Culture

There is no question that motivation is one of the hardest and yet important factors in life. It's the difference between success and failure, goal-setting and aimlessness, well-being and unhappiness. And yet, why is it so hard to get motivated - or even if we do, to keep it up?

That is the question that scientists led by Professor Carmen Sandi at EPFL and Dr Gedi Luksys at the University of Edinburgh have sought to answer. The researchers worked off previous knowledge that told them two things: First, that people differ a lot in their capacity to engage in motivated behavior and that motivational problems like apathy are common in neurodegenerative and psychiatric disorders. Second, to target an area of the brain called the "nucleus accumbens".

Sitting close to the bottom of brain, the nucleus accumbens has been the subject of a lot of research. The reason is that it was quickly found to be a major player in functions like aversion, reward, reinforcement, and motivation.

To test and quantify motivation, the EPFL team designed what is known as a "monetary incentive force task". The idea is that participants perform a task with increasing - and measurable - effort and get paid sums of money that correspond to their effort. Basically, do more and get paid more.

In this study, 43 men were scanned to measure-metabolites in the nucleus accumbens in their brains with a sophisticated brain-imaging technique called "proton magnetic resonance spectroscopy", or 1H-MRS. This can specifically measure the abundance of neurochemicals in the brain, such as neurotransmitters and metabolites. Because of this 1H-MRS is used even in clinical settings to determine neurological disorders.

Subsequently, each participant was asked to squeeze a device that measures force - a dynamometer to a given level of contraction in order to earn either 0.2, 0.5, or 1 Swiss franc. This procedure was repeated for a number of 120 consecutive trials, which made performance in the task quite demanding.

The idea of the experiment was that the different sums would push participants to decide if they were going to invest energy and perform the task accordingly at each trial. The scientists also ran the experiment under isolation and group conditions to investigate the influence of competition on performance.

Once they had gathered the behavioral data, the researchers processed it through a computational model that estimated the most appropriate parameters that should be measured with regard to utility, effort, and performance functions. This allowed them to interrogate whether particular neurotransmitter levels predicted specific motivational functions.

The analysis revealed that the key to performance - and, by extension, motivation - lies within the ratio of two neurotransmitters in the nucleus accumbens: glutamine and glutamate. Specifically, the ratio of glutamine to glutamate relates to our capacity for maintaining performance over a long period of time - what the researchers term "stamina".

Another discovery was that competition seems to boost performance even from the beginning of the task. This was especially the case for individuals with low glutamine-to-glutamate ratios in the nucleus accumbens.

"The findings provide novel insights in the field of motivation neuroscience," says Carmen Sandi. "They show that the balance between glutamine and glutamate can help predict specific, computational components of motivated performance. Our approach and data can also help us develop therapeutic strategies, including nutritional interventions, that address deficits in effort engagement by targeting metabolism."

Stimulating the nervous system using small electric current by acupuncture could tamp down systemic inflammation in the body, suggests new research in mice from a team of neuroscientists in the U.S. and China. The research, publishing August 12 in the journal Neuron, helps to map the neuroanatomical underpinnings of this ancient medical practice.

"Most Western medicine has been focusing on blocking the neural pathways of pain to relieve the symptoms, but there are so many pain pathways and so many ways to open each of them," says senior author Qiufu Ma, a researcher at Harvard Medical School who has been studying the neuroanatomic basis of pain for years. Inspired by the core ideology of traditional Chinese medicine, which is to treat a disease by addressing the root cause, Ma and his team aim to target inflammation, a common source of human diseases and pain.

Previous studies have shown direct vagal nerve stimulations in the neck region can help reduce inflammation, but these experimental approaches require invasive procedures. With this in mind, Ma and his team set out to investigate whether and how electric stimulation using acupuncture, which only involves inserting thin needles through the skin, can modulate inflammation.

The team began by giving mice a 15-minute electroacupuncture at 3 mA at a specific site on the abdomen. This acupoint, dubbed ST25, has been associated with nerves of the spleen, which is a major organ involved in immune responses.

The team then simulated a life-threatening inflammatory condition that is often seen in patients suffering severe bacterial or virus infections by injecting mice with a compound called lipopolysaccharide (LPS). After injecting the treated mice with LPS, researchers found the serum levels of pro-inflammatory molecules in these animals was significantly lower than that of the control group. The mice's survival rates also more than doubled. However, when the team gave mice the electroacupuncture after the LPS shot, the treated mice had much greater inflammation than those that were untreated and did not survive.

By comparing the effect of electroacupuncture in mice with an altered nervous system, the team determined that high intensity stimulation at the abdomen could excite norepinephrine-producing nerves that connect the spine and spleen. The norepinephrine then activated a particular type of receptors in the spleen that suppressed pro-inflammatory molecules. But when LPS was introduced first, another type of splenic receptors--pro-inflammatory in this case--became highly expressed, and the subsequent electroacupuncture therapy further enhanced inflammation.

"We were really surprised to find that the same input has completely opposite outcomes in different disease stages," Ma says. "But a lot of the time, a patient would only come to us if they already have the disease. So we wanted to find out if there is a way to reduce inflammation as a treatment."

The team then conducted electroacupuncture at a different acupoint, this time on mice's hindlegs. They found stimulation at a low intensity of 0.5 mA for 15 minutes could significantly reduce pro-inflammatory molecule levels either before or after LPS-injection. Mice's survival rate after electroacupuncture also increased by 1-fold or more. A genetically modified mice model suggests that low-level electroacupuncture at hindlegs reduced inflammation not though the spleen, but a different neural pathway involving the vagus nerves and the adrenal glands.

"Our study illustrated that electroacupuncture has neuroanatomic basis, but its efficacy and safety on humans need to be validated in clinical trials," Ma says. "There's still many questions unanswered about this medical practice and thus a lot of room to do more research."

(PROVO, Utah -- 10 Aug. 2020) To date, Congress has authorized roughly $3 trillion in COVID-19 relief assistance -- the largest relief package in history. With more COVID relief money on the way, a new study led by two Brigham Young University business professors finds these newly available funds led to a significant surge in health sector lobbying activity, especially within the pharmaceutical industry.

The research, publishing Wednesday, Aug. 12, in the Journal of General Internal Medicine, finds the lobbying expenditures ($248.4 million) and new lobbyist registrations (357) of the health sector represented nearly a fourth of all lobbying activity, across all industries, in the first quarter of 2020.

"This is like sharks to blood, or bees to honey, if you prefer a milder metaphor," said study author Bill Tayler, an accounting professor in the BYU Marriott School of Business. "Congress is giving out a lot of money, so the lobbyists are swarming. Lobbying activity levels are typically fairly stable, so when you see jumps like this, it's a big deal."

According to the analysis, health sector lobbying spending increased more than 10% in Q1 of 2020 while non-health sector increased only 1%. Meanwhile, the number of new lobbyists registered in the health sector increased a staggering 140% while non-health sector registrations increased only 63%.

The BYU researchers, in collaboration with colleagues from Johns Hopkins University, Columbia University and the University of Cincinnati, found that across all segments of health sector lobbying, the biggest lobbying increases came from the pharmaceutical industry. Indeed, 16 of the top 30 healthcare organizations in lobbyist expenditures were pharmaceuticals.

For example, Novartis International increased their lobbying expenditures by 259% this year, AbbVie Inc. increased theirs by 155% and Biogen Inc. increased their expenditures by a whopping 344%. The organization with the highest lobbying expenditures by far was Pharmaceutical Research and Manufacturers of America (PhRMA), a non-profit trade association largely sponsored by pharmaceutical companies, spending $11.5 million in the first quarter of 2020.

"This is the largest stimulus bill in history," said study coauthor John Barrick, a fellow accounting professor at BYU and expert on lobbying policy. "It's important to follow the money. Dollars spent on lobbying influence the allocation of funds and, right or wrong, I think that's what people need to know."

The data shows Big Pharma has had a very loud voice as Congress has tried to allocate funds to small businesses, the unemployed, healthcare and more.

Overall, the top 30 healthcare organizations (16 of which were pharmaceutical organizations) spent almost $100 million on lobbying in Q1 of 2020, which represented a 55% increase in lobbying spending over Q4 of 2019. The authors said the results of the study illustrate just how much the health sector and others are willing to invest to influence Congress' appropriation and allocation of funds.

"The return on investment on a dollar of lobbying appears much higher than a dollar of R&D," said study coauthor Shivaram Rajgopal, a professor of accounting and auditing at Columbia Business School. Added senior author Ge Bai: "The health sector's investment in lobbying has apparently generated handsome returns."

Astronomers using the Atacama Large Millimeter/submillimeter Array (ALMA), in which the European Southern Observatory (ESO) is a partner, have revealed an extremely distant and therefore very young galaxy that looks surprisingly like our Milky Way. The galaxy is so far away its light has taken more than 12 billion years to reach us: we see it as it was when the Universe was just 1.4 billion years old. It is also surprisingly unchaotic, contradicting theories that all galaxies in the early Universe were turbulent and unstable. This unexpected discovery challenges our understanding of how galaxies form, giving new insights into the past of our Universe.

"This result represents a breakthrough in the field of galaxy formation, showing that the structures that we observe in nearby spiral galaxies and in our Milky Way were already in place 12 billion years ago," says Francesca Rizzo, PhD student from the Max Planck Institute for Astrophysics in Germany, who led the research published today in Nature. While the galaxy the astronomers studied, called SPT0418-47, doesn't appear to have spiral arms, it has at least two features typical of our Milky Way: a rotating disc and a bulge, the large group of stars packed tightly around the galactic centre. This is the first time a bulge has been seen this early in the history of the Universe, making SPT0418-47 the most distant Milky Way look-alike.

"The big surprise was to find that this galaxy is actually quite similar to nearby galaxies, contrary to all expectations from the models and previous, less detailed, observations," says co-author Filippo Fraternali, from the Kapteyn Astronomical Institute, University of Groningen in the Netherlands. In the early Universe, young galaxies were still in the process of forming, so researchers expected them to be chaotic and lacking the distinct structures typical of more mature galaxies like the Milky Way.

Studying distant galaxies like SPT0418-47 is fundamental to our understanding of how galaxies formed and evolved. This galaxy is so far away we see it when the Universe was just 10% of its current age because its light took 12 billion years to reach Earth. By studying it, we are going back to a time when these baby galaxies were just beginning to develop.

Because these galaxies are so far away, detailed observations with even the most powerful telescopes are almost impossible as the galaxies appear small and faint. The team overcame this obstacle by using a nearby galaxy as a powerful magnifying glass -- an effect known as gravitational lensing -- allowing ALMA to see into the distant past in unprecedented detail. In this effect, the gravitational pull from the nearby galaxy distorts and bends the light from the distant galaxy, causing it to appear misshapen and magnified.

The gravitationally lensed, distant galaxy appears as a near-perfect ring of light around the nearby galaxy, thanks to their almost exact alignment. The research team reconstructed the distant galaxy's true shape and the motion of its gas from the ALMA data using a new computer modelling technique. "When I first saw the reconstructed image
of SPT0418-47 I could not believe it: a treasure chest was opening," says Rizzo.

"What we found was quite puzzling; despite forming stars at a high rate, and therefore being the site of highly energetic processes, SPT0418-47 is the most well-ordered galaxy disc ever observed in the early Universe," stated co-author Simona Vegetti, also from the Max Planck Institute for Astrophysics. "This result is quite unexpected and has important implications for how we think galaxies evolve." The astronomers note, however, that even though SPT0418-47 has a disc and other features similar to those of spiral galaxies we see today, they expect it to evolve into a galaxy very different from the Milky Way, and join the class of elliptical galaxies, another type of galaxies that, alongside the spirals, inhabit the Universe today.

This unexpected discovery suggests the early Universe may not be as chaotic as once believed and raises many questions on how a well-ordered galaxy could have formed so soon after the Big Bang. This ALMA finding follows the earlier discovery announced in May
of a massive rotating disc seen at a similar distance. SPT0418-47 is seen in finer detail, thanks to the lensing effect, and has a bulge in addition to a disc, making it even more similar to our present-day Milky Way than the one studied previously.

Future studies, including with ESO's Extremely Large Telescope, will seek to uncover how typical these 'baby' disc galaxies really are and whether they are commonly less chaotic than predicted, opening up new avenues for astronomers to discover how galaxies evolved.

Radiocarbon dating is set to become more accurate than ever after an international team of scientists improved the technique for assessing the age of historical objects.

The team of researchers at the Universities of Sheffield, Belfast, Bristol, Glasgow, Oxford, St Andrews and Historic England, plus international colleagues, used measurements from almost 15,000 samples from objects dating back as far as 60,000 years ago, as part of a seven-year project.

They used the measurements to create new international radiocarbon calibration (IntCal) curves, which are fundamental across the scientific spectrum for accurately dating artefacts and making predictions about the future. Radiocarbon dating is vital to fields such as archaeology and geoscience to date everything from the oldest modern human bones to historic climate patterns.

Archaeologists can use that knowledge to restore historic monuments or study the demise of the Neanderthals, while geoscientists on the Intergovernmental Panel on Climate Change (IPCC), rely upon the curves to find out about what the climate was like in the past to better understand and prepare for future changes.

Professor Paula Reimer, from Queen's University Belfast and head of the IntCal project, said: "Radiocarbon dating has revolutionised the field of archaeology and environmental science. As we improve the calibration curve, we learn more about our history. The IntCal calibration curves are key to helping answer big questions about the environment and our place within it."

The team of researchers have developed three curves dependent upon where the object to be dated is found. The new curves, to be published in Radiocarbon, are IntCal20 for the Northern Hemisphere, SHCal20 for the Southern Hemisphere, and Marine20 for the world's oceans.

Dr Tim Heaton, from the University of Sheffield and lead author on the Marine20 curve, said: "This is a very exciting time to be working in radiocarbon. Developments in the field have made it possible to truly advance our understanding. I look forward to seeing what new insights into our past these recalculated radiocarbon timescales provide."

The previous radiocarbon calibration curves developed over the past 50 years, were heavily reliant upon measurements taken from chunks of wood covering 10 to 20 years big enough to be tested for radiocarbon.

Advances in radiocarbon testing mean the updated curves instead use tiny samples, such as tree-rings covering just single years, that provide previously impossible precision and detail in the new calibration curves. Additionally, improvements in understanding of the carbon cycle have meant the curves have now been extended all the way to the limit of the radiocarbon technique 55,000 years ago.

Radiocarbon dating is the most frequently used approach for dating the last 55,000 years and underpins archaeological and environmental science. It was first developed in 1949. It depends upon two isotopes of carbon called stable 12C and radioactive 14C.

While a plant or animal is alive it takes in new carbon, so has the same ratio of these isotopes as the atmosphere at the time. But once an organism dies it stops taking in new carbon, the stable 12C remains but the 14C decays at a known rate. By measuring the ratio of 14C to 12C left in an object the date of its death can be estimated.

If the level of atmospheric 14C were constant, this would be easy. However, it has fluctuated significantly throughout history. In order to date organisms precisely scientists need a reliable historical record of its variation to accurately transform 14C measurements into calendar ages. The new IntCal curves provide this link.

The curves are created based on collecting a huge number of archives which store past radiocarbon but can also be dated using another method. Such archives include tree-rings from up to 14,000 years ago, stalagmites found in caves, corals from the sea and cores drilled from lake and ocean sediments. In total, the new curves were based upon almost 15,000 measurements of radiocarbon taken from objects as old as 60,000 years.

Alex Bayliss, Head of Scientific Dating at Historic England, said: "Accurate and high-precision radiocarbon dating underpins the public's enjoyment of the historic environment and enables better preservation and protection.

"The new curves have internationally important implications for archaeological methodology, and for practices in conservation and understanding of wooden built heritage."

Darrell Kaufman of the IPCC said: "The IntCal series of curves are critical for providing a perspective on past climate which is essential for our understanding of the climate system, and a baseline for modelling future changes."

Yoga improves symptoms of generalized anxiety disorder, a condition with chronic nervousness and worry, suggesting the popular practice may be helpful in treating anxiety in some people.

Led by researchers at NYU Grossman School of Medicine, a new study found that yoga was significantly more effective for generalized anxiety disorder than standard education on stress management, but not effective as cognitive behavioral therapy (CBT), the gold standard form of structured talk therapy that helps patients identify negative thinking for better responses to challenges.

"Generalized anxiety disorder is a very common condition, yet many are not willing or able to access evidence-based treatments," says lead study author Naomi M. Simon, MD, a professor in the Department of Psychiatry at NYU Langone Health. "Our findings demonstrate that yoga, which is safe and widely available, can improve symptoms for some people with this disorder and could be a valuable tool in an overall treatment plan."

For the study, publishing online Aug. 12 in JAMA Psychiatry, 226 men and women with generalized anxiety disorder were randomly assigned to three groups - either CBT, Kundalini yoga, or stress-management education, a standardized control technique.

After three months, both CBT and yoga were found to be significantly more effective for anxiety than stress management. Specifically, 54 percent of those who practiced yoga met response criteria for meaningfully improved symptoms compared to 33 percent in the stress-education group. Of those treated with CBT, 71 percent met these symptom improvement criteria.

However, after six months of follow-up, the CBT response remained significantly better than stress education (the control therapy), while yoga was no longer significantly better, suggesting CBT may have more robust, longer-lasting anxiety-reducing effects.

Study Details

The study involved an evidence-based protocol for CBT treatment of generalized anxiety disorder, including psychoeducation, cognitive interventions (focused on identifying and adapting maladaptive thoughts and worrying), and muscle relaxation techniques.

Kundalini yoga included physical postures, breathing techniques, relaxation exercises, yoga theory, and meditation/mindfulness practice.

The stress-management education control group received lectures about the physiological, psychological and medical effects of stress, as well as the antianxiety effects of lifestyle behaviors, such as reducing alcohol and smoking, and the importance of exercise and a healthy diet. Homework consisted of listening to educational material about stress, nutrition, and lifestyle.

Each treatment was administered in groups of three to six participants, over weekly two-hour sessions for 12 weeks with 20 minutes of daily homework assigned.

Can Yoga Help Treat Anxiety?

According to researchers, generalized anxiety disorder is a common, impairing, and undertreated condition, currently affecting an estimated 6.8 million Americans. While most people feel anxious from time to time, it is considered a disorder when worrying becomes excessive and interferes with day-to-day life. CBT is considered the gold standard first-line treatment. Medications, including antidepressants and sometimes benzodiazepines, may also be used. Yet, not everyone is willing to take medication which can have adverse side effects and there are challenges with accessing CBT for many, including lack of access to trained therapists and long waitlists.

"Many people already seek complementary and alternative interventions, including yoga, to treat anxiety," says Dr. Simon. "This study suggests that at least short-term there is significant value for people with generalized anxiety disorder to give yoga a try to see if it works for them. Yoga is well-tolerated, easily accessible, and has a number of health benefits."

According to Dr. Simon, future research should aim to understand who is most likely to benefit from yoga for generalized anxiety disorder to help providers better personalize treatment recommendations.

"We need more options to treat anxiety because different people will respond to different interventions, and having more options can help overcome barriers to care," she says. "Having a range of effective treatments can increase the likelihood people with anxiety will be willing to engage in evidence-based care."

What The Article Says: This essay describes the author's experience of having COVID-19.

Authors: Janet M. Shapiro, M.D., of the Icahn School of Medicine at Mount Sinai in New York, is the author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamacardio.2020.3247)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Survival of patients on the heart transplant waiting list was examined in this observational study.

Authors: Elizabeth L. Godfrey, B.S., of the Baylor College of Medicine in Houston, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamacardio.2020.2795)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Researchers in this randomized clinical trial assessed whether Kundalini yoga and cognitive behavioral therapy (CBT) for generalized anxiety disorder are each more effective than stress education and whether yoga is noninferior to CBT for the treatment of the disorder.

Authors: Naomi M. Simon, M.D., M.Sc., of the New York University Grossman School of Medicine in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapsychiatry.2020.2496)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

A novel strategy has been developed by Novateur Ventures, which provides new hope in battle against COVID-19. The study titled 'A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes' was published in Frontiers in Pharmacology, a leading peer-reviewed journal.

The strategy co-authored by Ali Ardakani, Founder & Managing Director at Novateur Ventures, and Dr. Colin D. Funk (Queen's University, Kingston) analyzes lipid mediators, known as leukotrienes, as the cause for hyperinflammatory response manifested in severe COVID-19 cases. Patients with severe COVID-19 develop an overwhelming state of inflammation with multi-organ dysfunction and leukotrienes have been overlooked.

"Globally the race to develop new therapeutics or repurpose existing drugs to cultivate an effective therapeutic treatment for COVID- 19 is urgent. At Novateur, our research has been well underway since the first cases were discovered," says Ardakani. "I am very pleased today to announce a strategy we believe can potentially impact COVID-19 patients in a safe and effective manner."

Since Novateur began their in-depth studies, only two treatments (remdesivir, dexamethasone) have demonstrated modest ability to reduce disease progression and severity; however, there is still a high unmet need for additional improvement. Leukotrienes have some of the most potent impacts on immune cell trafficking and vascular leakage in biological systems, two important steps that take place in COVID-19. Novateur's research proposes a simple treatment paradigm using two generic drugs, normally directed to blocking inflammation in airways of patients with asthma, to target the hyper-inflammatory response insevere COVID-19.This will be accomplished by a combination of a leukotriene biosynthesis blocker zileuton (Zyflo® controlled release formulation) and an inhibitor of the cysteinyl leukotriene 1 receptor montelukast (Singulair®). Both these agents, now generic, have been on the market for many years, and their activity and side effects in humans are well known.

In COVID-19, providing zileuton/montelukast combination prior to out-of-control host inflammatory cell recruitment to the lungs and before pulmonary edema sets in is paramount. Initiation of treatment with zileuton/montelukast should take place early on, shortly after a positive test is confirmed and before major symptoms arise. Currently it remains very difficult to predict which patients will progress to severe COVID-19 disease. The standard of care is basically symptomatic control (i.e. acetaminophen for fever and muscle pain) and observation. The proposed zileuton/montelukast combination could readily be added in this setting, with the goal to switch off the hyper-inflammatory response. The incentive to move forward quickly is vital to combat COVID-19 while waiting for a preventative vaccine or other treatments.

"Our journey studying COVID-19 and potential therapeutics is still at an early stage. We hope that our proposed treatment plan can effectively stop COVID-19 from becoming a life-threatening disorder," says Funk, a key leader in the leukotriene field. "Novateur will continue to concentrate its efforts on this global pandemic that has claimed the lives of so many. It is important to recognize the sharing of critical data and the very collaborative approach this fight has taken. We are working diligently with unprecedented speed to move a clinical trial forward as quickly as possible in the USA where cases of COVID-19 are high."

The enzyme serine palmitoyl-transferase can be used as a metabolically responsive "switch" that decreases tumor growth, according to a new study by a team of San Diego scientists, who published their findings Aug. 12 in the journal Nature.

By restricting the dietary amino acids serine and glycine, or pharmacologically targeting the serine synthesis enzyme phosphoglycerate dehydrogenase, the team induced tumor cells to produce a toxic lipid that slows cancer progression in mice. Further research is needed to determine how this approach might be translated to patients.

Over the last decade researchers have learned that removing the amino acids serine and glycine from animal diets slows the growth of some tumors. However, most research teams have focused on how these diets impact epigenetics, DNA metabolism, and antioxidant activity. In contrast, the researchers from the University of California San Diego and the Salk Institute for Biological Studies identified a dramatic impact of these interventions on tumor lipids, particularly those found on the surface of cells.

"Our work highlights the beautiful complexity of metabolism as well as the importance of understanding physiology across diverse biochemical pathways when considering such metabolic therapies," said Christian Metallo, a professor of bioengineering at the Jacobs School of Engineering at UC San Diego and the paper's corresponding author.

In this case, serine metabolism was the researchers' focus. The enzyme serine palmitoyl-transferase, or SPT, typically uses serine to make fatty molecules called sphingolipids, which are essential for cell function. But if serine levels are low, the enzyme can act "promiscuously" and use a different amino acid such as alanine, which results in the production of toxic deoxysphingolipids.

The team decided on this research direction after examining the affinity that certain enzymes have to serine and comparing them to the concentration of serine in tumors. These levels are known as Km or the Michaelis constant, and the numbers pointed to SPT and sphingolipids.

"By linking serine restriction to sphingolipid metabolism, this finding may enable clinical scientists to better identify which patients' tumors are most sensitive to serine-targeting therapies," Metallo said.

These toxic deoxysphingolipids are most potent at decreasing the growth of cells in "anchorage-independent" conditions--a situation where cells cannot easily adhere to surfaces that better mimics tumor growth in the body. Further studies are necessary to better understand the mechanisms through which deoxysphingolipids are toxic to cancer cells and what effects they have on the nervous system.

In the Nature study, the research team fed a diet low on serine and glycine to xenograft model mice. They observed that SPT turned to alanine to produce toxic deoxysphingolipids instead of normal sphingolipids. In addition, researchers used the amino-acid based antibiotic myriocin to inhibit SPT and deoxysphingolipid synthesis in mice fed low serine and glycine diets and found that tumor growth was improved.

Depriving an organism of serine for long periods of time leads to neuropathy and eye disease, Metallo pointed out. Last year, he co-lead an international team that identified reduced levels of serine and accumulation of deoxysphingolipids as a key driver of a rare macular disease called macular telangiectasia type 2, or MacTel. The work was published in the New England Journal of Medicine. However, serine restriction or drug treatments for tumor therapy would not require the prolonged treatments that induce neuropathy in animals or age-related diseases.

RIVERSIDE, Calif. -- Scientists at the University of California, Riverside, have used machine learning to identify hundreds of new potential drugs that could help treat COVID-19, the disease caused by the novel coronavirus, or SARS-CoV-2.

"There is an urgent need to identify effective drugs that treat or prevent COVID-19," said Anandasankar Ray, a professor of molecular, cell, and systems biology who led the research. "We have developed a drug discovery pipeline that identified several candidates."

The drug discovery pipeline is a type of computational strategy linked to artificial intelligence -- a computer algorithm that learns to predict activity through trial and error, improving over time.

With no clear end in sight, the COVID-19 pandemic has disrupted lives, strained health care systems, and weakened economies. Efforts to repurpose drugs, such as Remdesivir, have achieved some success. A vaccine for the SARS-CoV-2 virus could be months away, though it is not guaranteed.

"As a result, drug candidate pipelines, such as the one we developed, are extremely important to pursue as a first step toward systematic discovery of new drugs for treating COVID-19," Ray said. "Existing FDA-approved drugs that target one or more human proteins important for viral entry and replication are currently high priority for repurposing as new COVID-19 drugs. The demand is high for additional drugs or small molecules that can interfere with both entry and replication of SARS-CoV-2 in the body. Our drug discovery pipeline can help."

Joel Kowalewski, a graduate student in Ray's lab, used small numbers of previously known ligands for 65 human proteins that are known to interact with SARS-CoV-2 proteins. He generated machine learning models for each of the human proteins.

"These models are trained to identify new small molecule inhibitors and activators -- the ligands -- simply from their 3-D structures," Kowalewski said.

Kowalewski and Ray were thus able to create a database of chemicals whose structures were predicted as interactors of the 65 protein targets. They also evaluated the chemicals for safety.

"The 65 protein targets are quite diverse and are implicated in many additional diseases as well, including cancers," Kowalewski said. "Apart from drug-repurposing efforts ongoing against these targets, we were also interested in identifying novel chemicals that are currently not well studied."

Ray and Kowalewski used their machine learning models to screen more than 10 million commercially available small molecules from a database comprised of 200 million chemicals, and identified the best-in-class hits for the 65 human proteins that interact with SARS-CoV-2 proteins.

Taking it a step further, they identified compounds among the hits that are already FDA approved, such as drugs and compounds used in food. They also used the machine learning models to compute toxicity, which helped them reject potentially toxic candidates. This helped them prioritize the chemicals that were predicted to interact with SARS-CoV-2 targets. Their method allowed them to not only identify the highest scoring candidates with significant activity against a single human protein target, but also find a few chemicals that were predicted to inhibit two or more human protein targets.

"Compounds I am most excited to pursue are those predicted to be volatile, setting up the unusual possibility of inhaled therapeutics," Ray said.

"Historically, disease treatments become increasingly more complex as we develop a better understanding of the disease and how individual genetic variability contributes to the progression and severity of symptoms," Kowalewski said. "Machine learning approaches like ours can play a role in anticipating the evolving treatment landscape by providing researchers with additional possibilities for further study. While the approach crucially depends on experimental data, virtual screening may help researchers ask new questions or find new insight."

Ray and Kowalewski argue that their computational strategy for the initial screening of vast numbers of chemicals has an advantage over traditional cell-culture-dependent assays that are expensive and can take years to test.

"Our database can serve as a resource for rapidly identifying and testing novel, safe treatment strategies for COVID-19 and other diseases where the same 65 target proteins are relevant," he said. "While the COVID-19 pandemic was what motivated us, we expect our predictions from more than 10 million chemicals will accelerate drug discovery in the fight against not only COVID-19 but also a number of other diseases."

Ray is looking for funding and collaborators to move toward testing cell lines, animal models, and eventually clinical trials.

Optical-resolution photoacoustic microscopy (OR-PAM) is a powerful imaging tool with a superb ability to image rich optical absorption contrast in biological tissue. Most OR-PAM systems today rely on mechanical scanning to form an image, which restrains their imaging speed. To overcome the restraint, multifocal OR-PA computed tomography (MFOR-PACT) had been developed by utilizing a microlens array with multiple optical foci and an ultrasonic transducer array to detect PA signals in parallel. However, previous MFOR-PACT systems are complex and costly due to the use of an ultrasonic array and the associated multi-channel data acquisition system.

In a new paper published in Light: Science & Applications, a team of scientists, led by Professor Lihong Wang from Caltech Optical Imaging Laboratory (COIL), Andrew & Peggy Cherng Department of Medical Engineering and Department of Electrical Engineering, California Institute of Technology, Pasadena, USA, have developed a two-dimensional (2D) MFOR-PAM system utilizing a 2D microlens array for optical excitation and an acoustic ergodic relay to simultaneously detect the PA responses to the multifocal optical illuminations with a single-element ultrasonic transducer. This system, referred to as multifocal optical-resolution photoacoustic microscopy through an ergodic relay (MFOR-PAMER), can shorten the scanning time by at least 400 times compared to conventional OR-PAM systems at the same imaging resolution, while maintaining a simple and economic setup.

This novel MFOR-PAM system is centered around a key enabling element known as the acoustic ergodic relay (ER). For PA imaging, an ER--such as a light-transparent prism--can be used as an encoder to transform PA signals from different input positions into unique temporal signals. By recording the system impulse response of each input position in advance, the PA signals from the entire field-of-view can be detected in parallel upon a single laser shot. Then, the encoded PA signals can be decoded mathematically to reconstruct a 2D projection image of the object.

In addition, the system uses a microlens array to focus a wide-field laser beam into multiple optical focal spots. Unlike a conventional focusing lens that needs to scan a single optical focal spot across the entire FOV, the microlens array can reduce the time required to form an image by scanning multiple optical focal spots altogether.

These scientists summarize the operational principle of their system:

"Since the excitation pattern through the microlens array is known, each optical focal spot can be computationally localized. By combining the microlens array with the ergodic relay, we can improve the acoustically defined image resolution of the system to the optically defined image resolution, and improve the imaging speed by a factor equal to the number of microlens elements."

"Our MFOR-PAMER system has promising potential for many biomedical applications, such as utilizing ultra-violet (UV) illumination for high-speed, label-free histological study of biological tissues. This design can reduce the imaging time from several hours (with a conventional UV OR-PAM system) to less than a minute, significantly improving the efficiency of clinical histology and diagnostics." the scientists forecast.

The more democratic a country is, the greater the probability that its politicians decide in the same way as in neighbouring countries, without further analysis. This is according a research group that has studied political decision-making during the beginning of the Corona crisis.

Karl Wennberg and Abiel Sebhatu, professor and post-doctoral student, respectively, at the Institute for Analytical Sociology at Linköping University, together with colleagues in Uppsala and Gothenburg, have studied political decision-making in the OECD countries during the Corona crisis. Their results have now been published in the respected journal PNAS, Proceedings of the National Academy of Sciences.

The starting point for the research is that the majority of OECD countries introduced the same or similar restrictions (no large gatherings, school closures, travel restrictions, curfews and lockdowns) during a few weeks in March, although the circumstances in the countries themselves were very different.

"We found that the decisions were not based on, or had a very weak correlation to, standard epidemiological indicators such as number of cases, number of deaths, ICU capacity etc. More important has been how many neighbouring countries have already implemented measures", says Karl Wennberg.

The phenomenon whereby political measures spread without further analysis is called diffusion, and it usually appears when decisions are to be made in a highly uncertain environment.

It's true that during the pandemic, political decisions were made amidst considerable uncertainty. However the researchers conclude that timing, i.e. when measures are implemented, is important. Waiting too long leads to uncontrolled spread and overloaded healthcare, while acting too early or in the same way as others has disadvantages such as higher social and economic costs for mental ill-health and low economic activity, as well as the risk of a second wave when restrictions are eased. Also, restrictions are reliant on the population's willingness, ability and tenacity to follow them.

"One could expect that each country would conduct a detailed review of its own situation, and make decisions based on that. Considering how different the countries are, the phase of the pandemic they were in during the spring, their healthcare capacity, demographics, and how far the pandemic had advanced in each country, the homogeneity of the decision-making is striking", says Karl Wennberg.

The researchers also discuss the fact that the politicians are subject to internal pressure; they do not want to be blamed for being passive or behind the curve. They want to show decisiveness.

The research group also expresses concern about how the decision-making affects democracy. They have studied the degree of democracy in the country, in relation to the timing, i.e., when the restrictions were implemented. They conclude that the higher the level of democracy in a country, the slower the closure of schools and workplaces - all other things being equal. In democratic countries, however, it is more probable that they copy each other.

"Our analysis also shows us that legislation can limit people's freedom and rights. In May 2020, more than 100 countries had introduced variations of legislation which negatively affect democratic processes. The V-Dem Institute in Gothenburg estimates that up to 82 of the countries face considerable or medium risk of continued damage to democracy", says Karl Wennberg.

The Norwegian competitive athlete Birgit Skarstein is known in Norway for her participation in an expedition for the Lars Monsen TV series "Uten Grenser" (a remake of BBC's Beyond Boundaries). She is paralyzed from the waist down as the result of an accident. But a few years ago she walked onto the stage at the annual Sports Gala in Hamar.

An exoskeleton - an advanced robot technology - enabled this feat.

Exoskeletons are a type of outer framework, a wearable robotic device, that are used both in rehabilitation and to facilitate work tasks for people who need to do heavy lifting.

In rehabilitation, an exoskeleton can be used to help the user rebuild their body after an illness or accident, such as a spinal cord injury.

In work situations, exoskeletons are used as a supportive technology to make the job simpler or easier and to promote safer and more correct movement to prevent injuries and accidents. In other words, it's a useful, smart technology.

But as of today, this technology is primarily adapted for a western adult human being of average height and weight - and thus far from suitable for everyone.

Clear goal for the research

The average exoskeleton can accommodate a maximum height of 190 cm and a weight limit of 100 kg.

These parametres exclude many people from using this technology, whether for rehabilitation or to perform work tasks.

Norway has one of the world's tallest populations (approx. 180 cm for men, 168 cm for women). Indonesia has the shortest population in the world, with an average height of 157 cm. In countries like Bangladesh and Madagascar, women's average weight is 49 kg, while in the United States there are areas and states with many very overweight individuals. In Mississippi, for example, 40 per cent of the population is overweight.

"Technology is often developed for the average adult male, and being overweight is particularly challenging," says Roger A. Søraa. He studies robot technology and users at the Department of Interdisciplinary Studies of Culture and the Department of Neuromedicine and Movement Science at the Norwegian University of Science and Technology (NTNU).

Exoskeletons are often designed according to a one-size-fits-all principle. Søraa is focused on encouraging design that accommodates different heights and weights.

Søraa has a clear goal for robot technology research:

"We want to get exoskeleton designers to think more inclusively and develop robot technology that works for more people," he says.

"This is a glimpse into a future that we want to make inclusive. That includes adapting health technology that can contribute to a better life for the user to be more widely accessible," he said

Together with researcher Eduard Fosch-Villaronga at Leiden University in the Netherlands, Søraa recently published the article: Exoskeletons for all: The interplay between exoskeletons, inclusion, gender, and intersectionality in Paladyn, Journal of Behavioral Robotics.

Not fair to end users

Søraa and Villaronga have investigated three of the largest exoskeleton manufacturers and looked at their user criteria: the US-based Ekso Bionics and Indego, and Cyberdyne from Japan.

The researchers point out in the study that robot technology was historically regarded as part of a male sphere, and the criteria used to develop new technology reflect the biases that existed at the time. But these criteria shouldn't still be used today.

"Exoskeleton users come in many different shapes, sizes and genders. However, designers tend to resort to the one-size-fits-all principle. From an investment point of view, this may be cost effective, but it does not do justice to end users who risk being excluded from accessing the technology," the researchers said.

Making the technology accessible

To make this technology accessible to all, the researchers are proposing some tools for designers and manufacturers to help them become more inclusive. These are:

Make sure that exoskeletons can support both overweight and underweight people.

Be aware of the physical differences between men and women.

Make the exoskeleton as easy as possible to put on, even for users who lack upper body strength.

Create buttons in different patterns so that colour blind people can easily operate them without fear of pressing the wrong button.

Create buttons with different textures for the blind, and add auditory response sensors.

Involve a diverse group of employees and users at all levels in the development - think of the end user.

Think about the importance of including typically marginalized segments of society such as LGBTQ (different sexual orientations).

Remember that not everyone has grandchildren who can "teach them how to use digital technology."

Søraa has had research stays in both Japan and South Korea, and robotic technology is far more widespread there than here.

"In Japan you see robots being used more often, including at airports for carrying luggage and in the shipping industry where there's a lot of unloading and loading of goods. This type of robot technology is getting more and more common, so it's important for it to be adapted to different users," he says.

We will probably see more exoskeletons in the future, both in the health and labour sectors. But it's important that as many people as possible be able to use them, he says.