Background:

Screening rates for Human Immunodeficiency Virus (HIV) remain low despite guidelines by both the CDC and USPSTF recommending that all adolescents and adults be screened at least once. The aim of this quality improvement study was to increase HIV screening among eligible patients.

Internal ribosomal entry sites (IRESs) recruit the ribosome to promote translation, typically in an m7G cap-independent manner. Although IRESs are well-documented in viral genomes, they have also been reported in mammalian transcriptomes, where they have been proposed to mediate cap-independent translation of mRNAs. However, subsequent studies have challenged the idea of these "cellular" IRESs. Current methods for screening and discovering IRES activity rely on a bicistronic reporter assay, which is prone to producing false positive signals if the putative IRES sequence has a cryptic promoter or cryptic splicing sites. Here, we report an assay for screening IRES activity using a genetically encoded circular RNA comprising a split nanoluciferase (nLuc) reporter. The circular split nLuc reporter is less susceptible to the various sources of false positives that adversely affect the bicistronic IRES reporter assay and provides a streamlined method for screening IRES activity. Using the circular split nLuc reporter, we find that nine reported cellular IRESs have minimal IRES activity. Overall, the circular split nLuc reporter offers a simplified approach for identifying and validating IRESs and exhibits reduced propensity for producing the types of false positives that can occur with the bicistronic reporter assay.

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na⁺/K⁺-ATPase (IUBMB Enzyme Nomenclature). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (k_on), dissociation rate (k_off), and equilibrium (K_i) constants of CTS for the structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of K_i of the cardenolides digitoxigenin, essentially due to a reduction of k_on. In contrast, the K_i of the structurally related bufadienolide bufalin increased much less due to the reduction of its k_off partially compensating the decrease of its k_on. When evaluating the kinetics of 15 natural and semisynthetic CTS, we observed that both k_on and k_off correlated with K_i (Spearman test), suggesting that differences in potency depend on variations of both k_on and k_off. A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of k_off rather than an increase of k_on. Raising the temperature did not alter the k_off of digitoxin, generating a H (k_off) of –10.4 ± 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of k_on, k_off, and K_i of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds.

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Tactile controls are back in vogue. Apple added two new buttons to the iPhone 16, home appliances like stoves and washing machines are returning to knobs, and several car manufacturers are reintroducing buttons and dials to dashboards and steering wheels.

With this “re-buttonization,” as The Wall Street Journal describes it, demand for Rachel Plotnick’s expertise has grown. Plotnick, an associate professor of cinema and media studies at Indiana University in Bloomington, is the leading expert on buttons and how people interact with them. She studies the relationship between technology and society with a focus on everyday or overlooked technologies, and wrote the 2018 book Power Button: A History of Pleasure, Panic, and the Politics of Pushing (The MIT Press). Now, companies are reaching out to her to help improve their tactile controls.

Rachel Plotnick on...

• Researching the history of buttons
• The renaissance of physical controls
• Working with companies on “re-buttoning”

You wrote a book a few years ago about the history of buttons. What inspired that book?

Rachel Plotnick: Around 2009, I noticed there was a lot of discourse in the news about the death of the button. This was a couple years after the first iPhone had come out, and a lot of people were saying that, as touchscreens were becoming more popular, eventually we weren’t going to have any more physical buttons to push. This started to happen across a range of devices like the Microsoft Kinect, and after films like Minority Report had come out in the early 2000s, everyone thought we were moving to this kind of gesture or speech interface. I was fascinated by this idea that an entire interface could die, and that led me down this big wormhole, to try to understand how we came to be a society that pushed buttons everywhere we went.

Rachel Plotnick studies the ways we use everyday technologies and how they shape our relationships with each other and the world.Rachel Plotnick

The more that I looked around, the more that I saw not only were we pressing digital buttons on social media and to order things from Amazon, but also to start our coffee makers and go up and down in elevators and operate our televisions. The pervasiveness of the button as a technology pitted against this idea of buttons disappearing seemed like such an interesting dichotomy to me. And so I wanted to understand an origin story, if I could come up with it, of where buttons came from.

What did you find in your research?

Plotnick: One of the biggest observations I made was that a lot of fears and fantasies around pushing buttons were the same 100 years ago as they are today. I expected to see this society that wildly transformed and used buttons in such a different way, but I saw these persistent anxieties over time about control and who gets to push the button, and also these pleasures around button pushing that we can use for advertising and to make technology simpler. That pendulum swing between fantasy and fear, pleasure and panic, and how those themes persisted over more than a century was what really interested me. I liked seeing the connections between the past and the present.

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We’ve experienced the rise of touchscreens, but now we might be seeing another shift—a renaissance in buttons and physical controls. What’s prompting the trend?

Plotnick: There was this kind of touchscreen mania, where all of a sudden everything became a touchscreen. Your car was a touchscreen, your refrigerator was a touchscreen. Over time, people became somewhat fatigued with that. That’s not to say touchscreens aren’t a really useful interface, I think they are. But on the other hand, people seem to have a hunger for physical buttons, both because you don’t always have to look at them—you can feel your way around for them when you don’t want to directly pay attention to them—but also because they offer a greater range of tactility and feedback.

If you look at gamers playing video games, they want to push a lot of buttons on those controls. And if you look at DJs and digital musicians, they have endless amounts of buttons and joysticks and dials to make music. There seems to be this kind of richness of the tactile experience that’s afforded by pushing buttons. They’re not perfect for every situation, but I think increasingly, we’re realizing the merit that the interface offers.

What else is motivating the re-buttoning of consumer devices?

Plotnick: Maybe screen fatigue. We spend all our days and nights on these devices, scrolling or constantly flipping through pages and videos, and there’s something tiring about that. The button may be a way to almost de-technologize our everyday existence, to a certain extent. That’s not to say buttons don’t work with screens very nicely—they’re often partners. But in a way, it’s taking away the priority of vision as a sense, and recognizing that a screen isn’t always the best way to interact with something.

When I’m driving, it’s actually unsafe for my car to be operated in that way. It’s hard to generalize and say, buttons are always easy and good, and touchscreens are difficult and bad, or vice versa. Buttons tend to offer you a really limited range of possibilities in terms of what you can do. Maybe that simplicity of limiting our field of choices offers more safety in certain situations.

It also seems like there’s an accessibility issue when prioritizing vision in device interfaces, right?

Plotnick: The blind community had to fight for years to make touchscreens more accessible. It’s always been funny to me that we call them touchscreens. We think about them as a touch modality, but a touchscreen prioritizes the visual. Over the last few years, we’re seeing Alexa and Siri and a lot of these other voice-activated systems that are making things a little bit more auditory as a way to deal with that. But the touchscreen is oriented around visuality.

It sounds like, in general, having multiple interface options is the best way to move forward—not that touchscreens are going to become completely passé, just like the button never actually died.

Plotnick: I think that’s accurate. We see paradigm shifts over time with technologies, but for the most part, we often recycle old ideas. It’s striking that if we look at the 1800s, people were sending messages via telegraph about what the future would look like if we all had this dashboard of buttons at our command where we could communicate with anyone and shop for anything. And that’s essentially what our smartphones became. We still have this dashboard menu approach. I think it means carefully considering what the right interface is for each situation.

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Several companies have reached out to you to learn from your expertise. What do they want to know?

Plotnick: I think there is a hunger out there from companies designing buttons or consumer technologies to try to understand the history of how we used to do things, how we might bring that to bear on the present, and what the future looks like with these interfaces. I’ve had a number of interesting discussions with companies, including one that manufactures push-button interfaces. I had a conversation with them about medical devices like CT machines and X-ray machines, trying to imagine the easiest way to push a button in that situation, to save people time and improve the patient encounter.

I’ve also talked to people about what will make someone use a defibrillator or not. Even though it’s really simple to go up to these automatic machines, if you see someone going into cardiac arrest in a mall or out on the street, a lot of people are terrified to actually push the button that would get this machine started. We had a really fascinating discussion about why someone wouldn’t push a button, and what would it take to get them to feel okay about doing that.

In all of these cases, these are design questions, but they’re also social and cultural questions. I like the idea that people who are in the humanities studying these things from a long-term perspective can also speak to engineers trying to build these devices.

So these companies also want to know about the history of buttons?

Plotnick: I’ve had some fascinating conversations around history. We all want to learn what mistakes not to make and what worked well in the past. There’s often this narrative of progress, that things are only getting better with technology over time. But if we look at these lessons, I think we can see that sometimes things were simpler or better in a past moment, and sometimes they were harder. Often with new technologies, we think we’re completely reinventing the wheel. But maybe these concepts existed a long time ago, and we haven’t paid attention to that. There’s a lot to be learned from the past.

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No Blank Screens, London

The Regal North Hollywood is holding a showing of the new feature-length anime The Lord of the Rings: The War of the Rohirrim from 1.00pm on this Saturday (November 9) open to children aged nine to 14, and their parents. It's not entirely clear whether adult-without-kids can also attend, but I took a few moments to run through their pre-booking survey and it does seem that you get screened out if you state you're attending without kids.

T&Cs also state that no-one under the age of nine will be admitted (presumably because of MPAA ratings).

If this tickles your fancy (and you have kids 9 to 14), you can reserve (free!) your tickets here.

If you're unaware of the story, The War of the Rohirrim is set many years before the events of The Lord of the Rings and follows a historic event described by J.R.R. Tolkien in Appendix A of the book. As the filmmakers describe it, "...a sudden attack by Wulf, a clever and ruthless Dunlending lord seeking vengeance for the death of his father, forces Helm Hammerhand, the King of Rohan, and his people to make a daring last stand in the ancient stronghold of the Hornburg."

The anime debuts worldwide (in most locations) on December 13.

Early free screening details

Saturday, November 9th, 2024
Regal North Hollywood
6150 Laurel Canyon Blvd # 200, North Hollywood, CA 91606

1:00 pm. Open to children 9-14 and their parents
No one under 9 will be admitted.
Check-in will begin 60 minutes before the start of the show.

RESERVE YOUR TICKETS

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