Culture

Yoga and breathing exercises aid children with ADHD to focus

image: Sergey Kiselev is a head at Laboratory of Brain and Neurocognitive Development UrFU

Image: 
UrFU / Karina Golovanova.

Yoga and breathing exercises have a positive effect on children with attention deficit hyperactivity disorder (ADHD). After special classes, children improve their attention, decrease hyperactivity, they do not get tired longer, they can engage in complex activities longer. This is the conclusion reached by psychologists at Ural Federal University who studied the effect of exercise on functions associated with voluntary regulation and control in 16 children with ADHD aged six to seven years. The results of the study are published in the journal Biological Psychiatry.

"For children with ADHD, as a rule, the part of the brain that is responsible for the regulation of brain activity - the reticular formation - is deficient," said Sergey Kiselev, head of the Laboratory of Brain and Neurocognitive Development at UrFU, head of the study. "This leads to the fact that they often experience states of inadequate hyperactivity, increased distraction and exhaustion, and their functions of regulation and control suffer a second time. We used a special breathing exercise based on the development of diaphragmatic rhythmic deep breathing - belly breathing. Such breathing helps to better supply the brain with oxygen and helps the reticular formation to better cope with its role. When the reticular formation receives enough oxygen, it begins to better regulate the child's state of activity".

In addition to breathing exercises, psychologists used body-oriented techniques, in particular, exercises with polar states "tension-relaxation". The trainings took place three times a week for two to three months (depending on the program).

"Exercise has an immediate effect that appears immediately, but there is also a delayed effect. We found that exercise has a positive effect on regulation and control functions in children with ADHD and one year after the end of the exercise. This happens because the child's correct breathing is automated, it becomes a kind of assistant that allows better supply of oxygen to the brain, which, in turn, has a beneficial effect on the behavior and psyche of a child with ADHD," says Sergey Kiselev.

This technique was developed by the Russian neuropsychologist Anna Semenovich as part of a neuropsychological correction technique. UrFU psychologists tested how well this approach helps children with ADHD. But the study is pilot, says Kiselev. It showed that these exercises have a positive effect. However, more work needs to be done, involving more children with ADHD. This will also take into account factors such as gender, age, severity of the disease, concomitant problems in children (speech, regulatory, etc.).

Note

Attention deficit hyperactivity disorder is a disorder associated with impaired development of the child's nervous system. Most often it manifests itself at the age of seven or at the beginning of regular education. ADHD is characterized by inattention, excessive activity, and impulsive behavior.

Since 2013, the Laboratory of the Brain and Neurocognitive Development of UrFU has been conducting research on the maturation of the brain and mental processes in typically developing children, as well as in children with deviant development, in particular, those at risk of developing autism and ADHD, children with moderate traumatic brain injury severity. The laboratory is one of the leading Russian centers for the study of brain development and neurocognitive processes in children.

Credit: 
Ural Federal University

Lockdown led to positive lifestyle changes in older people

image: Professor Anna Whittaker

Image: 
University of Stirling

The COVID-19 lockdown was a catalyst for many older people to embrace technology, reconnect with friends and build new relationships with neighbours, according to University of Stirling research.

Understanding the coping mechanisms adopted by some over 60s during the pandemic will play a key role in developing interventions to help tackle loneliness, isolation and wellbeing in the future.

The study, led by the Faculty of Health Sciences and Sport, surveyed 1,429 participants - 84 percent (1,198) of whom were over 60 - and found many had adapted to video conferencing technology to increase online contact with existing social networks, while others reconnected with previous networks. Participants reported that lockdown had led them to engage with neighbours and other members of their communities for the first time, while several said social distancing had brought an additional meaning to life, by highlighting what was important to them.

Published in the International Journal of Environmental Research and Public Health, the paper comes six months after the study - funded under the Scottish Government Chief Scientist Office's Rapid Research in COVID-19 programme - reported in its preliminary findings that social distancing had increased feelings of loneliness in older people.

Professor of Behavioural Medicine, Anna Whittaker, who led the study, said: "Our research found that the COVID-19 lockdown triggered feelings of loneliness in older people - with many experiencing less social contact and support. However, the study also highlighted positive outcomes, for example, lockdown encouraged some older people to embrace and engage with technology - such as Zoom, Whatsapp or FaceTime - to stay in touch with loved-ones or participate in exercise classes or religious groups. Those who engaged in such activity were able to prevent high levels of loneliness, therefore, helping older adults to increase their digital literacy and use of remote social interactions could be a really important tool for addressing loneliness.

"Participants also reported actively looking for new social contact while restrictions were in place - such as contacting friends who they had not spoken to in years and increasing interactions with neighbours and other members of their communities. Significantly, many of our participants reported that social distancing has actually led them to find new sources of satisfaction in life.

"Our study also highlighted that encouraging safe social contact through physical activity and engaging with people in the community may be an effective way to reduce loneliness, improve wellbeing, increase social activity, and improve social support."

The study - which involved a survey conducted between May and July 2020 - examined the impact of social distancing during the pandemic on loneliness, wellbeing and social activity, including social support, in Scottish older adults.

Participants were asked about the strategies they adopted to increase social interaction during this time and reported that the way they interacted with their friends and family, faith, chosen group activities and, to a lesser extent, their employer and colleagues, had changed. More than 300 participants mentioned 'Zoom' - the video conferencing tool - in their answers.

More than 150 participants reported that their religious gatherings had moved online - replacing face-to-face gatherings - while 91 said that social gatherings with family and friends had changed in favour of online 'games nights'. New activities included bingo and quiz nights, while other activities moved online - such as bridge nights, book clubs, choir rehearsals, and dance and exercise classes.

The role of community - particularly neighbours - was mentioned by more than 300 participants and some reported the common experience of getting to know previously unknown neighbours and increase interaction with others in the community at local shops or parks. A pleasant Scottish summer also supported such interactions, several said.

At least 100 people said social interactions were linked to their physical activities - such as time spent outdoors while walking for exercise, walking the dogs or active commuting.

Professor Whittaker added: "Our research underlines the importance of addressing loneliness and social support in older adults - but particularly during situations where risk of isolation is high. Although specific to the pandemic, this study has wider implications of helping us to understand the impact of social distancing and social isolation on older people.

"The findings may be applicable in the future - both in and outwith pandemic situations. In Scotland, the recommendations for improvement may be through encouraging older adults to get to know their neighbours better, getting involved with local buddying systems and community initiatives, including via digital means, and engaging in physical activity, such as daily walks in the community."

Brian Sloan, Chief Executive of Age Scotland, said: "While it may prove difficult to consider any aspect of the pandemic positive as such, it is important and worthwhile to reflect on what it has taught us, both about ourselves and society and about the necessary tools to tackle Scotland's increased levels of loneliness and isolation.

"For example, we've seen first-hand how important the community response has been in terms of supporting older people throughout lockdown and it has been inspiring to witness how people across the country stepped in and stepped forward to help those in need around them. Even as restrictions ease, we hope to see this sense of community spirit continue.

"The ongoing impact of COVID-19 has also demonstrated just how important increased digital inclusion is and how easily those without access to technology can feel out of the loop. It's reassuring to see so many older people reporting that they have been able to embrace and engage with technology to stay connected and active.

"However, it's equally important to ensure those who are unable or do not wish to use the internet have alternative ways to stay connected to their communities and support networks.

"As we take steps towards recovery together, it is vital that no one is left behind and those most impacted are supported to play a full part in society again.

"We know we will be living with the ongoing effects of lockdown loneliness for a long time to come, and this research will be incredibly valuable when considering how best to tackle loneliness and isolation and to improve the wellbeing of older people going forward."

Credit: 
University of Stirling

New perspective on stress pandemics and human resilience from the analysis of COVID-19

A new analysis of the effects of SARS-CoV-2, the virus causing the current pandemic, on the human body has provided novel insights into the nature of resilience and how we deal with stressful situations. Using COVID-19 as an example, the findings provide a new framework that may be central to managing this disease, minimise the likelihood of ferocious viral outbreaks in the future and deal with other major stresses.

"COVID-19 has been a huge burden on society at all levels. Whilst the prospects are improving in countries with efficient vaccination schemes like the UK, the virus is still present, and new variants continue to pose considerable risks. Moreover, there are sustained effects such as Long COVID and the mental health burden of the pandemic to overcome," Martin Feelisch, Professor of Experimental Medicine and Integrative Biology at the University of Southampton explained.

"By analysing and re-ordering the information available in the literature we aimed to offer a systems-level view on the disease within a single framework that provides a coherent picture about the way this infection stresses the human body."

The research team involving physicians, chemical biologists and an authority on human nutrition, looked at COVID from a higher level than just a disease affecting the lungs and considered how the whole body deals with the various stresses the virus causes when viewed through the lens of electron exchange (also known as 'redox') processes. Electron exchange reactions are the foundation of all Life on Earth, underpinning human physiology and our ability to react to changes in demand and environmental conditions. While change is healthy in principle, some people experience unfavourable consequences when a major stress such as a viral infection is added to the stresses of daily life. What happens when such stresses act together is not yet fully understood, and COVID-19 was used as an example to look at the consequences of those interactions.

"COVID can present as a severe lung infection in one person while producing only minor symptoms in others, although it may have affected several other organs by then already. Arriving at a better understanding of how the body deals with different stresses while maintaining an appropriate redox balance would put us in a better position to treat patients acutely, protect the rest of the population and control disease spread. While the current vaccination success story is encouraging, emerging virus mutants show the threat continues, and we need to be better prepared in the future." Prof Feelisch continued.

Their analysis, published in the leading journal Antioxidants & Redox Signaling, revealed three key areas in the body's ability to cope with the stress of viral infections:

Firstly, nutrition emerges to be of utmost importance in maintaining the necessary redox balance and provide one's metabolism with the flexibility to adjust and combat the damaging effects of viral infection on cells and tissues. It also explains the greater susceptibility to disease in more deprived areas of the country because low income increases the risk for poor nutrition.

The second key finding was the importance of the endothelium - the inner lining of blood vessels that provides organs with oxygen and nutrients - in particular, a highly fragile layer on its surface that regulates nutrient/fluid exchange and protects blood cells from coming into close contact with the vessel wall. The research team have found that the crucial regulatory function performed by the endothelium has not been fully recognised in existing research and may also be essential to understanding the effects of Long COVID, where the body does not get back to its normal balance. They advise that routine monitoring of this cell layer in a non-invasive fashion, such as from under the tongue, may provide valuable insight into this and other stressful process and guide therapeutic approaches.

The final key observation was the role played by small molecules known as 'gasotransmitters'. These are used by all cells to sense changes in their environment and adapt. These molecules are part of a body-wide system that uses circulating blood as a communication highway to inform other organs how to best respond to the mixture of stresses experienced by other parts of the body, for example how to ramp up the metabolism in the liver to deal with an infection of the lung. Of all the molecules involved, nitric oxide appears to be fundamental in protecting the overall redox system.

Professor Feelisch concluded, "We need to make best use of the opportunity the current crisis has given us to learn more about how the body and individual cells deal with stresses. Our holistic framework should be interpreted as a 'call to action' and encourage investigators around the world to study whole-body redox regulation, find ways to monitor redox status and identify factors that are critical for health and resilience. The next pandemic could be just around the corner and if we do not learn from current events, chances are we will face the same problems all over again."

Credit: 
University of Southampton

Maternal stress during pregnancy may shorten lifespans of male lizard offspring

image: Mother fence lizards that experience stress during pregnancy give birth to male offspring with shortened telomeres, which is associated with shortened life spans, according to new research.

Image: 
Tracy Langkilde, Penn State

UNIVERSITY PARK, Pa. -- Mother fence lizards that experience stress during pregnancy give birth to male offspring with shortened telomeres, or bits of non-coding DNA that cap the ends of chromosomes, according to a Penn State-led study. Shorter telomeres are associated with decreased lifespan in humans; therefore, the team's findings may have implications for human longevity.

"Human men have shorter telomeres than women, which may partly explain why they have shorter lifespans of about seven years," said Tracy Langkilde, professor and Verne M. Willaman dean of the Eberly College of Science. "Our study shows that stress experienced by mothers during gestation could further shorten the telomeres, and therefore the lifespans, of their sons, thereby exacerbating these sex differences."

According to Langkilde, telomeres are short sections of non-coding DNA that cap the ends of chromosomes, like the plastic tips at the ends of shoelaces, and are responsible for protecting genomic integrity. They are known to decrease in length as an organism ages. Stressors, she added, can speed up this process.

"Stressors cause concentrations of the hormone corticosterone to rise; this is supposed to help an organism cope and respond appropriately," she said. "However, corticosterone can also induce oxidative stress [an imbalance between the body's free radicals and antioxidants] and decrease telomerase activity, both of which are known to exacerbate telomere shortening. What hasn't been known is how increased corticosterone in mothers affects telomere length, and thus lifespan, in offspring."

To examine the effects of maternal corticosterone and offspring telomere length, the researchers captured 22 pregnant female eastern fence lizards (Sceloporus undulatus) from Tennessee and Kentucky and randomly assigned them to one of two groups: those receiving a transdermal treatment of corticosterone or a control group. The team applied the corticosterone in amounts that are similar to those generated by lizards after exposure to a non-lethal attack by a predator or a heat challenge.

From the eggs laid by the mothers, 21 hatchlings were used for the project. The researchers collected blood from these hatchlings at 4-7 days of age. They isolated the DNA from the blood samples and measured telomere length using a quantitative PCR method. Their findings appeared on April 29 in the journal Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology.

The team found that the male offspring of corticosterone-treated mothers had telomeres that were more than 20% shorter than those from control mothers. In contrast, the telomere lengths of the mothers were unaffected by the mothers' exposure to corticosterone. Similarly, the telomere lengths of the female offspring were unaffected.

Estrogen may buffer the telomeres of mothers and daughters from the negative effects of increased corticosterone through its protective effect against oxidative stress and its promotion of telomerase activity, noted Langkilde.

"The connection between corticosterone concentration and telomere length has rarely been examined between generations," said David Ensminger, National Science Foundation postdoctoral research fellow in biology at UC Berkeley, future assistant professor of physiology at San Jose State University, and former graduate student in ecosystem science and management and in biology, Penn State. "We found a sex-specific effect of maternal corticosterone on offspring telomeres, explained by a tendency for a decrease in offspring telomere length of sons but not daughters."

Sue Siegel, research professor, Biomarker Core Lab, Department of Biobehavioral Health, said the findings are robust even though the sample size was small.

"Although care must be taken in drawing conclusions from this study due to the small sample size, the results are still statistically significant and suggest a negative impact of maternal corticosterone on the telomere length of sons," she said. "Further studies would help elucidate the underlying mechanism of corticosterone on telomere length."

Credit: 
Penn State

Businesses have a moral duty to explain how algorithms make decisions that affect people

Increasingly, businesses rely on algorithms that use data provided by users to make decisions that affect people. For example, Amazon, Google, and Facebook use algorithms to tailor what users see, and Uber and Lyft use them to match passengers with drivers and set prices. Do users, customers, employees, and others have a right to know how companies that use algorithms make their decisions? In a new analysis, researchers explore the moral and ethical foundations to such a right. They conclude that the right to such an explanation is a moral right, then address how companies might do so.

The analysis, by researchers at Carnegie Mellon University, appears in Business Ethics Quarterly, a publication of the Society for Business Ethics.

"In most cases, companies do not offer any explanation about how they gain access to users' profiles, from where they collect the data, and with whom they trade their data," explains Tae Wan Kim, Associate Professor of Business Ethics at Carnegie Mellon University's Tepper School of Business, who co-wrote the analysis. "It's not just fairness that's at stake; it's also trust."

In response to the rise of autonomous decision-making algorithms and their reliance on data provided by users, a growing number of computer scientists and governmental bodies have called for transparency under the broad concept of algorithmic accountability. For example, the European Parliament and the Council of the European Union adopted the General Data Protection Regulation (GDPR) in 2016, part of which regulates the use of automatic algorithmic decision systems. The GDPR, which launched in 2018, affects businesses that process the personally identifiable information of residents of the European Union.

But the GDPR is ambiguous about whether it involves a right to explanation regarding how businesses' automated algorithmic profiling systems reach decisions. In this analysis, the authors develop a moral argument that can serve as a foundation for a legally recognized version of this right.

In the digital era, the authors write, some say that informed consent--obtaining prior permission for disclosing information with full knowledge of the possible consequences--is no longer possible because many digital transactions are ongoing. Instead, the authors conceptualize informed consent as an assurance of trust for incomplete algorithmic processes.

Obtaining informed consent, especially when companies collect and process personal data, is ethically required unless overridden for specific, acceptable reasons, the authors argue. Moreover, informed consent in the context of algorithmic decision-making, especially for non-contextual and unpredictable uses, is incomplete without an assurance of trust.

In this context, the authors conclude, companies have a moral duty to provide an explanation not just before automated decision making occurs, but also afterward, so the explanation can address both system functionality and the rationale of a specific decision.

The authors also delve into how companies that run businesses based on algorithms can provide explanations of their use in a way that attracts clients while maintaining trade secrets. This is an important decision for many modern start-ups, including such questions as to how much code should be open source, and how extensive and exposed the application program interface should be.

Many companies are already tackling these challenges, the authors note. Some may choose to hire "data interpreters," employees who bridge the work of data scientists and the people affected by the companies' decisions.

"Will requiring an algorithm to be interpretable or explainable hinder businesses' performance or lead to better results?" asks Bryan R. Routledge, Associate Professor of Finance at Carnegie Mellon's Tepper School of Business, who co-wrote the analysis. "That is something we'll see play out in the near future, much like the transparency conflict of Apple and Facebook. But more importantly, the right to explanation is an ethical obligation apart from bottom-line impact."

Credit: 
Carnegie Mellon University

Access to overdose-reversing drugs declined during pandemic, researchers find

Boston - While overall emergency department visits have decreased during the pandemic, nonfatal opioid overdose visits have more than doubled. However, few patients who overdosed on opioids had received a prescription for naloxone, a medication designed to block the effects of opioids on the brain and rapidly reverse opioid overdose.

In a new study, clinician-researchers at Beth Israel Deaconess Medical Center (BIDMC) analyzed naloxone prescription trends during the COVID-19 pandemic in the United States and compared them to trends in opioid prescriptions and to overall prescriptions. The team's findings, published in the journal JAMA Health Forum, suggest patents with opioid misuse disorders may be experiencing a dangerous decrease in access to the overdose-reversing drug.

"In March of 2020, we saw a sharp reduction in the average number of individuals filling naloxone prescriptions each week, which far exceeded the decline in the number of people filling prescriptions for any medication," said corresponding author Ashley O'Donohue, PhD, an economist in the Center for Healthcare Delivery Science at BIDMC. "And since March 2020, there's been no statistically significant recovery in naloxone prescriptions, indicating that the number of individuals filling naloxone prescriptions has remained low throughout the pandemic."

Using data from a national pharmacy insurance claims database that includes claims from national retail pharmacies, mail-order pharmacies and specialty pharmacies, O'Donoghue and colleagues analyzed weekly trends in the number of patients filling naloxone prescriptions, opioid prescriptions and all prescriptions between May 2019 and December 2020.

The team found that the number of individuals filling prescriptions for any medication fell by 14 percent in the early months of the COVID-19 pandemic, while the number of individuals filling opioid prescriptions fell by just 9 percent. However, the number of people filling naloxone prescriptions fell by more than 25 percent, and the number of individuals with Medicare and commercial coverage filling naloxone prescriptions declined by nearly a third. Meanwhile, among patients with Medicaid coverage or patients who paid in cash, there was no statistically significant change in the number of individuals filling naloxone prescriptions.

"Our study identifies an urgent gap in necessary access to lifesaving medication for individuals covered by Medicare and commercial insurance during the pandemic," said senior author Jennifer P. Stevens, MD, MS, Director of the Center for Healthcare Delivery Science at BIDMC. "Continuing to distribute naloxone in densely populated areas and through community-based organizations could help mitigate some of the reductions in naloxone distribution via pharmacies and could also reduce some of the increases in fatal opioid overdose is during the COVID-19 pandemic."

Credit: 
Beth Israel Deaconess Medical Center

Sensors developed at URI can identify threats at the molecular level

image: URI doctoral student Peter Ricci (left) and Professor Otto Gregory test the Digital Dog Nose sensors platform in Gregory's Thin Film Sensors Laboratory at URI. The blue devices on the table represent the two latest versions of the Digital Dog Nose.

Image: 
Photo by Mike Platek

KINGSTON, R.I. - May 14, 2021 - We are frequently reminded of how vulnerable our health and safety are to threats from nature or those who wish to harm us.

New sensors developed by Professor Otto Gregory, of the College of Engineering at the University of Rhode Island, and chemical engineering doctoral student Peter Ricci, are so powerful that they can detect threats at the molecular level, whether it's explosive materials, particles from a potentially deadly virus or illegal drugs entering the country.

"This is potentially life-saving technology," said Gregory. "We have detected things at the part-per-quadrillion level. That's really single molecule detection."

Broad-Based Applications

Because Gregory's sensors are so small and so powerful, there is a wide range of applications.

"The platform is broad-based, so you can apply it to lots of different venues, with lots of different end users," said Gregory.

While his research is largely funded by the Department of Homeland Security, other government agencies have taken notice of Gregory's sensors.

The Department of Defense may be interested in using it to monitor wounds in soldiers and to detect roadside improvised explosive devices (IEDs).

If a soldier or first responder suffered an open wound from shrapnel, Gregory's sensors could help determine if the wound became infected.

"Hydrogen peroxide generated by the human body for wounds is an indication of how good or how bad antibiotics are working to fight the wound," said Ricci. "Our sensor could be used as a wearable device to sniff out peroxide coming from the wound at the part-per-billion level."

At Miami Heat basketball games, dogs have been used to sniff traces of COVID-19 coming from the pores in people's skin. In an article published in the prestigious journal Nature, Gregory stated that his sensors could be used for the same purpose.

"Where dogs are detecting it from the skin, our sensors would detect it from biomarkers in people's breath," Ricci said, who is from West Warwick.

The Coast Guard has shown an interest in using the technology to "sniff out" illegal drugs being smuggled into the United State aboard ships.

Shrinking the 'Digital Dog Nose'

"Anything that can typically be sniffed out by a dog we can do," said Gregory. "That's why we've called it the Digital Dog Nose."

The Digital Dog Nose was featured on shows such as CBS This Morning in November 2019, but what was once the size of a toolbox has been reduced to a quarter of the size of a pack of cigarettes.

"By decreasing the thermal mass of the sensor, we've decreased the amount of power required to run the sensor," said Gregory. "We started with a thermal mass on the order of grams. Now the thermal mass of our sensor is on the order of micrograms."

One of the keys to making a device as small and powerful as Gregory's is to find the right battery.

"We have partnered with a company that makes very thin, low-mass batteries in Colorado called ITN Energy Systems," Gregory said. "They make lithium batteries that are no thicker than a piece of paper. The process has been about finding the right partners, which helps us improve our catalysts and improve our sensor platform."

Passing the Test

In March 2021, the Naval Research Laboratory brought its mobile testing unit to URI's W. Alton Jones Campus to put Gregory's explosives sensors and others to the test.

"They set up a field test outside using their vapor test bed," said Ricci. "They were able to select an explosive molecule and deliver it to the sensor system. Knowing what the level was, they wanted to see how our sensor would respond. One of the tests was at the part-per-quadrillion level."

Staying a Step Ahead

As bad guys have developed new explosives or new ways to improvise on existing explosives, the good guys have tried to stay a step ahead.

"The Department of Homeland Security has asked us to be flexible enough to anticipate and adapt to emerging threats that may come several years down the road," said Gregory. "We can tweak our catalysts for a specific molecule that is the current threat. That's what we do with biomarkers. That's what we do with drugs. What's nice about this platform is that it's flexible."

Coming a Long Way

The sensors Gregory and Ricci have developed have been tested and improved upon over a long period of time. The professor's research was originally funded 20 years ago by the Defense Advanced Research Projects Agency (DARPA), a research and development agency of the United States Department of Defense that is responsible for the development of emerging technologies for use by the military.

After two years of DARPA funding, the Army funded the project for a year. The Department of Homeland Security has provided funding ever since.

"At the time, this research was very novel and very different," said Gregory. "DARPA funds projects that are high risk, high reward. We've demonstrated that the gamble they took on our concept back then has paid off."

Michael Silevitch, the Robert D. Black Distinguished Professor of Engineering at Northeastern University, has collaborated with Gregory on his research for more than 10 years.

"This is breakthrough technology," said Silevitch. "Otto's work on chemical detectors has evolved to the point of being ready for use in many applications, including the deployment of his sensors on a drone-based platform to help protect soft targets such as schools, shopping malls or places of worship."

Taking the New Steps

Now that the sensors are very small and lightweight, they could be attached to drones, leading to many new applications.

"We've been talking to drone companies about using our sensors on their drones," said Gregory. "Drones need very lightweight, portable power supplies and you have to tap into their wireless communication. It's a much different set of engineering conditions than using a robot arm that the Army is looking to use for roadside IEDs."

Gregory and Ricci are also working on sensor arrays, to differentiate one explosive, or threat, from another.

"We'll need an array of sensors to detect a specific explosive in the presence of other explosives or precursors," said Ricci. "If there's a plume of three different explosives, we may need to identify one from the others."

Ready to Use

Now that the sensors have proven to be effective, implementing them in real-world situations is just a matter of funding.

"Our sensor is not an off-the-shelf commercial product yet, but we have a potential partner," Gregory said. "We just need a customer to step up to the plate and say here's an order for 1,000 of these, can you deliver them?"

Credit: 
University of Rhode Island

New benefit increases Veterans' access to urgent care in the community

May 14, 2021 - Two years ago, the Veterans Affairs healthcare system (VA) began rolling out a new benefit, enabling Veterans to receive urgent care from a network of community providers - rather than visiting a VA emergency department or clinic. Progress toward expanding community care services for Veterans is the focus of a special supplement to the May issue of Medical Care. The journal is published in the Lippincott portfolio by Wolters Kluwer.

The urgent care benefit "provides a new way to deliver unscheduled, low-acuity acute care to Veterans," according to the new research by Anita Vashi, MD, MPH, MHS, of VA Palo Alto Health Care System and colleagues. The study is one of 12 research papers and commentaries on "Innovations in Community Care Programs, Policies, and Research" - focusing on Veterans' use of healthcare services in the community, and how VA centers interact with community care providers.

What's the best balance of VA and community care? That's the 'billion-dollar question'

Dr. Vashi and colleagues analyzed initial data on how Veterans are using the community urgent care benefit, which was implemented starting in June 2019. Eligible Veterans were able to receive urgent care from providers in VA's community network, without prior authorization. Focusing on minor illnesses and injuries that might otherwise lead to emergency department (ED) visits, the program was part of VA's "Maintaining Internal Systems and Strengthening Integrated Outside Networks" (MISSION) Act, designed to increase Veterans' access to health care in VA facilities and the community.

Through the first nine months of the program, 138,305 Veterans made a total of 175,821 urgent care visits to VA community network providers. That accounted for 2.4 percent of a cohort of 5.9 million potentially eligible Veterans. By comparison, 7.3 percent of Veterans visited a VA ED or clinic for lower-acuity (non-emergency) conditions during the same period.

Dr. Vashi and colleagues examined trends in community urgent care use, including factors associated with urgent care rather than ED visits. Urgent care visits generally increased over time and varied between regions. Most Veterans using urgent care lived in urban areas - more than 80 percent lived within 30 minutes of a VA primary care site. Most had no copays for urgent care visits.

Upper respiratory infections, back pain, and bronchitis were the most frequent reasons for community urgent care visits. Common procedures and treatments included chest x-rays, influenza or strep testing, and urinalysis. Average cost to VA for urgent care visits was $132, with total costs of about $23 million.

On analysis adjusting for other factors, women and younger Veterans were more likely to take advantage of the urgent care benefit. Driving time was a key factor: Veterans who lived more than 60 minutes from a VA ED or VA urgent care center were twice as likely to choose community urgent care services.

The study provides key information on how "early adopters" are taking advantage of the urgent care benefit. "As the program continues to expand and evolve, impacts on care coordination, medication safety, outcomes, and shifts in utilization of VA primary and emergency services must be evaluated," Dr. Vashi and coauthors write.

While most care is still provided at VA Medical Centers and outpatient sites, initiatives including the MISSION Act have greatly expanded Veterans' ability to seek care at private health care providers, clinics, and hospitals in the community. The papers in the new open-access supplement offer "a broad examination of the first two years of MISSION Act implementation, and highlights areas where additional research is needed to understand Veterans' perceptions, satisfaction and use of VA Community Care," according to an introductory guest editorial by Kristin Mattocks, PhD, of VA Central Western Massachusetts and colleagues.

The supplement papers are an important step toward providing the best experience for Veterans in choosing among their healthcare options. Dr. Mattocks and coauthors conclude: "The enduring challenge for VA - literally the 'billion dollar question' - is to determine what balance of in-person VA care, virtual VA care, and care in the community offers the optimal balance of timely, patient-centered and high-quality care."

Credit: 
Wolters Kluwer Health

New pre-clinical model could hold the key to better HIV treatments

image: Scanning electron micrograph of a human T lymphocyte (T cell) from a healthy donor's immune system.

Image: 
National Institute of Allergy and Infectious Diseases/NIH

A team led by researchers at Weill Cornell Medicine and Children's National Hospital has developed a unique pre-clinical model that enables the study of long-term HIV infection, and the testing of new therapies aimed at curing the disease.

Ordinary mice cannot be infected with HIV, so previous HIV mouse models have used mice that carry human stem cells or CD4 T cells, a type of immune cell that can be infected with HIV. But these models tend to have limited utility because the human cells soon perceive the tissues of their mouse hosts as "foreign," and attack--making the mice gravely ill.

By contrast, the new mouse model, described in a paper in the Journal of Experimental Medicine on May 14, avoids this problem by using a subset of human CD4 cells that mostly excludes the cells that would attack mouse tissue. The researchers showed that the mice can usefully model the dynamics of long-term HIV infection, including the virus's response to experimental therapies.

"We expect this to be a valuable and widely used tool for studying the basic science of HIV infection, and for speeding the development of better therapies," said co-first author Dr. Chase McCann. During the study, Dr. McCann was a Weill Cornell Graduate School student in the laboratory of senior author Dr. Brad Jones, associate professor of immunology in medicine in the Division of Infectious Diseases at Weill Cornell Medicine. Dr. McCann, who was supported at Weill Cornell by a Clinical and Translational Science Center (CTSC) TL1 training award, is now the Cell Therapy Lab Lead in the Center for Cancer and Immunology Research at Children's National Hospital in Washington, DC. The other co-first authors of the study are Dr. Christiaan van Dorp of Los Alamos National Laboratory and Dr. Ali Danesh, a senior research associate in medicine at Weill Cornell Medicine.

The invention of the new mouse model is part of a wider effort to develop and test cell therapies against HIV infection. Cell therapies, such as those using the patient's own engineered T cells, are increasingly common in cancer treatment and have achieved some remarkable results. Many researchers hope that a similar strategy can work against HIV and can potentially be curative. But the lack of good mouse models has hampered the development of such therapies.

Drs. Jones and McCann and their colleagues showed in the study that the cell-attacks-host problem found in prior mouse models is chiefly due to so-called "naïve" CD4 cells. These are CD4 cells that have not yet been exposed to targets, and apparently include a population of cells that can attack various mouse proteins. When the researchers excluded naïve CD4 cells and instead used only "memory" CD4 cells, which circulate in the blood as sentinels against infection following exposure to a specific pathogen, the cells survived indefinitely in the mice without causing major damage to their hosts.

The researchers observed that the human CD4 cells also could be infected and killed by HIV, or protected by standard anti-HIV drugs, essentially in the same way that they are in humans. Thus, they showed that the mice, which they termed "participant-derived xenograft" or PDX mice, served as a workable model for long-term HIV infection. This term is akin to the "patient-derived xenograft" PDX models used to study cancer therapies, while recognizing the contributions of people with HIV as active participants in research.

Lastly, the researchers used the new model to study a prospective new T-cell based therapy, very similar to one that is now being tested against cancers. They put memory CD4 T cells from a human donor into the mice to permit HIV infection, and then, after infection was established, treated the mice with another infusion of human T cells, these being CD8-type T cells, also called "killer T cells."

The killer T cells were from the same human donor and could recognize a vulnerable structure on HIV--so that they attacked the virus wherever they found it within the mice. To boost the killer T cells' effectiveness, the researchers supercharged them with a T cell-stimulating protein called IL-15.

The treatment powerfully suppressed HIV in the mice. And although, as often seen in human cases, the virus ultimately evolved to escape recognition by the killer T cells, the ease of use of the mouse model allowed the researchers to monitor and study these long-term infection and viral escape dynamics in detail.

"I think that the major impact of this model will be its acceleration of the development of T cell-based therapies that can overcome this problem of viral escape," Dr. Jones said.

He and his laboratory are continuing to study such therapies using the new mouse model, with engineered T cells from Dr. McCann's laboratory and others.

Credit: 
Weill Cornell Medicine

Most pediatric spinal fractures related to not wearing seatbelts

May 14, 2021 - Two thirds of all pediatric spinal fractures, especially in the adolescent population, occur in motor vehicle accidents (MVAs) where seatbelts are not utilized, reports a study in Spine. The journal is published in the Lippincott portfolio by Wolters Kluwer.

"Over 60 percent of pediatric spinal fractures occur in children ages 15 to 17, coinciding with the beginning of legal driving," according to the new research by Dr. Vishal Sarwahi, MD, of Cohen Children's Medical Center, New Hyde Park, NY, and colleagues. They emphasize the need for measures to increase seatbelt usage, particularly by younger drivers, and outline the potential trauma that can be avoided through proper seatbelt use.

Seatbelts save lives... and spines

Motor vehicle accidents are the leading cause of death amongst teenagers in the United States. Many previous studies have reported rising rates of pediatric spinal injuries, especially in teens aged 15 and older. This new study confirms that MVAs, in fact, cause most spinal fractures in children and adolescents, with high rates of other injuries. Spinal fractures in young patients are also associated with a three percent mortality rate, with many deaths occurring in unrestrained drivers and passengers.

Using the American College of Surgeons' National Trauma Data Bank, Dr. Sarwahi and his colleagues studied 34,563 pediatric patients (younger than 18 years) who sustained spinal fractures between 2009 and 2014. Many of the patients had multiple spinal fractures, with a total of 45,430 fractured vertebrae.

Overall, teenagers between age 15 and 17 years accounted for about 63 percent of spinal fractures, two-thirds of which occurred in MVAs. These findings show that around the time teens get their drivers' license, drivers and passengers are at highest risk for MVA resulting in spinal fracture.

Fifty-eight percent of the injured patients were male. Pediatric spinal fractures were found to be most common in the South: 38 percent, probably due to a lack of public transport resulting in more vehicles on the road.

The study also shows the impact of seatbelt use on these devastating injuries. "Nearly two-thirds of pediatric spinal fractures sustained in MVAs occurred in children who did not use belts," Dr. Sarwahi and co-authors write. Without seatbelts, the risks of severe or multiple injuries and death are substantially increased, with a significantly increased death rate from 29.3 percent to 70.7 percent - more than doubled.

Data on seatbelt use was available for nearly 19,000 patients, with approximately two-thirds of patients (65.9 percent) unrestrained. Almost half (44.2 percent) of unrestrained patients in MVAs were teenagers. Despite a larger percentage of MVAs occurring in the South overall, the percentage of spinal fractures from MVAs for unrestrained drivers and passengers was similar across all regions of the United States; approximately two-thirds of all teenagers across all regions - Northeast, Midwest, West, South - involved in MVAs did not wear seatbelts. This demonstrates the universality of teenage risk-taking behavior and identifies at-risk groups for risk modification strategies.

When seatbelts were worn, the rate of spinal fractures was substantially lower for all drivers and passengers. Seatbelt use lowered the risk of death by more than 20 percent. For young patients in MVAs, wearing seatbelts was also associated with lower rates of multiple vertebral fractures, other types of fractures in addition to spinal fracture, and head and brain injury.

While the percentage of drivers wearing seatbelts has risen steadily over the years, adolescents and young adults remain less likely to use these lifesaving devices. Dr. Sarwahi and colleagues discuss targeted approaches using technology and media awareness campaigns to increase seatbelt use among young people, as well as studies showing the importance of societal and cultural norms related to seatbelts. The researchers conclude: "Ensuring our new, young drivers wear protective devices can greatly reduce morbidity/mortality associated with MVA and can help save lives, and spines."

Credit: 
Wolters Kluwer Health

New cyanobacteria species spotlights early life

image: Anthocerotibacter panamensis, a newly discovered species of cyanobacteria, can help researchers study the dawn of oxygenic photosynthesis.

Image: 
Fay-Wei Li

ITHACA, NY, May 13, 2021 -- Cyanobacteria are one of the unsung heroes of life on Earth. They first evolved to perform photosynthesis about 2.4 billion years ago, pumping tons of oxygen into the atmosphere - a period known as the Great Oxygenation Event - which enabled the evolution of multicellular life forms.

Led by BTI faculty member Fay-Wei Li, researchers have discovered a new species of cyanobacteria, Anthocerotibacter panamensis, which could help illuminate how photosynthesis evolved to create the world as we know it. The work was published in Current Biology on May 13.

"We never intended to discover a new species," said Li. "It was a total accident."

His lab was working on a project to isolate cyanobacteria from hornwort plants, and noticed something weird in a sample from a rainforest in Panama. The researchers sequenced the cyanobacterium's DNA, and found that it belonged to a group called Gloeobacteria, which is extremely rare.

"Prior to this discovery, only two species of Gloeobacteria had been isolated," Li said. "There is also a third group of uncultured species from the Arctic and Antarctic regions, but no one knows how many species are in that group."

Gloeobacteria diverged from the more commonly studied Phycobacteria about 2 billion years ago. The two groups have many differences, and A. panamensis shares some traits with each.

Similar to other Gloeobacteria, the new species lacks thylakoids - the membrane-bound compartments that are the site of the light-dependent reactions of photosynthesis in Phycobacteria and plants.

"Now we can be pretty sure that the thylakoid evolved in Phycobacteria," Li said.

On the other hand, A. panamensis makes carotenoids - a group of compounds that help protect an organism from sun damage - in a fashion similar to Phycobacteria and plants, but different from the other Gloeobacteria.

"These results suggest that this particular carotenoid biosynthesis pathway evolved in the ancestor of all cyanobacteria, and then was lost in some Gloeobacteria," said Li.

Li said one of the more interesting findings is that A. panamensis has very few genes that encode the proteins that perform light-dependent reactions. The researchers found that the new species could still perform photosynthesis, but very slowly, which could be of interest to synthetic biologists.

"If you want to build a complete set of photosynthetic machinery with the fewest necessary components, then this species could inform how to do that," said Li. "Anthocerotibacter has a minimal set of photosystem subunits, but it still functions."

Credit: 
Boyce Thompson Institute

Teachers' gender, sexuality, and age affect perceptions of sexual misconduct of students

The United States has witnessed a steep rise in reports, arrests, and media coverage of teachers' sexual misconduct with students. A new study investigated the impact of perpetrators' gender, sexuality, and age on perceptions of teacher sexual misconduct. The study found that
responses to teachers' misconduct varied according to certain characteristics, which can influence whether victims report the misconduct.

The study, by researchers at Prairie View A&M University and the University of Nevada, Reno, appears in Feminist Criminology.

"Because sexual abuse of a child or adolescent in any context has substantial psychological, emotional, and physical consequences for the victim, teachers' sexual misconduct is a serious public health concern," says Kristan N. Russell, assistant professor of justice studies at Prairie View A&M University, who led the study. "Yet very little research has been done to examine the factors that affect how these cases are perceived."

Public perceptions are important, Russell argues, because they may contribute to the stigma experienced by victims, and also affect the willingness of victims to disclose or report these types of cases. Public perceptions also inform legal decision making regarding these cases.

The study's 495 respondents were recruited through a crowdsourcing website in 2019. They were over the age of 18 (average age was 36 years old) and predominantly White (60 percent), male (60 percent), and heterosexual (74 percent).

Respondents were asked to read one of eight randomly assigned fictional newspaper articles describing a case of a local teacher who engaged in sexual misconduct with a 17-year-old student. The articles described forms of nonsexual contact (sending nude photos and sexting) and forcible rape. Then the respondents answered questions about their perceptions of the case and their general attitudes toward cases of this type.

The articles varied by gender of the teacher (male or female), gender pairing of the teacher and student (opposite gender/heterosexual or same gender/homosexual), and age of the teacher (26 or 52 years). The pictures of the teacher, which were stock photos, varied by gender and age.

Although the study did not find evidence of significant interactions between gender, sexuality, and age, it did find that each of these factors affected respondents' perceptions. Specifically:

When the teacher was a woman, respondents perceived the relationship to be less detrimental to the student, the student to be more mature and responsible, and the relationship to be more acceptable.

Heterosexual pairings were perceived as more acceptable than same-sex pairings, with the student perceived as more mature and responsible in heterosexual pairings.

When the teacher was older, respondents perceived the teacher as more responsible and the student as having psychological issues contributing to the reasons for participating in the interaction. The age of the teacher did not relate significantly to respondents' perceptions of the impact of the relationship on the student.

The findings suggest that harmful aspects of teachers' sexual misconduct may be downplayed when the teacher is a woman, leading to underreporting of this type of misconduct by victims, the authors note. In addition, gender pairing affects perceptions, with heterosexual relationships less likely to be reported than homosexual relationships. This illustrates the persistence of stereotypes that depict gay people as predatory or pedophilic, and this, too, may contribute to reduced disclosure by victims in an effort to avoid stigmatization.

"Our findings can be used to develop trainings to inform teachers and students about the factors that influence perceptions and may contribute to underreporting, and strategies for intervening and reporting," suggests Kjerstin Gruys, assistant professor of sociology at the University of Nevada, Reno, coauthor of the study. "We hope that by educating people about what to be aware of in terms of laws and consent, and by allowing systematic and anonymous forms of reporting, students and staff can feel comfortable and safe reporting crimes."

Credit: 
Prairie View A&M University

Cataloging breast cells to find cancer origins

image: Mammary tissue is made up of a variety of cells, including epithelial (pink), immune (cyan), and fat (black) cells visible in this cross-section of a mouse mammary gland. CSHL Associate Professor Camila dos Santos' team identified and cataloged thousands of human and mouse breast cells to understand the origins of breast cancer.

Image: 
Camila dos Santos/dos Santos lab, CSHL/2021

What if you could predict which cells might become cancerous? Breast tissue changes dramatically throughout a woman's life, so finding markers for sudden changes that can lead to cancer is especially difficult. Cold Spring Harbor Laboratory (CSHL) Associate Professor Camila dos Santos and her team identified and cataloged thousands of normal human and mouse breast cell types. The new catalog redefines healthy breast tissue so that when something goes awry, scientists can pinpoint its origin.

Any breast cell could become cancerous. Dos Santos says:

"To understand breast cancer risk, you have to understand normal breast cells first, so when we think about preventive and even targeting therapies, you would be preventing the right cell types from developing to cancer cells."

A traditional way to catalog cells is by tracking a few signature genes related to the cell's function. To classify cells more extensively, dos Santos' team turned to a technique known as single-cell RNA sequencing. They tracked the activity of several genes in over 15,000 cells in mouse and human breast tissue. Samantha Henry, a Stony Brook University graduate student-in-residence in dos Santos' lab, says:

"We really created a whole catalog of many genes for each cell population to better define them. And when I say there were a lot of genes, there were a lot of genes and it took a long time to get through."

One cell group included estrogen receptor-positive cells, which are generally amenable to treatment. But dos Santos' team found that this group could be split into several subpopulations, where each one might have different responses to therapies.

The team, in collaboration with computational biologist CSHL Professor Adam Siepel and his team, learned that mice and human breast cells had similar genetic profiles, demonstrating why studies in mice are likely to be relevant to humans. Marygrace Trousdell, a computational science developer in the dos Santos lab, says:

"We're always finding ourselves struggling with definitive classifications of certain cell types. Sometimes I think I've seen every gene out there, and then something else will pop up."

Currently, the lab is trying to distinguish normal genetic shifts from those associated with cancer. Dos Santos hopes that her catalog of breast cell types will point to which kinds of cells to monitor and point researchers toward treatment options in the future.

Credit: 
Cold Spring Harbor Laboratory

New technology enables rapid sequencing of entire genomes of plant pathogens

Next-generation sequencing technology has made it easier than ever for quick diagnosis of plant diseases. "It's really exciting to see how sequencing technologies have evolved and how this new technology facilitates sequencing of entire genomes in such a short amount of time," said Yazmín Rivera, a plant pathologist with the United States Department of Agriculture's Plant Protection and Quarantine program, who recently published a research paper on the efficacy of Oxford Nanopore Technologies protocols.

"We wanted to provide an unbiased assessment of the technology and protocols available for long read sequencing," Rivera explained. Along with other plant pathologists, Rivera used the company's protocols to prepare RNA and DNA libraries from virus-infected plant material and from a plant pathogenic bacterium, respectively. After one hour of data sequencing, scientists had enough data to assemble small genomes.

"Diagnosticians will welcome an objective review of this technology," Rivera said. Rivera and her colleagues published their findings in Plant Health Progress, presenting a side-by-side comparison of the protocols that will allow the reader to identify which library preparation kit is best suited for their needs.

The ability to quickly obtain the entire genome of an organism has great implications for the plant pathology field. "Having more information readily available facilitates identification of emerging pathogens and of pathogens that are difficult to identify," explains Rivera. For more information, read "Comparison of Nanopore Sequencing Protocols and Real-Time Analysis for Phytopathogen Diagnostics"? published in the March issue of Plant Health Progress.

Credit: 
American Phytopathological Society

Compound may prevent risk of a form of arrhythmia from common medications

image: The research team included Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering at Washington University in St. Louis along with: Ira Cohen, MD, PhD, Distinguished Professor of Physiology and Biophysics, professor of medicine, and director of the Institute for Molecular Cardiology at the Renaissance School of Medicine at Stony Brook University; and Xiaoqin Zou, professor of physics, biochemistry, and a member of the Dalton Cardiovascular Research Center and Institute for Data Science and Informatics at the University of Missouri

Image: 
Washington University in St. Louis

Dozens of commonly used drugs, including antibiotics, antinausea and anticancer medications, have a potential side effect of lengthening the electrical event that triggers contraction, creating an irregular heartbeat, or cardiac arrhythmia called acquired Long QT syndrome. While safe in their current dosages, some of these drugs may have a more therapeutic benefit at higher doses, but are limited by the risk of arrhythmia.

Through both computational and experimental validation, a multi-institutional team of researchers has identified a compound that prevents the lengthening of the heart's electrical event, or action potential, resulting in a major step toward safer use and expanded therapeutic efficacy of these medications when taken in combination. The team found that the compound, named C28, not only prevents or reverses the negative physiological effects on the action potential, but does not cause any change on the normal action potential when used alone at the same concentrations. The results, found through rational drug design, were published online Friday, May 14 in the Proceedings of the National Academy of Sciences.

The research team was led by Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering at Washington University in St. Louis; Ira Cohen, MD, PhD, Distinguished Professor of Physiology and Biophysics, professor of medicine, and director of the Institute for Molecular Cardiology at the Renaissance School of Medicine at Stony Brook University; and Xiaoqin Zou, professor of physics, biochemistry, and a member of the Dalton Cardiovascular Research Center and Institute for Data Science and Informatics at the University of Missouri.

The drugs in question, as well as several that have been pulled from the market, cause a prolongation of the QT interval of the heartbeat, known as acquired Long QT Syndrome, that predisposes patients to cardiac arrhythmia and sudden death. In rare cases, Long QT also can be caused by specific mutations in genes that code for ion channel proteins, which conduct the ionic currents to generate the action potential. Although there are several types of ion channels in the heart, a change in one or more of them may lead to this arrhythmia, which contributes to about 200,000 to 300,000 sudden deaths a year, more than deaths from stroke, lung cancer or breast cancer.

The team selected a specific target, IKs, for this work because it is one of the two potassium channels that are activated during the action potential: IKr (rapid) and IKs (slow).

"The rapid one plays a major role in the action potential," said Cohen, one of the world's top electrophysiologists. "If you block it, Long QT results, and you get a long action potential. IKs is very slow and contributes much less to the normal action potential duration."

It was this difference in roles that suggested that increasing IKs might not significantly affect normal electrical activity but could shorten a prolonged action potential.

Cui, an internationally renowned expert on ion channels, and the team wanted to determine if the prolongation of the QT interval could be prevented by compensating for the change in current and inducing the Long QT Syndrome by enhancing IKs. They identified a site on the voltage-sensing domain of the IKs potassium ion channel that could be accessed by small molecules.

Zou, an internationally recognized expert who specializes in developing new and efficient algorithms for predicting protein interactions, and the team used the atomic structure of the KCNQ1 unit of the IKs channel protein to computationally screen a library of a quarter of a million small compounds that targeted this voltage-sensing domain of the KCNQ1 protein unit. To do this, they developed software called MDock to test the interaction of small compounds with a specific protein in silico, or computationally. By identifying the geometric and chemical traits of the small compounds, they can find the one that fits into the protein -- sort of a high-tech, 3D jigsaw puzzle. While it sounds simple, the process is quite complicated as it involves charge interactions, hydrogen bonding and other physicochemical interactions of both the protein and the small compound.

"We know the problems, and the way to make great progress is to identify the weaknesses and challenges and fix them," Zou said. "We know the functional and structural details of the protein, so we can use an algorithm to dock each molecule onto the protein at the atomic level."

One by one, Zou and her lab docked the potential compounds with the protein KCNQ1 and compared the binding energy of each one. They selected about 50 candidates with very negative, or tight, binding energies.

Cui and his lab then identified C28 using experiments out of the 50 candidates identified in silico by Zou's lab. They validated the docking results by measuring the shift of voltage-dependent activation of the IKs channel at various concentrations of C28 to confirm that C28 indeed enhances the IKs channel function. They also studied a series of genetically modified IKs channels to reveal the binding of C28 to the site for the in silico screening.

Cohen and his lab tested the C28 compound in ventricular myocytes from a small mammal model that expresses the same IKs channel as humans. They found that C28 could prevent or reverse the drug-induced prolongation of the electrical signals across the cardiac cell membrane and minimally affected the normal action potentials at the same dosage. They also determined that there were no significant effects on atrial muscle cells, an important control for the drug's potential use.

"We are very excited about this," Cohen said. "In many of these medications, there is a concentration of the drug that is acceptable, and at higher doses, it becomes dangerous. If C28 can eliminate the danger of inducing Q-T prolongation, then these drugs can be used at higher concentrations, and in many cases, they can become more therapeutic."

While the compound needs additional verification and testing, the researchers say there is tremendous potential for this compound or others like it and could help to convert second-line drugs into first-line drugs and return others to the market. With assistance from the Washington University Office of Technology Management, they have patented the compound, and Cui has founded a startup company, VivoCor, to continue to work on the compound and others like it as potential drug candidates. The work was accelerated by a Leadership and Entrepreneurial Acceleration Program (LEAP) Inventor Challenge grant Washington University in St. Louis in 2018 funded by the Office of Technology Management, the Institute of Clinical and Translational Sciences, the Center for Drug Discovery, the Center for Research Innovation in Biotechnology, and the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship.

"This work was done by an effective drug design approach: identifying a critical site in the ion channel based on understanding of structure-function relation, using in silico docking to identify compounds that interact with the critical site in the ion channel, validating functional modulation of the ion channel by the compound, and demonstrating therapeutic potential in cardiac myocytes," Zou said. "Our three labs form a great team, and without any of them, this would not be possible."

Credit: 
Washington University in St. Louis