Which Way Does The Solar Wind Blow? (Planetary Science)

Using supercomputers, researchers develop new software for improved space weather prediction

The surface of the sun churns with energy and frequently ejects masses of highly-magnetized plasma towards Earth. Sometimes these ejections are strong enough to crash through the magnetosphere — the natural magnetic shield that protects the Earth — damaging satellites or electrical grids. Such space weather events can be catastrophic.

Astronomers have studied the sun’s activity for centuries with greater and greater understanding. Today, computers are central to the quest to understand the sun’s behavior and its role in space weather events.

The bipartisan PROSWIFT (Promoting Research and Observations of Space Weather to Improve the Forecasting of Tomorrow) Act, passed into law in October 2020, is formalizing the need to develop better space weather forecasting tools.

“Space weather requires a real-time product so we can predict impacts before an event, not just afterward,” explained Nikolai Pogorelov, distinguished professor of Space Science at The University of Alabama in Huntsville, who has been using computers to study space weather for decades. “This subject – related to national space programs, environmental, and other issues – was recently escalated to a higher level.”

To many, space weather may seem like a distant concern, but like a pandemic — something we knew was possible and catastrophic — we may not realize its dangers until it’s too late.

“We don’t think about it, but electrical communication, GPS, and everyday gadgets can be effected by extreme space weather effects,” Pogorelov said.

Furthermore, the U.S. is planning missions to other planets and the moon. All will require very accurate predictions of space weather – for the design of spacecraft and to alert astronauts to extreme events.

With funding from the National Science Foundation (NSF) and NASA, Pogorelov leads a team working to improve the state-of-the-art in space weather forecasting.

The coronal mass ejection threaded by magnetic field lines in the equatorial slice colored by plasma temperature. [From Space Weather April 2020, with permission of the American Geophysical Union.]

“This research, blending intricate science, advanced computing and exciting observations, will advance our understanding of how the Sun drives space weather and its effects on Earth,” said Mangala Sharma, Program Director for Space Weather in the Division of Atmospheric and Geospace Sciences at NSF. “The work will help scientists predict space weather events and build our nation’s resilience against these potential natural hazards.”

The multi-institutional effort involves the NASA Goddard and Marshall Space Flight Centers, Lawrence Berkeley National Laboratory, and two private companies, Predictive Science Inc. and Space Systems Research Corporation.

Pogorelov uses the Frontera supercomputer at the Texas Advanced Computing Center (TACC) — the ninth fastest in the world — as well as at both the NASA Advanced Supercomputing (NAS) Facility at NASA’s Ames Research Center, and the San Diego Supercomputing Center, to improve the models and methods at the heart of space weather forecasting.

Turbulence plays a key role in the dynamics of the solar wind and coronal mass ejections. This complex phenomenon has many facets, including the role of shock-turbulence interaction and ion acceleration.

“Solar plasma is not in thermal equilibrium. This creates interesting features,” Pogorelov said.

Writing in the Astrophysical Journal in April 2021, Pogorelov, along with Michael Gedalin (Ben Gurion University of the Negev, Israel), and Vadim Roytershteyn (Space Science Institute) described the role of backstreaming pickup ions in the acceleration of charged particles in the universe. Backstreaming ions, either of interstellar or local origin, are picked up by the magnetized solar wind plasma and move radially outwards from the Sun.

“Some non-thermal particles can be further accelerated to create solar energetic particles that are particularly important for space weather conditions on Earth and for people in space,” he said.

Pogorelov performed simulations on Frontera to better understand this phenomenon and compare it with observations from Voyager 1 and 2, the spacecraft that explored the outer reaches of the heliosphere and are now providing unique data from the local interstellar medium.

One of the major focuses of space weather prediction is correctly forecasting the arrival of coronal mass ejections — the release of plasma and accompanying magnetic field from the solar corona — and determining the direction of the magnetic field it carries with it. Pogorelov’s team’s study of backstreaming ions help to do so, as does work published in the Astrophysical Journal in 2020 that used a flux rope-based magnetohydrodynamic model to predict the arrival time to Earth and magnetic field configuration of the July 12, 2012 coronal mass ejection. (Magnetohydrodynamics refers the magnetic properties and behavior of electrically conducting fluids like plasma, which plays a key role in dynamics of space weather).

“Fifteen years ago, we didn’t know that much about the interstellar medium or solar wind properties,” Pogorelov said. “We have so many observations available today, which allow us to validate our codes and make them much more reliable.”

Magnetic field line configuration of the coronal mass ejection inserted at the inner boundary R = 0.1 AU, shown with the red sphere. [Credit: Talwinder Singh, Tae K. Kim , Nikolai V. Pogorelov , and Charles N. Arge, with permission of the American Geophysical Union]

Pogorelov is a co-investigator on an on-board component of the Parker Solar Probe called SWEAP (Solar Wind Electrons, Protons, and Alphas instrument). With each orbit, the probe approaches the sun, providing new information about the characteristics of the solar wind.

“Soon it will penetrate beyond the critical sphere where the solar wind becomes superfast magnetosonic, and we’ll have information on the physics of solar wind acceleration and transport that we never had before,” he said.

As the probe and other new observational tools become available, Pogorelov anticipates a wealth of new data that can inform and drive the development of new models relevant to space weather forecasting. For that reason, alongside his basic research, Pogorelov is developing a software framework that is flexible, useable by different research groups around the world, and can integrate new observational data.

“No doubt, in years to come, the quality of data from the photosphere and solar corona will be improved dramatically, both because of new data available and new, more sophisticated ways to work with data,” he said. “We’re trying to build software in a way that if a user comes up with better boundary conditions from new science missions, it will be easier for them to integrate that information.”

Featured image: (Top panel, from left to right) July 12, 2012 coronal mass ejection seen in STEREO B Cor2, SOHO C2, and STEREO A Cor2 coronagraphs, respectively. (Bottom panel) The same images overlapped with the model results. [Credit: Talwinder Singh, Mehmet S. Yalim, Nikolai V. Pogorelov, and Nat Gopalswamy, with permission of The American Astronomical Society]


References:

(1) Singh, T., Kim, T. K., Pogorelov, N. V., & Arge, C. N. (2020). Application of a modified spheromak model to simulations of coronal mass ejection in the inner heliosphere. Space Weather, 18, e2019SW002405. https://doi.org/10.1029/2019SW002405

(2) Singh, T., Yalim, M. S., Pogorelov, N. V., and Gopalswamy, N., A Modified Spheromak Model Suitable for Coronal Mass Ejection Simulations, The Astrophysical Journal, vol. 894, no. 1, 2020. doi:10.3847/1538-4357/ab845f.


Provided by TACC

Fish Oil Taken During Pregnancy Boosts Brain Function in Children at Age 10 (Food)

Children born to mothers who took fish oil in their pregnancies have been shown to have faster problem-solving skills and better attention focus at age 10, according to findings from a study presented today at the 6th World Congress of Paediatric Gastroenterology, Hepatology and Nutrition.

This is the first study to examine the long-term effect of maternal supplementation with fish oil and/or 5-MTHF (folic acid) on the resting state network (RSN) functioning (this is ‘resting’ brain activity when a person is not engaged in a cognitive or active task) of children at school age and was funded by the European Union.

The children were assessed at age 10 using specialist rs-MRI brain scanning to measure RSN, alongside neuropsychological testing. The results of all groups were then compared for differences.

Professor Dr. Berthold Koletzko, Head of the Division of Metabolic and Nutritional Medicine at Dr. von Hauner Children’s Hospital, University of Munich Medical Centre, Munich, Germany, is one of the study’s authors. Professor Koletzko says that children born to mothers taking the DHA-rich fish oil in pregnancy showed beneficial effects with faster processing speed when solving complex problems, and better results in attention tests.

‘The results demonstrate that the quality of maternal nutrient supply during the period of rapid early brain development in pregnancy, has a lasting impact on later brain function at school age.

Therefore, women before and during pregnancy should be supported in achieving a good quality diet and be counselled on potential fish oil supplement use.’

Coordinator of the study and Director of the EURISTIKOS Excellence Centre for Paediatric Research at the University of Granada, Spain, Professor Christina Campoy, adds: ‘Our research provides evidence that children born to mothers who had taken fish oil during the second half of pregnancy had improved memory. Fish oil supplementation was associated with lesser functional connectivity of children’s brain networks, but this did not indicate poor cognitive neurodevelopment, rather the opposite.’

Folic acid supplementation did not lead to appreciable modification of brain function measures.

The study by researchers at the University of Granada, Spain, followed up on 57 children of mothers from a previous research programmeii who had been given 500mg of docosahexaenoic acid (DHA) and 150mg of eicosapentaenoic acid (EPA) fish oils per day, either with or without 400 μg of 5-MTHF (folic acid), folic acid alone, or placebo, during the second half of their pregnancies.

The authors stressed that although the sample size was small, a large number of validated techniques had been used to assess their hypothesis in the study and the data came from a well-established cohort (a group that is being followed up long term). They added that the results should be interpreted as preliminary data and cannot be considered to have general application, with further research being required.

Professor Magnus Domellöf, Chair of the ESPGHAN Nutrition Committee, commented on the research: ‘The results from this study indicate that early nutrition during pregnancy can have a significant impact on brain development in children, with the potential to enhance cognitive performance. We look forward to the outcomes of this study being tested in further trials.’


References:

(1) Campoy, C., et al. 2021. Long-term association between fish oil and/or 5-methyl-tetrahydrofolate supplementation during pregnancy and offspring brain resting state at 10 years old. Presented at the 6th World Congress of Paediatric Gastroenterology, Hepatology and Nutrition. (2) Decsi T, Campoy C, Koletzko B. Effect of N-3 polyunsaturated fatty acid supplementation in pregnancy: the Nuheal trial. Adv Exp Med Biol. 2005;569:109-13. doi: 10.1007/1-4020-3535-7_15.


Provided by ESPGHAN

How DNA Opens While Wrapped Around Proteins? (Biology)

Researchers from the Hubrecht Institute in Utrecht (The Netherlands) and the Max Planck Institute for Molecular Biomedicine in Münster (Germany) used computer simulations to reveal in atomic detail how a short piece of DNA opens while it is tightly wrapped around the proteins that package our genome. These simulations provide unprecedented insights into the mechanisms that regulate gene expression. The results were published in PLoS Computational Biology on the 3rd of June.

Every cell in the body contains two meters of DNA. In order to fit all the DNA in the cell’s small nucleus, the DNA is tightly packed in a structure known as chromatin. Chromatin is an array of identical smaller structures named nucleosomes. In a single nucleosome, DNA is wrapped around 8 proteins called histones. Chromatin is not uniformly compact across the genome. The tightness of the packaging is important in regulating which genes are expressed and therefore which proteins are produced by a cell.

Transitions from tightly to loosely packed DNA – from closed to open chromatin – are essential for cells to convert to another cell type. These cell conversions are hallmarks of development and disease, but are also often used in regenerative therapies. Understanding how such transitions occur may contribute to understanding diseases and optimizing therapeutical cell type conversions.

Computational nanoscope

One step in the opening of chromatin is the motion of DNA while wrapped in nucleosomes. Like all molecular structures in our cells, nucleosomes are dynamic. They move, twist, breathe, unwrap and wrap again. Visualizing these motions using experimental methods is often very challenging. One alternative is to use the so-called “computational nanoscope”

Researchers use the term computational nanoscope to refer to a set of computer simulation methods. These methods enable them to visualize the movements of molecules over time. Over the past years, the methods have become so accurate that researchers started referring to them as a computational nanoscope; observing the molecules moving on the computer is similar to observing them under a very high resolution nanoscope.

Nucleosomes breathing

Jan Huertas and Vlad Cojocaru, supported by Hans Schöler from the Max Planck Institute for Molecular Biomedicine (Münster, Germany), generated multiple real-time movies of the movements of nucleosomes, each covering one microsecond from the nucleosome lifetime. Using these movies, they monitored how the nucleosomes open and close in a motion known as nucleosome breathing.

In their new paper, published in PLoS Computational Biology, Huertas and Cojocaru describe what causes nucleosome breathing. First, they found that the order in which the building blocks of DNA are arranged – the DNA sequence – is important for nucleosome breathing.  Second, the dynamics of histone tails are essential for this process. These histone tails are flexible regions in the histones that play a role in the regulation of gene expression. While the role of histone tails has been studied intensively, little is known about how they influence the motions of single nucleosomes. With their simulations, Huertas and Cojocaru described the relationship between histone tails and nucleosome breathing in atomic detail.

Histone modifications

“Being able to observe the breathing of nucleosomes in computer simulations is very challenging. The fact that we have now been able to visualize this represents a major step towards simulating the complete spectrum of nucleosome dynamics, from breathing to unwrapping. It also allows us to study how these motions are affected by modifications of the histones, which occur in different cells and regions of our DNA. Our simulations revealed that two histone tails are responsible for keeping the nucleosome closed. Only when these flexible tails moved away from particular regions of DNA, the nucleosome was able to open,” says research leader Cojocaru.

Huertas, first author in the publication and recent PhD-graduate, adds: “Active (open) and inactive (closed) chromatin contain different modifications of histone tails. The next step is to perform simulations with such modifications. The atomic resolution of the simulations would allow us to pinpoint how each modification affects nucleosomes and chromatin dynamics.”

Towards understanding epigenetics

All three researchers are excited about the future of the use of atomistic computer simulations in understanding gene expression mechanisms in development and disease. “With the further increase of computational power available in the world, we will soon be able to simulate milliseconds of a nucleosome lifetime with all its atoms included. Furthermore, we will be able to routinely simulate multiple nucleosomes to study the effect of different modifications of histones on gene expression. This will give unprecedented insights into the mechanisms that regulate gene expression,” Cojocaru concludes.

Featured image: This image shows three microseconds from the life time of a nucleosome. Snapshots in time were taken every 4 nanoseconds and were superimposed on the core region of the histones (white). The positions of the DNA (yellow) and the flexible histone tails (blue, green, red, orange, cyan) in all snapshots are shown. The ample motion of the DNA arms is known as nucleosome breathing motion. Remarkably, in this nucleosome, the lower arm moves more than the upper one due to the DNA sequence. Credit: Jan Huertas and Vlad Cojocaru, ©MPI for Molecular Biomedicine, ©Hubrecht Institute.


Publication

Huertas J, Schöler HR, Cojocaru V (2021) Histone tails cooperate to control the breathing of genomic nucleosomes. PLoS Comput Biol 17(6): e1009013. doi:10.1371/journal.pcbi.1009013


Provided by Hubrecht Institute

70-year-old Coffee-killing Fungus Brought Back To Life To Fight the Disease (Biology)

Researchers have re-animated specimens of a fungus that causes coffee wilt to discover how the disease evolved and how its spread can be prevented.

Coffee Wilt Disease is caused by a fungus that has led to devastating outbreaks since the 1920s in sub-Saharan Africa, and currently affects two of Africa’s most popular coffee varieties: Arabica and Robusta.

“If we can understand how new types of diseases evolve, we can give growers the knowledge they need to reduce the risk of new diseases emerging.”

— Lily Peck

The new research shows that the fungus likely boosted its ability to infect coffee plants by acquiring genes from a closely related fungus, which causes wilt disease on a wide range of crops, including Panama disease in bananas.

The researchers say this knowledge could help farmers reduce the risk of new disease strains emerging, for example by not planting coffee together with other crops or by preventing the build-up of plant debris that could harbour the related fungus.

Sustainable solutions

The research team, from Imperial College London, the University of Oxford, and the agricultural not-for-profit CABI, also say that studying historical samples in CABI’s culture collection could provide a wealth of insights into how crop diseases evolve and find new, sustainable ways to fight them. The study is published today in BMC Genomics.

First author of the study Lily Peck is studying on the Science and Solutions for a Changing Planet Doctoral Training Partnership at the Grantham Institute and the Department of Life Sciences at Imperial. She said: “Using ever-higher volumes of chemicals and fungicides to fight emerging crop diseases is neither sustainable nor affordable for many growers.

“If we can instead understand how new types of diseases evolve, we can give growers the knowledge they need to reduce the risk of new diseases emerging in the first place.”

Coffee-specific strains

The team re-animated cryogenically frozen samples of the fungus that causes Coffee Wilt Disease. There have been two serious outbreaks of the disease, in the 1920s-1950s and between the 1990s-2000s, and it still causes damage.

Coffee berries on a branch, some green and some turning dark red
Early ripening of berries is an indication the disease is taking hold. Credit: CABI

For example, in 2011, 55,000 Robusta coffee trees were killed by wilt in Tanzania, destroying 160T of coffee in the process – equivalent to over 22 million cups of coffee.

In the outbreak beginning in the 1920s, Coffee Wilt Disease infected a wide range of coffee varieties, and was eventually brought under control in the 1950s by management practices such as burning infected trees, seeking natural resistance in coffee, and breeding programs that selected for more resistant plant varieties.

However, the disease re-emerged in the 1970s and spread extensively through the 1990s-2000s. Two separate disease populations have been identified with each only infecting specific types of coffee: one infecting Arabica coffee in Ethiopia, and the other infecting Robusta coffee in east and central Africa. The team wanted to investigate how the two strains had emerged.

Swapping genes

In a secure lab at CABI, they re-awakened two strains from the original outbreak, collected in the 1950s and deposited into CABI’s collection, and two strains each from the two coffee-specific fungal strains, with the most recent from 2003. They then sequenced the genomes of the fungi and examined their DNA for evidence of changes that could have helped them infect these specific coffee varieties.

They discovered the newer, variety-specific fungi have larger genomes than the earlier strains, and they identified genes that could have helped the fungi overcome plants’ defences and survive within the plants to trigger disease.

A coffee plant with no leaves and dark berries
A tree with wilt. Credit: CABI

These genes were also found to be highly similar to those found in a different, closely related fungus that affects over 120 different crops, including bananas in sub-Saharan Africa, causing Panama disease, which is currently devastating today’s most popular variety, the Cavendish banana.

While strains of this banana-infecting fungus are known to be able to swap genes, conferring the ability to infect new varieties, the potential transfer of their genes to a different species of fungi has not been seen before.

However, the team note that the two species sometimes live in close proximity on the roots of coffee and banana plants, and so it is possible that the coffee fungus gained these advantageous genes from its normally banana-based neighbour.

Coffee and bananas are often grown together, as coffee plants like the shade provided by the taller banana plants. The researchers say their study could suggest not growing crops with closely related diseases together, like banana and coffee, could reduce the possibility of new strains of coffee-killing fungi evolving.

The evolution of outbreaks

The researchers are now using the re-animated strains to infect coffee plants in the lab, in order to study exactly how the fungus infects the plant, potentially providing other ways to prevent the disease taking hold.

“Our aim is to replicate this study for many plant pathogens, eventually drawing up a ‘rule book’ of how pathogenicity evolves, helping us to prevent future outbreaks where possible.”

— Professor Timothy Barraclough

The insights could also be applied to different crop plants, where other closely related plant pathogens could make similar leaps, causing new diseases to emerge. Having shown the value of examining historical specimens of plant disease, the team plan to replicate the study with other diseases stored in CABI’s collection, which hosts 30,000 specimens collected from around the world over the past 100 years.

Lead researcher Professor Timothy Barraclough, from the Department of Zoology at Oxford and the Department of Life Sciences at Imperial, said: “The historical approach shows us what happens to a plant pathogen before and after a new outbreak of disease occurs. We can then study the mechanisms of evolution and improve predictions of how similar outbreaks could occur in the future.

“Our aim is to replicate this study for many plant pathogens, eventually drawing up a ‘rule book’ of how pathogenicity evolves, helping us to prevent future outbreaks where possible.”

Featured image: Fungal spores. Credit: CABI


Reference: Historical genomics reveals the evolutionary mechanisms behind multiple outbreaks of the host-specific coffee wilt pathogen Fusarium xylarioides’ by L. D. Peck, R. W. Nowell, J. Flood, M. J. Ryan and T. G. Barraclough is published in BMC Genomics.


Provided by University College London

URI Scientists Discover Function of Microbes Living in Oysters (Biology)

Research may inform coastal management, ecosystem health, aquaculture

Scientists from the University of Rhode Island have taken the first steps toward understanding the function of microbes that live on and in Eastern oysters, which may have implications for oyster health and the management of oyster reefs and aquaculture facilities.

            “Marine invertebrates like oysters, corals and sponges have a very active microbiome that could potentially play a role in the function of the organism itself,” said Ying Zhang, URI associate professor of cell and molecular biology. “We know very little about whether there are resident microbes in oysters, and if there are, what their function may be or how they may help or bring harm to the oyster.”

            Zhang and doctoral student Zachary Pimentel extracted the DNA of microbes living in or on the gut, gill, inner shell, mantle and other tissues of oysters to identify the microbes that live there. They then applied a metagenomics technology to reconstruct the genome of the most abundant microbes to better understand the nature of the oyster microbiome and the function of some of the microbes.

            “This was the first overview of what microbes live in certain parts of Eastern oysters,” said Pimentel, the lead author on a paper about the study published in May by the American Society for Microbiology. “In humans, we know that the microbes that live in the gut versus the skin are quite different. But we didn’t know about the compartmentalization of certain microbes in certain oyster tissues.”

            The researchers identified one microbe, a bacterium in the class Mollicutes, that gains energy from the consumption of chitin, a substance found throughout the marine environment. It was most abundant in the gut of the oysters and appears to be an indicator of a healthy oyster, but when found in other tissues, it may be correlated with infections.

            “When they’re abundant in the gut of healthy oysters, that may indicate that the oysters are happy to have them,” Zhang said. “But when the microbe gains abundance in other tissues, that may be a sign that the oyster is not doing well, maybe because the immune system is freaked out.”

            The same microbe was also discovered to consume arginine, an amino acid found in all organisms that is used to create proteins.

            “We’re really interested in that one because it has potential implications for the immune system of oysters,” Pimentel said. “Oysters rely on arginine for its immune response. A pathogen has been found to steal the arginine to hide from the oyster’s immune system, so it’s really interesting that there’s another microbe that uses arginine and has potential implications for oyster immunity.”

            Once the researchers have identified the function of key beneficial microbes, the next step is to learn when and where the microbes are acquired. 

            “One microbe was found to be abundant in adult oysters but very rare in larval samples,” Zhang said. “So they could be acquired at some point in their growth, but when and how they are acquired is a big question. If we know they are important and we can identify the source of where they came from, then perhaps we can help preserve the population of this specific microbe.”

            According to Zhang and Pimentel, oysters play an important role in building reefs, filtering water, and providing other ecological functions, in addition to their role in supporting the aquaculture industry. Further research about the microbiome of oysters could be beneficial to understanding more about oyster health and the health of their ecosystem.

            “We know for other organisms that the microbiome is a really important factor when considering health and disease, so we’re laying the groundwork for future research that might implicate certain microbes in important processes related to health and disease,” Pimentel said.

            “The more we know about oysters and their interactions with microbes, the more we’ll understand about how to conserve them,” added Zhang.


Reference: Zachary T. Pimentel et al., “Microbiome Analysis Reveals Diversity and Function of Mollicutes Associated with the Eastern Oyster, Crassostrea virginica”, mSphere, 2021. DOI: https://doi.org/10.1128/mSphere.00227-21


Provided by University of Rhode Island

Scientists Discover New Approach to Stabilize Cathode Materials (Chemistry)

Chemists studied an elusive material property, called a valence gradient effect, confirming its ability to stabilize high-nickel-content cathodes for next-generation electric vehicle batteries

A team of researchers led by chemists at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory has studied an elusive property in cathode materials, called a valence gradient, to understand its effect on battery performance. The findings, published in Nature Communications, demonstrated that the valence gradient can serve as a new approach for stabilizing the structure of high-nickel-content cathodes against degradation and safety issues.  

High-nickel-content cathodes have captured the attention of scientists for their high capacity, a chemical property that could power electric vehicles over much longer distances than current batteries support. Unfortunately, the high nickel content also causes these cathode materials to degrade more quickly, creating cracks and stability issues as the battery cycles.

In search of solutions to these structural problems, scientists have synthesized materials made with a nickel concentration gradient, in which the concentration of nickel gradually changes from the surface of the material to its center, or the bulk. These materials have exhibited greatly enhanced stability, but scientists have not been able to determine if the concentration gradient alone was responsible for the improvements. The concentration gradient has traditionally been inseparable from another effect called the valence gradient, or a gradual change in nickel’s oxidation state from the surface of the material to the bulk.  

In the new study led by Brookhaven Lab, chemists at DOE’s Argonne National Laboratory synthesized a unique material that isolated the valence gradient from the concentration gradient.

“We used a very unique material that included a nickel valence gradient without a nickel concentration gradient,” said Brookhaven chemist Ruoqian Lin, first author of the study. “The concentration of all three transition metals in the cathode material was the same from the surface to the bulk, but the oxidation state of nickel changed. We obtained these properties by controlling the material’s atmosphere and calcination time during synthesis. With sufficient calcination time, the stronger bond strength between manganese and oxygen promotes the movement of oxygen into the material’s core while maintaining a Ni2+ oxidation state for nickel at the surface, forming the valence gradient.”

Photo of Seong-Min Bak, Xiaojing Huang, Mingyuan Ge, and Yong Chu
The Hard X-ray Nanoprobe (HXN) research team. Pictured from left to right are Seong-Min Bak, Xiaojing Huang, Mingyuan Ge, and Yong Chu. © BNL

Once the chemists successfully synthesized a material with an isolated valence gradient, the Brookhaven researchers then studied its performance using two DOE Office of Science user facilities at Brookhaven Lab—the National Synchrotron Light Source II (NSLS-II) and the Center for Functional Nanomaterials (CFN).

At NSLS-II, an ultrabright x-ray light source, the team leveraged two cutting-edge experimental stations, the Hard X-ray Nanoprobe (HXN) beamline and the Full Field X-ray Imaging (FXI) beamline. By combining the capabilities of both beamlines, the researchers were able to visualize the atomic-scale structure and chemical makeup of their sample in 3-D after the battery operated over multiple cycles.

“Both beamlines have world-leading capabilities. You can’t do this research anywhere else,” said Yong Chu, leader of the imaging and microscopy program at NSLS-II and lead beamline scientist at HXN. “FXI is the fastest nanoscale beamline in the world; it’s about ten times faster than any other competitor. HXN is much slower, but it’s much more sensitive—it’s the highest resolution x-ray imaging beamline in the world.”

HXN beamline scientist Xiaojing Huang added, “At HXN, we routinely run measurements in multimodality mode, which means we collect multiple signals simultaneously. In this study, we used a fluorescence signal and a phytography signal to reconstruct a 3-D model of the sample at the nanoscale. The florescence channel provided the elemental distribution, confirming the sample’s composition and uniformity. The phytography channel provided high-resolution structural information, revealing any microcracks in the sample.”

Meanwhile at FXI, “the beamline showed how the valence gradient existed in this material. And because we conducted full-frame imaging at a very high data acquisition rate, we were able to study many regions and increase the statistical reliability of the study,” Lin said.

At the CFN Electron Microscopy Facility, the researchers used an advanced transmission electron microscope (TEM) to visualize the sample with ultrahigh resolution. Compared to the x-ray studies, the TEM can only probe a much smaller area of the sample and is therefore less statistically reliable across the whole sample, but in turn, the data are far more detailed and visually intuitive.  

By combining the data collected across all of the different facilities, the researchers were able to confirm the valence gradient played a critical role in battery performance. The valence gradient “hid” the more capacitive but less stable nickel regions in the center of the material, exposing only the more structurally sound nickel at the surface. This important arrangement suppressed the formation of cracks. 

The researchers say this work highlights the positive impact concentration gradient materials can have on battery performance while offering a new, complementary approach to stabilize high-nickel-content cathode materials through the valence gradient.

“These findings give us very important guidance for future novel material synthesis and design of cathode materials, which we will apply in our studies going forward,” Lin said.

This study was a collaborative effort among several universities and DOE laboratories, including research teams involved in DOE’s Battery500 Consortium, which aims to make lithium-metal battery cells with an energy density of 500 watt-hours per kilogram, more than double the energy density of today’s state-of-the-art batteries. The research was supported by DOE’s Office of Energy Efficiency and Renewable Energy, Vehicle Technologies Office and DOE’s Office of Science. Additional x-ray experiments were carried out at the Advanced Light Source (ALS) and the Advanced Photon Source (APS), two DOE Office of Science user facilities that are located at DOE’s Lawrence Berkeley National Laboratory and Argonne National Laboratory, respectively. Operations at NSLS-II, CFN, ALS, and APS are supported by the Office of Science.

Brookhaven National Laboratory is supported by the U.S. Department of Energy’s Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit https://energy.gov/science.

Featured image: Brookhaven chemist Ruoqian Lin, first author of the study. © BNL


Related Links


Provided by Brookhaven National Laboratory

Genetic Base Editing Treats Sickle Cell Disease in Mice (Biology)

Converting a pathogenic hemoglobin gene to a benign variant enables healthy blood cell production in an animal model of sickle cell disease.

Sickle cell disease (SCD) is the most common deadly genetic disorder, affecting more than 300,000 newborns worldwide each year. It leads to chronic pain, organ failure, and early death in patients. A team led by researchers at the Broad Institute of MIT and Harvard and St. Jude Children’s Research Hospital has now demonstrated a base editing approach that efficiently corrects the mutation underlying SCD in patient blood stem cells and in mice. This gene editing treatment rescued the disease symptoms in animal models, enabling the long-lasting production of healthy blood cells.

The root of SCD is two mutated copies of the hemoglobin gene, HBB, which cause red blood cells to transform from a circular disc into a sickle shape — setting off a chain of events leading to organ damage, recurrent pain, and early mortality. In this study, the researchers used a molecular technology called base editing to directly convert a single letter of pathogenic DNA into a harmless genetic variant of HBB in human blood-producing cells and in a mouse model of SCD.

“We were able to correct the disease-causing variant in both cell and animal models using a customized base editor, without requiring double-stranded DNA breaks or inserting new segments of DNA into the genome,” says co-senior author David Liu, Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute, professor at Harvard University, and Howard Hughes Medical Institute investigator. “This was a major team effort, and our hope is that base editing will provide a promising basis for a therapeutic strategy down the road for sickle cell disease.”

“Our study illustrates the power and excitement of multidisciplinary collaborations for creating novel mechanism-based cures for genetic diseases,” says co-senior author Mitchell Weiss, chair of the St. Jude Department of Hematology. “In particular, we combined expertise in protein engineering, base editing, and red blood cell biology to create a novel approach for treating and possibly curing sickle cell disease.”

The work appears today in Nature, led by co-first authors Gregory Newby at the Broad Institute and Jonathan Yen, Kaitly Woodard, and Thiyagaraj Mayuranathan at St. Jude Children’s Research Hospital.

AN IMPROVED APPROACH

Currently, the only established method to cure SCD is a bone marrow transplant — but finding an appropriate bone marrow donor for a patient is difficult, and patients who undergo a transplant can suffer dangerous side effects. While there are a number of gene editing treatments under development that avoid these risks by modifying a patient’s own bone marrow directly, these experimental therapies rely on introducing new DNA or cleaving genomic DNA in cells, which can also cause adverse effects.

For this work, the research team used what’s called an “adenine base editor,” a molecular tool developed in Liu’s lab that can target a specific gene sequence and convert the DNA base pair A•T to G•C, altering a gene at the level of a single pair of nucleotides. The base editor used in this study consists of a laboratory-evolved Cas9 variant — a CRISPR-associated protein that positions the base editor at the mutated HBB site in the genome — and a laboratory-evolved enzyme that converts the target A to a base that pairs like G. The base editor also guides the cell to repair the complementary DNA strand, completing the conversion of the target A•T base pair to G•C.

The single DNA mutation underlying sickle cell disease is an A in the healthy hemoglobin gene that has been altered to a T. While an adenine base editor cannot reverse this change, it can convert that T to a C. This edit transforms the dangerous form of hemoglobin into a naturally occurring, non-pathogenic variant called “hemoglobin Makassar.”

EDITING IN MODELS

The team first introduced the adenine base editor into isolated blood stem cells from human SCD patients. In these experiments, up to 80 percent of the pathogenic hemoglobin variants were successfully edited into the benign Makassar variant, with minimal instances of the editor causing undesired changes to hemoglobin.

The researchers transferred these edited blood stem cells into a mouse model to observe how they functioned in live animals. After 16 weeks, the edited cells still produced healthy blood cells.

“Sixteen weeks after transplantation, the total frequency of the edit maintained in stem cells — which could contain edits in both copies of their hemoglobin gene, in only one copy, or in neither copy — was 68 percent. And we were particularly excited to see that nearly 90 percent of cells contained at least one edited copy of hemoglobin,” explains Newby. “Even those cells with just one edited copy appeared to be protected from sickling.”

In a separate set of experiments, the researchers took blood stem cells from mice harboring the human sickle cell disease variant, edited them, and transplanted the edited cells into another set of recipient mice. Control mice transplanted with unedited cells showed typical symptoms: sickled red blood cells, consequences of short red blood cell lifetime, and an enlarged spleen. In contrast, mice transplanted with edited cells were improved compared to controls by every tested disease metric, with all measured blood parameters observed at levels nearly indistinguishable from healthy animals.

Finally, to confirm durable editing of the target blood stem cells, the researchers performed a secondary transplant, taking bone marrow from mice that had received edited cells 16 weeks previously and transferring the blood stem cells into a new set of mice. In the new animal cohort, edited cells continued to perform similarly to healthy blood stem cells, confirming that the effects of base editing were long-lasting. The team determined that editing at least 20 percent of pathogenic hemoglobin genes was sufficient to maintain blood metrics in the mice at healthy levels.

“In these final experimental phases, we demonstrated an editing threshold of about 20 percent that is necessary to mitigate this disease in mice. This base editing strategy is efficient enough to far exceed that benchmark,” explains Liu. “The approach offers promise as the basis of a potential one-time treatment, or perhaps even a one-time cure, for sickle cell disease.”

The researchers and other partners are working to move this concept safely and effectively into additional preclinical studies, with the eventual goal of reaching patients.

This work was supported in part by the US National Institutes of Health (U01 AI142756, RM1 HG009490, R01 EB022376, R35 GM118062, and P01 HL053749), the Bill and Melinda Gates Foundation, the Howard Hughes Medical Institute, the St. Jude Collaborative Research Consortium, the Doris Duke Foundation, the Assisi Foundation of Memphis, and ALSAC, the fundraising and awareness organization of St. Jude.

Featured image credit : Zayna Sheikh, Broad Communications


Paper(s) cited:

Newby GA, Yen JS, Woodard KJ, Mayuranathan T et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature. Online June 2, 2021. DOI: 10.1038/s41586-021-03609-w


Provided by Broad Institute

Immunotherapy after Bladder Cancer Surgery May Reduce Recurrence, Study Shows (Medicine)

New research from Memorial Sloan Kettering Cancer Center (MSK) medical oncologist Dean Bajorin, MD, and colleagues found that patients who received nivolumab (Opdivo®) after bladder cancer surgery reduced their overall risk for high-grade bladder cancer recurrence. This research was published today in the New England Journal of Medicine.

In this phase III randomized study, Dr. Bajorin and a team of investigators evaluated 709 patients who were at high risk for recurrence of urothelial cancer after removal of their bladder, ureter, or kidney for high-grade cancer. To evaluate for benefit, patients were randomized to receive either nivolumab or a placebo every two weeks for one year. Patients and physicians were blinded to the treatment. Both safety and quality of life were evaluated.

Dr. Bajorin and investigators found that in high-risk patients, nivolumab reduced recurrence after surgery compared to patients who received the placebo. The current standard of care following surgery that removes the bladder or kidney and ureter has been observation without adjuvant therapy — even in patients at high risk of recurrence and death. This is because no chemotherapy or immunotherapy has previously been shown to be of benefit. Participants who received nivolumab had disease-free survival of 21 months compared with 10.9 months in people receiving the placebo.

“We are very encouraged by the data and the results of the study,” said Dr. Bajorin, first and corresponding author of the study. “Despite available therapies for advanced metastatic bladder cancer, new options are needed to improve long-term disease control and patient survival. These findings have the potential to change the standard of care for bladder cancer.”

Urothelial cancers are tumors that start in the lining of the urine-collecting system that transports urine from the kidneys to the outside of our bodies. These cancers are often referred to as “bladder cancer” because most of them start in the bladder.

Dr. Bajorin and colleagues concluded that the survival data is not yet mature and will need additional research and follow-up. The primary endpoints of disease-free survival in the study population and disease free-survival in the subset of patients with PD-L1-positive tumors were met, and these findings are highly statistically significant and clinically relevant for a population of patients with a clear unmet medical need.

“The trial demonstrates that novel therapies can be identified as having patient benefit when the studies are conducted in a very rigorous fashion. We are hoping this treatment will get approval for all patients at high risk of recurrence after the US Food and Drug Administration has done a detailed review of all the data,” said Dr. Bajorin.

Making Pioneering Advances for Bladder Cancer Patients

Cancer immunotherapy was born at MSK a little over a century ago. Since then, physician-scientists across MSK have led the effort to develop immune-based treatments for different types of cancer. MSK has been at the epicenter of discoveries in the field, and the institution’s work is bringing exciting new treatment options to people around the world. MSK physicians have extensive experience using immunotherapy to treat people with melanoma, kidney cancer, lung cancer, and other cancers as well as handling immune-related side effects.

Without treatment, bladder cancer can be an aggressive disease. In 2021, it is estimated that there will be nearly 17,000 deaths due to bladder cancer in the United States — and numbers are expected to rise significantly in the next decade. 

“As physicians, we consistently strive to provide our patients with the most effective therapies and give those with advanced disease more options,” said Dr. Bajorin.

This trial was sponsored by Bristol Myers Squibb, Checkmate 274.


Reference: Dean F. Bajorin, J. Alfred Witjes, Jürgen E. Gschwend, Michael Schenker, et al., “Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma”, N Engl J Med 2021; 384:2102-2114
DOI: 10.1056/NEJMoa2034442


Provided by MSKCC

The Dream Team: Scientists Find Drug Duo That May Cure COVID-19 Together (Medicine)

Preclinical experiments show that the drugs cepharanthine and nelfinavir may be effective treatments for COVID-19

While preventative care for COVID-19 has made much noise (with vaccines having rolled out in most countries), the soaring infection rates indicate the need for effective treatments. Using cultured cells to study SARS-CoV-2 infections, researchers at the Tokyo University of Science and other institutions have discovered that the drugs cepharanthine and nelfinavir are effective at combating the virus, with the former preventing the virus from entering cells and the latter preventing the virus from replicating.

COVID-19 continues to claim lives across the world and is infecting millions more. Although several vaccines have recently become available, making significant strides towards preventing COVID-19, what about the treatment of those who already have the infection? Vaccines aren’t 100% effective, highlighting the need―now more than ever―for effective antiviral therapeutics. Moreover, some people can’t receive vaccines due to health issues, and new variants of SARS-CoV-2, the virus that causes COVID-19, that can penetrate vaccine-conferred immunity, are being reported, indicating that we need to think beyond prevention.

Given this need, a team of researchers based in Japan, the US, and the UK launched a project to develop effective therapeutics. This team included several researchers based at Tokyo University of Science: Visiting Professor Koichi Watashi, Dr. Hirofumi Ohashi, Professor Shin Aoki, Professor Kouji Kuramochi, and Assistant Professor Tomohiro Tanaka. Their goal was clear and simple: finding a cure for COVID-19.

To achieve this goal, the researchers first established an experimental system for screening drugs that may help to control infections. This system used a type of cells called VeroE6/TMPRSS2 cells, which were manipulated to efficiently be infected with and produce SARS-CoV-2. “To determine whether a drug of interest could help combat infection by SARS-CoV-2, we simply had to expose VeroE6/TMPRSS2 cells to both the drug and SARS-CoV-2 and then observe whether the drug’s presence served to hinder the virus’s efforts to infect cells,” explains Professor Watashi.

The researchers used this experimental system to screen a panel of drugs that are already approved for clinical use, including drugs like remdesivir and chloroquine that have already being approved or are being trialed as treatments for COVID-19. In an exciting outcome, the researchers found two drugs that provided effective SARS-CoV-2 suppression: cepharanthine, which is used to treat inflammation, and nelfinavir, which is approved for the treatment of HIV infection.

Cepharanthine inhibited the entry of the virus into cells by preventing the virus from binding to a protein on the cell membrane, which it uses as a gateway. In contrast, nelfinavir worked to prevent the virus from replicating inside the cell by inhibiting a protein that the virus relies on for replication. Given that these drugs have distinct antiviral mechanisms, using both of them together could be especially effective for patients, with computational models predicting that combined cepharanthine/nelfinavir therapy can hasten the clearance of SARS-CoV-2 from a patient’s lungs by as few as 4.9 days.

So, does this mean we will be seeing these new drugs in COVID-19 treatment centers? Of course, the drug duo isn’t ready to be rolled out into healthcare systems just yet. These findings justify further research into the clinical potential of cepharanthine/nelfinavir therapy, and only following this can we say for sure that it is useful and helpful.

Nevertheless, given the ongoing nature of the COVID-19 pandemic and the ever-increasing death toll, the development of cepharanthine/nelfinavir therapy may provide clinicians and patients with a much-needed new treatment option.

Reference

  • Title of original paper: Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment
  • Journal: iScience
  • DOI: 10.1016/j.isci.2021.102367

Provided by Tokyo Institute of Science