To better understand the mechanisms underlying HAND, researchers from Penn’s School of Dental Medicine and Perelman School of Medicine and from the Children’s Hospital of Philadelphia (CHOP) brought together their complementary expertise to create a laboratory model system using three of the types of brain cells thought to be involved. Led by doctoral student Sean Ryan, who was co-mentored by Kelly Jordan-Sciutto of Penn Dental Medicine and Stewart Anderson of CHOP and Penn Medicine, the model recapitulates important features of how HIV infection and ART affect the brain.

“Frankly the models we generally use in the HIV field have a lot of weaknesses,” says Jordan-Sciutto, co-corresponding author on the paper, which appears in the journal Stem Cell Reports. “The power of this system is it allows us to look at the interaction between different cell types of human origin in a way that is more relevant to patients than other models.”

In addition to studying HIV, members of the team plan to use the same model to shed light on the neurological mechanisms that underlie other conditions, such as schizophrenia, Alzheimer’s, and even normal aging.

“We’re collaborating with a variety of colleagues to use this system to study Alzheimer’s disease as well as schizophrenia,” says Anderson, co-corresponding author on the paper. “We have the components in a dish that we know are interacting in these diseases, and this gives us a new mix-and-match way to understand how certain cells are contributing to neuronal damage.”

Indeed, the impetus to create the model grew not out of HIV research but work that Ryan was pursuing in Anderson’s lab on schizophrenia.

“We had been looking at the role of microglia, the resident immune cells of the central nervous system,” says Ryan, first author on the work. “We wanted to see if we could see the mechanistic changes that occur with microglia in schizophrenia.”

To do so, Ryan and Anderson were interested in using human-induced pluripotent stem cells — adult cells that are reprogrammed to resemble embryonic stem cells — which can be coaxed into differentiating into a variety of different cell types.

But schizophrenia is a complicated disease with a variety of contributing genetic and environmental factors and a broad spectrum of presentations. Rather than looking at something complex, they sought to apply their new system to a disease that likewise causes neurological damage but does so in a more dramatic way and in which microglia are also implicated: HIV/AIDS infection.

They reached out to Jordan-Sciutto, who has deep experience investigating the mechanisms of HAND and was eager for the opportunity to develop a model superior to those currently available. Together, the scientists identified the three cell types they were most interested in studying: neurons, astrocytes, and microglia.

Neurons aren’t directly infected by HIV but are known to be damaged during infection. Meanwhile astrocytes are believed to interact with neurons, causing damage by sending pro-inflammatory factors into the spaces between cells, called synapses. And microglia, which are responsible for maintaining a healthy environment in the absence of disease, are seen to expand and contribute to inflammation during HIV infection.

After nailing the technical challenge of creating this tractable model in which each cell type is generated independently and then mixed together, the team used it to probe how HIV infection and ART impact the cells, both alone and in combination.

“A lot of people are taking PreEP [pre-exposure prophylaxis] if they’re in a situation where their risk of contracting HIV is heightened,” says Ryan. “Just as we want to understand the cognitive impacts of HIV, we also want to see whether these drugs alone are impacting the brain health of otherwise healthy people.”

The researchers looked at RNA expression in their cultures to get a sense of what proteins and signaling pathways were becoming activated in each scenario. During infection, they saw inflammatory pathways that had previously been implicated in HIV in earlier research. When they introduced the antiretroviral drug EFZ, which is not in common use in the United States but remains a frontline therapy in many other areas of the world, with an infection, the activity of most of these pathways was reduced.

“But this scenario involved its own unique response,” says Ryan. Certain pathways associated with inflammation and damage remained despite the introduction of EFZ.

“EFZ treatment of the tri-cultures that included HIV-infected microglia reduces inflammation by around 70%,” Ryan says. Interestingly, EFZ by itself also triggered inflammation, though to a lesser extent than infection.

“It seems a combination of infection and ART is creating its own unique response that is different from the sum of its parts,” Ryan says. “Knowing what pathways are still active due to ART could help us appropriately target additional therapies so patients don’t develop HAND.”

Many features of infection seen in the three-cell culture mirror what is known from HIV infection and ART treatment in people, giving the researchers confidence in the reliability of their model.

“Just looking at the microglia,” says Anderson, “we see in our system that they are taking on both of their normal roles in keeping key signaling systems balanced during their normal state and activating and causing damage when they’re fighting infection. We’re able to model normality and abnormality in a way we haven’t been able to before.”

For Jordan-Sciutto, the new system “is really going to change the way my lab operates going into the future.” She’s hopeful many other HIV scientists will take it up to further their studies as she also explores more aspects of HIV’s impact on the brain, such as how it navigates through the blood-brain barrier that normally protects the central nervous system from inflammation and infection.

The study authors give credit to the collaborative environment at Penn for this cross-disciplinary project. “Tentacles of this project extend from CHOP to the dental school to the vet school to the medical school,” says Anderson. “Penn is a very special place where people seem to be more likely to share their technologies around and let other people work with and develop them. This project is a great example of that.”

Kelly L. Jordan-Sciutto is vice chair and professor in the Department of Basic and Translational Sciences in Penn’s School of Dental Medicine, associate dean of graduate education, and director of biomedical graduate studies at the Perelman School of Medicine.

Rice University engineers already knew that size matters when using single-walled carbon nanotubes for their electrical properties. But until now, nobody had studied how electrons act when confronted with the Russian doll-like structure of multiwalled tubes.

The Rice lab of materials theorist Boris Yakobson has now calculated the impact of curvature of semiconducting double-wall carbon nanotubes on their flexoelectric voltage, a measure of electrical imbalance between the nanotube’s inner and outer walls.

This affects how suitable nested nanotube pairs may be for nanoelectronics applications, especially photovoltaics.

The theoretical research by Yakobson’s Brown School of Engineering group appears in the American Chemical Society journal Nano Letters.

In an 2002 study, Yakobson and his Rice colleagues had revealed how charge transfer, the difference between positive and negative poles that allows voltage to exist between one and the other, scales linearly to the curvature of the nanotube wall. The width of the tube dictates curvature, and the lab found that the thinner the nanotube (and thus larger the curvature), the greater the potential voltage.

When carbon atoms form flat graphene, the charge density of the atoms on either side of the plane are identical, Yakobson said. Curving the graphene sheet into a tube breaks that symmetry, changing the balance.

That creates a flexoelectric local dipole in the direction of, and proportional to, the curvature, according to the researchers, who noted that the flexoelectricity of 2D carbon “is a remarkable but also fairly subtle effect.”

But more than one wall greatly complicates the balance, altering the distribution of electrons. In double-walled nanotubes, the curvature of the inner and outer tubes differ, giving each a distinct band gap. Additionally, the models showed the flexoelectric voltage of the outer wall shifts the band gap of the inner wall, creating a staggered band alignment in the nested system.

“The novelty is that the inserted tube, the ‘baby’ (inside) matryoshka has all of its quantum energy levels shifted because of the voltage created by exterior nanotube,” Yakobson said. The interplay of different curvatures, he said, causes a straddling-to-staggered band gap transition that takes place at an estimated critical diameter of about 2.4 nanometers.

“This is a huge advantage for solar cells, essentially a prerequisite for separating positive and negative charges to create a current,” Yakobson said. “When light is absorbed, an electron always jumps from the top of an occupied valence band (leaving a ‘plus’ hole behind) to the lowest state of empty conductance band.

“But in a staggered configuration they happen to be in different tubes, or layers,” he said. “The ‘plus’ and ‘minus’ get separated between the tubes and can flow away by generating current in a circuit.”

The team’s calculations also showed that modifying the nanotubes’ surfaces with either positive or negative atoms could create “substantial voltages of either sign” up to three volts. “Although functionalization could strongly perturb the electronic properties of nanotubes, it may be a very powerful way of inducing voltage for certain applications,” the researchers wrote.

The team suggested its findings may apply to other types of nanotubes, including boron nitride and molybdenum disulfide, on their own or as hybrids with carbon nanotubes.

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“All particles in nature come in one of two types, depending on their ‘spin,’ a quantum property with no real analogue in classical physics,” said David Weiss, Distinguished Professor of Physics at Penn State and one of the leaders of the research team. “Bosons, whose spins are whole integers, can share the same quantum state, while fermions, whose spins are half integers, cannot. When the particles are cold or dense enough, bosons behave completely differently from fermions. Bosons form ‘Bose-Einstein condensates,’ congregating in the same quantum state. Fermions, on the other hand, fill available states one by one to form what is called a ‘Fermi sea.'”

Researchers at Penn State have now experimentally demonstrated that, when bosons expand in one dimension — the line of atoms is allowed spread out to become longer — they can form a Fermi sea. A paper describing the research appears March 27, 2020 in the journal Science.

“Identical fermions are antisocial, you can’t have more than one in the same place so when they are very cold they don’t interact,” said Marcos Rigol, professor of physics at Penn State and the other leader of the research team. “Bosons can be in the same place, but this becomes energetically too costly when their interactions are very strong. As a result, when constrained to move in one-dimension, their spatial distribution can look like that of non-interacting fermions. Back in 2004, David’s research group experimentally demonstrated this phenomenon, which was theoretically predicted in the 1960s.”

Even though the spatial properties of strongly interacting bosons and non-interacting fermions are the same in one dimension, bosons can still have the same velocities as each other, while fermions cannot. This is due to the fundamental nature of the particles.

“In 2005, Marcos, then a graduate student, predicted that when strongly interacting bosons expand in one dimension, their velocity distribution will form a Fermi sea,” said Weiss. “I was very excited to collaborate with him in demonstrating this striking phenomenon.”

The research team creates an array of ultracold one-dimensional gases made up of bosonic atoms (‘Bose gases’) using an optical lattice, which uses laser light to trap the atoms. In the light trap, the system is at equilibrium and the strongly interacting Bose gases have spatial distributions like fermions, but still have the velocity distributions of bosons. When the researchers shut off some of the trapping light, the atoms expand in one dimension. During this expansion, the velocity distribution of the bosons smoothly transforms into a one that is identical to fermions. The researchers can follow this transformation as it happens.

“The dynamics of ultracold gases in optical lattices are the source of many novel fascinating phenomena that only recently have started to be explored,” said Rigol. “For example, Dave’s group showed in 2006 that something as universal as temperature is not well defined after Bose gases undergo dynamics in one dimension. My collaborators and I related this finding to a beautiful underlying mathematical property of the theoretical models describing his experiments, known as ‘integrability.’ Integrability plays a central role in our newly observed dynamical fermionization phenomenon.”

Because the system is “integrable,” the researchers can understand it in great detail and by studying the dynamical behavior of these one-dimensional gases, the Penn State team hopes to address broad issues in physics.

“In the last half century many universal properties of equilibrium quantum systems have been elucidated,” said Weiss. “It has been harder to identify universal behavior in dynamical systems. By fully understanding the dynamics of one-dimensional gases, and then by gradually making the gases less integrable, we hope to identify universal principles in dynamical quantum systems.”

Dynamical, interacting quantum systems are an important part of fundamental physics. They are also increasing technologically relevant, as many actual and proposed quantum devices are based on them, including quantum simulators and quantum computers.

“We now have experimental access to things that if you would have asked any theorist working in the field ten years ago ‘will we see this in our lifetime?’ they would have said ‘no way,'” said Rigol.

In addition to Rigol and Weiss, the research team at Penn State includes Joshua M. Wilson, Neel Malvania, Yuan Le, and Yicheng Zhang. The research was funded by the U.S. National Science Foundation and the U.S. Army Research Office. Computations were performed at the Penn State Institute for Computational and Data Sciences.

New ages for fossilized vertebrates that lived just after the demise of the fauna that dominated the late Permian show that the ecosystem changes began hundreds of thousands of years earlier on land than in the sea, eventually resulting in the demise of up to 70% of terrestrial vertebrate species. The later marine extinction, in which nearly 95% of ocean species disappeared, may have occurred over the time span of tens of thousands of years.

Though most scientists believe that a series of volcanic eruptions, occurring in large pulses over a period of a million years in what is now Siberia, were the primary cause of the end-Permian extinction, the lag between the land extinction in the Southern Hemisphere and the marine extinction in the Northern Hemisphere suggests different immediate causes.

“Most people thought that the terrestrial collapse started at the same time as the marine collapse, and that it happened at the same time in the Southern Hemisphere and in the Northern Hemisphere,” said paleobotanist Cindy Looy, University of California, Berkeley, associate professor of integrative biology. “The fact that the big changes were not synchronous in the Northern and Southern hemispheres has a big effect on hypotheses for what caused the extinction. An extinction in the ocean does not, per se, have to have the same cause or mechanism as an extinction that happened on land.”

Members of Looy’s lab have conducted experiments on living plants to determine whether a collapse of Earth’s protective ozone layer may have irradiated and wiped out plant species. Other global changes — a warming climate, a rise in carbon dioxide in the atmosphere and an increase in ocean acidification — also occurred around the end of the Permian period and the beginning of the Triassic and likely contributed.

On land, the end-Permian extinction of vertebrates is best documented in Gondwana, the southern half of the supercontinent known as Pangea that eventually separated into the continents we know today as Antarctica, Africa, South America and Australia. There, in the South African Karoo Basin, populations of large herbivores, or plant eaters, shifted from the Daptocephalus assemblage to the Lystrosaurus assemblage. These groups are now extinct.

In the ocean, the extinction is best documented in the Northern Hemisphere, in particular by Chinese fossils. The end-Permian extinction is perhaps best associated with the demise of trilobites.

To improve on previous dates for the land extinction, an international team of scientists, including Looy, conducted uranium-lead dating of zircon crystals in a well-preserved volcanic ash deposit from the Karoo Basin. Looy, who is also a curator of paleobotany at the campus’s Museum of Paleontology and curator of gymnosperms at the University and Jepson Herbaria, confirmed that sediments from several meters above the dated layer were devoid of Glossopteris pollen, evidence that these seed ferns, which used to dominate late Permian Gondwanan floras, became extinct around that time.

At 252.24 million years old, the zircons — microscopic silicate crystals that form in rising magma inside volcanoes and are spewed into the atmosphere during eruptions — are 300,000 years older than dates obtained for the confirmed Permian-Triassic (P-T) boundary in China. This means that the sediment layer assumed to contain the P-T boundary in South Africa was actually at least 300,000 years too old.

Dates for an ash deposit in Australia, just above the layers that document the initial plant extinction, similarly came in almost 400,000 years older than thought. That work was published in January by Christopher Fielding and colleagues at the University of Nebraska in Lincoln.

“The Karoo Basin is the poster child for the end-Permian vertebrate turnover, but until recently, it was not well-dated,” Looy said. “Our new zircon date shows that the base of the Lystrosaurus zone predates the marine extinction with several hundred thousand years, similar to the pattern in Australia. This means that both the floral and faunal turnover in Gondwana is out of sync with the Northern Hemisphere marine biotic crisis.

“For some years now, we have known that — in contrast to the marine mass extinction — the pulses of disturbance of life on land continued deep into the Triassic Period. But that the start of the terrestrial turnover happened so long before the marine extinction was a surprise.”

In their paper, Looy and an international team of colleagues concluded “that greater consideration should be given to a more gradual, complex, and nuanced transition of terrestrial ecosystems during the Changhsingian (the last part of the Permian) and, possibly, the early Triassic.”

Looy and colleagues published their findings March 19 in the open access journal Nature Communications. Her co-authors are Robert Gastaldo of Colby College in Maine; Sandra Kamo of the University of Toronto in Ontario; Johann Neveling of the Council for Geosciences in Pretoria, South Africa; John Geissman of the University of Texas in Dallas and Anna Martini of Amherst College in Massachusetts. The research was funded by the National Science Foundation.