Culture

Both influenza virus M2, a proton-selective ion channel essential for efficient viral replication, and PB1-F2 protein, which localizes to the mitochondria and attenuates host antiviral immunity, are involved in the inflammatory response by stimulating NLRP3 inflammasome-dependent IL-1β secretion. However, the precise mechanisms by which these viral proteins activate the NLRP3 inflammasome remain unclear.

In this study, a research group at The Institute of Medical Science, The University of Tokyo (IMSUT) observed nucleus- and mitochondria-derived double-stranded DNA (dsDNA) in extracellular web-like structures in the cytoplasm and extracellular space around influenza virus-infected macrophages.

According to lead scientist Takeshi Ichinohe, Associate Professor, Division of Viral Infection of IMSUT, Oxidized DNA was included in these DNAs, and the research group found that the ion channel activity of the M2 protein and mitochondrial localization of the PB1-F2 protein is required for oxidized DNA release. While the oxidized DNA enhanced influenza virus-induced IL-1β secretion, inhibition of mitochondrial reactive oxygen species decreased the virus-induced IL-1β secretion. In addition, they showed that influenza virus stimulates IL-1β secretion from macrophages in a manner that is dependent on AIM2, a cytosolic DNA sensor. These results provide a missing link between influenza viral proteins and NLRP3 inflammaseome activation, and reveal the importance of influenza virus-induced oxidized DNA in inflammasomes activation.

You may recognize yourself. You're part of a group where everyone seems to agree more or less all the time. You may disagree, but you'd rather not speak up, and the others aren't voicing any disagreement either.

These meetings are dominated by a few individuals, or maybe just one person. Everyone else nods and smiles at the chairperson, at least until you talk to them one-on-one. Then it turns out that you weren't the only one who had unspoken objections.

"Basically, voicing disagreement is difficult. People in groups often have a tendency or desire to align with others, either certain group members or someone who is clearly the leader. Sometimes this tendency becomes so strong that people are afraid to stand out," says Frode Heldal, an associate professor of technology management at NTNU Business School.

But maybe you don't think you need to speak up? This is how things your group operates, you say, and it's working - sort of.

"It's working" can be destructive

"We have to have respect for things that work, but sometimes that by itself can be destructive" for how a group works together, says Heldal. "It can be just fine as long as the reality remains stable. But it doesn't always do that," he says.

The need for uncomfortable and challenging questions also varies depending on the task. If you play football, the need is different than if you are coming up with a strategic plan, Heldal says.

Occasionally, ambiguity and misunderstandings can cause small disagreements to balloon and feel large and unmanageable. In these corona times with so many digital encounters, picking up on body language and disagreements becomes even more challenging than usual. Voicing concerns or disagreement early is especially important in these situations.

Different jobs also have different cultures. In some places, expressing disagreement is seen as completely natural and necessary for good results. In other places, disagreement can be perceived as disrespectful and perhaps even unfair to a colleague, manager or the company.

For your group to find the best solutions, especially when the reality is changing, it can be crucial to have a culture where you feel empowered to speak up when you disagree.

"For your group to find the best solutions, especially when the reality is changing, it can be crucial that you have a culture where you feel empowered to speak up when you disagree."

Things work - until you meet the unexpected

Heldal is part of the Innovative Teams project at NTNU and recently had an article published in the Team Performance Management journal. He and his colleagues investigated the collaboration between Norwegian and Korean workers. The researchers found that the employees worked fine together on a daily basis, even though they did not understand each other.

Heldal summarized some of their findings in a Norwegian article inSPGR Innovative Teams:

"As a rule, the teams collaborated just fine, except when they had to detect and manage things that went wrong or were unexpected. Because the teams had not learned to understand each other - basically to discuss and reflect together - these situations mushroomed and were more time consuming and costly than they needed to be. Their collaborative techniques, which normally facilitated things working smoothly, actually masked the fact that they were not really that coordinated after all,"the article states.

Of course, it is quite possible for a group to function together just by everyone working independently and implicitly adapting the work to each other. Constantly disagreeing is not helpful, and long discussions can often be perceived as hampering progress. But when something unexpected happens, alternative understandings are often needed.

"This means that as a group people need to be able to challenge internal agreements. Often this is more about personal relationships in the group than the issue itself. Groups that are used to disagreeing openly generally handle changes better than groups that focus on agreement," Heldal says.

Practise challenging each other

It is possible to practise and improve your ability to disagree. The basis for this skill is being able to challenge others and to be challenged.

Professor Endre Sjøvold at NTNU's Department of Industrial Economics and Technology Management calls this approach "constructive confrontation."

"In this context, this training concept may be a little unfamiliar. But the underlying reflections have to do with practising a skill," says Heldal:

Set aside a set time for exercise.

Be disciplined in the carrying out the training.

Set goals.

Exercise a little and often rather than a lot and seldom.

Put the training into practice. You become good at what you do. This means that every time you don't bother to speak up when you disagree, you're getting better at letting things go.

"What we're really practising for when we challenge each other is to become better at accepting and recognizing divergent views," says Heldal.

"What we're really training for when we challenge each other is to become better at accepting and recognizing divergent views."

Ten training tips

First, you have to agree on the time and place to practise disagreeing. This can be before or after meetings you already have scheduled. Heldal has compiled a list for how to practise the skill.

"A list like this is a bit suffocating - it's long and extensive. But here's the trick to picking out a few training points, maybe down to one per workout: work on it a lot until it sticks," says Heldal.

Below are the ten training points. (For more details, see the fact box at the end of the article.)

Ask for the behaviour you want more of, not less of, from others.

When you get criticized - listen and don't defend yourself. Show that you are grateful.

Make decisions and acknowledge others' decisions.

Appoint a person who challenges the decisions made (devil's advocate). Take turns being in this role.

Challenge routines and habits.

Dare to challenge the expert.

Ask why. Request explanations.

Practise arguing for the views of others.

Be honest and clear. Don't package messages. But be constructive.

"Step on toes."

Where you start depends on the team's task and the current dynamic of the group.

Wait a minute - "Step on toes"?

"That last point, 'Step on toes', could be tough for some people and sounds a bit backwards for good teamwork," says Heldal.

The background is that many teams have a lot going on, especially about this point - people on the team are basically afraid to step on each other's toes. The result is that teams work at reduced power then.

"The most common argument against practising these tips is that people don't have time. But you don't usually need much time. Half an hour a week will help you and your team move forward, often in connection with your day-to-day work," says Heldal.

Remember that the ultimate goal is for you to become better at working together and finding the best solutions.

Training tips in detail

Ask for the behaviour you want more of, not less of, from others. Practise: Challenge the person next to you for behaviour you want more of.

When you get criticized - listen and don't defend yourself. Show that you are grateful. Practise: Receive feedback, including unpleasant feedback, with a thank you.

Make decisions and acknowledge others people's decisions. Practise: Take turns being in the leader role. For example, let the person who normally speaks least lead a meeting.

Appoint a person who challenges decisions (devil's advocate). Practise: Dedicate roles to play devil's advocate. Take turns in this role. The main task is to challenge decisions and come up with alternative views. The group is obliged to take these seriously.

Challenge routines and habits. Practise: Try something new, like changing the meeting room you always sit in. Bring in outsiders. Practise working on increasing curiosity, not uncertainty.

Dare to challenge the expert. Practise: Avoid expert roles, where one person owns certain areas of knowledge - even if the team consists of experts. Everyone should be able to challenge. Practise daring to challenge the expert. Experts can practise letting themselves and their knowledge be challenged by those who are not experts.

Ask why, ask for an explanation. Practise: Work on doing this so that it is perceived as constructive.

Practise arguing for the views of others. Practise: Change roles and positions.

Be honest and clear. Don't sugarcoat messages. But be constructive. Practise: Be concrete and straightforward about your own views, avoid packaging them.

"Step on toes". Practise: Challenge others in areas that may seem personal. Work on not taking things personally. The boundary is when suggestions do not contribute constructively to solving or performing the team's task. Speak up immediately if something seems unreasonable, and avoid bringing up old annoyances.

Study uses ridesourcing data to investigate the relationship between ridesourcing and public transit

It seeks to answer whether ridesourcing substitutes or complements public transit, and how the substitution effect changes over time and space

Study shows that the substitution effect is more common in the city center while complementary effect is more pronounced in the suburban areas

Singapore, 21 July 2020 - Ridesourcing apps like Uber, Grab, and DiDi have become ubiquitous in cities around the world but have also attracted much backlash from established taxi companies. Despite its adoption worldwide, regulation of ridesourcing services still varies greatly in different parts of the world - as policy makers struggle to assess its impact on the economy and society, with limited information and yet unidentified risks involved. One major consideration to improve mobility and sustainability in cities is whether ridesourcing apps serve as a substitute or complement for public transits. In an ideal situation, ridesourcing could complement transit service and help to reduce private car usage. However, as an alternative travel mode, it may also substitute for the transit.

To understand more about this and the impact upon cities, Hui Kong, Xiaohu Zhang, Jinhua Zhao from SMART Future Urban Mobility IRG and MIT JTL Urban Mobility Lab recently conducted a study that investigates the relationship between ridesourcing and public transit using ridesourcing data. Their findings were published in a research paper "How does Ridesourcing Substitute for Public Transit? A geospatial perspective in Chengdu, China" in the Journal of Transport Geography, and with a visualization of the study available here. Future Urban Mobility (FM) is an interdisciplinary research group (IRG) of Singapore-MIT Alliance for Research and Technology (SMART), MIT's research enterprise in Singapore.

Complement or Substitute

In the first such study undertaken by any researcher around the world to look into the substitution effect of each individual trip at the disaggregated level, SMART researchers used DiDi data in Chengdu, China, a major urban centre with a population of over 16 million people. They developed a three-level structure to recognize the potential substitution or complementary relationship between ridesourcing and public transit, while also investigating the impacts through exploratory spatiotemporal data analysis, and examining the factors influencing the degree of substitution via linear, spatial autoregressive, and zero-inflated beta regression models.

Through this, the researchers found that one third of DiDi trips potentially substitute for public transit, with a ridesourcing trip considered potentially a substitute for public transit if the trip can be effectively served by public transit.

The time of the day and the location does matter as well. The researchers found that the substitution rate is higher during the daytime (8am to 6pm) and more significant in the city center. Also, substitution trips appear more in the areas with higher building density and land use mixture. During the day, around 40% of DiDi trips have the potential to substitute for public transit, but the researchers found that this substitution rate decreases as the supply of transit decreases.

The researchers also found that the substitution effect is also more significant in the city centre and in more developed areas covered by subway lines, while peripheral and suburban areas were dominated by complementary trips. However they also note that house prices were positively correlated with the substitution rate, highlighting the importance of public transit to ensure less wealthy populations are served.

"High substitution rate implies the necessity of implementing ridesourcing regulations (e.g. spatial quotas, strategic pricing) or optimizing public transit service (e.g. shorten travel time, lower fee, improve crowdedness) in that area," said Dr Hui KONG, SMART FM Investigator and Postdoctoral Associate at JTL Urban Mobility Lab and MIT Transit Lab. "The lower substitution in suburban areas can highlight areas where the current public transit service is inadequate and would help regulators decide on where to implement new bus or train lines."

This research shows that ridesharing substitutes a large proportion of public transit. Therefore, it also amplifies the issue of digital divide. Afterall, most of the ridesourcing services rely on smartphone apps and credit card fare-paying. As a result, the unbanked population and the population that do not own a smartphone may not have access to ridesourcing services. Policymakers may have to rethink digitalisation efforts.

Human-resident microbes can influence both health and disease. Investigating the microbiome using next-generation sequencing(*1) technology has revealed examples of mutualism and conflict between microbes and humans.

Compared to bacteria, the viral component of the microbiome (i.e. the "virome") (*2) is understudied. Somatic tissues of healthy individuals are usually inaccessible for virome sampling. Therefore, there is limited understanding of the presence and distribution of viruses in tissues in healthy individuals and how virus infection associates with human gene expression and perturbs immunological homeostasis.

A research group at The Institute of Medical Science, The University of Tokyo (IMSUT) comprehensively described the "human tissue virome atlas" using a public database.

"The atlas we described will be useful to address the currently "hidden" associations between the human virome and human health and disease. Moreover, our analytic pipeline is versatile, and therefore, will be applicable to a variety of virological studies including the current COVID-19 pandemic.", said the lead scientist, Kei Sato, Associate Professor (Principal Investigator) in the Division of Systems Virology, Department of Infectious Disease Control, IMSUT.

Microbiome in the era of next-generation sequencing (NGS)

Advances in NGS methods in recent decades have made comprehensive surveys of a variety of microorganisms possible. Metagenomic analyses(*3) have explored microorganisms, including bacteria, phages, and viruses, in a variety of places on Earth, such as the oceans and soils. Perhaps the most deeply surveyed microbiome is that of humans.

The Human Microbiome Project aims to characterize bacteria, viruses, and other microorganisms in the human body. As they often live outside human cells, the human bacterial microbiome has been well described in multiple organs and samples via non-destructive sampling: the bacterial microbiome of the skin, oral cavity, and gastrointestinal tract (including feces) are well described. A major theme emerging from these studies is that, while certain microbial species are associated with pathology, many components of the microbiome likely play a symbiotic role in maintaining human health.

What is the "virome"

Many viruses are clearly human pathogens: HIV, influenza virus and a novel coronavirus (designated as SARS-CoV-2) are the causative agents of human diseases. On the other hand, similar to the case of the human bacterial microbiome, some viruses can chronically infect a broad range of human tissues without overt pathology. Previous studies have suggested that these viruses nonetheless have detrimental effects. For example, the human respiratory syncytial virus and human rhinoviruses may play important roles in the inception of childhood asthma and atopic asthma, respectively.

On the other hand, there are a few examples of viruses that exhibit protective effects. For example, GB virus C infection can be protective against HIV infection and improve survival. Thus, virus infections are associated with multiple aspects of human health, and so revealing the human "virome" would be beneficial for understanding the hidden mutualism and/or conflict between humans and viruses. Previous studies of the human virome have used specimens that are relatively easy to access in healthy individuals (e.g., blood or skin).

In other words, it is technically difficult to obtain the somatic tissues from inside the human body (e.g., brain and internal organs) of healthy individuals for virome investigation. Moreover, it remains unclear 1) what kinds of viruses infect various tissues in healthy individuals and 2) how these virus infections influence human gene expression and perturb the homeostasis of these tissues.

"Hidden" virome in the human body

To characterize the human virome in a tissue-specific manner, the research group performed meta-transcriptomic analysis(*4) using the RNA-sequencing dataset(*5) from the Genotype-Tissue Expression (GTEx) Project(*6) with SHIROKANE, a supercomputer in IMSUT. They analyzed 8,991 RNA-sequencing datasets obtained from 51 somatic tissues from 547 individuals and successfully detected 39 viral species in at least one tissue.

The research group then investigated associations between virus infection and human gene expression and human disease onset. They detected some expected relationships; for instance, hepatitis C virus infection in the liver was strongly associated with interferon-stimulated gene upregulation and pathological findings of chronic hepatitis. Presence of herpes simplex virus type 1 in one subject's brain was strongly associated with immune gene expression.

While torque teno virus was detected in a broad range of human tissues, it was not associated with interferon responses. Being notable in light of its association with lymphoproliferative disorders, Epstein-Barr virus infection in the spleen and blood was associated with an increase in plasma cells in healthy subjects. Human herpesvirus 7 was often detected in the stomach; intriguingly, it was associated with the proportion of human leukocytes in the stomach as well as digestive gene expression. Moreover, virus infections in local tissues was associated with systemic immune responses in circulating blood.

Associate Professor Sato emphasized the work's importance; "To our knowledge, this study is the first comprehensive investigation of the human virome in a variety of tissues in healthy individuals through meta-transcriptomic analysis. Further investigation of the associations described here, and application of this analytical pipeline to additional datasets, will be useful to reveal the impact of viral infections on human health" .

Discovery of cooler planet brings astronomers closer to finding more worlds in the habitable 'Goldilocks zone'

Found thanks to new method pioneered by University of Warwick team designed to spot planets orbiting further out from their star

NGTS-11b is among hundreds of 'lost' worlds that can now be rediscovered with the NGTS telescopes using this novel technique

The rediscovery of a lost planet could pave the way for the detection of a world within the habitable 'Goldilocks zone' in a distant solar system.

The planet, the size and mass of Saturn with an orbit of thirty-five days, is among hundreds of 'lost' worlds that University of Warwick astronomers are pioneering a new method to track down and characterise in the hope of finding cooler planets like those in our solar system, and even potentially habitable planets.

Reported in Astrophysical Journal Letters, the planet named NGTS-11b orbits a star 620 light years away and is located five times closer to its sun than Earth is to our own.

The planet was originally found in a search for planets in 2018 by the Warwick-led team using data from NASA's TESS telescope. This uses the transit method to spot planets, scanning for the telltale dip in light from the star that indicates that an object has passed between the telescope and the star. However, TESS only scans most sections of the sky for 27 days. This means many of the longer period planets only transit once in the TESS data. And without a second observation the planet is effectively lost. The University of Warwick led team followed up one of these 'lost' planets using the telescopes at the Next-Generation Transit Survey (NGTS) in Chile and observed the star for seventy-nine nights, eventually catching the planet transiting for a second time nearly a year after the first detected transit.

Dr Samuel Gill from the Department of Physics at the University of Warwick said: "By chasing that second transit down we've found a longer period planet. It's the first of hopefully many such finds pushing to longer periods.

"These discoveries are rare but important, since they allow us to find longer period planets than other astronomers are finding. Longer period planets are cooler, more like the planets in our own Solar System.

"NGTS-11b has a temperature of only 160°C - cooler than Mercury and Venus. Although this is still too hot to support life as we know it, it is closer to the Goldilocks zone than many previously discovered planets which typically have temperatures above 1000°C."

The Goldilocks zone refers to a range of orbits that would allow a planet or moon to support liquid water: too close to its star and it will be too hot, but too far away and it will be too cold.

Co-author Dr Daniel Bayliss from the University of Warwick said: "This planet is out at a thirty-five days orbit, which is a much longer period than we usually find them. It is exciting to see the Goldilocks zone within our sights."

Co-author Professor Pete Wheatley from the University of Warwick said: "The original transit appeared just once in the TESS data, and it was our team's painstaking detective work that allowed us to find it again a year later with NGTS.

"NGTS has twelve state-of-the-art telescopes, which means that we can monitor multiple stars for months on end, searching for lost planets. The dip in light from the transit is only 1% deep and occurs only once every 35 days, putting it out of reach of other telescopes. "

Dr Gill adds: "There are hundreds of single transits detected by TESS that we will be monitoring using this method. This will allow us to discover cooler exoplanets of all sizes, including planets more like those in our own Solar System. Some of these will be small rocky planets in the Goldilocks zone that are cool enough to host liquid water oceans and potentially extraterrestrial life."

Researchers from the Department of Computer Architecture and Technology at the University of Seville's School of Computer Engineering (ETSII) are working on a system that uses X-ray images of patients' lungs to help diagnose COVID-19. This system uses deep learning to train a neural network model that can distinguish between healthy patients, pneumonia patients and COVID-19 patients. This has been achieved using a freely accessible online database that medical professionals from around the world have been feeding with lung X-rays since the onset of the pandemic.

"The spread of the SARS-CoV-2 virus has turned COVID-19 into a global epidemic. The most commonly-used tests to diagnose the disease are invasive, time-consuming and resource-limited. Images obtained from magnetic resonances and/or X-rays are increasingly being used to facilitate diagnostic assistance tasks, having been successfully tested to identify lung problems. However, these diagnostic methods require a specialist, which limits mass uptake among the population," says University of Seville professor Manuel Jesús Domínguez. The researcher adds that processing tools can help reduce health professionals' workload by filtering out negative cases. In particular, advanced artificial intelligence techniques such as deep learning have proven highly effective in identifying patterns such as those found in diseased tissue.

Similarly, this work analyses the effectiveness of a deep learning model based on a VGG-16 neural network for the identification of pneumonia and COVID-19 using X-rays of the torso. The results, published in the journal 'Applied Sciences', reveal that this method is around 100% effective in the identification of COVID-19, proving that it can be used as an aid to diagnose this disease.

DNA methylation (*1) performs an essential function in mammalian ontogeny. It is also known that abnormalities in this process cause the development of cancers such as leukemia.

A research team working at The University of Tokyo and Kyoto University in Japan has announced that they have successfully identified specific target sites for the DNA methylases DNMT3A and DNMT3B (*2 ).

The researchers also found that DNMT3A specifically regulates differentiation-related genes and DNMT3B specifically regulates X-chromosomal genes during mammalian ontogeny.

These results were published in Nature Communications (online version).

" The results will lead to the elucidation of the regulatory mechanism of DNA methylation during the mammalian developmental process and also lead to a more detailed understanding of the onset mechanism of cancer and other diseases caused by abnormal DNA methylation.," said the principal investigator of this research, Professor Yasuhiro Yamada at the Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT).

?Two conserved de novo DNA methyltransferases, DNMT3A and DNMT3B

DNA methylation plays essential roles in mammalian development. Two conserved DNA methyltransferases, DNMT3A and DNMT3B are responsible for de novo establishment of DNA methylation patterns during mammalian development.

Somatic inactivating mutations in DNMT3A and DNMT3B have been reported in diseases such as hematologic cancers and immune disorders, suggesting that DNMT3A and DNMT3B are essential for proper maintenance of somatic cells. At present, the distinct functions of these two enzymes remain largely elusive.

To comprehensively identify the target sites for de novo DNA methylation by the DNMT3 enzymes, the research team took advantage of female mouse ES cells that lack most DNA methylation (2i/L ES cells) (*3), in combination with genetic ablation of Dnmt3a or Dnmt3b (Figure 1). They analyzed de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from Dnmt3 knockout (KO) 2i/L ES cells.

Both Dnmt3a and Dnmt3b KO 2i-MEFs exhibited a modest but global reduction in DNA methylation, which was particularly notable on the X chromosome in Dnmt3b KO cells. Although most genes were methylated similarly in both knockouts, they identified 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b KO 2i-MEFs, respectively.

Notably, Dnmt3a was exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes. Consistent with this, tissue-specific DNA methylation at PcG target developmental genes was substantially reduced in Dnmt3a KO embryos (Figure 2).

Finally, the research team found that human patients with DNMT3A mutant acute myeloid leukemia (AML) or harboring DNMT3B mutations associated with immunodeficiency, centromere, and facial anomalies (ICF) syndrome exhibited reduced DNA methylation at regions that were hypomethylated in Dnmt3a or Dnmt3b KO 2i-MEFs, respectively.

?Potential impact of the research

The researchers reported a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.

Professor Yamada states the work's importance as a potential for further; " For the first time in the world, we have succeeded in identifying the target genes of DNMT3A and DNMT3B during the mammalian developmental process, which up till now were unknown. Our findings may contribute to the development of a novel therapeutic approach for patients with DNMT3 mutations."

Lego could be used as a practical tool to train doctors in anaesthetic skills according to new research that has shown a simple task using the building bricks can help improve technical skills - a finding that could improve medical training and patient safety.

Scientists from the University of Nottingham's School of Psychology and School of Medicine developed a task where people copied shapes using bricks that they could see in a mirror. They found this simple training improved student performance in an ultrasound-guided regional anaesthesia task. The results of the study have been published in British Journal of Anaesthesia

Ultrasound-guided regional anaesthesia is when anaesthetists inject local anaesthetic medicines around specific nerves to provide pain relief after surgery. The anaesthetists commonly use an ultrasound machine to direct their injections into the correct position around the nerve and minimise the risks of the procedure. Training new doctors in these skills currently relies on extensive practice on expensive simulators and learning during clinical care.

Dr Hewson, Honorary Assistant Professor at the University of Nottingham and Consultant Anaesthetist at Nottingham University Hospitals NHS Trust explains: "Ultrasound guided regional anaesthesia is a vital skill practiced by anaesthetists around the world to reduce pain after surgery. These procedures require a high level of accuracy and skill and it is vital we find safe and reliable ways to help train doctors to perform them. We wanted to explore an inexpensive, accessible and self-directed educational tool to improve the ability of doctors to perform regional anaesthesia using ultrasound direction."

The educational tool required students to view in a mirror two-dimensional images of three-dimensional models constructed from Lego Duplo® bricks. They then had to recreate the models they could see in the mirror. After they had completed building the models, they were able to compare them directly with the originals. If they failed the task, they were asked to return to the mirror and make good any errors. Scientists measured the students ability to perform ultrasound-guided injections on a laboratory model before and after this training and saw that students exposed to the Lego training performed the ultrasound task significantly better than students who did not receive Lego training.

Professor Eamonn Ferguson from the University of Nottingham's School of Psychology helped to design the task and explains why it worked: "This research provides a simple and innovative solution to improving people's spatial rotation and awareness. That is, to perform many modern medical technical skills a doctor has to understand how a two-dimensional image of an organ relates to the three-dimensional world inside the body. This involves finding anatomical landmarks and understanding where you are in 3D space, from a 2D image with no usual cues of judging up-down, top-bottom, left-right. We found previously people with good mental rotation skills were better at regional anaesthesia, so we wanted to develop a way of developing these skills, in a simple, safe and inexpensive fashion. We did this by developing a simple task that mirrors - literally- the key features of ultrasound-guided regional anaesthesia - understanding 3D from 2D. We had people actively engage in building as this helps to coordinate eye-hand movement and 3D representations in the brain. This simple task was extremely effective. Ten to fifteen minutes on this simple Lego building task, can save on expensive time in the simulator. We were delighted with the results."

A new study (Budhagatapalli et al., 2020), which has recently been published in the Plant Biotechnology Journal, demonstrates how site-directed mutagenesis can be achieved in virtually any wheat germplasm of choice by intergeneric pollination of wheat with cas9/guide-RNA (gRNA)-transgenic maize.

For exemplification of this principle, new allelic variants were generated for the wheat genes BRASSINOSTEROID-INSENSITIVE 1 (BRI1) and SEMIDWARF 1 (SD1) which are involved in the regulation of the agronomically important trait plant height.

In total, 15 independent target gene-specific mutants were identified out of 174 wheat plants. Mutants were obtained in six wheat backgrounds, including the three spring-type common wheats BW, W5 and K15, the winter-type bread wheat S96, as well as the two durum wheats D6 and D7. Mutations were found in all three genomic target motifs addressed. None of the 15 mutants carried any transgene. The efficiency in mutant plant formation ranged from 3.6% to 50%.

"The major advances achieved in the present study include (1) much reduced genotype dependence, (2) the opportunity of creating a whole variety of wheat plants carrying different allelic variants of the target gene using just one cas9/gRNA-transgenic maize plant as well as (3) the production of target gene-specific mutants that are instantly true-breeding and generally free of any transgenes", says Dr. Nagaveni Budhagatapalli who played a key role in the study conducted at the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben.

However, there is still room for increasing the efficiency of this approach, e.g. by stronger Cas9 and gRNA expression at the relevant timepoint or by the development of improved protocols for in planta production of doubled haploids.

New Orleans, LA - A series of autopsies conducted by LSU Health New Orleans pathologists shows the damage to the hearts of COVID-19 patients is not the expected typical inflammation of the heart muscle associated with myocarditis, but rather a unique pattern of cell death in scattered individual heart muscle cells. They report the findings of a detailed study of hearts from 22 deaths confirmed due to COVID-19 in a Research Letter published in Circulation, available here.

"We identified key gross and microscopic changes that challenge the notion that typical myocarditis is present in severe SARS-CoV-2 infection," says Richard Vander Heide, M.D., Ph.D., Professor and Director of Pathology Research at LSU Health New Orleans School of Medicine. "While the mechanism of cardiac injury in COVID-19 is unknown, we propose several theories that bear further investigation that will lead to greater understanding and potential treatment interventions."

The team of LSU Health pathologists led by Dr. Vander Heide, an experienced cardiovascular pathologist, also found that unlike the first SARS coronavirus, SARS-CoV-2 was not present in heart muscle cells. Nor were there occluding blood clots in the coronary arteries.

Their previously reported results revealed diffuse alveolar damage (DAD) - damage to the small airspaces of the lung where gas exchange occurs - along with blood clots and bleeding in the small blood vessels and capillaries of the lung, were the major contributors to death.

"These findings, along with severely enlarged right ventricles, may indicate extreme stress on the heart secondary to acute pulmonary disease," adds Sharon Fox, MD, PhD, Associate Director of Research and Development in the Department of Pathology at LSU Health New Orleans School of Medicine.

The autopsies, believed to be some of the first reported from the US, were conducted on 22 patients who died of COVID-19 at University Medical Center in New Orleans. The majority were African American. The ten male and twelve female patients ranged in age from 44-79. Although there were other underlying conditions, the majority had high blood pressure, half had insulin-treated type 2 diabetes, and about 41% had obesity.

The LSU Health New Orleans pathologists, as have others, also found viral infection of some of the cells in the lining of the smaller blood vessels (endothelium). Although at low levels, it may be enough to cause dysfunction leading to individual cell death. The effects of the so-called "cytokine storm" (severe overreaction of the immune system cells fighting the infection) associated with COVID may also play a role.

"Given that inflammatory cells can pass through the heart without being present in the tissue proper, a role for cytokine-induced endothelial damage cannot be ruled out," says Dr. Vander Heide.

In addition to Drs. Vander Heide and Fox, the LSU Health New Orleans team included Pathology residents Aibek Akmatbekov, MD; Fernanda S. Lameira, MD; and Jack L. Harbert, MD. Guang Li, and J. Quincy Brown from Tulane, also participated.

(Boston)--In an attempt to address the escalating rate of self-inflicted firearm injury deaths in rural America, researchers are proposing interventions to reduce these suicides be community-based and include programs to reduce other diseases of despair, such as heart and liver diseases, diabetes and accidental opioid overdose. The recent decline in life expectancy of Americans has been attributed to these diseases of despair and appear to primarily afflict white rural America.

Given the gaps in understanding the socioeconomic and environmental factors related to firearm suicide deaths, researchers from Boston University School of Medicine (BUSM) sought to understand the patterns and clustering of rural counties in the U.S. based on firearm suicide and drug-related death rates in the context of economic and socioeconomic characteristics.

The researchers examined rural county-specific data from 2012 to 2016 of firearm suicide deaths, homicide rate, drug related mortality rate, opioid prescription rate, median home price, veteran population, violent crime rate, primary economic dependence of counties, county socioeconomic characteristics such as low employment, persistent poverty, population loss and whether the county is a retirement destination.

"Our findings suggest that the affected rural populations are very diverse and there are collective environmental risk factors, including the primary economies that play an important role in firearm suicide rates. Hence, focusing on actions related to firearms alone without considering the built environment may not reduce these deaths," explained corresponding author Bindu Kalesan, PhD, MPH, assistant professor of medicine at BUSM.

The study has important policy and prevention implications, researchers say. "While most programs focus on risk factors, including the temporary removal of firearms from home, safe storage and denying sale of firearms, we need to incorporate other factors such as primary economies, using a broader public health approach to target interventions in high-risk areas which can simultaneously reduce gun suicides and opioid deaths," added Kalesan, who also is an assistant professor of community health services at Boston University School of Public Health.

WASHINGTON (July 21, 2020) - Nitric oxide treatment can be pivotal in the world's fight against SARS-CoV-2, the coronavirus that causes COVID-19, according to a review from the George Washington University (GW). The article is published in the journal Nitric Oxide.

Nitric oxide is an antimicrobial and anti-inflammatory molecule with key roles in pulmonary vascular function in the context of viral infections and other pulmonary diseases. In SARS-CoV-1 infection, which led to the outbreak of SARS (severe acute respiratory syndrome) in 2003, nitric oxide inhibited viral replication by cytotoxic reactions through intermediates such as peroxynitrite. It is one of several potential COVID-19 treatments included in the U.S. Food and Drug Administration's emergency expanded access program.

"Nitric oxide plays key roles in maintaining normal vascular function and regulating inflammatory cascades that contribute to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)," said Adam Friedman, MD, interim chair and professor in the Department of Dermatology at the GW School of Medicine and Health Sciences and co-senior author of the review. "Interventions that are protective against ALI and ARDS can play a critical role for patients and health systems during the pandemic."

Coronaviruses are RNA viruses that primarily infect birds or livestock, but can mutate to be highly infectious and lethal in humans. There is currently no registered treatment or vaccine for COVID-19. The absence of a specific treatment and the high mortality rate of the virus dictate an urgent need for therapeutics that may control the replication and rapid spread of the virus.

The team, led by first author Nagasai Adusumilli, MBA, a fourth-year medical student at the GW School of Medicine and Health Sciences, reviewed data from between 1993 and 2020 on the pathogenesis of coronaviruses and the use of nitric oxide as a treatment for respiratory illness. The authors highlight the potential for inhaled nitric oxide contributing to better clinical outcomes and alleviating the rapidly rising strain on health care capacity due to COVID-19.

As groups continue to publish more results with their respective nitric oxide platforms, the team recommends that dosing and protocol variations should be examined in evaluating the studies.

"With the emergence of COVID-19 as a pandemic with the ability to overwhelm the body and our health care infrastructure, patients have a pressing need for effective agents that can slow the disease in their bodies and in their communities," Friedman said.

The authors suggest that if nitric oxide's efficacy is illustrated for COVID-19, its use as a treatment can be pivotal in the fight against the pandemic.

Friedman has been collaborating with co-senior author Joel Friedman, MD, PhD, professor of physiology and biophysics and of medicine at Albert Einstein College of Medicine, on research related to the use of nitric oxide in a broad range of medical indications for close to two decades, and together are developing nitric oxide-based therapeutics for COVID-19.

In immune-related disorders, therapy often involves identifying the molecules responsible for immune dysregulation and targeting them using drugs. This type of immune therapy is also used for cancer treatment, owing to the important role that immune cells play in cancer progression. One such type of a potential therapeutic target is an "immune checkpoint" protein called PD-L2, which is specifically expressed in immune cells called dendritic cells (DCs) and macrophages. PD-L2 plays various important functions in the regulation of different types of immune cells, including the suppression of T cells. Not surprisingly, this molecule has been extensively explored as a target protein in immunology and cancer immunology. But, despite years of research, exactly how this protein gets regulated has remained unclear until now.

Recently, a group of researchers at Tokyo University of Science, led by Professor Chiharu Nishiyama, made a significant leap towards this direction. In a new study published in the Journal of Immunology, the scientists dug deeper into the genetic and molecular basis of PD-L2 regulation. Prof Nishiyama says, "In our study, we investigated the gene expression mechanism of PD-L2, a cell-surface molecule that is specifically expressed in DCs and macrophages.''

The scientists began by focusing on DCs, which train other immune cells such as T cells to initiate a defense response against foreign molecules and cancer cells. In DCs, PD-L2 acts as a "checkpoint" that ensures that the immune cells do not incorrectly destroy healthy cells. Because the gene "Pdcd1lg2" is responsible for coding the PD-L2 protein, the scientists wanted to understand how this gene is regulated. A gene expresses its encoded protein through a series of coordinated cellular events that includes structural changes in the DNA caused by proteins known as "transcription factors," which bind to specific "regulatory" positions on the DNA. As the scientists wanted to know the exact events in PD-L2 regulation, they designed their experiments focusing on factors that regulate Pdcd1lg2. Previous studies had indicated that a transcription factor called PU.1 was involved in the development of other similar immune cells. The scientists wondered: was PU.1 involved in PD-L2 expression, too? Prof Nishiyama explains, "Previous studies had shown that the artificial expression of PU.1 on non-dendritic immune cells transformed these cells into DCs. This made us think if PU.1 had any role in the expression of PD-L2, one of the prominent surface proteins of DCs."

To begin with, the scientists studied the effect of "knocking down" PU.1 and a few other proteins in cell models. They found that in the absence of PU.1 and its associate molecule IRF4, the expression of PD-L2 was severely compromised. Once it was clear that PU.1 and IRF4 were involved in regulating the expression of PD-L2, the scientists carried out subsequent experiments using techniques such as "chromatin immunoprecipitation" to know exactly how this happens. They found out that PU.1 and IRF4 together bind to a region on the DNA called the "EICE sequence" and stimulate the expression of Pdcd1lg2 gene. It also became clear that PU.1 indirectly plays a role in altering the DNA molecule to a "relaxed" form by inducing chemical changes in the "histone" proteins, which are bound to the DNA in its "condensed" form. These chemical changes are also called "epigenetic modifications" and form an important regulatory mechanism for gene/protein expression in these cells.

In sum, this study sheds light on the molecular events that take place in the regulation of the PD-L2 protein. This paves the way for further development of drugs that can regulate this protein in immune disorders. Prof Nishiyama concludes, "We believe that our findings have remarkable potential to improve the therapeutic approach against immune system-mediated diseases."

Scientists have revealed a key factor that influences whether malignant cells will grow to form a tumour, in a new study published today in eLife.

The research combined the use of mouse breast mini-organs with continuous imaging at single-cell resolution to reveal how a tumour becomes established. The results provide insights into the behaviour of individual breast cancer cells that could lead to new strategies on how to handle the disease.

Most studies of cancer biology use tissue samples or cells where every cell has faulty mutations that have the potential to form a tumour. This means it is impossible to recreate the very first stages of disease when a single mutated cell overcomes its normal surroundings and develops into cancer.

"To study tumour initiation, models need to be established where only a few malignant cells expand in the context of their immediate non-tumour environment," explains lead author Ashna Alladin, a postdoctoral researcher in senior author Martin Jechlinger's lab at the European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. "We created a model of breast cancer development where only single cells activate cancer-promoting oncogenes within otherwise healthy breast tissue, and then followed the fate of these cancerous cells."

To develop their model, the team grew organoids (mini-organs) from mouse breast tissue which recreate the breast structure. They focused on tiny glands within the breast called 'acini'. They then introduced a cancer-promoting gene into a few individual cells within these acini. Some of the cells then had a second gene added, which allowed the cancer-promoting gene to be switched on in the presence of a drug called doxorubicin. This means the team could control which cells had the cancer-promoting gene switched on and were 'transformed' into malignant cells, and record when the cells were transformed.

The cells were also labelled so that they could be individually tracked every 10 minutes for up to four days using a method called light-sheet microscopy. In this way, the team could see exactly which cells went on to initiate a tumour, and which cells did not.

To determine what influences the individual malignant cells to develop a tumour, the researchers designed a computer algorithm that took all the information from the cell images and looked for common features associated with cells that went on to develop tumours. Of all the features tested, only one was significantly linked to the development of a tumour: the number of cells containing the cancer-promoting gene within a tumour. For every additional cell in a cluster that contained a cancer-promoting gene, the odds of this cluster forming a tumour increased nine times.

In line with the modeling approach, when the team looked at the images of the acini, they found that cells that went on to establish tumours at the end of the four-day imaging period could be seen to cluster together at the start of the imaging period. By contrast, the cells that didn't establish tumours were more sparsely located.

"Our results suggest that there is some interaction or signalling that occurs between malignant cells in close proximity that guides the initiation of a tumour within normal tissues," concludes senior author Martin Jechlinger, Group Leader at EMBL. "Our ability to image the fate of these malignant single cells among healthy tissue means that it is now possible to follow tumour initiation, growth and treatment via inhibition by drugs in a realistic model, thereby helping to bridge the gap between model systems and the clinic."

COLUMBUS, Ohio - Infusing prepared foods with an edible coating that contains green tea extract may lower consumers' chances of catching the highly contagious norovirus by eating contaminated food, new research suggests.

Norovirus, which causes vomiting and diarrhea, sickens an estimated 48 million people in the United States every year and causes about 3,000 deaths. It's transmitted from person to person and through consumption of contaminated water and food.

Lots of things we consume contain what are known in the industry as edible films: They can enhance appearance, like wax that makes apples shiny; hold contents together, like plastic drug capsules; and prevent contents from seeping together by, for example, being placed between a prepared pie crust and the filling.

"In many cases, an edible film is in a product, but you are not aware of it," said Melvin Pascall, professor of food science and technology at The Ohio State University and senior study author. "We don't have to put that on the label since the material is edible. That's another way in which we use packaging - and the consumer doesn't have to know."

Some edible films are also enriched with antimicrobial agents that can kill or slow the growth of organisms that cause illness, such as E. coli and mold.

In this new study led by Pascall, adding green tea extract to a film-forming substance created a safe-to-eat barrier that killed norovirus as well as two types of bacteria.

While most antimicrobial packaging advances to date have emphasized fighting bacteria, this finding holds promise for a newer area of research into the concept of using edible film to kill a virus, Pascall said.

"Norovirus is a tough virus to work with - it is a non-enveloped virus, which is the type more resistant to sanitizers and antimicrobial agents," he said. "However, because it has public health concerns and has been implicated in a number of foodborne outbreaks, we wanted to look at the effects of green tea extract on norovirus."

The study is published in the International Journal of Food Science.

Pascall and his team created the films with a base substance called chitosan, a sugar found in the exoskeleton of shellfish. Chitosan is marketed as a weight-loss supplement and used in agricultural and medicinal applications, and has been studied extensively as a safe and readily available compound for edible film development.

Previous studies have suggested that chitosan has antimicrobial properties. But norovirus might exceed its bug-fighting abilities: In this study, the researchers found that chitosan by itself did not kill the virus.

To test the effects of green tea extract, the researchers dissolved it alone in water and added it to a chitosan-based liquid solution and dried film. Several different concentrations of the extract showed effectiveness against norovirus cells, with the highest level tested in this study killing them all in a day.

"We had tested the chitosan by itself and it didn't show much antimicrobial activity against the virus," Pascall said. "But when we added the green tea extract to chitosan, we saw that the film had antiviral properties - so we concluded the antiviral properties were coming from the green tea extract."

The scientists introduced at least 1 million virus cells to the solution and dried films. Those containing green tea extract lowered the presence of virus cells within three hours. The films with the highest concentration of green tea extract reduced norovirus to undetectable levels by 24 hours after the exposure.

Though norovirus was the focus of this work, the researchers also found that green tea extract lowered E. coli K12 and listeria innocua, surrogates for bacteria that also cause foodborne illness, to undetectable levels within 24 hours.

This study didn't identify how the killing happens - typically an antimicrobial agent disables organisms in ways that cause them to die or render them unable to reproduce. The researchers used mouse norovirus cells because human norovirus cells don't grow well in a lab setting.

There is still a lot of work to do before green tea extract-infused films are ready to enter the market. A tricky part of adding natural substances to edible packaging is ensuring that enough is used to deliver the microbe-killing effect without changing the taste or smell of the food.

"A higher concentration of a natural antimicrobial might cause a large drop in the target organism, but at the same time it defeats the purpose of the food by adding an objectionable taste or odor," Pascall said. "There is also the impact of the natural compound on the material itself - it may cause the film to become too brittle or sticky. These are things food scientists have to consider when using antimicrobial agents, especially those from natural sources."

It's also too soon to tell which kinds of food would be the best candidates for antiviral edible films made with green tea extract. It depends on whether the food would be exposed to heat, moisture or acidic conditions, for example. There is also a chance another natural substance could do an even better job - Pascall is conducting similar studies with other extracts.