the other hand, seem to be able to tolerate this quite well and may even rely on the process to drive their evolution. When a flower is pollinated, the male pollen grows down the flower stigma towards the egg. When it gets there, it contributes DNA to both the nourishing tissue that surrounds the egg, and the egg itself. The nourishing tissue inspects the DNA and can abort the fertilisation if something is wrong. But, rarely, two pollen tubes, from two separate fathers, can try to fertilise simultaneously. When this happens, the second one doesn’t need to interact with the nourishing tissue and can directly add DNA to the egg, producing a plant with 3 parents. This has significant implications for plant breeding. As she explains to Chris Smith, Rita Gross-Hardt proved how it happens in an ingenious series of experiments...
Rita - Because we were expecting a really rare event, we thought it would be good to have something which is easy for us to score. And the best case scenario, we thought, is that all the seedlings which have just one father dropped dead and only the ones which have two fathers survive. So we decided to use a gene which confers a herbicide resistance. And we kind of "separated" this gene. We put one part into father one, and we took the other part into father two. The rationale behind this is that, if only one sperm from one father is inherited, the gene is not complete and is not expressed, so the plants are herbicide sensitive. By contrast, if an egg inherits the sperm from the two different fathers, the gene would be complemented and the tri-parental offspring would be herbicide resistant.
Chris - And what fraction, when you did this actually survived, in other words, had inherited both halves of the gene, one from each dad and therefore reconstituted a functional gene in the offspring?
Rita - Yeah, that is actually quite fascinating. We had to look at 10,000 seedlings to find one which is herbicide resistant.
Chris - And did you check, when you looked at the seedlings that appear to be resistant and therefore would appear to have three parents, did you go in and genetically confirm that was definitely the case?
Rita - Yes, we felt that was a very important step because, just getting a herbicide resistant plant did not feel comfortable for making such a strong claim that plants can have three parents. So we, in addition, checked whether we could find back the two halves of the gene, and then we also said that we would assume that such plants would have additional chromosomes. So a typical arabidopsis plant gets five chromosomes from the mother and five chromosomes from the father. What we found in these herbicide resistant plants was 15 chromosomes. So that fitted quite well to the idea that actually a second father had contributed its entire genome.
Chris - How does this actually happen though? What's the mechanism?
Rita - Actually there was a remarkable difference between what the first inheritance step was from father one, and the fusion that we observed with father two. The first father delivered its sperm not only to the egg cell but also to the adjacent nourishing tissue. This is normal and quite characteristic for flowering plants. Importantly, this nourishing tissue has a DNA checkpoint. So the first father's genetic material went through this genetic checkpoint. However, to our surprise, in many cases, genetic material from father two was only delivered to the egg cell but not to the nourishing tissue, thereby bypassing this DNA checkpoint.
Chris - Given that you've shown that this can happen, albeit with a lowish frequency, this must therefore be an important way in which plants can share genes, trade genes, gain additional genes from multiple parents. It must be, have been going on in evolutionary terms like this and have played quite an important role in the plants that we see around us today?
Rita - Yes, that is an absolutely correct point. So, during evolution, the increase in chromosome numbers is assumed to be really having played a major role in speciation. Why is that? Well, having additional chromosomes and duplications of chromosomes is kind of like a playground for evolution, so these genes can either be newly functionalised, they can be maintained in their function, or they can be deleted.
Chris - Why doesn't this totally screw up the ability of the plants to reproduce themselves though? Why don't they end up with what we call aneuploidy - the wrong numbers of chromosomes in their own gametes, their own eggs and sperm - when they want to reproduce subsequently?
Rita - Yeah, that's a very good question and I wish I could give you a good answer on that. The point is indeed, we have plants which have now three sets of chromosomes. That implies that, when it comes to the formation of germ cells, that these three sets need to be distributed. This can occur in an even fashion, but typically it occurs in an uneven fashion. Saying that, for example, chromosome number one is represented by one copy in a germ cell, whereas chromosome number two is represented by two copies. And this gives different ratios for gene products and that can cause turmoil and developmental problems. However, we saw that some 40% of these plants which had three chromosome sets were able to give rise to fertile offspring.
Chris - Was that just by chance do you think; just by luck they happen to select just one copy of everything in the one particular gamete that was successful, and so that's the one you saw, or do you think there's a mechanism at play here - nature has made provision for the fact that it's allowing this extra set of chromosomes to sneak through from time to time, so it's got a mechanism to deal with it when it happens?
Rita - There has been speculations, for example, that shutting down chromosome copies might do the job here, but, to my knowledge, this is not a clarified how plants actually manage to tolerate these extra chromosomes in comparison to animals, which are highly intolerant for this scenario.
Chris - Now, what are the implications of this? We've touched on why evolution might want to live with this because the benefits are obvious. Is there any implication in terms of where we see ourselves going from a plant breeding perspective?
Rita - Yes. We think that this has implications for plant because the combination of beneficial traits from three parents in i think a cross can speed up breeding processes. That is one aspect. A second aspect which we consider important is that plant breeders often have the problem that they cannot combine plants because they are not related enough, and this is actually detected in the nourishing tissue, which checks for the DNA quality and quantity. And then if the test is not past, the seed, simply aborts. If we now have a means that the second father is not going through this quality check, then there would be maybe an option to combine plants which we could previously not combine in such three parent crosses.
23:29 - Cannabis treatment for endometriosis
Cannabis treatment for endometriosis
Rafael Maldonado, Universitat Pompeu Fabra, Barcelona
One in ten women has the condition endometriosis; the consequences can include disabling menstrual pain, and infertility. The disease occurs, we think, when the lining of the uterus, instead of leaving the body as menstrual blood, instead passes in the reverse direction, upwards along the fallopian tubes and into the abdominal cavity, where it implants in various places and produces cysts that bleed painfully and provoke inflammation and adhesions. Now, Rafael Maldonado, from the Universitat Pompeu Fabra, Barcelona, has successfully recreated the condition in mice, and gone on to show that THC, one of the main psychoactive ingredients in cannabis, can reverse the activity of the disease, suggesting that this might be a fruitful avenue to pursue in human patients…
Rafael - I'm Rafael Maldonado, from the Universitat Pompeu Fabra, Barcelona. I'm director of the neuropharmacology research group. What we do is we extract some uterus tissue from normal mouth and we just implant this uterus tissue in the abdominal cavity. And of course we have a control animal where we just implant fat in the same places. Only the animal where we have implanted this uterus tissue is the one that express pain, but also expresses other manifestation similar to women that has endometriosis and emotional alteration and cognitive alteration.
Chris - So women who have endometriosis don't just get pain once a month when they're menstruating. They also get these other consequences you're describing, including decision making and cognitive impairments?
Rafael - That's correct.
Chris - So you've got this animal model then; it develops many of the symptoms of endometriosis. It means that you've now got an opportunity to try various therapies.
Rafael - Yes.
Chris - What did you decide to test?
Rafael - Well, we focused on the endocannabinoid system. This system is involved in the transmission and integration of pain; it's involved in day emotional control; it's involved in the cognitive control. So for these and other reasons, we have arguments to believe that we are going to be able to modify the manifestations of endometriosis.
Chris - What did you do then? You give the mice who've got either the control tissue or the mice that have got the uterine tissue, so they are endometriotic mice. You give them some THC - tetrahydrocannabinol - and you then ask what does this do to their symptomatology?
Rafael - Yeah, we give tetrahydrocannabinol at a dose that is equivalent to a medium dose in humans. We administered this cannabis chronically in the animal. And then the animal feels less pain. Then we evaluate the emotional component and we had decreased the cognitive impairment and we had decreased the size of the cyst at the peripheral level. So, we suppose that this effect is the combination of as central and a peripheral response produced by THC.
Chris - And when you look inside the animals, can you see any differences in the way the tissue is behaving when you treat the animals with THC?
Rafael - Yeah, we do. We observe a decrease in the size of the cyst. We observe a decrease in the size of the cyst that generates this disease that is called endometriosis.
Chris - Do you think it will be possible to dissect away some of the psychoactive effects of THC and still achieve these benefits so that people would potentially get the benefits for endometriosis, but none of the central consequences?
Rafael - Yeah. These are, these are the studies that we are doing right now trying to obtain just the beneficial effects avoiding the central psychoactive effects of THC.
27:45 - The nerves that allow us to enjoy a cuddle
The nerves that allow us to enjoy a cuddle
Francis McGlone, Liverpool John Moores University
The nervous system carries information about what touch from the skin to our brains. And different types of stimuli are carried in different classes of nerve fibres. Pain and temperature sensations are conveyed in one group of nerves, while fine touch and itch sensations are signalled by others. And we have a pretty good idea how this information is relayed to the brain. But there’s also one more recently identified class of nerve fibre - responsible for the pleasant sensations that accompany being stroked or massaged - that neuroscientists assumed, on the basis of the characteristics of the nerve cells involved, would travel alongside the pain and itch sensations. But when they did the experiment in humans to prove it, they got a surprise. Speaking with Chris Smith, Liverpool John Moores University's Francis McGlone…
Francis - Well, our research for a number of years now has been characterising the functional properties of a particular class of sensory nerves that innervate the skin called C fibres. And C fibres are classically understood for code for pain and itch. There's been another C fibre identified relatively recently that responds specifically to gentle touch. And this nerve fiber we hypothesise is the basis for why people like a cuddle, or they like to be stroked in, in consensual sort of relationships.
Chris - So in this case it's C for cuddle! But what was the question that you had to get at then?
Francis - Well, the question was its pathway centrally. So we record from these nerve fibres in humans using an amazing technique developed by the Swedes called microneurography. We can put a very fine electrode through the skin into an underlying nerve bundle and we can listen in specifically to particular classes of nerve fibres. So we know this nerve is in the skin and we know its response properties, which are really quite fascinating because this nerve fiber is tuned to respond optimally to the stroking velocities that people would report as most pleasant.
Chris - So you know a lot about basically what excites these nerve cells, but exactly how I become consciously excited when I'm stroked in this way, that that was the unknown?
Francis - Well, we've got the two ends of the, of the equation. We've got the first order neuron in the skin. What we don't know is the second order pathway - i.e. which spinal pathway is a C tactile afferent moving up towards the brain.
Chris - Is that not the same as the pathway that these other C fibres, these very small unmyelinated with very fine calibre nerve fibres take? They classically - we understand from, you know, physiology going back a long, long time - they go into the spinal cord, make some connections and then they go across to the other side of the spinal cord and whiz up to the brain. Is that different than you think?
Francis - Well, that was our major hypothesis. That was the whole basis of this study was to basically establish that the C tactile afferent took the same spinal pathway as the other classic C fibres, the ones that code for itch and the ones that code for pain. So that was our hypothesis that, when that is cut, response to pleasant touch would have disappeared.
Chris - Now when you say when it's cut, would this be in humans who are having either trauma to the spinal cord or purposeful interruption of those pathways for some reason?
Francis - Yes. So I should explain that in chronic neuropathic pain patients, the problem with chronic neuropathic pain, it is very difficult to switch it off, so, some years ago, neurosurgeons came up with an operative procedure where they basically put a needle into the spinal cord and the spinal cord has got loads of pathways coming up it, but there's a specific pathway called the spinothalamic tract, where we know all the C-nociceptors and the itch nerves are. So the neurosurgeon will put a needle into that and then they heat that needle up so that it basically cauterizes the spinothalamic tract and then it's quite incredible actually that, of 20 patients that took part in the current study, I think 18 or 19 after this operation, we're completely pain free. Their itch had gone, and of course we fully expected when we tested their response to present touch, that would have been absent as well - and it wasn't. We're having a real rethink now as to what's going on in terms of how this nerve fiber codes for the pleasantness of touch.
Chris - Do you think they've got a unique fiber bundle: these aggregate in some way within the substance of the spinal cord; they don't join those pain and itch and other pathways; they stay isolated and go up anatomically in a distinct area. And so when you do that lesion, you just miss them?
Francis - Uh, there is that possibility that we may, they may have a sub sort of pathway that travels up the spinothalamic track that we missed. But these operations completely removed itch. They completely remove pain, so they'd have to be hiding somewhere in order for us not to have detected them. There is just one maybe niggling problem is that when the surgeon is stimulating through that needle to make sure that he's in the right part of the spinal column, the patient is brought out of anaesthesia. And they're asked to respond when they feel anything. And of course if you're in the spinothalamic tract and you electrically stimulate it, clearly these patients will respond with "yeah, that's really painful!" So we're looking specifically with the surgical procedure for a response of pain from the participants. Now, it's just vaguely possible that, by doing that, we missed out another sort of sub-tract in the spinothalamic tract that has all the CTs. That's a possibility, but it's unlikely.
Chris - Is it possible that these slightly extraordinary nerve fibres are taking a completely different path entirely? Could it be that they're going up, say, the back part of the spinal cord, what we call the dorsal column pathway, which traditionally there's very fine touch in there, isn't there? If I want to tell which coin I've got in my pocket, when I reach in with my fingers, I'm using that pathway. Is it possible they're going up there?
Francis - Absolutely. I mean that's when we reasoned the um, results in our paper, we did make that point, that it's possible that these fibres are also going up the dorsal columns. And as you say, there is some evidence and some animal literature that that may be the case. It's surprising how little we really understand about the complexities of these afferent pathways coming up in the spinal cord. And what we're going to be doing next now is to let the brain tell us what's going on rather than somebody subjectively reporting whether that touch feels pleasant or not. So these patients, the next cohort of patients, we'll be running an fMRI analysis on them and stroking them again and see what the brain's telling us...
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