Culture

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.

A team of biologists led by Craig Albertson and Ph.D. student Chaise Gilbert at the University of Massachusetts Amherst report this week on their comparison between museum collections of cichlid fishes collected before a dam was closed in 1984 on the Tocantins River in the Amazon and contemporary specimens taken from the Tucuruí Reservoir by fishermen 34 years later.

Working with others in Brazil, Albertson's team tested the idea that these fish could be expected to show changes in body shape as a consequence to shifts in habitat and foraging behavior after the dam rapidly changed environmental conditions from a clear, flowing river to a deep, murky reservoir.

"The once-historic rapids and streams that characterized the system have disappeared from the surrounding area, which in turn has affected the abundance and variety of food sources available to native fishes," they write in Evolutionary Application this week.

Cichlid fishes are known in the scientific world for their ability to alter, in as little as a single season, aspects of body shape to match feeding conditions and other changes in the environment, Albertson says. The skeleton is especially sensitive to such environmental inputs, and studying cichlid fishes offers insights into how organisms, in general, may adapt to major human-induced environmental change.

Using geometric morphometrics, the researchers evaluated changes in six native species - from large fish-eating species to small opportunistic omnivores -across five genera representing distinct local varieties whose body shapes reflect their ecological roles.

To accomplish this, the researchers used many specimens from fish inventories collected before the dam closure in 1980-1982 now housed in the Instituto Nacional de Pesquisas da Amazônia fish collection, plus even earlier river survey specimens housed now at the Museu de Zoologia da Universidade de São Paulo.

Albertson explains, "Our overarching hypothesis is that the damming of the Tocantins and subsequent formation of the Tucuruí reservoir has induced shifts in habitat and foraging behavior and that the anatomy of resident cichlid populations has change in ways that allow them to adapt to this novel environmental conditions. This study represents a first step toward assessing this hypothesis."

Gilbert adds, "Was anything surprising? Yes! While we expected to see changes in generalist species - those that are already predisposed toward living in a variety of habitats - we were surprised to see shape changes in the specialists as well. Evolving to specialize on a particular prey-type or habitat, can provide a competitive advantage in the near term, but it can also be an evolutionary dead end in the face of a major environmental changes."

Not only are these specialist species still found in the area, but they seem to be just as capable of changing body shape as the generalists, the authors report.

Albertson reports further thatchanges across all species "tended to be associated with functionally relevant aspects of anatomy, including head, fin and body shape." They found that the regions of the body that changed over time are exactly those most likely to allow them to survive in their new environment, he adds.

WHAT:
New findings by scientists at the National Institutes of Health and their collaborators help explain why some people with COVID-19 develop severe disease. The findings also may provide the first molecular explanation for why more men than women die from COVID-19.

The researchers found that more than 10% of people who develop severe COVID-19 have misguided antibodies?autoantibodies?that attack the immune system rather than the virus that causes the disease. Another 3.5% or more of people who develop severe COVID-19 carry a specific kind of genetic mutation that impacts immunity. Consequently, both groups lack effective immune responses that depend on type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether these proteins have been neutralized by autoantibodies or?because of a faulty gene?were produced in insufficient amounts or induced an inadequate antiviral response, their absence appears to be a commonality among a subgroup of people who suffer from life-threatening COVID-19 pneumonia.

These findings are the first published results from the COVID Human Genetic Effort, an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals. The effort is co-led by Helen Su, M.D., Ph.D., a senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH; and Jean-Laurent Casanova, M.D., Ph.D., head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University in New York. Major contributions were made by Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology (LCIM); Steven Holland, M.D., director of the NIAID Division of Intramural Research and senior investigator in the NIAID LCIM; clinicians and investigators in hospitals in the Italian cities of Brescia, Monza and Pavia, which were heavily hit by COVID-19; and researchers at the Uniformed Services University of the Health Sciences in Bethesda, Maryland.

The wide variation in the severity of disease caused by SARS-CoV-2, the virus behind COVID-19, has puzzled scientists and clinicians. SARS-CoV-2 can cause anything from a symptom-free infection to death, with many different outcomes in between. Since February 2020, Drs. Su and Casanova and their collaborators have enrolled thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.

The researchers discovered that among nearly 660 people with severe COVID-19, a significant number carried rare genetic variants in 13 genes known to be critical in the body's defense against influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable type I interferons in response to SARS-CoV-2.

Examining nearly 1,000 patients with life-threatening COVID-19 pneumonia, the researchers also found that more than 10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. Biochemical experiments confirmed that the autoantibodies block the activity of interferon type I.

ARTICLE:
Q Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4570 (2020).

P Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4585 (2020).

WHO:
NIAID Director Anthony S. Fauci, M.D., NIAID Senior Investigator Helen C. Su, M.D., Ph.D., and Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology, are available for interviews.

CONTACT:
To schedule interviews, please contact NIAID Office of Communications, (301) 402-1663, NIAIDNews@niaid.nih.gov.

Researchers found rude emails at work can lead to significant distress for employees.

The researchers say that "active" email rudeness is overloaded with strong negative emotions. By comparison, "passive" email rudeness leaves people struggling with uncertainty.

Passive email rudeness may create problems for employees' sleep, which further puts them in a negative emotional state the next morning, thus creating a vicious cycle.

With the advent of the coronavirus pandemic and remote work on the rise, the sheer volume of email exchanges has skyrocketed. Electronic communication is efficient, but it's also distant and detached, and often can be rude.

Two studies led by a University of Illinois Chicago researcher show that dealing with rude emails at work can create lingering stress and take a toll on your well-being and family life.

The research, published by the Journal of Occupational Health Psychology, suggests impolite emails can have a negative effect on work responsibilities, productivity, and can even be linked to insomnia at night, which further relate to negative emotions the next morning.

"Given the prevalent use of emails in the workplace, it is reasonable to conclude this problem is becoming an increasing concern," said lead author Zhenyu Yuan, assistant professor of managerial studies in the College of Business Administration.

In the first study, Yuan and his co-authors surveyed 233 working employees in the U.S. about their impolite email experiences and collected their appraisals. In the second study, researchers conducted a diary study to examine the spillover effects of email rudeness on well-being, including employees' trouble falling and staying asleep.

There are two forms of email rudeness, Yuan notes. Active email rudeness -- demeaning or derogatory remarks from the sender made about the recipient -- suggests to the recipient that the sender has mistreated him or her. By comparison, passive email rudeness -- such as ignoring a request or opinion from the sender -- makes it difficult to know whether the receiver simply forgot to answer the email or actually intended to ignore it.

"Because emails are securely stored, people may have a tendency to revisit a disturbing email or constantly check for a response that they requested, which may only aggravate the distress of email rudeness," Yuan explained.

To mitigate this stress, the researchers urge employees to "psychologically detach" from a stressful workday after receiving rude emails. The best option is to unplug from work after-hours. Whenever possible, managers also should set clear and reasonable expectations regarding email communications.

"It should be noted that efforts to address email rudeness should not be interpreted as the same as creating pressure for employees and managers to always check their email and respond to emails (i.e., telepressure)," Yuan concluded.

"On the contrary, setting clear and reasonable communications norms can prove effective in addressing both."

Infectious viruses come in many shapes and sizes and use slightly different attack mechanisms to make humans and animals sick. But all viruses share something in common: They can only do damage by replicating inside the cells of another organism ­- their host.

This broad, fundamental process of how viruses trick host cells into making copies of the virus has had a team of Colorado State University scientists captivated for several years. A collaboration between the labs of Monfort Professor Tim Stasevich, in the Department of Biochemistry and Molecular Biology, and Associate Professor Brian Munsky, in the Department of Chemical and Biological Engineering, is on a mission to understand, in visual detail and with mathematical precision, all aspects of viral attack strategies, including how viruses invade host cell protein-making machinery. Their work, supported by grants from the National Institute of General Medicine and the W. M. Keck Foundation, could provide insight into predicting and fighting back against all manner of viral diseases.

For the first time ever, the team has shown an important mechanism in this host-attacking process, at the single-molecule level in living cells, and they have reproduced these behaviors in computational models. Their new experiments and models, published in Nature Structural and Molecular Biology, reveal in unprecedented detail how viruses initiate translation of genetic material into proteins.

Hijacking the host

Since viruses do not encode their own replication machinery, they hijack that of their host cells by stealing cellular machines called ribosomes, which are essential for making proteins from the genetic material found in RNA. Many viral genomes contain special RNA structures called Internal Ribosome Entry Sites, or IRES, that capture ribosomes from the host, forcing those ribosomes to make viral proteins.

Researchers know that when IRES-related RNA translation takes place, the virus has succeeded in commandeering the host's ribosomes. The CSU researchers invented a biosensor that lights up blue when viral translation is happening, and green when normal host translation is happening, in single living cells. This design allows them to differentiate between normal host processes and viral processes, in real time.

The sensor combines the relevant bits of virus (not the whole virus) that interact with and steal host ribosomes, along with two distinct protein tags that glow the moment RNA is translated. First author and graduate student Amanda Koch spent more than a year developing the sensor, with the goal of looking at host protein RNA translation, and virus-related RNA translation, at the same time.

Luis Aguilera, a postdoctoral researcher in the Munsky group, built a detailed computational model to reproduce Koch's fluorescence microscopy videos. By analyzing Koch's data through the lens of dozens of hypotheses and millions of possible combinations, Aguilera discovered complex biochemical mechanisms that the biochemists couldn't directly see. His models showed that both healthy human RNA and viral RNA fluctuate between states that actively express proteins and those that are silent.

Cellular stress

In addition to examining viral translation in normal cells, Koch's biosensor allows the researchers to visualize the effects of different types of stress that cells undergo when being attacked by a virus, and how, where and when normal versus viral translation increase or decrease. The integration of Koch's microscopy data and Aguilera's computational models revealed that the relationship between normal and IRES-mediated translation is largely one-sided - in healthy cells, normal translation dominates, but in cells under stress, IRES translation dominates.

The Stasevich and Munsky teams envision that the combination of their unique biochemical sensors and detailed computational analyses will provide powerful tools to understand, predict, and control how future drugs might work to inhibit viral translation without affecting host translation.

Future COVID-19 applications

As the researchers look ahead to the future, they have their sights next set on COVID-19. Although SARS-CoV-2 does not contain an IRES, according to Koch "our biosensor is modular and can easily incorporate pieces of SARS-CoV-2 to explore how it uniquely hijacks host replication machinery during infection."

"We are proving, more and more, that we can look at these nuanced dynamics of how viruses are sneaking past their hosts to infect a lot of cells and make us sick," Koch said.

Typically, computer models of climate become more and more complex as researchers strive to capture more details of our Earth's system, but according to a team of Penn State researchers, to assess risks, less complex models, with their ability to better sample uncertainties, may be a better choice.

"There is a downside to the very detailed, very complex models we often strive for," said Casey Helgeson, assistant research professor, Earth and Environmental Systems Institute. "Sometimes the complexity of scientific tools constrains what we can learn through science. The choke point isn't necessarily at the knowledge going into a model, but at the processing."

Climate risks are important to planners, builders, government officials and businesses. The probability of a potential event combined with the severity of the event can determine things like whether it makes sense to build in a given location.

The researchers report online in Philosophy of Science that "there is a trade-off between a model's capacity to realistically represent the system and its capacity to tell us how confident it is in its predictions."

Complex Earth systems models need a lot of supercomputer time to run. However, when looking at risk, uncertainty is an important element and researchers can only discover uncertainty through multiple runs of a computer model. Computer time is expensive.

"We need complex models to simulate the interactions between Earth system processes," said Vivek Srikrishnan, assistant research professor, Earth and Environmental Systems Institute. "We need simple models to quantify risks."

According to Klaus Keller, professor of geosciences, multiple model runs are important because many events of concern such as floods are, fortunately, the exception, not what is expected. They happen in the tails of the distribution of possible outcomes. Learning about these tails requires many model runs.

Simple models, while not returning the detailed, complex information of the latest complex model containing all the bells and whistles, can be run many times quickly, to provide a better estimate of the probability of rare events.

"One of the things we focus on are values embedded in the models and whether the knowledge being produced by those models provides decision makers with the knowledge they need to make the decisions that matter to them," said Nancy Tuana, DuPont/Class of 1949 Professor of Philosophy and Women's, Gender, and Sexuality Studies.

Determining an appropriate model that can address the question and is still transparent is important.

"We want to obtain fundamental and useful insights," said Keller. "Using a simple model that allows us to better quantify risks can be more useful for decision-makers than using a complex model that makes it difficult to sample decision-relevant outcomes."

Srikrishnan added, "We need to make sure there is an alignment between what researchers are producing and what is required for real-world decision making."

The researchers understand that they need to make both the producers and users happy, but sometimes the questions being asked do not match the tools being used because of uncertainties and bottlenecks.

"We need to ask 'what do we need to know and how do we go about satisfying the needs of stakeholders and decision makers?'" said Tuana.

In 1921, Albert Einstein received the Nobel Prize in physics for the discovery that light is quantized, interacting with matter as a stream of particles called photons. Since these early days of quantum mechanics, it is known that photons also possess momentum. The photon's ability to transfer momentum was used in a novel approach by scientists of the Max Born Institute, Uppsala University, and the European X-Ray Free-Electron Laser Facility to observe a fundamental process in the interaction of x-rays with atoms. The detailed experimental and theoretical results are reported in the journal Science.

Absorption as well as emission of a photon by an atom are fundamental processes of the interaction of light with matter. Much rarer are processes in which several photons simultaneously interact with one atom. The availability of intense laser beams since the 1960s has led to the development of "nonlinear optics", which observes and utilizes such processes.

Entirely new possibilities emerge if it is possible to use nonlinear optics with x-rays instead of visible light. The use of ultrashort flashes of x-rays allows for detailed insight into the motion of electrons and atomic nuclei in molecules and solids. This perspective was one of the drivers leading to the construction of x-ray lasers based on particle accelerators in several countries. When the European x-ray free-electron laser, the European XFEL, started operation in 2017, the scientific community made an important step in that direction. Nevertheless, progress in the use of nonlinear x-ray processes to study fundamental interaction with matter has been slower than expected. "Typically, the much stronger linear processes occlude the interesting nonlinear processes", says Prof. Ulli Eichmann from Max Born Institute for nonlinear optics and short pulse spectroscopy in Berlin.

The German-Swedish research team has now demonstrated a new method allowing to observe the nonlinear processes without being disturbed by the linear processes. To this end, the team made use of the momentum that is transferred between x-rays and atoms. When crossing a supersonic atomic beam with the x-ray beam, they can identify those atoms which have undergone the so-called stimulated Raman scattering process - a fundamental nonlinear process, where two photons of different wavelength hit an atom and two photons of the longer wavelength leave the atom. The results were reported in the journal Science.

"Photons transfer momentum to an atom - completely analogous to a billiard ball hitting another one", explains Eichmann. In the stimulated Raman process, both photons leave the atom in the exact same direction as the two incident photons, hence the momentum of the atom and its direction of flight remain essentially unchanged. The much more frequent linear processes, where one photon is absorbed followed by the emission of another photon, have a different signature: as the emitted photon is typically emitted in a different direction, the atom will be deflected. Observing the direction of the atoms the scientists could thus clearly discriminate the stimulated Raman process from other processes.

"The new method opens unique possibilities when combined in the future with two time-delayed x-ray pulses of different wavelength. Such pulse patterns have recently become available at x-ray lasers, like the European XFEL", explains Dr. Michael Meyer, researcher at the European XFEL. As x-ray pulses with different wavelength allow to specifically address particular atoms in a molecule, it is possible to observe in detail how the wavefunctions of electrons in molecules evolve over time. In the long run, the scientists hope to not only observe this evolution, but to influence it via tailored laser pulses. "Our approach allows for a better understanding of chemical reactions on the atomic scale and may help to steer the reactions in a desired direction. As the movement of electrons is the essential step in chemical and photochemical reactions occurring e.g. in batteries and solar cells, our approach may give new insight in such processes as well", says Jan-Erik Rubensson, professor at Uppsala University.

In one of the first studies to comprehensively analyze Y chromosomes of humans' two closest relatives, Denisovans and Neanderthals, researchers report what prior studies have suggested: early gene flow events between archaic and modern humans led to the eventual replacement of archaic Neanderthal Y chromosomes by introgressed Homo sapiens Y chromosomes. There was no replacement of Denisovan Y chromosomes with H. sapiens Y chromosomes. "Until [this] new study ... archaeologists had only limited Y chromosome data from two Neanderthals and no information on exchanges of Y chromosomes during the early meeting," writes Mikkel Heide Schierup in a related Perspective. A growing number of ancient DNA studies on Neanderthals, Denisovans and H. sapiens suggest intertwined evolutionary and population histories, including several admixture events between early modern and archaic humans. However, ancient nuclear and mitochondrial DNA sequences (mtDNA) have revealed phylogenetic discrepancies between the three groups that are hard to explain. For example, autosomal genomes show that Neanderthals and Denisovans are sister groups that split from modern humans more than 550,000 years ago. However, all but the earliest Neanderthal mtDNA samples are far more similar to those of modern humans than to those from Denisovans. These studies suggest that Neanderthals originally carried a Denisovan-like mtDNA, which was later wholly replaced through early admixture with early modern humans, likely between 350,000 and 150,000 years ago. While genomic data for the paternally inherited Y chromosome would help resolve puzzling gene flows, virtually none of the male Neanderthal and Denisovan remains studied to date contain well-preserved Y chromosome DNA. To address this gap in the data, Martin Petr and colleagues used a targeted capture-based DNA sequencing approach to enrich and extract Y chromosome sequences from the less-than-well-preserved remains of three male Neanderthals and two male Denisovans. Petr et al. found that, like maternally inherited mtDNA, modern human and Neanderthal Y chromosomes were more related to each other than to the Denisovan Y, supporting the suggestion that interbreeding between early humans and Neanderthals and subsequent selection led to the total replacement of more ancient Denisovan-like genetic material in late Neanderthals.