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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals

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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals

As a professor of pediatrics and cellular and molecular medicine at University of California San Diego School of Medicine, Alysson R. Muotri, PhD, has long studied how the brain develops and what goes wrong in neurological disorders. For almost as long, he has also been curious about the evolution of the human brain — what changed that makes us so different from preceding Neanderthals and Denisovans, our closest evolutionary relatives, now extinct?

Evolutionary studies rely heavily on two tools — genetics and fossil analysis — to explore how a species changes over time. But neither approach can reveal much about brain development and function because brains do not fossilize, Muotri said. There is no physical record to study.So Muotri decided to try stem cells, a tool not often applied in evolutionary reconstructions. Stem cells, the self-renewing precursors of other cell types, can be used to build brain organoids — “mini brains” in a laboratory dish. Muotri and colleagues have pioneered the use of stem cells to compare humans to other primates, such as chimpanzees and bonobos, but until now a comparison with extinct species was not thought possible.

In a study published February 11, 2021 in Science, Muotri’s team catalogued the differences between the genomes of diverse modern human populations and the Neanderthals and Denisovans, who lived during the Pleistocene Epoch, approximately 2.6 million to 11,700 years ago. Mimicking an alteration they found in one gene, the researchers used stem cells to engineer “Neanderthal-ized” brain organoids.

“”It’s fascinating to see that a single base-pair alteration in human DNA can change how the brain is wired,” said Muotri, senior author of the study and director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. “”We don’t know exactly how and when in our evolutionary history that change occurred. But it seems to be significant, and could help explain some of our modern capabilities in social behavior, language, adaptation, creativity and use of technology.”

The team initially found 61 genes that differed between modern humans and our extinct relatives. One of these altered genes — NOVA1 — caught Muotri’s attention because it’s a master gene regulator, influencing many other genes during early brain development. The researchers used CRISPR gene editing to engineer modern human stem cells with the Neanderthal-like mutation in NOVA1. Then they coaxed the stem cells into forming brain cells and ultimately Neanderthal-ized brain organoids.

Brain organoids are little clusters of brain cells formed by stem cells, but they aren’t exactly brains (for one, they lack connections to other organ systems, such as blood vessels). Yet organoids are useful models for studying genetics, disease development and responses to infections and therapeutic drugs. Muotri’s team has even optimized the brain organoid-building process to achieve organized electrical oscillatory waves similar to those produced by the human brain.

The Neanderthal-ized brain organoids looked very different than modern human brain organoids, even to the naked eye. They had a distinctly different shape. Peering deeper, the team found that modern and Neanderthal-ized brain organoids also differ in the way their cells proliferate and how their synapses — the connections between neurons — form. Even the proteins involved in synapses differed. And electrical impulses displayed higher activity at earlier stages, but didn’t synchronize in networks in Neanderthal-ized brain organoids.

According to Muotri, the neural network changes in Neanderthal-ized brain organoids parallel the way newborn non-human primates acquire new abilities more rapidly than human newborns.

“This study focused on only one gene that differed between modern humans and our extinct relatives. Next we want to take a look at the other 60 genes, and what happens when each, or a combination of two or more, are altered,” Muotri said.

“We’re looking forward to this new combination of stem cell biology, neuroscience and paleogenomics. The ability to apply the comparative approach of modern humans to other extinct hominins, such as Neanderthals and Denisovans, using brain organoids carrying ancestral genetic variants is an entirely new field of study.””

To continue this work, Muotri has teamed up with Katerina Semendeferi, professor of anthropology at UC San Diego and study co-author, to co-direct the new UC San Diego Archealization Center, or ArchC.

“We will merge and integrate this amazing stem cell work with anatomic comparisons from several species and neurological conditions to create downstream hypotheses about brain function of our extinct relatives,” Semendeferi said. “This neuro-archealization approach will complement efforts to understand the mind of our ancestors and close relatives, like the Neanderthals.”

Co-authors of the study include: Cleber A. Trujillo, Isaac A. Chaim, Emily C. Wheeler, Assael A. Madrigal, Justin Buchanan, Sebastian Preissl, Allen Wang, Priscilla D. Negraes, and Ryan Szeto, UC San Diego; Edward S. Rice, Nathan K. Schaefer, Ashley Byrne, Maximillian Marin, Christopher Vollmers, Angela N. Brooks, Richard E. Green, UC Santa Cruz; Roberto H. Herai, Pontifícia Universidade Católica do Paraná; Alik Huseynov, Imperial College London; Mariana S.A. Ferraz, Fernando da S. Borges, Alexandre H. Kihara, Universidade Federal do ABC; Jonathan D. Lautz, Stephen E.P. Smith, Seattle Children’s Research Institute and University of Washington; Beth Shapiro, UC Santa Cruz and Howard Hughes Medical Institute; and Gene W. Yeo, UC San Diego, Agency for Science, Technology and Research (Singapore) and National University of Singapore.

Funding for this research came, in part, from the Neanderthal Brain Foundation, National Institutes of Health (grants U19MH1073671, K12GM068524, K01AA026911), Brain and Behavior Research Foundation (NARSAD Independent Investigator Grant), National Science foundation (grant 1754451), Gordon and Betty Moore Foundation (grant GBMF3804), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes, Brazil), FAPESP (São Paulo Research Foundation, grant 2017/26439-0), CNPq (Brazil’s National Council for Scientific and Technological Development, grants 431000/2016-6, 312047/2017-7) and Loulou Foundation.

Disclosure: Alysson R. Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and brain organoid modeling focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

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This alloy is kinky

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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals


Researchers have uncovered a remarkable metal alloy that won’t crack at extreme temperatures due to kinking, or bending, of crystals in the alloy at the atomic level.  A metal alloy composed of niobium, tantalum, titanium, and hafnium has shocked materials scientists with its impressive strength and toughness at both extremely hot and cold temperatures, a combination of properties that seemed so far to be nearly impossible to achieve. In this context, strength is defined as how much force a material can withstand before it is permanently deformed from its original shape, and toughness is its resistance to fracturing (cracking). The alloy’s resilience to bending and fracture across an enormous range of conditions could open the door for a novel class of materials for next-generation engines that can operate at higher efficiencies.

The team, led by Robert Ritchie at Lawrence Berkeley National Laboratory (Berkeley Lab) and UC Berkeley, in collaboration with the groups led by professors Diran Apelian at UC Irvine and Enrique Lavernia at Texas A&M University, discovered the alloy’s surprising properties and then figured out how they arise from interactions in the atomic structure. Their work is described in a study that was published April 11, 2024 in Science.

“The efficiency of converting heat to electricity or thrust is determined by the temperature at which fuel is burned — the hotter, the better. However, the operating temperature is limited by the structural materials which must withstand it,” said first author David Cook, a Ph.D. student in Ritchie’s lab. “We have exhausted the ability to further optimize the materials we currently use at high temperatures, and there’s a big need for novel metallic materials. That’s what this alloy shows promise in.”

The alloy in this study is from a new class of metals known as refractory high or medium entropy alloys (RHEAs/RMEAs). Most of the metals we see in commercial or industrial applications are alloys made of one main metal mixed with small quantities of other elements, but RHEAs and RMEAs are made by mixing near-equal quantities of metallic elements with very high melting temperatures, which gives them unique properties that scientists are still unraveling. Ritchie’s group has been investigating these alloys for several years because of their potential for high-temperature applications.

“Our team has done previous work on RHEAs and RMEAs and we have found that these materials are very strong, but generally possess extremely low fracture toughness, which is why we were shocked when this alloy displayed exceptionally high toughness,” said co-corresponding author Punit Kumar, a postdoctoral researcher in the group.

According to Cook, most RMEAs have a fracture toughness less than 10 MPa√m, which makes them some of the most brittle metals on record. The best cryogenic steels, specially engineered to resist fracture, are about 20 times tougher than these materials. Yet the niobium, tantalum, titanium, and hafnium (Nb45Ta25Ti15Hf15) RMEA alloy was able to beat even the cryogenic steel, clocking in at over 25 times tougher than typical RMEAs at room temperature.

But engines don’t operate at room temperature. The scientists evaluated strength and toughness at five temperatures total: -196°C (the temperature of liquid nitrogen), 25°C (room temperature), 800°C, 950°C, and 1200°C. The last temperature is about 1/5 the surface temperature of the sun.

The team found that the alloy had the highest strength in the cold and became slightly weaker as the temperature rose, but still boasted impressive figures throughout the wide range. The fracture toughness, which is calculated from how much force it takes to propagate an existing crack in a material, was high at all temperatures.

Unraveling the atomic arrangements

Almost all metallic alloys are crystalline, meaning that the atoms inside the material are arranged in repeating units. However, no crystal is perfect, they all contain defects. The most prominent defect that moves is called the dislocation, which is an unfinished plane of atoms in the crystal. When force is applied to a metal it causes many dislocations to move to accommodate the shape change. For example, when you bend a paper clip which is made of aluminum, the movement of dislocations inside the paper clip accommodates the shape change. However, the movement of dislocations becomes more difficult at lower temperatures and as a result many materials become brittle at low temperatures because dislocations cannot move. This is why the steel hull of the Titanic fractured when it hit an iceberg. Elements with high melting temperatures and their alloys take this to the extreme, with many remaining brittle up to even 800°C. However, this RMEA bucks the trend, withstanding snapping even at temperatures as low as liquid nitrogen (-196°C).

To understand what was happening inside the remarkable metal, co-investigator Andrew Minor and his team analyzed the stressed samples, alongside unbent and uncracked control samples, using four-dimensional scanning transmission electron microscopy (4D-STEM) and scanning transmission electron microscopy (STEM) at the National Center for Electron Microscopy, part of Berkeley Lab’s Molecular Foundry.

The electron microscopy data revealed that the alloy’s unusual toughness comes from an unexpected side effect of a rare defect called a kink band. Kink bands form in a crystal when an applied force causes strips of the crystal to collapse on themselves and abruptly bend. The direction in which the crystal bends in these strips increases the force that dislocations feel, causing them to move more easily. On the bulk level, this phenomenon causes the material to soften (meaning that less force has to be applied to the material as it is deformed). The team knew from past research that kink bands formed easily in RMEAs, but assumed that the softening effect would make the material less tough by making it easier for a crack to spread through the lattice. But in reality, this is not the case.

“We show, for the first time, that in the presence of a sharp crack between atoms, kink bands actually resist the propagation of a crack by distributing damage away from it, preventing fracture and leading to extraordinarily high fracture toughness,” said Cook.

The Nb45Ta25Ti15Hf15 alloy will need to undergo a lot more fundamental research and engineering testing before anything like a jet plane turbine or SpaceX rocket nozzle is made from it, said Ritchie, because mechanical engineers rightfully require a deep understanding of how their materials perform before they use them in the real world. However, this study indicates that the metal has potential to build the engines of the future.

This research was conducted by David H. Cook, Punit Kumar, Madelyn I. Payne, Calvin H. Belcher, Pedro Borges, Wenqing Wang, Flynn Walsh, Zehao Li, Arun Devaraj, Mingwei Zhang, Mark Asta, Andrew M. Minor, Enrique J. Lavernia, Diran Apelian, and Robert O. Ritchie, scientists at Berkeley Lab, UC Berkeley, Pacific Northwest National Laboratory, and UC Irvine, with funding from the Department of Energy (DOE) Office of Science. Experimental and computational analysis was conducted at the Molecular Foundry and the National Energy Research Scientific Computing Center — both are DOE Office of Science user facilities.



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Giant galactic explosion exposes galaxy pollution in action

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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals


A team of international researchers studied galaxy NGC 4383, in the nearby Virgo cluster, revealing a gas outflow so large that it would take 20,000 years for light to travel from one side to the other.

The discovery was published today in the journal Monthly Notices of the Royal Astronomical Society.

Lead author Dr Adam Watts, from The University of Western Australia node at the International Centre for Radio Astronomy Research (ICRAR), said the outflow was the result of powerful stellar explosions in the central regions of the galaxy that could eject enormous amounts of hydrogen and heavier elements.

The mass of gas ejected is equivalent to more than 50 million Suns.

“Very little is known about the physics of outflows and their properties because outflows are very hard to detect,” Dr Watts said.

“The ejected gas is quite rich in heavy elements giving us a unique view of the complex process of mixing between hydrogen and metals in the outflowing gas.

“In this particular case, we detected oxygen, nitrogen, sulphur and many other chemical elements.”

Gas outflows are crucial to regulate how fast and for how long galaxies can keep forming stars. The gas ejected by these explosions pollutes the space between stars within a galaxy, and even between galaxies, and can float in the intergalactic medium forever.

The high-resolution map was produced with data from the MAUVE survey, co-led by ICRAR researchers Professors Barbara Catinella and Luca Cortese, who were also co-authors of the study.

The survey used the MUSE Integral Field Spectrograph on the European Southern Observatory’s Very Large Telescope, located in northern Chile.

“We designed MAUVE to investigate how physical processes such as gas outflows help stop star formation in galaxies,” Professor Catinella said.

“NGC 4383 was our first target, as we suspected something very interesting was happening, but the data exceeded all our expectations.

“We hope that in the future, MAUVE observations reveal the importance of gas outflows in the local Universe with exquisite detail.”



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AI and physics combine to reveal the 3D structure of a flare erupting around a black hole

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Scientists believe the environment immediately surrounding a black hole is tumultuous, featuring hot magnetized gas that spirals in a disk at tremendous speeds and temperatures. Astronomical observations show that within such a disk, mysterious flares occur up to several times a day, temporarily brightening and then fading away. Now a team led by Caltech scientists has used telescope data and an artificial intelligence (AI) computer-vision technique to recover the first three-dimensional video showing what such flares could look like around Sagittarius A* (Sgr A*, pronounced sadge-ay-star), the supermassive black hole at the heart of our own Milky Way galaxy.

The 3D flare structure features two bright, compact features located about 75 million kilometers (or half the distance between Earth and the Sun) from the center of the black hole. It is based on data collected by the Atacama Large Millimeter Array (ALMA) in Chile over a period of 100 minutes directly after an eruption seen in X-ray data on April 11, 2017.

“This is the first three-dimensional reconstruction of gas rotating close to a black hole,” says Katie Bouman, assistant professor of computing and mathematical sciences, electrical engineering and astronomy at Caltech, whose group led the effort described in a new paper in Nature Astronomy.

Aviad Levis, a postdoctoral scholar in Bouman’s group and lead author on the new paper, emphasizes that while the video is not a simulation, it is also not a direct recording of events as they took place. “It is a reconstruction based on our models of black hole physics. There is still a lot of uncertainty associated with it because it relies on these models being accurate,” he says.

Using AI informed by physics to figure out possible 3D structures

To reconstruct the 3D image, the team had to develop new computational imaging tools that could, for example, account for the bending of light due to the curvature of space-time around objects of enormous gravity, such as a black hole.

The multidisciplinary team first considered if it would be possible to create a 3D video of flares around a black hole in June 2021. The Event Horizon Telescope (EHT) Collaboration, of which Bouman and Levis are members, had already published the first image of the supermassive black hole at the core of a distant galaxy, called M87, and was working to do the same with EHT data from Sgr A*. Pratul Srinivasan of Google Research, a co-author on the new paper, was at the time visiting the team at Caltech. He had helped develop a technique known as neural radiance fields (NeRF) that was then just starting to be used by researchers; it has since had a huge impact on computer graphics. NeRF uses deep learning to create a 3D representation of a scene based on 2D images. It provides a way to observe scenes from different angles, even when only limited views of the scene are available.

The team wondered if, by building on these recent developments in neural network representations, they could reconstruct the 3D environment around a black hole. Their big challenge: From Earth, as anywhere, we only get a single viewpoint of the black hole.

The team thought that they might be able to overcome this problem because gas behaves in a somewhat predictable way as it moves around the black hole. Consider the analogy of trying to capture a 3D image of a child wearing an inner tube around their waist. To capture such an image with the traditional NeRF method, you would need photos taken from multiple angles while the child remained stationary. But in theory, you could ask the child to rotate while the photographer remained stationary taking pictures. The timed snapshots, combined with information about the child’s rotation speed, could be used to reconstruct the 3D scene equally well. Similarly, by leveraging knowledge of how gas moves at different distances from a black hole, the researchers aimed to solve the 3D flare reconstruction problem with measurements taken from Earth over time.

With this insight in hand, the team built a version of NeRF that takes into account how gas moves around black holes. But it also needed to consider how light bends around massive objects such as black holes. Under the guidance of co-author Andrew Chael of Princeton University, the team developed a computer model to simulate this bending, also known as gravitational lensing.

With these considerations in place, the new version of NeRF was able to recover the structure of orbiting bright features around the event horizon of a black hole. Indeed, the initial proof-of-concept showed promising results on synthetic data.

A flare around Sgr A* to study

But the team needed some real data. That’s where ALMA came in. The EHT’s now famous image of Sgr A* was based on data collected on April 6-7, 2017, which were relatively calm days in the environment surrounding the black hole. But astronomers detected an explosive and sudden brightening in the surroundings just a few days later, on April 11. When team member Maciek Wielgus of the Max Planck Institute for Radio Astronomy in Germany went back to the ALMA data from that day, he noticed a signal with a period matching the time it would take for a bright spot within the disk to complete an orbit around Sgr A*. The team set out to recover the 3D structure of that brightening around Sgr A*.

ALMA is one of the most powerful radio telescopes in the world. However, because of the vast distance to the galactic center (more than 26,000 light-years), even ALMA does not have the resolution to see Sgr A*’s immediate surroundings. What ALMA measures are light curves, which are essentially videos of a single flickering pixel, which are created by collecting all of the radio-wavelength light detected by the telescope for each moment of observation.

Recovering a 3D volume from a single-pixel video might seem impossible. However, by leveraging an additional piece of information about the physics that are expected for the disk around black holes, the team was able to get around the lack of spatial information in the ALMA data.

Strongly polarized light from the flares provided clues

ALMA doesn’t just capture a single light curve. In fact, it provides several such “videos” for each observation because the telescope records data relating to different polarization states of light. Like wavelength and intensity, polarization is a fundamental property of light and represents which direction the electric component of a light wave is oriented with respect to the wave’s general direction of travel. “What we get from ALMA is two polarized single-pixel videos,” says Bouman, who is also a Rosenberg Scholar and a Heritage Medical Research Institute Investigator. “That polarized light is actually really, really informative.”

Recent theoretical studies suggest that hot spots forming within the gas are strongly polarized, meaning the light waves coming from these hot spots have a distinct preferred orientation direction. This is in contrast to the rest of the gas, which has a more random or scrambled orientation. By gathering the different polarization measurements, the ALMA data gave the scientists information that could help localize where the emission was coming from in 3D space.

Introducing Orbital Polarimetric Tomography

To figure out a likely 3D structure that explained the observations, the team developed an updated version of its method that not only incorporated the physics of light bending and dynamics around a black hole but also the polarized emission expected in hot spots orbiting a black hole. In this technique, each potential flare structure is represented as a continuous volume using a neural network. This allows the researchers to computationally progress the initial 3D structure of a hotspot over time as it orbits the black hole to create a whole light curve. They could then solve for the best initial 3D structure that, when progressed in time according to black hole physics, matched the ALMA observations.

The result is a video showing the clockwise movement of two compact bright regions that trace a path around the black hole. “This is very exciting,” says Bouman. “It didn’t have to come out this way. There could have been arbitrary brightness scattered throughout the volume. The fact that this looks a lot like the flares that computer simulations of black holes predict is very exciting.”

Levis says that the work was uniquely interdisciplinary: “You have a partnership between computer scientists and astrophysicists, which is uniquely synergetic. Together, we developed something that is cutting edge in both fields — both the development of numerical codes that model how light propagates around black holes and the computational imaging work that we did.”

The scientists note that this is just the beginning for this exciting technology. “This is a really interesting application of how AI and physics can come together to reveal something that is otherwise unseen,” says Levis. “We hope that astronomers could use it on other rich time-series data to shed light on complex dynamics of other such events and to draw new conclusions.”



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