Researchers Reveal the Inner Workings of a Viral DNA-Packaging Motor (Chemistry)

Trilogy of papers provide insight into a critical step in how some viruses reproduce

A group of researchers have discovered the detailed inner workings of the molecular motor that packages genetic material into double-stranded DNA viruses. The advance provides insight into a critical step in the reproduction cycle of viruses such as pox- herpes- and adeno-viruses. It could also give inspiration to researchers creating microscopic machines based on naturally occurring biomotors.

The research was conducted by scientists from Duke University, the University of Minnesota, the University of Massachusetts and the University of Texas Medical Branch (UTMB). The results appear online in a trilogy of papers published in Science Advances, Proceedings of the National Academy of Sciences and Nucleic Acids Research.

“There were several missing pieces of information that prevented us from understanding how these kinds of DNA packaging motors work, which hindered our ability to design therapeutics or evolve new technologies,” said Gaurav Arya, professor of mechanical engineering and materials science, biomedical engineering, and chemistry at Duke. “But with new insights and simulations, we were able to piece together a model of this fantastic mechanism, which is the most detailed ever created for this kind of system.”

Viruses come in many varieties, but their classification generally depends upon whether they encode their genetic blueprints into RNA or single- or double-stranded DNA. The difference matters in many ways and affects how the genetic material is packaged into new viruses. While some viruses build a protein container called a capsid around newly produced RNA or DNA, others create the capsid first and then fill it with the genetic material.

“Trying to see the motor attached to the virus is like trying to see the details in the Statue of Liberty’s torch by taking a photo of the entire statue.”

— JOSHUA PAJAK.

Most double-stranded DNA viruses take the latter route, which presents many challenges. DNA is negatively charged and does not want to be crammed together into a small space. And it’s packaged into an extremely dense, nearly crystalline structure, which also requires a lot of force.

“The benefit of this is that, when the virus is ready to infect a new cell, the pressure helps inject DNA into the cell once it’s punctured,” said Joshua Pajak, a doctoral student working in Arya’s laboratory. “It’s been estimated that the pressure exceeds 800 PSI, which is almost ten times the pressure in a corked bottle of champagne.”

Forcing DNA into a tiny capsid at that amount of pressure requires an extremely powerful motor. Until recently, researchers only had a vague sense of how that motor worked because of how difficult it is to visualize. The motor only assembles on the virus particle, which is enormous compared to the motor.

“Trying to see the motor attached to the virus is like trying to see the details in the Statue of Liberty’s torch by taking a photo of the entire statue,” said Pajak.

But at a recent conference, Pajak learned that Marc Morais, professor of biochemistry and molecular biology at UTMB, and Paul Jardine, professor of diagnostic and biological sciences at the University of Minnesota, had been working on this motor for years and had the equipment and skills needed to see the details. Some of their initial results appeared to match the models Pajak was building with what little information was already available. The group grew excited that their separate findings were converging toward a common mechanism and quickly set about solving the mystery of the viral motor together.

A trio of studies has revealed how a viral DNA packaging motor works, potentially providing insights for new therapeutics or synthetic molecular machines. Each of five proteins scrunches up in turn, dragging the DNA up along with them, before releasing back into their original helical pattern. © Pratt School of Engineering

In a paper published in Science Advances, Morais and his colleagues resolved the details of the entire motor in one of its configurations. They found that the motor is made up of five proteins attached to one another in a ring-like formation. Each of these proteins are like two suction cups with a spring in between, which allows the bottom portion to move vertically in a helical formation so that it can grab onto the helical backbone of DNA.

“Because you could fit about 100,000 of these motors on the head of a pin and they’re all jiggling around, getting a good look at them proved difficult,” said Morais. “But after my UTMB colleagues Michael Woodson and Mark White helps us image them with a cryo-electron microscope, a general framework of the mechanism fell into place.”

In a second paper, published in Nucleic Acids Research, the Morais group captured the motor in a second configuration using x-ray crystallography. This time the bottom suction cups of the motor were all scrunched up together in a planar ring, leading the researchers to imagine that the motor might move DNA into the virus by ratcheting between the two configurations.

“Joshua pieced together lots of clues and information to create this model. But a model is only useful if it can predict new insights that we didn’t already know.”

— GAURAV ARYA

To test this hypothesis, Pajak and Arya performed heavy-duty simulations on Anton 2, the fastest supercomputer currently available for running molecular dynamics simulations. Their results not only supported the proposed mechanism, but also provided information on how exactly the motor’s cogs contort between the two configurations.

While the tops of the proteins remain statically attached to the virus particle, their bottom halves move up and down in a cyclic pattern powered by an energy-carrying molecule called ATP. Once all the proteins have moved up—dragging the DNA along with them—the proteins release the byproduct of the ATP chemical reaction. This causes the lower ring to release the DNA and reach back down into their original helical state, where they once again grab on to more ATP and DNA to repeat the process.

“Joshua pieced together lots of clues and information to create this model,” said Arya. “But a model is only useful if it can predict new insights that we didn’t already know.”

At its core, the model is a series of mechanical actions that must fit together and take place in sequential order for everything to work properly. Pajak’s simulations predicted a specific series of mechanical signals that tell the bottoms of the proteins whether or not they should be gripping the DNA. Like a line of dominoes falling, removing one of the signaling pathways from the middle should stop the chain reaction and block the signal.

“All technology is inspired by nature in one way or another. Now that we really know how this molecular motor works, hopefully it will inspire other researchers to create new inventions using these same mechanisms.”

— GAURAV ARYA

To validate this prediction, the researchers turned to Jardine and colleagues Shelley Grimes and Dwight Anderson to see if removing one of the signaling dominoes actually stopped the motor from packaging DNA. A third paper, published in PNAS, shows that the sabotage worked. After mutating a domino in the signaling pathway so that it was unable to function, the motor could still bind and burn fuel just as well as ever, but it was much worse at actually packaging DNA.

“The new mechanism predicted by the high-resolution structures and the detailed predictions provided a level of detail greater than we ever previously had,” said Jardine. “This allowed us to test the role of critical components of the motor, and therefore assess the validity of this new mechanism as we currently understand it.”

The result is a strong indication that the model is very close to describing how the motor behaves in nature. The group plans to continue their highly integrated structural, biochemical and simulation approach to further test and refine the proposed model. They hope that that this fundamental understanding could potentially be used to someday fight disease or create a synthetic molecular motor.

“All technology is inspired by nature in one way or another,” said Arya. “Now that we really know how this molecular motor works, hopefully it will inspire other researchers to create new inventions using these same mechanisms.”

This work was supported by the National Institutes of Health (GM118817, GM122979, GM127365) and the National Science Foundation (MCB1817338). Cryo-EM data were also collected at NIH-supported regional cryo-EM imaging facilities (1U24 GM116787-01, 1U24 GM116792-01). Simulations were performed on Anton 2 supercomputer made available by D.E. Shaw Research and hosted at the Pittsburgh Supercomputing Center via the NIH (R01GM116961) and the Comet supercomputer hosted at the San Diego Supercomputer Center via the NSF (ACI-1053575).

Featured image: Five proteins, each different colors, make up the viral DNA-packaging motor that researchers now have a full understanding of © Pratt School of Engineering


REFERENCES:

  • “Viral Packaging ATPases Utilize a Glutamate Switch to Couple ATPase Activity and DNA Translocation.” Joshua Pajak, Rockney Atz, Brendan J. Hilbert, Marc C. Morais, Brian A. Kelch, Paul Jardine, and Gaurav Arya. PNAS, April 27, 2021 118 (17) e2024928118. DOI: 10.1073/pnas.2024928118
  • “A Viral Genome Packaging Motor Transitions Between Cyclic and Helical Symmetry to Translocate dsDNA,” Michael Woodson, Joshua Pajak, Bryon P. Mahler, Wei Zhao, Wei Zhang, Gaurav Arya, Mark A. White, Paul J. Jardine and Marc C. Morais. Science Advances, 07 May 2021: Vol. 7, no. 19, eabc1955. DOI: 10.1126/sciadv.abc1955
  • “Atomistic Basis Of Force Generation, Translocation, and Coordination in a Viral Genome Packaging Motor,” Joshua Pajak, Erik Dill2, Emilio Reyes-Aldrete, Mark A. White, Brian A.Kelch, Paul J. Jardine, Gaurav Arya1, and Marc C. Morais. Nucleic Acids Research, 2021. DOI: 10.1093/nar/gkab372

Provided by Duke Pratt School of Engineering

The Biodegradable Battery (Chemistry)

The number of data-transmitting microdevices, for instance in packaging and transport logistics, will increase sharply in the coming years. All these devices need energy, but the amount of batteries would have a major impact on the environment. Empa researchers have developed a biodegradable mini-capacitor that can solve the problem. It consists of carbon, cellulose, glycerin and table salt. And it works reliably.

The fabrication device for the battery revolution looks quite unconspicuous: It is a modified, commercially available 3D printer, located in a room in the Empa laboratory building. But the real innovation lies within the recipe for the gelatinous inks this printer can dispense onto a surface. The mixture in question consists of cellulose nanofibers and cellulose nanocrystallites, plus carbon in the form of carbon black, graphite and activated carbon. To liquefy all this, the researchers use glycerin, water and two different types of alcohol. Plus a pinch of table salt for ionic conductivity.

A sandwich of four layers

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The biodegradable battery consists of four layers, all flowing out of a 3D printer one after the other. The whole thing is then folded up like a sandwich, with the electrolyte in the center. Image: Gian Vaitl / Empa

To build a functioning supercapacitor from these ingredients, four layers are needed, all flowing out of the 3D printer one after the other: a flexible substrate, a conductive layer, the electrode and finally the electrolyte. The whole thing is then folded up like a sandwich, with the electrolyte in the center.

What emerges is an ecological miracle. The mini-capacitor from the lab can store electricity for hours and can already power a small digital clock. It can withstand thousands of charge and discharge cycles and years of storage, even in freezing temperatures, and is resistant to pressure and shock.

Biodegradable power supply

Best of all, though, when you no longer need it, you could toss it in the compost or simply leave it in nature. After two months, the capacitor will have disintegrated, leaving only a few visible carbon particles. The researchers have already tried this, too.

“It sounds quite simple, but it wasn’t at all,” says Xavier Aeby of Empa’s Cellulose & Wood Materials lab. It took an extended series of tests until all the parameters were right, until all the components flowed reliably from the printer and the capacitor worked. Says Aeby: “As researchers, we don’t want to just fiddle about, we also want to understand what’s happening inside our materials.”

Together with his supervisor, Gustav Nyström, Aeby developed and implemented the concept of a biodegradable electricity storage device. Aeby studied microsystems engineering at EPFL and came to Empa for his doctorate. Nyström and his team have been investigating functional gels based on nanocellulose for some time. The material is not only an environmentally friendly, renewable raw material, but its internal chemistry makes it extremely versatile.

“The project of a biodegradable electricity storage system has been close to my heart for a long time,” Nyström says. “We applied for Empa internal funding with our project, Printed Paper Batteries, and were able to start our activities with this funding. Now we have achieved our first goal.”

Application in the Internet of Things

The supercapacitor could soon become a key component for the Internet of Things, Nyström and Aeby expect. “In the future, such capacitors could be briefly charged using an electromagnetic field, for example, then they could provide power for a sensor or a microtransmitter for hours.” This could be used, for instance, to check the contents of individual packages during shipping. Powering sensors in environmental monitoring or agriculture is also conceivable – there’s no need to collect these batteries again, as they could be left in nature to degrade.

After two months buried in the soil, the capacitor has disintegrated, leaving only a few visible carbon particles. Image: Gian Vaitl/ Empa.

The number of electronic microdevices will also be increasing due to a much more widespread use of near-patient laboratory diagnostics (“point of care testing”), which is currently booming. Small test devices for use at the bedside or self-testing devices for diabetics are among them. “A disposable cellulose capacitor could also be well suited for these applications”, says Gustav Nyström.

Featured image: Xavier Aeby and Gustav Nyström invented a fully printed biodegradable battery made from cellulose and other non-toxic components. Image: Gian Vaitl / Empa


Literature

X Aeby, A Poulin, G Siqueira, MK Hausmann, G Nyström; Fully 3D Printed and Disposable Paper Supercapacitors; Advanced Materials (2021); doi.org/10.1002/adma.202101328


Provided by EMPA

Hollings Research Finds New Link Between Aging, Cancer And Mitochondrial Function in T-cells (Medicine)

MUSC Hollings Cancer Center researchers are finding solutions to the aging-related changes that reduce anti-cancer immunity. Besim Ogretmen, Ph.D., and colleagues found a novel link between aging, metabolism and anti-cancer T-cell function. Their work, published in Cell Reports, sheds light on an important pathway that cannot be ignored during cancer treatment.

Two broad questions in cancer research are: How can cancer treatments be improved, and what is the link between cancer and aging?

“We know that the protective T-cell response deteriorates with age. Mitochondrial function is now thought to be one of the central regulators of the aging process. Our experiments connected the dots with what was previously shown and highlighted some surprising and important pathways,” said Ogretmen, who is the SmartState Endowed Chair in Lipidomics and Drug Discovery.

All cells in the human body, except red blood cells, contain structures called mitochondria. Mitochondria are a cell’s central powerhouse — they produce the chemical energy necessary for survival. Ogretmen’s prior studies showed that a particular type of fatty molecule, called ceramide, causes mitochondrial dysfunction in cancer cells. In terms of cancer, mitochondrial dysfunction is thought to be a good thing since it weakens the cancer cells.

However, mitochondrial dysfunction might not be completely beneficial for cancer treatment. “We know that increased ceramide signaling is linked with aging, but it is important that we understand if this is also occurring in immune cells. Immunotherapy is becoming an increasingly important part of cancer treatment, so we must better understand the immune system in older people,” he said.

When ceramide signaling is blocked, the anti-cancer function of aging T-cells is restored, making them perform like younger cells again. © MUSC

Aging stress produces the bioactive sphingolipid called ceramide. This lipid promotes mitochondrial dysfunction by a biological mechanism called mitophagy, where the broken mitochondria are selectively destroyed to kill cancer cells. However, scientists do not know if T-cells use this same pathway or if their immune functions are changed by ceramide signaling.

The results, which were surprising, showed ceramide signaling weakens anti-tumor T-cells. The data showed that:

  • Aging decreases T-cell survival and function.
  • Aging stress induces mitophagy in T-cells.
  • Blocking certain ceramide molecules improves the anti-tumor function of aging T-cells.

“What this tells us is that ceramides need to be carefully controlled in a cancer setting,” said Ogretmen. This is particularly important because there are several FDA-approved drugs, such as FTY720 for multiple sclerosis, that increase ceramide signaling. Systemic increase of ceramide signaling in cancer patients may be harmful because it weakens the anti-cancer function of the patient’s immune system, he said.

Using multiple molecular methods, the team observed that T-cells from old mice, which were equivalent to approximately 50- to 60-year-old humans, had more ceramide accumulation in their mitochondria, which led to dysfunction. These cells had lower anti-tumor functions in cell culture and in cancer animal models. This biological pathway was confirmed by blocking ceramide signaling. Inhibiting ceramide metabolism by genetic or pharmacological means prevented mitophagy and restored the anti-cancer function of the aging T-cells, making them perform like younger counterparts.

“Our work was aided by a really strong team of collaborators and funding support from Hollings Cancer Center. The Team Science Award allowed us to generate this data, which has developed into something larger. We just resubmitted an NIH program project grant that focuses on the role of sphingolipids in T-cells and cancer,” he said.

The team will continue to piece together the biological pathways and processes to ensure that these findings are applicable to humans. The next step is to understand how aging induces ceramide stress. In general, stress can invoke dormant cancers, and this may be related to ceramide signaling.

“Understanding the mechanism of ceramides and lipid metabolism in T-cells has broad implications in aging and immune cells in general. Our work is important because it allows us to understand autoimmune diseases and infections more fully, not just cancer.” There is also a potential link to lifestyle choices and stress, which may accelerate the aging process of T-cells, he said.

Featured image: Dr. Besim Ogretmen’s team discovered that blocking certain ceramide molecules improves the anti-tumor function of aging T-cells. Photo by Marquel Coaxum


Reference: Silvia Vaena, Paramita Chakraborty et al., “Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response”, Cell Reports, 35(5), 2021. DOI: https://doi.org/10.1016/j.celrep.2021.109076


Provided by MUSC

Researchers Discover Potential New Approach To Treating Psoriatic Joint Inflammation (Medicine)

An international team of researchers, led by UC Davis Health, has developed a new therapeutic approach to treating psoriatic arthritis, a chronic inflammatory disease affecting the joints. 

Using a novel chemical blocker targeting chemokine proteins, the researchers were able to significantly reduce skin and joint inflammation in a mouse model with psoriasis and psoriatic arthritis. 

What is psoriatic arthritis?

Psoriatic arthritis affects up to a third of patients with psoriasis, an auto-immune skin inflammation. It creates mobility and functional changes that make it painful for patients to use their hands or walk. Some of these changes are irreversible.

Psoriatic arthritis is tough to treat.

“There is a clear need for better treatments using alternative approaches to joint inflammation,” said Sam T. Hwang, professor and chair of dermatology at UC Davis and senior author of the study. 

Understanding the mechanism behind joint inflammation

Chemokines are small molecules with a critical role in the body’s response to inflammation and infection. They help guide the migration of immune cells to the site of injury or trauma. Chemokines need receptors to function. One specific chemokine receptor is CCR6.

The researchers assessed the role of CCR6 and its binding partner CC chemokine ligand 20 (CCL20) in inflammation linked to psoriatic arthritis and psoriasis. They looked at the potential of the CCR6/CCL20 combo as an effective therapeutic target.

They measured the CCR6 and the CCL20 levels in the joint fluid and tendon tissues of patients with psoriatic arthritis. CCR6 is a critical agent for the migration of T cells – a type of white blood cells – in skin psoriasis. The new study showed that CCR6 plays a similar role in joint inflammation. The team also found that CCL20 is present at very high levels in inflamed joint fluid.

“We observed a significant increase of both CCR6 and CCL20 in the connective tissue of mice with psoriasis and psoriatic arthritis,” Hwang noted. “This high presence was also confirmed in inflamed human tendon biopsies.”

The presence of CCL20 at the site of the inflammation makes it a very attractive target for arthritis therapy.

The connective tissue linking tendons and ligaments with the bones is called the enthesis. It is an important site of inflammation in psoriatic arthritis. The study found that entheses are distinct locations which CCR6+ T cells appear to locate and, therefore, cause inflammation.

“It is critical to identify the specific tissues where inflammation in the joints first occurs before it spreads and damages the cartilage and the bone,” Hwang said.

Blocking the function of the CCR6 chemokine

The researchers tested the ability of a novel engineered protein- known as CCL20 locked dimer (CCL20LD)- in blocking the CCR6 function in a mouse model with psoriatic arthritis. The protein profoundly reduced both skin and joint inflammation by shutting the CCR6’s power to attract T cells.

“The success of CCL2OLD in blocking CCR6 function in a mouse model shows potential for treating psoriatic arthritis in humans,” Hwang said. “Definitely, this requires more testing and clinical trials to explore its effectiveness and safety.”

The study was published in the journal Arthritis & Rheumatology.

Co-authors on this study are Zhenrui Shi at University of California, Davis and Sun Yat-sen University, China; Neal Millar, Emma Garcia-Melchor, Flavia Sunzini and Moeed Akbar at the University of Glasgow; Xuesong Wu, Mimi Nguyen, Douglas Rowland, Machelle Wilson, Mindy Huynh and Timothy Law at the University of California, Davis; Anthony Getschman and Brian Volkman at the Medical College of Wisconsin; Smriti Kundu Raychaudhuri and Siba P. Raychaudhuri at the University of California School of Medicine, Davis, and VA Medical Center Sacramento.

This study was supported by a Pfizer ASPIRE award and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (ROI_AR063091_01A1), a Translational Research Grant from the National Psoriasis Foundation, a New Investigator award from the National Psoriasis Foundation, a Small Business Innovation Research grant (1R43AR074363-01), a grant from National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (UL1 TR001860), a fellowship grant from Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and a Medical Research Council, UK (MR/R020515/1). Hwang is a holder on the patent for CCL20LD and has an unpaid role as medical director at XLock Biosciences, which produces the protein.


Reference: Shi et al. (2021). Targeting the CCR6/CCL20 axis in entheseal and cutaneous Inflammation, Arthritis & Rheumatology, DOI:10.1002/art.41882.


Provided by UC Davis Health

Is Earth’s Core Lopsided? Strange Goings-on In Our Planet’s Interior (Planetary Science)

Model of how Earth’s inner core froze into solid iron implies it may be only 500 million years old

For reasons unknown, Earth’s solid-iron inner core is growing faster on one side than the other, and it has been ever since it started to freeze out from molten iron more than half a billion years ago, according to a new study by seismologists at the University of California, Berkeley.

The faster growth under Indonesia’s Banda Sea hasn’t left the core lopsided. Gravity evenly distributes the new growth — iron crystals that form as the molten iron cools — to maintain a spherical inner core that grows in radius by an average of 1 millimeter per year.

But the enhanced growth on one side suggests that something in Earth’s outer core or mantle under Indonesia is removing heat from the inner core at a faster rate than on the opposite side, under Brazil. Quicker cooling on one side would accelerate iron crystallization and inner core growth on that side.

This has implications for Earth’s magnetic field and its history, because convection in the outer core driven by release of heat from the inner core is what today drives the dynamo that generates the magnetic field that protects us from dangerous particles from the sun.

“We provide rather loose bounds on the age of the inner core — between half a billion and 1.5 billion years — that can be of help in the debate about how the magnetic field was generated prior to the existence of the solid inner core,” said Barbara Romanowicz, UC Berkeley Professor of the Graduate School in the Department of Earth and Planetary Science and emeritus director of the Berkeley Seismological Laboratory (BSL). “We know the magnetic field already existed 3 billion years ago, so other processes must have driven convection in the outer core at that time.”

The youngish age of the inner core may mean that, early in Earth’s history, the heat boiling the fluid core came from light elements separating from iron, not from crystallization of iron, which we see today.

“Debate about the age of the inner core has been going on for a long time,” said Daniel Frost, assistant project scientist at the BSL. “The complication is: If the inner core has been able to exist only for 1.5 billion years, based on what we know about how it loses heat and how hot it is, then where did the older magnetic field come from? That is where this idea of dissolved light elements that then freeze out came from.”

Freezing iron

Asymmetric growth of the inner core explains a three-decade-old mystery — that the crystallized iron in the core seems to be preferentially aligned along the rotation axis of the earth, more so in the west than in the east, whereas one would expect the crystals to be randomly oriented.

Evidence for this alignment comes from measurements of the travel time of seismic waves from earthquakes through the inner core. Seismic waves travel faster in the direction of the north-south rotation axis than along the equator, an asymmetry that geologists attribute to iron crystals — which are asymmetric — having their long axes preferentially aligned along Earth’s axis.

A cut-away of Earth’s interior shows the solid iron inner core (red) slowly growing by freezing of the liquid iron outer core (orange). Seismic waves travel through the Earth’s inner core faster between the north and south poles (blue arrows) than across the equator (green arrow). The researchers concluded that this difference in seismic wave speed with direction (anisotropy) results from a preferred alignment of the growing crystals — hexagonally close packed iron-nickel alloys, which are themselves anisotropic — parallel with Earth’s rotation axis. © Graphic by Daniel Frost

If the core is solid crystalline iron, how do the iron crystals get oriented preferentially in one direction?

In an attempt to explain the observations, Frost and colleagues Marine Lasbleis of the Université de Nantes in France and Brian Chandler and Romanowicz of UC Berkeley created a computer model of crystal growth in the inner core that incorporates geodynamic growth models and the mineral physics of iron at high pressure and high temperature.

“The simplest model seemed a bit unusual — that the inner core is asymmetric,” Frost said. “The west side looks different from the east side all the way to the center, not just at the top of the inner core, as some have suggested. The only way we can explain that is by one side growing faster than the other.”

The model describes how asymmetric growth — about 60% higher in the east than the west — can preferentially orient iron crystals along the rotation axis, with more alignment in the west than in the east, and explain the difference in seismic wave velocity across the inner core.

“What we’re proposing in this paper is a model of lopsided solid convection in the inner core that reconciles seismic observations and plausible geodynamic boundary conditions,” Romanowicz said.

Frost, Romanowicz and their colleagues will report their findings in this week’s issue of the journal Nature Geoscience.

Probing Earth’s interior with seismic waves

Earth’s interior is layered like an onion. The solid iron-nickel inner core — today 1,200 kilometers (745 miles) in radius, or about three-quarters the size of the moon — is surrounded by a fluid outer core of molten iron and nickel about 2,400 kilometers (1,500 miles) thick. The outer core is surrounded by a mantle of hot rock 2,900 kilometers (1,800 miles) thick and overlain by a thin, cool, rocky crust at the surface.

Convection occurs both in the outer core, which slowly boils as heat from crystallizing iron comes out of the inner core, and in the mantle, as hotter rock moves upward to carry this heat from the center of the planet to the surface. The vigorous boiling motion in the liquid-iron outer core produces Earth’s magnetic field.

According to Frost’s computer model, which he created with the help of Lasbleis, as iron crystals grow, gravity redistributes the excess growth in the east toward the west within the inner core. That movement of crystals within the rather soft solid of the inner core — which is close to the melting point of iron at these high pressures — aligns the crystal lattice along the rotation axis of Earth to a greater degree in the west than in the east.

The model correctly predicts the researchers’ new observations about seismic wave travel times through the inner core: The anisotropy, or difference in travel times parallel and perpendicular to the rotation axis, increases with depth, and the strongest anisotropy is offset to the west from Earth’s rotation axis by about 400 kilometers (250 miles).

The model of inner core growth also provides limits on the proportion of nickel to iron in the center of the earth, Frost said. His model does not accurately reproduce seismic observations unless nickel makes up between 4% and 8% of the inner core — which is close to the proportion in metallic meteorites that once presumably were the cores of dwarf planets in our solar system. The model also tells geologists how viscous, or fluid, the inner core is.

“We suggest that the viscosity of the inner core is relatively large, an input parameter of importance to geodynamicists studying the dynamo processes in the outer core,” Romanowicz said.

Frost and Romanowicz were supported by grants from the National Science Foundation (EAR-1135452, EAR-1829283).

Featured image: A new model by UC Berkeley seismologists proposes that Earth’s inner core grows faster on its east side (left) than on its west. Gravity equalizes the asymmetric growth by pushing iron crystals toward the north and south poles (arrows). This tends to align the long axis of iron crystals along the planet’s rotation axis (dashed line), explaining the different travel times for seismic waves through the inner core. © Graphic by Marine Lasbleis


Reference: Frost, D.A., Lasbleis, M., Chandler, B. et al. Dynamic history of the inner core constrained by seismic anisotropy. Nat. Geosci. (2021). https://doi.org/10.1038/s41561-021-00761-w


Provided by University of California Berkeley

New Study Further Advances the Treatment of Chronic Pain (Medicine)

LIH and RTI International put forward the mode of action of natural painkiller conolidine, and develop new molecule with enhanced pharmacological properties 

Building on their previous findings, scientists from the Immuno-Pharmacology and Interactomics group at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH), in collaboration with the Center for Drug Discovery at RTI International (RTI), a nonprofit research institute, have demonstrated that conolidine, a natural painkiller derived from the pinwheel flower and traditionally used in Chinese medicine, interacts with the newly identified opioid receptor ACKR3/CXCR7 that regulates opioid peptides naturally produced in the brain. The researchers also developed a synthetic analogue of conolidine, RTI-5152-12, which displays an even greater activity on the receptor. These findings, which were published on June 3rd in the prestigious international journal ‘Signal Transduction and Targeted Therapy’ (Nature publishing group), further advance the understanding of pain regulation and open alternative therapeutic avenues for the treatment of chronic pain. 

Opioid peptides are small proteins that mediate pain relief and emotions, including euphoria, anxiety, stress and depression, by interacting with four classical receptors (“molecular switches”) in the brain. Dr Andy Chevigné, Head of Immuno-Pharmacology and Interactomics, and his team had previously identified the chemokine receptor ACKR3 as a novel fifth atypical opioid receptor, with high affinity for various natural opioids (Nature Communications, Meyrath et al. 2020). ACKR3 functions as a ‘scavenger’ that ‘traps’ the secreted opioids and prevents them from binding to the classical receptors, thereby dampening their analgesic activity and acting as a regulator of the opioid system.

In the current study, the researchers identified ACKR3 as the most responsive target for conolidine, an alkaloid with analgesic properties, by screening over 240 receptors for their ability to be activated or inhibited by this molecule.

We confirmed that conolidine binds to the newly identified opioid receptor ACKR3, while showing no affinity for the other four classical opioid receptors. By doing so, conolidine blocks ACKR3 and prevents it from trapping the naturally secreted opioids, which in turn increases their availability for interacting with classical receptors. We believe that this molecular mechanism is at the basis of the beneficial effects of this traditionally used medicine on pain relief”, said Dr Martyna Szpakowska, first author of the publication and scientist within the LIH Immuno-Pharmacology and Interactomics group.

In parallel to characterising the interaction between conolidine and ACKR3, the two teams went a step further. The scientists developed a modified variant of conolidine — which they called “RTI-5152-12” — which exclusively binds to ACKR3 with an even higher affinity. Like LIH383, a patented compound previously developed by Dr. Andy Chevigné and his team, RTI-5152-12 is postulated to increase the levels of opioid peptides that bind to classical opioid receptors in the brain, resulting in heightened painkilling activity. The LIH-RTI research teams established a collaboration agreement and filed a joint patent application in December 2020.

The discovery of ACKR3 as a target of conolidine further emphasises the role of this newly discovered receptor in modulating the opioid system and, consequently, in regulating our perception of pain”, said Dr. Chevigné, corresponding author of the publication and leader of the LIH Immuno-Pharmacology and Interactomics group.

Our findings could also mean that conolidine, and potentially also its synthetic analogues, could carry new hope for the treatment of chronic pain and depression, particularly given the fact that conolidine was reported to trigger fewer of the detrimental side-effects — namely addiction, tolerance and respiratory problems —  associated with commonly used opioid drugs like morphine and fentanyl”.

Our work could therefore set the basis for the development of a new class of drugs with alternative mechanism of action, thereby contributing to tackling the public health crisis linked to the increasing misuse of and addiction to opioid drugs”, says Dr. Ojas Namjoshi, co-corresponding author of the publication and lead scientist on the study at RTI.

Once again, we have built on the findings of our excellent fundamental research and translated them into applications with the potential of tangibly improving clinical outcomes for patients”, said Prof Markus Ollert, Director of the LIH Department of Infection and Immunity. “We are grateful to the Luxembourg National Research Fund, the Ministry of Higher Education and Research and the European Commission for the generous support”.   


FUNDING AND RESEARCH TEAMS

This study was supported by funds from the Luxembourg Institute of Health (LIH), the Luxembourg National Research Fund (Pathfinder “LIH383”, INTER/FWO “Nanokine” grant 15/10358798, INTER/FNRS grants 20/15084569, PoC “Megakine” 19/14209621, PRIDE 11012546 “NextImmune” and 14254520 “I2TRON”), F.R.S.-FNRS-Télévie (grants 7.4593.19, 7.4529.19 and 7.8504.20) and by RTI International Internal Research and Development Funds (awarded to O. Namjoshi). M. Meyrath and C. Palmer are Luxembourg National Research Fund PhD fellows (grants AFR-3004509 and AFR-14616593). C. Palmer is part of the Marie Skłodowska-Curie Actions – Innovative Training Networks ONCORNET2.0 “ONCOgenic Receptor Network of Excellence and Training” (MSCA-ITN-2020-ETN). The authors wish to thank Manuel Counson for technical assistance in binding competition experiments.

The study was performed in close collaboration with the Center for Drug Discovery of RTI International (USA).


Reference: Szpakowska, M., Decker, A.M., Meyrath, M. et al. The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7. Sig Transduct Target Ther 6, 209 (2021). https://doi.org/10.1038/s41392-021-00548-w


Provided by Luxembourg Institute of Health

Is Elevated Level of Lung Protein an Early Predictor for COPD? (Medicine)

The UNC School of Medicine lab of Mehmet Kesimer, PhD, discovered MUC5AC is more reliably associated with the manifestation of COPD than another well-known mucus protein, revealing a possible biomarker of disease initiation, prognosis, and therapueutic effectiveness.

Airway mucus consists of various proteins such as long mucins MUC5AC and MUC5B, both of which contribute greatly to the proper gel-like consistency of this most essential bodily fluid. UNC School of Medicine researchers led by mucin expert Mehmet Kesimer, PhD, had previously discovered that the total mucin concentrations in the lungs are associated with COPD disease progression and could be used as diagnostic markers of chronic bronchitis, a hallmark condition for patients with COPD. Kesimer and colleagues now report that one of these mucins, MUC5AC, is more closely and reliably associated with the development of COPD than is its brother, MUC5B.

The research, published in The Lancet Respiratory Medicine, shows that MUC5AC is found at elevated levels in smokers who had not yet developed COPD but whose lung function wound up decreasing over the course of the three-year study. Former smokers at-risk for COPD, on the other hand, had normal levels of MUC5AC at the start of the study and maintained proper lung function over three years. MUC5AC hyperconcentration in the lungs may be a key factor in predicting the risks and rates of progression to more severe disease, according to the study.

Recent nationwide efforts have focused on early- or pre-COPD to predict the risks of progression to COPD amongst smokers.

“Currently, we cannot forecast which individuals in the at-risk smokers group will progress to COPD because we don’t have an objective biological marker to underpin the disease-causing pathways. Our research shows that MUC5AC could be a predictor of who will develop COPD from the large group of aging “at-risk” smokers,” said Kesimer, senior author of the study, professor in the UNC Department of Pathology and Laboratory Medicine, and member of the UNC Marsico Lung Institute. “We think MUC5AC could be a new biomarker for COPD prognosis and it could be a biomarker for testing the effectiveness of therapeutic strategies.”

MUC5AC could also become a target for pharmaceutical developers whose goal it is to halt COPD disease progression and help patients live more normal, active lives.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease that causes obstructed airflow from the lungs and affects about 16 million people in the United States. Symptoms include breathing difficulty, coughing, mucus production, and wheezing. It’s typically caused by long-term exposure to irritants, such as particulate matter like cigarette smoke. The two main conditions that contribute to COPD are chronic bronchitis, an inflammation of the lining of the bronchial tubes due to chronic mucin/mucus accumulation; and emphysema, when the tiny air sacs at the end of the smallest air passages of the lungs are destroyed.

There are some treatment options for COPD to attempt to slow disease progression and reduce symptoms, but treatments often don’t work well, especially during late stages of the condition, and there is no cure.

The Kesimer Lab in the UNC Marsico Lung Institute uses various techniques, including mass spectrometry, to identify and measure the different biological mechanisms involved in lung conditions. For this study, the UNC team of scientists were able to measure the concentrations of MUC5AC and MUC5B in different groups of people, including people who had never smoked cigarettes, who had quit smoking, and who continue to smoke with or without COPD.

Smoking cigarettes has long been known to be a major risk factor for COPD, but Kesimer’s work suggests that quiting smoking decreases the odds of developing COPD as we age.

“Our data indicate that increased MUC5AC concentrations in the airways may

contribute to the initiation of COPD, as well as disease progression, symptom exacerbation, and how the disease progesses over time, in general,”Kesimer said. “We did not observe the same association with MUC5B.”

The best thing an aging person can do to avoid the inevitable decline associated COPD is quit smoking immediately before airway obstruction sets in due to mucin/mucus accumulation. Through Kesimer’s work, though, it might be possible to pinpoint which individuals are at the highest immediate risk for developing COPD soon.

Giorgio Radicioni, Agathe Ceppe, Amina A. Ford, Neil Alexis, Esin Ozkan, Wanda O’Neal and Richard C. Boucher were other significant contributors to this study from the UNC Marsico Lung Institute. A total 20 authors from 14 different institutions contributed to the study as a part of a nationwide COPD study called SPIROMICS.

The National Heart, Lung, and Blood Institute, part of the National Institutes of Health, funded this work.

Featured image: Mucin proteins (green) in a sample of airway mucus. © UNC Health


  • Reference: Giorgia Radicioni, Agathe Ceppe et al., “Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort”, The Lancet, 2021. DOI: https://doi.org/10.1016/S2213-2600(21)00079-5

Provided by UNC Health

Research Reveals, New IgM Antibodies Administered Intranasally to Fight COVID-19 More Potent Than Commonly Used Ones (Medicine)

A nasal therapy, built upon on the application of a new engineered IgM antibody therapy for COVID-19, was more effective than commonly used IgG antibodies at neutralizing the COVID-19 virus in animal models, according to research recently published by The University of Texas Health Science Center at Houston (UTHealth), The University of Texas Medical Branch at Galveston (UTMB Health), the University of Houston, and IGM Biosciences, Inc. 

The study was published today in Nature.

Researchers engineered IgM antibodies and found that in all cases, these antibodies were significantly more potent than standard IgG antibodies in neutralizing the COVID-19 virus. One of the engineered IgM antibodies, IGM-6268, demonstrated a significantly increased potency against the original SARS-CoV-2 and emerging variants such as the current U.K., South African, and Brazilian variants of concern (VOC) and variants of interest (VOI), as well as the antibody escape mutants for the current Emergency Use Authorization antibodies. Additionally, IGM-6268 was shown to be highly effective for prophylaxis and treatment in mouse models when administered intranasally. 

“High viral load in the respiratory tract correlates with severe illness and mortality in patients with COVID-19,” said Zhiqiang An, PhD, director of UTHealth Texas Therapeutics Institute, professor and Robert A. Welch Distinguished University Chair in Chemistry at McGovern Medical School at UTHealth, and faculty member at MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences and one of the corresponding authors on the study. “Respiratory mucosal antibodies are key to clearing SARS-CoV-2 infection and reducing viral transmission and IgM antibodies are nature’s first line of defense against pathogens such as viruses.”

The current government-approved antibodies, which are all IgG antibodies, are administered intravenously at high doses and don’t directly target the main sites of viral infection.

“SARS-CoV-2 has evolved mutations that severely compromise the neutralizing activities of multiple IgG monoclonal antibodies, including those under clinical trials and authorized for emergency use. Therefore, developing new antibody therapies that can overcome these challenges is an urgent unmet need, and we are pleased with the data published today,” An said.

“Synergizing the strengths of multiple institutions from academia and industry is the key to the rapid translation from ideas to therapeutic candidates. This is another example of such success. The cross-institutional and academic-industry collaborations should be expanded to other disease indications,” said Pei-Yong Shi, PhD, professor and co-senior author of the study from the Department of Biochemistry and Molecular Biology at UTMB Health.

This antibody has been licensed to biotech partner IGM Biosciences for drug development.

“The ability to use potently neutralizing IgM antibodies against SARS-CoV-2 with broad coverage of VOCs, VOIs, and viral escape mutants, is a very exciting application of the IGM platform,” said Fred Schwarzer, CEO of IGM Biosciences. “We are grateful to our collaborators at UTHealth, UTMB Health, and our scientists at IGM for the exceptional work described in Nature today.”

Additional UTHealth authors: Zhiqiang Ku, PhD; Xiaohua Ye, PhD; Wei Xiong, MD, PhD; Junquan Liu, PhD; Ningyan Zhang, PhD; Hang Su, and Hui Deng.  

Other authors include Xuping Xie, PhD; Antonio E. Muruato, PhD; Jing Zou, PhD; Yang Liu, PhD; and Vineet D. Menachery, PhD, with UTMB Health; Xinli Liu, PhD; and Sujit Biswaswith the University of Houston; and Paul R. Hinton; Dean C. Ng, PhD; Yu-An Cao, PhD; Kevin B. Carlin, PhD; Elizabeth J. Haanes, PhD; Bruce A. Keyt, PhD; Stephen F. Carroll, PhD; Deepal Pandya, and Sachi Rahman with IGM Biosciences.

The work was supported by grants from the Cancer Prevention and Research Institute of Texas, the National Institutes of Health, the Welch Foundation, the Sealy Smith Foundation, the Kleberg Foundation, the John S. Dunn Foundation, the Amon G. Carter Foundation, the Gillson Longenbaugh Foundation, and the Summerfield Robert Foundation.

Featured image: Zhiqiang An, PhD, was one of the lead authors of a study that revealed engineered IgM antibodies were more potent than standard ones against COVID-19. (Photo by UTHealth)


Provided by UT Health

How To Obtain Immune Bovine Milk to Strengthen The Body Against COVID-19 (Food)

Physiologically, milk contains biocomponents that are highly protective against infections. In light of this, the AGR-149-Infectious Diseases group at the University of Cordoba’s Department of Animal Health is doing research that focuses on cow’s milk as a possible source of Covid-19 control. The results have been published, partially, in the journal Frontiers in Immunology.

This is possible due to “crossed immunity”, and there is already evidence of the protection it provides, explained one of the principal investigators, Mari Carmen Borge. “It has been shown that the immune cells that the vaccinated animal generates against bovine coronavirus are capable of controlling other coronaviruses as well, such as SARS-CoV-2, which causes Covid-19”.

Antonio Arenas, principal investigator on the project, spoke of the similarity that exists between Bovine Coronavirus (BCoV) and SARS-CoV-2 to explain the effectiveness of this technique. “There are a number of highly conserved structures of the virus that are similar in both viruses. In fact, both belong to the genus Betacoronavirus. Thus, cow’s milk could have a total or partial blocking action against SARS-CoV-2”.

In this way, these bovine antibodies could neutralize the virus in people who are already infected, or help prevent the disease in those who have not been vaccinated, or who have been, but have not developed immunity.

Thus, the aim is to come up with a supplement that would boost the immune system through a dairy preparation with a high level of antibodies, helping the system control infection through different immune pathways.

The animals from which the milk is extracted have been previously vaccinated with commercial BCoV vaccines, thus generating high levels of antibodies. However, the time when milk is most effective is just after a birth: “then the level of immunoglobulin in the milk increases – what is called colostrum – but it has a certain duration,” Arenas added.

Now the scientific challenge is to be able to extend the colostrum period, and also to study how to always ensure the same level of antibodies in the final product. Plans call for it to be marketed in single-dose format as of September. “For this, we have to readjust the reproduction cycles of bovine farms in order to always maintain a set of animals with high antibodies”, the researcher explained.

This dairy preparation, which anyone can consume, has already been tested on more than 300 people. Amongst them, no serious Covid-19 process has been detected. As soon as it goes on the market an observational test will be carried out. In any case, it will not be harmful to health, and it could become a natural resource providing people with a certain level of immunity.

There are other technological challenges: herd management, hygiene processes, conservation, packaging, marketing, medical, etc., that make this a holistic and complex project.


Reference: Arenas A, Borge C, Carbonero A, Garcia-Bocanegra I, Cano-Terriza D, Caballero J, Arenas-Montes A. (2021) Bovine Coronavirus Immune Milk Against COVID-19. Front Immunol. DOI: 10.3389/fimmu.2021.637152


Provided by University of Cordoba