New Perspective to Understand And Treat A Rare Calcification Disease (Biology)

Researchers developed a new animal model to study a rare genetic disease that can lead to blindness at the age of 40-50.

As part of an international collaboration, researchers from ELTE Eötvös Loránd University developed a new animal model to study a rare genetic disease that can lead to blindness at the age of 40-50. The new model could open up new perspectives in our understanding of this metabolic disease and will also help to identify new potential drug candidates, according to the recent study published in Frontiers in Cell and Developmental Biology.

Pseudoxanthoma elasticum (PXE) is a rare genetic disease with symptoms that usually manifest in adolescence or in early adulthood. The symptoms are caused by the appearance of hydroxyapatite crystal deposits in the subcutaneous connective tissue and retina and later can also appear in the vascular system. Excessive calcification in the retina can lead to blindness, while the crystals in the walls of the blood vessels result in the loss of their elasticity and in the development of severe vascular diseases.

The researchers of the DanioLab Research Group at the Department of Genetics of the ELTE Eötvös Loránd University, supported by the Diagnostics and Therapy Excellence Program, collaborated with researchers from the ELKH-RCNS Institute of Enzymology, Semmelweis University Institute of Physiology, and the US National Human Genome Research Institute (NHGRI) to create a new model for PXE. The researcher used zebrafish (Danio rerio), a popular model of genetic research, to gain a better understanding of this rare genetic disease.

Why is zebrafish a good animal model?

PXE usually develops in patients carrying mutations in the ABCC6 gene, encoding a cell membrane transporter protein. The zebrafish genome harbors three variants (so-called paralogues) of this gene: abcc6a is located on chromosome 6, while abcc6b.1 and abcc6b.2 are located on chromosome 3. Closer examination of the three paralogues, using new sequencing methods, revealed that only abcc6a and abcc6b.1 have a protein-coding function. In contrast, abcc6b.2 has lost its active role and is present as a pseudogene in the genome of the zebrafish.

The research team at ELTE Eötvös Loránd University successfully created and characterized mutant lines in the two protein-coding ABCC6 paralogues using the CRISPR/Cas9 genome-editing system, to understand if they have synergistic effects in the fish. “To our surprise, only abcc6a homozygous mutant animals showed defects in calcification. These could be observed relatively early, already at larval stages, indicating that loss of function of this gene in zebrafish affects calcification similarly to that seen in human patients. By adulthood, the skeletal system of the mutant animals was severely distorted. The spine is spectacularly twisted due to the excessive calcification between the vertebrae” – said Máté Varga, the head of the DanioLab Research Group at ELTE Eötvös Loránd University.

The new model will provide new opportunities for a better understanding of this metabolic disease and could become an important asset for future clinical research. The mutant lines created in the project will be used to test drug candidates with the potential to ameliorate PXE symptoms.

Featured image: As part of an international collaboration, researchers from ELTE Eötvös Loránd University developed a new animal model to study a rare genetic disease. © Photo: Dániel Csete, Semmelweis University Institute of Physiology

Reference: Dávid Czimer, Klaudia Porok et al., “A New Zebrafish Model for Pseudoxanthoma Elasticum”, Front. Cell Dev. Biol., 09 March 2021 |

Provided by ELTE

Dark Energy Survey Physicists Open New Window Into Dark Energy (Astronomy)

For the first time, DES scientists can combine measurements of the distribution of matter, galaxies, and galaxy clusters to advance our understanding of dark energy.BY NATHAN COLLINS

The universe is expanding at an ever-increasing rate, and while no one is sure why, researchers with the Dark Energy Survey (DES) at least had a strategy for figuring it out: They would combine measurements of the distribution of matter, galaxies and galaxy clusters to better understand what’s going on.

Reaching that goal turned out to be pretty tricky, but now a team led by researchers at the Department of Energy’s SLAC National Accelerator Laboratory, Stanford University and the University of Arizona have come up with a solution. Their analysis, published today in Physical Review Letters, yields more precise estimates of the average density of matter as well as its propensity to clump together – two key parameters that help physicists probe the nature of dark matter and dark energy, the mysterious substances that make up the vast majority of the universe.

“It is one of the best constraints from one of the best data sets to date,” says Chun-Hao To, a lead author on the new paper and a graduate student at SLAC and Stanford working with Kavli Institute for Particle Astrophysics and Cosmology Director Risa Wechsler.

An early goal

When DES set out in 2013 to map an eighth of the sky, the goal was to gather four kinds of data: the distances to certain types of supernovae, or exploding stars; the distribution of matter in the universe; the distribution of galaxies; and the distribution of galaxy clusters. Each tells researchers something about how the universe has evolved over time. 

Ideally, scientists would put all four data sources together to improve their estimates, but there’s a snag: The distributions of matter, galaxies, and galaxy clusters are all closely related. If researchers don’t take these relationships into account, they will end up “double counting,” placing too much weight on some data and not enough on others, To says.

To avoid mishandling all this information, To, University of Arizona astrophysicist Elisabeth Krause and colleagues have developed a new model that could properly account for the connections in the distributions of all three quantities: matter, galaxies, and galaxy clusters. In doing so, they were able to produce the first-ever analysis to properly combine all these disparate data sets in order to learn about dark matter and dark energy.

Improving estimates 

Adding that model into the DES analysis has two effects, To says. First, measurements of the distributions of matter, galaxies and galaxy clusters tend to introduce different kinds of errors. Combining all three measurements makes it easier to identify any such errors, making the analysis more robust. Second, the three measurements differ in how sensitive they are to the average density of matter and its clumpiness.  As a result, combining all three can improve the precision with which the DES can measure dark matter and dark energy.

In the new paper, To, Krause and colleagues applied their new methods to the first year of DES data and sharpened the precision of previous estimates for matter’s density and clumpiness.

Now that the team can incorporate matter, galaxies and galaxy clusters simultaneously in their analysis, adding in supernova data will be relatively straightforward, since that kind of data is not as closely related with the other three, To says.

“The immediate next step,” he says, “is to apply the machinery to DES Year 3 data, which has three times larger coverage of the sky.” This is not as simple as it sounds: While the basic idea is the same, the new data will require additional efforts to improve the model to keep up with the higher quality of the newer data, To says.

“This analysis is really exciting,” Wechsler said. “I expect it to set a new standard in the way we are able to analyze data and learn about dark energy from large surveys, not only for DES but also looking forward to the incredible data that we will get from the Vera Rubin Observatory’s Legacy Survey of Space and Time in a few years.”

The research was a collaborative effort within the Dark Energy Survey and was supported by the National Science Foundation and the Department of Energy’s Office of Science. 

Featured image: A map of the sky showing the density of galaxy clusters, galaxies and matter in the universe over the part of the sky observed by the Dark Energy Survey. The left panel shows the galaxy density in that part of the sky, while the middle panel shows matter density and the right shows galaxy cluster density. Red areas are more dense, and blue areas are less dense, than average. (Chun-Hao To/Stanford University, SLAC)

Citation: C. To et al. (DES Collaboration), “Dark Energy Survey Year 1 Results: Cosmological Constraints from Cluster Abundances, Weak Lensing, and Galaxy Correlations”, Physical Review Letters, 6 April 2021 (10.1103/PhysRevLett.126.141301)

Provided by SLAC

Leptin Puts The Brakes On Eating Via Novel Neurocircuit (Neuroscience)

Energy balance includes modulation of dopamine reward signaling

Since the discovery of leptin in the 1990s, researchers have wondered, how does leptin, a hormone made by body fat, suppress appetite? Despite tremendous gains in the intervening three decades, many questions still remain. Now, a new study in mice describes novel neurocircuitry between midbrain structures that control feeding behaviors that are under modulatory control by leptin. The study appears in Biological Psychiatry, published by Elsevier.

John Krystal, MD, editor of Biological Psychiatry, said of the findings, “Omrani and colleagues shed light on how, in non-obese animals, leptin puts the brakes on overeating.”

Leptin acts as a critical link between the body and the brain, providing information about metabolic state and exerting control over energy balance. The importance of leptin is illustrated by the finding that animals deficient for leptin rapidly become obese without its regulatory stop on feeding behavior.

Roger Adan, PhD, of the Department of Translational Neuroscience, University Medical Center Utrecht and University Utrecht, the Netherlands, who led the study, said, “This process is shaped by communication between bodily fat storages (via a hormone called leptin) and the brain’s dopamine reward system. This leptin-dopamine axis is critically important for body weight control, but its modes of action were not well understood.”

Leptin suppresses eating by signaling to brain regions that control eating behaviors, but it also decreases the reward value inherent in foods, engaging the brain’s dopamine (DA) reward system. That food-reward pathway was known to involve dopaminergic neurons of the ventral tegmental area (VTA) signaling to the nucleus accumbens (NAc), but most of those DA neurons do not contain receptors for leptin.

The work used a combination of powerful technologies, including optogenetics, chemogenetics and electrophysiology to map the new microcircuitry.

“Although leptin receptors are present on [some] dopamine neurons that signal food reward,” said Professor Adan, also of the Department of Translational Neuroscience, University Medical Center Utrecht and University Utrecht, “we discovered that leptin receptors are also present on inhibitory neurons that more strongly regulate the activity of dopamine neurons. Some of these inhibitory neurons suppressed food seeking when [animals were] hungry, whereas others [did so] only when [animals were] in a sated state.”

Dr. Krystal said of the study, “It turns out that leptin plays key modulatory roles in an elegant circuit that unites midbrain and limbic reward circuitry. By inhibiting hypothalamic neurons and ultimately suppressing the activity of dopamine neurons in the midbrain that signal reward and promote feeding, leptin reduces food intake in animals under conditions when caloric intake has exceeded energy use.”

Ultimately, Professor Adan said, “Targeting these neurons may provide a new avenue for the treatment of anorexia nervosa and to support dieting in people with obesity.”

Notes for editors
The article is “Identification of novel neurocircuitry through which leptin targets multiple inputs to the dopamine system to reduce food reward seeking,”by Azar Omrani, Veronne de Vrind, Bart Lodder, Iris Stoltenborg, Karlijn Kooij, Inge Wolterink-Donselaar, Mieneke Luijendijk-Berg, Keith Garner, Lisanne van ‘t Sant, Annemieke Rozeboom, Suzanne Dickson, Frank Meye, Roger Adan ( It appears as an Article in Press in Biological Psychiatry, published by Elsevier.

Featured image: Summary diagram of the modulatory effect of leptin on the mesolimbic DA system. © Elsevier

Provided by Elsevier

‘Brain glue’ Helps Repair Circuitry in Severe TBI (Neuroscience)

Reparative hydrogel mimics the composition and mechanics of the brain

At a cost of $38 billion a year, an estimated 5.3 million people are living with a permanent disability related to traumatic brain injury in the United States today, according to the Centers for Disease Control and Prevention. The physical, mental and financial toll of a TBI can be enormous, but new research from the University of Georgia provides promise.

In a new study, researchers at UGA’s Regenerative Biosciences Center have demonstrated the long-term benefits of a hydrogel, which they call “brain glue,” for the treatment of traumatic brain injury. The new study provides evidence that not only does the gel protect against loss of brain tissue after a severe injury, but it also might aid in functional neural repair.

Brain damage following significant TBI commonly results in extensive tissue loss and long-term disability. There currently are no clinical treatments to prevent the resulting cognitive impairments or tissue loss.

Reported on March 5 in Sciences Advances, the new finding is the first to provide visual and functional evidence of the repair of brain neural circuits involved in reach-to-grasp movement in brain glue-implanted animals following severe TBI.

“Our work provides a holistic view of what’s going on in the recovery of the damaged region while the animal is accomplishing a specific reach-and-grasp task,” said lead investigator Lohitash Karumbaiah, an associate professor in the University of Georgia’s College of Agricultural and Environmental Sciences.

Created by Karumbaiah in 2017, brain glue was designed to mimic the structure and function of the meshwork of sugars that support brain cells. The gel contains key structures that bind to basic fibroblast growth factor and brain-derived neurotrophic factor, two protective protein factors that can enhance the survival and regrowth of brain cells after severe TBI.

In a prior short-term study, Karumbaiah and his team showed that brain glue significantly protected brain tissue from severe TBI damage. In this new research, to harness the neuroprotective capacity of the original, they further engineered the delivery surface of protective factors to help accelerate the regeneration and functional activity of brain cells. After 10 weeks, the results were apparent.

“Animal subjects that were implanted with the brain glue actually showed repair of severely damaged tissue of the brain,” said Karumbaiah. “The animals also elicited a quicker recovery time compared to subjects without these materials.”

To measure the glue’s effectiveness, the team used a tissue-clearing method to make brain tissue optically transparent, which allowed them to visually capture the immediate response of cells in the reach-to-grasp circuit using a 3D imaging technique.

“Because of the tissue-clearing method, we were able to obtain a deeper view of the complex circuitry and recovery supported by brain glue,” said Karumbaiah. “Using these methods along with conventional electrophysiological recordings, we were able to validate that brain glue supported the regeneration of functional neurons in the lesion cavity.”

Karumbaiah pointed out that the RTG circuit is evolutionarily similar in rats and humans. “The modulation of this circuit in the rat could help speed up clinical translation of brain glue for humans,” he said.

With support from UGA’s Innovation Gateway, Karumbaiah has filed for a patent on the brain glue. He is also partnering with Parastoo Azadi, technical director of analytical services at the UGA Complex Carbohydrate Research Center, and GlycoMIP, a $23 million, National Science Foundation-funded Materials Innovation Platform, created to advance the field of glycomaterials through research and education.

“Doing the behavioral studies, the animal work and the molecular work sometimes takes a village,” said Karumbaiah. “This research involved a whole cross-section of RBC undergraduate and graduate students, as well as faculty members from both UGA and Duke University.”

The collaborative research effort provided five UGA RBC fellow undergraduates with an experiential learning opportunity and to publish their first paper. This is the first publication for Rameen Forghani, an aspiring M.D.-Ph.D. undergraduate working in the Karumbaiah lab.

Forghani said the undergraduate team “learned how to collaborate on this project” and about the impact of moving lab research to patients who need treatment.

“My fellow undergraduates and I were empowered to take ownership of a piece of the project and see it through from the planning stages of data analysis to writing and being published,” said Forghani. “As an aspiring, early-career physician-scientist, working on a project that has translational impact and directly addresses a very relevant clinical problem is very exciting to me.”

Charles Latchoumane, research scientist in the Karumbaiah lab and first author on the study, divides his time between UGA and Lausanne, Switzerland, where he works at NeurRestore, a research center aimed at restoring lost neurological function for people suffering from Parkinson’s disease or from neurological disorders following a head injury or stroke.

“This study has been four to five years in the making,” said Latchoumane. “Our collaborative research is so painstakingly documented that, after you read about it, you have to believe there is new hope for severe victims of brain injury.”

This work was supported by grants to Karumbaiah from the National Institutes of Health (RO1NS099596, R24GM137782), the Regenerative Engineering and Medicine Center seed grant program, and an Alliance for Regenerative Rehabilitation Research and Training technology development grant.

Featured image: Lohitash Karumbaiah at work in his lab. (Photo by Dorothy Kozlowski/UGA)

Reference: Charles-Francois V. Latchoumane et al., “Engineered glycomaterial implants orchestrate large-scale functional repair of brain tissue chronically after severe traumatic brain injury”, Science Advances  05 Mar 2021: Vol. 7, no. 10, eabe0207 DOI: 10.1126/sciadv.abe0207

Provided by University of Georgia

Scientists Uncover Mutations That Make Cancer Resistant To Therapies Targeting KRAS (Medicine)

Key Takeaways

  • Cancer drugs that inhibit the protein expressed by a mutated form of the KRAS gene might be approved later this year, but cancer cells often develop additional mutations that make them resistant to such targeted drugs.
  • Investigators have identified some of these mutations in a patient and identified strategies to overcome them.

The treatment landscape for KRAS-mutant cancers is rapidly evolving.

— Jessica J. Lin, MD, Center for Thoracic Cancers, Massachusetts General Hospital

A gene called KRAS is one of the most commonly mutated genes in all human cancers, and targeted drugs that inhibit the protein expressed by mutated KRAS have shown promising results in clinical trials, with potential approvals by the U.S. Food and Drug Administration anticipated later this year. Unfortunately, cancer cells often develop additional mutations that make them resistant to such targeted drugs, resulting in disease relapse. Now researchers led by a team at Massachusetts General Hospital (MGH) have identified the first resistance mechanisms that may occur to these drugs and identified strategies to overcome them. The findings are published in Cancer Discovery.

One mutated version of KRAS that commonly arises in cancer cells is called KRAS(G12C), and it produces a mutated KRAS protein that allows the cells to grow and spread in the body. “Now, with the development of KRAS(G12C) inhibitors, the treatment landscape for KRAS-mutant cancers is rapidly evolving,” says co–lead author Jessica J. Lin, MD, an attending physician in the Center for Thoracic Cancers and the Termeer Center for Targeted Therapies at MGH. “KRAS(G12C) inhibitors adagrasib and sotorasib have recently demonstrated promising efficacy and safety in advanced KRAS(G12C)-mutant cancers.”

Although these may be life-saving therapies for many patients, resistance to the drugs is anticipated. Such was the case for a woman in an early clinical trial of adagrasib for lung cancer. After an initial reduction in tumor size, her tumor started growing again.

Analyses by Lin and her colleagues revealed various new tumor mutations in addition to KRAS(G12C). Interestingly, many of these mutations ultimately reactivated the signaling pathway driven by KRAS in cells (called the RAS-MAPK pathway), which is involved in cell growth and division. In addition, the team found a novel KRAS(Y96D) mutation, which further alters the structure of the KRAS(G12C) protein so that it is no longer effectively blocked by adagrasib, sotorasib or other inhibitors. However, experiments revealed that one KRAS(G12C) inhibitor, which binds in a different way to the active state of KRAS, could still overcome this multi-mutant KRAS protein.

“Our results suggest a role for the rational design of distinct KRAS inhibitors to overcome resistance to KRAS(G12C) inhibitors in patients,” says Lin. “Additionally, the convergence of different mutations towards RAS-MAPK reactivation suggests that the greater impact for KRAS(G12C) inhibitors may be in combination with other drugs such as downstream RAS-MAPK pathway inhibitors. These are all areas that need to be further explored.”

Lin emphasizes that this study represents only the tip of the iceberg. “We need to extend our findings and better understand the scope of resistance mechanisms that occur in patients treated with KRAS(G12C) inhibitors and other mutant-specific KRAS inhibitors,” she says. “Ongoing efforts to comprehensively understand the mechanisms of resistance to mutant-specific KRAS inhibitors will be pivotal in developing novel therapeutic approaches and improving care for patients with KRAS-mutant cancers.”

Along with Lin, Noritaka Tanaka, PhD, and Chendi Li, PhD, served as co–lead authors of the study. Co–senior authors were Aaron Hata, MD, PhD, an investigator in the Mass General Center for Cancer Research, Rebecca Heist, MD, MPH, an attending physician in the Center for Thoracic Cancers and the Termeer Center for Targeted Therapy, and Ryan Corcoran, MD, PhD, director of the Gastrointestinal Cancer Center Program and scientific director of the Termeer Center. Additional co-authors included Meagan Ryan, PhD, Junbing Zhang, PhD, Leslie Kiedrowski, MS, MPH, Alexa Michel, Mohammed Syed, Katerina Fella, Mustafa Sakhi, MS, Islam Baiev, Dejan Juric, MD, Justin Gainor, MD, Samuel Klempner, MD, Jochen Lennerz, MD, PhD, Giulia Siravegna, PhD, and Liron Bar-Peled, PhD.

This research was supported by the Mark Foundation for Cancer Research, Stand Up To Cancer and the American Cancer Society.

Reference: Noritaka Tanaka, Jessica J. Lin, Chendi Li, Meagan B. Ryan, Junbing Zhang, Lesli A Kiedrowski, Alexa G. Michel, Mohammed U. Syed, Katerina A. Fella, Mustafa Sakhi, Islam Baiev, Dejan Juric, Justin F. Gainor, Samuel J. Klempner, Jochen K. Lennerz, Giulia Siravegna, Liron Bar-Peled, Aaron N. Hata, Rebecca S. Heist and Ryan B. Corcoran, “Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation”, Cancer Discovery, 2021. DOI: 10.1158/2159-8290.CD-21-0365

Provided by Massachusetts General Hospital

Researchers Reveal Elusive Inner Workings Of Antioxidant Enzyme With Therapeutic Potential (Chemistry)

University of Nebraska Medical Center researchers reveal elusive inner workings of antioxidant enzyme with therapeutic potential

Mitochondria, known as the powerhouses within human cells, generate the energy needed for cell survival. However, as a byproduct of this process, mitochondria also produce reactive oxygen species (ROS). At high enough concentrations, ROS cause oxidative damage and can even kill cells. An overabundance of ROS has been connected to various health issues, including cancers, neurological disorders, and heart disease.

An enzyme called manganese superoxide dismutase, or MnSOD, uses a mechanism involving electron and proton transfers to lower ROS levels in mitochondria, thus preventing oxidative damage and maintaining cell health. More than a quarter of known enzymes also rely on electron and proton transfers to facilitate cellular activities that are essential for human health. However, most of their mechanisms are unclear because of the difficulties in observing how protons move.

Researchers from the University of Nebraska Medical Center (UNMC) and the Department of Energy’s (DOE’s) Oak Ridge National Laboratory (ORNL) have now observed the complete atomic structure of MnSOD, including its proton arrangements, with neutron scattering. The findings, published in Nature Communications, reveal how protons are used as tools to help MnSOD transfer electrons for reducing ROS levels. The work could help experts develop MnSOD-based treatments and design therapeutic drugs that mimic its antioxidant behavior. The neutron study also opens an avenue for studying other enzymes that utilize electron and proton transfers.

“Using neutrons, we were able to see MnSOD features that were completely unexpected, and we believe this will revolutionize how people think this enzyme and other enzymes like it operate,” said Gloria Borgstahl, a UNMC professor and corresponding author of the new study.

MnSOD works by targeting superoxide, a reactive molecule that leaks from the mitochondrial energy production process and is the chemical precursor for other harmful ROS. The enzyme’s active site turns superoxide into less toxic products by using its manganese ion to move electrons to and from the reactive molecule. The manganese ion is capable of stealing an electron from a superoxide molecule, converting it to oxygen. This stolen electron can then be given to another superoxide to make hydrogen peroxide.

For this biochemical reaction to work, a series of proton movements need to take place between the enzyme’s amino acids and other molecules at its active site. The protons act as instruments that enable the electrons to move. Until now, the enzyme’s sequence of electron and proton transfers, also known as its catalytic mechanism, had not been defined at the atomic level because of challenges in tracking how protons are shuttled between molecules. A fundamental understanding of this catalytic process could inform therapeutic approaches that harness this enzyme’s antioxidant abilities.

Proton transfers are not easily seen because they occur in the form of atomic hydrogen, which x-rays and other techniques for observing atoms have difficulty detecting. Neutrons, on the other hand, are sensitive to lighter elements like hydrogen and thus can pinpoint proton movements. Neutrons are also well suited for this research because they do not interact with electrons, unlike other atom-visualizing techniques. Thus, they can be used to study the inner workings of electron-transfer enzymes without disturbing their electronic state.

“Because neutrons are particles that do not interact with charge, they don’t interfere with the electronic properties of metals, which makes them an ideal probe for analyzing metal-containing enzymes, like MnSOD,” said Leighton Coates, an ORNL neutron scattering scientist involved with this study. “Additionally, neutrons don’t cause radiation damage to materials, allowing us to collect multiple snapshots of the same sample as it shifts between electronic states.”

Using MaNDi, the macromolecular neutron diffractometer at ORNL’s Spallation Neutron Source (SNS), the research team was able to map out the entire atomic structure of MnSOD and track how the enzyme’s protons change when it gains or loses an electron. By analyzing the neutron data, the scientists traced the pathways of protons as they moved around the active site. Using this information, the team built a model of a proposed catalytic mechanism, detailing how electron and proton transfers enable MnSOD to regulate superoxide levels.

Their analysis suggests that catalysis involves two internal proton transfers between the enzyme’s amino acids and two external proton transfers that originate from solvent molecules. While the results of this study confirm some past predictions of the enzyme’s biochemical nature, several aspects were unexpected and challenge previously held beliefs.

For example, the team uncovered cyclic proton transfers occurring between a glutamine amino acid and a manganese-bound solvent molecule. This interaction is a central part of the catalytic process, as it allows the enzyme to cycle between its two electronic states. The researchers also found the proton movements within the active site to be unusual, as several amino acids did not have a proton where they normally would. The study demonstrates the dramatic effects a metal has on the chemistry of the active site that is usually not accounted for.

“Our results suggest that this mechanism is more complex and atypical than what past studies had theorized,” said Jahaun Azadmanesh, a researcher at UNMC and study co-author.

As a next step in the project, the researchers are now planning to examine the enzyme’s structure when it is bound to a superoxide substrate. They also aim to study mutated components of MnSOD to gain more details regarding how each amino acid influences catalysis. Another research goal is to expand their neutron analysis to other enzymes that rely on electron and proton transfers to carry out cellular tasks.

“Over a fourth of all known enzyme activities involve electron and proton transfers,” said Azadmanesh. “MnSOD is just one enzyme in a sea of many others, and with neutrons, we can study their catalytic mechanisms to a level of detail that hasn’t been possible before.”

This research was supported by the NASA EPSCoR program, the Fred & Pamela Buffett NCI Cancer Center, the Nebraska Research Initiative, and the DOE Office of Science. This research also used resources at the Center for Structural Molecular Biology at ORNL.

Featured image: The mitochondria in human cells depend on manganese superoxide dismutase to keep the amount of harmful reactive oxygen molecules under control. Researchers have now obtained a complete atomic portrait of the enzyme, providing key information about the catalytic mechanism within its active site, situated between the green and blue subunits and the yellow and pink subunits. © ORNL/Jill Hemman

Reference: Azadmanesh, J., Lutz, W.E., Coates, L. et al. Direct detection of coupled proton and electron transfers in human manganese superoxide dismutase. Nat Commun 12, 2079 (2021).

Provided by Oak Ridge National Laboratory

A New Type of Battery That Can Charge Ten Times Faster Than a Lithium-ion Battery Created (Chemistry)

Moreover, it is safer in terms of potential fire hazards and has a lower environmental impact

It is difficult to imagine our daily life without lithium-ion batteries. They dominate the small format battery market for portable electronic devices, and are also commonly used in electric vehicles. At the same time, lithium-ion batteries have a number of serious issues, including: a potential fire hazard and performance loss at cold temperatures; as well as a considerable environmental impact of spent battery disposal.

According to the leader of the team of researchers, Professor in the Department of Electrochemistry at St Petersburg University Oleg Levin, the chemists have been exploring redox-active nitroxyl-containing polymers as materials for electrochemical energy storage. These polymers are characterised by a high energy density and fast charging and discharging speed due to fast redox kinetics. One challenge towards the implementation of such a technology is the insufficient electrical conductivity. This impedes the charge collection even with highly conductive additives, such as carbon.

Looking for solutions to overcome this problem, the researchers from St Petersburg University synthesised a polymer based on the nickel-salen complex (NiSalen). The molecules of this metallopolymer act as a molecular wire to which energy-intensive nitroxyl pendants are attached. The molecular architecture of the material enables high capacitance performance to be achieved over a wide temperature range.

‘We came up with the concept of this material in 2016. At that time, we began to develop a fundamental project “Electrode materials for lithium-ion batteries based on organometallic polymers”. It was supported by a grant from the Russian Science Foundation. When studying the charge transport mechanism in this class of compounds, we discovered that there are two keys directions of development. Firstly, these compounds can be used as a protective layer to cover the main conductor cable of the battery, which would be otherwise made of traditional lithium-ion battery materials. And secondly, they can be used as an active component of electrochemical energy storage materials,’ explains Oleg Levin.

Professor in the Department of Electrochemistry at St Petersburg University Oleg Levin © SPbU

The polymer took over three years to develop. In the first year, the scientists tested the concept of the new material: they combined individual components to simulate the electrically conducting backbone and redox-active nitroxyl-containing pendants. It was essential to make certain that all parts of the structure worked in conjunction and reinforced each other. The next stage was the chemical synthesis of the compound. It was the most challenging part of the project. This is because some of the components are extremely sensitive and even the slightest error of a scientist may cause degradation of the samples.

Of the several polymer specimens obtained, only one was found to be sufficiently stable and efficient. The main chain of the new compound is formed by complexes of nickel with salen ligands. A stable free radical, capable of rapid oxidation and reduction (charge and discharge), has been linked to the main chain via covalent bonds.

‘A battery manufactured using our polymer will charge in seconds – about ten times faster than a traditional lithium-ion battery. This has already been demonstrated through a series of experiments. However, at this stage, it is still lagging behind in terms of capacity – 30 to 40% lower than in lithium-ion batteries. We are currently working to improve this indicator while maintaining the charge-discharge rate,’ says Oleg Levin.

The cathode for the new battery has been fabricated – a positive electrode for use in chemical current sources. Now we need the negative electrode – the anode. In fact, it does not have to be created from scratch – it can be selected from the existing ones. Paired together they will form a system that, in some areas, may soon supersede lithium-ion batteries.

‘The new battery is capable of operating at low temperatures and will be an excellent option where fast charging is crucial. It is safe to use – there is nothing that may pose a combustion hazard, unlike the cobalt-based batteries that are widespread today. It also contains significantly less metals that can cause environmental harm. Nickel is present in our polymer in a small amount, but there is much less of it than in lithium-ion batteries,’ says Oleg Levin.

Featured image: Symbolic representation of the chemical formula of the new polymer © Anatoliy A. Vereshchagin

Reference: A. A. Vereshchagin, D. A. Lukyanov, I. R. Kulikov, N. A. Panjwani, E. A. Alekseeva, J. Behrends, O. V. Levin, Batteries & Supercaps 2021, 4, 336.

Provided by St. Petersburg State University

Hubble Spots Double Quasars in Merging Galaxies (Astronomy)

NASA’s Hubble Space Telescope is “seeing double.” Peering back 10 billion years into the universe’s past, Hubble astronomers found a pair of quasars that are so close to each other they look like a single object in ground-based telescopic photos, but not in Hubble’s crisp view.

The researchers believe the quasars are very close to each other because they reside in the cores of two merging galaxies. The team went on to win the “daily double” by finding yet another quasar pair in another colliding galaxy duo.

A quasar is a brilliant beacon of intense light from the center of a distant galaxy that can outshine the entire galaxy. It is powered by a supermassive black hole voraciously feeding on inflating matter, unleashing a torrent of radiation.

“We estimate that in the distant universe, for every 1,000 quasars, there is one double quasar. So finding these double quasars is like finding a needle in a haystack,” said lead researcher Yue Shen of the University of Illinois at Urbana-Champaign.

The discovery of these four quasars offers a new way to probe collisions among galaxies and the merging of supermassive black holes in the early universe, researchers say.

Quasars are scattered all across the sky and were most abundant 10 billion years ago. There were a lot of galaxy mergers back then feeding the black holes. Therefore, astronomers theorize there should have been many dual quasars during that time.

“This truly is the first sample of dual quasars at the peak epoch of galaxy formation with which we can use to probe ideas about how supermassive black holes come together to eventually form a binary,” said research team member Nadia Zakamska of Johns Hopkins University in Baltimore, Maryland.

The team’s results appeared in the April 1 online issue of the journal Nature Astronomy.

These two Hubble Space Telescope images reveal two pairs of quasars that existed 10 billion years ago and reside at the hearts of merging galaxies. Each of the four quasars resides in a host galaxy. These galaxies, however, cannot be seen because they are too faint, even for Hubble. The quasars within each pair are only about 10,000 light-years apart — the closest ever seen at this cosmic epoch. Quasars are brilliant beacons of intense light from the centers of distant galaxies that can outshine their entire galaxies. They are powered by supermassive black holes voraciously feeding on infalling matter, unleashing a torrent of radiation. The quasar pair in the left-hand image is catalogued as J0749+2255 and the pair on the right as J0841+4825. The two pairs of host galaxies inhabited by each double quasar will eventually merge. The quasars will then tightly orbit each other until they eventually spiral together and coalesce, resulting in an even more massive, but solitary black hole. The image for J0749+2255 was taken Jan. 5, 2020. The J0841+4825 snapshot was taken Nov. 30, 2019. Both images were taken in visible light with Wide Field Camera 3. Credits: NASA, ESA, H. Hwang and N. Zakamska (Johns Hopkins University), and Y. Shen (University of Illinois, Urbana-Champaign)

Shen and Zakamska are members of a team that is using Hubble, the European Space Agency’s Gaia space observatory, and the Sloan Digital Sky Survey, as well as several ground-based telescopes, to compile a robust census of quasar pairs in the early universe.

The observations are important because a quasar’s role in galactic encounters plays a critical part in galaxy formation, the researchers say. As two close galaxies begin to distort each other gravitationally, their interaction funnels material into their respective black holes, igniting their quasars.

Over time, radiation from these high-intensity “light bulbs” launch powerful galactic winds, which sweep out most of the gas from the merging galaxies. Deprived of gas, star formation ceases, and the galaxies evolve into elliptical galaxies.

“Quasars make a profound impact on galaxy formation in the universe,” Zakamska said. “Finding dual quasars at this early epoch is important because we can now test our long-standing ideas of how black holes and their host galaxies evolve together.”

Astronomers have discovered more than 100 double quasars in merging galaxies so far. However, none of them is as old as the two double quasars in this study.

The Hubble images show that quasars within each pair are only about 10,000 light-years apart. By comparison, our Sun is 26,000 light-years from the supermassive black hole in the center of our galaxy.

The pairs of host galaxies will eventually merge, and then the quasars also will coalesce, resulting in an even more massive, single solitary black hole.

Finding them wasn’t easy. Hubble is the only telescope with vision sharp enough to peer back to the early universe and distinguish two close quasars that are so far away from Earth. However, Hubble’s sharp resolution alone isn’t good enough to find these dual light beacons.

Astronomers first needed to figure out where to point Hubble to study them. The challenge is that the sky is blanketed with a tapestry of ancient quasars that flared to life 10 billion years ago, only a tiny fraction of which are dual. It took an imaginative and innovative technique that required the help of the European Space Agency’s Gaia satellite and the ground-based Sloan Digital Sky Survey to compile a group of potential candidates for Hubble to observe.

Located at Apache Point Observatory in New Mexico, the Sloan telescope produces three-dimensional maps of objects throughout the sky. The team pored through the Sloan survey to identify the quasars to study more closely.

Video: This simulation shows the brilliant, flickering light from a pair of quasars. Astronomers in a recent study deduced that the blinking light is a telltale sign of the presence of two quasars and not a single object. Quasars reside at the hearts of galaxies. They are ignited by monster black holes voraciously feeding on infalling matter, unleashing a torrent of radiation. A quasar’s light fluctuates in brightness based on how much material its black hole is gobbling up at the time. This quasar pair is pouring out light because their galaxies are in the process of merging, which provides plenty of fuel for their hungry black holes. The quasars appear close together because they, too, are in the process of merging, along with their galaxies. The quasars were first identified by the European Space Agency’s Gaia spacecraft, which measures small changes in the brightness of stars. The quasar pair is too far away for Gaia to resolve. Instead, the pair looks like a single bright object. However, Gaia also measured an apparent “jiggle” in the light. The “jiggle” is a signal of the independent flickering light between two separate quasars, similar to a pair of alternating lights on a railroad-crossing signal. The Hubble Space Telescope is sharp enough to resolve the quasar pair, which astronomers had suspected from the Gaia data.Credits: NASA, ESA, and J. Olmsted (STScI)

The researchers then enlisted the Gaia observatory to help pinpoint potential double-quasar candidates. Gaia measures the positions, distances, and motions of nearby celestial objects very precisely. But the team devised a new, innovative application for Gaia that could be used for exploring the distant universe. They used the observatory’s database to search for quasars that mimic the apparent motion of nearby stars. The quasars appear as single objects in the Gaia data. However, Gaia can pick up a subtle, unexpected “jiggle” in the apparent position of some of the quasars it observes.

The quasars aren’t moving through space in any measurable way, but instead their jiggle could be evidence of random fluctuations of light as each member of the quasar pair varies in brightness. Quasars flicker in brightness on timescales of days to months, depending on their black hole’s feeding schedule.

This alternating brightness between the quasar pair is similar to seeing a railroad crossing signal from a distance. As the lights on both sides of the stationary signal alternately flash, the sign gives the illusion of “jiggling.”

When the first four targets were observed with Hubble, its crisp vision revealed that two of the targets are two close pairs of quasars. The researchers said it was a “light bulb moment” that verified their plan of using Sloan, Gaia, and Hubble to hunt for the ancient, elusive double powerhouses.

Team member Xin Liu of the University of Illinois at Urbana-Champaign called the Hubble confirmation a “happy surprise.” She has long hunted for double quasars closer to Earth using different techniques with ground-based telescopes. “The new technique can not only discover dual quasars much further away, but it is much more efficient than the methods we’ve used before,” she said.

Their Nature Astronomy article is a “proof of concept that really demonstrates that our targeted search for dual quasars is very efficient,” said team member Hsiang-Chih Hwang, a graduate student at Johns Hopkins University and the principal investigator of the Hubble program. “It opens a new direction where we can accumulate a lot more interesting systems to follow up, which astronomers weren’t able to do with previous techniques or datasets.”

The team also obtained follow-up observations with the National Science Foundation NOIRLab’s Gemini telescopes. “Gemini’s spatially-resolved spectroscopy can unambiguously reject interlopers due to chance superpositions from unassociated star-quasar systems, where the foreground star is coincidentally aligned with the background quasar,” said team member Yu-Ching Chen, a graduate student at the University of Illinois at Urbana-Champaign.

Although the team is convinced of their result, they say there is a slight chance that the Hubble snapshots captured double images of the same quasar, an illusion caused by gravitational lensing. This phenomenon occurs when the gravity of a massive foreground galaxy splits and amplifies the light from the background quasar into two mirror images. However, the researchers think this scenario is highly unlikely because Hubble did not detect any foreground galaxies near the two quasar pairs.

Galactic mergers were more plentiful billions of years ago, but a few are still happening today. One example is NGC 6240, a nearby system of merging galaxies that has two and possibly even three supermassive black holes. An even closer galactic merger will occur in a few billion years when our Milky Way galaxy collides with neighboring Andromeda galaxy. The galactic tussle would likely feed the supermassive black holes in the core of each galaxy, igniting them as quasars.

Future telescopes may offer more insight into these merging systems. NASA’s James Webb Space Telescope, an infrared observatory scheduled to launch later this year, will probe the quasars’ host galaxies. Webb will show the signatures of galactic mergers, such as the distribution of starlight and the long streamers of gas pulled from the interacting galaxies.

The Hubble Space Telescope is a project of international cooperation between NASA and ESA (European Space Agency). NASA’s Goddard Space Flight Center in Greenbelt, Maryland, manages the telescope. The Space Telescope Science Institute (STScI) in Baltimore, Maryland, conducts Hubble science operations. STScI is operated for NASA by the Association of Universities for Research in Astronomy in Washington, D.C.

Featured image: This artist’s conception shows the brilliant light of two quasars residing in the cores of two galaxies that are in the chaotic process of merging. The gravitational tug-of-war between the two galaxies stretches them, forming long tidal tails and igniting a firestorm of starbirth. Quasars are brilliant beacons of intense light from the centers of distant galaxies. They are powered by supermassive black holes voraciously feeding on infalling matter. This feeding frenzy unleashes a torrent of radiation that can outshine the collective light of billions of stars in the host galaxy. In a few tens of millions of years, the black holes and their galaxies will merge, and so will the quasar pair, forming an even more massive black hole. A similar sequence of events will happen a few billion years from now when our Milky Way galaxy merges with the neighboring Andromeda galaxy. Credits: NASA, ESA, and J. Olmsted (STScI)

Reference: Shen, Y., Chen, YC., Hwang, HC. et al. A hidden population of high-redshift double quasars unveiled by astrometry. Nat Astron (2021).

Provided by NASA

Moffitt Researchers Demonstrate Tissue Architecture Regulates Tumor Evolution: Location Matters (Medicine)

Tumors are genetically diverse with different mutations arising at different times throughout growth and development. Many models have tried to explain how genetic heterogeneity arises and what impact these alterations have on tumor growth. In a new article published in Nature Communications, Moffitt Cancer Center researchers show how the location of the tumor and spatial constraints put on it by the surrounding tissue architecture impact genetic heterogeneity of tumors.

Genetic differences are apparent among tumors from different patients, as well as within different regions of the same tumor of an individual patient. Some of these mutations may benefit the tumor and become selected for, such as mutations that allow the tumor to grow faster and spread to other sites. This type of tumor evolution is known as Darwinian evolution. Alternatively, other cellular mutations may have no immediate impact on the tumor but still accumulate over time, known as neutral evolution. Researchers in Moffitt’s Center of Excellence for Evolutionary Therapy wanted to determine how the surrounding tissue architecture impacts these different types of tumor evolution patterns and genetic heterogeneity.

The team used mathematical modeling to determine how spatial constraints impact tumor evolution with a focus on the three-dimensional architecture of ductal carcinoma of the breast. They used a well-studied model of tumor evolution and altered variables related to spatial constraints and cell mixing and demonstrated that the surrounding tissue architecture greatly affects the genetic heterogeneity of tumors over time. For example, the ductal network of breast tissue is similar to the trunk and branches of a tree. A tumor that forms within the wider region of the base of the duct has less spatial constraints placed on it compared to a tumor that initially forms in the smaller ductal branches. As a result, a tumor near the base tends to acquire mutations over an extended time and will have more genetic heterogeneity due to neutral evolution. On the other hand, a tumor within the smaller ductal regions tends to undergo accelerated genetic changes that result in one mutation becoming dominant due to Darwinian evolution, – also known as clonal sweep.

“Two otherwise identical tumors may realize dramatic differences in fitness depending on constraints imposed by tissue architecture,” said Sandy Anderson, Ph.D., study author and director of the Center of Excellence for Evolutionary Therapy at Moffitt. “On the cell scale, any given subclone may have a selective advantage. Yet, the effective outcome of this subclonal advantage depends on the surrounding competitive context of that cell. In other words, cell-specific phenotypic behavior can be ‘overridden’ by the tissue architecture, allowing the tumor to realize increased fitness.”

The study sheds light on the important role that tumor location has in the development and progression of cancer and helps explain the wide variety of mutational patterns observed among different patients.

“Our approach adds clarity to the debate of neutral tumor evolution by exploring a key mechanism behind both interpatient and intratumoral tumor heterogeneity: competition for space,” said Jeffrey West, Ph.D., study co-author and postdoctoral fellow in the Integrated Mathematical Oncology Department at Moffitt.

Their work was supported by the National Cancer Institute (U54CA193489, U01CA232382), Moffitt’s Center of Excellence for Evolutionary Therapy, the Wellcome Trust (108861/7/15/7) and the Wellcome Centre for Human Genetics (203141/7/16/7).

Featured image: Darwinian Evolution © Moffitt Cancer Center

Reference: West, J., Schenck, R.O., Gatenbee, C. et al. Normal tissue architecture determines the evolutionary course of cancer. Nat Commun 12, 2060 (2021).

Provided by Moffitt Cancer Center