Nerve Cell Activity Shows How Confident We Are (Neuroscience)

Should I or shouldn’t I? The activity of individual nerve cells in the brain tells us how confident we are in our decisions. This is shown by a recent study by researchers at the University of Bonn. The result is unexpected – the researchers were actually on the trail of a completely different evaluation mechanism. The results are published in the journal Current Biology.

The participants had to choose between two different snacks. The further they moved the slider to the left or right end, the more confident they were in their choice. © AG Mormann/Uni Bonn

You are sitting in a café and want to enjoy a piece of cake with your cappuccino. The Black Forest gateau is just too rich for you and is therefore quickly eliminated. Choosing between the carrot cake and the rhubarb crumble is much trickier: The warm weather favors the refreshingly fruity cake. Carrot cake, however, is one of your all-time favorites. So what to do?

Every day we have to make decisions, and we are much more confident about some of them than others. Researchers at the University Hospital Bonn have now identified nerve cells in the brain whose activity indicates the confidence in decisions. A total of twelve men and women took part in their experiment. “We showed them photos of two different snacks, for example a chocolate bar and a bag of chips,” explains Prof. Dr. Dr. Florian Mormann from the Department of Epileptology. “They were then asked to use a slider to indicate which of these alternatives they would rather eat.” The more they moved the slider from its center position towards the left or right photo, the more confident they were in their decision.

Fire rate and confidence are related

Participants had to judge a total of 190 different snack pairs in this way. At the same time, the scientists recorded the activity of 830 nerve cells each in the so-called temporal lobe. “We discovered that the frequency of the electrical pulses in some neurons, in other words their ‘firing rate’, changed with increasing decision confidence,” explains Mormann’s colleague Alexander Unruh-Pinheiro. “For instance, some fired more frequently, the more confident the respective test person was in their decision.”

Ultra-fine electrodes implanted in the temporal lobes of epileptic patients enable researchers to visualize the activity of individual nerve cells. © Christian Burkert

It is the first time that such a correlation between activity and decision confidence has been identified. The affected neurons are located in a brain region that plays a role in memory processes. “It is possible that we not only store what decision we made, but also how confident we were in it,” speculates Mormann. “Perhaps such a learning process saves us from future wrong decisions.”

Ethical reasons usually prohibit the study of the state of individual neurons in living humans. However, the participants in the study suffered from a severe form of epilepsy. In this form of the disease, the characteristic seizures always start in the same area of the brain. One possible treatment is therefore to remove this epileptic focus surgically. To pinpoint the exact location of the defective site, the doctors at the Clinic for Epileptology implant several electrodes in the patient. These are distributed over the entire potentially affected area. At the same time, they also allow an insight into the functioning of individual nerve cells in the brain.

Researchers at the University of Bonn were originally looking for a completely different phenomenon: When we make a decision, we assign a subjective value to each of the alternatives. “There is evidence that this subjective value is also reflected in the activity of individual neurons,” says Mormann. “The fact that we instead came across this connection between fire behavior and decision confidence surprised even us.”

References: Alexander Unruh-Pinheiro, Michael R. Hill, Bernd Weber, Jan Boström, Christian E. Elger, Florian Mormann: Single Neuron Correlates of Decision Confidence in the Human Medial Temporal Lobe. Current Biology; http://dx.doi.org/10.1016/j.cub.2020.09.021 link: https://www.cell.com/current-biology/fulltext/S0960-9822(20)31352-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS096098222031352X%3Fshowall%3Dtrue#main-menu

Provided by University Of Bonn

A New Look At Sunspots (Astronomy)

NASA’s extensive fleet of spacecraft allows scientists to study the Sun extremely close-up – one of the agency’s spacecraft is even on its way to fly through the Sun’s outer atmosphere. But sometimes taking a step back can provide new insight.

One of the largest sunspots seen in early January 2014, as captured by NASA’s Solar Dynamics Observatory. An image of Earth has been added for scale. ©NASA/SDO

In a new study, scientists looked at sunspots – darkened patches on the Sun caused by its magnetic field – at low resolution as if they were trillions of miles away. What resulted was a simulated view of distant stars, which can help us understand stellar activity and the conditions for life on planets orbiting other stars.

“We wanted to know what a sunspot region would look like if we couldn’t resolve it in an image,” said Shin Toriumi, lead author on the new study and scientist at ?the Institute of Space and Astronautical Science at JAXA. “So, we used the solar data as if it came from a distant star to have a better connection between solar physics and stellar physics.”

Sunspots are often precursors to solar flares – intense outbursts of energy from the surface of the Sun – so monitoring sunspots is important to understanding why and how flares occur. Additionally, understanding the frequency of flares on other stars is one of the keys to understanding their chance of harboring life. Having a few flares may help build up complex molecules like RNA and DNA from simpler building blocks. But too many strong flares can strip entire atmospheres, rendering a planet uninhabitable.

To see what a sunspot and its effect on the solar atmosphere would look like on a distant star, the scientists started with high-resolution data of the Sun from NASA’s Solar Dynamics Observatory and JAXA/NASA’s Hinode mission. By adding up all the light in each image, the scientists converted the high-resolution images into single datapoints. Stringing subsequent datapoints together, the scientists created plots of how the light changed as the sunspot passed across the Sun’s rotating face. These plots, which scientists call light curves, showed what a passing sunspot on the Sun would look like if it were many light-years away.

“The Sun is our closest star. Using solar observing satellites, we can resolve signatures on the surface 100 miles wide,” said Vladimir Airapetian, co-author on the new study and astrophysicist at NASA’s Goddard Space Flight Center in Greenbelt, Maryland. “On other stars you might only get one pixel showing the entire surface, so we wanted to create a template to decode activity on other stars.”

The new study, published in the Astrophysical Journal, looked at simple cases where there is just one group of sunspots visible across the entire face of the Sun. Even though NASA and JAXA missions have continually gathered observations of the Sun for over a decade, these cases are quite rare. Usually there are either several sunspots – such as during the solar maximum, which we are now moving toward – or none at all. In all the years of data, the scientists only found a handful of instances of just one isolated sunspot group.

Studying these events, the scientists found the light curves differed when they measured different wavelengths. In visible light, when a singular sunspot appears at the center of the Sun, the Sun is dimmer. However, when the sunspot group is near the edge of the Sun, it’s actually brighter due to faculae – bright magnetic features around sunspots – because, near the edge, the hot walls of their nearly vertical magnetic fields become increasingly visible.

The scientists also looked at the light curves in x-ray and ultraviolet light, which show the atmosphere above the sunspots. As the atmospheres above sunspots are magnetically heated, the scientists found brightening there at some wavelengths. However, the scientists also unexpectedly discovered that the heating could also cause a dimming in the light coming from the lower temperature atmosphere. These findings may provide a tool to diagnose the environments of spots on the stars.

“So far we’ve done the best-case scenarios, where there’s only one sunspot visible,” Toriumi said. “Next we are planning on doing some numerical modeling to understand what happens if we have multiple sunspots.”

By studying stellar activity on young stars in particular, scientists can glean a view of what our young Sun may have been like. This will help scientists understand how the young Sun – which was overall more dim but active – impacted Venus, Earth and Mars in their early days. It could also help explain why life on Earth started four billion years ago, which some scientists speculate is linked to intense solar activity.

Studying young stars can also contribute to scientists’ understanding of what triggers superflares – those that are 10 to 1000 times stronger than the biggest seen on the Sun in recent decades. Young stars are typically more active, with superflares happening almost daily. Whereas, on our more mature Sun, they may only occur once in a thousand years or so.

Spotting young suns that that are conducive to supporting habitable planets, helps scientists who focus on astrobiology, the study of the origin evolution, and distribution of life in the universe. Several next generation telescopes in production, which will be able to observe other stars in x-ray and ultraviolet wavelengths, could use the new results to decode observations of distant stars. In turn, this will help identify those stars with appropriate levels of stellar activity for life – and that can then be followed up by observations from other upcoming high-resolution missions, such as NASA’s James Webb Space Telescope.

Provided by NASA/GODDARD SPACE FLIGHT CENTER

CMS Sees Evidence Of Top Quarks In Collisions Between Heavy Nuclei (Physics)

The result opens the path to study in a new and unique way the extreme state of matter that is thought to have existed shortly after the Big Bang.

The CMS collaboration has seen evidence of top quarks in collisions between heavy nuclei at the Large Hadron Collider (LHC).

CMS candidate event for a top quark and antitop quark producing an electron, a muon and jets originating from bottom (b) quarks. (Image: CERN)

This isn’t the first time this special particle – the heaviest known elementary particle – has “made an appearance” at particle colliders. The top quark was first observed in proton–antiproton collisions at the Tevatron collider 25 years ago, and has since been spotted and studied in proton–proton and proton–nucleus collisions at the LHC. But the new finding, described in a paper just accepted for publication in Physical Review Letters, is sure to excite experimentalists and theorists alike, for analysis of top quarks in heavy-nuclei collisions offers a new and unique way to study the quark–gluon plasma that forms in these collisions and is thought to have existed in the early moments of the universe. In addition, such analysis could cast new light on the arrangement of quarks and gluons inside heavy nuclei.

There isn’t exactly a shortage of particles, or “probes”, with which to investigate the quark–gluon plasma. The LHC experiments have long been using several types of particle to study the properties of this extreme state of matter, in which quarks and gluons are not confined within composite particles but instead roam like particles in a liquid with small frictional resistance. But all of the existing probes provide time-averaged information about the plasma. By contrast, the top quark, owing to the particular way in which it transforms, or “decays” into other particles, can provide snapshots of the plasma at different times of its lifetime.

“Faster-moving top quarks provide later-time snapshots. By assembling snapshots taken with top quarks at a range of different speeds, we hope that it will eventually be possible to create a movie of the quark–gluon plasma’s evolution,” explains CERN-based researcher Guilherme Milhano, who co-authored a theoretical study on probing the quark–gluon plasma with top quarks. “The new CMS result represents the very first step down that road.”

The CMS collaboration saw evidence of top quarks in a large data sample from lead–lead collisions at an energy of 5.02 TeV. The team searched for collisions producing a top quark and a top antiquark. These quarks decay very quickly into a W boson and a bottom quark, which in turn also decay very rapidly into other particles. The CMS physicists looked for the particular case in which the final decay products are charged leptons (electrons or their heavier cousins muons) and “jets” of multiple particles originating from bottom quarks.

After isolating and counting these top–antitop collision events, CMS estimated the probability for lead–lead collisions to produce top–antitop pairs via charged leptons and bottom quarks. The result has a statistical significance of about four standard deviations, so it doesn’t yet cross the threshold of five standard deviations that is required to claim observation of top-quark production. But it represents significant evidence of the process – there’s only a 0.003% chance that the result is a statistical fluke. What’s more, the result is consistent with theoretical predictions, as well as with extrapolations from previous measurements of the probability in proton–proton collisions at the same collision energy.

“Our result demonstrates the capability of the CMS experiment to perform top-quark studies in the complex environment of heavy-nuclei collisions,” says CMS physicist Georgios Krintiras, a postdoctoral researcher at the University of Kansas, “and it’s the first stepping stone in using the top quark as a new and powerful probe of the quark–gluon plasma.”

Provided by CERN

RUDN University Ecologists Developed New Models To Identify Environmental Pollution Sources (Nature)

According to a team of ecologists from RUDN University, polycyclic aromatic hydrocarbons (PAHs) can be used as pollution indicators and help monitor the movement of pollutants in environmental components such as soils, plants, and water. To find this out, the team conducted a large-scale study of a variety of soil, water, and plant samples collected from a vast area from China to the Antarctic. The results of the study were published in the Applied Geochemistry journal.

According to a team of ecologists from RUDN University, polycyclic aromatic hydrocarbons (PAHs) can be used as pollution indicators and help monitor the movement of pollutants in environmental components such as soils, plants, and water. To find this out, the team conducted a large-scale study of a variety of soil, water, and plant samples collected from a vast area from China to the Antarctic. ©RUDN Univerisity.

Geochemical barriers mark the borders between natural environments at which the nature of element transfer changes dramatically. For example, the concentration of oxygen rapidly increases at groundwater outlets, because different chemical elements oxidize and accumulate on the barrier. A team of ecologists from RUDN University was the first in the world to suggest a model that describes the energy of mass transfer, i.e. the movement of matter in an ecosystem. In this model, polycyclic aromatic hydrocarbons (PAHs) are used as the markers of moving substances. PAHs are mainly toxic organic substances that accumulate in the soil. The team used their composition to monitor pollutions and track down their sources. To do so, the ecologists calculated the physical and chemical properties of PAHs and classified them.

“We developed a model that shows the accumulation, transformation, and migration of PAHs. It is based on quantitative measurements that produce more consistent results than descriptive visualizations. This helped us understand how physical and chemical properties of PAHs determine their accumulation in the environment,” said Prof. Aleksander Khaustov, a PhD in Geology and Mineralogy, from the Department of Applied Ecology at RUDN University.

PAHs can form due to natural causes (e.g. wildfires) or as a result of human activity, for example as the waste products of the chemical and oil industry. The team studied 142 water, plant, soil, and silt samples from different geographical regions. Namely, some samples were taken in the hydrologic systems of the Kerch Peninsula, some came from leather industry areas in China, from the vicinity of Irkutsk aluminum smelter, and different regions of the Arctic and Antarctic. Several snow samples were taken on RUDN University campus in Moscow. All collected data were unified, and then the amount of PAHs in each sample was calculated. After that, the results were analyzed in line with the thermodynamic theory to calculate entropy, enthalpy, and Gibbs energy variations. The first value describes the deviation of an actual process from the ideal one; the second one shows the amounts of released or consumed energy, and the third points out the possibility of mass transfer.

“Though our samples were not genetically uniform, they allowed us to apply thermodynamic analysis to matter and energy transfer in natural dissipative systems,” added Prof. Aleksander Khaustov.

The team identified several factors that have the biggest impact on PAHs accumulation. For example, in the ecosystems surrounding leather facilities in China, the key factor turned to be entropy variations, while on RUDN University campus it was the changes in Gibbs energy. The team described three types of processes that are characterized by the reduction, stability, or increase of all three thermodynamic parameters, respectively. Based on this classification and the composition of PAHs one can monitor pollution and track down its source.

References: Aleksander Khaustov, Margarita Redina, “Fractioning of the polycyclic aromatic hydrocarbons in the components of the non-equilibrium geochemical systems (thermodynamic analysis)”, Applied Geochemistry, Volume 120, September 2020, 104684, doi: https://doi.org/10.1016/j.apgeochem.2020.104684 link: https://www.sciencedirect.com/science/article/abs/pii/S0883292720301761?via%3Dihub

Provided by RUDN University

Graphene Microbubbles Make Perfect Lenses (Material Science)

New method generates precisely controlled graphene microbubbles with perfectly spherical curvature for lenses.

Tiny bubbles can solve large problems. Microbubbles–around 1-50 micrometers in diameter–have widespread applications. They’re used for drug delivery, membrane cleaning, biofilm control, and water treatment. They’ve been applied as actuators in lab-on-a-chip devices for microfluidic mixing, ink-jet printing, and logic circuitry, and in photonics lithography and optical resonators. And they’ve contributed remarkably to biomedical imaging and applications like DNA trapping and manipulation.

Photonic jet focused by a graphene oxide microbubble lens. ©H. Lin et al.

Given the broad range of applications for microbubbles, many methods for generating them have been developed, including air stream compression to dissolve air into liquid, ultrasound to induce bubbles in water, and laser pulses to expose substrates immersed in liquids. However, these bubbles tend to be randomly dispersed in liquid and rather unstable.

According to Baohua Jia, professor and founding director of the Centre for Translational Atomaterials at Swinburne University of Technology, “For applications requiring precise bubble position and size, as well as high stability–for example, in photonic applications like imaging and trapping–creation of bubbles at accurate positions with controllable volume, curvature, and stability is essential.” Jia explains that, for integration into biological or photonic platforms, it is highly desirable to have well controlled and stable microbubbles fabricated using a technique compatible with current processing technologies.

Balloons in graphene

Jia and fellow researchers from Swinburne University of Technology recently teamed up with researchers from National University of Singapore, Rutgers University, University of Melbourne, and Monash University, to develop a method to generate precisely controlled graphene microbubbles on a glass surface using laser pulses. Their report is published in the peer-reviewed, open-access journal, Advanced Photonics.

In situ optical microscopic images showing the process of the microbubble generation and elimination. ©H. Lin et al.

The group used graphene oxide materials, which consist of graphene film decorated with oxygen functional groups. Gases cannot penetrate through graphene oxide materials, so the researchers used laser to locally irradiate the graphene oxide film to generate gases to be encapsulated inside the film to form microbubbles–like balloons. Han Lin, Senior Research Fellow at Swinburne University and first author on the paper, explains, “In this way, the positions of the microbubbles can be well controlled by the laser, and the microbubbles can be created and eliminated at will. In the meantime, the amount of gases can be controlled by the irradiating area and irradiating power. Therefore, high precision can be achieved.”

Such a high-quality bubble can be used for advanced optoelectronic and micromechanical devices with high precision requirements.

The researchers found that the high uniformity of the graphene oxide films creates microbubbles with a perfect spherical curvature that can be used as concave reflective lenses. As a showcase, they used the concave reflective lenses to focus light. The team reports that the lens presents a high-quality focal spot in a very good shape and can be used as light source for microscopic imaging.

Lin explains that the reflective lenses are also able to focus light at different wavelengths at the same focal point without chromatic aberration. The team demonstrates the focusing of a ultrabroadband white light, covering visible to near-infrared range, with the same high performance, which is particularly useful in compact microscopy and spectroscopy.

Jia remarks that the research provides “a pathway for generating highly controlled microbubbles at will and integration of graphene microbubbles as dynamic and high precision nanophotonic components for miniaturized lab-on-a-chip devices, along with broad potential applications in high resolution spectroscopy and medical imaging.”

References: Han Lin et al., “Near perfect microlenses based on graphene microbubbles,” Adv. Photon. 2(5), 055001, doi 10.1117/1.AP.2.5.055001. Link: https://www.spiedigitallibrary.org/journals/advanced-photonics/volume-2/issue-05/055001/Near-perfect-microlenses-based-on-graphene-microbubbles/10.1117/1.AP.2.5.055001.full?SSO=1

Provided by SPIE

Oldest Monkey Fossils Outside Of Africa Found (Paleontology)

Three fossils found in a lignite mine in southeastern Yunan Province, China, are about 6.4 million years old, indicate monkeys existed in Asia at the same time as apes, and are probably the ancestors of some of the modern monkeys in the area, according to an international team of researchers.

Reconstruction of M. pentelicus from Shuitangba ©Mauricio Antón

“This is significant because they are some of the very oldest fossils of monkeys outside of Africa,” said Nina G. Jablonski, Evan Pugh University Professor of Anthropology, Penn State. “It is close to or actually the ancestor of many of the living monkeys of East Asia. One of the interesting things from the perspective of paleontology is that this monkey occurs at the same place and same time as ancient apes in Asia.”

The researchers, who included Jablonski and long-time collaborator Xueping Ji, department of paleoanthropology, Yunnan Institute of Cultural Relics and Archaeology, Kunming, China, studied the fossils unearthed from the Shuitangba lignite mine that has yielded many fossils. They report that “The mandible and proximal femur were found in close proximity and are probably of the same individual,” in a recent issue of the Journal of Human Evolution. Also uncovered slightly lower was a left calcaneus — heel bone — reported by Dionisios Youlatos, Aristotle University of Thessaloniki, Greece, in another paper online in the journal, that belongs to the same species of monkey, Mesopithecus pentelicus.

Photograph of the fossilized jawbone of a Miocene monkey, M. pentelicus. ©Xueping Ji, Yunnan Institute of Cultural Relics and Archaeology.

“The significance of the calcaneus is that it reveals the monkey was well adapted for moving nimbly and powerfully both on the ground and in the trees,” said Jablonski. “This locomotor versatility no doubt contributed to the success of the species in dispersing across woodland corridors from Europe to Asia.”

The lower jawbone and upper portion of the leg bone indicate that the individual was female, according to the researchers. They suggest that these monkeys were probably “jacks of all trades” able to navigate in the trees and on land. The teeth indicate they could eat a wide variety of plants, fruits and flowers, while apes eat mostly fruit.

Fossilized heel bone of M. pentelicus ©Xueping Ji, Yunnan Institute of Cultural Relics and Archaeology

“The thing that is fascinating about this monkey, that we know from molecular anthropology, is that, like other colobines (Old World monkeys), it had the ability to ferment cellulose,” said Jablonski. “It had a gut similar to that of a cow.”

These monkeys are successful because they can eat low-quality food high in cellulose and obtain sufficient energy by fermenting the food and using the subsequent fatty acids then available from the bacteria. A similar pathway is used by ruminant animals like cows, deer and goats.

“Monkeys and apes would have been eating fundamentally different things,” said Jablonski. “Apes eat fruits, flowers, things easy to digest, while monkeys eat leaves, seeds and even more mature leaves if they have to. Because of this different digestion, they don’t need to drink free water, getting all their water from vegetation.”

These monkeys do not have to live near bodies of water and can survive periods of dramatic climatic change.

“These monkeys are the same as those found in Greece during the same time period,” said Jablonski. “Suggesting they spread out from a center somewhere in central Europe and they did it fairly quickly. That is impressive when you think of how long it takes for an animal to disperse tens of thousands of kilometers through forest and woodlands.”

While there is evidence that the species began in Eastern Europe and moved out from there, the researchers say the exact patterns are unknown, but they do know the dispersal was rapid, in evolutionary terms. During the end of the Miocene when these monkeys were moving out of Eastern Europe, apes were becoming extinct or nearly so, everywhere except in Africa and parts of Southeast Asia.

“The late Miocene was a period of dramatic environmental change,” said Jablonski. “What we have at this site is a fascinating snapshot of the end of the Miocene — complete with one of the last apes and one of the new order of monkeys. This is an interesting case in primate evolution because it testifies to the value of versatility and adaptability in diverse and changing environments. It shows that once a highly adaptable form sets out, it is successful and can become the ancestral stock of many other species.”

References: Nina G.Jablonski, Denise F.Sug et al., “Mesopithecus pentelicus from Zhaotong, China, the easternmost representative of a widespread Miocene cercopithecoid species”, Journal of Human Evolution
Volume 146, September 2020, 102851, doi: https://doi.org/10.1016/j.jhevol.2020.102851 link: https://www.sciencedirect.com/science/article/pii/S0047248420301123?via%3Dihub

Provided by Penn State

Hubble Sees Swirls of Forming Stars (Astronomy)

At around 60 million light-years from Earth, the Great Barred Spiral Galaxy, NGC 1365, is captured beautifully in this image by the NASA/ESA Hubble Space Telescope. Located in the constellation of Fornax (the Furnace), the blue and fiery orange swirls show us where stars have just formed and the dusty sites of future stellar nurseries.

Located in the constellation of Fornax (the Furnace), the blue and fiery orange swirls show us where stars have just formed and the dusty sites of future stellar nurseries. ©European Space Agency

At the outer edges of the image, enormous star-forming regions within NGC 1365 can be seen. The bright, light-blue regions indicate the presence of hundreds of baby stars that formed from coalescing gas and dust within the galaxy’s outer arms.

This Hubble image was captured as part of a joint survey with the Atacama Large Millimeter/submillimeter Array (ALMA) in Chile. The survey will help scientists understand how the diversity of galaxy environments observed in the nearby universe, including NGC 1365 and other galaxies such as NGC 2835 and NGC 2775, influence the formation of stars and star clusters. Expected to image over 100,000 gas clouds and star-forming regions beyond our Milky Way, the PHANGS survey is expected to uncover and clarify many of the links between cold gas clouds, star formation, and the overall shape and morphology of galaxies.

Provided by NASA Goddard

RUDN University Chemists Developed A Domino Reaction For Producing New Antitumor Drugs (Medicine)

A team of chemists from RUDN University suggested a new reaction to produce organic compounds in one vessel. The end products turned out to be effective against the cells of carcinomas, including drug-resistant ones. The new reaction was described in the Bioorganic Chemistry journal.

A team of chemists from RUDN University suggested a new reaction to produce organic compounds in one vessel. The end products turned out to be effective against the cells of carcinomas, including drug-resistant ones. ©RUDN University

For many organic substances synthesis is a multistage process of step-by-step molecule assembly. At each stage, only one chemical bond is formed. After each step, the product is purified and used in the next reaction. Domino reactions are a cascade of reactions that happen one after another in one vessel without any additional reagents. A team of chemists from RUDN University in collaboration with University of Bari, identified a number of substances that initiate a domino synthesis of chromenoisoquinolineamine derivatives. Similar compounds are used as anti-inflammatory and antitumor drugs, and some of them can potentially treat Alzheimer’s disease.

The team suggested using salicylaldehyde (a derivative of salicylic acid) and homophthalonitrile and catalyzing the reaction with ammonium formate that is cheap and eco-friendly. The initial reagents were mixed with water and isopropyl alcohol and put into a microwave reactor where the mixture was heated up to 150°C for 20 minutes. The researchers used salicylaldehydes with different substituents and as a result, received 19 derivatives of chromenoisoquinolineamines with 43-85% yields of respective reaction products.

To analyze the medical potential of the new substances, the chemists tested their effect on human cancerous cells. Cisplatin that is used in chemotherapy and is known to kill tumor cells was taken as a benchmark for comparison. The team chose the cells of breast and colon cancers, as well as three strains of ovary cancer cells (two of which were cisplatin-resistant) for the test. All new substances turned out to be toxic for tumor cells, including the resistant strains. The researchers selected two compounds that proved to be efficient even in low concentrations and ran computer modeling. According to it, the reason for their efficiency was an additional amine group that forms a stable bond with the nucleotides of the cancer cells DNA.

“In our work, we searched for new compounds with promising therapeutic properties, as well as for ways to synthesize them. Our approach allows for the synthesis of tumor-combating substances in the course of one domino reaction that is extremely efficient: four new bonds are created within one synthetic operation. We worked together with our Italian partners, and the study was supported by the Russian Science Foundation. In the future, we plan to improve our methodology and develop three- and four-component reactions on its basis,” said Alexey Festa, a Candidate of Chemical Sciences, and a senior lecturer at the Department of Organic Chemistry, RUDN University.

References: Xiaoyi Yue, Leonid G.Voskressenskya, et al., “Reductive domino reaction to access chromeno[2,3-c]isoquinoline-5-amines with antiproliferative activities against human tumor cells”, Bioorganic Chemistry, Volume 104, November 2020, 104169 doi: https://doi.org/10.1016/j.bioorg.2020.104169 link: https://www.sciencedirect.com/science/article/abs/pii/S0045206820314668?via%3Dihub

Provided by RUDN University

New Research Provides Fresh Hope For Children Suffering From Rare Muscle Diseases (Medicine)

Results of an international study published today in Autophagy and led by researchers from Monash University, School of Biological Sciences, provides renewed hope for children suffering from a progressive and devastating muscle disease.

Stephen Greenspan and Laura Zah were devastated when they learned their son Alexander had a rare genetic mutation, which causes a deadly neuromuscular disease with no known treatment or cure.

Metformin rescues muscle function in BAG3 myofibrillar myopathy models. ©Taylor & Francis

But the results of an international study published today in Autophagy and led by researchers from Monash University, School of Biological Sciences, provides renewed hope for children suffering from the progressive and devastating muscle disease. Known as myofibrillar myopathies, these rare genetic diseases lead to progressive muscle wasting, affecting muscle function and causing weakness.

Using the tiny zebrafish, Associate Professor Robert Bryson-Richardson from the School of Biological Sciences and his team of researchers were able to show that a defect in protein quality control contributes to the symptoms of the diseases.

“We tested 75 drugs that promote the removal of damaged proteins in our zebrafish model and identified nine that were effective” explained first author Dr Avnika Ruparelia, who completed her student and post-doctoral training in the team working on the disease. “Importantly two of these are already approved for human use in other conditions.”

“We found that one of the drugs, metformin, which is normally used to treat diabetes, removed the accumulating damaged protein in the fish, prevented muscle disintegration and restored their swimming ability,” said Associate Professor Bryson-Richardson, who led the study.

The most severe form of the myofibrillar myopathy, caused by a mutation in the gene BAG3, starts to affect children between 6 and 8 years of age. The disease is usually fatal before the age of 25 due to respiratory or cardiac failure.

In the case of Alexander (who was born in 2003) clinicians were able to draw on the study’s information to prescribe metformin – which is so far proving positive.

“Initially, we were devastated by our son’s diagnosis. Alexander has a rare mutation that causes a deadly neuromuscular disease. No treatment or cure was known. In desperation we formed the charitable organization, Alexander’s Way, to promote and sponsor research into this disease. Upon learning of our awful problem, A/Prof Bryson-Richardson was compassionate, and found a way to share with us his pre-publication results about the disease and metformin. The research conducted by Robert Bryson-Richardson and Avnika Ruparelia has given us hope, and we thank them deeply for their work and compassion,” said Alexander’s father, Stephen.

“This is a wonderful outcome, as initially we thought that because of the rarity of the mutation, it was unlikely that there would ever be a treatment or therapeutic intervention available,” said Alexander’s mother, Laura Zah. “Compared to previous case studies, the progression of our son’s disease has been slower, likely due to metformin. Another boy, Marco, who is affected by this disease also takes metformin, and is presently judged by his mother to be stable. Metformin may have given us more time with our boys and more time to work for a cure.”

Associate Professor Bryson-Richardson said the repurposing of existing drugs provided a very rapid route to clinical use, as there was already existing safety data for the drug. This is especially important for these rare diseases as the patient numbers are low, meaning it might not be possible to do clinical trials with novel drugs.

“We have identified metformin as a strong candidate to treat BAG3 myofibrillar myopathy, and also myofibrillar myopathy due to mutations in other genes (we showed similar defects in protein quality control in three other forms) and in cardiomyopathy due to mutations in BAG3,” he said.

“Given that metformin is taken by millions of people for diabetes and known to be very safe this makes clinical translation highly feasible, and in fact many patients are now taking it.”

Stephen and Laura Zah are the founders of the charitable organisation Alexander’s Way Research Fund which they established to promote and sponsor research into myofibrillar myopathies.

“The research conducted by Monash scientists has given us hope, and we thank them deeply for their compassion – they have given us time,” said Laura Zah.

References: Avnika A. Ruparelia , Emily A. McKaige, Caitlin Williams, Keith E. Schulze, Margit Fuchs , Viola Oorschot, Emmanuelle Lacene , Mirella Meregalli , Clara Lee , Rita J. Serrano , Emily C. Baxter , Keyne Monro , Yvan Torrente , Georg Ramm, Tanya Stojkovic , Josée N. Lavoie & Robert J. Bryson-Richardson, “Metformin rescues muscle function in BAG3 myofibrillar myopathy models”, Journal Autophagy, doi: https://doi.org/10.1080/15548627.2020.1833500 link: https://www.tandfonline.com/doi/full/10.1080/15548627.2020.1833500

Provided by Taylor And Francis Group