Culture

Tskuba, Japan - Whether it's our diets, building strength, or as part of medical advancements, it is no secret that proteins form an important part of our lives. Tracking how proteins work and move in cells, and purifying engineered proteins, are important tools for researchers. Traditional approaches to label proteins of interest, called "tagging," have the disadvantage of interfering with protein characteristics, including function and localization. Sometimes, these tags can also cross-react, which makes the information they provide nonspecific. A successful protein tagging system needs to be highly specific and have high affinity.

In a study published in September 2020 in Frontiers in Plant Science, researchers from the University of Tsukuba, led by Professor Kenji Miura, have described a new tagging system for detecting and purifying proteins in plant cells. This approach uses a short sequence called a "RAP tag" to label proteins. An antibody, PMab-2, is then able to specifically recognize the RAP tag and can be used to purify the proteins of interest.

In describing this approach, Professor Miura says, "The high affinity and specificity of immunoaffinity chromatography using monoclonal antibodies makes it a very powerful tool, especially for the purification of proteins expressed at low levels." A hurdle to applying this approach, however, is the high cost of reagents, especially that of antibodies.

To get around this, Professor Miura and colleagues explored whether they could produce the PMab-2 antibody in the plant model Nicotiana benthamiana, a relative of the tobacco plant. Not only could they successfully produce PMab-2, they went on to show that the plant-produced PMab-2 behaved similarly to that produced in animal cells. This discovery opens the door to reducing the cost of antibody production, and could be applied more widely across scientific fields.

Testing the feasibility of a RAP-tagged/ PMab-2 affinity purification approach, the researchers then expressed RAP-tagged proteins in plant cells. They found that these tagged proteins could be specifically identified using the PMab-2 antibody. Moreover, RAP-tagged recombinant proteins, involving the fusion of sequences from more than one protein, and protein complexes were also expressed in these cells and identified by PMab-2. These proteins could also be purified from plant cells using the PMab-2 antibody, indicating that the RAP tag can be used for both protein detection and purification from soluble plant extracts.

"Plants are an extremely valuable resource for molecular biology," explains Professor Miura. "They can be used as bioreactors to produce large amounts of proteins because they are unlikely to suffer from contamination issues faced by bacterial and mammalian cell systems."

The results presented by the team show that this approach has the potential to be widely applied across the molecular sciences.

Osaka, Japan. Quantum computers are the new frontier in advanced research technology, with potential applications such as performing critical calculations, protecting financial assets, or predicting molecular behavior in pharmaceuticals. Researchers from Osaka City University have now solved a major problem hindering large-scale quantum computers from practical use: precise and accurate predictions of atomic and molecular behavior.

They published their method to remove extraneous information from quantum chemical calculations on Sept. 17 as an advanced online article in Physical Chemistry Chemical Physics, a journal of the Royal Society of Chemistry.

"One of the most anticipated applications of quantum computers is electronic structure simulations of atoms and molecules," said paper authors Kenji Sugisaki, Lecturer and Takeji Takui, Professor Emeritus in the Department of Chemistry and Molecular Materials Science in Osaka City University's Graduate School of Science.

Quantum chemical calculations are ubiquitous across scientific disciplines, including pharmaceutical therapy development and materials research. All of the calculations are based on solving physicist Erwin Schrödinger's equation, which uses electronic and molecular interactions that result in a particular property to describe the state of a quantum-mechanical system.

"Schrödinger equations govern any behavior of electrons in molecules, including all chemical properties of molecules and materials, including chemical reactions," Sugisaki and Takui said.

On classical computers, such precise equations would take exponential time. On quantum computers, this precision is possible in realistic time, but it requires "cleaning" during the calculations to obtain the true nature of the system, according to them.

A quantum system at a specific moment in time, known as a wave function, has a property described as spin, which is the total of the spin of each electron in the system. Due to hardware faults or mathematical errors, there may be incorrect spins informing the system's spin calculation. To remove these 'spin contaminants,' the researchers implemented an algorithm that allows them to select the desired spin quantum number. This purifies the spin, removing contaminants during each calculation--a first on quantum computers, according to them.

"Quantum chemical calculations based on exactly solving Schrödinger equations for any behavior of atoms and molecules can afford predictions of their physical-chemical properties and complete interpretations on chemical reactions and processes," they said, noting that this is not possible with currently available classical computers and algorithms. "The present paper has given a solution by implementing a quantum algorithm on quantum computers."

The researchers next plan to develop and implement algorithms designed to determine the state of electrons in molecules with the same accuracy for both excited- or ground-state electrons.

A new study conducted by researchers at the University of Eastern Finland found that the PLCG2-P522R genetic variant, which protects against Alzheimer's disease, enhances several key functions of immune cells. The results obtained in the study highlight the importance of immune cells as a target of future development of new therapies for Alzheimer's disease.

Alzheimer's disease is the most common form of dementia with more than 40 million affected people worldwide. To this day, there are no existing therapies for the effective prevention or treatment of the disease. Many recently identified Alzheimer's disease-associated risk genes are expressed preferentially or exclusively in microglia, the immune cells of the brain. A study conducted in collaboration with the University of Eastern Finland and the German DZNE institute investigated the role of the microglia-specific Plcg2-P522R genetic variant in Alzheimer's disease and found that it enhances several immune cell-specific functions. The results were published in the Molecular Neurodegeneration journal.

A genome-wide association study from 2017, which included a Finnish cohort of Alzheimer's disease patients and healthy controls, identified Alzheimer's disease-associated risk loci in three genes, TREM2, ABI3 and PLCG2, which are mainly expressed in microglia. Several genetic variants of the TREM2 gene have been found to increase the risk for Alzheimer's disease. These TREM2 variants lead to a partial loss of function of the receptor and impair the activation of microglia. Consequently, the removal of β-amyloid, which accumulates in the brain during Alzheimer´s disease, is reduced. Recently, it has been shown that the phospholipase C gamma 2 (PLCγ2) enzyme is involved in the signaling pathway initiated by TREM2. The PLCG2-P522R variant reduces the risk of developing Alzheimer's disease, but its effects on immune cell functions have not been previously described.

"It is interesting how several Alzheimer's disease-associated risk genes affect microglial cell functions through the same signaling pathway. It shows that targeting this pathway and the cellular functions it regulates may have significant therapeutic potential in the future," says Postdoctoral Researcher Mari Takalo from the Institute of Biomedicine of the University of Eastern Finland.

Protective variant sensitizes and activates immune cells

For this study, a mouse model carrying the Plcg2-P522R genetic variant was developed using the CRISPR-Cas9 gene editing technique in collaboration with the research group of German Professor Christian Haass at the DZNE Institute. The researchers found that the Plcg2-P522R variant increases PLCγ2 enzyme activity and enhances cell viability, phagocytic activity, and immune response in peripheral macrophages as well as in microglia-like cells. The results are in line with a recently published study in which deletion of the PLCG2 gene in microglial cells produced from human-induced stem cells had opposite effects.

"It is intriguing that results generated from cells of different origins that have been exposed to different methods of genetic modification, all point in a similar direction. Although this is just the beginning of research related to the role of PLCγ2 in the context of Alzheimer's disease, these results encourage to continue with further studies," Early Stage Researcher Rebekka Wittrahm says.

The study also looked at the effects of the protective Plcg2-P522R variant in the brain of mice. The changes observed in both the RNA expression analysis and the PET imaging study measuring microglial cell activity suggest increased microglial cell activity in Plcg2-P522R mice.

"Microglial cells with the protective genetic modification seem to be more sensitive to various environmental stimuli and thus, may become more efficient at removing material harmful to the brain, such as β-amyloid. Further research is needed to find out exactly how sensitized microglial cells react in the presence of Alzheimer's disease-related changes in the aging brain," Takalo sums up.

"It is pivotal that we are able to study the role of genes associated with Alzheimer's disease comprehensively at the University of Eastern Finland, from the identification of the risk gene to further functional studies in animal models and patient cohorts," says Professor Mikko Hiltunen, who spearheads the research group.

The framework, published in Frontiers in Microbiology, was applied on transmission data of the influenza virus, and offers to be a new tool for anticipating the consequences of microbial diversity and optimizing disease control measures.

Estimating fitness variation among microorganisms, meaning their aptitude to survive and reproduce in given conditions, allows to predict their infection trajectories in single hosts and transmission in host populations. Among two viral strains, which will be the one to win against the host's immune response, or upon administration of drugs and vaccines? In virus dynamics, understanding in detail such scenarios is crucial, given the increase in resistance to antivirals and other evolutionary changes. Nowadays, this understanding is enhanced via mathematical models, but the majority of current approaches describe limited scenarios, focusing on competitive exclusion, where one strain of the virus always wins over another because it has higher fitness.

The Mathematical Modelling of Biological Processes research group from Instituto Gulbenkian de Ciência developed a mathematical framework that enables extension beyond such limitation. Based on the Lotka-Volterra model, widely used in ecology, the researchers propose a framework that allows, in addition, verification of scenarios of frequency-dependent competition between microbial strains in a host leading up to transmission. "We applied this framework to a dataset obtained from previous studies, where they estimated different parameters related to differences in transmission fitness between two influenza virus strains in ferrets", explains Erida Gjini, lead author of the study. "We went further and, by considering more complex interactions between viruses and the role of stochasticity in transmission, we showed that for the same dataset our model predicts a scenario of coexistence between strains and reveals a higher transmitted viral load", concludes the researcher.

The advantage of this framework lies in its simplicity and generality: the model can be applied to other ecological scenarios of microbial competition, while allowing exploration of more outcomes from the competitive dynamics between two strains.

This study was developed at Instituto Gulbenkian de Ciência and in collaboration with the Master program in Biostatistics at the Faculty of Sciences, University of Lisbon.

Researchers at Tokyo Institute of Technology (Tokyo Tech) have developed a high-performance reusable ruthenium-based catalyst for the production of primary amines. Their method represents a major advance for the development of efficient catalysts that enable selective conversion of alcohols into primary amines under mild reaction conditions.

Primary amines are extremely versatile building blocks that are used in the preparation of many kinds of dyes, detergents, pharmaceuticals and agricultural chemicals. So far, several methods have been developed to produce primary amines using catalysts containing ruthenium, cobalt and platinum, all of which require the addition of molecular hydrogen. Synthesis of primary amines by direct substitution of alcohols with ammonia has been a longstanding challenge.

Now, researchers at Tokyo Tech report a heterogeneous[1] ruthenium-based catalyst (Ru-MgO/TiO2) capable of driving direct amination[2] of alcohols to produce primary amines without having to introduce hydrogen gas. They showed that the catalyst works at low temperatures, of around 100°C. The ready availability of alcohols and low cost of ammonia make the system both cost-effective and environmentally friendly.

Compared with previous ruthenium-based systems, Ru-MgO/TiO2 achieved higher yields (up to 94%) of the desired primary amines. Reuse experiments showed that after base treatment, the catalyst could be reused three times without significant loss of activity.

Their study, published in Chemical Science, suggests that the MgO component of the catalyst plays an important role in enhancing reactivity through electron donation from MgO to Ru.

The researchers point out that the new catalytic system could be applied to a variety of alcohols, and could serve as a design guide for other new heterogeneous catalysts.

In addition, Ru-MgO/TiO2 could provide an efficient synthetic route for the production of 2,5-bis(aminomethyl)furan (BAMF), an attractive compound used as a hardener for epoxy resins, which are used in many types of coatings and adhesives. Using biomass-derived 2,5-bis(hydroxymethyl)furan (BHMF) as a substrate, the study showed the desired BAMF was obtained at 86% yield, outperforming previous systems.

Chimpanzees, gorillas and orangutans are our closest relatives, and like us they have relatively large brains and they are very intelligent. But do animals with larger brains really perform better in cognitive tests? A research team from the German Primate Center (DPZ) - Leibniz Institute for Primate Research in Göttingen has for the first time systematically investigated the cognitive abilities of lemurs, which have relatively small brains compared to other primates. Conducting systematic tests with identical methods revealed that cognitive abilities of lemurs hardly differ from those of monkeys and great apes. Instead, this study revealed that the relationship between brain size and cognitive abilities cannot be generalized and it provides new insights into the evolution of cognitive abilities in primates.

Humans and non-human primates are among the most intelligent living beings. Their brain size may underly their intelligence as primates have relatively large brains in relation to their body size. For example, it is assumed that larger brains enable faster learning and better memory capacities. Within primates, however, species can differ up to 200-fold in brain size. A team of researchers from the German Primate Center (DPZ) has now investigated whether the cognitive performances of lemurs with their relatively small brains differ from those of other primates.

Using a comprehensive standardized test series of cognitive experiments, the so-called "Primate Cognition Test Battery" (PCTB), small children, great apes as well as baboons and macaques have already been tested for their cognitive abilities in the physical and social domain. Cognitive skills in the physical domain include the understanding of spatial, numerical and causal relationships between inanimate objects, while cognitive skills in the social domain deal with intentional actions, perceptions and the understanding of the knowledge of other living beings. Initial studies have shown that children possess a better social intelligence than non-human primates. In the physical domain, however, the species hardly differed even though they show great variation in their relative brain sizes.

For the first time, researchers of the "Behavioral Ecology and Sociobiology Unit" of the DPZ have now tested three lemur species with the PCTB. Lemurs are the most basal living primates and represent the evolutionary link between primates and other mammals, which is why they serve as a living model of primates' origin of cognitive abilities. The study examined ring-tailed lemurs, black-and-white ruffed lemurs and grey mouse lemurs, which differ in their social system, diet and brain size, not only among each other, but also compared to the previously tested Old World monkeys and great apes.

The results of the new study show that despite their smaller brains lemurs' average cognitive performance in the tests of the PCTB was not fundamentally different from the performances of the other primate species. This is even true for mouse lemurs, which have brains about 200 times smaller than those of chimpanzees and orangutans. Only in tests examining spatial reasoning primate species with larger brains performed better. However, no systematic differences in species performances were neither found for the understanding of causal and numerical relationships nor in tests of the social domain. Neither diet, nor social system or brain size could explain the results from the PCTB experiments. "With our study we show that cognitive abilities cannot be generalized, but that species instead differ in domain-specific cognitive skills," says Claudia Fichtel, one of the two first authors of the study funded by the German Research Foundation. "Accordingly, the relationship between brain size and cognitive abilities cannot be generalized".

The study represents the first systematic and comparative investigation of cognitive abilities in lemurs and provides important insights into the evolution of cognitive abilities in primates. However, the research team also emphasizes that further comparative studies in a variety of other species are essential to answer the many questions about the relationship between brain size, diet, social life and cognition.

The behavior of cells is controlled by their environment. Besides biological factors or chemical substances, physical forces such as pressure or tension are also involved. Researchers from Karlsruhe Institute of Technology (KIT) and Heidelberg University developed a method that enables them to analyze the influence of external forces on individual cells. Using a 3D printing process, they produced micro-scaffolds, each of which has four pillars on which a cell is located. Triggered by an external signal, a hydrogel inside the scaffold swells and pushes the pillars apart, so that the cell must "stretch." The work is part of the "3D Matter Made to Order" (3DMM2O) Cluster of Excellence. The researchers report on their results in Science Advances (DOI: 10.1126/sciadv.abc2648).

Many cellular biological processes, such as wound healing or the development of tissue, are strongly influenced by the properties of their environment. Cells react, for example, to biological factors or chemical substances. However, research is increasingly focusing on physical forces acting on the cells: How exactly do the cells adapt to these forces?

Within the framework of the German-Japanese University Consortium HeKKSaGOn and in cooperation with Australian scientists, the 3DMM2O team has taken a particularly ingenious approach to this question. For the production of their cell "stretching racks" they used "direct laser writing", a special 3D printing process in which a computer-controlled laser beam is focused into a special printer ink liquid. Its molecules react only at the exposed areas and form a solid material there. All other areas remain liquid and can be washed away. "This is an established method in our Cluster of Excellence for building three-dimensional structures - on the micrometer scale and below," explains Marc Hippler from the KIT Institute of Applied Physics, lead author of the publication.

In the current case, the researchers used three different printer inks: The first ink, made of protein-repellent material, was used to form the actual micro-scaffold. Using a second ink of protein-attracting material, they then produced four horizontal bars that are connected to one of the scaffold pillars each. The cell is anchored to these four bars. The real showstopper, however, is the third ink: The scientists used it to "print" a mass inside the scaffold. If they then add a special liquid, the hydrogel swells. It thus develops a force sufficient to move the pillars - and the bars with them. This, in turn, has the effect of stretching the cell that is fixed to the bars.

Cells counteract deformation

The scientists of the Cluster of Excellence placed two completely different cell types on their micro stretching rack: human bone tu-mor cells and embryonic mouse cells. They found that the cells counteract the external forces with motor proteins and thus greatly increase their tensile forces. When the external stretching force is removed, the cells relax and return to their original state. "This be-havior is an impressive demonstration of the ability to adapt to a dynamic environment. If the cells were unable to recover, they would no longer fulfill their original function - for example wound closure," says Professor Martin Bastmeyer from the Zoological Institute of KIT.

As the team further discovered, a protein called NM2A (non-muscle myosin 2A) plays a decisive role in the cells' response to mechani-cal stimulation: Genetically modified bone tumor cells that cannot produce NM2A were barely able to counteract the external defor-mation.

Work in the cluster of excellence was carried out by Heidelberg scientists from the field of biophysical chemistry as well as physics and cell- and neurobiology from KIT. Members of the German-Japanese University Consortium HeKKSaGOn include, among oth-ers, Heidelberg University, Karlsruhe Institute of Technology and Osaka University.

Cluster of Excellence 3D Matter Made to Order

In the 3D Matter Made to Order (3DMM2O) Cluster of Excellence, scientists of Karlsruhe Institute of Technology and Heidelberg Uni-versity conduct interdisciplinary research into innovative technolo-gies and materials for digital scalable additive manufacture to en-hance the precision, speed, and performance of 3D printing. Work is aimed at completely digitizing 3D manufacture and materials pro-cessing from the molecule to the microstructure. In addition to fund-ing as a cluster of excellence under the Excellence Strategy compe-tition launched by the federation and the federal states, 3DMM3O is financed by Carl Zeiss Foundation.

People with bone, joint and muscle pain saw their symptoms worsen during lockdown - according to new research from the University of East Anglia.

A new study published today shows that the majority of people with musculoskeletal pain reported increased symptoms - as the nation adhered to new government restrictions designed to stop the spread of the Covid-19 pandemic.

And those who experienced most social isolation and loneliness were less likely to access healthcare.

The findings are the result of a survey of more than 600 people across the UK to see how people with bone, joint and muscle pain coped in lockdown.

The study was led by Dr Toby Smith, from UEA's School of Health Sciences, and Prof Alex MacGregor, from UEA's Norwich Medical School.

Dr Toby Smith said: "Bone, joint and muscle pain is a major cause of disability for people across the UK. People with these problems often experience pain, joint stiffness, fatigue and muscle weaknesses.

"Bone, joint and muscle diseases are frequently managed with a combination of physical activity and medications.

"Our results show that the coronavirus pandemic is a major challenge to people's health and wellbeing, both to young and older people.

"When lockdown happened, we were worried that this may become a much greater problem - particularly for those with bone, joint and muscle pain.

"We wanted to know how the new restrictions might be affect pain, and better-understand who is most at risk of experiencing flare-ups, or reduced wellbeing due to social isolation and loneliness."

The team launched an online survey in late April, five weeks after the start of lockdown in a group of 678 patients with a range of musculoskeletal diseases - to see how the restrictions impacted their wellbeing and ability to access healthcare.

Prof MacGregor, who also works at the Rheumatology Department at the Norfolk and Norwich University Hospital (NNUH), said: "We found that the majority of survey participants, just over 53 per cent, reported that their musculoskeletal symptoms had worsened since the start of lockdown.

"A third of patients reported needing to access either their GP or hospital rheumatology department. As might be expected, those who accessed healthcare reported significantly greater pain, stiffness and poorer general health.

"And we found that those who reported greater social isolation and loneliness were less likely to access healthcare.

"Most respondents, just over 88 per cent, reported little difficulty accessing medication, but 44 per cent of needed the assistance of others to do this.

"This survey, conducted in the early stages of the UK lockdown, suggests that there have been immediate negative consequences for people with musculoskeletal disease.

"Despite the swift transformations in the configuration of healthcare that have taken place, patients have in the main been able to access primary care and hospital rheumatology departments. However, those with higher levels of social isolation access healthcare the least.

"Should further isolation measures need to be enforced as we have seen in some part of the UK as the pandemic continues, particular efforts should be made to protect and support the socially isolated as a vulnerable group.

"Healthcare providers should reach out to individual patients who do not come forward for advice, and who might be silently struggling with their disease," he added.

A novel optical switch makes it possible to precisely control the lifespan of genetic "copies". These are used by the cell as building instructions for the production of proteins. The method was developed by researchers from the universities of Bonn and Bayreuth. It may significantly advance the investigation of dynamic processes in living cells. The study is published in the journal Nature Communications.

Metaphorically speaking, every human cell contains in its nucleus a huge library of tens of thousands of books, the genes. Each of these books in turn contains the building instructions for a protein. When the cell needs a certain protein, a transcription of the corresponding instructions is made. These transcriptions are called mRNAs (RNA is a slightly modified form of DNA).

A cellular mechanism ensures that the mRNA transcriptions are "shredded" again after a short time. This ensures that the protein is only produced as long as it is actually needed. Several decades ago, researchers came up with the idea of using this shredder for their own purposes: By specifically attaching a marker to certain mRNAs, they ensure that the transcriptions are not used as building instructions at all, but are destroyed immediately: a process also known as RNA silencing. The cell then lacks the corresponding protein. This makes it possible to find out which function it would actually be responsible for.

Bacterial molecule as light-dependent switch

The approach that the groups from Bonn and Bayreuth have now published is based on this method. However, it is nowhere near as crude, but allows a far more differentiated control over the lifespan of the mRNA copies. "We use a bacterial molecule to control the shredding of mRNA transcriptions with the help of light," explains Prof. Dr. Günter Mayer, who heads the Chemical Biology & Medicinal Chemistry Research Group at the LIMES Institute of the University of Bonn.

The bacterial molecule with the abbreviation PAL acts as a kind of switch. It changes its shape under the influence of blue light. In the process, a pocket is exposed that can bind to certain molecules. "We searched a huge library of artificially produced short RNA molecules called aptamers," says Mayer. "Eventually we came across an aptamer that's a good match for the pocket in the PAL molecule."

The researchers have now coupled this aptamer to one of the molecular markers that can attach to mRNAs and thereby release them for degradation. "When we irradiate the cell with blue light, PAL binds to the marker via the aptamer and thus puts it out of action," explains Mayer's colleague Sebastian Pilsl. "The mRNA is then not destroyed, but translated into the corresponding protein." As soon as the researchers switch off the blue light, PAL releases the label again. Now it can attach itself to the mRNA, which is then shredded.

This will in future enable researchers to investigate exactly where and when a protein is needed in a cell, simply by immersing an area of the cell in blue light at a certain time and then looking at the consequences. In the current study they applied this to proteins that play an important role in the regulation of the cell cycle and cell division. The combination of aptamer and degradation marker is introduced into the cell by genetic engineering. This means that it generates the light-dependent degradation signal itself; it does not have to be supplied from outside.

Gene transcriptions can be specifically switched off

The aptamer can be combined with any markers, each of which in turn serves as a shredder signal for a specific mRNA. "This method can therefore be used to switch off practically every mRNA molecule in the cell in a controlled manner," emphasizes Prof. Dr. Andreas Möglich from the University of Bayreuth. In the recently published pilot study, it all worked both simply and reliably. The researchers therefore see great potential in their method for the investigation of dynamic processes in living cells and organisms.

A researcher at the University of Maryland, Baltimore County (UMBC) has developed a unique method to improve class participation in a graduate-level thermodynamics course by incorporating theater improvisation activities in the classroom. Erin Lavik, associate dean for research and faculty development and professor of chemical, biochemical, and environmental engineering at UMBC, wanted to find a way to encourage better participation in a thermodynamics seminar, and thought that allowing students to warm up to each other through theater exercises might improve their confidence when discussing complex topics. Based on her case studies of class participation on days when improv activities were conducted and also on anonymous survey feedback from students, Lavik confirmed that the improv activities led to a higher rate of engagement and participation. The findings are published in Biomedical Engineering Education.

The research was conducted over the course of the Fall 2019, Spring and Summer 2020 terms, and the improvisation techniques were used both in person and digitally, after remote learning became the new normal. Lavik used a variety of improv games at the beginning of class periods. One example is "Yes, and," which encourages students to listen to each other and build upon what the previous person said in order to create a nonsensical story.

The importance of listening in this game fosters an attentive classroom. Everyone is expected to participate at least once in the story, which creates a community of students that are primed to pay attention and respond to one another easily. In the survey data that Lavik collected, students said that when the improv games took place, they felt more alert, engaged, and ready to participate.

These findings are situated in a larger body of evidence indicating that doing improvisation exercises can support alertness. Students who believe that they are able to improvise and think on their feet use that knowledge to reduce their anxiety both in their studies and in general. The positive reinforcement associated with the activities after their completion was intended to leave students feeling more comfortable talking and making mistakes in the course.

Now that most university instruction is taking place online, participation in seminars and discussions is more important than ever, but these platforms make it even less likely that students will participate actively. However, given that the improvisation activities can be done completely online and show promising initial results, Lavik believes that the technique might help to engage everyone more effectively.

"The improv exercises often led to laughter, especially the exercises that were inspired by thermodynamics," says Lavik. "It helps create an environment where it is ok to try out new ideas and experiment. It is easier to ask questions when people feel like they are part of a group."

The use of this interdisciplinary method has proven to be highly effective at engaging students and creating a classroom community, especially important given the common limitations of online learning. Providing a final note on the benefits of this project, Lavik says, "We can do a lot to augment learning by being creative across disciplines. This is just one example of why it is so important to talk across our expertise, sharing ideas and techniques across different fields."

New research from Public Health England (PHE) presented at this week's ESCMID Conference on Coronavirus Disease (ECCVID) shows up to half of UK key workers from a cohort of just under 3,000 individuals recruited (including police, fire and healthcare workers) who had self-reported symptoms of COVID-19 did not test positive for antibodies to the disease. This suggests that their symptoms were due to other conditions. The study was presented by Ranya Mulchandani, PHE, Birmingham, UK in collaboration with PHE colleagues and academic partners across the UK.

Screening for SARS-CoV-2 antibodies is under way in some key worker groups; however, how this adds to self-reported COVID-19 illness is unclear. In this study, the team investigated the association between self-reported belief of COVID-19 illness and seropositivity.

The authors carried out a study of three key worker groups which took place at six acute NHS hospitals and two Police and Fire & Rescue sites across England in June 2020. They recruited individuals from three streams: (A) Police and Fire (B) healthcare workers and (C) healthcare workers with previously positive PCR result for COVID-19 (this last group was used to assess the immunoassay sensitivities, namely the ability of the antibody tests to correctly identify those with SARS-CoV-2 antibodies or 'true positive' rate.

The team used a study-specific questionnaire to collect self-reported signs and symptoms of COVID-19 and compared this with serology results from two SARS-CoV2 immunoassays (Nucleoprotein - Roche Elecsys ® and Spike-protein - EUROIMMUN).

Between 01 and 26 June, 2847 individuals were recruited: 1147 from Stream A, 1546 from Stream B and 154 from Stream C. 943 of the 2847 participants (33%) reported belief they had had COVID-19, having experienced compatible symptoms; however, 466 (49%) of these were seronegative on both antibody assays, meaning it is very unlikely they had had COVID-19. The Roche Elecsys ® and EUROIMMUN assays had 96.6% and 93.3% sensitivity respectively.

The researchers found that symptomatic but seronegative individuals had significantly earlier dates of symptom onset than the symptomatic seropositive individuals, shorter illness duration and a much lower reporting frequency of anosmia (lost of sense of taste and smell).

Self-reported belief of COVID-19 was common among the frontline worker cohort. About half of these individuals were seronegative, despite a high sensitivity (accuracy) of serology in this cohort, at least in individuals with previous positive PCR results. These data suggest that self-reported symptoms substantially overestimate COVID-19 disease relative to serology, and that in the key worker cohort studied, many mistook non-COVID-19 respiratory disease, particularly during the early part of the COVID-19 outbreak, as COVID-19.

Ranya Mulchandani, UK-FETP Field Epidemiology Fellow at Public Health England and the study's lead author, said: "In the course of this study, we tested just under a thousand people who thought they had had COVID-19 due to compatible symptoms. We found that half of them lacked any evidence of having had the infection, testing negative for the presence of antibodies. This was also true for a substantial number of frontline health workers. Although these findings are still subject to peer review, it is possible that a large number of people in the general population incorrectly believe that they have already had COVID-19. It is crucial that people do not get complacent and continue to observe government health advice, including social distancing and good hand hygiene, even if they think they have been infected in the past."

New research presented the ESCMID Conference on Coronavirus Disease (ECCVID, online 23-25 September) shows that the severe COVID-19 immunological profile, represented by changes in cell populations and circulating inflammatory proteins, is already partly present in older healthy individuals.

"Some of these dysregulations might not be a direct result of the infection but rather an underlying profile that is permissive to a more severe form of the disease," explains co-author Ozlem Bulut, Radbound University Medical Center, Nijmegen, Netherlands.

The majority of individuals who experience COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), present a mild, self-limiting respiratory infection and recover in a few days. However, the disease can also progress and cause a severe acute respiratory distress syndrome (ARDS) in around 10-15% of the patients.

The fatality rate of COVID-19 increases with age, reaching more than 20% in patients over 80 years of age. A hyperinflammatory profile and various dysregulated immunological processes are linked to disease severity, however, whether these are caused by the disease or play an underlying role in disease pathogenesis is not yet clear.

In this study, the authors investigated a series of immune cell populations and 28 circulating inflammatory markers previously linked with COVID-19 severity in two cohorts of healthy Western European individuals: the first one including 324 people with an age range of 18-71, and the second one including 452 people with an age range of 18-75.

"After correcting the data for the sex of the participants, we observed that many inflammatory markers and changes in cell populations linked with severe COVID-19 correlate with age in healthy individuals," explains senior co-author Professor Mihai Netea, also of Radboud University Medical Center, Nijmegen, Netherlands.

These parameters include changes to white blood cells including increased non-classical monocyte numbers, a critical decrease in T lymphocytes, particularly some types of CD8+ and CD4+ lymphocytes and naïve regulatory T cells, elevated circulating levels of monocyte chemoattractant protein 1 (MCP1) that induces immune cell accumulation in organs, osteoprotegerin (OPG) that may increase survival of certain cell populations, hepatocyte growth factor (HGF) that activates both immune and epithelial cells, and declined concentrations of receptor activator of nuclear factor kappa-Β ligand (RANKL/TRANCE). Interleukin-6, a marker of inflammation and one of the major biomarkers of COVID-19 severity, also increases with age in both cohorts.

The authors conclude: "Age is one of the biggest risk factors of COVID-19 severity and fatality. Our results suggest that the severe COVID-19 immunological profile, represented by changes in cell populations and circulating inflammatory proteins, is already partly present in aged healthy individuals. Therefore, some of these dysregulations might not be a direct result of the infection but rather an underlying profile that is permissive to a more severe form of the disease. In conclusion, the identified markers might explain the high susceptibility of older individuals to severe COVID-19 and inform efforts to prevent and treat the disease."

New research presented at the ESCMID Conference on Coronavirus Diseases (ECCVID, online 23-25 September) suggests that the higher risk of poor COVID-19 outcomes in men could be explained by differences in circulating proteins and immune system cells compared with women. The study is by Gizem Kilic, Radbound University Medical Center, Nijmegen, Netherlands, and colleagues.

Although the disease symptoms of COVID-19 caused by SARS-CoV-2 are mild in most of the cases, elderly people and individuals with co-morbidities such as cardiovascular diseases and diabetes are more susceptible to COVID-19, especially in the case of males. However, why males are more susceptible to develop severe infections has not yet been fully understood.

In this study, the authors analysed the levels of circulating inflammatory proteins and whole blood cell populations related to COVID-19 infection severity in two healthy Western European cohorts and investigated whether these immune parameters vary between sexes.

They detected and quantified the levels of 96 circulating proteins, and also the white blood cell population. "Following the age adjustment of data by statistical modelling, we identified several circulating inflammatory proteins and cell populations which might be behind the higher susceptibility of males to develop severe infection and COVID-19 disease," explains senior co-author Professor Mihai Netea, also of Radboud University Medical Center, Nijmegen, Netherlands.

The team found that certain while blood cells in the immune system, including total, naïve, memory T and naïve CD4+ T cell counts that are reported to decrease with COVID-19 severity were also lower in healthy males. However, levels of an important growth factor in T cell generation, interleukin-7, were similar in males and females.

Furthermore, they discovered that molecules involved in inflammation including monocyte chemoattractant protein-1 (MCP-1), interleukin-8, hepatocyte growth factor (HGF) that stimulates immune and epithelial cells, and S100 calcium binding protein A12 (S100A12 or EN-RAGE) levels were high in healthy males of both cohorts and also in patients in the intensive care unit. This indicates that immune mediators that contribute to a more severe COVID-19 infection are already intrinsically higher in males.

The authors conclude: "Sex is one of the major factors which influence our immune system response. Our results suggest that differences between the sexes in the baseline characteristics of the immune system such as circulating proteins and immune cell populations might explain the predisposition of males over females to develop severe COVID-19 infection."

A new study into the causes of sensorimotor impairments prevalent among autistic people could pave the way for better treatment and management in the future, say psychologists.

Publishing findings in the leading journal BRAIN [today: Friday 25 September], the scientists from the universities of Exeter and Bath present fresh evidence that sensorimotor difficulties associated with autism are likely caused by a number of complex and precise neurobiological processes, including differences in the way autistic people perceive the world around them.

Common sensorimotor features associated with autism can include sensory overload and impaired hand-eye coordination but also general clumsiness. In addition to the well-documented challenges traditionally associated with autism - notably in social communication and interaction, and restricted and repetitive patterns of behaviours - these impairments represent a major hurdle for individuals and typically will last throughout their lives.

Yet, despite this, surprisingly little is known about the origins or mechanisms underlying these behavioural traits and their specific impacts on an individual's quality of life. For this study researchers used state-of-the-art mobile eye-tracking and motion capture technology to understand more about the causes of these difficulties and how they might be better managed.

Enlisting over 150 people both with and without autism, they tested a number of processes and mechanisms associated with sensorimotor difficulties. Most significantly, they found that many processes that were previously thought to underpin these movement difficulties in autism actually do not appear to be impaired. The research is part of a South West Doctoral Training Partnership studentship in affiliation with the ESRC and was led by Tom Arthur - a PhD student at both the universities of Exeter and Bath.

He explains: "This study looked at how individuals control their hand-eye movements when picking up and lifting things - anyone who's lifted an empty suitcase they thought was full of clothes will know that we usually do this in a very predictive way.

"Our results showed that autistic people lift new objects in just as predictive a way as non-autistic people. These findings go against many existing research theories, and indicate that previous conclusions in the field may have been a bit too broad or simplistic. This is important, because many daily living skills and behaviours depend on an individual's ability to predict the world and act upon their prior expectations".

Co-author Dr Gavin Buckingham from the Department of Sport and Health Sciences at the University of Exeter added: "It is increasingly clear that sensory and movement-based difficulties are core characteristics of autism that have implications for most autistic people's lives. However, there is currently a real lack of scientific understanding about these features and an absence of evidence-based interventions for managing these daily living difficulties."

Professor Mark Brosnan, Director of the Centre for Applied Autism Research at the University of Bath, said: "By advancing our understanding of the challenges that autistic people experience when trying to predict an unpredictable world, this research will have great implications for practice. Already the team are exploring the practical implications of this research within Virtual Reality Environments."

It is hoped such work could form the basis of future teaching and coaching interventions that aim to combat autism-related sensorimotor difficulties.

Autism is a neurodevelopmental condition which is diagnosed in 1- 2% of individuals typically on the basis of persistent difficulties with social communication and interaction and / or restricted and repetitive patterns of behaviours, activities or interests. In addition, sensorimotor impairments are considered as 'cardinal' features of autism.

Experts identify five key factors for strategies to ease lockdown restrictions - knowledge of infection levels, community engagement, public health capacity, health system capacity, and border control measures.

Analysing the successes and failures of nine high-income countries and regions across these five domains, the authors find an absence of clear and consistent strategies for exiting restrictions and identify key cross-country lessons that can still be learnt.

Experience with past pandemics in Asia Pacific meant they were more prepared than European countries, where policies of economic austerity have weakened health system in the years leading up to the current crisis.

An ambition to achieve a 'Zero COVID' strategy (eliminating domestic transmission), like in New Zealand, should be considered by other governments, suggest the authors.

Authors of a review of policies, based on the experiences of nine high-income countries and regions' easing of lockdown measures, published in The Lancet journal, are urging governments to consider five key factors in lockdown exit strategies.

The report analyses nine countries and regions' strategies for easing COVID-19 restrictions from a first wave of infections: five in the Asia Pacific (Hong Kong, Japan, New Zealand, Singapore, South Korea) and four in Europe (Germany, Norway, Spain, the United Kingdom).

After instituting full or partial lockdowns, many governments face the challenge of reopening society while balancing health, social, and economic considerations. Meanwhile, WHO has warned that a premature lifting of lockdowns could spark a resurgence of infections and cause worse damage to the economy than caused by lockdowns. [1]

Lead author, Dr Helena Legido-Quigley, National University of Singapore and London School of Hygiene & Tropical Medicine, says, "COVID-19 is a serious disease that will be with us for a long time. There is increasing realisation that easing of lockdown is not about returning to a pre-pandemic normal, and governments have to find strategies that will prevent rapid growth of infections in ways that are sustainable and acceptable to the public over many months." [2]

Dr Legido-Quigley adds, "Our review of international experiences identifies lessons governments can learn from each other's successes and failures. We are not advising that the exact same measures should be replicated in different countries, but it is not too late for governments to consider novel policy solutions developed by other countries and adapt them to fit their own context." [2]

Co-author on the paper, Professor Martin McKee, London School Hygiene & Tropical Medicine, UK says, "As some countries around the world begin to see a resurgence in cases and retighten restrictions, it is imperative that countries learn the lessons that we've laid out for the future. There are no simple solutions but great benefits from learning from the experiences of others." [2]

The authors identify key learnings from these countries experiences which have implications for lockdown exit strategies worldwide:

A clear plan with a transparent decision-making process is essential, ideally explicitly stating the levels or phases of easing restrictions, the criteria for moving to the next level or phase, and the containment measures that each level or phase entails.

Governments should have robust systems in place to closely monitor the infection situation before easing measures. The authors point out that the R value is important, but caution that this requires high quality data in real time (like in Hong Kong) to be accurate and needs to be interpreted using epidemiological knowledge. For example, a small localised outbreak can drive a country's R value up but does not require a national lockdown to be controlled.

For communities to reopen safely, control measures to reduce transmission will be needed for some time, including face masks and social distancing. New Zealand's social bubbles provide a successful example of sustainable measures, as they allow for social interaction while reducing transmission. For control measures to work, governments must educate and engage with the public, building trust, and selecting appropriate measures that the public are willing to comply with. The public should be directly involved in the process of producing measures appropriate for the local context.

Each country must have an effective find, test, trace, isolate, and support system in place before easing lockdown restrictions. Spain and the UK have struggled to achieve this. Drive-through and walk-through screening in South Korea encourage proactive testing of potential case contacts and offers an effective model for expanding case finding. Furthermore, any test, trace, isolate, and support system needs to be supported by sustained investment in public health capacity and health system capacity including facilities, supplies, and workforce.

Finally, there is a strong argument for adopting a so-called zero-COVID strategy, like in New Zealand, which aims to eliminate domestic transmission, particularly considering emerging evidence on the effects of long COVID (which occurs in people who have survived COVID-19 but continue to have symptoms for longer than expected).

Another co-author on the paper, Professor Yik-Ying Teo, Saw Swee Hock School of Public Health, National University of Singapore, says, "In reviewing international experiences, we were concerned about the large divergence in government preparedness. There is an urgent need to understand the contextual differences that have led to such contrasting results, and to identify common principles that governments can follow to protect their people and economy." [2]

The authors identify five key areas to consider when easing lockdowns - knowledge of infection levels, community engagement, public health capacity, health system capacity, and border control measures.

They point out that responses so far have varied significantly across countries.

In particular, the methods and success of contact tracing and isolation have varied significantly across countries. Many Asian countries, except Japan, promptly did extensive testing, tracing, and isolating of all cases (ie, not just severe cases) from the start of the outbreak, strengthened by innovative surveillance technology, whereas these processes have been considerably delayed in most of Europe, except Germany (where existing resources were redeployed quickly). Furthermore, confirmed cases are mostly isolated at institutions in Asia rather than at home, such as in Europe.

Wearing of face coverings to protect others was, at least initially, adopted to a much greater extent in Asia than in Europe. This is partially to do with greater cultural acceptance. For example, in Hong Kong, Japan, and South Korea, the habit of wearing face coverings was already widespread before the pandemic.

Experience with previous epidemics like SARS and MERS meant that many Asian countries had robust healthcare and public health infrastructure already in place. There has historically been a high level of public acceptance of strict rules in times of crisis, with the majority accepting a trade-off between their personal rights and public health. In Europe, public health systems in Spain and the UK have struggled with the consequences of a decade of austerity.