Culture

"We have studied which temperatures are preferable and which are harmful in humans, cattle, pigs, poultry, and agricultural crops and found that they are surprisingly similar," says Senthold Asseng, Professor of Digital Agriculture at TUM. According to the study, preferable temperatures range from 17 to 24 degrees Celsius.

When does it become too hot for humans?

At high humidity, mild heat strain for humans begins at about 23 degrees Celsius and at low humidity at 27 degrees Celsius. "If people are exposed to temperatures above 32 degrees Celsius at extremely high humidity or above 45 degrees Celsius at extremely low humidity for a lengthy period of time, it can be fatal," says Prof. Asseng. "During extreme heat events with temperatures far above 40 degrees Celsius, such as those currently being observed on the U.S North West Coast and in Canada, people require technical support, for example in the form of air-conditioned spaces."

To mitigate increasing heat strain, Prof. Asseng cites a variety of strategies, including increasing natural shade from trees or structural shading. Cities and buildings can be made more temperature-passive, for example, by using roof and wall insulation or by using lighter, reflective roof and wall colors to reduce heat strain.

How do high temperatures affect livestock?

In cattle and pigs, heat strain occurs at 24 degrees Celsius with high humidity and at 29 degrees Celsius with low humidity. The milk yield from cows can decrease by 10 to 20 percent when exposed to heat stress, and the fattening performance in pigs is also reduced. The comfortable temperature range for poultry is 15 to 20 degrees. Chickens experience mild heat strain at 30 degrees Celsius. At 37 degrees Celsius and above, they experience severe heat stress and their egg laying rate declines.

Heat stress overall leads to reduced growth in cattle and dairy cows, pigs, chickens and other livestock, which means both lower yields and reproductive performance. "There are examples of evolutionary adaptations to warm weather in terrestrial mammals. Transylvanian naked chickens are more heat tolerant than other varieties of chickens because of a complex genetic mutation that suppresses feather growth. They are naturally air-conditioned because they lack feathers on their necks," says Prof. Asseng.

How do crops react to high temperature?

"In crops, the optimal temperature zone and temperature thresholds seem to be more diverse due to differences between species and varieties," explains Prof. Asseng.

Cold-temperate crops such as wheat, for example, do better at cooler temperatures, while warm-temperature crops such as corn are sensitive to frost but can tolerate warmer temperatures. Strategies to reduce heat stress in crop production include changes in planting dates to avoid heat stress later in the season, irrigation (if feasible), switching to more heat-resistant crops, and breeding to increase heat tolerance.

How is climate change affecting life on Earth?

"By the end of the century, 45 to 70 percent of the global land area could be affected by climate conditions in which humans cannot survive without technological support, such as air conditioning. Currently, it's 12 percent," says Prof. Asseng. This means that in the future, 44 to 75 percent of the human population will be chronically stressed by heat. A similar increase in heat stress is expected for livestock, poultry, agricultural crops and other living organisms.

"Genetic adaptation to a changing climate often takes many generations. The time available is too short for many higher forms of life. If current climate trends persist, many living things could be severely affected or even disappear completely from Earth due to temperature change," concludes Prof. Asseng.

Plastics are a growing problem for natural ecosystems around the globe, and in particular for our marine and freshwater environments. Rivers are the leading source of plastic pollution, as it has been estimated that they deliver several million metric tons of plastic annually to our oceans from poor land-based waste management. The problem is that the estimates made for plastics flowing from the rivers are tens to hundreds of times higher than the quantity of plastics floating on the ocean's surface. So where is all of this river-derived plastic actually going - is there a missing plastic 'sink' somewhere in the ocean? Are the estimates correct?

In a paper published today in Science, Dr. Lisa Weiss and her colleagues from the Centre of Education and Research on Mediterranean Environments (CEFREM), a joint research laboratory between the University of Perpignan (UPVD) and the French National Centre for Scientific Research (CNRS), and a team of researchers from a number of research institutions in France and the University of Barcelona in Spain demonstrate that current river flux assessments are overestimated by two to three orders of magnitude from previous estimates. This would explain why a large volume of microplastics seems to disappear into a mysterious ocean 'plastic sink'.

However, these findings do not suggest that plastics are less of a problem than previously thought. In fact, through their analyses, researchers actually found that plastics remain at the ocean's surface much longer than previously estimated - further exacerbating the effects of plastic pollution on natural systems.

The mysterious ocean plastic sink

Rivers are the main source of plastic discharge into the oceans. According to current assessments, the floating stock of microplastics on the ocean's surface - from tens to hundreds of metric tons - is just a small fraction of the millions of metric tons that are discharged by rivers each year. This unequal balance has led to the 'plastic sink' hypothesis whereby the amount of microplastics in the 'plastic sink' plus the plastics at the surface would equal those presumably discharged by rivers into the sea.

According to the study's lead author Dr. Lisa Weiss from the CEFREM laboratory at the University of Perpignan, 'The in situ data that we now have for microplastics in rivers, compared to early empirical modelling studies, allowed us to assemble a robust database which we were then able to analyse to obtain a more reliable estimate for the quantity of microplastics being discharged from rivers into the sea. This process revealed several significant methodological errors in previous flux estimates. When we then corrected these mistakes we found that the global river flux estimates are two to three orders of magnitude less than previously thought. Further, we found that the average residence time for microplastics at the surface of the oceans may actually be a few years as opposed to only several days, as previously estimated."

According to the study's lead author Dr. Lisa Weiss from the CEFREM laboratory at the University of Perpignan, 'The in situ data that we now have for microplastics in rivers, compared to early empirical modelling studies, allowed us to assemble a robust database which we were then able to analyse to obtain a more reliable estimate for the quantity of microplastics being discharged from rivers into the sea. This process revealed several significant methodological errors in previous flux estimates. When we then corrected these mistakes we found that the global river flux estimates are two to three orders of magnitude less than previously thought. Further, we found that the average residence time for microplastics at the surface of the oceans may actually be a few years as opposed to only several days, as previously estimated."

"We can now confirm that the search for the missing 'plastic sink' is over, as the missing plastics have been found through the correction of the river flux estimate", states Professor Miquel Canals, head of the Consolidated Research Group on Marine Geosciences at the University of Barcelona and one of the co-authors of the study.

The new study identifies the main methodological mistakes which led to inaccurate assessments of the fluxes and overall mass of microplastics discharged by rivers into the sea at a global scale. In particular, mistakes were made because of a systematic overestimation of the average microplastic particle weight in river samples; from the integration of incompatible data that were obtained through different sampling techniques; and from assessments based on the relation between microplastic fluxes and the MPW index (mismanaged plastic waste).

A fight without borders to preserve our planet's oceans

Marine waste does not care about borders and has reached the most remote corners of our oceans and seas. According to Dr. Wolfgang Ludwig, the Director of the CEFREM laboratory and co-author of the study, "the only way we are going to have a chance at winning the fight against microplastic pollution will be to target the sources where microplastic waste is generated. We need to take action at the human level. We need to change our consumption habits, better manage our waste and we need to do this at a global scale."

"Our study shows that marine microplastic pollution not only comes from developing countries - with little to no waste management - as one might think, but also comes from countries with well-established waste management systems. If we were to stop the discharge of microplastics from rivers to the sea today, the amount of floating particles and their harmful effects on marine ecosystems would persist for at least another several years", states Dr Ludwig.

Next steps...

The impacts of plastics on the marine environment is an emerging field of scientific research that has generated a large number of scientific publications over the last few years. Still, we have only just begun to understand how plastics cycle in the oceans. There are many plastic size classes, oceanic compartments and land-to-sea transfer processes for which further research is urgently needed to properly evaluate the stock sizes and exchange fluxes between compartments. Going forward, we will need the best available science if we are to have a chance at winning the battle against plastic pollution. To do this, the scientific community must work together to overcome inertia from the past, correct mistakes and work with common protocols and guidelines in order to provide the best possible decision-making advice needed to protect our oceans and seas.

Originally discovered as a bacterial mode of defense against invading viruses, the remarkable ability of CRISPR-Cas9 to modify specific locations of DNA has made it a researcher favorite among gene editing tools. The ongoing effort to explore further possibilities of the CRISPR-Cas9 system is ushering in newer developments to this tool. In one of the latest refinements of the technique, as illustrated in a study published in BioDesign Research, scientists from Stanford University, USA have developed a CRISPR-Cas9 system that induces highly effective silencing of target genes.

The versatility of CRISPR-Cas9 based gene editing is largely achieved by modifying the Cas9 protein itself. In this approach, the endonuclease property of the Cas9 protein is removed, yielding a deactivated Cas9, or dCas9. Many effector proteins, including a wide variety of gene expression-altering enzymes, are then fused with dCas9 for targeted binding to specific sites on the DNA. When fused with an activating or repressing transcription factor, the dCas9 complex upregulates or downregulates the target gene, respectively. However, the gene-altering ability of such complexes is transient, as the effects persist only while the effector domains of the regulatory proteins remain physically bound or actively targeted to the region of interest.

For practical purposes, such as suppressing the effect of a disease-causing mutation, a longer-lasting effect of silencing is desirable. Dr. Lei S. Qi from Stanford University, the corresponding author of the study, and colleagues explain this concept further: "The Cas9 endonuclease, that stops the expression of a target gene, is analogous to a brake which stops the car by breaking its engine. In a modified dCas9-repressor fusion system, that contains a transcriptional repressor, the car remains stopped as long as one holds down the brake pedal actively. However, we aimed to develop a silencing system that, like a parking gear, prevents wheel movement until you switch the car out of it".

To achieve this goal, the researchers adopted an approach based on the epigenetic regulation of the eukaryotic genome where gene expression is altered stably and reversibly by the direct modification of genomic regions. Epigenetic silencing involves methylation of both histone proteins and DNA. In the present study, Dr. Qi and his colleagues fused dCas9 protein with a transcription repressor domain KRAB (Krüppel-associated box) and DNA methylating domains of DNMT3L and DNMT3A- two potent epigenetic modifiers. They named the construct dCas9-KAL and tested its silencing capacity in a cell-based reporter system. When stably integrated into human cells expressing fluorescent protein EGFP, the dCas9-KAL construct, designed to localize at the promoter of EGFP, repressed fluorescence for weeks.

The success in developing a robust and long-term epigenetic repressor has multifold implications. Successful silencing of critical or disease-inducing genetic elements can provide better treatment options for cancer and other genetic ailments. Additionally, the unique construct-synthetic reporter system developed in this study will help the scientists in assessing the activity of various domains or their combinations fused to dCas9. As Dr. Muneaki Nakamura from Stanford University, the lead author of the study, explains: "Since its adoption, CRISPR-Cas9 has revolutionized the face of genetic modification. Our system, as a powerful addition to the CRISPR toolbox, will facilitate further research in the field. It can be used to better engineer cells with desired behaviors, which could find use in the development of custom cell types with wide-ranging research and therapeutic applications,". reflects Dr. Qi.

The team's findings certainly make a noteworthy addition to the molecular Swiss knife that is the CRISPR-Cas9 system!

NDIANAPOLIS--Indiana University School of Medicine researchers are developing a new, noninvasive brain stimulation technique to treat neurological disorders, including pain, traumatic brain injury (TBI), epilepsy, Parkinson's disease, Alzheimer's disease and more.

"Given the increasing use of brain stimulation in human brain study and treatment of neurological diseases, this research can make a big impact on physicians and their patients," said Xiaoming Jin, PhD, associate professor of anatomy, cell biology and physiology.

When someone experiences a brain injury, nerve injury, or neurodegeneration, such as in epilepsy and TBI, there is damage to the brain which can lead to loss and damage of nerve or neurons and development of hyperexcitability that underlies some neurological disorders such as neuropathic pain and epilepsy.

"The conventional treatment is mainly to try to directly inhibit such hyperexcitability," Jin said, "but we found the initial damage of the brain or nerve system was caused by a loss of brain tissue, which causes the nervous system to compensate for loss of function by working harder, so we need to stimulate activity instead of inhibit it."

The technique, described in a newly published paper in Neurotherapeutics, uses a new type of magnetoelectric nanoparticles that can be delivered to a specific part of the brain using a magnetic field. After, a magnetic wave can be emitted to stimulate neural activity in that particular part of the brain. The method is noninvasive, good for stimulating deep brain function and is more efficient than traditional methods of brain stimulation, without the need for genetic manipulation.

"This is the only new type of nanoparticle that allows us to effectively stimulate the brain without doing any invasive procedures," Jin said. "We can inject the nanoparticle as a solution into the vein and then bring it to any part of the body. When you apply a magnet on the head, you can localize and deliver the nanoparticle to the targeted brain region."

The team has been working on the technique for five years in collaboration with the University of Miami and hopes to begin studying the method in humans in the next couple of years. The study has received funding from the Defense Advanced Research Projects Agency (DARPA) of the United States Department of Defense, National Science Foundation, as well as the Indiana Clinical and Translational Sciences Institute (CTSI), which helped provide funding for a medical neuroscience graduate student, Tyler Nguyen, to participate in the research. Read the full published paper in Neurotherapeutics.

Ibaraki, Japan - The flavor of a tomato is an interaction between its taste and aroma. Now, researchers from Japan and the United States have revealed that the pigments that determine the colors of tomatoes also affect their flavor.

In a study published this month, researchers from University of Tsukuba developed a new method to rapidly measure the pigment profiles of tomatoes and used the technique to explore how pigments affect the taste and aroma of different tomato varieties.

The color of tomatoes is produced by combinations of different types of pigments, including carotenoids and chlorophylls. These pigments can also affect the accumulation of flavor-related compounds such as sugars, which affect the taste of tomatoes, and volatile organic compounds (VOCs), which determine the aroma. As tomato fruits ripen from green to red, the amounts of pigments and flavor-related compounds change but until now the relationship between color and flavor has been unclear.

"Pigments like carotenoids have no taste," says lead author Professor Miyako Kusano, "but they are precursors for compounds called apocarotenoid-VOCs (AC-VOCs) which produce the fruity/floral smell of tomatoes and increase the perception of sweetness--characteristics that appeal to consumers."

Traditional methods for identifying and measuring pigments can be slow, so the researchers developed a simple method to rapidly analyze large numbers of samples. Using the new technique, the team measured the amounts of carotenoids and chlorophylls in 157 different varieties of tomato and then analyzed the flavors of each variety to find the links between pigments and flavor.

The results showed that tomato varieties with an abundance of chlorophyll also had a high sugar content, contributing to a sweet taste. They also found that the carotenoid profiles of the fruit reflected the appearance of the fruit, as well as AC-VOC levels.

"The pigment profile of one of the orange-colored varieties called "Dixie Golden Giant" was particularly interesting," explains Professor Kusano. "It had very high levels of AC-VOCs, but the carotenoid content wasn't that high. We discovered that the pigment prolycopene was abundant in this variety, which explained the high AC-VOC levels."

The carotenoid content of fruit is influenced by growing conditions, like temperature and amount of light. By looking at the pigment profiles and AC-VOC content of fruits in different environments, it may be possible to find ways of improving AC-VOC production, which is good for both consumers and producers.

Given its speed, the new method developed by the team is a powerful tool for analyzing pigment concentrations in large numbers of samples and could also be used for other fruits and vegetables.

Elephants and their forebears were pushed into wipeout by waves of extreme global environmental change, rather than overhunting by early humans, according to new research.

The study, published today in Nature Ecology & Evolution, challenges claims that early human hunters slaughtered prehistoric elephants, mammoths and mastodonts to extinction over millennia. Instead, its findings indicate the extinction of the last mammoths and mastodonts at the end of the last Ice Age marked the end of progressive climate-driven global decline among elephants over millions of years.

Although elephants today are restricted to just three endangered species in the African and Asian tropics, these are survivors of a once far more diverse and widespread group of giant herbivores, known as the proboscideans, which also include the now completely extinct mastodonts, stegodonts and deinotheres. Only 700,000 years ago, England was home to three types of elephants: two giant species of mammoths and the equally prodigious straight-tusked elephant.

An international group of palaeontologists from the universities of Alcalá, Bristol, and Helsinki, piloted the most detailed analysis to date on the rise and fall of elephants and their predecessors, which examined how 185 different species adapted, spanning 60 million years of evolution that began in North Africa. To probe into this rich evolutionary history, the team surveyed museum fossil collections across the globe, from London's Natural History Museum to Moscow's Paleontological Institute. By investigating traits such as body size, skull shape and the chewing surface of their teeth, the team discovered that all proboscideans fell within one of eight sets of adaptive strategies.

"Remarkably for 30 million years, the entire first half of proboscidean evolution, only two of the eight groups evolved," said Dr Zhang Hanwen, study coauthor and Honorary Research Associate at the University of Bristol's School of Earth Sciences.

"Most proboscideans over this time were nondescript herbivores ranging from the size of a pug to that of a boar. A few species got as big as a hippo, yet these lineages were evolutionary dead-ends. They all bore little resemblance to elephants."

The course of proboscidean evolution changed dramatically some 20 million years ago, as the Afro-Arabian plate collided into the Eurasian continent. Arabia provided crucial migration corridor for the diversifying mastodont-grade species to explore new habitats in Eurasia, and then into North America via the Bering Land Bridge.

"The immediate impact of proboscidean dispersals beyond Africa was quantified for the very first time in our study," said lead author Dr Juan Cantalapiedra, Senior Research Fellow at the University of Alcalá in Spain.

"Those archaic North African species were slow-evolving with little diversification, yet we calculated that once out of Africa proboscideans evolved 25 times faster, giving rise to a myriad of disparate forms, whose specialisations permitted niche partition between several proboscidean species in the same habitats. One case in point being the massive, flattened lower tusks of the 'shovel-tuskers'. Such coexistence of giant herbivores was unlike anything in today's ecosystems."

Dr Zhang added: "The aim of the game in this boom period of proboscidean evolution was 'adapt or die'. Habitat perturbations were relentless, pertained to the ever-changing global climate, continuously promoting new adaptive solutions while proboscideans that didn't keep up were literally, left for dead. The once greatly diverse and widespread mastodonts were eventually reduced to less than a handful of species in the Americas, including the familiar Ice Age American mastodon."

By 3 million years ago the elephants and stegodonts of Africa and eastern Asia seemingly emerged victorious in this unremitting evolutionary ratchet. However, environmental disruption connected to the coming Ice Ages hit them hard, with surviving species forced to adapt to the new, more austere habitats. The most extreme example was the woolly mammoth, with thick, shaggy hair and big tusks for retrieving vegetation covered under thick snow.

The team's analyses identified final proboscidean extinction peaks starting at around 2.4 million years ago, 160,000 and 75,000 years ago for Africa, Eurasia and the Americas, respectively.

"It is important to note that these ages do not demarcate the precise timing of extinctions, but rather indicate the points in time at which proboscideans on the respective continents became subject to higher extinction risk," said Dr Cantalapiedra.

Unexpectedly, the results do not correlate with the expansion of early humans and their enhanced capabilities to hunt down megaherbivores.

"We didn't foresee this result. It appears as if the broad global pattern of proboscidean extinctions in recent geological history could be reproduced without accounting for impacts of early human diasporas. Conservatively, our data refutes some recent claims regarding the role of archaic humans in wiping out prehistoric elephants, ever since big game hunting became a crucial part of our ancestors' subsistence strategy around 1.5 million years ago," said Dr Zhang.

"Although this isn't to say we conclusively disproved any human involvement. In our scenario, modern humans settled on each landmass after proboscidean extinction risk had already escalated. An ingenious, highly adaptable social predator like our species could be the perfect black swan occurrence to deliver the coup de grâce."

Understanding how viral infection occurs can provide important clues for researchers to develop strategies to prevent viral transmission and develop effective therapeutic agents and vaccines. SARS-CoV-2, the causative agent of COVID-19, enters the host cells through interaction between the virus's spike protein and the extracellular receptor binding domain of ACE2. The viral entry into the cells is completed by various proteases, which allow the viral and cell membranes to fuse together. While it is known that the upper respiratory tract becomes compromised in the early infection, the exact types of the cells that the virus infects at the earliest stage have not yet been identified.

Led by Director KOH Gou Young, scientists from the Center for Vascular Research within the Institute for Basic Science, South Korea, have recently uncovered the processes involved in the earliest stages of COVID-19 infection. The group accomplished this by combining immunofluorescence staining (IFS) and single-cell RNA-sequencing (scRNA-seq) of the molecules that are involved in the viral entry process. Through this, Koh and his colleagues identified the exact target of the coronavirus at the cellular level by comparing the results of the subjects infected with COVID-19 with those of healthy controls.

The researchers first looked for the presence of ACE2, TMPRSS2, and FURIN, which are the predominant SARS-CoV-2 entry-related molecules, on the surfaces of various types of cells in the nasal epithelium. It was found that these proteins were present in high quantities on ciliated cells. Moreover, the apical (upper) sides of these cells showed higher levels of these molecules in comparison to the basal (bottom) side. The levels of these proteins were highest in fully differentiated multiciliated cells. On the other hand, viral entry proteins were not found in the undifferentiated epithelial cells or secretory cells such as the goblet cells.

Next, the researchers further studied these nasal epithelial cells using scRNA-seq and visualized the cells into different clusters using UMAP. Samples were collected from 4 patients on the first day of their COVID-19 diagnosis, which were compared against 2 samples from healthy donors. It was found that the fraction of multicilial cells was greatly reduced in the samples from infected patients, while there was an increase in the secretory cells and differentiating cells. This hinted that multicilial cells were the first to be attacked and killed off by the virus, which are then replaced by the latter types of cells.

The study also measured the level of SARS-CoV-2 mRNA transcripts within the various types of cells. Among all the epithelial cells in COVID-19 infected patients, 38% of the cells were labeled as SARS-CoV-2hi cells. Up to 75% of the detected genes in these cells were of viral origin, compared to less than 1% for other clusters of cells. This means that these cells serve as the main factories for the mass production of SARS-CoV-2 viruses. While it was not possible to directly identify these cells through RNA seq due to the fact that they primarily produce viral mRNA, the researchers employed pseudo-time-trajectory analysis to predict their differentiation paths. The differentiation trajectory showed that SARS-CoV-2hi cells likely originated from ciliated cells. Further IFS analysis on the infected patients' samples conclusively determined that up to 85% of SARS-CoV-2 factories were in fact multiciliated cells.

This study was able to determine that multiciliated cells in the nasal epithelium are the first cells that are targeted in the early COVID-19 infection. This implies that targeting these cells using specific treatments, such as through nasal sprays, can be an ideal strategy to curb COVID-19 infection in the early stages.

A water disinfectant created on the spot using just hydrogen and the air around us is millions of times more effective at killing viruses and bacteria than traditional commercial methods, according to scientists from Cardiff University.

Reporting their findings today in the journal Nature Catalysis, the team say the results could revolutionise water disinfection technologies and present an unprecedented opportunity to provide clean water to communities that need it most.

Their new method works by using a catalyst made from gold and palladium that takes in hydrogen and oxygen to form hydrogen peroxide - a commonly used disinfectant that is currently produced on an industrial scale.

Over four million tonnes of hydrogen peroxide are made in factories each year, where it is then transported to the places it is used and stored. This means that stabilising chemicals are often added to the solutions during the production process to stop it degrading but these reduce its effectiveness as a disinfectant.

Another common approach to disinfecting water is the addition of chlorine; however, it has been shown that chlorine can react with naturally occurring compounds in water to form compounds which, in high doses, can be toxic to humans.

The ability to be able to produce hydrogen peroxide at the point of use would overcome both efficacy and safety issues currently associated with commercial methods.

In their study, the team tested the disinfection efficacy of commercially available hydrogen peroxide and chlorine compared to their new catalytic method.

Each was tested for its ability to kill Escherichia coli in identical conditions, followed by subsequent analysis to determine the processes by which the bacteria were killed using each method.

The team showed that as the catalyst brought the hydrogen and oxygen together to form hydrogen peroxide, it simultaneously produced a number of highly reactive compounds, known as reactive oxygen species (ROS), which the team demonstrated were responsible for the antibacterial and antiviral effect, and not the hydrogen peroxide itself.

The catalyst-based method was shown to be 10,000,000 times more potent at killing the bacteria than an equivalent amount of the industrial hydrogen peroxide, and over 100,000,000 times more effective than chlorination, under equivalent conditions.

In addition to this, the catalyst-based method was shown to be more effective at killing the bacteria and viruses in a shorter space of time compared to the other two compounds.

It is estimated that around 785 million people lack access to water and 2.7 billion experience water scarcity at least one month a year.

In addition to this, inadequate sanitation--a problem for around 2.4 billion people around the world--can lead to deadly diarrheal diseases, including cholera and typhoid fever, and other water-borne illnesses.

Co-author of the study Professor Graham Hutchings, Regius Professor of Chemistry at the Cardiff Catalysis Institute, said: "The significantly enhanced bactericidal and virucidal activities achieved when reacting hydrogen and oxygen using our catalyst, rather than using commercial hydrogen peroxide or chlorination shows the potential for revolutionising water disinfection technologies around the world.

"We now have proven one-step process where, besides the catalyst, inputs of contaminated water and electricity are the only requirements to attain disinfection.

"Crucially, this process presents the opportunity to rapidly disinfect water over timescales in which conventional methods are ineffective, whilst also preventing the formation of hazardous compounds and biofilms, which can help bacteria and viruses to thrive."

As many expectant mothers know, getting enough folate is key to avoiding neural tube defects in the baby during pregnancy. But for the individuals who carry certain genetic variants, dealing with folate deficiency can be a life-long struggle which can lead to serious neurological and heart problems and even death.

Now a Donnelly Centre study offers clues to how to recognize early those who are most at risk.

Defects in an enzyme called MTHFR, or 5,10-methylenetetrahydrofolate reductase, which modifies folate, or vitamin B9 as it is also known, to produce other essential cellular components, can increase a person's need for folate. MTHFR deficiency occurs when a person inherits two defective copies of this gene, one from each parent. Disease severity depends on the exact changes in the composition of the amino-acid residues which make up the protein and which are encoded by the two copies of the gene that a person carries.

"The benefit of recognizing MTHFR deficiency early is that you can start preventative therapy, including a high folate diet, very early in life and prevent or reduce the most severe effects," says Fritz Roth, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at the Temerty Faculty of Medicine and senior author on a new study into the genetic causes of the disorder.

Their findings are published in the American Journal of Human Genetics.

There are likely thousands of variants circulating in the population whose effects on folate metabolism--and health--remain unknown. Knowing which variants impair enzyme function can help predict, and possibly prevent, the negative consequences associated with MTHFR deficiency.

Which is why Roth's team decided to construct all possible MTHFR variants to identify the ones that don't function properly and therefore could impact health. Known as deep mutational scanning, the approach entails substituting each of the enzyme's 656 amino-acid residues with another of the 20-naturally occurring amino-acids, and testing how well the altered enzyme functions.

The research is part of a wider effort to experimentally test human variant functions that is happening in labs around the world including the Atlas of Variant Effects Alliance co-founded by Roth. A related "Impact of Genomic Variation on Function" initiative is being launched this fall by the National Institutes of Health in the U.S.

"The point of this work is to be ready and know the damaging variants ahead of time instead of waiting for the variant to be identified in a patient and then do experiments on it," says Roth, who is also Senior Investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health Systems and holds Canada Excellence Research Chair in Integrative Biology. "We want to be ready when a new one comes along."

To test variant function, the researchers introduced each variant one at a time into Baker's yeast cells which had been engineered to lack their own version of the MTHFR gene without which they cannot grow on a given medium. Human MTHFR variants were then scored as functional or nonfunctional, or somewhere in between, based on their ability to rescue yeast growth.

While the most damaging mutations which abolish MTHFR function are rare, other variants can impact the enzyme in more subtle ways to make it less efficient. Indeed, as many as half of humans carry at least one copy of an MTHFR variant known as A222V, with the amino-acid alanine changed into valine at position 222. For the 10% of women who carry two copies, a folate-rich diet may be sufficient to stave off the risk of birth defects.

But having a copy of A222V might significantly raise disease risk (in both men and women) if another gene variant whose function is not known is also present in the same individual. To test this, Roth's team examined all MTHFR variants, but this time together with A222V.

"A variant could have one effect in the normal reference human background but have a stronger effect together with this common A222V variant and we wanted to investigate that," says Roth.

They found that the common A222V variant can impact the effect of other variants, which on their own might not impair enzyme function. Different amino acids changes within the same gene can interact with each other to impact enzyme function, so that identifying interactions for variant combination before they are seen in patients might help predict disease severity.

"Clinical geneticists will usually be right in saying that this common variant is not a big deal, and that you can overcome its effects by getting more dietary folate, but a major point of our paper is that A222V also changes the impact of other variants," says Roth.

"MTHFR is just the beginning. Having an atlas of maps for other disease-related genes could help us better interpret individual genomes and allow earlier diagnosis and prevention when we see a concerning variants."

While autistic individuals are less likely to use substances, those who do so are more likely to self-medicate for their mental health symptoms, according to new research from the University of Cambridge and published today in The Lancet Psychiatry.

There is significant debate about substance use of autistic adolescents and adults. Some studies indicate that autistic individuals are less likely to use substances, whereas others suggest that autistic individuals are at greater risk of substance misuse or abuse. The team at the Autism Research Centre in Cambridge used a 'mixed methods' design to consider both the frequency of substance use among autistic individuals, as well as their self-reported experiences of substance use.

Overall, 1,183 autistic and 1,203 non-autistic adolescents and adults (aged 16-90 years) provided information about the frequency of their substance use via an anonymous, online survey; of this group, 919 individuals also gave more in-depth responses about their experiences of substance use.

Autistic adults were less likely than non-autistic peers to use substances. Only 16% of autistic adults, compared to 22% of non-autistic adults, reported drinking on three or more days per week on average. Similarly, only 4% of autistic adults reported binge-drinking compared to 8% of non-autistic adults.

There were also some sex differences in patterns of substance use: autistic males were less likely than non-autistic males to report ever having smoked or used drugs. In contrast, the team did not find differences in the patterns of frequency of smoking or drug use between autistic and non-autistic females.

However, despite lower rates of substance use overall, the qualitative findings of the study provide a much less hopeful picture: autistic adults were nearly nine times more likely than non-autistic peers to report using recreational drugs (such as marijuana, cocaine and amphetamines) to manage unwanted symptoms, including autism-related symptoms.

Drugs were used to reduce sensory overload, help with mental focus, and provide routine, among other reasons. Several autistic participants also indirectly referenced using substances to mask their autism. Past research has shown that this behavioural management (also known as 'camouflaging' or 'compensating') has been linked to emotional exhaustion, worse mental health, and even increased risk of suicide among autistic adults.

Autistic adolescents and adults were also over three times more likely than others to report using substances to manage mental health symptoms, including anxiety, depression, and suicidal thoughts. Several participants specifically noted that they used drugs for self-medication. However, this self-medication was not always viewed as negative by participants, and several noted that using recreational drugs allowed them to reduce the doses of prescribed medications for mental health conditions, which was a welcome change due to the sometimes significant side effects from their prescribed medications.

Another area of concern was the strong association between vulnerability and substance use among autistic teenagers and adults. Previous work from the Cambridge team suggests that autistic adults may be much more likely to have adverse life experiences and be at greater risk of suicide than others. The findings of the new study indicate that autistic individuals are over four times more likely to report vulnerability associated with substance use compared to their non-autistic peers, including dependence/addiction, using drugs to deal with past trauma, and substance use associated with suicide.

In addition, the study identified two new areas of vulnerability not been previously reported: being forced, tricked, or accidentally taking drugs; and childhood use of substances (at the age of 12 years or younger).

Elizabeth Weir, a PhD student at the Autism Research Centre in Cambridge, and the lead researcher of the study, said: "Whether or not the substances currently classed as 'recreational' could be used medically remains an open question. It is evident that the current systems of health and social care support are not meeting the needs of many autistic teenagers and adults.

"No one should feel that they need to self-medicate for these issues without guidance from a healthcare professional. Identifying new forms of effective support is urgent considering the complex associations between substance use, mental health, and behaviour management--particularly as camouflaging and compensating behaviours are associated with suicide risk among autistic individuals."

Dr Carrie Allison, Director of Research Strategy at the Autism Research Centre and a member of the research team, said: "While some of our results suggest lower likelihood of substance use overall, physicians should not assume that their autistic patients aren't using drugs. Drug use can be harmful so healthcare providers should aim to establish trusting relationships with autistic and non-autistic patients alike to foster frank and honest conversations about substance use."

Professor Simon Baron-Cohen, Director of the Autism Research Centre and a member of the team, said: "We continue to see new areas in which autistic adults experience vulnerability: mental health, physical health, suicide risk, lifestyle patterns, the criminal justice system, and so on. Substance use is now another area that we need to consider when developing new forms of support for autistic individuals. It is essential that we ensure that autistic people have equal access to high quality social and healthcare that can appropriately support their specific needs; and, unfortunately, it seems clear that our current systems are still not meeting this mark."

New research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College London, in collaboration with the University of Liverpool and the Karolinska Institute, has shown that many of the symptoms in fibromyalgia syndrome (FMS) are caused by antibodies that increase the activity of pain-sensing nerves throughout the body.

The results show that fibromyalgia is a disease of the immune system, rather than the currently held view that it originates in the brain.

The study, published today in the Journal of Clinical Investigation, demonstrates that the increased pain sensitivity, muscle weakness, reduced movement, and reduced number of small nerve-fibres in the skin that are typical of FMS, are all a consequence of patient antibodies.

The researchers injected mice with antibodies from people living with FMS and observed that the mice rapidly developed an increased sensitivity to pressure and cold, as well as displaying reduced movement grip strength. In contrast, mice that were injected with antibodies from healthy people were unaffected, demonstrating that patient antibodies cause, or at least are a major contributor to the disease.

Furthermore, the mice injected with fibromyalgia antibodies recovered after a few weeks, when antibodies had been cleared from their system. This finding strongly suggests that therapies which reduce antibody levels in patients are likely to be effective treatments. Such therapies are already available and are used to treat other disorders that are caused by autoantibodies.

Dr David Andersson, the study's primary investigator from King's IoPPN said "The implications of this study are profound. Establishing that fibromyalgia is an autoimmune disorder will transform how we view the condition and should pave the way for more effective treatments for the millions of people affected. Our work has uncovered a whole new area of therapeutic options and should give real hope to fibromyalgia patients.

"Previous exploration of therapies has been hampered by our limited understanding of the illness. This should now change. Treatment for FMS is focussed on gentle aerobic exercises, as well as drug and psychological therapies designed to manage pain, although these have proven ineffective in most patients and have left behind an enormous unmet clinical need."

Current estimates suggest that at least 1 in 40 people are affected by FMS worldwide (80% of which are women) and is commonly characterised by widespread pain throughout the body, as well as fatigue (often referred to as 'fibro fog') and emotional distress. It most commonly develops between the ages of 25 and 55, although children can also get it.

Dr Andreas Goebel, the study's principle clinical investigator from the University of Liverpool said, "When I initiated this study in the UK, I expected that some fibromyalgia cases may be autoimmune. But David's team have discovered pain-causing antibodies in each recruited patient. The results offer amazing hope that the invisible, devastating symptoms of fibromyalgia will become treatable."

Professor Camilla Svensson, the study's primary investigator from Karolinska Institute said, "Antibodies from people with FMS living in two different countries, the UK and Sweden, gave similar results, which adds enormous strength to our findings. The next step will be to identify what factors the symptom-inducing antibodies bind to. This will help us not only in terms of developing novel treatment strategies for FMS, but also of blood-based tests for diagnosis, which are missing today.

Dr Craig Bullock, Research Discovery and Innovations Lead at Versus Arthritis said "Fibromyalgia affects millions of people in the UK and can have a devastating impact on quality of life. It causes pain all over the body, fatigue, disturbed sleep and regular flare-ups where symptoms get even worse.

"Fibromyalgia is a particularly difficult condition to diagnose and manage because its causes are unknown. This research shows that antibodies found in human blood can cause fibromyalgia-like symptoms in mice, suggesting that these antibodies play a crucial role in the condition. Further research is needed but this offers hope to the millions of people with fibromyalgia that an effective treatment could be found in the relatively near future."

Scientists have long searched in vain for a class of brain cells that could explain the visceral flash of recognition that we feel when we see a very familiar face, like that of our grandmothers. But the proposed "grandmother neuron"—a single cell at the crossroads of sensory perception and memory, capable of prioritizing an important face over the rabble—remained elusive.

Now, new research reveals a class of neurons in the brain's temporal pole region that links face perception to long-term memory. It's not quite the apocryphal grandmother neuron—rather than a single cell, it’s a population of cells that collectively remembers grandma's face. The findings, published in Science, are the first to explain how our brains inculcate the faces of those we hold dear.

"When I was coming up in neuroscience, if you wanted to ridicule someone's argument you would dismiss it as 'just another grandmother neuron'—a hypothetical that could not exist," says Winrich Freiwald, professor of neurosciences and behavior at The Rockefeller University.

"Now, in an obscure and understudied corner of the brain, we have found the closest thing to a grandmother neuron: cells capable of linking face perception to memory."

Have I seen that face before?

The idea of a grandmother neuron first showed up in the 1960s as a theoretical brain cell that would code for a specific, complex concept, all by itself. One neuron for the memory of one’s grandmother, another to recall one’s mother, and so on. At its heart, the notion of a one-to-one ratio between brain cells and objects or concepts was an attempt to tackle the mystery of how the brain combines what we see with our long-term memories.

Scientists have since discovered plenty of sensory neurons that specialize in processing facial information, and as many memory cells dedicated to storing data from personal encounters. But a grandmother neuron—or even a hybrid cell capable of linking vision to memory—never emerged. "The expectation is that we would have had this down by now," Freiwald says. "Far from it! We had no clear knowledge of where and how the brain processes familiar faces."

Recently, Freiwald and colleagues discovered that a small area in the brain’s temporal pole region may be involved in facial recognition. So the team used functional magnetic resonance imaging as a guide to zoom in on the TP regions of two rhesus monkeys, and recorded the electrical signals of TP neurons as the macaques watched images of familiar faces (which they had seen in-person) and unfamiliar faces that they had only seen virtually, on a screen.

The team found that neurons in the TP region were highly selective, responding to faces that the subjects had seen before more strongly than unfamiliar ones. And the neurons were fast—discriminating between known and unknown faces immediately upon processing the image.

Interestingly, these cells responded threefold more strongly to familiar over unfamiliar faces even though the subjects had in fact seen the unfamiliar faces many times virtually, on screens. “This may point to the importance of knowing someone in person,” says neuroscientist Sofia Landi, first author on the paper. “Given the tendency nowadays to go virtual, it is important to note that faces that we have seen on a screen may not evoke the same neuronal activity as faces that we meet in-person.”

A tapestry of grandmothers

The findings constitute the first evidence of a hybrid brain cell, not unlike the fabled grandmother neuron. The cells of the TP region behave like sensory cells, with reliable and fast responses to visual stimuli. But they also act like memory cells which respond only to stimuli that the brain has seen before—in this case, familiar individuals—reflecting a change in the brain as a result of past encounters. "They're these very visual, very sensory cells—but like memory cells," Freiwald says. "We have discovered a connection between the sensory and memory domains."

But the cells are not, strictly speaking, grandmother neurons. Instead of one cell coding for a single familiar face, the cells of the TP region appear to work in concert, as a collective.

"It’s a 'grandmother face area' of the brain," Freiwald says.

The discovery of the TP region at the heart of facial recognition means that researchers can soon start investigating how those cells encode familiar faces. "We can now ask how this region is connected to the other parts of the brain and what happens when a new face appears," Freiwald asks. "And of course, we can begin exploring how it works in the human brain."

In the future, the findings may also have clinical implications for people suffering from prosopagnosia, or face blindness, a socially isolating condition that affects about one percent of the population. "Face-blind people often suffer from depression. It can be debilitating, because in the worst cases they cannot even recognize close relatives," Freiwald says.

"This discovery could one day help us devise strategies to help them.”

The COVID-19 catastrophe in India has resulted in more than 30 million people infected with the virus and nearly 400,000 deaths, though experts are concerned that the figures most likely are much higher. Meanwhile, another public health crisis has emerged along with COVID-19: the widespread misuse of antibiotics.

During India's first surge of COVID-19, antibiotic sales soared, suggesting the drugs were used to treat mild and moderate cases of COVID-19, according to research led by Washington University School of Medicine in St. Louis. Such use is considered inappropriate because antibiotics are only effective against bacterial infections, not viral infections such as COVID-19, and overuse increases the risk for drug-resistant infections.

"Antibiotic resistance is one of the greatest threats to global public health," said the study's senior author, infectious diseases specialist Sumanth Gandra, MD, an associate professor of medicine and an associate hospital epidemiologist at Barnes-Jewish Hospital. "Overuse of antibiotics lessens their ability to effectively treat minor injuries and common infections such as pneumonia, which means that these conditions can become serious and deadly. Bacteria that have become resistant to antibiotics don't have boundaries. They can spread to any person in any country."

The study, conducted in collaboration with McGill University in Canada, is published July 1 in PLOS Medicine. Giorgia Sulis, MD, PhD, a postdoctoral researcher at McGill, is the first author.

Antibiotics are life-saving medications. However, unchecked, germs learn to defy the antibiotics designed to kill them while also multiplying in force. Along with more illnesses and deaths, antibiotic resistance leads to increased hospital stays and medical costs.

In high-income countries such as the United States, United Kingdom and Canada, overall antibiotic use plunged in 2020, even during COVID-19 peaks. "This is because physicians in high-income countries generally did not prescribe antibiotics for mild and moderate COVID-19 cases," Gandra explained. "The uptick in India indicates that COVID-19 guidelines were not followed."

Also worrisome are prior data analyses concluding that COVID-19 cases and deaths in India surpass the official estimates. "In reality, the problem is likely much worse," said Gandra, who also serves on a World Health Organization (WHO) committee focused on reducing antibiotic prescriptions in low- and middle-income countries.

With nearly 1.4 billion people, India is the world's second most populous country. "India is essential to study because it is the largest consumer of antibiotics in the world, and it's basically a poster child for antibiotic misuse in low- and middle-income countries with similar health-care practices," Gandra explained. "In general, these countries excessively prescribe antibiotics in primary care settings. Therefore, we suspect the pandemic has also spurred inappropriate antibiotic use in many low- and middle-income countries."

Antibiotic use increased despite guidelines from the Indian Health Ministry and WHO urging against antibiotics for mild and moderate forms of COVID-19, which account for more than 90% of the cases. "Antibiotics should only be given to patients who develop secondary bacterial illnesses," Gandra said. "This was not the case, indicating the need for policy changes in India, especially in light of the current crisis and the possibility of a devastating third wave."

In India, an unregulated private sector accounts for 75% of health care and 90% of antibiotic sales, Gandra said. "This allows for antibiotic overprescription," he said. "Low- and middle-income countries tend to skip diagnostic testing for respiratory illnesses because most patients cannot afford it, so they receive antibiotics under the assumption that their illness is bacterial. In the U.S., however, patients with a cold or a cough usually undergo testing for bacterial infections such as strep throat and only receive antibiotics if the tests are positive."

To assess the pandemic's impact on antibiotic use, researchers analyzed monthly sales of all antibiotics in India's private health sector from January 2018 through December 2020. The data came from an Indian branch of IQVIA, a U.S.-based health information technology company.

Specifically, researchers examined the total sales volume of all antibiotics as well as the individual sales volume for azithromycin. The latter was studied because some countries experienced a spike in azithromycin sales early in the pandemic after observational studies suggested the antibiotic could help treat COVID-19 (subsequent studies disputed the claim).

The researchers determined that a total of 16.29 billion doses of antibiotics were sold in India in 2020, which is slightly less than the amounts sold in 2018 and in 2019. However, when researchers focused on adult doses, usage increased from 72.6% in 2018 and 72.5% in 2019 to 76.8% in 2020.

Additionally, sales of azithromycin for adults in India increased from 4% in 2018 and 4.5% in 2019 to 5.9% in 2020. The study also showed notable increases in the sales of doxycycline and faropenem, two antibiotics commonly used to treat respiratory infections.

The researchers used previously published studies to compare India's antibiotic use with use of such drugs in the U.S. and other high-income countries. In those countries, the researchers found that adult antibiotic use decreased drastically during the pandemic compared with such use in 2018 and 2019.

"It's critical to acknowledge that antibiotic use in high-income countries plummeted in 2020," Gandra said. "People isolated, schools and offices closed, and fewer people got the flu and, overall, stayed healthier compared with the pre-pandemic years. This reduced the overall need for antibiotics, as did canceling dental procedures and outpatient surgeries.

"India also had restrictions and experienced dramatic decreases in malaria, dengue, chikungunya and other and infections typically treated with antibiotics," he said. "Antibiotic use should have gone down, but it didn't. Not only that but antibiotic use increased along with the rise of COVID cases."

After statistically adjusting for seasonality and mandatory lockdown periods, researchers estimated that COVID-19 likely contributed to 216.4 million excess doses of antibiotics for adults and 38 million excess doses of azithromycin for adults from June 2020 through September 2020, a four-month period of peak COVID-19 activity in India. "Our results indicate that almost everybody who was diagnosed with COVID-19 received an antibiotic in India," Gandra said.

Azithromycin is a vital drug for treating typhoid fever, non-typhoidal Salmonella and traveler's diarrhea. "Unnecessary use will lead to resistance among the bacteria that cause these illnesses," Gandra said. "These infections are highly prevalent in India and other low- and middle-income countries ... and azithromycin is the only effective oral treatment option available for typhoid fever in Pakistan."

Researchers also studied hydroxychloroquine, an anti-malarial drug touted as a potential treatment for COVID-19 earlier in the pandemic. In India, sales of the drug decreased after the government issued an emergency order imposing stronger restrictions on the sale of hydroxychloroquine. Gandra said the Indian government should strongly consider mandating similar restrictions for azithromycin and other antibiotics.

"The most recent wave in India is at least four times the first wave, and preliminary research shows a similar reliance on using antibiotics to treat mild and moderate COVID-19 cases," he said. "The medium- and long-term consequences on bacterial resistance patterns are highly concerning, highlighting the need for urgent antibiotic stewardship measures, including mass vaccination."

Computer models have been standard tools in basic biomedical research for many years. However, around 70 years after the first publication of an ion current model of a nerve cell by Hodgkin & Huxley in 1952, researchers at Graz University of Technology (TU Graz), in collaboration with the Medical University of Graz and the Memorial Sloan Kettering Cancer Center in New York, have finally succeeded in developing the world's first cancer cell model, thus launching "an essential tool for modern cancer research and drug development," reports a delighted Christian Baumgartner. The head of the Institute of Health Care Engineering with European Testing Center of Medical Devices at TU Graz is senior author of the publication in which the digital model is presented in the journal PLoS Computational Biology.

Excitable and non-excitable cells

Digital cell models have so far focused on excitable cells such as nerve or cardiac muscle cells, allowing the simulation of electrophysiological processes not only at the cellular level, but also at the tissue and organ level. These models are already being used to support diagnosis and therapy in everyday clinical practice. The international research team led by Baumgartner focused on the specific electrophysiological properties of non-excitable cancer cells for the first time.

In excitable cells, an electrical stimulus triggers so-called action potentials. This leads to short-term changes in electrical potential lasting milliseconds at the cell membrane that transmit "electrical" information from cell to cell. Through this mechanism, neural networks communicate or the heart muscle is activated, which contracts as a result. It is known from experimental studies that "non-excitable" cells also exhibit characteristic fluctuations of potential at the cell membrane. However, compared to excitable cells, the potential changes occur very slowly and over the entire cell cycle, i.e. over hours and days, and serve as a signal for the transition between the individual cell cycle phases," explains Christian Baumgartner. Together with the deputy head of the institute, Theresa Rienmüller, and PhD student Sonja Langthaler, Christian Baumgartner was the first to pursue the idea of developing a simulation model of these mechanisms.

Lung tumour example

Pathological changes in cell membrane voltage, particularly during the cell cycle, are fundamental to cancer development and progression. Sonja Langthaler continues in detail: "Ion channels connect the outside to the inside of a cell. They enable the exchange of ions such as potassium, calcium or sodium and thereby regulate the membrane potential. Changes in the composition of ion channels, as well as altered functional behaviour of the same, can result in disruptions in cell division, possibly even affecting cell differentiation and thus transforming a healthy cell into a diseased (carcinogenic) cell."

For their digital cancer cell model, the team chose the example of the human lung adenocarcinoma cell line A549. The computer model simulates the rhythmic oscillation of the membrane potential during the transition between cell cycle phases and enables prediction of the changes in membrane potential that are caused by drug-induced switching on and off of selected ion channels. "So we get information about the effects of targeted interventions on the cancer cell," Baumgartner adds.

"Freezing" cancer cells during growth or inducing them to commit suicide

The activity of certain ion channels can also drive the division of diseased cells and thus accelerate tumour growth. If ion channels are now manipulated in a targeted manner, as is the case with new, promising agents and drugs, the cell membrane voltage and thus the entire electrophysiological system can be thrown off track, so to speak. "This could be used to arrest cancer cells at a certain phase in the cell cycle, but also to induce premature cell death (apoptosis). One could "freeze" cancer cells while they are growing or induce them to commit suicide. And it is precisely such mechanisms that can be simulated with the help of models." Baumgartner and his team see the first digital cancer cell model as the beginning of more comprehensive research. In order to increase the level of detail of the model, plans for further experimental and measurement validations have been made and submitted to the Austrian Science Fund FWF for funding.

Chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) is a disabling disease, in which people have great difficulties in carrying out their daily activities. Despite its high prevalence, there are still no effective tools for its diagnosis, monitoring and treatment. To better understand and promote follow-up, as well as stratify fatigue in these patients, Vall d'Hebron, the Universitat Autònoma de Barcelona (UAB) and the Universitat Politècnica de Catalunya · BarcelonaTech (UPC) have developed a mobile application that could be useful in the assessment of the severity of fatigue in this syndrome, especially in women. The results of the study in which this technology has been tested have been published in the journal Sensors.

The technology developed by the UAB and UPC researchers consists of a chest strap with a sensor capable of measuring certain cardiac hemodynamic variables, connected via Bluetooth to a mobile app. The mobile application allows you to record and monitor heart rate variability and share the analyzed results with the medical staff who supervise patients.

Specifically, this study analyzed the relationship between heart rate variability and severity of symptoms among women and men with CFS/ME. This parameter is closely related to heart rate, that is, the number of beats per minute of the heart. However, the time that passes between two consecutive beats is not always exactly the same, but small differences that fall within normality can be detected: this is what is known as heart rate variability (HRV).

In previous studies published in the Journal of Translational Medicine, HRV had already been related to the assessment of the severity of fatigue in women with CFS/ME. "Specifically, we had observed that this variability was lower in patients with CFS/ME, especially in the most disabling cases", explains Dr. Jesús Castro, coordinator of the laboratory in Chronic Fatigue Syndrome / Myalgic Encephalomyelitis of the Rheumatology group of the Vall d'Hebron Research Institute (VHIR). A priori, it is considered positive to have a high variability, as it is an indicator of the proper functioning of the autonomic nervous system. "In this work we wanted to verify the relationship between HRV and the syndrome in both women and men with CFS/ME compared to healthy controls and its usefulness for monitoring patients", adds Dr. Castro.

In line with previous studies, it was found that HRV measurement with mobile app technology could predict the severity of disabling fatigue in patients with chronic fatigue syndrome/myalgic encephalomyelitis. This was especially observed in the case of women, but this relationship was not so clear in the case of men. "We demonstrated that the use of the app would be especially useful for the monitoring of women suffering from this syndrome, which clearly have a lower variability of heart rate compared to healthy women", says Dr. Rosa M Escorihuela, from the Department of Psychiatry and Legal Medicine of the UAB. Thus, HRV would be a good predictor marker of the severity of fatigue during the clinical course of the disease.

The study was carried out with 77 patients with this CFS/ME (32 men and 45 women) and their results were compared with those of a control group. The HRV evaluation was carried out in 3 sessions of 5 minutes, separated between one and three weeks and under controlled conditions.

This study has been carried out, in part, thanks to the R&D project PID2019-107473RB-C21, coordinated by researchers from the UAB and the UPC, and funded by the Ministry of Science and Innovation.

An improved non-invasive technology

Dr. Juan Ramos Castro, from the Electronic and Biomedical Instrumentation group and the Department of Electronic Engineering at the UPC, comments that "the experience of the UAB and UPC research groups has made it possible to correct the most important limitations presented by this technology such as errors in the measurement of cardiac variability produced by incorrect placement of the chest strap and / or the movement and breathing of the patient during recording, and obtaining the records under controlled conditions to reduce the influence of other external factors. The results of the analysis are stored in a single and secure server and can be consulted through a specific platform". Dr. Lluís Capdevila, researcher at the Department of Basic, Evolutionary and Educational Psychology and the Sports Research Institute of the UAB, adds that "it is a non-invasive technology that is easy to use by patients or users, through your mobile device. In this way, they can perform self-assessments in ecological situations and could be monitored in real time".

As Dr. Lluís Capdevila comments, "the same system originated and has been used successfully for real-time monitoring and follow-up of the relationship between physical effort and recovery, both in athletes and in the general population. For example, sports clubs such as Futbol Club Barcelona (women's basketball and soccer sections) or New York City FC have used this system, and national teams such as the Spanish Basketball Federation, the Spanish Field Hockey Federation (men's and female), or the Spanish Federation of Mountain Sports and Climbing".

Vall d'Hebron, member of the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

In Catalonia it is estimated that there are currently between 350,000 and 500,000 people affected by chronic fatigue syndrome / myalgic encephalomyelitis, and 2 out of 3 affected people are women. Worldwide, a prevalence of between 17 and 25 million people with this affectation is estimated. In addition, these numbers are predicted to double by 2030 due to persistent COVID-19, a condition in which patients have similar symptoms: this is known as postviral chronic fatigue syndrome, which has been previously described in other coronaviruses (SARS-CoV-1 and MERS) for other viruses such as Ebola, Epstein-Barr and Cytomegalovirus.

Severe fatigue is the main symptom of CFS/ME, in addition to problems with immediate memory and speed of information processing and concentration, intolerance to physical / mental exercise, pain and dizziness. This syndrome can be very disabling, but even so, there are currently no diagnostic biomarkers or specific therapeutic options, so it is important that experts in the field work in a coordinated way to improve the care and management of these patients.

In this sense, Drs. José Alegre and Jesús Castro, both from Vall d'Hebron, are members for Spain in the European Network on Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (EUROMENE), which includes 55 professionals from 22 European countries. A consensus document on therapeutic and diagnostic approaches for this syndrome was recently published in the journal Medicina.

This document brings together the diagnostic criteria used in the participating countries as well as the experience of professionals in the management and treatment of patients, taking into account both pharmacological and non-pharmacological therapies. In addition, experts present recommendations, from Europe and internationally, for the care of these patients. "It is necessary to have a health system that takes into account patients with chronic fatigue syndrome / myalgic encephalomyelitis, a pathology that has a great socioeconomic impact", says Dr. José Alegre, from the Experience Unit in Syndromes of Central Awareness of the Rheumatology Service of the Vall d'Hebron University Hospital. Experts consider that it would be necessary to have between 2 and 4 specialist doctors for every million inhabitants with the support of a multidisciplinary team, such as nurses, physiotherapists, rehabilitators, occupational therapists, psychologists, nutritionists, social workers, etc.

It should be noted that not all countries have the same services for the care of patients with CFS/ME. In this sense, Catalonia is leading in terms of the care of these patients, since in our territory there are various units formed in this area to diagnose and treat this syndrome. Specifically, Vall d'Hebron has an Experience Unit in Central Sensitization Syndromes, within the Rheumatology Service, which works on both chronic fatigue syndrome / myalgic encephalomyelitis and fibromyalgia.