P-glycoprotein Removes Alzheimer’s-associated Toxin From The Brain (Neuroscience)

Discovery could lead to new Alzheimer’s treatment

A team of SMU biological scientists has confirmed that P-glycoprotein (P-gp) has the ability to remove a toxin from the brain that is associated with Alzheimer’s disease.    

The finding could lead to new treatments for the disease that affects nearly 6 million Americans. It was that hope that motivated lead researchers James W. McCormick and Lauren Ammerman to pursue the research as SMU graduate students after they both lost a grandmother to the disease while at SMU. 

In the Alzheimer’s brain, abnormal levels of amyloid-β proteins clump together to form plaques that collect between neurons and can disrupt cell function. This is believed to be one of the key factors that triggers memory loss, confusion and other common symptoms from Alzheimer’s disease. 

“We were able to demonstrate both computationally and experimentally that P-gp, a critical toxin pump in the body, is able to transport this amyloid-β protein,” said John Wise, associate professor in the SMU Department of Biological Sciences and co-author of the study published in PLOS ONE.

“If you could find a way to induce more P-glycoprotein in the protective blood-brain barrier for people who are susceptible to Alzheimer’s disease, perhaps they could take such a treatment and it would help postpone or prevent the onset of the disease,” he said. Wise stressed that the theory needs more research. 

The SMU (Southern Methodist University) study also provides strong evidence for the first time that P-gp may be able to pump out much larger toxins than previously believed.  

(A) The first frame of SMU’s simulation shows amyloid-β bound to the drug binding domains of P-gp. (B) The final frame of the same simulation shows P-gp pushing an amyloid protein through the cell membrane to outside the cell.  © SMU

P-gp is nature’s way of removing toxins from cells. Similar to how a sump pump in your house removes water from the basement, P-gp swallows harmful drugs or toxins within the cell and then spits them back outside the cell.

“You find P-gp wherever the body is looking to protect an organ from toxins, and the brain is no exception,” explained co-author Pia Vogel, SMU professor and director of SMU’s Center for Drug Discovery, Design and Delivery

Amyloid-β’s large size created questions about whether P-glycoprotein could actually inhale it and pump it back out.   

“Amyloid-β is maybe five times bigger than the small, drug-like molecules that P-glycoproteins are well-known to move. It would be like taking New York pizza and trying to stuff that whole slice in your mouth and swallow it,” Wise said.

The fact that P-gp appears to be able to do just that “greatly expands the possible range of things that P-gp can transport, which opens the possibility that it may interact with other factors that were previously thought impossible,” said McCormick, a former SMU graduate student in biological sciences. 

The research was personal

SMU researchers might never have investigated the link between P-gp and amyloid-β proteins if not for McCormick’s dogged pursuit of the connection. The Ph.D. student, who graduated in 2017, had seen preliminary work suggesting that P-gp might play a role in pulling amyloid protein out of the brain and asked his faculty advisors, Vogel and Wise, if he could take some time to check it out. 

The professors concede they first tried to discourage him because they were more focused on P-gp’s role in creating resistance to chemotherapy in cancer patients. However, McCormick was “passionate,” about figuring out if P-gp might be able to shield someone from getting Alzheimer’s, Vogel said.   

He devoted hours of his own time to use a computer-generated model of P-glycoprotein that he and Wise created. The model allows researchers to dock nearly any drug to the P-gp protein and observe how it would behave in P-gp’s “pump.” Vogel, Wise and other SMU scientists have been studying the protein for years to identify compounds that might reverse chemotherapy failure in aggressive cancers. 

McCormick completed the computational work with the help of his fiancé, Ammerman, who got her Ph.D in biology from SMU in May.

Together, they ran multiple simulations of the P-gp protein using SMU’s high performance computer, ManeFrame II, and found that each time, P-gp was able to “swallow” amyloid-β proteins and push them out of cells.  

“For the scientist in me, it was just absolutely amazing that this pump could consume something that big,” Vogel said. “John [Wise] and I did not predict that would be possible.”

Two in vitro experiments confirmed the computational work

The researchers conducted two experiments in the lab to confirm the computational results.  

In one experiment, Ammerman used lab-purchased amyloid-β proteins that had been dyed fluorescent green, allowing them to be easily spotted easily in a microscope. In multiple trials, Ammerman exposed human cells to these amyloid-β proteins. She used two types of human cells — one where P-gp was strongly expressed and one where P-gp was not. This allowed Ammerman to test the difference between the two and see if P-gp was pumping amyloid-β out.       

The amyloid proteins were clearly shown to be pushed out of the human cells that had overexpressed P-gp in them, supporting the theory that P-gp removes amyloid proteins on contact. 

Another in vitro experiment reached the same conclusion from a different direction. Former graduate student Gang (Mike) Chen worked in SMU’s Center for Drug Discovery, Design and Delivery to show that an Alzheimer’s-linked amyloid-β caused changes in the P-gp’s usage of adenosine triphosphate (ATP), indicating that there was a physical interaction between the two. 

ATP hydrolysis produces the energy that P-gp uses to transport toxins or drugs out of the cell. When no toxins are present, P-gp’s rate of ATP stays pretty low. When challenged with transporting cargo, P-gp’s ATP hydrolysis activity usually increases quite dramatically.

“Even though our work can’t help our grandparents, I hope that it might help others in the future,” Ammerman said. “The more we know, the more power we have – and researchers after us – to address and target these devastating diseases.”

Featured image: Lauren Ammerman and James McCormick, who are getting married in November, sought to do research on Alzheimer’s disease after both SMU graduate students lost a grandmother to the disease. © SMU

Reference: McCormick JW, Ammerman L, Chen G, Vogel PD, Wise JG (2021) Transport of Alzheimer’s associated amyloid-β catalyzed by P-glycoprotein. PLoS ONE 16(4): e0250371. doi:10.1371/journal.pone.0250371

Provided by SMU

Study Reveals Recipe for Even More Powerful COVID-19 Vaccines (Medicine)

NEIDL, Broad scientists say next-generation vaccines could stimulate another arm of the immune system, imparting better protection against coronavirus variants

A new study looking at the way human cells activate the immune system in response to SARS-CoV-2 infection could open the door to even more effective and powerful vaccines against the coronavirus and its rapidly emerging variants keeping the global pandemic smoldering.

Researchers from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the Broad Institute of MIT and Harvard say it’s the first real look at exactly what types of “red flags” the human body uses to enlist the help of T cells—killers sent out by the immune system to destroy infected cells. Until now, COVID vaccines have been focused on activating a different type of immune cell, B cells, which are responsible for creating antibodies. Developing vaccines to activate the other arm of the immune system—the T cells—could dramatically increase immunity against coronavirus, and importantly, its variants.

In their findings, published in Cell, the researchers say current vaccines might lack some important bits of viral material capable of triggering a holistic immune response in the human body. Based on the new information, “companies should reevaluate their vaccine designs,” says Mohsan Saeed, a NEIDL virologist and the co-corresponding author of the paper.

Saeed, a BU School of Medicine assistant professor of biochemistry, performed experiments on human cells infected with coronavirus. He isolated and identified those missing pieces of SARS-CoV-2 proteins inside one of the NEIDL’s Biosafety Level 3 (BSL-3) labs. “This was a big undertaking because many research techniques are difficult to adapt for high containment levels [such as BSL-3],” Saeed says. “The overall coronavirus research pipeline we’ve created at the NEIDL, and the support of our entire NEIDL team, has helped us along the way.”

A photo of Mohsan Saeed working at a computer
Mohsan Saeed, BU NEIDL virologist, says the new findings could be a gamechanger for coronavirus vaccine design. Photo courtesy of Mohsan Saeed

Saeed got involved after he was contacted by genetic sequencing experts at the Broad Institute, computational geneticists Pardis Sabeti and Shira Weingarten-Gabbay. They hoped to identify fragments of SARS-CoV-2 that activate the immune system’s T cells. 

“The emergence of viral variants, an active area of research in my lab, is a major concern for vaccine development,” says Sabeti, a leader in the Broad Institute’s Infectious Disease and Microbiome Program. She is also a Harvard University professor of systems biology, organismic and evolutionary biology, and immunology and infectious disease, as well as a Howard Hughes Medical Institute investigator.

“We swung into full action right away because my laboratory had [already] generated human cell lines that could be readily infected with SARS-CoV-2,” Saeed says. The group’s efforts were spearheaded by two members of the Saeed lab: Da-Yuan Chen, a postdoctoral associate, and Hasahn Conway, a lab technician.

From the outset of COVID pandemic in early 2020, scientists around the world knew the identity of 29 proteins produced by SARS-CoV-2 virus in infected cells—viral fragments that now make up the spike protein in some coronavirus vaccines, such as the Moderna, Pfizer-BioNTech, and Johnson & Johnson vaccines. Later, scientists discovered another 23 proteins hidden inside the virus’ genetic sequence; however, the function of these additional proteins was a mystery until now. The new findings of Saeed and his collaborators reveal—unexpectedly and critically—that 25 percent of the viral protein fragments that trigger the human immune system to attack a virus come from these hidden viral proteins.

How exactly does the immune system detect these fragments? Human cells contain molecular “scissors”—called proteases—that, when the cells are invaded, hack off bits of viral proteins produced during infection. Those bits, containing internal proteins exposed by the chopping-up process—like the way the core of an apple is exposed when the fruit is segmented—are then transported to the cell membrane and pushed through special doorways. There, they stick outside the cell acting almost like a hitchhiker, waving down the help of passing T cells. Once T cells notice these viral flags poking through infected cells, they launch an attack and try to eliminate those cells from the body. And this T cell response isn’t insignificant—Saeed says there are links between the strength of this response and whether or not people infected with coronavirus go on to develop serious disease.

“It’s quite remarkable that such a strong immune signature of the virus is coming from regions [of the virus’ genetic sequence] that we were blind to,” says Weingarten-Gabby, the paper’s lead author and postdoctoral fellow in the Sabeti lab. “This is a striking reminder that curiosity-driven research stands at the basis of discoveries that can transform the development of vaccines and therapies.”

“Our discovery … can assist in the development of new vaccines that will mimic more accurately the response of our immune system to the virus,” Sabeti says.

T cells not only destroy infected cells but also memorize the virus’ flags so that they can launch an attack, stronger and faster, the next time the same or a different variant of the virus appears. That’s a crucial advantage, because Saeed and his collaborators say the coronavirus appears to delay the cell’s ability to call in immune help.

“This virus wants to go undetected by the immune system for as long as possible,” Saeed says. “Once it’s noticed by the immune system, it’s going to be eliminated, and it doesn’t want that.”

Based on their findings, Saeed says, a new vaccine recipe, incorporating some of the newly discovered internal proteins making up the SARS-CoV-2 virus, would be effective in stimulating an immune response capable of tackling a wide swath of newly emerging coronavirus variants. And given the speed with which these variants continue to appear around the world, a vaccine that can provide protection against all of them would be a game changer. 

This research was supported by the National Institute of Health, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium, a Human Frontier Science Program Fellowship, a Gruss-Lipper Postdoctoral Fellowship, a Zuckerman STEM Leadership Program Fellowship, a Rothschild Postdoctoral Fellowship, the Cancer Research Institute/Hearst foundation, a National Science Foundation Graduate Research Fellowship, EMBO Long- Term Fellowships, a Cancer Research Institute/Bristol-Myers Squibb Fellowship, the Parker Institute for Cancer Immunotherapy, the Emerson Collective, the G. Harold and Leila Y. Mathers Charitable Foundation, the Bawd Foundation, Boston University startup funds, the Mark and Lisa Schwartz Foundation, the Massachusetts Consortium for Pathogen Readiness, the Ragon Institute of MGH, MIT and Harvard, and the Frederick National Laboratory for Cancer Research.

Featured image: When Broad Institute researchers reached out for help exploring the molecular effects of coronavirus infection, Mohsan Saeed (center) and members of his NEIDL lab, Da-Yuan Chen (left) and Hasahn Conway (right), were ready to leap into action: they had already created human cell lines that could be readily infected with SARS-CoV-2. Photo courtesy of Saeed lab

Provided by Boston University

Pioneering Chemistry Approach Could Lead to More Robust Soft Electronics (Chemistry)

A new approach to studying conjugated polymers made it possible for an Army-funded research team to measure, for the first time, the individual molecules’ mechanical and kinetic properties during polymerization reaction. The insights gained could lead to more flexible and robust soft electronic materials, such as health monitors and soft robotics.

Conjugated polymers are essentially clusters of molecules strung along a backbone that can conduct electrons and absorb light. This makes them a perfect fit for creating soft optoelectronics, such as wearable electronic devices; however, as flexible as they are, these polymers are difficult to study in bulk because they aggregate and fall out from solution.

“Conjugated polymers are a fascinating class of materials due to their inherent optical and electronic properties which are dictated by their polymer structure,” said Dr. Dawanne Poree, program manager, U.S. Army Combat Capabilities Development Command, known as DEVCOM, Army Research Laboratory. “These materials are highly relevant to a number of applications of interest to Army and DoD including portable electronics, wearable devices, sensors, and optical communication systems. To date, unfortunately, it has been difficult to develop conjugated polymers for targeted applications due to a lack of viable tools to study and correlate their structure-property relationships.”

With Army funding, researchers at Cornell University employed an approach they pioneered on other synthetic polymers, called magnetic tweezers, that allowed them to stretch and twist individual molecules of the conjugated polymer polyacetylene. The research was published in the journal Chem.

“Through the use of novel single-molecule manipulation and imaging approaches, this work provided the first observations of single-chain behaviors in conjugated polymers which lays the foundation for the rational design and processing of these materials to enable widespread application,” Poree said.

Previous efforts to address the solubility of conjugated polymers have often relied upon chemical derivatization, in which the structures are modified with functional groups of atoms. However, that approach can affect the polymer’s innate properties.

“The conjugated polymer is really a prototype,” said Dr. Peng Chen, the Peter J.W. Debye professor of chemistry and chemical biology at Cornell. “You always modify it to tailor it for applications. We are hoping everything we measured – the fundamental properties of synthesis kinetics, the mechanical property – become benchmark numbers for people to think about other polymers of the same category.”

In 2017, Chen’s group was the first to use the magnetic tweezers measurement technique to study living polymerization, visualizing it at the single-molecule level. The technique had already been used in the biophysics field for studying DNA and proteins, but no one had successfully extended it to the realm of synthetic polymers.

The process works by affixing one end of a polymer strand to a glass coverslip and the other end to a tiny magnetic particle. The researchers then use a magnetic field to manipulate the conjugated polymer, stretching or twisting it, and measuring the response of a single polymer chain that grows.

The amounts are so small, they stay soluble in solution, the way bulk amounts normally would not.

The team measured how long chains of conjugated polymers, which consist of hundreds of thousands of monomer units, grow in real time. They discovered these polymers add a new monomer per second, a much faster growth than their nonconjugated analogs.

“We found that while growing in real time, this polymer forms conformational entanglements,” Chen said. “All polymers we have studied form conformational entanglements, but for this conjugated polymer this conformational entanglement is looser, allowing it to grow faster.”

By pulling and stretching individual conjugated polymers, so-called force extension measurements, the researchers were able to assess their rigidity and better understand how they can bend in different directions while remaining conjugated and retaining electron conductivity.

They also discovered the polymers displayed diverse mechanical behaviors from one individual chain to the next–behaviors that had been predicted by theory but never observed experimentally.

The findings highlight both the uniqueness of conjugated polymers for a range of applications as well as the strength of using a single-molecule manipulation and imaging technique on synthetic materials.

“Now we have a new way to study how these conjugated polymers are made chemically and what is the fundamental mechanical property of this type of material,” Chen said. “We can study how these fundamental properties change when you start tailoring them for application purposes. Maybe you can make it more mechanically flexible and make the polymer longer, or adjust the synthesis condition to either synthesize the polymer in a faster or slower way.”

Featured image: A new approach to studying conjugated polymers made it possible for an Army-funded research team to measure, for the first time, the individual molecules’ mechanical and kinetic properties during polymerization reaction. The insights gained could lead to more flexible and robust soft electronic materials, such as health monitors and soft robotics. (Udit Chakraborty, Cornell University)

Provided by US Army Research Laboratory

Researchers Uncover Unique Properties Of A Promising New Superconductor (Material Science)

An international team of physicists led by the University of Minnesota has discovered that a unique superconducting metal is more resilient when used as a very thin layer. The research is the first step toward a larger goal of understanding unconventional superconducting states in materials, which could possibly be used in quantum computing in the future. 

The collaboration includes four faculty members in the University of Minnesota’s School of Physics and Astronomy—Associate Professor Vlad Pribiag, Professor Rafael Fernandes, and Assistant Professors Fiona Burnell and Ke Wang—along with physicists at Cornell University and several other institutions. The study is published in Nature Physics, a monthly, peer-reviewed scientific journal published by the Nature Research.

Niobium diselenide (NbSe2) is a superconducting metal, meaning that it can conduct electricity, or transport electrons from one atom to another, with no resistance. It is not uncommon for materials to behave differently when they are at a very small size, but NbSe2 has potentially beneficial properties. The researchers found that the material in 2D form (a very thin substrate only a few atomic layers thick) is a more resilient superconductor because it has a two-fold symmetry, which is very different from thicker samples of the same material.

Motivated by Fernandes and Burnell’s theoretical prediction of exotic superconductivity in this 2D material, Pribiag and Wang started to investigate atomically-thin 2D superconducting devices. 

“We expected it to have a six-fold rotational pattern, like a snowflake.” Wang said. “Despite the six-fold structure, it only showed two-fold behavior in the experiment.” 

“This was one of the first times [this phenomenon] was seen in a real material,” Pribiag said.

The researchers attributed the newly-discovered two-fold rotational symmetry of the superconducting state in NbSe2 to the mixing between two closely competing types of superconductivity, namely the conventional s-wave type—typical of bulk NbSe2—and an unconventional d- or p-type mechanism that emerges in few-layer NbSe2. The two types of superconductivity have very similar energies in this system. Because of this, they interact and compete with each other.

Pribiag and Wang said they later became aware that physicists at Cornell University were reviewing the same physics using a different experimental technique, namely quantum tunneling measurements. They decided to combine their results with the Cornell research and publish a comprehensive study.

Burnell, Pribiag, and Wang plan to build on these initial results to further investigate the properties of atomically thin NbSe2 in combination with other exotic 2D materials, which could ultimately lead to the use of unconventional superconducting states, such as topological superconductivity, to build quantum computers.

“What we want is a completely flat interface on the atomic scale,” Pribiag said. “We believe this system will be able to give us a better platform to study materials to use them for quantum computing applications.”

In addition to Pribiag, Fernandes, Burnell, Wang, the collaboration included University of Minnesota physics graduate students Alex Hamill, Brett Heischmidt, Daniel Shaffer, Kan-Ting Tsai, and Xi Zhang; Cornell University faculty members Jie Shan and Kin Fai Mak and graduate student Egon Sohn; Helmuth Berger and László Forró, researchers at Ecole Polytechnique Fédérale de Lausanne in Switzerland; Alexey Suslov, a researcher at the National High Magnetic Field Laboratory in Tallahassee, Fla.; and Xiaoxiang Xi, a professor at Nanjing University in China. 

The University of Minnesota research was supported primarily by the National Science Foundation (NSF) through the University of Minnesota Materials Research Science and Engineering Center (MRSEC). The research at Cornell was supported by the Office of Naval Research (ONR) and NSF. The work in Switzerland was supported by the Swiss National Science Foundation.

Featured image: A team of physicists led by the University of Minnesota has discovered that the unique superconducting metal Niobium diselenide (NbSe2) is more resilient when used as a very thin layer. The above diagram depicts the different s-, p-, and d-wave superconducting states in the metal. Photo credit: Alex Hamill and Brett Heischmidt, University of Minnesota

Reference: Hamill, A., Heischmidt, B., Sohn, E. et al. Two-fold symmetric superconductivity in few-layer NbSe2. Nat. Phys. (2021). https://doi.org/10.1038/s41567-021-01219-x

Provided by University of Minnesota

The Give and Take of Mega-Flares From Stars (Planetary Science)

  • How do flares, or outbursts, from young stars affect planets that orbit around them?
  • The largest study of star-forming regions in X-rays using NASA’s Chandra X-ray Observatory seeks to answer that question.
  • Researchers identified flares from over 1,000 young stars, many of which are much more powerful than those seen from our Sun today.
  • This study will help scientists learn more about both the beneficial and destructive impacts these flares can have.

These two images contain some of the thousands of stars from a new survey by NASA’s Chandra X-ray Observatory, as reported in our latest press release. This was the largest survey of star formation ever conducted in X-rays, covering some 24,000 individual stars in 40 different regions. The study outlines the link between very powerful flares, or outbursts, from young stars and the impact they could have on planets in orbit around them.

Within this large dataset, scientists identified over a thousand young stars that gave off flares that are vastly more energetic than the most powerful flare ever observed by modern astronomers on the Sun, the “Solar Carrington Event” in 1859. “Super” flares are at least one hundred thousand times more energetic than the Carrington Event and “mega” flares up to 10 million times more energetic.

The Lagoon Nebula (left) is an area about 4,400 light years from Earth in the Milky Way galaxy where stars are actively forming. This field-of-view shows the southern portion of a large bubble of hydrogen gas, plus a cluster of young stars. The Chandra data (purple) have been combined with infrared data (blue, gold, and white) from the Spitzer Space Telescope in this composite image.

The Lagoon Nebula (M8) © Chandra Observatory

A sequence of X-ray images from Chandra show a young star (called “Lagoon 180402.88−242140.0”) in the Lagoon Nebula that experienced a “mega-flare”. This flare was about 250,000 more energetic than the most powerful flare observed by modern astronomers on the Sun, and lasted for about three and a half hours. It was followed by a smaller flare. The total duration of the movie covers almost 23 hours and 27 images are included. This star is only about 1.5 million years old — compared to the Sun’s age of 4.5 billion years — and has a mass about three times that of the Sun. (Note: The apparent changes in the shape of the X-ray source are caused by noise rather than a true change in shape.)

Lagoon Nebula Flare (timelapse, 27 exposures) © Chandra Observatory

The image on the right shows the star-forming region called RCW 120, which is also in the Milky Way, but slightly farther away at a distance of about 5,500 light years. This view of RCW 120, which has the same wavelengths and colors as the Lagoon composite, contains an expanding bubble of hydrogen gas, about 13 light years across. This structure may be sweeping up material into a dense shell and triggering the formation of stars.

RCW 120 © Chandra Observatory

The powerful flares observed by Chandra in this research occur in all of the star-forming regions and among young stars of all different masses, including those similar to the Sun. The scientists recorded the flares at all different stages in the evolution of young stars, ranging from early stages when the star is heavily embedded in dust and gas and surrounded by a large planet-forming disk, to later stages when planets would have formed and the disks are gone. The team found several super-flares occur per week for each young star less than about 5 million years old, averaged over the whole sample, and about two mega-flares every year.

Over the past two decades, scientists have argued that these giant flares can help “give” planets to still-forming stars by driving gas away from disks of material that surround them. This can trigger the formation of pebbles and other small rocky material that is a crucial step for planets to form. On the other hand, these flares may “take away” from planets that have already formed by blasting any atmospheres with powerful radiation, possibly resulting in their complete evaporation and destruction in less than 5 million years.

This work was presented at the recent meeting of the American Astronomical Society and is described in a paper led by Getman that was accepted for publication in The Astrophysical Journal, and is available here. NASA’s Marshall Space Flight Center manages the Chandra program. The Smithsonian Astrophysical Observatory’s Chandra X-ray Center controls science from Cambridge, Massachusetts, and flight operations from Burlington, Massachusetts.

Provided by Chandra Observatory

How A Supermassive Black Hole Originates? (Cosmology)

UC Riverside-led study points to a seed black hole produced by a dark matter halo collapse

Supermassive black holes, or SMBHs, are black holes with masses that are several million to billion times the mass of our sun. The Milky Way hosts an SMBH with mass a few million times the solar mass. Surprisingly, astrophysical observations show that SMBHs already existed when the universe was very young. For example, a billion solar mass black holes are found when the universe was just 6% of its current age, 13.7 billion years. How do these SMBHs in the early universe originate?

A team led by a theoretical physicist at the University of California, Riverside, has come up with an explanation: a massive seed black hole that the collapse of a dark matter halo could produce.

Dark matter halo is the halo of invisible matter surrounding a galaxy or a cluster of galaxies. Although dark matter has never been detected in laboratories, physicists remain confident this mysterious matter that makes up 85% of the universe’s matter exists. Were the visible matter of a galaxy not embedded in a dark matter halo, this matter would fly apart.

“Physicists are puzzled why SMBHs in the early universe, which are located in the central regions of dark matter halos, grow so massively in a short time,” said Hai-Bo Yu, an associate professor of physics and astronomy at UC Riverside, who led the study that appears in Astrophysical Journal Letters. “It’s like a 5-year-old child that weighs, say, 200 pounds. Such a child would astonish us all because we know the typical weight of a newborn baby and how fast this baby can grow. Where it comes to black holes, physicists have general expectations about the mass of a seed black hole and its growth rate. The presence of SMBHs suggests these general expectations have been violated, requiring new knowledge. And that’s exciting.”

A seed black hole is a black hole at its initial stage — akin to the baby stage in the life of a human.

“We can think of two reasons,” Yu added. “The seed — or ‘baby’ — black hole is either much more massive or it grows much faster than we thought, or both. The question that then arises is what are the physical mechanisms for producing a massive enough seed black hole or achieving a fast enough growth rate?”

“It takes time for black holes to grow massive by accreting surrounding matter,” said co-author Yi-Ming Zhong, a postdoctoral researcher at the Kavli Institute for Cosmological Physics at the University of Chicago. “Our paper shows that if dark matter has self-interactions then the gravothermal collapse of a halo can lead to a massive enough seed black hole. Its growth rate would be more consistent with general expectations.”

In astrophysics, a popular mechanism used to explain SMBHs is the collapse of pristine gas in protogalaxies in the early universe.

“This mechanism, however, cannot produce a massive enough seed black hole to accommodate newly observed SMBHs — unless the seed black hole experienced an extremely fast growth rate,” Yu said. “Our work provides an alternative explanation: a self-interacting dark matter halo experiences gravothermal instability and its central region collapses into a seed black hole.”

The explanation Yu and his colleagues propose works in the following way:

Dark matter particles first cluster together under the influence of gravity and form a dark matter halo. During the evolution of the halo, two competing forces — gravity and pressure — operate. While gravity pulls dark matter particles inward, pressure pushes them outward. If dark matter particles have no self-interactions, then, as gravity pulls them toward the central halo, they become hotter, that is, they move faster, the pressure increases effectively, and they bounce back. However, in the case of self-interacting dark matter, dark matter self-interactions can transport the heat from those “hotter” particles to nearby colder ones. This makes it difficult for the dark matter particles to bounce back.

Yu explained that the central halo, which would collapse into a black hole, has angular momentum, meaning, it rotates. The self-interactions can induce viscosity, or “friction,” that dissipates the angular momentum. During the collapse process, the central halo, which has a fixed mass, shrinks in radius and slows down in rotation due to viscosity. As the evolution continues, the central halo eventually collapses into a singular state: a seed black hole. This seed can grow more massive by accreting surrounding baryonic — or visible — matter such as gas and stars.

“The advantage of our scenario is that the mass of the seed black hole can be high since it is produced by the collapse of a dark matter halo,” Yu said. “Thus, it can grow into a supermassive black hole in a relatively short timescale.”

The new work is novel in that the researchers identify the importance of baryons–ordinary atomic and molecular particles — for this idea to work.

“First, we show the presence of baryons, such as gas and stars, can significantly speed up the onset of the gravothermal collapse of a halo and a seed black hole could be created early enough,” said Wei-Xiang Feng, Yu’s graduate student and a co-author on the paper. “Second, we show the self-interactions can induce viscosity that dissipates the angular momentum remnant of the central halo. Third, we develop a method to examine the condition for triggering general relativistic instability of the collapsed halo, which ensures a seed black hole could form if the condition is satisfied.”

Over the past decade, Yu has explored novel predictions of dark matter self-interactions and their observational consequences. His work has shown that self-interacting dark matter can provide a good explanation for the observed motion of stars and gas in galaxies.

“In many galaxies, stars and gas dominate their central regions,” he said. “Thus, it’s natural to ask how the presence of this baryonic matter affects the collapse process. We show it will speed up the onset of the collapse. This feature is exactly what we need to explain the origin of supermassive black holes in the early universe. The self-interactions also lead to viscosity that can dissipate angular momentum of the central halo and further help the collapse process.”

The study was funded by the U.S. Department of Energy; NASA; the Kavli Institute for Cosmological Physics; and the John Templeton Foundation.

The research paper is titled “Seeding Supermassive Black Holes with Self-Interacting Dark Matter: A Unified Scenario with Baryons.”

Featured image: Hai-Bo Yu is a theoretical physicist at UC Riverside with expertise in the particle properties of dark matter. © Samantha Tieu.

Provided by University of California Riverside

Ionic Zinc Inhibits SARS-CoV-2 Main Protease and Virus Replication (Biology)

Arulandu Arockiasamy and colleagues in their recent paper showed that ionic zinc not only inhibits SARS-CoV-2 main protease but also viral replication in vitro.

Covid-19 pandemic caused by SARS-CoV-2 is a major clinical challenge. Several studies recently suggested that zinc deficiency in covid-19 patients leads to extended duration to recovery, higher morbidity and a higher mortality in elderly. While, clinical trails with Zinc demonstrated positive clinical outcome with a decreased rate of mortality.

Zinc is an essential trace element that is crucial for growth, development, and the maintenance of immune function. Several studies also suggested that zinc possesses antiviral properties against a number of viral species. Although mechanistic studies are lacking, zinc appears to inhibit viral protease and polymerase enzymatic processes, as well as physical processes such as virus attachment, infection, and uncoating. Unfortunately, these mechanisms have not been well scrutinized in clinical studies, where zinc may provide inexpensive and effective adjunct treatments for many viral infections.

Now, Arulandu Arockiasamy and colleagues presented the first crystal structure of main protease ionic zinc complex at 1.9 Å and provided the structural basis of viral replication inhibition. They showed that the zinc ion is coordinated by the catalytic dyad His41 and Cys145 and revealed, a tetrahedral coordination geometry of a Zinc-bound complex with two strongly coordinated water molecules at the main protease active site.

Complex crystal structure of Mpro dimer with Zinc (grey sphere) bound at the active site of both protomers. On the right, catalytic dyad Cys145 and His41 of Mpro is shown with bound Zinc in tetrahedral coordination geometry. © Arulandu Arockiasamy et al.

“We hypothesized that the two strongly coordinated water molecules, W1 & W2 at an inter-atomic distance of 2.23 Å and 1.98 Å, impart stability to the Zinc^2+ inhibited complex.”

They also showed that, ionic zinc not only inhibits SARS-CoV-2 main protease but also viral replication. But how? Well, by forming a stable complex at the active site with the help of two water molecules.

In addition, it has been shown that, zinc complexes such as zinc glycinate and zinc gluconate failed to produce any antiviral effects in their cell culture experiments.

Finally, they suggested that, constant doses of Zinc-ionophore combination may be required for effective inhibition of SARS-CoV-2 main protease.

Reference: Love Panchariya, Wajahat Ali Khan, Shobhan Kuila, Kirtishila Sonkar, Sibasis Sahoo, Archita Ghoshal, Ankit Kumar, Dileep Kumar Verma, Abdul Hasan, Shubhashis Das, Jitendra K. Thakur, Rajkumar Halder, Sujatha Sunil, Arockiasamy Arulandu, “Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro”, bioRxiv 2021.06.15.448551; doi: https://doi.org/10.1101/2021.06.15.448551

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New Super-resolution Microscopy Method Approaches the Atomic Scale (Medicine)

Scientists at Weill Cornell Medicine have developed a computational technique that greatly increases the resolution of atomic force microscopy, a specialized type of microscope that “feels” the atoms at a surface. The method reveals atomic-level details on proteins and other biological structures under normal physiological conditions, opening a new window on cell biology, virology and other microscopic processes.

In a study, published June 16 in Nature, the investigators describe the new technique, which is based on a strategy used to improve resolution in light microscopy.

To study proteins and other biomolecules at high resolution, investigators have long relied on two techniques: X-ray crystallography and cryo-electron microscopy. While both methods can determine molecular structures down to the resolution of individual atoms, they do so on molecules that are either scaffolded into crystals or frozen at ultra-cold temperatures, possibly altering them from their normal physiological shapes. Atomic force microscopy (AFM) can analyze biological molecules under normal physiological conditions, but the resulting images have been blurry and low resolution.

“Atomic force microscopy can easily resolve atoms in physics, on solid surfaces of silicates and on semiconductors, so it means that in principle the machine has the precision to do that,” said senior author Dr. Simon Scheuring, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. “The technique is a bit like if you were to take a pen and scan over the Rocky Mountains, so that you get a topographic map of the object. In reality, our pen is a needle that is sharp down to a few atoms and the objects are single protein molecules.”

However, biological molecules have many small parts that wiggle, blurring their AFM images. To address that problem, Dr. Scheuring and his colleagues adapted a concept from light microscopy called super-resolution microscopy. “Theoretically it wasn’t possible by optical microscopy to resolve two fluorescent molecules that were closer together than half the wavelength of the light,” he said. However, by stimulating the adjacent molecules to fluoresce at different times, microscopists can analyze the spread of each molecule and pinpoint their locations with high precision.

Instead of stimulating fluorescence, Dr. Scheuring’s team noted that the natural fluctuations of biological molecules recorded over the course of AFM scans yield similar spreads of positional data. First author Dr. George Heath, who was a postdoctoral associate at Weill Cornell Medicine at the time of the study and is now a faculty member at the University of Leeds, engaged in cycles of experiments and computational simulations to understand the AFM imaging process in greater detail and extract the maximum of information from the atomic interactions between tip and sample.

Using a method like super-resolution analysis, they were able to extract much higher resolution images of the moving molecules. Continuing the topographic analogy, Dr. Scheuring explained that “if the rocks (i.e., atoms) wiggle a little bit up and down, you can detect this one, then that one, and then you average all detections over time and you receive high-resolution information.”

Because previous AFM studies have routinely collected the necessary data, the new technique can be applied retroactively to the blurry images the field has generated for decades. As an example, the new paper includes an analysis of an AFM scan of an aquaporin membrane protein, originally acquired during Dr. Scheuring’s doctoral thesis. The reanalysis generated a much sharper image that matches X-ray crystallography structures of the molecule closely. “You basically get quasi-atomic resolution on these surfaces now,” said Dr. Scheuring. To showcase the power of the method, the authors provide new high-resolution data on annexin, a protein involved in cell membrane repair, and on a proton-chloride antiporter of which they also report structural changes related to its functional.

Besides allowing researchers to study biological molecules under physiologically relevant conditions, the new method has other advantages. For example, X-ray crystallography and cryo-electron microscopy rely on averaging data from large numbers of molecules, but AFM can generate images of single molecules. “Instead of having observations of hundreds of molecules, we observe one molecule a hundred times and calculate a high-resolution map,” said Dr. Scheuring.

Imaging individual molecules as they carry out their functions could open entirely new types of analysis. “Let’s say you have a [viral] spike protein that’s in one conformation and then it gets activated and goes into another conformation,” said Dr. Scheuring. “You would in principle be able to calculate a high-resolution map from that same molecule as it transits from one conformation to the next, not from thousands of molecules in one or the other conformation.” Such high-resolution single molecule data could provide more detailed information and avoid the potentially misleading results that can occur when averaging data from many molecules. Furthermore, the map might reveal new strategies for precisely redirecting or interrupting such processes.

Additional study co-authors include Drs. Ekaterina Kots, Shifra Lansky, George Khelashvili, and Harel Weinstein from the Department of Physiology and Biophysics at Weill Cornell Medicine and Dr. Janice Robertson from the Department of Biochemistry and Molecular Biophysics at Washington University.

Featured image: Localization AFM & X-ray structure © Weill Cornell Medicine, University of Leeds & Washington University

Reference: Heath, G.R., Kots, E., Robertson, J.L. et al. Localization atomic force microscopy. Nature 594, 385–390 (2021). https://doi.org/10.1038/s41586-021-03551-x

Provided by Weill Cornell Medicine

Bruisable Artificial Skin Could Help Prosthetics, Robots Sense Injuries (Chemistry)

When someone bumps their elbow against a wall, they not only feel pain but also might experience bruising. Robots and prosthetic limbs don’t have these warning signs, which could lead to further injury. Now, researchers reporting in ACS Applied Materials & Interfaces have developed an artificial skin that senses force through ionic signals and also changes color from yellow to a bruise-like purple, providing a visual cue that damage has occurred.

Scientists have developed many different types of electronic skins, or e-skins, that can sense stimuli through electron transmission. However, these electrical conductors are not always biocompatible, which could limit their use in some types of prosthetics. In contrast, ionic skins, or I-skins, use ions as charge carriers, similar to human skin. These ionically conductive hydrogels have superior transparency, stretchability and biocompatibility compared with e-skins. Qi Zhang, Shiping Zhu and colleagues wanted to develop an I-skin that, in addition to registering changes in electrical signal with an applied force, could also change color to mimic human bruising.

The researchers made an ionic organohydrogel that contained a molecule, called spiropyran, that changes color from pale yellow to bluish-purple under mechanical stress. In testing, the gel showed changes in color and electrical conductivity when stretched or compressed, and the purple color remained for 2–5 hours before fading back to yellow. Then, the team taped the I-skin to different body parts of volunteers, such as the finger, hand and knee. Bending or stretching caused a change in the electrical signal but not bruising, just like human skin. However, forceful and repeated pressing, hitting and pinching produced a color change. The I-skin, which responds like human skin in terms of electrical and optical signaling, opens up new opportunities for detecting damage in prosthetic devices and robotics, the researchers say.

The authors acknowledge funding from the National Natural Science Foundation of China, the Program for Guangdong Introducing Innovative and Entrepreneurial Teams, Shenzhen Science and Technology Program, 2019 Special Program for Central Government Guiding Local Science and Technology Development: Environmental Purification Functional Materials Research Platform, Shenzhen Key Laboratory of Advanced Materials Product Engineering and the CUHK-Shenzhen Presidential Fund.

The study, “Colorimetric Ionic Organohydrogels Mimicking Human Skin for Mechanical Stimuli Sensing and Injury Visualization”, published in
ACS Applied Materials & Interfaces

Featured image: An artificial skin attached to a person’s knee develops a purple “bruise” when hit forcefully against a metal cabinet.Credit: Adapted from ACS Applied Materials & Interfaces 2021, DOI: 10.1021/acsami.1c04911

Provided by ACS