Culture

A mathematician from RUDN University developed a matrix representation of set functions. This approach is vivid and easy to check, and it makes the calculations easier. Among other things, the new development can be applied to cooperative game theory. The results of the work were published in the Information Sciences journal.

Specialists in cooperative game theory study methods of coplex decision-making in situations with multiple criteria. In such a situation, groups (or coalitions) of players have to come up with a decision that is the most profitable for all of them. Set functions are one of the tools used to work with cooperative game theory. In these functions, the input data are sets of elements that can have different values. Simple explicit questions are quite rare in real life; therefore, the data on different elements can support or neutralize each other. Combinations of elements called coalitions can assume their own values. To work with this apparatus, scientists require an intuitive mathematical language. A mathematician from RUDN University suggested his approach to it.

"Our contribution to the mathematical language of cooperative game theory is based on the familiar notions of matrices and vectors. We have developed a formal approach to manipulations with set functions based on linear algebra. Our results can be practically applied to multicriteria decision analysis, group decision-making, operations with dependent goals, economic theories based on cooperative games, and aggregate functions theory," said Prof. Gleb Beliakov, a Candidate of Physics and Mathematics from RUDN University.

Prof. Beliakov wanted to develop a universal approach that would make expressions equally understandable and convenient for mathematicians, engineers, economists, and specialists in computer science. The best option for it was linear algebra operations based on matrices. Operations with matrices are included in most software packages and are also useful for parallel computations.

The scientist obtained matrix expressions by transforming a derived set function expression. A derived function shows how a function transforms when its variables change. Having calculated a derived function, a specialist can give an accurate analysis of a certain situation. In linear algebra, treating an exponential set this way can simplify calculation methods and support effective implementation of many formulae in software. Prof. Beliakov also suggested new formulae for finding the Shapley vector--a version of 'fair distribution' in which the profit of each player is equal to their average contribution to respective coalitions. The new method makes it easier to obtain the Shapley vector in practical applications.

"Set functions are used in economics, decision-making, fuzzy logic, and operational research. An exponential set is a particularly effective tool to model input variables in corporate games. The new apparatus could simplify calculations and support software implementation of many formulae using existing linear algebra packages," added Prof. Gleb Beliakov from RUDN University.

For their growth, cells need various nutrients and vitamins. So-called solute carriers (SLC), proteins that can transport such substances across the boundaries of cellular membranes, play a central role in metabolism. Scientists in Giulio Superti-Furga's research group at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have now discovered that the previously uncharacterised protein SLC25A51 acts as a transporter into the mitochondria for the coenzyme NAD. This molecule has already been associated with numerous physiological and pathological processes such as ageing, neurological diseases and the metabolism of cancer cells. Therefore, the results of this study not only open up new possibilities to study the biological role of NAD but also potentially provide the basis for new therapeutic approaches. The work has now been published in the journal Nature Communications.

Solute carriers (SLC) are proteins that act as transporters and enable the entry and exit of nutrients and waste products into and from the cell and its organelles. Many of these transporter proteins are still relatively poorly studied and the question of how some nutrients enter and leave cells often remains unanswered. So far, it has not yet been clarified how mitochondria gain access to an important cofactor of our metabolism, the so-called NAD (nicotinamide adenine dinucleotide). In scientific literature, there were only references to mitochondrial NAD transporters in plants and yeast. Lead author Enrico Girardi and the research group of CeMM Scientific Director Giulio Superti-Furga, in cooperation with scientists from the University of Bari (Italy), have now identified the protein responsible for the important transport of NAD into mitochondria: SLC25A51.

Measurement of nutrient pathways provided evidence

For their studies, the scientists used a specially created cell line library, which allows investigating pairwise genetic interactions of two SLCs. Their genes are deactivated both individually and in pairs; the effects of these interventions on cell growth can then be measured. Among the combination-related large number of interactions measured, some around the previously uncharacterised gene SLC25A51 stood out. The other interacting SLCs transport various nutrients, but all of them could be associated with NAD via known metabolic processes. "By accurately quantitatively measuring certain nutrients in the cells, we found that the presence of SLC25A51 correlated with the amount of NAD and that cells lacking SLC25A51 had extremely low levels of this molecule in their mitochondria," explains senior author Giulio Superti-Furga. "In our study, we also show that the already known NAD transporter in yeast and SLC25A51 play a similar role in the human cell."

Important part of the scientific puzzle

The question of the existence of a mitochondrial NAD transporter in humans has been discussed for some time. Giulio Superti-Furga also explains: "The results of our research, which have also been confirmed in two other independent studies by US laboratories, provide an important answer to this question and open up the opportunity of influencing the NAD content in this key organelle. NAD is associated with many physiological and pathological processes such as ageing, neurological diseases and the metabolism of cancer cells. Our study, therefore, represents an important contribution to understanding the biological role of this molecule. At the same time, we also see the enormous therapeutic potential arising from the possibility of a possible modulation of the NAD content in mitochondria by the transporter SLC25A51."

In The Social Dilemma, the Netflix documentary that has been in the news recently for its radical revelations, former executives at major technology companies like Facebook, Twitter, and Instagram, among others, share how their ex-employers have developed sophisticated algorithms that not only predict users' actions but also know which content will keep them hooked on their platforms. The knowledge that technology companies are preying on their users' digital activities without their consent and awareness is well-known. But Associate Professor Jon Truby and Clinical Assistant Professor Rafael Brown at the Centre for Law and Development at Qatar University have pulled the curtain on another element that technology companies are pursuing to the detriment of people's lives, and investigated what we can do about it. "We had been working on the digital thought clone paper a year before the Netflix documentary aired. So, we were not surprised to see the story revealed by the documentary, which affirm what our research has found," says Prof Brown, one of the co-authors.

Published in Information & Communications Technology Law, their paper identifies "digital thought clones," which act as digital twins that constantly collect personal data in real-time, and then predict and analyze the data to manipulate people's decisions. Activity from apps, social media accounts, gadgets, GPS tracking, online and offline behavior and activities, and public records are all used to formulate what they call a "digital thought clone". The paper defines digital thought clone as "a personalized digital twin consisting of a replica of all known data and behavior on a specific living person, recording in real-time their choices, preferences, behavioral trends, and decision making processes."

"Currently existing or future artificial intelligence (AI) algorithms can then process this personalized data to test strategies in real-time to predict, influence, and manipulate a person's consumer or online decisions using extremely precise behavioral patterns, and determine which factors are necessary for a different decision to emerge and run all kinds of simulations before testing it in the real world," says Prof Truby, a co-author of the study.

An example is predicting whether a person will make the effort to compare online prices for a purchase, and if they do not, charging a premium for their chosen purchase. This digital manipulation reduces a person's ability to make choices freely. Outside of consumer marketing, imagine if financial institutions use digital thought clones to make financial decisions, such as whether a person would repay a loan. What if insurance companies judged medical insurance applications by predicting the likelihood of future illnesses based on diet, gym membership, the distance applicants walk in a day--based on their phone's location history--and their social circle, as generated by their phone contacts and social media groups, and other variables?

The authors suggest that the current views on privacy, where information is treated either as a public or private matter or viewed in contextual relationships of who the information concerns and impacts, are outmoded. A human-centered framework is needed, where a person can decide from the very beginning of their relationship with digital services if their data should be protected forever or until they freely waive it. This rests on two principles: the ownership principle that data belongs to the person, and that certain data is inherently protected; and the control principle, which requires that individuals be allowed to make changes to the type of data collected and if it should be stored. In this framework, people are asked beforehand if data can be shared with an unauthorized entity.

The European Union's landmark General Data Protection Regulation and the California Consumer Privacy Act of 2018 can serve as a foundation for governments everywhere to legislate on digital thought clones and all that they entail. But the authors also raise critical moral and legal questions over the status of these digital thought clones. "Does privacy for humans mean their digital clones are protected as well? Are users giving informed consent to companies if their terms and conditions are couched in misleading language?" asks Prof Truby.

A legal distinction must be made between the digital clone and the biological source. Whether the digital clone can be said to have attained consciousness will be relevant to the inquiry but far more important would be to determine whether the digital clone's consciousness is the same as that of the biological source.

The world is at a crossroads: should it continue to do nothing and allow for total manipulation by the technology industry or take control through much-needed legislation to ensure that people are in charge of their digital data? It's not quite a social dilemma.

Plants have the unique capability to sense and adapt to changes in their environment

This information is stored in the form of 'epigenetic memory' which can be passed on to the offspring, resulting in defects in growth and development.

Researchers have identified two proteins responsible for erasing plant memory to maximise chances of offspring survival.

Researchers at the University of Warwick have uncovered the mechanism that allows plants to pass on their 'memories' to offspring, which results in growth and developmental defects.

In order to survive and thrive, plants have the unique capability to sense and remember changes in their environment. This is linked to the chemical modification of DNA and histone proteins, which alters the way in which DNA is packaged within the cell's nucleus and genes are expressed - a process known as epigenetic regulation.

Usually, this epigenetic information is reset during sexual reproduction to erase any inappropriate 'memories' from being passed on to ensure the offspring grows normally. In the paper, 'A new role for histone demethylases in the maintenance of plant genome integrity' published in the journal elife, it was found that some plants were unable to forget this information and passed it on to their offspring, thereby affecting their chances of survival.

The researchers identified two proteins in Thale Cress (Arabidopsis), previously known only to control the initiation and timing of flowering, that are also responsible for controlling 'plant memory' through the chemical modification (demethylation) of histone proteins.

They showed that plants unable to reset these chemical marks during sexual reproduction, passed on this 'memory' to subsequent generations, resulting in defects in growth and development.

Some of these defects were linked to the activation of selfish DNA elements, also known as 'jumping genes' or transposons, thus indicating that the erasure of such 'memory' is also critical for maintaining the integrity of plant genomes by silencing transposons.

Prof. Jose Gutierrez-Marcos, a senior author on the paper from the School of Life Sciences at the University of Warwick commented:

"Our study into the proteins that regulate plant memory has shown how important it is for chemical marks to be reset during sexual reproduction in order to avoid offspring inheriting inappropriate 'memories' that lead to growth and developmental defects associated with genome instability.

"The next step is to work out how to manipulate such 'memories' for plant breeding purposes, so that subsequent generations show greater adaptability to allow them to thrive in a changing environment."

Virologists at the Rega Institute at KU Leuven (Belgium) have developed a vaccine candidate against Covid-19 based on the yellow fever vaccine, which as a result also works against yellow fever. Results published today in Nature show that the vaccine protects hamsters from infection with the SARS-CoV-2 coronavirus after a single dose. The vaccine is also effective in monkeys. The team is currently preparing for clinical trials.

To engineer their vaccine, tentatively named RegaVax, the team led by Professor Johan Neyts and Kai Dallmeier inserted the genetic code of the SARS-CoV-2 spikes into the genetic code of the yellow fever vaccine. The researchers tested the vaccine in healthy hamsters and monkeys. Another group of the animals received a placebo.

The researchers first vaccinated the hamsters and then dripped the virus into their noses. Ten days after a single vaccine dose, most of the hamsters were protected against the virus. Three weeks after vaccination, all hamsters were protected. "They also didn't develop any lung infections. The lungs of the hamsters in the control groups, by contrast, showed clear signs of infection and disease," Neyts explains.

The team also tested the vaccine in monkeys. "In some of the monkeys, we observed neutralising antibodies already seven days after vaccination. After fourteen days, high titers of neutralizing antibodies were measured in all animals. This is very fast. Moreover, in the vaccinated animals, the virus was completely or nearly completely gone from their throats."

Long-lasting immunity

"Ours is the only vaccine currently in development against Covid-19 that also protects against yellow fever," explains professor Neyts. Previously, the Rega team used the yellow fever vaccine as the foundation for vaccine candidates against Zika, Ebola, and rabies. "The effectiveness and safety of the yellow fever vaccine, which has been in use for 80 years, is well-established. More than 500 million people have already received this vaccine. One dose offers fast protection against yellow fever that in nearly all cases lasts for life."

"A vaccine that works against Covid-19 and yellow fever could offer an important contribution to the WHO's campaign to eradicate yellow fever by 2026," Neyts continues. "Especially now that we know there are mosquito species present in Asia that can transmit the yellow fever virus."

RegaVax works after one dose, unlike many of the front-runners in the race today, which require a repeat vaccination after one month. "This has important logistical implications, in particular for countries with a less advanced medical system," explains professor Neyts. "Additionally, we expect that the vaccine will offer long-lasting immunity to Covid-19. It could therefore be an ideal candidate for repeat vaccinations when immunity decreases in people who have received one of the first-generation vaccines."

Finally, the vaccine can be stored at 2-8 °C, while some vaccines require a cold chain with temperatures down to -70 °C. That's already challenging in the Western world, but it may be nearly impossible to vaccinate large populations in remote tropical and subtropical regions," Neyts explains.

"An inexpensive, single-dose vaccine that rapidly protects against infection, that can be stored and transported at fridge temperature, and that may, like the yellow fever vaccine on which it is based, result in long-lasting immunity, provides an important and much-needed diversification of the Covid-19 vaccine landscape," Neyts concludes.

His team is now preparing for clinical trials next year and has joined forces with a specialised and accredited company that will produce the vaccine candidate for testing in humans.

New technique

RegaVax is a vector vaccine: it uses the genetic code of the yellow fever vaccine virus as a carrier (or vector) for the genetic code of the coronavirus spikes. "When working with a related virus, such as the Zika virus, pieces of the genetic code of the yellow fever vaccine virus are swapped with a similar piece of the code of the targeted virus. Using this strategy the team recently developed a Zika vaccine candidate. However, since SARS-CoV-2 is unrelated to yellow fever, a new technology had to be developed to insert an entirely unrelated genetic sequence in the yellow fever vaccine backbone. This concerns an important innovation in the vaccine field."

Virus inhibitors

"Mind you: vaccines are not a solution for people who are already ill. That is why we are also developing a cure to help Covid-19 patients," Neyts concludes. "We recently published on the protective activity of the Japanese flu drug favipiravir in hamsters. We have identified some other existing medicines or combinations thereof that inhibit the virus. We are now first exploring their effect in infected hamsters. At the same time, we aim to develop new and powerful virus inhibitors against SARS-CoV-2. For this purpose, we have already tested more than 1.6 million molecules in our fully automated high biosafety laboratory. We're looking for a needle in a haystack."

Radio has always proved to be a medium that adapts easily to crisis situations. Throughout history, at times of major natural disasters and health emergencies, radio has played a leading role thanks to the fact that is the most universal, simplest and most accessible of media.

In the current crisis caused by covid-19, radio has again stood out as being an essential medium to stay informed, according to the study by Rodero (2020). The results indicate that radio is the medium that scores highest for its treatment of information about the pandemic.

The main goal of a recent article published in Index.comunicación by Emma Rodero, director of the UPF Media Psychology Lab at the Department of Communication, and María Blanco-Hernández, a researcher at the International University of La Rioja, was to demonstrate the influence of radio in crisis situations and describe the main initiatives that the medium is implementing relating to covid-19.

Thus, the authors have conducted a review of the state of affairs that has revealed the importance of radio in such situations. In addition, a detailed analysis of the information provided by the main domestic and international radio stations after the onset of the pandemic has allowed collating the most interesting initiatives implemented in each of them.

Increase in radio listening during the pandemic around the world

In Spain, the study by Rodero (2020) recorded an increase in radio consumption during the pandemic of almost one point. Most listeners tuned in between one and two hours a day; between 30 minutes and an hour and between two and three hours. The peak slot continued to be mornings, but due to lockdown, listening was more spread throughout the day, with increased listening especially in the afternoon and at midday. The broadcasters that experienced the highest increase were conventional general stations, while music stations suffered a decrease.

This upward trend in consumption during the pandemic has also been recorded in other countries. In the UK, Radiocentre has recorded an increase in commercial radio listening of 1 hour and 45 minutes. Broadcasters with a younger audience, like Fun Kids, have extended their broadcasting hours targeting children. The BBC puts increased consumption at 18%. In Italy, according to the Association of European Radios, the number of listeners has increased by 2.4%. In the United States there has been a 28% increase in consumption. In Chile, four out of five people heard the radio during the week, and two thirds did so daily. In Australia, listeners have heard an average of 1 hour and 46 minutes of radio a week during the pandemic and 72% of Australians are listening to as much or more radio during this crisis. In India, 82% of the population has been listening to radio during the pandemic with a 23% increase. In South Africa, a survey by the National Association of Broadcasters estimated at 36% the number of listeners who claim to be listening to more radio due to the pandemic.

Adaptation of labour relations, formats and content

Radio stations have had to adapt to the new situation with professionals working from home and schedules modified to include content on the coronavirus. As in other crises, listening has increased, and the medium is helping to alleviate the psychological effects of the pandemic.

The study reflects some specific cases of adaptation such as that of Cadena Cope, "where between just 20 and 30% of workers have attended the workplace in person", or the case of the United Kingdom "where community radio stations have innovated and improved their ingenuity presenting programmes, providing entertainment and information". It also cites the case of Ràdio UNDAV (National University of Avellaneda) in Argentina, which has created a procedure manual for radio operators explaining the technical mechanisms through which to perform tasks remotely. In the field of music, one of the initiatives that has had greatest reach in Spain is the proposal by Jordi Cruz of Cadena 100. The idea was to use the song entitled Resistiré (I will resist) by Dúo Dinámico (1988) as the anthem of the pandemic, in order to raise the spirits of all citizens.

The study concludes that the technical simplicity of radio has been an ally in allowing the stations to continue broadcasting regularly. Radios worldwide have responded with all kinds of initiatives. Many have dedicated special programmes or podcasts to the pandemic, some with up-to-date information, others reviewing the history or the causes of the pandemic, others reflecting the reality and its effects, and others with a clear mission to help clear up doubts about the disease.

This central role of radio is also seen in the number of initiatives that different stations around the world have organized, such as competitions and acts of solidarity to help all those affected. Once again, as has happened at other times of emergency in history, radio is playing a major role.

Transportation - Taking to the skies

If air taxis become a viable mode of transportation, Oak Ridge National Laboratory researchers have estimated they could reduce fuel consumption significantly while alleviating traffic congestion.

Air taxis, small aerial vehicles that provide point-to-point, on-demand travel, have proven to save time, but their impact on fuel use remains largely unquantified.

An ORNL study focused on the energy used by air taxis between downtown Los Angeles and Los Angeles International Airport, a route in which congestion is severe during peak hours.

"Our modeling, which can be applied to any congested route, showed that diverting 3-20% of traffic on this route could reduce the traffic and vehicle fuel use from 15-74%," ORNL's Zhenhong Lin said. "The key insight is that if only a small share of travelers in congested areas switched to air taxis, you would create a win-win-win outcome for commuters, the economy and the environment."

Media Contact: Jennifer Burke, 865.414.6835, burkejj@ornl.gov

Image: https://www.ornl.gov/sites/default/files/2020-11/airTaxi_730x457.jpg

Caption: An ORNL model using air taxis on the heavily traveled route between downtown Los Angeles and Los Angeles International Airport revealed that fuel consumption is significantly reduced if even a small percentage of commuters switched to air taxis. Credit: Andy Sproles/ORNL, U.S. Dept. of Energy

Biology - Fungi speak

Oak Ridge National Laboratory and collaborators have discovered that signaling molecules known to trigger symbiosis between plants and soil bacteria are also used by almost all fungi as chemical signals to communicate with each other.

As researchers study how these signals regulate fungal growth, this understanding could inform development of hardier crops and treatments for fungal diseases in plants and humans.

The molecules are called LCOs, short for lipo-chitooligosaccharides, and are used by bacteria to form nodules on plant roots where bacteria convert atmospheric nitrogen into a form that fuels plant growth. The study demonstrated that diverse species across the fungal kingdom also produced LCOs, which play roles in shaping fungal communities.

"Preliminary findings indicate that LCOs benefit fungi associated with plants but not those that do not interact with plants," ORNL's Jessy Labbe said. "This inspires questions about how we might use these mechanisms to our benefit."

Media Contact: Kim Askey, 865.576.2841, askeyka@ornl.gov

Image: https://www.ornl.gov/sites/default/files/2020-11/IMG_8444.JPG

Caption: Fungi use signaling molecules called LCOs to communicate with each other and to regulate growth. Credit: Jessy Labbe/ORNL, U.S. Dept. of Energy

Radiation - Video game visualization

Researchers at Oak Ridge National Laboratory are developing a first-of-a-kind toolkit drawing on video game development software to visualize radiation data.

Using data sets originally produced by ORNL for analysis of NASA radioisotope power systems, the toolkit leverages gaming development software such as Unreal Engine® to couple three-dimensional radiation transport results with CAD geometries in a cinematic -- yet scientific -- format.

Visualization of radiation data is difficult because it is multidimensional and affected by interactions with physical materials such as a nuclear-powered spacecraft. This visualization process makes it possible to illustrate nuanced results and highlight specific features of radiation fields. These techniques can be used to inform the design phase of any nuclear project or to communicate radiation results.

An overview of these visualization techniques was presented by ORNL's Mike Smith and Scott Greenwood at the American Nuclear Society Virtual Winter Meeting in November.

Media Contact: Lynne Degitz, 865-466-6383, degitzlk@ornl.gov

Image: https://www.ornl.gov/sites/default/files/2020-11/Radiation%20-%20video%20game%20visualization.jpg

Caption: The image shows a visualization of a radiation transport simulation for a spaceflight radioisotope power system and complex interactions of radiation fields with operational environments. Credit: Michael B. R. Smith and M. Scott Greenwood/ORNL, U.S. Dept. of Energy

Climate - Global change, global analyses

Diverse evidence shows that plants and soil will likely capture and hold more carbon in response to increasing levels of carbon dioxide in the atmosphere, according to an analysis published by an international research team led by Oak Ridge National Laboratory.

But that change in land-based carbon storage, called the terrestrial sink, is likely to slow in the future, allowing more carbon dioxide to build in the atmosphere and accelerating the pace of environmental change.

More than 60 scientists integrated evidence from experiments, remote sensing, forest inventories and other sources to improve understanding of the interrelated processes that influence carbon storage. Building this scientific consensus began with a workshop in 2018.

"Bringing together experts with this breadth of experience was critical in tackling these complex questions," said ORNL's Anthony Walker, who led the workshop. "Tying the many lines of evidence together using a systems approach and a standard metric for CO2 response provided great insights into what we know and where additional data are needed."

Media Contact: Kim Askey, 865.576.2841, askeyka@ornl.gov

Image: https://www.ornl.gov/sites/default/files/2020-11/Climate%20%E2%80%93%20Global%20change%20analyses.jpg

Caption: Scientists assessed the many interrelated processes that determine how plants respond to increases in atmospheric carbon dioxide and how that might change in the future. Credit: Dobie Gillispie/ORNL, U.S. Dept. of Energy

New Orleans, LA - A team of LSU Health New Orleans researchers reports for the first time that deleting one of the inhibitors of the RPE65 gene in a mouse model that carries a human disease mutation prevents degeneration of cone photoreceptors that are used for daytime high-resolution color vision. Their findings are published in PNAS available here.

More than 100 DNA variants in the RPE65 gene are reported as pathogenic mutations causing retinal degenerative diseases. They include a group of inherited childhood blinding diseases called Leber congenital amaurosis (LCA). While a new gene therapy may improve vision for some with RPE65 gene mutations, there is currently no effective therapy that arrests progressive retinal degeneration in LCA.

Previously, the researchers identified three inhibitors of RPE65. The one involved in the current study is called fatty acid transport protein 4 (FATP4). They found that the survival of cone photoreceptors is increased nearly 10-fold in the mouse model of LCA lacking FATP4 in the retina. They also discovered that partial reduction of FATP4 in the retina can improve the survival and visual function of cone photoreceptors. These findings establish FATP4 as a promising therapeutic target to preserve daytime color vision in patients.

"The role of FATP4 in disease progression of retinal dystrophies associated with RPE65 mutations was completely unknown," notes Nicolas Bazan, MD, PhD, Boyd Professor, Ernest and Yvette C. Villere Endowed Chair for Retinal Degenerative Diseases and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine. "This study is the first to uncover that FATP4 plays a pivotal role in photoreceptor survival and function in retinal dystrophies."

According to the National Institutes of Health, Leber congenital amaurosis primarily affects the retina, the specialized tissue at the back of the eye that detects light and color. Beginning in infancy, people with LCA typically have severe visual impairment. The National Library of Medicine says Leber congenital amaurosis occurs in 2 to 3 per 100,000 newborns. It is one of the most common causes of blindness in children.

"Our findings have allowed us to envision a strategy to mitigate the cone photoreceptor degeneration and vision loss in patients with RPE65 mutations as well as in other mutations," adds Minghao Jin, PhD, Professor of Neuroscience and Ophthalmology at LSU Health New Orleans School of Medicine.

DOAC (direct oral anticoagulant) pills are used in the treatment of atrial fibrillation by preventing blood clots. Even though blood clots are thought to contribute to complications from the new coronavirus infection, users of this class of drug do not seem to be protected against severe COVID-19, reports a large Swedish registry study from Karolinska Institutet published in The Journal of Internal Medicine.

Early during the ongoing pandemic, there were reports that many patients with severe COVID-19 had blood clots in their pulmonary arteries and other parts of the body.

"Our hypothesis was that blood clots per se could contribute to the severe functional deterioration of the lungs and other organs that is associated with COVID-19, so one would think that preventative treatment with anticoagulants would provide some protection," says Benjamin Flam, doctoral student at the Department of Physiology and Pharmacology, Karolinska Institutet, and specialist doctor in anaesthesiology and intensive care at Karolinska University Hospital.

To find out if this was the case, the team from KI conducted a registry based study of patients on anticoagulant medication for reasons other than COVID-19. The study included over 100,000 Swedes between the ages of 45 and 84 with atrial fibrillation being treated with DOACs. The control groups included over 350,000 individuals with cardiovascular disease who were not on such medication.

The researchers then examined the rates of hospitalisation, intensive care and fatality due to COVID-19 between 1 February and 31 May 2020, adjusting for such factors as age, sex, place of residence and other diseases and medication.

The results of the observational study show that DOAC use did not reduce the rate of hospitalisation, intensive care or fatality due to COVID-19.

"Our findings suggest that early DOAC treatment doesn't protect against severe COVID-19, but these should be treated with caution since there might remain differences between the groups that are difficult to measure," says Benjamin Flam. "Also, our study says nothing about whether other types of anticoagulants could be effective, but a good many clinical studies are being done around the world."

When pathogens enter a plant, infected cells set off an alarm before they die. They discharge methylsalicylic acid, which is later transformed into salicylic acid, triggering an immune response. Hence, salicylic acid is a stress signal in plants, but it also participates in regulating plant growth and development. In humans, salicylic acid proofed to be useful in a different way: Already in prehistoric times people realized that when they were drinking willow bark tea or taking other willow bark preparations, fever dropped and pain disappeared. Centuries later, scientists developed salicylic acid derivatives such as Aspirin and Ibuprofen. These so called non-steroidal anti-inflammatory drugs (NSAIDs) suppress the inflammatory response of mammalian cells, thereby making us feel better when we have a cold. But how do they affect plants?

Losing the sense of direction

"When I got the idea, I had a really serious toothache and I had some Ibuprofen at hands," explains Shutang Tan, who at that time was a postdoc at the Institute of Science and Technology (IST) Austria working in the group of Professor Ji?í Friml. "I simply used the tablets from the pharmacy and I took the same amount as in my previous experiments with salicylic acid. Then, I observed the effect of the Ibuprofen on Arabidopsis seedlings." The primary roots of the plant were significantly shorter and instead of growing downward, they were curling up, unable to respond to gravity. Furthermore, the plants developed fewer or no lateral roots at all.

Together with colleagues at the IST Austria and six other research institutions Shutang Tan looked at the effects of 20 different painkillers on Arabidopsis seedlings. "We found that all of the painkillers we tested, including Aspirin and Ibuprofen, were interfering with the auxin flow," explains Tan. The plant hormone auxin is essential for all developmental processes within a plant. It is especially responsible for a plants ability to stretch its leaves towards the sun and its roots towards the center of the earth. So called PIN proteins regulate the flow of auxin from one cell to the other, depending on which side of the cell they are sitting. If the PIN proteins are not at the right location within the cell, the flow of auxin is disturbed, leading to a faulty development of the plant. Hence, the painkillers seemed to interfere with the localization of the PIN proteins. But it didn't stop there.

Complex dynamics within plant cells

Looking closely, the scientists discovered that the effect is not limited to PIN proteins, but that the drugs interfere with the whole endomembrane system, suppressing the movement and trafficking of substances within the cells. The painkillers impair the dynamics of the cytoskeleton of the cells, a network of interlinking proteins, which among many other things gives the cell its shape and is involved in the uptake of extracellular material. Together with Markus Geisler's group at the University of Fribourg, Switzerland, the researchers at IST Austria uncovered that one group of painkillers, including the drugs Meclofenamic acid and Flufenamic acid, directly target an immunophilin-like protein, called TWISTED DWARF1, to realize these physiological and cellular activities.

Furthermore, the scientists were able to show, that NSAIDs have similar physiological and cell biological effects as auxin transport inhibitors - important chemical tools in cell biology, which interfere with the transport of auxin. "It would be very interesting to find out, if these auxin transport inhibitors can also be used as painkillers in animals. That is one big question we still need to answer" concludes Tan. Together with IST Professor Ji?í Friml, Shutang Tan, who is now establishing his own laboratory at the University of Science and Technology of China, wants to investigate which additional proteins within the plant are targeted by the painkillers and what pathways they use to do so.

Rates of soil erosion and alluvium accumulation in North America accelerated 10-fold after Europeans colonized the continent, according to new research carried out by scientists from China, Belgium and USA.

In a paper published today in Nature Communications, the researchers show how humans have altered the North American landscape at a rate far in excess of what nature alone can achieve. The results, they suggest, may have implications for instructing land management and restoration efforts.

Prof. David Kemp from China University of Geosciences in Wuhan said "On nearly every continent, humans are altering the natural landscape, and modifying the land to meet our needs for agriculture, energy and water security. One key consequence of our actions is an increase in sediment movement, particularly soil erosion.

"We knew already that when European colonizers started farming in North America there was an increase in erosion. This led to the deposition of large amounts of river and floodplain sediment, known as alluvium. Our study quantifies this increase across the continent as a whole, and reveals an order of magnitude jump in rates of alluvium deposition soon after Europeans arrived".

Prof. Veerle Vanacker, of Université catholique de Louvain, explained "When we use these data to quantify landscape change, we find that in the past century humans have moved as much sediment on North America as it would take natural processes to move in up to 3000 years."

She added "What these findings mean is that anthropogenic activities have unprecedented impact on sediment dynamics. Unsustainable land use practices entail large societal costs in terms of soil fertility decline, flooding and stream degradation and direct costs for soil and watershed restoration. The study improves our ability to set benchmarks for erosion monitoring and control. "

Prof. Peter Sadler of University of California, Riverside, added "To arrive at our conclusions, we compiled and analysed a large database of alluvium accumulation rates that extend back to a time well before the first Europeans lived on the continent.

"What really stood out in these data was the observation that for the past 40,000 years, rates of alluvium accumulation hardly changed at all and the landscape was quite stable. It was only in the last 200 years that the rates suddenly increased - right around the time that Europeans started intensive farming."

INDIANAPOLIS--Researchers at Indiana University School of Medicine have published their work about a specific type of childhood cancer in the peer-reviewed, international oncology journal, Cancers. This research involves a combination therapy that significantly slows tumor growth in models, which includes a model established from cells taken from tumors donated by Tyler Trent. This is the first published manuscript that includes Trent's tumor model.

Trent was a Purdue University student and sports superfan who died on January 1, 2019, after waging a long and valiant fight against an aggressive form of bone cancer known as osteosarcoma. In the publication's acknowledgments, the researchers dedicated the study to Trent's memory, saying they will always remember him for his courageous battle, his passion for cancer advocacy, and the generous donation of his tumor tissue for research.

"We are so proud to honor Tyler's legacy with this first publication, laying the foundation for future research to build upon," said Karen E. Pollok, PhD, who led the study. Pollok is an associate professor of pediatrics at IU School of Medicine. "We still have more work to do, but are hopeful that new therapies for osteosarcoma will be possible as we learn more about how to block different tumors from growing."

The Precision Genomics team at Riley Children's Health found a genetic variation in Trent's tumors (named after him as TT1 and TT2) known as the MYC-RAD21 signature, which has been found in tumors that tend to recur. Pollok said there are two drugs that can block its effects, a Chk1 inhibitor and a bromodomain inhibitor. Her team tested each drug individually, as well as in combination. They found that in models with the TT2 tumor, they could stop the tumors from growing by using one of the drugs individually, but using both drugs together blocked tumor growth substantially during a four-week treatment. The research team also determined that the combination treatment was well-tolerated.

"This research is allowing us to forge a path to improving outcomes for children, adolescents and young adults with a very aggressive bone cancer," said Jamie Renbarger, MD, another one of the lead researchers. Renbarger was one of Tyler's doctors and also leads the IU Precision Health Initiative pediatric sarcoma disease research team. She is also the Caroline Symmes Professor of Pediatric Cancer Research at IU School of Medicine. "We are hopeful that this program will lead the way in finding cures for more children."

The tumor started growing in the models again after stopping the therapy, leading researchers to consider next steps in their scientific process. Future research topics will include learning to understand how the tumors adapt to treatments and finding ways to optimize the combination therapy.

"The findings and research going on with Tyler's tumor models is incredibly encouraging and comforting to Tony and I," said Kelly Trent, who is Tyler Trent's mother. "It was at the core of who Tyler was to want to be used for good and to help at this capacity. We are so grateful for Dr. Pollok and Dr. Renbarger's work."

Trent was diagnosed with osteosarcoma for the first time when he was 15 years old. In the years that followed while he was a patient at Riley Hospital for Children at IU Health, he donated several tumor samples to cancer researchers at IU School of Medicine. He also encouraged other people to do the same, becoming a national advocate for cancer research. People have donated millions of dollars for cancer research in his name, including more than $189,000 for the Tyler Trent Cancer Research Endowment for Riley Hospital. The Trent family and Riley Children's Foundation worked together to create the endowment fund, which supports pediatric research being conducted by IU School of Medicine researchers.

HSE University scientists have for the first time in the world investigated the impact of delayed reinforcement signals in neurofeedback (NFB) training. They have experimentally proven that reducing the delay in feedback (decreasing feedback latency) can significantly increase the efficacy of training. This opens up new potential for the use of NFB for cognitive enhancement, self-regulation, and the treatment of a broad range of neurological disorders from anxeity and depression to epilepsy. The study was published in the Journal of Neural Engineering.

Neurofeedback (NFB) is a neuromodulation technology that allows a person to adjust the parameters of his or her own brain activity. Typically NFB uses electroencephalography (EEG) data reflecting changes in the potential of the electric field on the surface of the human head. EEG parameters are presented to the subject as, for example, a visual stimulus (column height on the screen, screen brightness) together with the task to change these parameters in the desired direction. By focusing on the NFB signal, the subject tries to remember the relationship between the parameter and their mental state. This allows a person to 'feel' the activity of their brain and learn how to control it. Often times such learning occurs subconsciously, i.e. without the use of any specific strategy.

Previous results from HSE University researchers have shown that in the majority of modern NFB systems the reinforcement signal lags behind the changes in neuronal activity, leading to ineffective learning and a wide dispersion of NFB therapy outcomes.
In order to provide access to the realm of small delays, the scientists developed a new mathematical method of filtering the EEG signal, allowing rapid estimation of the parameters of the rhythmic activity of the brain.

'This method gave us access to a previously unknown area of brain interaction with minimal latency in responses from the external system. It allows the brain to perceive an artificially created feedback loop as part of its own neural network. This is a qualitative leap that opens a new era in neurofeedback paradigm research,' says Alexey Ossadtchi, Director of the Centre for Bioelectric Interfaces at HSE University.

This development allowed the scientists to conduct a ground-breaking study on the impact of feedback latency on the efficacy of neurofeedback training. Forty subjects were trained to increase the power of their own parietal alpha rhythm based on a feedback signal displayed on a computer screen.

Participants in the experiment were divided into four groups. Those in the first group received a feedback signal with the shortest achievable delay at the time of the test, 240 ms. HSE University scientists have now managed to achieve a feedback loop reinforcing instantaneous narrow-band rhythm power with a total delay of less than 110 ms. Feedback signals for the subjects in the second and third groups were artificially delayed by 250 and 500 ms respectively, and for the subjects in the fourth group the feedback was not at all associated with their brain activity.

It turned out that the subjects from the group with the minimum delay achieved a certain level of alpha rhythm power after fewer training sessions compared with subjects from the other groups. Moreover, the analysis of alpha rhythm power after training showed that only the subjects from the group with the minimum delay displayed a sustained increase in rhythm power. This result is particularly important, as achieving sustainable changes is the main goal of the NFB therapy.

Researchers at the University of São Paulo (USP) in Brazil have demonstrated for the first time that in COVID-19 patients an immune mechanism known as the inflammasome participates in activation of the inflammatory process that can damage several organs and even lead to death.

An article reporting the findings of the study, which was supported by FAPESP, has just been published in the Journal of Experimental Medicine. According to the authors, the findings support the use of inflammasome activation both as a marker of disease prognosis, helping medical teams identify high-risk patients at an early stage, and as a potential therapeutic target in severe COVID-19.

“Drugs already approved for human use are capable of inhibiting inflammasome activation. These drugs can now be tested in the context of infection by SARS-CoV-2,” Dario Zamboni, a professor at USP’s Ribeirão Preto Medical School (FMRP-USP) and principal investigator for the study, told Agência FAPESP.

Almost all immune cells are equipped with the protein complex that constitutes the inflammasome, he explained. When one of these proteins identifies a sign of danger, such as a viral or bacterial particle, for example, the defense machinery is activated. As a result, the cell enters a process of programmed death (a type of inflammatory death called pyroptosis) and releases into the bloodstream signaling molecules called cytokines that attract to the site a veritable army of white blood cells. This is the onset of an inflammatory response that is ultimately designed to destruct the potential threat to the organism.

“The response to various pathogens involves inflammasome activation, and most of the time this blocks the infection and protects the organism. However, in some COVID-19 patients, the defense system appears to be overactivated, and we’re now trying to understand why this happens,” Zamboni said.

The involvement of this immune mechanism in the systemic inflammation that is characteristic of severe COVID-19 has been studied by scientists in several countries over the past few months. The Ribeirão Preto group is the first to demonstrate the activation of a specific type of inflammasome in response to infection by SARS-CoV-2 in patients.

“It’s important to recall that there’s more than one kind of inflammasome. What varies is the protein responsible for mediating activation of the protein complex,” Zamboni said. “We observed the presence of the inflammasome mediated by NLRP3, one of the most common and well-studied proteins. Other kinds may also participate in the response to SARS-CoV-2.”

Three angles of investigation

The conclusions presented in the article were based on three sets of experiments. The first involved immune cells from healthy donors infected with the novel coronavirus in the laboratory. The only white blood cells used in the experiment were monocytes.

“The viral dose administered to the culture is considered low, roughly one virus per cell. Even so, 75% of the monocytes died after 24 hours, evidencing the virus’s destructive potential,” Zamboni said.

The presence of lactate dehydrogenase (LDH) in the culture medium told the researchers that the cells were dying by pyroptosis: LDH is released when the cell membrane is breached and cellular contents escape into the bloodstream, a phenomenon typical of inflammatory cell death. The presence of cytokines IL-18 (interleukin-18) and IL-1β (interleukin-1 beta) suggested that this “serial cellular suicide” was associated with activation of the NLRP3 inflammasome, which was confirmed by analysis under the microscope.

“When this kind of inflammasome is activated, the proteins that form the complex, and are normally distributed throughout the cytoplasm, cluster together in what are called puncta, or specks, which can be observed under a microscope,” Zamboni said. “This, in turn, activates caspase-1, the enzyme that ‘processes’ the precursors of pro-inflammatory cytokines such as IL-18 and IL-1β so that they become ‘mature’ and active.”

The second set of experiments involved clinical samples from 124 patients undergoing treatment for moderate or severe COVID-19 between April and July at the general and teaching hospital (“Hospital de Clínicas”) run by FMRP-USP. The results were compared with data from patients hospitalized for other reasons, who served as a control group.

The researchers performed immunoenzymatic tests (based on antigen-antibody reactions) and used molecular probes to confirm that the white blood cells from COVID-19 patients had much larger amounts of IL-18 and active caspase-1 on average.

They observed under the microscope that puncta were more abundant in the immune cells of donors infected by SARS-CoV-2. Statistical analysis showed that the more evidence of inflammasome activation a patient displayed on admission to hospital, the worse the patient’s clinical progression and the higher the probability of death.

The third and last group of experiments used samples of lung tissue obtained during a minimally invasive autopsy procedure from five people who died after being infected by SARS-CoV-2. The analysis evidenced the presence of white blood cells infected by the virus, and puncta characteristic of the NLRP3 inflammasome inside the cells.

Next steps

The assays performed to date were supported by FAPESP via a Thematic Project and a Regular Research Grant awarded to Zamboni, who is also a member of the Center for Research on Inflammatory Diseases (CRID), a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP and hosted by FMRP-USP.

The same group of more than 40 researchers is now working to find out whether other kinds of inflammasome are involved in the response to the novel coronavirus and why the pathogen activates this immune mechanism so intensely.

“We’re conducting experiments in which we compare inflammasome activation in response to SARS-CoV-2 and other viruses, such as the H1N1 flu virus,” Zamboni said.

Separately, the scientists are testing the use of a drug to inhibit the NLRP3 inflammasome in patients with severe COVID-19. Promising preliminary results have been published on medRxiv (read more at: agencia.fapesp.br/33958).

“We’re looking for other drugs capable of inhibiting the NLRP3 inflammasome for testing in a clinical trial,” Zamboni said. “As we discover more about inflammasome activation mechanisms in COVID-19, we can identify drugs that reduce the inflammatory process more effectively.”

Tissue oxygenation is a measure of the oxygen level in biological tissue and is a useful clinical biomarker for tissue viability. Abnormal levels may indicate the presence of conditions such as sepsis, diabetes, viral infection, or pulmonary disease, and effective monitoring is important for surgical guidance as well as medical care.

Several techniques exist for the measurement of tissue oxygenation, but they all have some limitations. For instance, pulse oximetry is robust and low-cost but cannot provide a localized measure of oxygenation. Near-infrared spectroscopy, on the other hand, is prone to noisy measurements due to pressure-sensitive contact probes. Spatial frequency domain imaging (SFDI) has emerged as a promising noncontact technique that maps tissue oxygen concentrations over a wide field of view. While simple to implement, SFDI has its own limitations: it requires a sequence of several images for its predictions to be accurate and is prone to errors when working with single snapshots.

In a new study published in the Journal of Biomedical Optics, researchers from Johns Hopkins University, Mason T. Chen and Nicholas J. Durr, have proposed an end-to-end technique for accurate calculation of tissue oxygenation from single snapshots, called OxyGAN. They developed this approach using a class of machine-learning framework called a conditional generative adversarial network (cGAN), which utilizes two neural networks -- a generator and a discriminator -- simultaneously on the same input data. The generator learns to produce realistic output images, while the discriminator learns to determine whether a given image pair forms a correct reconstruction for a given input.

Using conventional SDFI, the researchers obtained oxygenation maps for the human esophagus (ex vivo), hands and feet (in vivo), and a pig colon (in vivo) under illumination with two different wavelengths (659 and 851 nm). They trained OxyGAN with the feet and esophagus samples and saved the hand and colon samples to later test its performance. Further, they compared its performance with a single-snapshot technique based on a physical model and a two-step hybrid technique that consisted of a deep-learning model to predict optical properties and a physical model to calculate tissue oxygenation.

The researchers found that OxyGAN could measure oxygenation accurately, not only for the samples it had seen during training (human feet), but also for the samples it had not seen (human hand and pig colon), demonstrating the robustness of the model. It performed better than both the single-snapshot model and the hybrid model by 24.9% and 24.7%, respectively. Moreover, the scientists optimized OxyGAN to compute ~10 times faster than the hybrid model, enabling real-time mapping at a rate of 25 Hz. Frédéric Leblond, Associate Editor for the Journal of Biomedical Optics, comments, "Not only does this paper represent significant advances that can contribute to the practical clinical implementation of spatial frequency domain imaging, but it will also be part of a relatively small (although rapidly increasing in size) pool of robust published work using AI-type methods to deal with real biomedical optics data."

While the algorithm of OxyGAN could be optimized further, this approach holds promise as a novel technique to measure tissue oxygenation.