Culture

When Dr. Stephen Smith of Seattle Children's Research Institute came down with muscle aches, gastrointestinal distress and a sudden loss of smell in late February, he suspected he had COVID-19. The testing criteria had yet to be expanded to include individuals with Smith's symptoms and so he did what many scientists with his expertise would do: he developed a way to test himself.

The fruits of his curiosity, now published in The Journal of Infectious Diseases, offer a reliable way to quantify whether an individual has neutralizing antibodies that could prevent the novel coronavirus from infecting cells using a method that is more broadly applicable than those currently available.

"If you think you've had COVID-19 and go to the doctor, they can test your blood and tell you whether or not you have antibodies to COVID-19, but that doesn't tell you whether your antibodies are any good at functionally blocking the virus from binding to cells," Smith said. "There are tests on the market now that can tell you that, but they are expensive and take a long time to get results. We wanted to develop a way to give you additional information about your immune status without all the barriers that make it difficult to use in a community setting."

The newly developed diagnostic could have a range of potential commercial applications from broad community testing to assessing vaccine responses and screening for convalescent plasmas that have particularly high levels of neutralizing antibodies as a potential treatment.

Cell-free test looks at protein interactions

The novel coronavirus enters cells when the viral spike protein binds to the ACE2 protein on the surface of human cells. Neutralizing antibodies that block this binding are thought to contribute to immunity to the virus in people who recover from COVID-19.

Smith applied a technique called immunoprecipitation detected by flow cytometry (IP-FCM) to study the interactions between the proteins and to look for evidence that antibodies were inhibiting the interaction and blocking the virus from binding to cells. Instead of relying on live cells and viruses like other available blood tests, IP-FCM uses recombinant - or lab-made - proteins and instruments commonly available in commercial serological labs.

"Other tests that provide insight into immunity work by taking antibodies from your blood and mixing them together with a virus and then exposing that mixture to live cells. Three days later they can determine immunity based on whether your blood prevented the viruses from infecting the cells or not," Smith said. "Our cell-free test can provide that same information overnight."

Collaborative science launches innovative study

Smith is among a small group of scientists in the U.S. who have pioneered IP-FCM to study the interactions between proteins. His lab in Seattle Children's Center for Integrative Brain Research uses IP-FCM to uncover new treatments for autism by studying the more than 100 genetic variations known to contribute to the condition.
To apply his expertise to the current pandemic, Smith collaborated with Drs. Lisa Frenkel and Whitney Harrington from the research institute's Center for Global Infectious Global Disease Research who are following a community cohort of Seattle Children's employees who were never hospitalized and had recovered from mild to moderate COVID-19. The researchers hope by tracking their recovery and taking blood samples over time as part of the Seattle Children's Recovered SARS2 Cohort study they can shed light on the immune responses to the novel coronavirus.

Funding in part by Seattle Children's COVID-19 Research Fund helped Smith design and launch the study.

Using IP-FCM, Smith tested the blood samples from 24 cohort participants. The test showed that 92% of the participants had antibodies to the novel coronavirus at an average of a little over a month post-infection. Results were validated with 30 control samples.

"Not only did the participants have antibodies, but our test also showed that their antibodies were pretty effective at neutralizing the binding between the spike protein and the cell's receptor," he said. "It's consistent with other studies from cell-based tests showing that people who get COVID do make neutralizing antibodies."

Interestingly, when researchers looked at the test results against other data gathered from the cohort, they found that those who mounted a fever had higher levels of antibodies. The research team also plans to retest the samples to see how antibody levels change over time.

"It's going to be very important to look at people over a longer time period to track their antibody levels and whether or not they get re-infected," Smith said. "Until we do those studies, we really don't know how these clinical measures of antibody neutralization relate to susceptibility in the real world."

Identifying new drug candidates for COVID-19

In addition to exploring opportunities to commercialize the diagnostic, Smith and his team are now using the test to rapidly screen thousands of approved drugs that could potentially interfere with the binding between ACE2 and the spike protein.

Lab manager, Edward Gniffke, and Stanford University undergraduate and summer intern, Kaleb Tsegay, helped run the initial screen that could potentially identify drugs capable of preventing or treating COVID-19.

"We already have some compounds that look like they are inhibiting, which is pretty exciting," Smith said. "This first line screen will help us pinpoint the most promising agents for further tests."

CAMBRIDGE, MA -- People with amyotrophic lateral sclerosis (ALS) suffer from a gradual decline in their ability to control their muscles. As a result, they often lose the ability to speak, making it difficult to communicate with others.

A team of MIT researchers has now designed a stretchable, skin-like device that can be attached to a patient's face and can measure small movements such as a twitch or a smile. Using this approach, patients could communicate a variety of sentiments, such as "I love you" or "I'm hungry," with small movements that are measured and interpreted by the device.

The researchers hope that their new device would allow patients to communicate in a more natural way, without having to deal with bulky equipment. The wearable sensor is thin and can be camouflaged with makeup to match any skin tone, making it unobtrusive.

"Not only are our devices malleable, soft, disposable, and light, they're also visually invisible," says Canan Dagdeviren, the LG Electronics Career Development Assistant Professor of Media Arts and Sciences at MIT and the leader of the research team. "You can camouflage it and nobody would think that you have something on your skin."

The researchers tested the initial version of their device in two ALS patients (one female and one male, for gender balance) and showed that it could accurately distinguish three different facial expressions -- smile, open mouth, and pursed lips.

MIT graduate student Farita Tasnim and former research scientist Tao Sun are the lead authors of the study, which appears today in Nature Biomedical Engineering. Other MIT authors are undergraduate Rachel McIntosh, postdoc Dana Solav, and research scientist Lin Zhang. Yuandong Gu of the A*STAR Institute of Microelectronics in Singapore and Nikta Amiri, Mostafa Tavakkoli Anbarani, and M. Amin Karami of the University of Buffalo are also authors.

A skin-like sensor

Dagdeviren's lab, the Conformable Decoders group, specializes in developing conformable (flexible and stretchable) electronic devices that can adhere to the body for a variety of medical applications. She became interested in working on ways to help patients with neuromuscular disorders communicate after meeting Stephen Hawking in 2016, when the world-renowned physicist visited Harvard University and Dagdeviren was a junior fellow in Harvard's Society of Fellows.

Hawking, who passed away in 2018, suffered from a slow-progressing form of ALS. He was able to communicate using an infrared sensor that could detect twitches of his cheek, which moved a cursor across rows and columns of letters. While effective, this process could be time-consuming and required bulky equipment.

Other ALS patients use similar devices that measure the electrical activity of the nerves that control the facial muscles. However, this approach also requires cumbersome equipment, and it is not always accurate.

"These devices are very hard, planar, and boxy, and reliability is a big issue. You may not get consistent results, even from the same patients within the same day," Dagdeviren says.

Most ALS patients also eventually lose the ability to control their limbs, so typing is not a viable strategy to help them communicate. The MIT team set out to design a wearable interface that patients could use to communicate in a more natural way, without the bulky equipment required by current technologies.

The device they created consists of four piezoelectric sensors embedded in a thin silicone film. The sensors, which are made of aluminum nitride, can detect mechanical deformation of the skin and convert it into an electric voltage that can be easily measured. All of these components are easy to mass-produce, so the researchers estimate that each device would cost around $10.

The researchers used a process called digital imaging correlation on healthy volunteers to help them select the most useful locations to place the sensor. They painted a random black-and-white speckle pattern on the face and then took many images of the area with multiple cameras as the subjects performed facial motions such as smiling, twitching the cheek, or mouthing the shape of certain letters. The images were processed by software that analyzes how the small dots move in relation to each other, to determine the amount of strain experienced in a single area.

"We had subjects doing different motions, and we created strain maps of each part of the face," McIntosh says. "Then we looked at our strain maps and determined where on the face we were seeing a correct strain level for our device, and determined that that was an appropriate place to put the device for our trials."

The researchers also used the measurements of skin deformations to train a machine-learning algorithm to distinguish between a smile, open mouth, and pursed lips. Using this algorithm, they tested the devices with two ALS patients, and were able to achieve about 75 percent accuracy in distinguishing between these different movements. The accuracy rate in healthy subjects was 87 percent.

Enhanced communication

Based on these detectable facial movements, a library of phrases or words could be created to correspond to different combinations of movements, the researchers say.

"We can create customizable messages based on the movements that you can do," Dagdeviren says. "You can technically create thousands of messages that right now no other technology is available to do. It all depends on your library configuration, which can be designed for a particular patient or group of patients."

The information from the sensor is sent to a handheld processing unit, which analyzes it using the algorithm that the researchers trained to distinguish between facial movements. In the current prototype, this unit is wired to the sensor, but the connection could also be made wireless for easier use, the researchers say.

The researchers have filed for a patent on this technology and they now plan to test it with additional patients. In addition to helping patients communicate, the device could also be used to track the progression of a patient's disease, or to measure whether treatments they are receiving are having any effect, the researchers say.

"There are a lot of clinical trials that are testing whether or not a particular treatment is effective for reversing ALS," Tasnim says. "Instead of just relying on the patients to report that they feel better or they feel stronger, this device could give a quantitative measure to track the effectiveness."

'Foreign disinformation' social media campaigns are linked to falling vaccination rates, reveals an international time trends analysis, published in the online journal BMJ Global Health.

Every 1 point increase in effort is tied to an average 2% drop in annual coverage around the globe, and a 15% increase in the number of negative tweets about vaccination, shows the study, which forms part of a BMJ Collection on Democracy and Health published for the World Health Summit this weekend.

Last year, the World Health Organization (WHO) listed vaccine hesitancy--reluctance or refusal to be vaccinated because of safety concerns---as one of the top 10 threats to world health.

While vaccine hesitancy isn't new, the proliferation of 'anti-vaxx' messaging on social media is of particular public health concern, given that vaccination is seen as a key route out of the current coronavirus pandemic, say the researchers.

Deliberate 'disinformation' campaigns by foreign agencies on social media also have their part to play, they add.

To gauge the impact of social media use and foreign disinformation campaigns on vaccine hesitancy around the world, the researchers analysed two different dimensions of social media activity for up to 190 countries.

These were: the public use of Twitter to organise action/resistance; and the amount of tweets expressing negative sentiments about vaccines.

They also drew on national survey data about public attitudes to vaccination safety and annual vaccination rates for the 10 most commonly reported vaccine doses between 2008 and 2018.

They used recognised analytical tools to measure sentiment (Polyglot Python Library); public use of social media to organise (Digital Society Project or DSP); foreign sources of disinformation (Varieties of Democracy Institute expert network + DSP); public attitudes to vaccine safety (2019 Wellcome Global Monitor).

They also logged measures of GDP (gross domestic product) per head of the population for each country and levels of internet usage.

Analysis of all the data revealed that the prevalence of foreign disinformation activity was "highly statistically and substantively significant" in predicting a drop in average vaccination rates.

A one-point shift upwards in the five-point disinformation scale was associated with an average fall in the annual vaccination rate of 2 percentage points, and a cumulative drop of 12 percentage points across the decade.

A belief that vaccines are inherently unsafe was associated with organisation of action/resistance on social media: and the more organisation on social media, the greater was the level of belief that vaccines are unsafe.

Foreign disinformation was also associated with negative social media activity about vaccination, boosting the number of negative vaccine tweets by 15%, on average.

While the study is unique, it wasn't able to specify the particulars of foreign disinformation campaigns or the prevalence of anti-vacccination propaganda, the researchers acknowledge.

What's more, Twitter isn't used in every country, and the survey data were only available at one point in time.

Nevertheless, write the researchers: "Foreign disinformation campaigns are robustly associated with declines in [average] vaccination rates. The use of social media to organise offline action is highly associated with an increase in public belief in vaccines being unsafe.

"Both of these findings suggest that combating disinformation and misinformation regarding vaccines online is critical to reversing the growth in vaccine hesitancy around the world."

They add: "These findings are especially salient in the context of the COVID-19 pandemic, given that the vaccines under development will require deployment globally to billions of people in the next year."

Public outreach and education campaigns will, of course, be needed, but they won't be enough by themselves to counter the tide of mistrust, they emphasise.

"First, governments must mandate that social media companies are responsible for taking down anti-vaccination content (whether originating from genuine domestic actors or foreign propaganda operations)," they advise.

"Second, foreign disinformation campaigns should be addressed at their source. A preponderance of such campaigns amplifying anti-vaccination content originate from within Russia or via pseudo-state actors informally associated with Russia," they warn.

None of this will be easy, they acknowledge, because it means reconciling the principles of free speech with the policing of social media for "damaging falsehoods," and persuading Russia to adopt a ceasefire on internet information warfare in the interests of the health of its own people.

But they conclude: "We urge policy makers to take the time before a COVID-19 vaccine is available for mass distribution as an opportunity for action against social media factors contributing to vaccine hesitancy."

Politicians are unlikely to be punished or rewarded for their failures or successes in managing the coronavirus pandemic at the next election, suggests an analysis of survey data from the US, the UK and India, published in the online journal BMJ Global Health.

This is despite the fact that most survey participants think health is a key policy area and that their government is to blame for the spread of COVID-19, shows the study, which forms part of a BMJ Collection on Democracy and Health published for the World Health Summit this weekend.

Health is often politicised, but it's not clear if public health issues influence public opinion and if these opinions might translate into voting behaviour.

The researchers reasoned that because it is global in scope and the focus of intense media interest, the COVID-19 pandemic therefore offers a unique opportunity to observe the interplay between public opinion and electoral politics.

How political leaders and parties have handled the pandemic has been front and centre of news coverage, suggesting that if public health matters to voting intentions, COVID-19 would seem to be a perfect storm, say the researchers.

To explore this further, they ran surveys on the health and economic impacts of the pandemic in the US, UK, and India during mid April to early June, recruiting nearly 3000 participants, half of whom came from the US.

The format of the survey involved revealing key facts about either the economic impact of the pandemic or the health impact (2 'treatment' groups), or revealing no key facts (comparison group).

Respondents were then asked questions designed to uncover attitudes towards their government, including its leader, and potential voting intentions if an election were held that day. They were also asked if they held their government responsible for the spread of COVID-19.

The economic facts covered the scale of job losses, overall shrinkage of the economy, and the impact on the stock market in each of the three countries. The health facts covered the numbers of projected hospital admissions, including the need for intensive/critical care, and the numbers of deaths in each of the countries, emphasising the lack of a cure or effective vaccine for COVID-19.

The researchers expected that compared with respondents in the comparison group, those in the two 'treatment' groups would either favour or disfavour the incumbent government and blame it for the pandemic.

But that's not what the responses indicated. More than 85% of respondents agreed that health was a key policy area for which their government had some responsibility (90%+ agree).

Yet while more than half the respondents thought their government was to blame for the spread of the pandemic, those given key facts about the pandemic were no more likely to favour or disfavour the incumbent government, or blame it for the pandemic, than those in the comparison group---what is known as a 'null' result.

The researchers acknowledge that they recruited many fewer people than they had hoped in the UK, and the survey platform they used is biased towards young men in all countries and, in the case of India, relatively more educated men, so unlikely to be completely nationally representative.

The surveys were also carried out some time before elections were expected--years in the case of the UK and India.

But they write: "the null findings contained in this study suggest that politicians are unlikely to be punished or rewarded for their failures or successes in managing COVID?19 in the next election."

They are tempted to conclude that public health issues have little influence on voter preferences in most election cycles. "It is not clear, for example, that the depression in life expectancies in the US, the continuing underperformance of the NHS in the UK, and the low?level of public sector health expenditure in India has had much impact on elections in those countries," they say.

"The urgency with which the COVID?19 pandemic has ripped through social, economic and political landscapes may challenge these complacencies - but only if [people en masse] make connections between the state of public health and what public officials can do," they suggest.

"If public health is politically inconsequential, this also raises questions about the impact of political institutions on health outcomes," they add.

Movement in animals is complex, especially in human beings. A variety of neurons coordinate the activity and inactivity of our muscles, and without that coordination we'd fall flat on our face when we went for a walk.

Scientists have known for quite some time how motor neurons in the spinal cord that activate muscles are organized to generate more forceful output, to transition from walking to jogging to running, for example. Little is known, however, about how spinal inhibitory interneurons work to inhibit, or silence, other neurons and related muscle groups in coordination with the active muscle groups across changing speeds.

Now a Northwestern University research team has discovered in a study of zebrafish that there is a very orderly relationship between when these critical inhibitory neurons are born, their participation in different speeds of movement and what part of a motor neuron they innervate. As a result of this compartmental setup, the amounts of inhibition received by the motor neurons are tuned to different speeds of movement.

Zebrafish is a model organism whose spinal cord works in a fashion similar to our own. Leaning more about the undulating movement of the swimming fish will allow scientists to better understand how humans walk.

The study will be published Oct. 23 by the journal Science.

"A better understanding of how circuits in the spinal cord are organized to coordinate movements puts us in a better position to repair things when damaged or diseased," said David McLean, corresponding author of the study.

"The fact that we see this pattern in the spinal cord, a relatively primitive part of the nervous system, and in fish, a relatively primitive vertebrate, means that nervous systems made use of this compartmental scheme to regulate activity much earlier than we would have expected," he said. "It's a bit like discovering parts for a combustion engine during an archaeological dig."

McLean is an associate professor of neurobiology in the Weinberg College of Arts and Sciences. He studies the development and functional organization of motor networks. With his research into how these networks control the direction and speed of movements, McLean hopes to reveal broad principles that help explain disorders impacting our capacity to move, such as Parkinson's disease, epilepsy and spinal injury.

"As neuroscientists, our job is to make sense of the enormous complexity we find in the nervous system that generates behavior," McLean said. "One way we do that is to look for patterns that give us a sense that there is an underlying logic -- an algorithm that bridges species and is useful in other parts of the brain. This, I think, is one such pattern."

In their study, McLean and his team used a number of cutting-edge approaches, including using lasers and fluorescent proteins to light up individual neurons and their connections in the transparent fish. They also used electrophysiology in genetically modified fish to characterize function in intact, behaving animals.

The researchers found that inhibitory neurons born first are active during the fastest movements and are most effective at silencing motor output by innervating motor neuron axons, closest to where activity is generated. Next to develop are interneurons active at intermediate speeds that strongly inhibit motor neuron cell bodies, followed by those active at slow speeds that weakly inhibit dendrites.

Collectively, the arrangement of inhibitory inputs in different structural compartments simplifies the process of ensuring appropriate patterns of motor output at different speeds, McLean said, since different cell types can provide a stronger or weaker 'veto' over motor output depending on when they are active.

"This compartmental pattern exists in other animals and brain regions, but using zebrafish we discovered clear functional consequences by watching the circuits develop, similar to understanding how a car works by following the assembly line," said Sandeep Kishore, first author of the study and a research associate in McLean's lab.

During early development of the zebrafish, inhibitory networks controlling the most forceful movements are the first to become functional, followed by those controlling more subtle, controlled movements.

"This makes some sense when you consider human development, where our first actions are kicking movements in the womb," McLean said. "Only later do we require and acquire finer motor skills."

CLEVELAND--More than 103,000 rental units spread across the city proper are potentially vulnerable to lead contamination because they were built before 1978 when lead paint was outlawed. According to a new study from Case Western Reserve University's Center on Urban Poverty and Community Development at the Jack, Joseph and Morton Mandel School of Applied Social Sciences, over one-third of these units are in poor condition and of very low market value. This can present the dual challenge of requiring potentially costly repairs in buildings where there is little equity to leverage financing, and results in potential risk of lead poisoning to children who may live in them.

Using a variety of public records--including assessed market value, sales, foreclosure and tax history, code violations, building permits and rental registry data--the researchers examined every rental property in the city from 2016-18 on factors related to the likelihood that the property could have lead-safety problems. Property owners were categorized according to whether they were companies or individuals, the number and types of properties they held and the property values and conditions represented in their portfolios.

"The issue is that the majority of families with young children in Cleveland rent homes in the private rental market," said Claudia Coulton, the study's co-author, a Distinguished University Professor and co-director of the poverty center. "Improving these properties--and working with these property owners-- is a key element in moving toward a lead-safe Cleveland."

"The majority of the city's rental housing stock carries a significant risk of lead exposure to children because of age, deferred maintenance and low-market value, so understanding the rental landscape is crucial," said Rob Fischer, an associate professor at the Mandel School and study co-author.

Key findings:

Single-family homes make up most of the city's rental properties, accounting for nearly half of all rental units. Another 24% of properties are two-family homes; 21% are small buildings (with three to 20 units); and 12% are large buildings (with more than 20 units).

Nearly two-thirds of Cleveland's rental properties are maintained in above average or good condition and have average market values, but the remainder are of relatively low value and in rather poor condition.

Among Cleveland landlords in 2018, more than 80% were listed as individual owners, owned only one property in the city of Cleveland and either lived or had a business address within Cuyahoga County. A significant proportion of the landlords (43%) had property that was classified as being in "bad condition" and/or of "very low market value" (29%).

Based on a combination over a dozen landlord characteristics, researchers divided the city's landlords into three categories: Type 1 were owners of single- or two-family homes in good condition and of average or above-average market value; Type 2 landlords owned mostly doubles in bad condition with low market value; and Type 3 landlords were larger operators, often corporate, holding properties of varying sizes and condition. These categories inform how best to engage and support different landlords.

Partnering with Lead Safe Cleveland Coalition, the research helps inform the continued implementation of the Lead Safe Home Fund, a first-of-its-kind, public-private partnership aimed at assisting landlords and tenants with accessing the resources they need to make housing lead safe throughout Cleveland, Fischer said.

The Lead Safe Home Fund will provide property owners and families with effective and equitable support for home repair and lead poisoning prevention. The Fund is structured to be flexible and nimble, with a five-year, $99.4 million target budget. CHN Housing Partners, a lender and the region's largest provider of affordable housing, will administer the home loans and grants.

"Our role is to help property owners--especially those 'mom-and-pop' landlords--improve the quality of the units they rent and get their Lead Safe Certification," said Kevin J. Nowak, executive director of CHN Housing Partners. "This research helps us better understand their assets and challenges. We are tailoring our grants, loans and incentives to meet property owners where they are, so that they can access the resources they need in a comprehensive, straight-forward way.

Regulators have failed to properly address patient safety on discharge from hospital in England, leaving the physical wellbeing and dignity of patients continuously at risk at a time when they should be returning safely home, finds new research.

The research, 'Leaving hospital: A step too far for risk-based regulation?' investigates the reasons for the lack of effective regulations from a legal standpoint. It was published in the journal, Medical Law Review* and was funded by the National Institute for Health Research Greater Manchester Patient Safety Translational Research Centre (GM PSTRC) which is a partnership between The University of Manchester and Salford Royal hospital.

Victoria Moore, who led the research, is from the centre's Safer Care Systems and Transitions theme, and said: "Being discharged from hospital can be a dangerous time for patients, but this is an area that regulators haven't recognised as a group and as such haven't paid much attention to. This leaves patients vulnerable. My research investigates why this is the case. The answer lies in the regulatory approach that dominates regulation within the NHS."

Risk-based regulation is the regulatory approach underpinning health and social care regulations in England. To be successful, this approach requires the risk to patient safety to be appropriately identified, fully understood and prioritised by all regulators involved.

Victoria continued: "Within healthcare regulation in England there are a number of regulators, so it is virtually impossible for all of them to have a unified understanding of the risk posed by discharge. This has resulted in a lack of action by any one regulator."

The research identifies that in hospital discharge, there are three main weaknesses in risk-based regulation and these have been created by the sheer number of regulators involved.

The first is when identifying risk, as regulators don't possess a complete overview of all relevant information. This is because of the limited information-sharing mechanisms between the regulators. Therefore, judgements have to be made about what information to share and with which regulator. This is problematic given that successful risk-based regulation is heavily dependent upon the availability of sufficient information to identify risks and inform decision-making.

The number of statutory regulators and the limited nature of information-sharing leads to a second important weakness; it's virtually impossible for all regulators to have a unified understanding of the risks posed by discharge from hospital. Risks will be understood based on the nature of information available, which will vary due to the number of regulators involved.

Finally, the research explains that successful risk-based regulation relies on being able to correctly prioritise risk. This can only happen if regulators have gathered enough information and all understand and agree the regulatory aims.

Victoria concludes: "The combination of the three weaknesses I've identified in my research means the risk posed to the safety of patients on discharge from hospital is neither uniformly recognised by the statutory regulators within the English NHS, nor sufficiently addressed. Professional regulators in particular appear to have a poor awareness of the risk and their role in addressing it. Until regulators can accurately identify this risk, build a unified understanding of its causes and consequences, and prioritise it appropriately, this unacceptable status quo will remain."

The Director of the Greater Manchester PSTRC, Prof Stephen Campbell states that "we know discharge from hospital can be a key patient safety issue and regulation needs reliable and attributable information. This research helps identify key areas for improvement especially the need for a unified understanding of the risk posed by discharge and information-sharing".

Edge Localised Modes, ELMs for short, are one of the disturbances of the plasma confinement that are caused by the interaction between the charged plasma particles and the confining magnetic field cage. During ELM events, the edge plasma loses its confinement for a short time and periodically throws plasma particles and energy outwards onto the vessel walls. Typically, one tenth of the total energy content can thus be ejected abruptly. While the present generation of medium-sized fusion devices can cope with this, large devices such as ITER or a future power plant would not be able to withstand this strain.

Experimental methods to attenuate, suppress or avoid ELMs have already been successfully developed in current fusion devices (see PI 3/2020). After extensive previous work, it has now been possible for the first time by means of computational simulations to identify the trigger responsible for the explosive onset of these edge instabilities and to reconstruct the course of several ELM cycles - in good agreement with experimentally observed values. A publication accepted in the scientific journal Nuclear Fusion explains this important prerequisite for predicting and avoiding ELM instabilities in future fusion devices.

The ELM instability builds up after a quiet phase of about 5 to 20 milliseconds - depending on the external conditions - until in half a millisecond between 5 and 15 percent of the energy stored in the plasma is flung onto the walls. Then the equilibrium is restored until the next ELM eruption follows.

The plasma theorists around first author Andres Cathey of IPP, who come from several laboratories of the European fusion programme EUROfusion, were able to describe and explain the complex physical processes behind this phenomenon in detail: as a non-linear interplay between destabilising effects - the steep rise in plasma pressure at the plasma edge and the increase in current density - and the stabilising plasma flow. If the heating power fed into the plasma is changed in the simulation, the calculated result shows the same effect on the repetition rate of the ELMs, i.e. the frequency, as an increase of the heating power in a plasma experiment at ASDEX Upgrade tokamak: experiment and simulation are in Agreement.

Although the processes take place in a very short time, their simulation requires a great deal of computing effort. This is because the simulation must resolve into small calculation steps both the short ELM crash and the long development phase between two ELMs - a calculation problem that could only be solved with one of the fastest supercomputers currently available.

For the simulations the JOREK code was used, a non-linear code for the calculation of tokamak plasmas in realistic geometry, which is being developed in European and international cooperation with strong contributions from IPP.

Hitting a specific point on a screen with a laser pointer during a presentation isn't easy - even the tiniest nervous shaking of the hand becomes one big scrawl at a distance. Now imagine having to do that with several laser pointers at once. That is exactly the problem faced by physicists who try to build quantum computers using individual trapped atoms. They, too, need to aim laser beams - hundreds or even thousands of them in the same apparatus - precisely over several metres such as to hit regions only a few micrometres in size that contain the atoms. Any unwanted vibration will severely disturb the operation of the quantum computer.

At ETH in Zurich, Jonathan Home and his co-workers at the Institute for Quantum Electronics have now demonstrated a new method that allows them to deliver multiple laser beams precisely to the right locations from within a chip in such a stable manner that even the most delicate quantum operations on the atoms can be carried out.

Aiming for the quantum computer

To build quantum computers has been an ambitious goal of physicists for more than thirty years. Electrically charged atoms - ions - trapped in electric fields have turned out to be ideal candidates for the quantum bits or qubits, which quantum computers use for their calculations. So far, mini computers containing around a dozen qubits could be realized in this way. "However, if you want to build quantum computers with several thousand qubits, which will probably be necessary for practically relevant applications, current implementations present some major hurdles," says Karan Mehta, a postdoc in Home's laboratory and first author of the study recently published in the scientific journal "Nature". Essentially, the problem is how to send laser beams over several metres from the laser into a vacuum apparatus and eventually hit the bull's eye inside a cryostat, in which the ion traps are cooled down to just a few degrees above absolute zero in order to minimize thermal disturbances.

Optical setup as an obstacle

"Already in current small-scale systems, conventional optics are a significant source of noise and errors - and that gets much harder to manage when trying to scale up", Mehta explains. The more qubits one adds, the more complex the optics for the laser beams becomes which is needed for controlling the qubits. "This is where our approach comes in", adds Chi Zhang, a PhD student in Home's group: "By integrating tiny waveguides into the chips that contain the electrodes for trapping the ions, we can send the light directly to those ions. In this way, vibrations of the cryostat or other parts of the apparatus produce far less disturbance."

The researchers commissioned a commercial foundry to produce chips which contain both gold electrodes for the ion traps and, in a deeper layer, waveguides for laser light. At one end of the chips, optical fibres feed the light into the waveguides, which are only 100 nanometres thick, effectively forming optical wiring within the chips. Each of those waveguides leads to a specific point on the chip, where the light is eventually deflected towards the trapped ions on the surface.

Work from a few years ago (by some of the authors of the present study, together with researchers at MIT and MIT Lincoln Laboratory) had demonstrated that this approach works in principle. Now the ETH group has developed and refined the technique to the point where it is also possible to use it for implementing low-error quantum logic gates between different atoms, an important prerequisite for building quantum computers.

High-fidelity logic gates

In a conventional computer chip, logic gates are used to carry out logic operations such as AND or NOR. To build a quantum computer, one has make sure that it can to carry out such logic operations on the qubits. The problem with this is that logic gates acting on two or more qubits are particularly sensitive to disturbances. This is because they create fragile quantum mechanical states in which two ions are simultaneously in a superposition, also known as entangled states.

In such a superposition, a measurement of one ion influences the result of a measurement on the other ion, without the two being in direct contact. How well the production of those superposition states works, and thus how good the logic gates are, is expressed by the so-called fidelity. "With the new chip we were able to carry out two-qubit logic gates and use them to produce entangled states with a fidelity that up to now could only be achieved in the very best conventional experiments", says Maciej Malinowski, who was also involved in the experiment as a PhD student.

The researchers have thus shown that their approach is interesting for future ion trap quantum computers as it is not just extremely stable, but also scalable. They are currently working with different chips that are intended to control up to ten qubits at a time. Furthermore, they are pursuing new designs for fast and precise quantum operations that are made possible by the optical wiring.

About half of the people with multiple sclerosis have the HLA-DR15 gene variant. A study led by the University of Zurich has now shown how this genetic predisposition contributes to the development of the autoimmune disease multiple sclerosis in combination with environmental factors. The decisive factor is the shaping of a repertoire of immune cells which - although they are effective in fighting off pathogens such as Epstein-Barr virus - also attack brain tissue.

Multiple sclerosis is an autoimmune disease that damages the brain and the spinal cord and often severely limits a person's quality of life. It affects about 2.5 million people worldwide, most of them young adults. The cause of the disease is a complex interaction between genetic factors and environmental influences such as smoking or infections.

Genetic variation and viruses as risk factors

For almost 50 years now, it has been known that a gene variant called HLA-DR15 is strongly associated with multiple sclerosis (MS). This gene variant is responsible for up to 60 percent of genetic risk. If carriers of this common gene (about a quarter of the healthy population is HLA-DR15 positive) are also infected with the Epstein-Barr virus and have a symptomatic course of infection called Pfeiffer's disease (also known as glandular fever or infectious mononucleosis), the risk of MS increases 15-fold.

UZH Professor Roland Martin, Head of the Department of Neuroimmunology and MS Research at the University Hospital Zurich, says: "There are therefore clear indications that the interaction between HLA-DR15 and infectious agents such as Epstein-Barr virus is significant for the development of the disease, even though the exact mechanisms behind this have not been understood until now."

An interdisciplinary, international study led by Martin has now shown that the immune cells of people with HLA-DR15 recognize certain microbes - such as the Epstein-Barr virus - very effectively, but that this "fitness" can also lead to an undesired immune reaction against the person's own brain tissue.

Individual training for immune cells

The gene products of HLA-DR15 control how the adaptive immune system shapes an immune repertoire that allows the body to recognize and fight pathogens. One of the locations of HLA-DR15 molecules is on the surface of white blood cells. There, they present protein fragments from bacteria, viruses and body cells to the T lymphocytes of the immune system.

The T lymphocytes - which later control the immune response - learn to distinguish between foreign proteins and the body's own tissue. This individual training of immune cells takes place first in the thymus and then in the blood. Since there are many more possible pathogens than T lymphocytes, each T lymphocyte must be able to respond to many different antigens and probably also many different pathogens.

Identifying the fragments presented

The researchers first investigated which fragments HLA-DR15 captured and presented to the immune cells. To do this, they used two novel antibodies that recognize the two variants of HLA-DR15 that occur in MS patients with a very high level of specificity. They found that the HLA-DR15 molecules in the thymus mainly present fragments of themselves. This is new information that was not previously known.

The T lymphocytes that have been trained in this way then migrate into the blood. There, they also learn to recognize fragments of the Epstein-Barr virus if the carrier of the genetic variant becomes infected with it. The fragments from the virus have a much stronger activating effect than the HLA-DR15 fragments.

As a result, the T lymphocytes not only keep virus-infected cells in check, but can also migrate to the brain and react with the body's own proteins that trigger an autoimmune reaction in the case of MS. Nearly 100 percent of people with MS are infected with the Epstein-Barr virus. It is the greatest environmental risk factor for MS. The researchers also often found a reaction to fragments of the intestinal bacterium Akkermansia muciniphila, which occurs in abnormally high numbers in MS patients.

Good immune defenses come with a risk of MS

Summarizing, Martin states that "The most important genetic risk factor for MS therefore shapes a repertoire of T lymphocytes that responds very well to certain infectious agents such as Epstein-Barr virus and intestinal bacteria." However, as the experiments have shown, this group of T lymphocytes also reacts to proteins found in the brain by way of a kind of cross-reactivity. "The disadvantage of this fitness is therefore that those affected also become susceptible to an immune response against their own brain tissue, which can lead to multiple sclerosis."

Therefore, these results have for the first time illustrated how the combination of genetic predisposition and certain environmental factors can trigger an autoimmune disease. "Our work has shed light on mechanisms that are likely to play a role in a number of other autoimmune diseases," says Martin. "In addition to improving our understanding of underlying causes of the disease, this could also lead to the development of new treatments".

The March 2014 landslide in Oso, Washington, about 55 miles northeast of Seattle, became the deadliest landslide event in United States history. Forty-three people died and 49 homes and structures were destroyed.

A University of Washington engineer who analyzed the event's aftermath began to investigate the circumstances that can make landslides so deadly. The resulting study shows that certain human actions increase the chance of surviving a devastating event, and suggests simple behavioral changes could save more lives than expensive engineering solutions.

The open-access study, published in the October issue of GeoHealth, suggests key actions that range from opening doors and windows to continuing to move and make noise if you do get buried.

"There are in fact some really simple, cost-effective measures that can be taken that can dramatically improve the likelihood that one will survive a landslide," said senior author Joseph Wartman, a UW professor of civil and environmental engineering.

Worldwide, landslides cause on average more than 4,000 deaths a year recently, with about 25 to 50 of those deaths occurring each year in the U.S. These events may become more frequent as wildfires fueled by warmer temperatures can leave slopes bare and more vulnerable to slides.

Wartman and a UW graduate student compiled and analyzed records of 38 landslides that affected occupied buildings. Most of the data came from the U.S., but it included landslides from around the world for which there were detailed records.

The authors recorded the geologic details of each landslide, as well as the reports from survivors of the events. They used newspaper articles, scientific papers, medical examiner reports and other documents to produce a detailed catalog of fatalities caused by landslides hitting occupied buildings. The events, spanning from 1881 to 2019, included the Oso mudslide and the 2018 mudslide in Southern California, as well as events in Bangladesh, Philippines, China, Malaysia, Australia and New Zealand.

Their analysis showed behavioral factors, such as a having an awareness of local landslide hazards and moving to a higher floor of a building during an event, had the strongest association with survival.

"Simply by being on an upper floor, an individual can increase their odds of survival by up to a factor of twelve. This is a powerful finding that we need to consider when we design the layout and vertical access routes in homes," said first author William Pollock, who did the work for his UW doctorate in civil and environmental engineering and is now a lecturer in the department.

The analysis showed many things they predicted would be important, including the size or the intensity of landslide events, made little difference to the death toll for landslides below about 20 feet depth. Similarly, the distance between a building and the landslide slope, or an inhabitant's age and gender, didn't make a big difference to their survival.

But the researchers found some behaviors, despite being performed by only a small number of people, often save lives. According to their results, those actions are:

Before an event

Be informed about potential hazards, from hazard maps or other sources

Talk to people who have experienced these events

Move areas of high occupancy, such as bedrooms, upstairs or to the downhill side of a building

During an event

Move away from the threat -- don't approach an active landslide

Escape vertically by moving upstairs or even on countertops to avoid being swept away

Identify and relocate to interior, ideally unfurnished, areas of a building that offer more protection

Open downhill doors and windows to let debris escape

After an event

If caught in landslide debris, continue to move and make noise to alert rescuers

The results suggest practical ways to lower the number of lives lost to landslides in the United States, Wartman said. He hopes the information can be incorporated in education and community awareness programs.

"This is a message of hope," Wartman said. "What this work suggests is that a modest investment put toward social science, policy and education could have a very marked effect in protecting people from landslides."

Residents who want to know if they are vulnerable to landslides can contact a local agency, such as the Washington State Department of Natural Resources, to learn more about local risks. Federal legislation is pending to make this information more easily accessible across the United States, Wartman said.

Ravens, crows, magpies and their relatives are known for their exceptional intelligence, which allows them to solve complex problems, use tools or outsmart their conspecifics. One capability, however, that we humans value highly, seems to be missing from their behavioral repertoire: generosity. Only very few species within the crow family have so far been found to act generously in experimental paradigms, while the highly intelligent ravens, for example, have demonstrated their egoistic tendencies in multiple studies. Lisa Horn of the of the Department of Behavioral and Cognitive Biology of the University of Vienna could now demonstrate, together with Jorg Massen of Utrecht University and an international team of researchers, that the social life of corvids is a crucial factor for whether the birds benefit their group members or not.

"Spontaneous generosity, without immediately expecting something in return, is a cornerstone of human society whose evolutionary foundations are still not fully understood. One hypothesis postulates that raising offspring cooperatively may have promoted the emergence of a tendency to willingly benefit group members in early human groups. Another hypothesis speculates that only increased tolerance towards group members and a reduced level of aggression made such generous behavior possible. While researchers found evidence for both hypotheses when investigating other non-human primates, results from other animal taxa have so far been missing", explains lead author Lisa Horn.

That is why Horn and her colleagues tested generous behavior in multiple species from the crow family. Some of the tested species raise their offspring cooperatively, while others do not. Additionally, some of the species nest in close proximity with their conspecifics, thereby demonstrating their high levels of tolerance, while other species jealously guard their territories against other members of their own species. In the experiment, the birds operated a seesaw mechanism by landing on a perch, which brought food into reach of their group members. If the birds wanted to grab the food themselves, they would have had to leave the perch and the seesaw would tilt back, thereby moving the food out of reach again. Since the birds thus could not get anything for themselves the authors argued that only truly generous birds would continue to deliver food to their group members throughout multiple experimental sessions.

Raising offspring cooperatively and high tolerance as driving factors for generosity

It became evident that this behavior was displayed most strongly by these corvid species that work together to raise their offspring cooperatively. Among male birds, the researchers also found evidence for the hypothesis that high tolerance towards conspecifics is important for the emergence of generous behavior. Males from species that commonly nest in very close proximity to each other were particularly generous. These results seem to support the hypotheses that raising offspring cooperatively and increased levels of tolerance may have promoted the emergence of generous tendencies not only in humans, but also in other animals. "What fascinates me the most is that in animals that are so different from us evolutionary mechanisms very similar to the ones in our human ancestors seem to have promoted the emergence of generous behavior", concludes Horn. More studies with different bird species, like the similarly intelligent parrots, or other animal taxa are, however, needed to further investigate these connections.

It is probably the immune response to, rather than the virus in itself, that causes sudden confusion and other symptoms from the nervous system in some patients with COVID-19. This is shown by a study of cases involving six Swedish patients, now published in the journal Neurology.

With accumulated experience of the disease, it has become evident that symptoms and signs from the nervous system is common in patients suffering from COVID-19.

Symptoms reported in the acute phase of the disease have included, for example, delirium, personality changes, and memory problems, all of which are signs of brain impairment or failure. These signs occur more frequently in more severe cases, and are usually temporary.

To date, it remains unclear whether SARS-CoV-2, the virus causing COVID-19, has the capacity to infect the brain and central nervous system directly. The current study from the University of Gothenburg indicates that, more likely, the patient's immune response is what may underlie the effects on the nervous system.

In the study, cerebrospinal fluid (CSF) samples were taken from six hospitalized patients at Sahlgrenska University Hospital in Gothenburg with moderate or severe COVID-19 and signs of brain impairment. The samples were analyzed for biomarkers that reflect how the brain is reacting to infections.

Every patient exhibited markedly elevated levels of the inflammation (immune activation) markers neopterin and beta-2-microglobulin, suggesting substantial activation of the brain's immune cells. In two cases, an increase in the protein neurofilament light (NfL), a marker that is sensitive to nerve-cell damage, was also seen.

On the other hand, no impact was observed on markers for damage to the blood-brain barrier, local antibody production or a raised white blood-cell count, which are otherwise common in virus infections in the central nervous system.

As for proof of actual SARS-CoV-2 invasion, the results from the analysis were uncertain, but most indications are that no virus was present in the cerebrospinal fluid, at least not to any significant degree.

Magnus Gisslén, Professor of Infectious Diseases at Sahlgrenska Academy, University of Gothenburg, and Chief Physician at the Department of Infectious Diseases, Sahlgrenska University Hospital, heads the Academy's clinical research on COVID-19.

"Overall, we see an unusual picture with marked inflammation and sometimes nerve-cell injury, but without a recruitment of immune-system cells from the bloodstream, detectable virus or damage to the blood-brain barrier, which are usually found in viral infections in the brain," he says.

The researchers emphasize that the mechanisms behind the symptoms seem to diverge from those of other viral infections. The first author of the study is Arvid Edén, PhD in Infectious Diseases at Sahlgrenska Academy, University of Gothenburg, and senior consultant at the Department of Infectious Diseases, Sahlgrenska University Hospital.

"It's an urgent priority for us to learn more about how COVID-19 affects the nervous system, not least so that we can determine which types of treatment may be suitable to counteract or mitigate the effects of infection with SARS-CoV-2 on the brain, both in the acute phase and in the longer term," Edén says.

Every cell in our body constantly divides to form new cells. This happens without us even thinking about it. However, every single time a cell divides, a complicated process has to unfold just the right way for our cells to avoid sickness and death.

The most essential step in this process is DNA replication, where the DNA in a mother cell is copied into its two daughter cells. Here, many molecules have to work together in order to assemble two new, identical DNA strings.

Writing for a prestigious international journal Nature, researchers from the University of Copenhagen have discovered how MCM proteins ensure that DNA replication proceeds at the right pace and thus avoids unnecessary molecular collisions, which could damage their genomes.

Even more importantly, the new findings explain how mother cells manage to instruct their daughters to keep the pace of their DNA replication within physiological limits. In simple terms, the new findings discovered nothing less than how an essential skill required for life continuation is preserved in cell's memory.

'We have quite many of these MCM proteins inside our cells. We can see them in the microscope, but for decades, scientists did not know what the vast majority of them actually do. From an evolutionary standpoint, it did not make sense to maintain a huge surplus of proteins only as back up, with no other important function. We have now solved this "MCM paradox" by finding that all those many MCM proteins in our cells actually have a defined function', says first author Hana Sedlackova, PhD student at the Novo Nordisk Foundation Center for Protein Research.

Exploiting cancer weaknesses

To explain the new finding by an analogy, researchers found that the excess of young MCM proteins is used by cells to slow down the DNA replication by adding "speed bumps" ahead of their older siblings, that 'drive' the DNA replication engine. And while it may seem impractical to slow down this process, the body has a very good reason to do so.

'These new results show that most of MCM proteins work a bit like speed bumps on a busy street. If they were not there, the traffic would go too fast and accidents could easily happen. Our study shows that the same thing happens in the cell: If the newly born MCM proteins cannot be passed by other cells on to their daughters, DNA is replicated too quickly, and this can be fatal for the cell. Just like a car, the DNA replication engine loses its maneuverability when it goes too fast'," explains professor Jiri Lukas, Executive Director at the Novo Nordisk Foundation Center for Protein Research.

The researchers suggest that their findings could potentially help exploit the weaknesses of cancer cells.

"During our work, we have also found that the young MCM proteins require a 'molecular babysitter' (a protein called MCMBP), which protects them and escorts them to DNA, where they can be useful. Without such protection, molecular roadblocks that slow down DNA replication cannot be made. While DNA in normal cell can be viewed as a nice new highway that allows reasonably fast speed, DNA in cancer cells is riddled by 'potholes', where every fast car (or a molecular motor that replicates DNA) is bound to crash. Based on our new findings, we are currently testing the idea that genetic of pharmacological removal of the MCMBP, and the resulting high speed of DNA replication, can be tolerated by normal cells but lethal to cancer cells" says Jiri Lukas.

The researchers managed to map the proteins and find their function using a variety of high-tech equipment such as CRISPR-Cas9 and HaloTag. Using 4D imaging, they were then able to label native MCM proteins and observe how they are born in the mother cells, how they are inherited by their daughters, and how their functions are changed in the absence of MCMBP the 'MCM babysitter'.

A new way of producing an enzyme called fucosyltransferase VI (FTVI) in the lab could help enhance the therapeutic potential of cord blood transplants.

Cord blood is currently used to treat more than 80 life-threatening conditions, ranging from cancer and immune deficiency to metabolic and genetic disorders. The therapy is predicated on the idea that stem cells in the cord blood will traffic to the bone marrow, where they can help rebuild a healthy blood and immune system that has been damaged by disease. But cord blood stem cells are not naturally adept at this process--which is why several drugmakers have turned to FTVI as a way of enhancing the cells' homing ability.

FTVI is an enzyme involved in tagging cells with sugar molecules in a way that alters migration patterns in the body. In clinical trials, cord blood stem cells treated with FTVI showed enhanced engraftment following infusion into cancer patients. Yet most commercial sources of FTVI available today have only limited enzymatic activity. Plus, they tend to be made using various expression systems that either produce enzymes with low activity or are costly and generate low yields.

Seeking a better manufacturing platform, a team led by Jasmeen Merzaban at KAUST engineered yeast cells and silkworm larvae to express the human version of FTVI. Working with collaborators in Japan, KAUST researchers from several teams came together to devise a purification scheme for obtaining the enzyme at high yields; they then tested how efficiently the end-product could alter human stem cells.

The researchers showed that their yeast- and silkworm-derived FTVI far outperformed commercial sources of the enzyme made in standard expression systems. "Now, these enzymes can be used ex vivo on stem cells to enhance their migration toward the bone marrow during a transplant," Merzaban says.

Alternatively, researchers could take advantage of the new yeast- and silkworm-produced FTVI for drug screening efforts. First author of the study, Asma Al-Amoodi, points out that many metastatic cancers exhibit enhanced activity of FTVI and similar enzymes. "We could envision using such enzymes to screen for small molecule inhibitors that block metastasis," she says.