Dead Cells today has received its final major update, The End is Near, after seven years of development.

This will be the 35th update to the game, which has received a number of DLCs to expand gameplay and reference other popular games, from Castlevania to Hollow Knight.

The End is Near expands on the curse mechanic, with three new mobs, three new weapons, and three new mutations.

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One of the best roguelikes on PC is getting a farewell of sorts this week. Twitchy slashfest Dead Cells received its final major update, introducing new enemies, fresh weapons, and a few mutations. Unfortunately, all this new stuff is very cursed. In other words, it all toys with the game's "curse" status effect, a hex that causes you to be killed if you take even a single hit. You'll probably die a few times as a result of this update, which in some ways is a fitting finalé for this fast-paced jar smasher of a game. You can see the new features in the trailer below.

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One of the best roguelikes on PC is getting a farewell of sorts this week. Twitchy slashfest Dead Cells received its final major update, introducing new enemies, fresh weapons, and a few mutations. Unfortunately, all this new stuff is very cursed. In other words, it all toys with the game's "curse" status effect, a hex that causes you to be killed if you take even a single hit. You'll probably die a few times as a result of this update, which in some ways is a fitting finalé for this fast-paced jar smasher of a game. You can see the new features in the trailer below.

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Enlarge / Muscle atrophy is a known hazard of spending time on the International Space Station. (credit: NASA)

Muscle-on-chip systems are three-dimensional human muscle cell bundles cultured on collagen scaffolds. A Stanford University research team sent some of these systems to the International Space Station to study the muscle atrophy commonly observed in astronauts.

It turns out that space triggers processes in human muscles that eerily resemble something we know very well: getting old. “We learned that microgravity mimics some of the qualities of accelerated aging,” said Ngan F. Huang, an associate professor at Stanford who led the study.

Space-borne bioconstructs

“This work originates from our lab’s expertise in regenerative medicine and tissue engineering. We received funding to do a tissue engineering experiment on the ISS, which really helped us embark on this journey, and became curious how microgravity affects human health,” said Huang. So her team got busy designing the research equipment needed to work onboard the space station. The first step was building the muscle-on-chip systems.

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While humans won’t be regenerating entire limbs like sea stars, some new genetic work with fruit flies has yielded some surprising results. A team from the University of Tokyo found that certain genes from simple organisms that help them regenerate body parts and tissues can be transferred into other animals. These genes then suppressed an intestinal issue in the flies and could potentially reveal some new mechanisms for rejuvenation in more complex organisms. The findings are detailed in a study published August 1 in the journal BMC Biology.

[Related: These fingernail-sized jellyfish can regenerate tentacles—but how?]

Some animals including jellyfish and flatworms can regenerate their whole bodies. While scientists still don’t really know how, there are possibly specific genes that allow regeneration. These same genes may also maintain long-term stem cell functions.

Stem cells can divide and renew themselves over a long period of time and are kind of like a skeleton key. While they aren’t necessarily specialized, they can potentially become more specialized cells, including blood cells and brain cells, over time. Mammals and insects who have very limited regenerative skills may have lost these genes over the course of evolution. 

“It is unclear whether reintroducing these regeneration-associated genes in low regenerative animals could affect their regeneration and aging processes,” study co-author and University of Tokyo Graduate School of Pharmaceutical Sciences biologist Yuichiro Nakajima said in a statement.

In this new study, Nakajima and the team focused on the group of genes that is unique to animals with high regenerative capacity like flatworms. These genes are called HRJDs, or highly regenerative species-specific JmjC domain-encoding genes. They transferred the HRJDs into the fruit fly (Drosophila melanogaster) and tracked their health with a blue dye. They nicknamed the fly Smurf, thanks to this hue. 

Initially, they hoped that these HRJD-boosted fruit flies would regenerate tissue if injured. This didn’t happen. However, the team had a fruit fly intestine expert Hiroki Nagai onboard, who noticed something else. There were some novel phenotypes–or the characteristics like eye color or hair color that comes from a specific gene.  

“HRJDs promoted greater intestinal stem cell division, whilst also suppressing intestinal cells that were mis-differentiating, or going wrong in aged flies,” said Nakajima. 

This is different to how antibiotics may suppress the mis-differentiated intestinal cells, but suppress intestinal stem cell division. 

[Related: Hydras can regrow their heads. Scientists want to know how they do it.]

“For this reason, HRJDs had a measurable effect on the lifespans of fruit flies, which opens the door, or at least provides clues, for the development of new anti-aging strategies,” said  Nakajima. “After all, human and insect intestines have surprisingly much in common on a cellular level.”

Fruit flies are famous test subjects in biological research. They share 75 percent of the genes that cause diseases in humans, reproduce quickly, and their genetic code is fairly easy to change. However, even with their relatively short lives and rapid-fire reproduction and maturating rates, it still took about two months to study their full aging process. 

In future studies, the team would like to take a closer look at how HRJD’s work on a molecular level. 

“Details of the molecular workings of HRJDs are still unresolved. And it’s unclear whether they work alone or in combination with some other component,” said Nakajima. “Therefore, this is just the start of the journey, but we know now that our modified fruit flies can serve as a valuable resource to uncover unprecedented mechanisms of stem cell rejuvenation in the future. In humans, intestinal stem cells decrease in activity with age, so this research is a promising avenue for stem cell-based therapies.”

The post Swapping genes can help fruit flies regenerate cells appeared first on Popular Science.

Chaos and comedy. Death and rebirth. Luck and, uh, running out of luck. A good roguelike doesn't treat the player like other games do. Roguelikes won't guide you helpfully along a path, or let you cinematically snatch victory from the jaws of defeat. They're more likely to dangle you deep between the jaws of defeat and fumble the rope until you go sliding down defeat's hungry gullet. This is their beauty, and it's a part of why we keep coming back for another go. Next time everything will go right. Next time you'll find the right pair of poison-proof loafers, the perfect co-pilot for your spaceship, a stash of stronger, better ropes. Next time.

Here's our list of the 19 best roguelikes on PC you can play in 2024.

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Chaos and comedy. Death and rebirth. Luck and, uh, running out of luck. A good roguelike doesn't treat the player like other games do. Roguelikes won't guide you helpfully along a path, or let you cinematically snatch victory from the jaws of defeat. They're more likely to dangle you deep between the jaws of defeat and fumble the rope until you go sliding down defeat's hungry gullet. This is their beauty, and it's a part of why we keep coming back for another go. Next time everything will go right. Next time you'll find the right pair of poison-proof loafers, the perfect co-pilot for your spaceship, a stash of stronger, better ropes. Next time.

Here's our list of the 19 best roguelikes on PC you can play in 2024.

Read more

Dead Cells was blessed with several excellent animated trailers, each one produced by French animation studio Bobbypills. Now the slick metroidvania is getting a full animated television series from the same folks, and the first trailer is below.

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Stephen Cass: Hello and welcome to Fixing the Future, an IEEE Spectrum podcast where we look at concrete solutions to tough problems. I’m your host Stephen Cass, a senior editor at IEEE Spectrum. And before I start, I just wanted to tell you that you can get the latest coverage of Spectrum‘s most important beats, including AI, climate change, and robotics, by signing up for one of our free newsletters. Just go to spectrum.ieee.org/newsletters to subscribe.

We all love our mobile devices where the progress of Moore’s Law has meant we’re able to pack an enormous amount of computing power in something that’s small enough that we can wear it as jewelery. But their Achilles heel is power. They eat up battery life requiring frequent battery changes or charging. One company that’s hoping to reduce our battery anxiety is Exeger, which wants to enable self-charging devices that convert ambient light into energy on the go. Here to talk about its so-called Powerfoyle solar cell technology is Exeger’s founder and CEO, Giovanni Fili. Giovanni, welcome to the show.

Giovanni Fili: Thank you.

Cass: So before we get into the details of the Powerfoyle technology, was I right in saying that the Achilles heel of our mobile devices is battery life? And if we could reduce or eliminate that problem, how would that actually influence the development of mobile and wearable tech beyond just not having to recharge as often?

Fili: Yeah. I mean, for sure, I think the global common problem or pain point is for sure battery anxiety in different ways, ranging from your mobile phone to your other portable devices, and of course, even EV like cars and all that. So what we’re doing is we’re trying to eliminate this or reduce or eliminate this battery anxiety by integrating— seamlessly integrating, I should say, a solar cell. So our solar cell can convert any light energy to electrical energy. So indoor, outdoor from any angle. We’re not angle dependent. And the solar cell can take the shape. It can look like leather, textile, brushed steel, wood, carbon fiber, almost anything, and can take light from all angles as well, and can be in different colors. It’s also very durable. So our idea is to integrate this flexible, thin film into any device and allow it to be self-powered, allowing for increased functionality in the device. Just look at the smartwatches. I mean, the first one that came, you could wear them for a few hours, and you had to charge them. And they packed them with more functionality. You still have to charge them every day. And you still have to charge them every day, regardless. But now, they’re packed with even more stuff. So as soon as you get more energy efficiency, you pack them with more functionality. So we’re enabling this sort of jump in functionality without compromising design, battery, sustainability, all of that. So yeah, so it’s been a long journey since I started working with this 17 years ago.

Cass: I actually wanted to ask about that. So how is Exeger positioned to attack this problem? Because it’s not like you’re the first company to try and do nice mobile charging solutions for mobile devices.

Fili: I can mention there, I think that the main thing that differentiates us from all other previous solutions is that we have invented a new electrode material, the anode and the cathode with a similar almost like battery. So we have anode, cathode. We have electrolytes inside. So this is a—

Cass: So just for readers who might not be familiar, a battery is basically you have an anode, which is the positive terminal—I hope I didn’t forgot that—cathode, which is a negative terminal, and then you have an electrolyte between them in the battery, and then chemical reactions between these three components, and it can get kind of complicated, produce an electric potential between one side and the other. And in a solar cell, also there’s an anode and a cathode and so on. Have I got that right, my little, brief sketch?

Fili: Yeah. Yeah. Yeah. And so what we add to that architecture is we add one layer of titanium dioxide nanoparticles. Titanium dioxide is the white in white wall paint, toothpaste, sunscreen, all that. And it’s a very safe and abundant material. And we use that porous layer of titanium nanoparticles. And then we deposit a dye, a color, a pigment on this layer. And this dye can be red, black, blue, green, any kind of color. And the dye will then absorb the photons, excite electrons that are injected into the titanium dioxide layer and then collected by the anode and then conducted out to the cable. And now, we use the electrons to light the lamp or a motor or whatever we do with it. And then they turn back to the cathode on the other side and inside the cell. So the electrons goes the other way and the inner way. So the plus, you can say, go inside ions in the electrolytes. So it’s a regenerative system.

So our innovation is a new— I mean, all solar cells, they have electrodes to collect the electrons. If you have silicon wafers or whatever you have, right? And you know that all these solar cells that you’ve seen, they have silver lines crossing the surface. The silver lines are there because the conductivity is quite poor, funny enough, in these materials. So high resistance. So then you need to deposit the silver lines there, and they’re called current collectors. So you need to collect the current. Our innovation is a new electrode material that has 1,000 times better conductivity than other flexible electrode materials. That allows us as the only company in the world to eliminate the silver lines. And we print all our layers as well. And as you print in your house, you can print a photo, an apple with a bite in it, you can print the name, you can print anything you want. We can print anything we want, and it will also be converting light energy to electric energy. So a solar cell.

Cass: So the key part is that the color dye is doing that initial work of converting the light. Do different colors affect the efficiency? I did see on your site that it comes in all these kind of different colors, but. And I was thinking to myself, well, is the black one the best? Is the red one the best? Or is it relatively insensitive to the visible color that I see when I look at these dyes?

Fili: So you’re completely right there. So black would give you the most. And if you go to different colors, typically you lose like 20, 30 percent. But fortunately enough for us, over 50 percent of the consumer electronic market is black products. So that’s good. So I think that you asked me how we’re positioned. I mean, with our totally unique integration possibilities, imagine this super thin, flexible film that works all day, every day from morning to sunset, indoor, outdoor, can look like leather. So we’ve made like a leather bag, right? The leather bag is the solar cell. The entire bag is the solar cell. You wouldn’t see it. It just looks like a normal leather bag.

Cass: So when you talk about flexible, you actually mean this— so sometimes when people talk about flexible electronics, they mean it can be put into a shape, but then you’re not supposed to bend it afterwards. When you’re talking about flexible electronics, you’re talking about the entire thing remains flexible and you can use it flexibly instead of just you can conform it once to a shape and then you kind of leave it alone.

Fili: Correct. So we just recently released a hearing protector with 3M. This great American company with more than 60,000 products across the world. So we have a global exclusivity contract with them where they have integrated our bendable, flexible solar film in the headband. So the headband is the solar cell, right? And where you previously had to change disposable battery every second week, two batteries every second week, now you never need to change the battery again. We just recharge this small rechargeable battery indoor and outdoor, just continues to charge all the time. And they have added a lot of extra really cool new functionality as well. So we’re eliminating the need for disposable batteries. We’re saving millions and millions of batteries. We’re saving the end user, the contractor, the guy who uses them a lot of hassle to buy this battery, store them. And we increase reliability and functionality because they will always be charged. You can trust them that they always work. So that’s where we are totally unique. The solar cell is super durable. If we can be in a professional hearing protector to use on airports, construction sites, mines, whatever you use, factories, oil rig platforms, you can do almost anything. So I don’t think any other solar cell would be able to pass those durability tests that we did. It’s crazy.

Cass: So I have a question. It kind of it’s more appropriate from my experience with utility solar cells and things you put on roofs. But how many watts per square meter can you deliver, we’ll say, in direct sunlight?

Fili: So our focus is on indirect sunlight, like shade, suboptimal light conditions, because that’s where you would typically be with these products. But if you compare to more of a silicon, which is what you typically use for calculators and all that stuff. So we are probably around twice as what they deliver in this dark conditions, two to three times, depending. If you use glass, if you use flexible, we’re probably three times even more, but. So we don’t do full sunshine utility scale solar. But if you look at these products like the hearing protector, we have done a lot of headphones with Adidas and other huge brands, we typically recharge like four times what they use. So if you look at— if you go outside, not in full sunshine, but half sunshine, let’s say 50,000 lux, you’re probably talking at about 13, 14 minutes to charge one hour of listening. So yeah, so we have sold a few hundred thousand products over the last three years when we started selling commercially. And - I don’t know - I haven’t heard anyone who has charged since. I mean, surely someone has, but typically the user never need to charge them again, just charge themself.

Cass: Well, that’s right, because for many years, I went to CES, and I often would buy these, or acquire these, little solar cell chargers. And it was such a disappointing experience because they really would only work in direct sunlight. And even then, it would take a very long time. So I want to talk a little bit about, then, to get to that, what were some of the biggest challenges you had to overcome on the way to developing this tech?

Fili: I mean, this is the fourth commercial solar cell technology in the world after 110 or something years of research. I mean, the Americans, the Bell Laboratory sent the first silicon cell, I think it’s in like 1955 or something, to space. And then there’s been this constant development and trying to find, but to develop a new energy source is as close to impossible as you get, more or less. Everybody tried and everybody failed. We didn’t know that, luckily enough. So just the whole-- so when I try to explain this, I get this question quite a lot. Imagine you found out something really cool, but there’s no one to ask. There’s no book to read. You just realize, “Okay, I have to make like hundreds of thousands, maybe millions of experiments to learn. And all of them, except finally one, they will all fail. But that’s okay.” You will fail, fail, fail. And then, “Oh, here’s the solution. Something that works. Okay. Good.” So we had to build on just constant failing, but it’s okay because you’re in a research phase. So we had to. I mean, we started off with this new nanomaterials, and then we had to make components of these materials. And then we had to make solar cells of the components, but there were no machines either. We have had to invent all the machines from scratch as well to make these components and the solar cells and some of the non-materials. That was also tough. How do you design a machine for something that doesn’t exist? It’s pretty difficult specification to give to a machine builder. So in the end, we had to build our own machine building capacity here. We’re like 50 guys building machines, so.

But now, I mean, today we have over 300 granted patents, another 90 that will be approved soon. We have a complete machine park that’s proprietary. We are now building the largest solar cell factory— one of the largest solar cell factories in Europe. It’s already operational, phase one. Now we’re expanding into phase two. And we’re completely vertically integrated. We don’t source anything from Russia, China; never did. Only US, Japan, and Europe. We run the factories on 100 percent renewable energy. We have zero emissions to air and water. And we don’t have any rare earth metals, no strange stuff in it. It’s like it all worked out. And now we have signed, like I said, global exclusivity deal with 3M. We have a global exclusivity deal with the largest company in the world on computer peripherals, like mouse, keyboard, that stuff. They can only work with us for years. We have signed one of the large, the big fives, the Americans, the huge CE company. Can’t tell you yet the name. We have a globally exclusive deal for electronic shelf labels, the small price tags in the stores. So we have a global solution with Vision Group, that’s the largest. They have 50 percent of the world market as well. And they have Walmart, IKEA, Target, all these huge companies. So now it’s happening. So we’re rolling out, starting to deploy massive volumes later this year.

Cass:So I’ll talk a little bit about that commercial experience because you talked about you had to create verticals. I mean, in Spectrum, we do cover other startups which have had these— they’re kind of starting from scratch. And they develop a technology, and it’s a great demo technology. But then it comes that point where you’re trying to integrate in as a supplier or as a technology partner with a large commercial entity, which has very specific ideas and how things are to be manufactured and delivered and so on. So can you talk a little bit about what it was like adapting to these partners like 3M and what changes you had to make and what things you learned in that process where you go from, “Okay, we have a great product and we could make our own small products, but we want to now connect in as part of this larger supply chain.”

Fili: It’s a very good question and it’s extremely tough. It’s a tough journey, right? Like to your point, these are the largest companies in the world. They have their way. And one of the first really tough lessons that we learned was that one factory wasn’t enough. We had to build two factories to have redundancy in manufacturing. Because single source is bad. Single source, single factory, that’s really bad. So we had to build two factories and we had to show them we were ready, willing and able to be a supplier to them. Because one thing is the product, right? But the second thing is, are you worthy supplier? And that means how much money you have in the bank. Are you going to be here in two, three, four years? What’s your ISO certifications like? REACH, RoHS, Prop 65. What’s your LCA? What’s your view on this? Blah, blah, blah. Do you have professional supply chain? Did you do audits on your suppliers? But now, I mean, we’ve had audits here by five of the largest companies in the world. We’ve all passed them. And so then you qualify as a worthy supplier. Then comes your product integration work, like you mentioned. And I think it’s a lot about— I mean, that’s our main feature. The main unique selling point with Exeger is that we can integrate into other people’s products. Because when you develop this kind of crazy technology-- “Okay, so this is solar cell. Wow. Okay.” And it can look like anything. And it works all the time. And all the other stuff is sustainable and all that. Which product do you go for? So I asked myself—I’m an entrepreneur since the age of 15. I’ve started a number of companies. I lost so much money. I can’t believe it. And managed to earn a little bit more. But I realized, “Okay, how do you select? Where do you start? Which product?”

Okay, so I sat down. I was like, “When does it sell well? When do you see market success?” When something is important. When something is important, it’s going to work. It’s not the best tech. It has to be important enough. And then, you need distribution and scale and all that. Okay, how do you know if something is important? You can’t. Okay. What if you take something that’s already is— I mean, something new, you can’t know if it’s going to work. But if we can integrate into something that’s already selling in the billions of units per year, like headphones— I think this year, one billion headphones are going to be sold or something. Okay, apparently, obviously that’s important for people. Okay, let’s develop technology that can be integrated into something that’s already important and allow it to stay, keep all the good stuff, the design, the weight, the thickness, all of that, even improve the LCA better for the environment. And it’s self-powered. And it will allow the user to participate and help a little bit to a better world, right? With no charge cable, no charging in the wall, less batteries and all that. So our strategy was to develop such a strong technology so that we could integrate into these companies/partners products.

Cass: So I guess the question there is— so you come to a company, the company has its own internal development engineers. It’s got its own people coming up with product ideas and so on. How do you evangelize within a company to say, “Look, you get in the door, you show your demo,” to say, product manager who’s thinking of new product lines, “You guys should think about making products with our technology.” How do you evangelize that they think, “Okay, yeah, I’m going to spend the next six months of my life betting on these headphones, on this technology that I didn’t invent that I’m kind of trusting.” How do you get that internal buy-in with the internal engineers and the internal product developers and product managers?

Fili: That’s the Holy Grail, right? It’s very, very, very difficult. Takes a lot of time. It’s very expensive. And the point, I think you’re touching a little bit when you’re asking me now, because they don’t have a guy waiting to buy or a division or department waiting to buy this flexible indoor solar cell that can look like leather. They don’t have anyone. Who’s going to buy? Who’s the decision maker? There is not one. There’s a bunch, right? Because this will affect the battery people. This will affect the antenna people. This will affect the branding people. It will affect the mechanic people, etc., etc., etc. So there’s so many people that can say no. No one can say yes alone. All of them can say no alone. Any one of them can block the project, but to proceed, all of them have to say yes. So it’s a very, very tough equation. So that’s why when we realized this— this was another big learning that we had that we couldn’t go with the sales guy. We couldn’t go with two sales guys. We had to go with an entire team. So we needed to bring our design guy, our branding person, our mechanics person, our software engineer. We had to go like huge teams to be able to answer all the questions and mitigate and explain.

So we had to go both top down and explain to the head of product or head of sustainability, “Okay, if you have 100 million products out in five years and they’re going to be using 50 batteries per year, that’s 5 billion batteries per year. That’s not good, right? What if we can eliminate all these batteries? That’s good for sustainability.” “Okay. Good.” “That’s also good for total cost. We can lower total cost of ownership.” “Okay, that’s also good.” “And you can sell this and this and this way. And by the way, here’s a narrative we offer you. We have also made some assets, movies, pictures, texts. This is how other people talk about this.” But it’s a very, very tough start. How do you get the first big name in? And big companies, they have a lot to risk, a lot to lose as well. So my advice would be to start smaller. I mean, we started mainly due to COVID, to be honest. Because Sweden stayed open during COVID, which was great. We lived our lives almost like normal. But we couldn’t work with any international companies because they were all closed or no one went to the office. So we had to turn to Swedish companies, and we developed a few products during COVID. We launched like four or five products on the market with smaller Swedish companies, and we launched so much. And then we could just send these headphones to the large companies and tell them, “You know what? Here’s a headphone. Use it for a few months. We’ll call you later.” And then they call us that, “You know what? We have used them for three months. No one has charged. This is sick. It actually works.” We’re like, “Yeah, we know.” And then that just made it so much easier. And now anyone who wants to make a deal with us, they can just buy these products anywhere online or in-store across the whole world and try them for themselves.

And we send them also samples. They can buy, they can order from our website, like development kits. We have software, we have partnered up with Qualcomm, early semiconductor. All the big electronics companies, we’re now qualified partners with them. So all the electronics is powerful already. So now it’s very easy now to build prototypes if you want to test something. We have offices across the world. So now it’s much easier. But my advice to anyone who would want to start with this is try and get a few customers in. The important thing is that they also care about the project. If we go to one of these large companies, 3M, they have 60,000 products. If they have 60,001, yeah. But for us, it’s like the project. And we have managed to land it in a way. So it’s also important for them now because it just touches so many of their important areas that they work with, so.

Cass: So in terms of future directions for the technology, do you have a development pathway? What kind of future milestones are you hoping to hit?

Fili: For sure. So at the moment, we’re focusing on consumer electronics market, IoT, smart home. So I think the next big thing will be the smart workplace where you see huge construction sites and other areas where we connect the workers, anything from the smart helmet. You get hit in your head, how hard was it? I mean, why can’t we tell you that? That’s just ridiculous. There’s all these sensors already available. Someone just needs to power the helmet. Location services. Is the right person in the right place with the proper training or not? On the construction side, do you have the training to work with dynamite, for example, or heavy lifts or different stuff? So you can add the geofencing in different sites. You can add health data, digital health tracking, pulse, breathing, temperature, different stuff. Compliance, of course. Are you following all the rules? Are you wearing your helmet? Is the helmet buttoned? Are you wearing the proper other gear, whatever it is? Otherwise, you can’t start your engine, or you can’t go into this site, or you can’t whatever. I think that’s going to greatly improve the proactive safety and health a lot and increase profits for employers a lot too at the same time. In a few years, I think we’re going to see the American unions are going to be our best sales force. Because when they see the greatness of this whole system, they’re going to demand it in all tenders, all biggest projects. They’re going to say, “Hey, we want to have the connected worker safety stuff here.” Because you can just stream-- if you’re working, you can stream music, talk to your colleagues, enjoy connected safety without invading the privacy, knowing that you’re good. If you fall over, if you faint, if you get a heart attack, whatever, in a few seconds, the right people will know and they will take their appropriate actions. It’s just really, really cool, this stuff.

Cass: Well, it’ll be interesting to see how that turns out. But I’m afraid that’s all we have time for today, although this is fascinating. But today, so Giovanni, I want to thank you very much for coming on the show.

Fili: Thank you so much for having me.

Cass: So today we were talking with Giovanni Fili, who is Exeger’s founder and CEO, about their new flexible powerfoyle solar cell technology. For IEEE Spectrum‘s Fixing the Future, I’m Stephen Cass, and I hope you’ll join me next time.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell's resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host's genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell's transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

"What's really amazing about cells is that they are incredibly complex. What's really difficult about studying cells is that they are incredibly complex," jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. "Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology."

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich's lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore. 

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side's entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell's transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn't need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

"The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact," Weiskopf says. "It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?"

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.  

"The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that's how we figured out that the pore is much bigger than we anticipated," Schwartz says. "We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications."

This research was carried out, in part, using MIT.nano facilities.

Former Dead Cells lead designer Sébastien Benard is none too chuffed about publisher Motion Twin's decision to end development of the well-regarded roguelike Metroidvania. A few days ago, Motion Twin announced that the 35th major Dead Cells update, aptly titled The End Is Near, would be its last. Benard feels this is a betrayal of both the game's community and its current development team, Evil Empire, a spin-off studio who took the reins in 2019.

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Dead Cells developers Motion Twin have announced their roguelike Metroidvania will receive its final update with the launch of the appropriately titled Update 35: 'The End Is Near'. It's been a pretty great run as these things go: over the course of seven years, Dead Cells has received four major DLC expanions, a mobile release and, of course, 35 of those big title updates. However, current custodians Evil Empire are now moving on to greener, "secret projects"-flavoured pastures - the emphasis being on pastures plural there, if their Xweet about it is anything to go by, too.

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