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CLEVELAND--A team led by Case Western Reserve University medical researchers has developed a potential treatment method for Pelizaeus-Merzbacher disease (PMD), a fatal neurological disorder that produces severe movement, motor and cognitive dysfunction in children. It results from genetic mutations that prevent the body from properly making myelin, the protective insulation around nerve cells.

Using mouse models, the researchers identified and validated a new treatment target--a toxic protein resulting from the genetic mutation. Next, they successfully used a family of drugs known as ASOs (antisense oligonucleotides) to target the ribonucleic acid (RNA) strands that created the abnormal protein to stop its production. This treatment reduced PMD's hallmark symptoms and extended lifespan, establishing the clinical potential of this approach.

By demonstrating effective delivery of the ASOs to myelin-producing cells in the nervous system, researchers raised the prospect for using this method to treat other myelin disorders that result from dysfunction within these cells, including multiple sclerosis (MS).

Their research was published online July 1 in the journal Nature.

"The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment," said Paul Tesar, principal investigator on the research, a professor in the Department of Genetics and Genome Sciences at the School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics. "Our results open the door for the development of the first treatment for PMD as well as a new therapeutic approach for other myelin disorders."

Study co-authors include an interdisciplinary team of researchers from the medical school, Ionis Pharmaceuticals Inc., a Carlsbad, California-based pioneer developer of RNA-targeted therapies, and Cleveland Clinic. First author Matthew Elitt worked in Tesar's lab as a Case Western Reserve medical and graduate student.

PMD attacks the young

PMD is a rare, genetic condition involving the brain and spinal cord that primarily affects boys. Symptoms can appear in early infancy and begin with jerky eye movements and abnormal head movements. Over time, children develop severe muscle weakness and stiffness, cognitive dysfunction, difficulty walking and fail to reach developmental milestones such as speaking. The disease cuts short life-expectancy, and people with the most severe cases die in childhood.

The disease results from errors in a gene called proteolipid protein 1 (PLP1). Normally, this gene produces proteolipid protein (PLP) a major component of myelin, which wraps and insulates nerve fibers to allow proper transmission of electrical signals in the nervous system. But a faulty PLP1 gene produces toxic proteins that kill myelin producing cells and prevent myelin from developing and functioning properly--resulting in the severe neurological dysfunction in PMD patients.

PMD impacts a few thousand people around the world. So far, no therapy has lessened symptoms or extended lifespans.

For nearly a decade, Tesar and his team have worked to better understand and develop new therapies for myelin disorders. They have had a series of successes, and their myelin-regenerating drugs for MS are now in commercial development.

Latest research

In the current laboratory work, the researchers found that suppressing mutant PLP1 and its toxic protein restored myelin-producing cells, produced functioning myelin, reduced disease symptoms and extended lifespans.

After validating that PLP1 was their therapeutic target, the researchers pursued pre-clinical treatment options. They knew mutations in the PLP1 gene produced faulty RNA strands that, in turn, created the toxic PLP protein.

So they teamed with Ionis Pharmaceuticals, a leader in RNA-targeted therapeutics and pioneer of ASOs. These short strings of chemically modified DNA can be designed to bind to a specific RNA target and block production of its protein product.

And that's exactly what happened in their studies. The result was improved myelin and locomotion, and substantial extension of lifespan. "ASOs provided an opportunity to cut the disease-causing protein off at its source," Elitt said.

The successful clinical use of ASOs is relatively new, yet recent developments seem promising. In 2016, the U.S. Food and Drug Administration approved the first ASO drug for a neurological disorder, spinal muscular atrophy. The drug, Spinraza, was developed by Ionis and commercialized by Biogen Inc. More ASO therapies are in development, and clinical trials and hold promise for addressing many neurological diseases that as of now have no effective treatment options.

Tesar said that ongoing and planned experiments in his laboratory will help guide future clinical development of ASO therapy for PMD. For example, researchers want to understand more about how well the treatment works after the onset of symptoms, how long it lasts, how often treatment needs to be given and whether it might be effective for all PMD patients, regardless of their specific form of the disease.

"While important research questions remain, I'm cautiously optimistic about the prospect for this method to move into clinical development and trials for PMD patients," Tesar said. "I truly hope our work can make a difference for PMD patients and families."

A new, ultra-rapid formulation of insulin reached peak activity in pigs with diabetes about twice as fast as a commercially available option, according to new research. The formulation, which peaked in as little as 9 minutes, could improve quality-of-life for patients with diabetes by allowing them to more quickly manage their blood sugar levels during mealtimes. Type 1 diabetes is one of the most common chronic conditions, affecting about 40 million people around the world. Patients with diabetes usually receive routine injections of insulin to control their blood sugar levels, but current insulin formulations suffer from various drawbacks. For example, even fast-acting insulin treatments can take as long as 90 minutes to peak in activity, making them less than ideal for patients who need quick and effective blood sugar control during mealtimes. Here, Joseph Mann and colleagues designed a faster-acting insulin formulation based on polymer excipients, compounds that maintain the insulin in a less aggregated form that more closely mimics how the hormone is naturally released in the body. The scientists used a high-throughput screen to evaluate various excipients, and integrated the top-performing candidate into an insulin formulation named UFAL. When injected into pigs with diabetes, the new formulation reached peak activity in 9 minutes - twice as fast as the commercially available insulin formulation Humalog, which peaked in 25 minutes. Furthermore, UFAL was safe in rats and outperformed Humalog and similar rapid-acting insulin analogs in a model that simulates drug activity in humans. The authors caution that more work is needed to pin down their formulation's activity and safety in people, as pigs show different insulin dynamics compared with humans.

What The Study Did: The clinical findings of four children who experienced neurological symptoms associated with COVID-19 are presented in this case series.

Authors: Yael Hacohen, M.D., Ph.D., of University College London, 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/jamaneurol.2020.2687)

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

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Media advisory: The full study is linked to this news release.

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What The Viewpoint Says: The need for and implementation of telemedicine for patients with substance use disorder in the era of COVID-19 is discussed in this Viewpoint.

Authors: Lewei (Allison) Lin, M.D., M.S., of the University of Michigan in Ann Arbor, 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.2020.1698)

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Media advisory: The full article is linked to this news release.

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Adults who meet recommended weekly physical activity levels have a lower risk of death, finds a US study published by The BMJ today.

The survival benefits are similar regardless of intensity of activity, although they are slightly higher for vigorous than light to moderate activity, the findings show.

Inadequate physical activity is a worldwide public health issue. It has been estimated that physical inactivity was responsible for 6-10% of the global burden of major chronic non-communicable diseases and 9% of early deaths in 2008 at a cost of $53.8 billion to healthcare systems worldwide in 2013.

Growing evidence that physical activity may prevent many chronic diseases and reduce mortality has led to governments setting out recommended activity levels.

The 2018 US guidelines recommend at least 150 minutes of moderate intensity, or at least 75 minutes of vigorous intensity aerobic activity per week. They also suggest adults should engage in muscle strengthening activity of moderate or greater intensity on at least two days per week.

But evidence that meeting these recommendations is linked to reduced mortality is unclear.

So an international team of researchers set out to determine the association between sufficient physical activity according to the 2018 US guidelines and death from any cause as well as eight specific causes including cardiovascular disease (CVD), cancer, chronic lower respiratory tract diseases, accidents and injuries, Alzheimer's disease, and diabetes.

Their findings are based on 479,856 US adults aged 18-85 years who reported the amount of leisure time spent in aerobic physical activity and muscle strengthening activity per week as part of the National Health Interview Surveys from 1997 to 2014.

This data was then linked to national death records over an average of nearly nine years.

During the study period, only 16% (76,384) participants fully met the recommended activity levels and 59,819 participants died.

Compared with participants who did not meet the recommended activity levels, those who engaged in sufficient muscle strengthening activity had an 11% lower risk of death from any cause, while those who engaged in sufficient aerobic activity had a 29% lower risk of death from any cause.

Those who fully met the recommended activity levels - both sufficient muscle strengthening and aerobic activities - achieved even larger survival benefits (40% lower risk of death from any cause).

In addition, adults who engaged in sufficient aerobic activity were at reduced risk of death from all eight specific causes, while those who engaged in sufficient strengthening activity were at reduced risk of death from three causes (CVD, cancer, and chronic lower respiratory tract disease).

This is an observational study, so can't establish cause, and relied on participants self-reporting activity levels. But the authors also point out some strengths, including the large sample size representative of the US population, and their ability to adjust for potentially influential factors, such as lifestyle and underlying conditions.

"Our findings support that the physical activity levels recommended in the 2018 physical activity guidelines for Americans provide important survival benefits," they write. "Additionally, in accordance with the guidelines, more physical activity than the minimum recommendation could provide greater health benefits."

What The Study Did: This online survey study investigated how common were symptoms of depression, anxiety, insomnia and acute stress and potential risk factors in the general population in China during the COVID-19 pandemic.

Authors: Yan-Ping Bao, Ph.D., and Lin Lu, M.D., Ph.D., of Peking University in Beijing, are the corresponding authors.

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

(doi:10.1001/jamanetworkopen.2020.14053)

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

The immune system protects our body from constant attack by viruses, bacteria, and other pathogens. Much of this protection is provided by hematopoietic immune cells, which are derived from the bone marrow and specialize in fighting pathogens. They include macrophages, which remove pathogens; T cells, which kill infected virus-producing cells; and B cells producing antibodies that neutralize pathogens. However, immune functions are not restricted to these "specialists", and many more cell types are able to sense when they are infected and contribute to the immune response against pathogens.

Structural cells provide essential building blocks of the body and play an important role in shaping the structure of tissue and organs. Most notably, epithelial cells constitute the surface of the skin, while also separating tissues and organs from each other; endothelial cells coat the inside of all blood vessels; and fibroblast provide the connective tissue that keeps tissues and organs in shape. Structural cells are often regarded as simple and rather uninteresting components of the body, despite their well-established roles in autoimmune diseases (such as rheumatoid arthritis and inflammatory bowel disease) and in cancer. In their new study, Thomas Krausgruber, Nikolaus Fortelny and colleagues in Christoph Bock's laboratory at CeMM focused on elucidating the role of structural cells in immune regulation by pursuing a systematic, genome-wide analysis of epigenetic and transcriptional regulation of structural cells in the body.

To that end, the CeMM researchers established a comprehensive catalog of immune gene activity in structural cells, applying high-throughput sequencing technology (RNA-seq, ATAC-seq, ChIPmentation) to three types of structural cells (epithelium, endothelium, fibroblasts) from twelve different organs of healthy mice. This dataset uncovered widespread expression of immune genes in structural cells as well as highly cell-type-specific and organ-specific patterns of gene regulation. Bioinformatic analysis detected genes that control a complex network of interactions between structural cells and hematopoietic immune cells, indicating potential mechanisms by which structural cells contribute to the response to pathogens.

Interestingly, many immune genes showed epigenetic signatures that are normally associated with high gene expression, while the observed expression in structural cells obtained from healthy mice was lower than expected based on their epigenetic signatures. CeMM researchers therefore hypothesized that these genes are epigenetically pre-programmed for rapid upregulation when their activity is needed - for example in response to a pathogen. To test this hypothesis, they joined forces with Andreas Bergthaler's laboratory at CeMM, capitalizing on their expertise in viral immunology and infection biology.

When the mice were infected with a virus (LCMV) that triggers a broad immune response, many of those genes that were epigenetically poised for activation became upregulated and contributed to the transcriptional changes that structural cells showed in response to viral infection. These results suggest that structural cells implement an "epigenetic potential" that pre-programs them to engage in rapid immune responses. As an additional validation, the researchers triggered an artificial immune response by injecting cytokines into mice, and they indeed found that many of the same genes were upregulated.

The new study has uncovered a striking complexity of immune gene regulation in structural cells. These results highlight that structural cells are not only essential building blocks of the body, but also contribute extensively to its defense against pathogens. Moreover, the presented data constitute an important first step toward understanding what "structural immunity" might mean for the immune system, and it may help develop innovative therapies for some of the many diseases that involve the immune system.

According to the researchers, the study shows that spending cuts to alcohol services represent a false economy since decreases in expenditure are linked to increased hospital admissions which inevitably are costly to society and the economy.

In March 2012 the Health and Social Care Act (HSCA) transferred the responsibilities of commissioning specialist drug and alcohol services from the NHS to local authorities. In 2018 there were nearly 25,000 deaths related to alcohol in England, and data collected during the COVID-19 pandemic has shown that nearly one in five daily drinkers have further increased the amount they drink since lockdown (Alcohol Change UK, 2020).

Published in The British Journal of Psychiatry, the study showed an association between the level of spending on treatments for alcohol misuse at the local authority level and the number of alcohol related hospital admissions since the HSCA has come into force.

According to the analysis, if the average local authority reduced its net annual spending by 5 per cent on treatment for those with alcohol misuse problems there would be an expected associated average increase of 60 alcohol related hospital admissions for that local authority per 100,000 people per year. To put this reduction in spending into context 5 per cent of annual expenditure per local authority is on average 18p per person.

This is the first study known to assess the relationships between alcohol-related hospitalisations, the provision of specialist alcohol treatment and money spent on alcohol services at the local authority level in England. This in turn has been affected by reductions in the government's public health grant to local authorities.

Lead author Dr Emmert Roberts from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) King's College London said: 'Our results show that the rate of alcohol related hospital admissions is associated with a reduction in net spending for treatment of alcohol misuse, suggesting that local authority funding cuts to specialist alcohol treatment services may be displacing costs onto the NHS hospital system. The drug and alcohol budget may be seen as easier to cut than other local authority budgets especially as they are now not protected by ringfencing. An average reduction in spend of 18p per person appears to have large consequences on the number of people needing hospital treatment for problems relating to alcohol.'

The study analysed data from 2012 to 2019 on the expenditure on alcohol services, the provision of specialist alcohol treatment and the level of alcohol related hospitalisation from 152 local authorities in England. The study showed that, since the HSCA was passed, on average local authorities have decreased annual net spending on treatment for alcohol misuse treatment by £147 per 1000 people and the net spending for prevention and reducing alcohol misuse by £88 per 1000 people.

On average the number of hospitalisations where either the main reason for admission or one of the secondary diagnoses is an alcohol-related condition has increased by about 60 per 100,000 population per year, according to the study.

Researchers found a large variation in the figures between local authorities, and several authorities with the largest average number of alcohol related hospital admissions also showed the largest net spending cuts for alcohol misuse treatment. For example, one local authority had one of the highest average increases in alcohol related hospital admissions at 107 per 100,000 people per year, but also one of the largest decreases in expenditure for alcohol misuse treatment at £1,820 per 1000 people per year.

Dr Roberts commented: 'Our study indicates that local authority areas in England most in need of adequately funded specialist alcohol treatment due to high levels of alcohol dependence and deprivation are not receiving targeted increases in funding, and that the national rise that we are seeing in alcohol-related hospitalisations may be fuelled by cuts to specialist alcohol treatment services.'

Senior author, Professor Colin Drummond from the IoPPN said: 'Our study shows a relationship between the spending cuts for alcohol services and alcohol-related hospital admissions and, as 1 in 10 people in hospital have alcohol dependence, we believe these cuts represent a false economy.

'Alongside this the COVID-19 pandemic has implications for alcohol services since research shows a general increase in alcohol consumption and that those already drinking heavily have increased their alcohol intake. This combined with significant reduction in support from specialist alcohol treatment services due to social distancing, is likely to produce an increase in demand for services as the pandemic progresses. With alcohol treatment services already depleted due to cuts to the local authority's public health grants, they will be ill equipped to respond to a surge in demand.'

This research was supported by the Medical Research Council (MRC) and part funded by the National Institute of Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, and the NIHR Applied Research Collaboration South London at King's College Hospital NHS Foundation Trust.

Real-world mobile phone data suggests a decline in the number of trips people made per day began before state-level stay-at-home policies were implemented, and the decline was strongly correlated with a reduction of COVID-19 case growth in the 25 most affected counties across the USA, according to a modelling study published in The Lancet Infectious Diseases journal.

The authors say their analysis supports the role of social distancing as an effective way to control the spread of COVID-19 in the USA until a vaccine is available. However, they note the study does not account for other infection control measures (eg, wearing face masks and handwashing), which are also likely to have contributed to the decline in the case growth rate during March.

Dr Lauren M Gardner, Johns Hopkins University, USA, says, "Our results strongly support the conclusion that social distancing played a crucial role in the reduction of case growth rates in multiple US counties during March and April, and is therefore an effective mitigation policy for COVID-19 in the USA . Critically, we also found that behavioural changes were already underway in many US counties days to weeks before state-level or local-level stay-at-home policies were implemented." [2]

She continues: "If individual-level actions were not taken and social distancing behaviour was delayed until the state-level directives were implemented, COVID-19 would have been able to circulate unmitigated for additional weeks in some locations, inevitably resulting in more infections and deaths. This demonstrates that it is within the power of each US resident to help slow the spread of COVID-19." [2]

Within the first four months of COVID-19 being reported in the USA, the virus spread to every state and to more than 90% of counties. The policy response was highly decentralised during this period - when and how county and state-level stay-at-home policies were implemented varied significantly, making the effectiveness of social distancing difficult to assess.

This study uses real-world mobile phone movement data as an indicator of social distancing. It compares local case growth with how individuals actually modified their movement patterns, rather than relying on assumed compliance with local stay-at-home policies.

Daily mobility data was taken from mobile network records between Jan 1 to April 20, 2020, to capture trends in movement patterns for each US county, and compared to baseline patterns before COVID-19 (Jan 8 to Jan 31, 2020) to generate a social distancing metric. [3] Additionally, a COVID-19 daily growth rate ratio was calculated for each county, using local epidemiological data on recorded cases (starting from Mar 16 after more widespread testing was underway).

Using these metrics, the authors created statistical models that evaluated how social distancing (measured by relative change in movement patterns) affected the rate of new infections in each of the 25 counties in the USA with the highest number of confirmed COVID-19 cases on April 16, 2020.

For all 25 most affected counties, the correlation between movement patterns and case growth was significant, with the correlation considered strong for 20 of the 25 counties.

From Jan 24 to April 17, 2020, mobility dropped to 35-63% of the normal patterns in the 25 most affected counties - ranging from 35% of normal levels of movement in New York City to 63% in Harris County.

There was a lag of 9-12 days before the effects of decreases in movement were observed on COVID-19 transmission, which is in line with expectations after accounting for the time for symptoms to manifest after infection, worsen, and be reported.

Individuals began to reduce their movement in early March, indicating social distancing began well before the first US state-level stay-at-home directive (implemented by California on March 21). While this could partly be explained by some county-level policies that were put in place before state-level ones, the initial decline in movement began in 21 out of 25 counties before any formal regulation (including county-level) was put in place.

Although social distancing has consistently been shown to have positive effects on COVID-19 transmission in China, the authors say that their work extends these results to the USA.

Moving forward, they note that practices such as handwashing, face mask use, and self-isolation when people get sick, may become more widespread and help in controlling the virus, but stress that social distancing will remain one of the most important ways to control the spread infections until a vaccine is available.

Co-author Dr Hamada Badr, Johns Hopkins University, USA, says, "Individuals seem to have anticipated public health directives in March and April, despite a mixed political message. As stay-at-home policies begin to relax, we urge individuals and governments to make safe and data-driven decisions, to respond to the potential risk of increased infections. More timely, consistent and decisive policy implementation of social distancing and other known effective mitigation measures is urgently needed." [2]

The authors note some additional limitations of their study. They were unable to differentiate between low-risk and high-risk trips involved in the movement patterns, so they acknowledge that their social distancing metric does not account for this. For example, multiple trips alone to a park are probably lower risk than a single trip to a grocery store (without using other physical distancing strategies, such as wearing a face mask). They also note that there may be errors in the case data due to reporting issues and limited COVID-19 testing capacity.

Light pollution is increasingly being recognized as yet another of humanity's many impacts on the rest of the natural world. Artificial light at night, or "ALAN" to use the researchers' name for the phenomenon, can alter foraging behavior, migration patterns, mortality rates and even the very physical structure of animals.

But there has been little research into the effect of ALAN on invasive species--species that are not indigenous, or native, to an area--which can sometimes cause significant economic and ecological damage.

However, as anyone who has a porch light can see, nocturnal insects such as moths, flies and beetles are attracted to this artificial light. These invertebrates are food sources for nocturnal predators such as bats, birds and frogs--including what is perhaps the most iconic invasive species of all time, the cane toad.

Cane toads feed on nocturnal insects, and Assistant Professor Hirotaka Komine with Tokyo University of Agriculture and Technology (TUAT) along with their colleagues from Australia's James Cook University wanted to find out whether the artificially large food source that ALAN makes available in a particular location had any impact on the cane toad.

They published their findings on April 16 in Scientific Reports.

They set up six outdoor enclosures, each with an artificial light attached, in different rural areas around Townsville, Queensland. They then placed cane toads that they had locally captured in the enclosures just before sunset. After the toads had feasted overnight on whatever invertebrate delectable treats had been attracted to the ALAN, the toads were euthanized and dissected to measure the contents of their bellies.

The researchers varied the amount of light, and controlled for the affects of rainfall, wind speed, and temperature, which also have an impact on the availability of sources of food. They found that when the lights were on, the percentage of flying insects that the toads consumed increased significantly.

But the toads did not eat as many flying bugs when the moon was bright. The same reduction in bug consumption happened in those areas that were closer to urban areas that already suffered from ample ambient ALAN. In both cases, the extra light diluted the impact of the lamps the researchers had set up.

"This tells us that in order to control the growth of this invasive species," said conservation biologist Hirotaka Komine. "More careful management of artificial light in rural areas such as that from highway lampposts or scattered buildings, could go a long way in reducing the food resources available."

The researchers added that light management approaches should also consider the lunar cycle, such as reducing light use where possible during dark lunar phases.

Stamp-sized device comprises a suite of clinical-grade sensors, including temperature and pulse oximetry

Device sits at the base of the throat to pick up vibratory signatures of breathing, coughing, swallowing

Since developing the device, researchers have tested it on more than 50 physicians, rehabilitation specialists and patients at Shirley Ryan AbilityLab and Northwestern Memorial Hospital

Researcher: 'We are already seeing clear vital sign differences collected by the sensor between patients with COVID-19 and healthy-matched controls'

Research group has partnered with BARDA to continue developing and deploying the device to help fight the pandemic

EVANSTON, Ill. -- Although it might be tempting to rely on your fitness tracker to catch early signs of COVID-19, Northwestern University researchers caution that consumer wearables are not sophisticated enough to monitor the complicated illness.

The Northwestern team, led by bioelectronics pioneer John A. Rogers, published a perspective today (July 1) in the journal Science Advances, in which they differentiate between popular consumer electronics and clinical-grade monitoring systems.

Rogers co-authored the perspective with Dr. Shuai Xu, a Northwestern Medicine dermatologist, and Hyoyoung Jeong, a postdoctoral fellow in the Rogers lab.

"According to the Journal of the American Medical Association, the three most important early symptoms for COVID-19 are fever, shortness of breath and coughing," Rogers said. "For a wearable technology, you want to track those key symptoms. A conventional wearable device, such as a fitness tracker, sits on the wrist or finger -- not the anatomical location that is most relevant to COVID-19."

This past spring, the Rogers group and researchers at Shirley Ryan AbilityLab introduced a novel wearable device and set of data algorithms specifically tailored to catch early signs and symptoms associated with COVID-19 and to monitor patients as the illness progresses. About the size of a postage stamp, the soft, flexible, wireless device sits just below the suprasternal notch, the visible dip at the base of the throat -- an ideal location for monitoring respiratory health.

More recently, Rogers' team added a wearable, flexible pulse oximeter to pair with the suprasternal-mounted device. This allows physicians to continuously monitor for silent hypoxia, an often asymptomatic feature marked by alarmingly low blood oxygen levels. Adding this feature will help the device, and accompanying algorithms, give a fuller picture of the disease's onset, progression and response to treatment.

"The device measures very tiny vibrations on the skin and has an embedded temperature sensor for fever," Rogers said. "As you cough and breathe, it counts coughs, monitors the intensity of cough and senses labored breathing. The location on the throat also is close enough to the carotid artery that it can measure mechanical signatures of blood flow, monitoring heart rate."

"This sensor system targets key symptoms for COVID-19, with the goal to identify the infection earlier in patients," Xu said. "It's a suite of clinical-grade sensors wrapped into one small device. And once it's placed on the throat, people don't even realize that it's there."

Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Biomedical Engineering in Northwestern's McCormick School of Engineering, professor of neurological surgery at Northwestern University Feinberg School of Medicine and director of the Querrey Simpson Institute for Bioelectronics (QSIB).

Xu is an assistant professor of dermatology at Feinberg and of biomedical engineering at McCormick. He also is the medical director of QSIB.

Differences between COVID-19 patients and healthy controls

Since launching the device in April, the team has tested it on 52 COVID-19-positive physicians, nurses, rehabilitation specialists and patients at Shirley Ryan AbilityLab and Northwestern Memorial Hospital. The device was tested both in the hospital and in the home.

From these tests, Rogers and his team have collected 3,000 hours of data, which will continue to strengthen the device's algorithms. Eventually, the machine-learning algorithms will become smart enough to distinguish between a COVID-like cough and more benign coughs from allergies, colds or dryness. The team expects to test 500 subjects by the end of the year.

"We are already seeing clear vital sign differences collected by the sensor between patients with COVID-19 and healthy-matched controls," said Arun Jayaraman, a researcher assistant scientist at Shirley Ryan AbilityLab, who leads the algorithm development. "We're working together to develop predictive algorithms for detecting the disease earlier."

Thoracic surgeon remotely monitors patients

Dr. Ankit Bharat, chief of thoracic surgery at Northwestern Medicine who performed the first double-lung transplant on a COVID-19 patient in the United States, is actively testing the device on his pulmonary patients. The device wirelessly transmits data to a HIPAA-protected cloud, where automated algorithms produce graphical summaries tailored to facilitate rapid, remote monitoring. This allows Bharat to continue monitoring his patients well after they have been dismissed from the hospital.

"It has provided valuable information about each patient's respiratory status," Bharat said. "We hope that as we gain experience with this device, it will greatly enhance our ability to monitor patients remotely. Under the circumstances of the pandemic, remote monitoring capabilities improve efficiency in medical care while increasing protection to health care workers against the virus."

Continued research and deployment

To accelerate manufacturing and deployment, Rogers and Xu launched technology startup Sonica Health, based on intellectual property (IP) jointly developed by Northwestern and the Shirley Ryan AbilityLab. The IP related to this project has been optioned through Northwestern's Innovation and New Ventures Office. The effort is supported by the Biomedical Advanced Research Deployment Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services.

Sonica Health previously partnered with BARDA for technology focused on chronic obstructive pulmonary disease (COPD). Now the partnership has expanded to focus on early detection of COVID-19 and other respiratory infections in high-risk clinical populations and, in collaboration with another spinout from QSIB, Sibel Health, to provide the pulse oximetry sensor.

With BARDA's support, Sonica Health and Sibel Health will jointly submit the device and associated algorithms for Food and Drug Administration (FDA) approval later this month. The overall goal is an FDA-cleared platform that gives an early warning of COVID-19 contraction, helping reduce the transmission of the virus.

The study states that failing to encourage tourists to do more on behalf of wildlife represents a missed opportunity for conservation. "We argue that the combination of emotional engagement and knowledge-driven action provided by wildlife-based tours will pave the way for a new area of conservation-oriented tourism" says Dr. Alvaro Fernández-Llamazares, the lead-author of the study from the University of Helsinki.

"Some years ago I took a whale-watching tour in Iceland, and it surprised me to see that while the guide provided very detailed information about the ecology, life cycle and foraging habits of whales, she did not mention any single time the huge conservation threats that these animals are facing. My colleagues had noticed similar patterns in other corners of the world. Concerned about this, we decided to thoroughly review the academic literature on wildlife-based tourism and examine to which extent was conservation messaging lacking in wildlife-based tours," explains Dr. Fernández-Llamazares.

The authors carried out a comprehensive review of the academic literature on wildlife-based tourism, finding out that indeed conservation messaging is virtually absent from many mainstream wildlife-based tourism operations. Operators often fail to give information on wildlife conservation and opportunities for tourists to engage in conservation action.

Whale-watching tour in Húsavík (Iceland). Information on cetacean conservation and threats to the marine environment is argued to be limited in many whale-watching tours. Credit: Á. Fernández-Llamazares.

"There is increasing research evidence that wildlife-based tourism could help to transform the environmental knowledge, attitudes and behaviours of tourists through first-hand encounters with wildlife, complemented by effective conservation messaging," says Dr. Fernández-Llamazares. "However, such conservation messaging is not always a priority for many wildlife-based tourism operators, who often fail to provide a well-designed environmental interpretation".

Tools to engage tourists in wild-life conservation

The study documents new avenues that are broadening the potential of wildlife-based tourism, using alternative forms of communicating conservation-related messages. For example, empirical research shows that combining the emotional response of viewing wildlife with the educational benefits of a tailored interpretative programme provides tourism operators with numerous opportunities to cultivate the conservation potential of a tourism experience.

"I have experienced it myself: when you have the opportunity to see wildlife in situ, it creates a deep emotional connection between you and wildlife. However, as tourists we do not always have the tools to act beyond that experience, to transform the emotional bonds towards environmental stewardship," says Aina Brias-Guinart, co-author of the study from the University of Helsinki. "For this reason, in this study, we thought of a set of principles that wildlife-based tourism operators could use to maximize the conservation potential of the tourist experience".

The study introduces a toolbox of ideas for improving the conservation messaging of wildlife-based tourism operations, based on five principles: promote positive messaging, provide actionable information, engage tourists in research and practice, link experience with consumption choices and foster long-term interactions. These ideas focus on amplifying the emotional engagement among tourists participating in wildlife-based tours, and on empowering them to take purposeful conservation action.

While scientists still don't fully understand the diverse nature of RNA molecules, it is believed that the proteins binding to them, called RNA-binding proteins, are associated with many disease formation. A research led by biomedical scientists from City University of Hong Kong (CityU) has developed a novel detection method, called CARPID, to identify binding proteins of specific RNAs in the living cells. It is expected the innovation can be applied in various cell researches, from identifying biomarkers of cancer diagnosis to detecting potential drug targets for treating viral diseases.

The research was co-led by Dr Yan Jian, Dr Zhang Liang, and Dr Chan Kui-ming who are all from the Department of Biomedical Sciences (BMS) at CityU, in collaboration with scientists mainly from Northwest University in Xi'an. Their findings were published in the scientific journal Nature Methods, titled "CRISPR-assisted detection of RNA-protein interactions in living cells".

Binding proteins determine RNA functions

The central dogma of molecular biology suggests that DNA is transcribed to RNA and RNA is translated into protein. But actually, only about 2% of RNAs code for protein. The rest 98%, named as non-coding RNAs (ncRNA) has been regarded as "dark matter" for their yet mysterious functions.

In recent years, scientists have put many efforts into unveiling their actual functions, especially the long non-coding RNAs (lncRNA, meaning ncRNA with more than 200 nucleotides in length). LncRNA has become widely accepted as important cellular components participating in the regulation of gene expression. "LncRNA is the most interesting RNA species", described Dr Yan. It is also the reason why the team has chosen lncRNA as the research subject.

Although lncRNA will not produce protein, they will react with proteins, and the interaction will determine their functions. Therefore, the identification of the binding proteins is crucial in understanding the lncRNA functions. However, current methods demonstrate quite some limitations, for example generating false positive signals, and cannot be done in living cells.

Two steps of CARPID: navigation and biotin-labelling

To overcome the limitations of the existing method, the research team came up with a novel method that jointly leverages the existing state-of-the-art gene-editing technology CRISPR/dCasRx system for RNA targeting, and the proximity biotin-labelling technology to identify the protein-protein interactions in living cells.

The team named the novel method CARPID, short for CRISPR-Assisted RNA-Protein Interaction Detection. "CARPID can sensitively detect binding proteins of RNAs in any lengths or concentrations whereas most other methods can only be applied to very long non-coding RNAs," said Dr Yan.

The method is composed of two parts: navigation and proximity biotin-labelling. First, the team employed the CRISPR/CasRx system to navigate so that the CARPID components, including a "labelling tool" called BASU, can be near the targeted RNA. BASU is an engineered biotin ligase, a kind of enzyme that would add biotin (a kind of vitamin with strong binding) to proteins that bind with that targeted RNA. In this way, those proteins which are near the targeted RNA would be labelled.

After the "labelling", the team then used a biotin-binding protein called streptavidin to identify those proteins labelled by BASU. In this way, the binding proteins were revealed easily.

High specificity and applicability for lncRNAs of different lengths

To test the specificity of CARPID, the team applied it on three different lncRNAs, namely DANCR, XIST, and MALAT1. Experiment results showed that there was not much overlapping of binding proteins. This demonstrated the high specificity and applicability of the CARPID method for lncRNAs of different lengths and expression levels.

"This high level of specificity is achieved because the navigation by CRISPR is very precise. We can even obtain the information of exactly which section of the RNA that protein binding occurred," explained Dr Yan.

Also, CARPID would not affect the physiological condition of the targeted cell, and the cell is still alive with normal gene expression landscape after the whole process. "With this new method, we can obtain dynamic results if we check the same RNA target at different times," added Dr Zhang.

Powered by the proteomic (analysis of the protein) technique developed by Dr Zhang, the team was able to find and validate two previously uncharacterized binding proteins of a lncRNA in mammalian cells.

Enables detection of the binding proteins of viral RNA

The team believed CARPID has broad application, including the detection of the binding proteins of viral RNA. "For example, SARS-CoV-2 is an RNA virus that causes COVID-19. Once the virus infects cells, we could apply CARPID to detect what cellular proteins are recruited by this virus for the viral life cycle. If we depleted the binding proteins, we are likely to suppress the viral replication. This information may help us identify potential antiviral drug targets," Dr Yan elaborated.

Moreover, many lncRNAs are used as diagnostic biomarkers for cancer as they become more abundant in cancer cells than normal cells. CARPID can be applied to detect the binding proteins of these lncRNAs in cancer cells which may help find tumorigenic mechanisms and potential protein targets for cancer diagnosis or treatment.

It took the team about one year to develop CARPID and most of the experiments were done in CityU. Their next step would be trying to apply it to research on stem cell and DANCR, a lncRNA that generally works as a tumour promoter.

When Alzheimer's disease strikes, the entire brain doesn't crumble at once. Instead the mind unravels like grim clockwork, beginning with the telltale degradation of a group of brain cells in the entorhinal cortex. These so-called vulnerable neurons are responsible for shuttling experiences into memories. They are always the first to go.

Figuring out why patients lose these vulnerable neurons early on could be the key to discovering novel treatments for Alzheimer's. Now, a new study sheds light on the inner workings of this subset of neurons and describes the molecular factors that render entorhinal brain cells uniquely sensitive to degeneration.

"If we can understand the peculiarities of the brain's most vulnerable neurons, we can potentially open up new avenues for treatment," says Jean-Pierre Roussarie, senior research associate in the late Paul Greengard's Laboratory of Molecular and Cellular Neuroscience, who published the findings in Neuron.

"The smushy bowl of the brain"

So far, attempts to develop a treatment for Alzheimer's have largely failed. But most efforts undertaken have centered on the accumulation of Aβ peptides, which form plaques throughout the brain. These plaques are the first sign of Alzheimer's, and the most studied.

The second sign of the disease is less celebrated, but may hold more promise. After the initial amyloid plaques form in the brain, a jumble of tau proteins known as neurofibrillary tangles clog the insides of neurons. Unlike amyloid plaques, this latter protein clump initially clusters solely within a distinct group of cells of the entorhinal cortex. The sheer predictability of the process makes it an attractive therapeutic target.

But until now, scientists knew little about the nuances that make vulnerable neurons tick and tangle. With that in mind, the researchers set out to catalogue the genetic factors that render entorhinal neurons uniquely vulnerable to neurofibrillary tangles.

"There has been one trial after another, and we have accumulated a huge knowledge of the mechanisms that produce amyloid plaques," Roussarie says. "But what is going on downstream of the amyloid accumulation, and how these plaques trigger neurofibrillary tangles within vulnerable neurons, is much more of a puzzle. It is a place where we could discover novel therapeutic targets."

The biggest barrier to studying these brain cells was the absence of any easy way to distinguish vulnerable neurons from their neighbors. For Roussarie and his colleagues, BacTRAP provided an answer. Developed at Rockefeller by Greengard and Nathaniel Heintz, bacTRAP technology makes it possible to catalogue proteins within specific populations of neurons in mice.

"We needed something like a microdissection of these neurons from the complex and smushy bowl of the brain," says Marc Flajolet, acting head of the lab and coauthor on the study.

BacTRAP allowed the researchers to isolate the vulnerable neurons and analyze how they differ, genetically, from more resilient brain cells. A Princeton University team led by Olga Troyanskaya then designed computer algorithms to help the team focus upon only the genetic anomalies likely to be most relevant to neurodegeneration.

"The goal was to form a big-picture view, rather than a list of genes," Flajolet says. "Only by way of these sophisticated data-analysis frameworks can you get to the bottom of something as complicated as the neurodegenerative cascade in Alzheimer's disease."

From neurofibrillary tangles to therapeutic targets

The findings highlight a suite of genes that are likely involved in making entorhinal cortex neurons easy targets for degeneration.

The most compelling among them is thought to play a major role in the early stages of Alzheimer's--deciding whether tau proteins clump into neurofibrillary tangles in the first place. The gene produces a protein called PTBP1, a so-called splice factor that directs cells to create one of two subtypes of tau protein. Prior studies have shown that the characteristic protein clumps of Alzheimer's occur specifically when the ratio of these two flavors of tau is disrupted--and the new findings suggest the disease might be driven by cells whose tau-variant levels are disturbed.

"When tau popped out, there was a lot of excitement," says Vicky Yao, an assistant professor in computer science at Rice University, and co-author of the Neuron report. "Once we figure out what makes neurons more vulnerable, that can lead to multiple avenues to decrease their vulnerability."

Successful strategies for preventing and treating neurodegeneration will likely involve diverse approaches, adds Roussarie. Future drugs may need to target plaque formulation as well as neurofibrillary tangles, for example, and the first step toward preventing the latter will be to understand what makes some neurons prone to tangling in the first place.

"The diversity of neurons was just not taken into account before," Roussarie says. "A lot of people are studying neurofibrillary tangles, but only now are we beginning to address it through the prism of neuron vulnerability."

PROVIDENCE, R.I. [Brown University] -- When picturing dinosaur tracks, most people imagine a perfectly preserved mold of a foot on firm layer of earth. But what if that dinosaur was running through mud, sinking several inches -- or even up to their ankles -- into the ground as it moved?

Using sophisticated X-ray-based technology, a team of Brown University researchers tracked the movements of guineafowl to investigate how their feet move below ground through various substrates and what those findings could mean for understanding fossil records left behind by dinosaurs.

They found that regardless of the variability in substrates, or the guineafowl moving at different speeds, sinking at different depths or engaging in different behaviors, the birds' overall foot movement remained the same: The toes spread as they stepped onto the substrate surface, remained spread as the foot sank, collapsed and drew back as they were lifted from the substrate, and exited the substrate in front of the point of entry, creating a looping pattern as they walked.

And part of what that means is that fossilized dinosaur tracks that look distinct from each other, and appear to be from different species, might instead come from the same dinosaurs.

"This is the first study that's really shown how the bird foot is moving below ground, showing the patterns of this subsurface foot motion and allowing us to break down the patterns that we're seeing in a living animal that has feet similar to those of a dinosaur," said Morgan Turner, a Ph.D. candidate at Brown in ecology and evolutionary biology and lead author of the research. "Below ground, or even above ground, they're responding to these soft substrates in a very similar way, which has potentially important implications for our ability to study the movement of these animals that we can't observe directly anymore."

The findings were published on Wednesday, July 1, in the Royal Society journal Biology Letters.

To make the observations, Turner and her colleagues, Professor of Biology and Medical Science Stephen Gatesy and Peter Falkingham, now at Liverpool John Moores University, used a 3D-imaging technology developed at Brown called X-ray Reconstruction of Moving Morphology (XROMM). The technology combines CT scans of a skeleton with high-speed X-ray video, aided by tiny implanted metal markers, to create visualizations of how bones and muscles move inside humans and animals. In the study, the team used XROMM to watch guineafowl move through substrates of different hydration and compactness, analyzing how their feet moved underground and the tracks left behind.

Sand, typically a dense combination of quartz and silica, does not lend itself well to X-ray imaging, so the team used poppy seeds to emulate sand. Muds were made using small glass bubbles, adding various amount of clay and water across 107 trials to achieve different consistencies and realistic tracks.

They added metal markers underneath the claws of the guineafowl to allow for tracking in 3D space. It's these claw tips that the researchers think are least disturbed by mud flow and other variables that can impact and distort the form of the track.

Despite the variation, the researchers observed a consistent looping pattern.

"The loops by themselves I don't think are that interesting," Gatesy said. "People are like, 'That's nice. Birds do this underground. So what?' It was only when [Turner] went back into it and said, 'What if we slice those motion trails at different depths as if they were footprints?' Then we made the nice connection to the fossils."

By "slicing" through the 3D images of the movement patterns at different depths, the researchers found similarities between the guineafowl tracks and fossilized dinosaur tracks.

"We don't know what these dinosaurs were doing, we don't know what they were walking through exactly, we don't know how big they were or how deep they were sinking, but we can make this really strong connection between how they were moving and some level of context for where this track is being sampled from within that movement," Turner said.

By recognizing the movement patterns, as well as the entry and exit point of the foot through various substrates, the team says they're able to gain a better understanding of what a dinosaur track could look like.

"You end up generating this big diversity of track shapes from a very simple foot shape because you're sampling at different depths and it's moving in complicated ways," Gatesy said. "Do we really have 40 different kinds of creatures, each with a differently shaped foot, or are we looking at some more complicated interaction that leaves behind these remnants that are partly anatomical and partly motion and partly depth?"

To further their research, the team spent time at the Beneski Museum of Natural History at Amherst College in Massachusetts, which is home to an expansive collection of penetrative tracks discovered in the 1800s by geologist Edward Hitchcock.

Hitchcock originally believed that his collection housed fossil tracks from over 100 distinct animals. Because of the team's work with XROMM, Gatesy now thinks it's possible that at least half of those tracks are actually from the same dinosaurs, just moving their feet in slightly different ways or sampled at slightly different depths.

"Going to museum together and being able to pick out these features and say, 'We think this track is low in the loop and we think this one is high,' that was the biggest moment of insight for me," Turner said.

Turner says she hopes their research can lead to a greater interest in penetrative tracks, even if they seem a little less pretty or polished than the tracks people are used to seeing in museums.

"They have so much information in them," Turner said, "and I hope that this gives people a lens, a new way to view these footprints and appreciate the movement preserved within in them."