Friday, July 31, 2020

Voting: Should It Be Hard?

An argument for how more access to voting (not less) is not only fair but makes for a more deliberative voting population (also posted on Medium).

Image of “Vote” with three hands of different color shades reaching up toward it. Public domain image via Mohamed Hassan.
(public domain image from Mohamed Hassan)
“Voting should take some effort. It means more that way.”

This was a statement I copied from a social media post of an old acquaintance, but I have heard the same sentiment from many others. They say that voting is important, perhaps the most important assertion of someones feelings that they can make, and so a certain amount of inconvenience is necessary to adequately motivate someone to deliberate on important options and make an informed choice. This logic usually then takes a leap and leads to the conclusion that all voting should be in person; mail-in voting is “too easy” to encourage people to make good choices.

However, the danger of using in-person voting as an explicit barrier to entry to filter out those who do not “care enough” about voting is that the burden of in-person voting is not the same across an entire population. Thus, accepting in-person voting as the mechanism that imposes costs (and requires effort) is an implicit statement that some votes are less valuable than others not because the voter cares less but because the voter happens to be more burdened by the process of in-person voting. But voting is meant to be a vehicle for those who will be affected by government actions to have a voice in deciding who will make up the government that takes those actions. Those who are the most burdened by lack of infrastructure, for example, should certainly not be attenuated; if anything, their voices should be amplified.

Furthermore, it is false to suggest that voting by mail is far easier than voting in person. Voting by mail requires considerable deliberation, care, and effort to complete. Just because someone receives a ballot in the mail (which they may have had to go through a process to register to receive) does not mean that they will open it, complete it (perhaps bubbling in tens to hundreds of bubbles), package it properly to return, and deposit to a mailbox. You could argue that if someone lives next to a polling location, it would be much easier to wander in and vote electronically with little deliberation (just tapping randomly on a screen) than it would be to actually fill out and return a mail-in ballot properly. In fact, if we were to abolish in-person voting entirely so that everyone would have to vote by mail, my guess is that many voters who found in-person voting very convenient might start skipping some elections because they couldn’t be bothered with the longer process of mail-in voting.

And that’s the big point — asymmetries of convenience create biased voting demographics. The issue is not that voting by mail is “so convenient” (because it isn’t!); it is that voting in person is, for some, prohibitively inconvenient. There should be a space for both kinds of voting (and possibly more). If we really want a representative sample of a population, we have to ensure our sampling methods do not inadvertently (or otherwise) exclude parts of the population that will be affected by the outcome of the process of voting that they were excluded from.

If you really do want voting to “take some effort”, it should be motivational effort that is equally applicable to everyone and not physical effort that varies from person to person or community to community. Where do we get that motivational-effort barrier? From very large numbers of people voting. If large numbers of people vote, then each person feels that their vote is inconsequential, and so the costs of voting will always be larger than the benefits. This surplus in the costs of voting will always present a motivational barrier, and the size of that barrier will be similar across the large population of voters. Thus, magnifying the costs of voting is best accomplished by magnifying the number of people voting; it is poorly accomplished by magnifying the physical distance between some voters and their voting location.

How to Read Epidemiological Parameters: Going from R0 to Predicting Number of Deaths

Basic guide for using CDC data to understand how many people must die for a society to reach herd immunity (also posted on Medium)

David J. Sencer CDC Museum in Atlanta, GA (public domain image from Jim Gathany, downloaded from Wikimedia Commons)
David J. Sencer CDC Museum in Atlanta, GA (public domain image from Jim Gathany)

An epidemic is not a single number. Knowing exactly how bad an epidemic is requires knowing both how quickly it is going to spread and how bad its effects will be on those who are affected by it. To make matters worse, parameters that characterize each of these separate factors usually cannot simply be “multiplied together” to understand their composed effects. They have to be filtered through dynamical models that properly account for depletion and saturation effects in populations. So it is understandable that the average person might have a hard time making sense of CDC estimates of such parameters, and it is not surprising that there are a lot of misconceptions and misperceptions about these topics.

Let’s take the CDC COVID-19 Pandemic Planning Scenario report (as of May 20, 2020). This looks like a simple document at first, but it may be difficult to understand how to pull all of these numbers together. For a variety of reasons, parameters of interest to epidemiologists are difficult to estimate from data. One method to mitigate issues with incomplete or noisy data is to make assumptions that help fill in the gaps, but then your analysis is only as good as your assumptions. To be conservative and to understand how sensitive predictions are to these assumptions, the CDC has come up with five different “scenarios” that stretch across a wide range of assumptions. To keep things simple, we will focus on “Scenario 5: Current Best Estimate”, which is the CDC’s best guess at where these epidemiological parameters are.

It is best to start with everyone’s favorite epidemiological parameter, R0. This is the so-called “basic reproduction number.” It is a measure of how fast a contagious infection can spread. R0 is the combination of three factors:

  • The rate of interaction between an infectious (contagious) person and others in the population (referred to as “contact rate” below in some places)
  • The probability that an infectious person will infect someone that they come in contact with
  • How long an infectious person stays infectious (we assume that after this period, they are in a permanent recovered state where they are immune to further infection)

Essentially, R0 is a ratio of the rate that an infectious person infects others to the rate that an infectious person becomes well. This ratio can be interpreted as the number of people an infectious person infects before they themselves stop being infectious. If R0 is less than 1, then a disease will naturally die out because (on average) those infected will not be able to infect someone else before they become well. If R0 is greater than 1, then we have a so-called endemic. That means that the infectious disease will be constantly maintained at some background level; some fraction of the population will always be either currently infectious or recovered. Interestingly, this fraction is not 100%. As an infectious disease spreads through a population, the number of those who are susceptible to further infection declines to a point where it is rare for infectious individuals to encounter them (contacts with infected and recovered are far more common). This means that when susceptible individuals are rare, each infectious individual spreads less of the infection during the time window that they are infectious. This is the so-called herd immunity. A fraction of the population can stably remain susceptible because they are protected by the large numbers of others who have already had the disease and buffer them against contact with those who are currently infectious. The fraction of the population that will remain susceptible at the so-called endemic equilibrium is 1/R0. Likewise, the fraction of those in a population that must have been infected (or vaccinated, if possible) in order to achieve herd immunity is (1–1/R0). I should note that this simplified model assumes that infectious people eventually become recovered and stay that way; things get more complicated if immunity is not long lasting.

So what does the endemic equilibrium (“herd immunity”) look like for COVID-19 (assuming long-lasting immunity)? Here is what CDC estimates for R0.

CDC estimates of R0 for COVID-19 for different scenarios. R0 is shown to be 2.5 in most likely scenario.
CDC estimates of R0 for COVID-19

Again, focusing only on Scenario 5, we take R0=2.5, which means that any infectious person will have an opportunity to infect 2.5 other people on average. So we then estimate that 1/R0=1/2.5=40% of the population will be able to avoid infection so long as the other 60% of the population goes through an infection or is vaccinated. So exactly how many people is that? In the United States, the population is a little over 325 million people (compare this to the world population of 7.8 billion people). So that means that 60% of the 325M people in the USA must be infected to achieve herd immunity. That’s 195M people in the USA (4.68 billion people worldwide).

But not everyone who is infected sees symptoms let alone has to go to a hospital or suffers an early death. If we go back to the CDC data, we see that…

CDC estimates for asymptotic ratio and symptomatic case fatality ratio for COVID-19. Most likely estimates are 35% and 0.004.
CDC estimates for asymptotic ratio and symptomatic case fatality ratio for COVID-19

Again, looking at Scenario 5, we see that 35% of those who have an infection show no symptoms. We also see that those other 65% who show symptoms will suffer fatality at an overall (averaged across age groups) rate of 0.004 (i.e., 0.4%). That seems like a very small number! But we have to keep in mind that this is a very contagious disease (any infectious person infects 2.5 other people). So we need to combine the information on contagion with the information on case fatality rate. For the 325M people in the USA, we already calculated that 195M will have the disease. So then, at the endemic equilibrium (“herd immunity”):

  • 195M*65% = 127M people will have shown symptoms in the USA
  • 127M*0.4% = 508,000 people will die in the USA

And worldwide, we would expect 12.2M people will die. So even at that very small case fatality rate, there will be a lot of death (and even those that escape symptoms may still feel long-term effects of COVID-19 that we are only starting to understand now). Just as a reference, 38,000 people died in car accidents in 2018 in the USA. We try to prevent deaths by car accidents by preventing car accidents and trying to make cars safe so that people will survive accidents that happen. When we ask people to wear masks and social distance, this is not unlike people’s legal obligation to wear seatbelts and drive cars that meet safety standards.

Now, a lot of people say that there is no way to prevent these deaths, and so it is better to suffer them early instead of dragging out our march to the endemic equilibrium. In order to evaluate whether this is a good argument, we should take a look at another part of the CDC data:

CDC estimates for symptomatic case hospitalization ratio for COVID-19. Most likely overall estimate is 0.041.
CDC estimates for symptomatic case hospitalization ratio for COVID-19

Focusing on Scenario 5’s “Overall” estimate, we see that each person who shows symptoms will have a 3.4% chance of being hospitalized. So that means we can estimate that for the population of 325M people in the USA, the 127M people we calculated above to show symptoms, 3.4% of them will have to be hospitalized, meaning that COVID-19 contribute 4.318M patients to hospitals in the USA (103M COVID-19 hospital patients worldwide). The question is whether we have enough hospital beds in the USA to accommodate these 4.318M people all at once. If we do not, then those that would have otherwise recovered will have to suffer through the disease without the support of medical professionals and medical technology. In other words, the case fatality rate for this subset of COVID-19 symptomatic individuals turned away from hospitals may rise to much higher than the 0.4% mentioned above. So this is really the essence of the movement to flatten the curve (e.g., by wearing masks and social distancing to reduce the effective contact rate). Even if it is impossible to avoid the 508,000 deaths predicted above, if infections can be spread out over a long amount of time, we can help to ensure that at any instant there will be enough hospital beds. Furthermore, if we stretch out the infection curve far enough, we may develop a vaccine within the curve’s duration. Vaccinations are a game changer because they provide a quick shortcut (that is hopefully much safer than a full-blown infection) to herd immunity.

But if we wanted to reduce that 508,000 without a vaccine, how would we do it? Remember that I said that R0 (a parameter of infection spread) is determined in part by the rate that an infectious individual contacts other individuals in the population. If we can devise long-term behavioral or technological methods to reduce this contact rate (beyond temporary inconveniences, such as wearing masks), then we can change R0 for COVID-19 for good (or at least for a sufficiently long time), thereby meaning that our endemic equilibrium (“herd immunity”) will occur with a much higher number of people who avoid infection (and even vaccination) entirely. How do we do that? Here are three potentially powerful ways.

  • We can remove hand shaking and other similar kinds of contact as a greeting (thereby bringing the baseline contact rate for every individual in the population to a much lower level than it was before COVID-19).
  • We can develop rapid, highly available, and frequent testing protocols that can quickly identify infected individuals so that they can be isolated (thereby bringing their personal contact rate much lower than others).
  • We can develop sophisticated contact-tracing techniques that can further identify potentially infected individuals so that they can be isolated (thereby bringing their personal contact rate much lower than others).

These behavioral and technological changes can actually improve our long-term COVID-19 outcome even if a vaccine is not developed. So it may not be inevitable that hundreds of thousands of more people have to die (at the time of this writing, over 110,000 people in the USA had death certificates that indicated COVID-19 as a cause of death).

Medical professionals can develop vaccines, researchers can develop novel technologies, and we can all alter our behaviors. Unfortunately, there are additional challenges in the near future that will make all of this even more urgent. In particular, we are facing a flu season ahead of us. Individuals who contract COVID-19 and the seasonal flu simultaneously may be in an untenable situation. Additionally, the medical system will face demands not only from COVID-19 but from those with the flu (but possibly not COVID-19) who also need hospitalization. Normally the medical system would have enough capacity to serve the seasonal flu population (although there are still seasonal flu deaths every year, just not as much as COVID-19). However, if the medical system has to face flu and COVID-19 along with baseline demands and any other emergent demands (other pandemics, etc.), then that will put our society as a whole in an untenable situation. The flu shot may be especially important to encourage this season.

Of course, there are many other interesting figures in that CDC report that we could further analyze that relate to how long the average COVID-19 hospital patient takes to recover, which would help us figure out more quantitative details about the amount of each of the kinds of possible actions discussed above will be necessary to prevent hospitals reaching capacity. For now, I will leave that analysis as an exercise for the reader. In the meanwhile, get some rest, stay safe, and stay healthy!

Friday, June 12, 2020

Animal Behavior virtual conferences for Summer/Fall 2020 that are free (or nearly free)

A silver lining of COVID-19 is that amazing conferences have become far easier and far cheaper to attend. For interdisciplinary researchers, you can now dip your toe into venues that you might not otherwise be able to justify spending the resources on. So it is a great time to branch out!

As an example, there are FOUR virtual Animal Behavior conferences that will be taking place soon this summer or early fall. They are free or nearly free (at least for students), and all of them are still accepting talk/poster abstracts at the time of this posting. If you are doing empirical or theoretical work in animal behavior and would normally present your work at a more methods-based conference, this is a great opportunity to get feedback from the larger behavior community. If you are not currently directly researching behavior, you might really enjoy just hearing reports of great, state-of-the-art research into animal behavior.

My background is in engineering, and I have found that animal behavior conferences to be the most educational and useful in generating bio-inspiration for me. These conferences showcase how animals interact with each other and the world around them in potentially adaptive ways. Plus, it's a great showcase of natural history for those who don't feel like they are naturally naturalists!

So check these out. And this is probably not an exhaustive list!
  • ABS 2020 Virtual Meeting [USA animal behavior]
  • Animal Behavior Live [new annual venue; global]
  • ASAB Virtual Conference [British animal behaviour]
  • ASSAB Virtual Conference [Australian animal behaviour]
    • Free registration
    • [ info coming soon ]
    • Conference: 28th September – 1st October, 2020
    • https://www.assab.org/

Tuesday, June 02, 2020

Zoom Virtual Background for Short/Coffee Breaks ("I'll be right back!")

You might know that Zoom has a non-verbal feedback option under the Participants list that includes a "need a break." You could use this to indicate when you have stepped away, but it is intended to indicate to the speaker that you are requesting a break.

So what is an option to indicate to everyone that you have stepped away and aren't just having video problems? One option is to create a virtual background that includes some status signage (or, alternatively, you can make the signage part of your profile picture that shows when your camera is off). Here is an image I put behind me to indicate to others that I've stepped away very briefly and will be back soon.
You can download and use the image above. You can also download the PowerPoint version so you can make edits to it. Here I am with my virtual background behind me. Of course, normally I would only put this up when I was out of the room. :-)


Another option is to print out a tiny version of the image above and hang it in front of your camera. :-)

Monday, May 04, 2020

Reduce Student Anxiety: Introduce them to "What-If Grades" in Canvas Gradebook

Are your students getting anxious and wondering what their final grades might look like under different “what-if” scenarios related to any assignments yet to be graded? A lot of faculty and students don’t realize that the Canvas gradebook supports “What-If Grades”, which allow a student to click on any grade (even ones not posted) and change it to a hypothetical version to see what the hypothetical effect would be on their final grade.

Check it out:

Monday, April 06, 2020

Teaching on Zoom: Fixing Problems with Students Joining Authentication-Only Rooms

To help prevent "#Zoombombing" while still allowing for all of the features that, when not being exploited, provide for productive digital classroom experiences, many universities have recommended that faculty turn on authentication-only Zoom rooms for their classes. For most students, this means that they may have to follow one extra click when joining their classrooms that leads them through the single-sign-on (SSO) process and handoff back to Zoom. Unfortunately, this process is not as simple for some students, especially if they already have their own non-University Zoom accounts.

Here are the instructions (also linked as a PDF or a DOCX) I have been giving to my students to help ensure that they access my authentication-only Zoom classroom using their university account. Of course, there are a few small aspects of these instructions that are customized for ASU, but it would be easy to modify the instructions for your institution.



Instructions for Accessing Zoom Room as Authenticated ASU Zoom User


To help mitigate problems related to "Zoom-bombing", your course Zoom link may be configured to only allow authenticated ASU users into the room. If you are having trouble connecting to the Zoom class room with your properly authenticated ASU account, you should try following these steps:
  1. DO NOT use the normal link to enter the room
  2. Instead, go to https://asu.zoom.us/ and then click on the Log In button
  3. Once you are logged in to ASU Zoom, click on the "JOIN A MEETING" link in the top right of ASU Zoom
  4. Use the Zoom ID: (10-digit code from your instructor; also at the end of course link)
These steps are designed to ensure that you are logged in to Zoom with your ASU ID.

If the above steps still do not let you into the room, then you need to open your Zoom app and make sure to "Switch Account" to your ASU account. Follow these steps:
  1. Open your Zoom application
  2. Click on your profile image, as in the image below, and go to "Switch Account"


  3. Select "Sign In with SSO", as shown below:
  4. Use "asu" as the Company Domain, as shown below:
  5. Follow the prompts to login to ASU Zoom and return to your application
  6. Use your course’s meeting ID (or the normal course link) to connect to the Zoom room

Those steps should help ensure that you are able to get into the class Zoom room with your authenticated ASU Zoom account.

Monday, March 23, 2020

Teaching on Zoom: Automatic Subtitle Captions on a Whiteboard

In the wake of COVID-19, faculty are looking for ways in which they can extend their original in-class teaching approaches to on-line while maintaining high accessibility.

I recently saw a request by someone using Zoom for whiteboard capability with automatic, real-time captions that have subtitles for the audio. This capability does not currently exist in Zoom's native whiteboard. However, real-time subtitles are available in presentation applications like Microsoft Powerpoint. In addition, Zoom annotations (if enabled) allow a presenter (or anyone in a Zoom room) to annotate any shared screen as if it was a Zoom whiteboard. So I came up with the following solution to the whiteboard-with-subtitltes problem. Note that other variations on this solution exist, but this particular solution was crafted to be the most generalizable and prevent the most conflicts with Zoom and Microsoft competing for access to a single microphone.

Here are a list of steps to make it happen. You can also see the video below if you prefer to see a demo of these steps.
  1. Open a Zoom room on a desktop machine that runs PowerPoint 2019 or later (including Office 365 versions of PowerPoint)
    • Do not share audio or video
  2. From the Zoom room, share the desktop that powerpoint will use when it goes into full-screen mode during a presentation
  3. Start a blank PowerPoint presentation
  4. Click on the "Toggle Subtitles" button shown in the bottom left corner of the PowerPoint presentation
    • You should now see live subtitles being added to your presentation as you speak
  5. Join your Zoom room from a tablet device
    • This time, connect with audio so that your audience listens to you through your tablet presence
    • You should see the shared, blank PowerPoint screen on the tablet device
  6. Use the "Annotations" button in the bottom left of the tablet view to open the annotations
    • Note that "Annotations" has to be enabled for your Zoom room
    • You can find the setting to enable Annotations in the advanced settings on your Zoom web portal
    • When annotations are enabled, anyone can use them, and so make sure you trust your audience
  7. Use your tablet (perhaps with stylus) to draw on the white screen provided by PowerPoint as PowerPoint subtitles below your writing
    • You can use the eraser and clear (trash can) buttons to get a blank screen
  8. If you are going to record, I recommend using "Record to Cloud" from the tablet device
    • Again, the goal is to take the load off of the desktop machine that is doing the live captioning
Here is a video I put together that demonstrates the above steps:


Monday, December 02, 2019

Woodpeckers can ring and run too

Our Ring Pro video doorbell recently caught this red-headed ding-dong ditcher visiting our front door:


We answered this ring, but we weren't around about an hour later when it returned!


After checking with our neighbors, we found that gila woodpeckers have apparently been terrorizing some other doorbells and surveillance cameras in the area as well. It is pretty adorable... until you have to replace the device.

In this case, hopefully being startled twice by the Ring's chime is enough to encourage it to move on!

Monday, August 12, 2019

Tribute to Mom, Eileen Pavlic (1942–2019)

My mother, Eileen Pavlic, died on Tuesday, August 6, 2019, due to complications from a stroke. She had been battling cancer for a year, and immunotherapy had been working well to reduce the extent of her cancer. She was enthusiastic about the progress of the treatment and had even started to buy new clothes, anticipating at least another year of life. Then, surprisingly and very sadly, she suffered a stroke. We learned that metastatic cancer is a risk factor for stroke, and so this outcome was not a complete surprise to the doctors even though it was devastating to us. She was buried in an outfit that she had recently ordered and had never had the opportunity to wear herself.

We know she was very impressed and encouraged with the immunotherapy she received, and so I hope you will consider donating to the Pelotonia Institute for Immuno-Oncology (PIIO) or another reputable charity advancing the use of immunotherapy for the treatment and possible cure for cancer. 

I shared the comments below during her funeral on August 9, 2019. You can also read her obituary on-line.


A Son's Tribute to His Mother, Eileen M. Pavlic (September 22, 1942 – August 6, 2019)


Looking back on your life with someone is less like watching a movie from beginning to end but more like drawing lottery balls from a tumbling urn. There’s one random memory. Then another. Then another. It is only after drawing enough of them that we can look back on them, sort them out, and start seeing hints of a bigger picture. That’s how it was for me when thinking about what to say today, and I only hope this story comes across a little smoother than those lottery balls.

She always wanted me to become a medical doctor, and I was excited to oblige when I was younger. Books and models mom and dad would get me about anatomy and physiology were interesting to me, but ultimately, I think the real source of the appeal was not the content so much as the connection with her. At some point, I pivoted away from medicine toward things like mathematics, computing, and, ultimately, engineering. Even mom might not see how this has anything to do with her, but from my perspective looking back, I remember the young me watching her navigate a DOS prompt, manipulate revealed codes in WordPerfect documents, and designing merge fields for office automation, and she became my model for someone who could learn to use tools around her to do great things. She never viewed herself as a teacher – she would often excuse herself from philosophical discussions that dad and I would have by saying that “she didn’t go to college” – but she was one of my greatest teachers. Today, I teach college students, and I only hope that some of them could be as motivated by me as I was by her. And it’s no surprise to me that biology has shown up in a lot of my engineering research, which sometimes makes me think that the younger version of me is still trying to turn my PhD into an MD to make mom proud.

So, yeah, looking back on life with mom is a little like drawing lottery balls. And by giving me the opportunity to do so, mom’s given me one last lesson – that being her son was winning the jackpot.


Thursday, April 25, 2019

Long, non-coding RNA serve an important role in the regulatory pathway controlling human skin wound healing

It seems like there has been a lot of cool wound-healing research results published lately. At the end of March, there was the result that bacteriophages hide their bacterial hosts from being cleared by mammalian immune response. Last week there was the result that aphids soldier nymphs use their own wound-healing proteins to plug gall holes. And now there's this new result on the mechanism underlying the role of long, noncoding RNA (lncRNA) in wound healing of human skin.

So what's long, non-coding RNA? The DNA in the human genome has to be converted to RNA, in much the same way computer code might be converted into assembly language, before it can then be converted into proteins (like assembly language being converted into object code that can actually be executed by the computer). Up until recently, biology has focused entirely on this pipeline -- DNA to RNA to protein. However, there are some bits of DNA that stop at RNA, which are termed "non-coding RNA" because they don't end up producing any proteins. They just float around until they naturally break down. However, there are hints that they are not merely intermediate transitional objects and that they can be functional molecules themselves. One of those hints is that they can be consistently turned on ("up-regulated") in certain situations. However, this doesn't mean that they're actually doing anything. There are technical details that make it useful to distinguish whether these non-coding RNA are short or long. I won't get into those. Just know, for the reset of this post, that "lncRNA" represents "long, non-coding RNA", which is a type of these mysterious molecules. When healthy human skin is wounded, the normal response happens to involve the up-regulation of one of these lncRNA's is consistently generated more than in undamaged tissue, but no one knows why.

In this paper, they show that the molecule actually sequesters other mechanisms within the tissue that would normally turn off the migration of cells important for wound healing. So the lncRNA's are functional -- they get turned on when the skin is wounded, and that sets of a chain reaction that disables other mechanisms that would normally keep wound healing processes turned off. So the lncRNA's are an important step in the regulatory network. That's very cool. It not only helps scientists understand wound healing but also one more way in which lncRNA's can be functional -- not just junk molecules floating around waiting to be broken back down.

Here is the primary source:

"Human skin long noncoding RNA WAKMAR1 regulates wound healing by enhancing keratinocyte migration"
by Li et al.
PNAS (2019), early edition
https://doi.org/10.1073/pnas.1814097116

Significance
=====
Although constituting the majority of the transcriptional output of the human genome, the functional importance of long noncoding RNAs (lncRNAs) has only recently been recognized. The role of lncRNAs in wound healing is virtually unknown. Our study focused on a skin-specific lncRNA, termed “wound and keratinocyte migration-associated lncRNA 1” (WAKMAR1), which is down-regulated in wound-edge keratinocytes of human chronic nonhealing wounds compared with normal wounds under reepithelialization. We identified WAKMAR1 as being critical for keratinocyte migration and its deficiency as impairing wound reepithelialization. Mechanistically, WAKMAR1 interacts with DNA methyltransferases and interferes with the promoter methylation of the E2F1 gene, which is a key transcription factor controlling a network of migratory genes. This line of evidence demonstrates that lncRNAs play an essential role in human skin wound healing.
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Abstract
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An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-β signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed “wound and keratinocyte migration-associated lncRNA 1” (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds.
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