Culture

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.

When researchers at Lund University in Sweden performed advanced analyses of sputum from the airways of severely ill Covid-19 patients, they found high levels of neutrophil extracellular traps (NETs). It is already a known fact that NETs can contribute to sputum thickness, severe sepsis-like inflammation and thrombosis. After being treated with an already existing drug, the NETs were dissolved and patients improved. The study has now been published in Molecular & Cellular Proteomics.

Using advanced fluorescence microscopy, the researchers examined sputum in the airways of three severely ill Covid-19 patients. The results showed that the samples contained large amounts of one of the immune system's most important agents against bacteria: neutrophils. Neutrophils can form neutrophil extracellular traps (NETs) to capture and neutralise pathogens - primarily bacteria but also viruses.

"We are aware that NETs contribute to sputum viscosity and severe sepsis-like inflammation as well as increase risk of thrombosis i.e. blood clots. We also see these three clinical findings in severely ill Covid-19 patients", says Adam Linder, researcher at Lund University and infectious disease physician at Skåne University Hospital.

Patients with cystic fibrosis can also suffer from increased sputum viscosity. In these cases, a DNase drug is sometimes used to degrade DNA, of which NETs are primarily composed. Could the same drug have an effect on severe Covid 19 cases? A pilot study was conducted after the researchers could see in laboratory test tubes that the DNase preparation degraded the NETs. Five severely ill Covid-19 patients, who required high-flow oxygen therapy and were on the verge of needing mechanical ventilation, were treated with the preparation.

"The patients responded very well to the treatment. Dependency on oxygen therapy diminished for all of them, and they no longer needed oxygen therapy at all after four days. None of them needed to be moved to the intensive care unit, and all of them have recovered and been discharged", says Adam Linder.

Analyses of the patients' sputum showed that they had high levels of NETs prior to the start of treatment, and that these levels were substantially reduced after treatment (see image).

"We have also examined other inflammation parameters using advanced mass spectrometry. Once the drug treatment started, the proinflammatory signalling diminished, which shows that the inflammation was subsiding. Plasma leakage and the viral load were also reduced", says Tirthankar Mohanty, researcher at Lund University.

Even if the results are positive, Adam Linder emphasises that the study is small and that additional research is needed. The researchers are consequently carrying out a phase-2, randomised clinical trial at Skåne University Hospital to examine whether aerosolised DNase (Pulmozyme) is an effective treatment for respiratory failure in conjunction with Covid-19.

"Much of what we see in patients with this pathology could be explained by NETs, but the study needs to be repeated, and in a randomised manner. We also need to know more about when the drug should be administered for the best results", concludes Adam Linder.

Hundreds of genetic drivers affect sexual and reproductive behaviour

Combined with social factors, these can affect longevity and health

An Oxford-led team, working with Cambridge and international scholars, has discovered hundreds of genetic markers driving two of life's most momentous milestones - the age at which people first have sex and become parents.

In a paper published today in Nature Human Behaviour, the team linked 371 specific areas of our DNA, called genetic variants (known locations on chromosomes), 11 of which were sex-specific, to the timing of first sex and birth. These variants interact with environmental factors, such as socioeconomic status and when you were born, and are predictors of longevity and later life disease.

The researchers conducted a Genome-Wide Association Study (GWAS), a search across the entire human genome, to see if there is a relationship between reproductive behaviour and a particular genetic variant. In the largest genomic study ever conducted to date, they combined multiple data sources to examine age at first sex (N=387,338) and birth (N=542,901) in men and women. They then calculated a genetic score, with all genetic loci combined explaining around 5-6% of the variability in the average age at sexual debut or having a first child.

Professor Melinda Mills, Director of the Leverhulme Centre for Demographic Science at the University of Oxford and Nuffield College, and the study's first author says, 'Our study has discovered hundreds additional genetic markers that shape this most fundamental part of our lives and have the potential for deeper understanding of infertility, later life disease and longevity.'

The genetic signals were driven by social factors and the environment but also by reproductive biology, with findings related to follicle-stimulating hormone, implantation, infertility, and spermatid differentiation.

Professor Mills adds 'We already knew that childhood socioeconomic circumstances or level of education were important predictors of the timing of reproduction. But we were intrigued to find literally not only hundreds of new genetic variants, but also uncover a relationship with substance abuse, personality traits such as openness and self-control, ADHD and even predictive of some diseases and longevity .'

Professor Mills says, 'We demonstrated that it is a combination of genetics, social predictors and the environment that drives early or late reproductive onset. It was incredible to see that the genetics underlying early sex and fertility were related to behavioural dis-inhibition, like ADHD, but also addiction and early smoking. Or those genetically prone to postpone sex or first birth had better later life health outcomes and longevity, related to a higher socioeconomic status in during childhood.'

Genetic factors driving reproductive behaviour are strongly related to later life diseases such as Type 2 diabetes and cardiovascular disease.

'It is exciting that the genetics underlying these reproductive behaviours may help us understand later life disease.'

Professor Mills concludes, 'Starting your sexual journey early is rooted in childhood inequality but also has links with health problems, such as cervical cancer and depression. We found particularly strong links between early sexual debut, ADHD and substance abuse, such as early age at smoking. We hope our findings lead to better understanding of teenage mental and sexual health, infertility, later life disease and treatments to help.'

Researchers have developed a more efficient platform for studying proteins that play a key role in regulating gene expression. The approach uses engineered yeast cells to produce enzyme and histone proteins, conduct biochemical assays internally, and then display the results.

"Biomedical and biotech researchers are interested in the mechanisms that allow histones to regulate gene activity," says Alison Waldman, first author of a paper on the work and a Ph.D. student at North Carolina State University. "But the conventional tools for histone research are unwieldy and slow. We wanted to develop something faster and less expensive - and we did."

In complex organisms, chromosomes are largely made up of DNA and a group of proteins called histones. These histones are important for packing the DNA into chromosomes properly, but also play a role in regulating gene expression. In other words, they help determine when and how specific genes are turned on or off.

One of the features that makes histones challenging to study is that they often have chemical modifications that, alone or in combination, alter the role the histone plays in gene expression.

"Histones essentially serve as docking sites for other proteins that influence gene expression, and the chemical modifications we see on histones play a role in determining which proteins have access to a given gene," says Balaji Rao, co-corresponding author of the paper and a professor of chemical and biomolecular engineering at NC State.

And to make matters more complicated, this is a dynamic process. A histone may have no modifications, it may retain a modification for the entire life of the cell, or modifications may be added and removed repeatedly. There is, in short, a lot going on. And enzymes are the catalysts responsible for all of those changes. Basically, enzymes are the mechanism for attaching or removing histone modifications.

So if you really want to understand what's going on with histones, you have to understand the chemical modifications. But if you want to understand the chemical modifications, you need to understand which enzymes are present and what they are doing.

Conventional methods for understanding how enzymes modify a histone involve using one of two techniques. First, you could use chemical synthesis to create enzymes and histone proteins, then conduct an assay in a test tube to see what happens. Second, you could genetically engineer one bacteria to produce an enzyme and engineer other bacteria to produce histone proteins, then harvest the relevant proteins, purify them, then conduct an assay to see what happens.

"Our technique uses a genetically modified yeast cell to produce both the enzyme and the histone," Waldman says. "The chemical modification takes place within the cell, and the resulting modified histone is sent to and displayed on the surface of the cell."

"In other words, the yeast cell makes the relevant proteins, does the assay for you, and then displays the result on top," says Albert Keung, co-corresponding author of the work and an assistant professor of chemical and biomolecular engineering at NC State.

The modified yeast platform is significantly faster than conventional techniques. For example, examining a single enzyme/histone pairing would take a couple days, instead of a week.

"But it's easier to scale up than existing techniques, so you would save substantially more time if you were looking at a lot of proteins," Keung says.

"In addition, there are some proteins that can't be made using chemical synthesis, or that can't be purified," Rao says. "Our technique doesn't require chemical synthesis or purification, which means we can look at proteins that were difficult or impossible to assay in the past."

The researchers demonstrated the utility of the technique by having engineered yeast cells produce two types of histones and a well-studied enzyme called p300, which adds a specific acetyl group modification to histones.

"We've shown that our technique works," Waldman says. "The next step is to begin expanding the modifications we're looking at and scaling up the process."

Near-death experiences are known from all parts of the world, various times and numerous cultural backgrounds. This universality suggests they may have a biological origin and purpose, but exactly what this could be has been largely unexplored.

A new study conducted jointly by the University of Copenhagen (Denmark) and the University of Liege (Belgium) and published in Brain Communications shows how near-death experiences in humans may have arisen from evolutionary mechanisms.

"Adhering to a preregistered protocol, we investigated the hypothesis that thanatosis is the evolutionary origin of near-death experiences", says Daniel Kondziella, a neurologist from Rigshospitalet, Copenhagen University Hospital.

When attacked by a predator, as a last resort defense mechanism, animals can feign death to improve their chances of survival, one example being the opossum. This phenomenon is termed thanatosis, also known as death-feigning or tonic immobility. "As a survival strategy," Daniel Kondziella adds, "thanatosis is probably as old as the fight-or-flight response."

Charlotte Martial, neuropsychologist from the Coma Science Group at ULiège explains: "We first show that thanatosis is a highly preserved survival strategy occurring at all major nodes in a cladogram ranging from insects to fish, reptiles, birds and mammals, including humans. We then show that humans under attack by big animals such as lions or grizzly bears, human predators such as sexual offenders, and 'modern' predators such as cars in traffic accidents can experience both thanatosis and near-death experiences. Furthermore, we show that the phenomenology and the effects of thanatosis and near-death experiences overlap."

Steven Laureys, neurologist and head of GIGA Consciousness research unit and Centre du Cerveau (ULiège, CHU Liège) is excited: "In this paper, we build a line of evidence suggesting that thanatosis is the evolutionary foundation of near-death experiences and that their shared biological purpose is the benefit of survival."

The authors propose that the acquisition of language enabled humans to transform these events from relatively stereotyped death-feigning under predatory attacks into the rich perceptions that form near-death experiences and extend to non-predatory situations.

"Of note, the proposed cerebral mechanisms behind death-feigning are not unlike those that have been suggested to induce near-death experiences, including intrusion of rapid eye movement sleep into wakefulness," Daniel Kondziella explains. "This further strengthens the idea that evolutionary mechanisms are an important piece of information needed to develop a complete biological framework for near-death experiences."

No previous work has tried to provide such a phylogenetic basis. Steven Laureys concludes, "this may also be the first time we can assign a biological purpose to near-death experiences, which would be the benefit of survival."

And Daniel Kondziella adds, "after all, near-death experiences are by definition events that are always survived, without exception."

A team of scientists has devised a more accurate way to predict the effects of climate change on plants and animals -- and whether some will survive at all.

Frequently, ecologists assess an organism's fitness relative to the climate by quantifying its functional traits.

"These are physical properties you can measure -- height, diameter, the thickness of a tree," said UC Riverside biologist Tim Higham. "We believe more information is needed to understand how living things will respond to a changing world."

The team, led by Higham, outlines an alternative model for researchers in an article published today in the journal Trends in Ecology and Evolution.

This new model incorporates the functional traits of an organism as well as environmental variables, such as temperature, habitat structure, and the speed of wind or water an organism interacts with. The team calls these "ecomechanical models."

As oceans rise, strong storms will reach farther inland. The intensity of hurricanes, and the proportion of hurricanes that reach very intense levels, will likely increase with climate change. As a result, Higham said that fluids will exert greater forces on anything in their path. These forces could cause organisms with roots, such as trees, to break or be uprooted.

"If you measure the functional traits of a tree, and we know the speed of the wind, we can predict how much bending will occur," Higham said. "At certain wind speeds, the tree will potentially come down."

The way wind disperses seeds, or how insects and birds fly in the face of strong winds, can potentially influence their fitness. When considering the fate of living things, the physics governing the way they move through space is another important factor accounted for by this new framework. In this sense, ecomechanical models are not limited to understanding the impacts of climate change.

"They can help scientists understand evolutionary patterns and how animals interact differently with their environment as they grow," Higham said.

Environmental conditions can affect how some animals attach to surfaces. For example, geckos can use their famous adhesive system to attach to smooth surfaces. However, the real-world is not often smooth. Therefore, understanding how geckos attach requires knowledge of both the animal's functional traits and the environment's texture, for example.

In order to facilitate use of this model by many different types of scientists, the research team urges the expansion of freely available online databases in which functional traits of organisms have been described in a uniform, standardized way.

This work was years in the making, the product of a working group funded by the National Science Foundation. The group is composed of 24 scientists from Arizona State University; Claremont Colleges; University of British Columbia; University of Illinois, Clark University; the University of Calgary, The State University of Northern Rio de Janeiro, Brazil; Rutgers University; University of Waterloo in Ontario, Canada; University of Washington; George Washington University; Trinity University; UC Berkeley; Cornell University; Towson University, and the American Museum of Natural History.

Many of the participating faculty identify as members of underrepresented groups in science. "Including faculty in early career stages, and from a diversity of backgrounds and lived experiences was of paramount importance to us as we created the working group," said Lara Ferry, biologist and President's Professor from Arizona State University. "We know the best results come from the collective contributions of many different perspectives."

Should these recommendations become widely adopted, the research team feels there will be profound impacts on multiple areas of biology.

"The use of ecomechanical models can help us understand the rules of life," Higham said.

NEW YORK, NY (July 1, 2021)--Lowering levels of a hormone called PTHrP can prevent metastases and improve survival in mice with pancreatic cancer and could lead to a new way to treat patients, according to a study from cancer researchers at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center and with collaborators at the University of Pennsylvania.

When patients are first diagnosed with pancreatic cancer, the cancer usually has spread to other organs. Because of these metastases, nearly all patients will succumb to their cancer within one year of diagnosis, but no drugs exist to prevent metastasis.

In an effort to find treatments, cancer researchers at Columbia--led by Anil K. Rustgi, MD, and Jason R. Pitarresi, PhD--investigated a hormone called PTHrP. Although PTHrP (parathyroid hormone-related protein) is often highly active in patients with pancreatic cancer, its role in metastasis was unclear.

Loss of PTHrP Dramatically Improves Survival in Mice

The researchers first manipulated the levels of PTHrP in mice with pancreatic cancer. Elimination of PTHrP from mice--with genetic engineering or with an antibody that targets the hormone--not only eliminated metastasis and enhanced overall survival, but also dramatically reduced the size of the initial tumors in the pancreas.

Even in mice with a highly aggressive form of pancreatic cancer, the increase in survival was dramatic, increasing from a median of 111 days to 192 days, with near complete elimination of metastases. The 73% increase in survival, the researchers say, is one of the largest observed in mice with this type of pancreatic cancer, which closely resembles human cancers.

The striking results with mice led the researchers to test the anti-PTHrP antibodies in human pancreatic cancer cells. The results from these experiments were also encouraging: Among 3D organoids derived from pancreatic cancer patients under an IRB-approved protocol, anti-PTHrP antibodies greatly reduced growth and viability of the cells.

Two-Pronged Attack on Cell Growth and Metastasis

Targeting PTHrP attacks pancreatic cancer in two ways, the researchers say. It reduces the ability of the tumor cells to transition from an epithelial state to a mesenchymal state, which is necessary for the creation of new metastases. And targeting PTHrP also prevents the growth of primary and secondary tumors.

"We think these findings provide a strong rationale for further developing anti-PTHrP therapy towards clinical trials," says Rustgi, who adds that the antibody used in the study has the potential to be used in people and credits Richard Kremer, MD, PhD, of McGill University for developing the antibodies. 

"We are hopeful that a drug targeting PTHrP could be used to treat most patients with pancreatic cancer," he says, "because the vast majority have tumors with high levels of PTHrP. There is the potential application to other cancers as well."

Potential with Other Cancers

The researchers originally began investigating PTHrP because its gene is often amplified when another nearby gene, KRAS, is amplified. KRAS has long been recognized as a cancer-promoting gene in pancreatic and other cancers. 

For patients, that may mean anti-PTHrP therapies may have potential in other cancers that are known to harbor KRAS amplifications.

For researchers, the finding also suggests a wider search for cancer-causing genes is needed.

"We feel that PTHrP may have been previously overlooked as a mere passenger gene co-amplified with KRAS, but our study shows that PTHrP has its own tumor-promoting functions," Pitarresi says. "It suggests other so-called 'passenger' genes may have bigger roles in cancer than we initially thought and should be examined more closely."  Rustgi notes "it might open up for combinatorial therapies of targeting the KRAS pathway with an antibody to PTHrP."

SAN FRANCISCO, CA--June 28, 2021--While vaccines are doing a remarkable job of slowing the COVID-19 pandemic, infected people can still die from severe illness and new medications to treat them have been slow to arise. What kills these patients in the end doesn't seem to be the virus itself, but an over-reaction of their immune system that leads to massive inflammation and tissue damage.

By studying a type of immune cells called T cells, a team of Gladstone scientists has uncovered fundamental differences between patients who overcome severe COVID-19 and those who succumb to it. The team, working together with researchers from UC San Francisco and Emory University, also found that dying patients harbor relatively large numbers of T cells able to infiltrate the lung, which may contribute to the extensive lung deterioration that is a hallmark of fatal COVID-19.

The findings, published in the scientific journal Cell Reports, could pave the way for new treatments. Currently, patients who are hospitalized for severe COVID-19 mostly receive dexamethasone, a drug used to reduce inflammation.

"Dexamethasone has been a life saver for many patients," says Gladstone Associate Investigator Nadia Roan, PhD, a senior and corresponding author of the study. "But it is not always sufficient. Our study suggests that it may also be beneficial to directly prevent excess immune cells, including inflammatory T cells, from entering the lung and causing further damage. This approach could be a good complement to anti-inflammatory treatments for COVID-19 patients in the intensive care unit."

The work could also help with disease prognosis.

"Some patients can fall seriously ill from the virus," says Warner Greene, MD, PhD, senior investigator at Gladstone and co-senior author of the study. "We are in dire need for effective ways to anticipate the course of disease, as well as to alleviate lung damage in people with severe COVID-19."

An Imbalance of T Cells

T cells are a crucial component of a successful immune response to many viruses, including SARS-CoV-2, the virus that causes COVID-19. And they are markedly depleted from the blood during severe COVID-19.

To characterize the features of the T cells that remain, the scientists obtained blood samples that had been collected from COVID-19 patients in an intensive care unit (ICU). While about half of these patients eventually recovered, the other half died of the disease. By examining samples taken at different times during the patients' stay in the ICU, the scientists were able to discern trends that they could relate to the disease outcome.

Much has already been learned about the immune response of COVID-19 patients during active infection or after convalescence. For example, studies from convalescent individuals, including Roan's own previous work, reveal how the immune system may provide long-term immunity. Less clear, however, is how the immune system may protect from severe illness or, conversely, contribute to its worsening and to death. To understand the cause of fatalities, the researchers needed to compare fatal to non-fatal severe cases.

Using CyTOF, a technique implemented in Roan's lab that distinguishes the many types of T cells circulating in the body, the scientists found profound differences between the ICU patients' T-cell response to the virus.

"The T-cell response to SARS-CoV-2 increased in patients who were eventually discharged from the ICU and recovered," says Roan, who is also an associate professor of urology at UC San Francisco. "But in patients who eventually died, we sometimes could not detect any T-cell response, or their response decreased over time."

Differences also extended to the composition of the patients' T cells that recognize the SARS-CoV-2 virus. In particular, patients who survived harbored a growing number of T cells called Th1, which are known as important fighters of viral infection. Roan's team found molecular features on the Th1 cells that may explain why they were able to multiply in these patients.

By contrast, they found that patients who died had an elevated number of T cells secreting an inflammatory molecule that would contribute to a worsening of their lung condition. These patients also held more regulatory T cells recognizing the virus. Regulatory T cells normally help quiet down the immune response once infection subsides.

"Perhaps in these patients, regulatory T cells were activated too early and prevented effector T cells from ever mounting an adequate immune response to SARS-CoV-2," says Roan. "This could help explain the patients' paltry response to the virus."

Based on these findings, doctors might be able to predict the course of illness from the relative abundance of Th1 and regulatory T cells that recognize SARS-CoV-2 in a patient's blood.

Roan cautions, however, "Our findings show correlations, not causes. The immune system is complex, with many moving parts and possible interactions between them. Proving the cause of fatality will require further studies."

Stemming the Flow of Lung-Homing Cells

Another potential cause of fatality that the team discovered was a surge in T cells able to infiltrate the lungs of dying patients. By contrast, these cells decreased over time in the patients who recovered.

The scientists call these lung-homing cells "bystander T cells," because they are T cells that do not directly recognize the SARS-CoV-2 virus.

"Our study suggests that during severe COVID-19, bystander T cells are recruited from the blood into the lung, where they may contribute to immune-mediated pathology," says Roan.

What triggers the surge of bystander T cells in severe COVID-19 cases remains unclear, but may be in part mediated by proteins secreted by the lung that recruit these cells. Regardless, stemming their flow into the lung may help reduce lung damage and accelerate the recovery of patients with severe illness.

This approach is particularly promising, as drugs that antagonize a molecule found on the surface of the bystander T cells are already approved for the treatment of metastatic cancer.

"Our next step is to test these drugs in a mouse model of severe COVID-19," says Roan. "We hope that after further scrutiny, such drugs could rapidly be tested as adjunctive treatment for COVID-19."