Culture

The Nagoya University Institute of Transformative Bio-Molecules (WPI-ITbM) research team of Designated Associate Professor Tsuyoshi Hirota, Postdoctoral Fellow Simon Miller, Professor Kenichiro Itami and graduate student Tsuyoshi Oshima (Research Fellowship for Young Scientists, JSPS), in collaboration with the group of Professor Ben Feringa and Postdoctoral Fellow Dušan Kolarski of Groningen University in the Netherlands, have achieved a world first: fully reversible manipulation of the period of the circadian clock using light, by exchanging part of a compound with a light-activated switch.

Waking in the morning, sleeping at night - the majority of our biological activities repeat within a daily cycle. The internal process which governs this rhythm is known as the circadian clock. While it is understood that the circadian clock is controlled by the combined functions of clock genes and clock proteins, the process by which it is possible to control and stabilize the rhythm over the lengthy period of a day has been shrouded in mystery. In order to tackle this question, the researchers established a chemical biology process for large-scale analysis of the effect of compounds on the circadian rhythm in cultured human cells, elucidating the significant molecular mechanisms which determine the daily period.

This large-scale chemical screening identified two compounds - TH303 and its analogue TH129 - which lengthened the circadian clock period. The research team then worked on elucidating how these compounds interact with the clock protein CRY1 at a molecular level using X-ray crystallography. They found that part of these compounds, known as a benzophenone, possessed a similar structure to the cis isomer of azobenzene, a light-activated switch. When they then analyzed the response to light of GO1323, a variant of TH129 in which benzophenone is displaced by azobenzene, they found that its structure changed to the cis isomer under ultraviolet light, and back to the trans isomer under white light. According to computer simulations, the cis isomer of GO1323 interacts identically to TH129 with CRY1, while the trans isomer has no interaction with it.

Thus, when exposed to ultraviolet light, the circadian clock period of cultured human cells which had been treated with GO1323 was extended compared with those which had been kept in the dark. Furthermore, when exposed to white light, these cells' circadian clock period returned to normal, proving that the process is reversible. As ultraviolet light is damaging to cells, the research team had to find a way to adapt the process to use a non-harmful area of the spectrum to extend the period. They synthesized GO1423, containing tetraorthofluoroazobenzine. This compound changes to its cis isomer under green light, and to its trans isomer under violet light, while maintaining the other desirable characteristics of GO1323. When cells treated with GO1423 were exposed to green light, their circadian rhythm period was extended compared with those which had been kept in the dark, and when exposed to violet light, the effect was reversed. Thus, the researchers succeeded in producing a reversible method for controlling the circadian clock period using visible light.

Control of the circadian clock using methods such as these is expected to contribute to the treatment of related diseases such as sleep disorders, metabolic syndrome and cancer, and this research achievement represents an important and exciting step forward in the field.

Abusive bosses may retain their positions by taking superficial steps to repair their social images following outbursts, without acting meaningfully to change their behaviors, according to research led by a University of Wyoming business management expert.

Shawn McClean, an assistant professor in UW's College of Business, joined colleagues from the University of Iowa, the University of Nebraska-Lincoln and Texas A&M University in conducting the research, which appears in the journal Personnel Psychology. Their study also was featured in Harvard Business Review, a preeminent business magazine.

"Our study shows that supervisors are often driven by simply repairing their social image rather than making genuine amends and changing their behavior," McClean says. "As a result, employees may seemingly forgive abusive supervisors who try to 'fake nice' after abusive behavior, thus reinforcing the cycle of abuse."

The researchers surveyed 79 bosses who volunteered to participate in the study from fields including education, health care, retail and consulting. The study gathered information about how the bosses acted following incidents in which they told their subordinates they were incompetent, invaded their privacy or made negative comments about them to others.

Rather than take steps to genuinely repair damage caused by their abusive behavior, such as offering sincere apologies, many of the bosses were more concerned about repairing their social images, the researchers found. The bosses did small favors for employees with the express purpose of getting employees to view them more favorably, while also engaging in self-promoting behaviors, such as highlighting how hard they work or showcasing past successes.

"Consequently, even though abusive bosses may appear on the surface to be considerate to their victims following one of their abusive episodes, the bosses in our study reported behavior that was instead a superficial attempt at impression management," the researchers wrote in their Harvard Business Review article. "As a result, toxic bosses were not likely to change their ways, mainly because their focus was on covering up their bad behavior through manipulative ingratiation and self-promotion behaviors, not on actually changing their toxic behaviors."

The researchers suggest that breaking the cycle of self-centered, manipulative and uncivil behavior by bosses requires organizational leaders to implement zero-tolerance policies for toxic supervisory behavior -- and adhere to those policies, even when bosses appear to strive to make up for their bad behaviors. Sanctions, rather than forgiveness, are more likely to change behaviors.

"That said, a boss's behavior can never be fully regulated by organizational policy; in the end, whether a boss fails to exhibit common decency and civil behavior to his employees is ultimately up to them," the researchers wrote. "Sincere apologies and reconciliations on the part of the offending boss are the only sustainable way of regaining credibility and moving forward from a lapse in civil behavior."

Our state of consciousness changes significantly during stages of deep sleep, just as it does in a coma or under general anesthesia. Scientists have long believed - but couldn't be certain - that brain activity declines when we sleep. Most research on sleep is conducted using electroencephalography (EEG), a method that entails measuring brain activity through electrodes placed along a patient's scalp. However, Anjali Tarun, a doctoral assistant at EPFL's Medical Image Processing Laboratory within the School of Engineering, decided to investigate brain activity during sleep using magnetic resonance imaging, or MRI. According to Dimitri Van De Ville, who heads the lab, "MRI scans measure neural activity by detecting the hemodynamic response of structures throughout the brain, thereby providing important information in addition to EEGs." During these experiments, Tarun relied upon EEG to identify when the study participants had fallen asleep and pinpoint the different stages of sleep. Then she examined the MRI images to generate spatial maps of neural activity and determine different brain states.

Difficult data to obtain

The only catch was that it wasn't easy to perform brain MRIs on participants while they were sleeping. The machines are very noisy, making it hard for participants to reach a state of deep sleep. But working with Prof. Sophie Schwartz at the University of Geneva and Prof. Nikolai Axmacher at Ruhr-Universität Bochum, Tarun could leverage simultaneous MRI and EEG data from around thirty people. The brain-activity data were covered a period of nearly two hours while participants were sleeping in an MRI machine. "Two hours is a relatively long time, meaning we were able to obtain a set of rare, reliable data," says Tarun. "MRIs carried out while a patient is performing a cognitive task usually last around 10-30 minutes."

Brain activity during sleep

After checking, analyzing and comparing all the data, what Tarun found was surprising. "We calculated exactly how many times networks made up of different parts of the brain became active during each stage of sleep," she says. "We discovered that during light stages of sleep - that is, between when you fall asleep and when you enter a state of deep sleep - overall brain activity decreases. But communication among different parts of the brain becomes much more dynamic. We think that's due to the instability of brain states during this phase." Van De Ville adds: "What really surprised us in all this was the resulting paradox. During the transition phase from light to deep sleep, local brain activity increased and mutual interaction decreased. This indicates the inability of brain networks to synchronize."

The role of default-mode networks and the cerebellum

Consciousness is generally associated with neural networks that may be linked to our introspection processes, episodic memory and spontaneous thought. "We saw that the network between the anterior and posterior regions broke down, and this became increasingly pronounced with increasing sleep depth," says Van De Ville. "A similar breakdown in neural networks was also observed in the cerebellum, which is typically associated with motor control." For now, the scientists don't know exactly why this happens. But their findings are a first step towards a better understanding of our state of consciousness while we sleep. "Our findings show that consciousness is the result of interactions between different brain regions, and not in localized brain activity," says Tarun. "By studying how our state of consciousness is altered during different stages of sleep, and what that means in terms of brain network activity, we can better understand and account for the wide range of brain functions that characterize us as human beings."

In a promising result for the success of vaccines against COVID-19, rhesus macaque monkeys infected with the human coronavirus SARS-CoV-2 developed protective immune responses that might be reproduced with a vaccine. The work was carried out at the California National Primate Research Center at the University of California, Davis and is published Jan. 22 in the journal Nature Communications.

"These results suggest that vaccines inducing durable protective immunity against SARS-CoV-2 do so by stimulating robust germinal center responses - a question that can be effectively answered using the rhesus model," said Smita Iyer, assistant professor of pathology, microbiology and immunology at the UC Davis School of Veterinary Medicine and Center for Immunology and Infectious Diseases.

The immune response to coronavirus plays a protective role in recovery from disease, and most patients make a full recovery, Iyer said. But an uncontrolled immune response or "cytokine storm" is also implicated in causing severe complications in some people.

Animal studies are critical to conclusively identify markers of vaccine-mediated protection, by telling us which immune cells triggered by the vaccine are protective. Understanding immune determinants of protection against infection and disease is crucial to enhance vaccine efficacy, Iyer said.

Signs of an effective immune response

Iyer and colleagues infected eight rhesus macaques at the CNPRC with SARS-CoV-2 virus isolated from the first human patient treated at UC Davis. At the time (early March) the case was the first known example of "community transmission" in the U.S. that could not be traced to someone arriving from another country.

The researchers followed immune responses in the animals over about two weeks. The animals showed either mild disease that was quickly resolved or no symptoms, with a brief and transient immune response, Iyer said.

The animals showed all the signs of producing an effective immune response to a viral infection. They made a type of helper cell called Th1 cells in the blood, lungs and lymph nodes, and produced both IgM-type antibodies and the higher-affinity IgG antibodies associated with long-term immune protection.

Importantly, structures called germinal centers developed in the lymph nodes near the lungs. These contained cells called T follicular helper, or Tfh, cells. Germinal centers and Tfh cells are associated with generating plasma cells, which remain in the body for many years to produce antibodies against pathogens the immune system has seen before. These plasma cells allow the immune system to "remember" and react to infections that occurred years or decades previously.

"These results suggest that vaccines that induce Th1-Tfh responses will support immunity," Iyer said.

There is a saying that you can't teach old dogs new tricks. When it comes to canine behavioral problems, age is only one factor that can predict how well a pet may respond to clinical intervention. In a paper published in Frontiers in Veterinary Science, researchers provide the first evidence on the importance of not just a dog's age, sex and size on treatment success, but the owner's personality and the kind of bond that human and animal share.

The study analyzed the physiological and psychological characteristics of 131 dog-owner pairs who attended a veterinary behavioral service over a six-month period. The statistical results were based on a behavioral assessment questionnaire that was given at the beginning, middle and end of the research program, along with other baseline assessments. Data collected included various types of aggressive behavior, signs of separation anxiety, and the animal's energy and excitability levels.

The team at the University of Pennsylvania's School of Veterinary Medicine (PennVet) found that while the dogs that showed the most improvement were those that started with the least desirable behaviors, such as being overly aggressive or excitable, other results were counterintuitive. For example, canines with owners who considered themselves conscientious did not show significant behavioral improvement compared to others.

"This was a surprising result, which was in some ways at odds with the findings from a previous study," said Dr. Lauren Powell, lead author of the paper and a postdoctoral researcher at the University of Pennsylvania, referring to a 2018 paper in PLOS One that investigated the associations between owner personality and psychological status with the prevalence of canine behavior problems.

There could be at least a couple of explanations for these conflicting results, according to Powell. Conscientious dog owners in the current study, for instance, may have already exhausted the limits of reducing undesirable behaviors like a dog's aggression toward strangers.

"Another explanation is that conscientious owners may be more aware of their dog's behavior and report changes in a more accurate manner, whereas less conscientious owners may only report major changes, like the absence of bites," Powell noted.

Identifying the factors that predict success or failure in correcting canine behavioral problems may help veterinarians provide better guidance to owners in the future. For example, the study revealed a negative relationship between introverted owners and fearful dogs in terms of treatment outcomes. In such cases, a veterinarian could use that information to explain to the pet owner why the dog needs to choose when it wants to interact or be left alone.

"Veterinarians that are able to pick out situations where dogs may be at risk for low improvement can also be more proactive during the follow-up, reaching out to the clients more frequently and empathetically," Powell explained.

One reason why veterinary scientists are interested in improving behavioral outcomes is that research has consistently shown that poor canine behavior is a leading cause of pet abandonment. An estimated 3.3 million dogs end up in animal shelters in the United States each year, and about 670,000 are euthanized, according to the American Society for the Prevention of Cruelty to Animals (ASPCA).

While the PennVet team has no immediate plans for follow-up studies, Powell said it would be valuable to investigate why so many problem behaviors did not appear to respond to treatment.

"This would involve more detailed follow-up of cases to look at issues such as owner compliance with treatment protocols, owners' decisions to euthanize or rehome their dogs, and why some owners failed to complete the study," she said.

Questions about why such affluent western societies are facing a reversal in life expectancy are sounding loud alarm bells for Professor Fran Baum, Matthew Flinders Distinguished Professor and Director of the Southgate Institute for Health, Society and Equity.

Professor Baum is lead author of a study that offers a new perspective on why women live longer than men - noting with concern that while women live longer, many of the recognised social determinants of health are worse for women than men.

The study serves an important reminder of why policy makers need to receive more carefully nuanced research that drills into specific gender data that can best inform public health policy initiatives.

"We need gendered analysis to shape public policy discussion on health inequities - something which is sadly lacking at present in this country," says Professor Baum.

"Shining a gender lens is vital and contributes to more complex understanding of health inequities and how to reduce them."

The new paper - "New Perspective on Why Women Live Longer Than Men: An Exploration of Power, Gender, Social Determinants, and Capitals," by Fran Baum, Connie Musolino, Hailay Abrha Gesesew and Jennie Popay - has been published in International Journal of Environmental Research and Public Health (doi.org/10.3390/ijerph18020661)

The paper highlights that since 2006, in all countries in the world, women have lived longer than men, but paradoxically report more illness than men.

Professor Baum says this situation has been amplified during COVID-19, with such high numbers of women around the world engaged in vulnerable frontline health provision and essential work services.

No existing explanations account fully for these differences in life expectancy, although they do highlight the complexity and interaction of biological, social and health service factors.

"We know that poverty is bad for health, although more women live in poverty than men yet are less likely to die younger than men," says Professor Baum.

The paper explores a global picture of gendered life expectancy difference (GLED) using a novel combination of epidemiological and sociological methods - highlighting the equally important differences between average life expectancies in different countries and between different groups within countries. This included comparative case analysis offering explanations for GLED in Australia and Ethiopia.

"The Australian and Ethiopian cases demonstrated the complex economic, cultural, symbolic and social factors underpinning this difference, highlighting how similarities and differences are gendered within and between the countries," says Professor Baum.

The new study sits neatly within a strengthening international women's equity push, with Professor Baum being part of a Lancet-led global commission investigating gender and health, investigating what impacts the effectiveness of different programs.

"We note that the same answer cannot be effectively applied to both genders - and yet that is not being addressed by public health and equity policy," says Professor Baum. "This needs to change - now."

During a pandemic, decisions have to be made under time pressure and amid scientific uncertainty, with potential disagreements among experts and models. With COVID-19, especially during the first wave, there was uncertainty about the virus transmissibility, the disease severity, the future evolution of the pandemic and the effectiveness of the proposed policy interventions, such as wearing face masks or closing schools. Together with a group of epidemiologists and economists, including the Nobel Prize winner Lars Peter Hansen, Bocconi professors Massimo Marinacci, AXA-Bocconi Chair in Risk, and Valentina Bosetti investigated how modern decision theory can help policymakers navigate through the uncertainty that characterizes this pandemic and possible future ones.

More in detail, they interpret the problem of a policymaker taking policy decisions about the COVID emergency as happening in an environment characterized by three layers of uncertainty: uncertainty about models, across models, and within models. Uncertainty about models relates to the fact that models are, by design, simplifications of more complex phenomena, and hence are necessarily misspecified, at least to some extent. For instance, they might not include some variables that are instead important. Uncertainty across models encompasses both the proliferation of different models and the fact that the parameters of each single model are unknown. In the COVID-19 context, these parameters include the effective reproduction number (the now famous Rt index) and the disease latent period. Finally, uncertainty within models accounts for the fact that - apart from deterministic models, that however are often oversimplistic - even a fully specified model has uncertain outcomes. For example, when flipping coins or rolling dice, we have full knowledge of the probability model but still cannot anticipate the outcome, because the latter is random.

In front of this complexity, formal decision rules can be of great help. A formal decision problem consists of a set of actions, a set of consequences and a set of environment states, plus a function that associates a consequence to each action-state couple. In the case of COVID-19, the considered actions may be different durations of school closures, while consequences include both the benefits of this kind of action (e.g. reducing infections, hospitalizations and deaths) and its costs (worse education for children, struggles for working parents, etc.) and also depend on the environment state (i.e. the pandemic and economic situation). A formal decision rule is then a function that associates the "best" action to the observed data.

"Various decision rules exist and picking the best one for a particular situation remains a non-trivial problem," says Professor Bosetti, &laquohowever this approach can help weed out bad solutions from the debate."

"Policymakers can check their decisions by asking whether they can be justified using a formal decision rule," explains Professor Marinacci. "Used this way, formal decision rules can help policymakers clarify the problem, test their intuition, and avoid reasoning mistakes that have been documented in psychological studies, like confirmation and optimism bias."

"In practical terms, ensuring that policy options are in line with formal decision rules could be achieved by including a decision analyst in the group of advisors. This would assist policymakers not only in accounting for all sources of uncertainty while taking decisions, but also in communicating this uncertainty transparently, either to the citizens, or to a potential investigating committee. Being open about the degree of uncertainty surrounding the scientific evidence used to guide policy choices is a valuable way of retaining public trust and avoiding that single self-described experts over-influence both citizens and policymakers."

Researchers from Nanyang Technological University (Singapore), Shanghai Jiao Tong University, and University of Hong Kong published a new paper in the Journal of Marketing that examines why and how charitable organizations can increase donations by soliciting consumers after retailers' price promotions.

The study, forthcoming in the Journal of Marketing, is titled "Do Promotions Make Consumers More Generous? The Impact of Price Promotions on Consumers' Donation Behavior" and is authored by Kuangjie Zhang, Fengyan Cai, and Zhengyu Shi.

Giving Tuesday, a global generosity movement, takes place each year on the Tuesday after US Thanksgiving (immediately after Black Friday and Cyber Monday sales). Charitable donations generally see a big boost on Giving Tuesday. This year, American consumers donated a total of US$2.47 billion on Giving Tuesday to various charitable causes, including $808 million in donations made online.

Giving Tuesday was initiated by the 92nd Street Y and United Nations Foundation in the post-Thanksgiving season as a response to growing concerns about the consumerism and materialism associated with Black Friday and Cyber Monday sales. Given the large sales volume achieved in these promotion events, the media has portrayed Black Friday as America's greediest holiday.

An important question thus arises: Can price promotions lead to potential positive social consequences and contribute to a better world? Zhang explains that, "Price promotions can have a positive effect on consumers' donation behavior because the monetary savings from price promotions increase consumers' perceived resources. We also show that the positive effect of price promotions on consumers' donation behavior is stronger when consumers focus on the amount of money saved, when the purchase falls within their budget, and when the monetary savings can be realized immediately." Furthermore, charitable organizations can benefit the most when they solicit donations immediately after price promotions. These findings not only help explain the success of Giving Tuesday, but also provide insights to other organizations about the best timing for their charitable campaigns.

Specifically, these findings help charitable organizations make three important decisions: 1) who to target (consumers who have participated in price promotions); 2) when to solicit donations (immediately after consumers make purchases); and 3) how to increase effectiveness (charitable organizations should pair their donation appeals with promotions for necessities (vs. indulgences) that offer immediate discounts (vs. future rebates)). Further, the donation appeals should direct consumers' focus toward the money they saved (vs. spent) in the promotion. Charitable organizations can take advantage of these insights to better optimize their donation appeals.

"Our research also suggests that firms can use price promotions as great opportunities to collaborate with charitable organizations," adds Cai. For example, the outdoor brand Patagonia has committed since 2016 to donate 100% of its profits from Black Friday to charities. Unfortunately, in traditional cause-related marketing practices, consumers might doubt a firm's prosocial motivation because the benefits for the charity are contingent on consumers' purchases from the firm. But by soliciting donations after consumers complete their purchases, firms can cultivate a purer image of corporate social responsibility. This strategy was exemplified recently by Ralph Lauren, which partnered with the World Health Organization to fight against the COVID-19 pandemic by soliciting donations from customers immediately after they submitted their orders on the store's official online shop. This collaborative strategy between firms and nonprofit organizations can create a win-win situation that benefits stakeholders and contributes to a better world.

Although electric vehicles that reduce greenhouse gas emissions attract many drivers, the lack of confidence in charging services deters others. Building a reliable network of charging stations is difficult in part because it's challenging to aggregate data from independent station operators. But now, researchers reporting January 22 in the journal Patterns have developed an AI that can analyze user reviews of these stations, allowing it to accurately identify places where there are insufficient or out-of-service stations.

"We're spending billions of both public and private dollars on electric vehicle infrastructure," says Omar Asensio (@AsensioResearch), principal investigator and assistant professor in the School of Public Policy at the Georgia Institute of Technology. "But we really don't have a good understanding of how well these investments are serving the public and public interest."

Electric vehicle drivers have started to solve the problem of uncertain charging infrastructure by forming communities on charge station locator apps, leaving reviews. The researchers sought to analyze these reviews to better understand the problems facing users.

With the aid of their AI, Asensio and colleagues were able to predict whether a specific station was functional on a particular day. They also found that micropolitan areas, where the population is between 10,000 and 50,000 people, may be underserved, with more frequent reports of station availability issues. These communities are mostly located in states in the West and Midwest, such as Oregon, Utah, South Dakota, and Nebraska, along with Hawaii.

"When users are engaging and sharing information about charging experiences, they are often engaging in prosocial or pro-environmental behavior, which gives us rich behavioral information for machine learning," says Asensio. But compared to analyzing data tables, texts can be challenging for computers to process. "A review could be as short as three words. It could also be as long as 25 or 30 words with misspellings and multiple topics," says co-author Sameer Dharur of Georgia Institute of Technology. Users sometimes even throw smiley faces or emojis into the texts.

To address the problem, Asensio and his team tailored their algorithm to electric vehicle transportation lingo. They trained it with reviews from 12,720 US charging stations to classify reviews into eight different categories: functionality, availability, cost, location, dealership, user interaction, service time, and range anxiety. The AI achieved a 91% accuracy and high learning efficiency in parsing the reviews in minutes. "That's a milestone in the transition for us to deploy these AI tools because it's no longer 'can the AI do as good as human?'" says Asensio. "In some cases, the AI exceeded the performance of human experts."

As opposed to previous charging infrastructure performance evaluation studies that rely on costly and infrequent self-reported surveys, AI can reduce research costs while providing real-time standardized data. The electric vehicle charging market is expected to grow to $27.6 billion by 2027. The new method can give insight into consumers' behavior, enabling rapid policy analysis and making infrastructure management easier for the government and companies. For instance, the team's findings suggest that it may be more effective to subsidize infrastructure development as opposed to the sale of an electric car.

While the technology still faces some limitations--like the need to reduce requirements for computer processing power--before rolling out large-scale implementation to the electric vehicle charging market, Asensio and his team hope that as the science progresses, their research can open doors to more in-depth studies about social equity on top of meeting consumer needs.

"This is a wake-up call for us because, given the massive investment in electric vehicle infrastructure, we're doing it in a way that is not necessarily attentive to the social equity and distributional issues of access to this enabling infrastructure," says Asensio. "That is a topic of discussion that's not going away and we're only beginning to understand."

DURHAM, N.C. - Biomedical engineers at Duke University have demonstrated that human muscle has an innate ability to ward off the damaging effects of chronic inflammation when exercised. The discovery was made possible through the use of lab-grown, engineered human muscle, demonstrating the potential power of the first-of-its-kind platform in such research endeavors.

The results appear online on January 22 in the journal Science Advances.

"Lots of processes are taking place throughout the human body during exercise, and it is difficult to tease apart which systems and cells are doing what inside an active person," said Nenad Bursac, professor of biomedical engineering at Duke. "Our engineered muscle platform is modular, meaning we can mix and match various types of cells and tissue components if we want to. But in this case, we discovered that the muscle cells were capable of taking anti-inflammatory actions all on their own."

Inflammation is not inherently good or bad. When the body is injured, an initial low-level inflammation response clears away debris and helps tissue rebuild. Other times, the immune system overreacts and creates an inflammatory response that causes damage, like the often deadly cytokine storms brought on by some cases of COVID-19. And then, there are diseases that lead to chronic inflammation, such as rheumatoid arthritis and sarcopenia, which can cause muscle to waste away and weaken its ability to contract.

Among many molecules that can cause inflammation, one pro-inflammatory molecule in particular, interferon gamma, has been associated with various types of muscle wasting and dysfunction. While previous research in humans and animals has shown that exercise can help mitigate the effects of inflammation in general, it has been difficult to distinguish what role the muscle cells themselves might play, let alone how they interact with specific offending molecules, such as interferon gamma.

"We know that chronic inflammatory diseases induce muscle atrophy, but we wanted to see if the same thing would happen to our engineered human muscles grown in a Petri dish," said Zhaowei Chen, a postdoctoral researcher in Bursac's laboratory and first author of the paper. "Not only did we confirm that interferon gamma primarily works through a specific signaling pathway, we showed that exercising muscle cells can directly counter this pro-inflammatory signaling independent of the presence of other cell types or tissues."

To prove that muscle alone is capable of blocking interferon gamma's destructive powers, Bursac and Chen turned to an engineered muscle platform that the laboratory has been developing for nearly a decade. They were first to grow contracting, functional human skeletal muscle in a Petri dish, and since then the lab has been improving its processes by, for example, adding immune cells and reservoirs of stem cells to the recipe.

In the current study, the researchers took these fully functional, lab-grown muscles and inundated them with relatively high levels of interferon gamma for seven days to mimic the effects of a long-lasting chronic inflammation. As expected, the muscle got smaller and lost much of its strength.

The researchers then applied interferon gamma again, but this time also put the muscle through a simulated exercise regime by stimulating it with a pair of electrodes. While they expected the procedure to induce some muscle growth, as shown in their previous studies, they were surprised to discover that it almost completely prevented the effects of the chronic inflammation. They then showed that simulated exercise inhibited a specific molecular pathway in muscle cells, and that two drugs used to treat rheumatoid arthritis, tofacitinib and baricitinib, which block the same pathway, had the same anti-inflammatory effect.

"When exercising, the muscle cells themselves were directly opposing the pro-inflammatory signal induced by interferon gamma, which we did not expect to happen," said Bursac. "These results show just how valuable lab-grown human muscles might be in discovering new mechanisms of disease and potential treatments. There are notions out there that optimal levels and regimes of exercise could fight chronic inflammation while not overstressing the cells. Maybe with our engineered muscle, we can help find out if such notions are true."

When tetrapods (four-limbed vertebrates) began to move from water to land roughly 390 million years ago it set in motion the rise of lizards, birds, mammals, and all land animals that exist today, including humans and some aquatic vertebrates such as whales and dolphins.

The earliest tetrapods originated from their fish ancestors in the Devonian period and are more than twice as old as the oldest dinosaur fossils. They resembled a cross between a giant salamander and a crocodile and were about 1-2 meters long, had gills, webbed feet and tail fins, and were still heavily tied to water. Their short arms and legs had up to eight digits on each hand and foot and they were probably ambush predators, lurking in shallow water waiting for prey to come near.

Scientists know how the fins of fish transformed into the limbs of tetrapods, but controversies remain about where and how the earliest tetrapods used their limbs. And, while many hypotheses have been proposed, very few studies have rigorously tested them using the fossil record.

In a paper published January 22 in Science Advances an international team of researchers examined three-dimensional digital models of the bones, joints, and muscles of the fins and limbs of two extinct early tetrapods and a closely related fossil fish to reveal how function of the forelimb changed as fins evolved into limbs. The research led by Julia Molnar, Assistant Professor at New York Institute of Technology College of Osteopathic Medicine and Stephanie Pierce, Thomas D. Cabot Associate Professor of Organismic and Evolutionary Biology at Harvard University, discovered three distinct functional stages in the transition from fins to limbs, and that these early tetrapods had a very distinct pattern of muscle leverage that didn't look like a fish fin or modern tetrapod limbs.

To reconstruct how limbs of the earliest known tetrapods functioned, Molnar, Pierce and co-authors John Hutchinson (Royal Veterinary College), Rui Diogo (Howard University), and Jennifer Clack (University of Cambridge) first needed to figure out what muscles were present in the fossil animals. A challenging task as muscles are not preserved in fossils, and the muscles of modern fish fins are completely different from those of tetrapod limbs. The team spent several years trying to answer the question, how exactly did the few simple muscles of a fin become dozens of muscles that perform all sorts of functions in a tetrapod limb?

"Determining what muscles were present in a 360-million-year-old fossil took many years of work just to get to the point where we could begin to build very complicated musculoskeletal models," said Pierce. "We needed to know how many muscles were present in the fossil animals and where they attached to on the bones so we could test how they functioned".

They built three-dimensional musculoskeletal models of the pectoral fin in Eusthenopteron (a fish closely related to tetrapods that lived during the Late Devonian period about 385 million years ago) and the forelimbs of two early tetrapods, Acanthostega (365 million years old living towards the end of the Late Devonian period) and Pederpes (348-347 million years old living during the early Carboniferous period). For comparison, they also built similar models of the pectoral fins of living fishes (coelacanth, lungfish) and forelimbs of living tetrapods (salamander, lizard).

To determine how the fins and limbs worked, the researchers used computational software originally developed to study human locomotion. This technique had been used recently to study locomotion in the ancestors of humans and also dinosaurs like T. rex, but never in something as old as an early tetrapod.

Manipulating the models in the software, the team were able to measure two functional traits: the joint's maximum range of motion and the muscles' ability to move the fin or limb joints. The two measurements would reveal trade-offs in the locomotor system and allow the researchers to test hypotheses of function in extinct animals.

The team found the forelimbs of all terrestrial tetrapods passed through three distinct functional stages: a "benthic fish" stage that resembled modern lungfish, an "early tetrapod" stage unlike any extinct animal, and a "crown tetrapod" stage with characteristics of both lizards and salamanders.

"The fin from Eusthenopteron had a pattern that was reminiscent of the lungfish, which is one of the closest living relatives of tetrapods," said Pierce. "But the early tetrapod limbs showed more similarities to each other than either fish or modern tetrapods."

"That was perhaps the most surprising," said Molnar. "I thought Pederpes, and possibly Acanthostega, would fall pretty well within the range of modern tetrapods. But they formed their own distinct cluster that didn't look like a modern tetrapod limb or a fish fin. They were not smack dab in the middle but had their own collection of characteristics that probably reflected their unique environment and behaviors."

The results showed that early tetrapod limbs were more adapted for propulsion rather than weight bearing. In the water, animals use their limbs for propulsion to move themselves forward or backward allowing the water to support their body weight. Moving on land, however, requires the animal act against gravity and push downward with their limbs to support their body mass.

This doesn't mean that early tetrapods were incapable of moving on land, but rather they didn't move like a modern-day living tetrapod. Their means of locomotion was probably unique to these animals that were still very much tied to the water, but were also venturing onto land, where there were many opportunities for vertebrate animals but little competition or fear from predators.

"These results are exciting as they independently support a study I published last year using completely different fossils and methods", said Pierce. "That study, which focused on the upper arm bone, indicated that early tetrapods had some capacity for land movement but that they may not have been very good at it."

The researchers are closer to reconstructing the evolution of terrestrial locomotion, but more work is needed. They plan to next model the hind limb to investigate how all four limbs worked together. It has been suggested that early tetrapods were using their forelimbs for propulsion, but modern tetrapods get most of their propulsive power from the hind limb.

"We plan to look for any evidence of a shift from forelimb driven locomotion toward hind limb driving locomotion, like modern tetrapods," said Molnar. Looking at the forelimb and hind limb together could reveal more about the transition from water to land and how tetrapods eventually came to dominate the terrestrial realm.

New research suggests the majority of people in the UK are willing to use privacy-encroaching tracking technology and support the introduction of 'immunity passports' to protect themselves and others in the COVID-19 pandemic.

The study, published today in the journal PLOS ONE, found more than two thirds of respondents overall would accept some form of smartphone tracking app to help manage social distancing and the relaxation of a full public lockdown.

However, its findings are not reflected in the number of people who have downloaded the NHS Test and Trace app, prompting calls for this issue to be addressed.

Lead author Professor Stephan Lewandowsky, Chair in Cognitive Psychology at the University of Bristol, said: "Attitudes were surprisingly permissive and this is good news for public health. But there appears to be a significant gap between what people say they're willing to do and what they actually do, which needs further investigation. Lack of uptake is a big problem because such systems need more than half - 56 per cent - of the general population on board to be effective in helping control a pandemic.

"As of the end of last month, nearly 21 million people in the UK had downloaded the app, which is more than 10 million below target for it to work properly. There could be many reasons for this, which could be technological barriers, confusion, or simply lack of awareness. But the fact respondents were very receptive and open to such tools should be encouraging and indicates while people don't want to throw away their privacy, they are willing to make compromises perhaps for the greater good."

The research comprised two online surveys with more than 3,500 respondents in total, the first carried out in March 2020 and the second in April 2020, when COVID-19 case numbers had reached nearly 100,000 and resulted in almost 15,000 deaths. The NHS Test and Trace app, a decentralised tool relying on Google/Apple Bluetooth technology, was later introduced in September 2020.

Both surveys presented at least two scenarios - an app, using smartphone tracking data to identify and contact those who may have been exposed to people with COVID-19, which people can choose to download. The second scenario proposed this app was compulsory for all mobile phone users and enabled the Government to use the data to locate anyone violating lockdown orders and enforce them with fines and arrests.

In both surveys, the levels of acceptance for each scenario were broadly the same. Around 70 per cent of respondents accepted the opt-in app and almost two thirds, some 65 per cent overall, accepted the mandatory version with tighter enforcement. When a sunset clause was introduced, resulting in all data being deleted after two weeks, acceptance levels of both scenarios rose to more than 75 per cent. Acceptance increased further still to more than 85 per cent when, on top of the time limit, an opt-out clause was provided.

Professor Lewandowsky said: "Such high levels of acceptance were quite unexpected but welcome. It would be concerning if people didn't care at all about their privacy, but the fact they indicated even greater acceptance with additional measures to preserve it is reassuring and suggests careful consideration before being willing to surrender it."

The second survey also explored attitudes towards so-called immunity passports, which could be issued to people who carry COVID-19 antibodies as an indication they are immune to the virus and unable to spread it. Resistance to the idea was relatively low and more than 60 per cent of respondents wanted one for themselves.

Professor Lewandowsky said: "Only 20 per cent of people strongly opposed the idea, mainly on grounds of fairness, which was surprisingly low. It's fascinating how people seem increasingly receptive to their personal data being used to inform themselves and others about what they can and can't do.

"As a follow-up, it would be beneficial to know whether people have relaxed their privacy attitudes as an exception due to the emergency situation or if our findings show a wider acceptance of privacy-encroaching technologies, for example continuous monitoring of your power consumption at home or tracking of location by law enforcement authorities."

The research forms part of an international project with similar surveys being conducted in countries across the world, including Australia, the United States, Taiwan, Japan, Switzerland, Germany, and Spain.

On January 22 in Current Biology, a team of Harvard-led researchers presented the most complete genome yet assembled of one of the major Rafflesiaceae lineages, Sapria himalayana.

The species is found in Southeast Asia and its mottled red and white flower is about the size of a dinner plate. (It's more famous cousin, Rafflesia arnoldii, produces blossoms nearly three feet in diameter, the largest in the world.)

The genetic analysis revealed an astonishing degree of gene loss and surprising amounts of gene theft from its ancient and modern hosts. These findings bring unique perspectives into the number and kind of genes it takes to be an endoparasite (an organism that is completely dependent on its host for all nutrients), along with offering new insights into how far the genomes of flowering plants can be altered and still remain functional.

The analysis sheds light on a species of flowers who's evolutionary and genomic history is largely unknown because they lack a traditional body, spend most of their lives inside their hosts, and lack the machinery to perform photosynthesis (which keeps most plants alive).

What struck the group immediately was the striking degree of gene loss Sapria experienced as they abandoned their bodies and adapted to become endoparasites. Nearly half of all genes found in most flowering plants are absent in the Sapria genome. That extent of gene loss is more than four times the degree of loss in other plant parasites. Many of the genes lost include what are considered the key genes responsible for photosynthesis, which converts light into energy.

"In many ways, it's a miracle that these plants exist today, let alone that they seem to have persisted for tens of millions of years," said Charles Davis, who led the project and is a professor of organismic and evolutionary biology at the Faculty of Arts and Sciences and curator of vascular plants in the Harvard University Herbaria. "They've really jettisoned many things we identify as a typical plant yet they are deeply embedded within the plant tree of life."

At the same time, the data demonstrated an underlying evolutionary convergence to becoming a parasite because Sapria and the parasitic plants the researchers compared them to lost many of the same types of genes despite evolving separately.

"We concluded that there is a common genomic or genetic roadmap to how plant parasites evolve," said Cai Liming '20, Ph.D., a researcher at the University of California, Riverside, who helped lead the study as a graduate student in the Davis Lab while at the Harvard Graduate School of Arts and Sciences.

The scientists also identified dozens of genes that came into the Sapria genome through a process called horizontal (or lateral) gene transfer instead of the traditional parent-to-offspring transmission. Basically, it means Sapria stole this DNA from their host instead of getting it passed down to them.

The researchers then reconstructed the lateral gene transfers they detected to put together a hidden history of former hosts going back millions of years.

They estimate they've sequenced about 40% the genome, believing that this is the core and that the remaining portions are likely repeat regions.

The research collaboration included scientists from across the country and around the world, including former students in the Davis lab and collaborators in Thailand and Malaysia. Along with Cai, researchers from Harvard included Timothy Sackton, the director of bioinformatics for the FAS Informatics Group; Brian Arnold, a former bioscientist with the group; Danielle Khost, a current bioscientist with the group; and Claire Hartmann, director of the Bauer Core Facility.

"[The project] was really an illustration of how these new sequencing technologies are really opening up the possibility of addressing questions that were just not feasible to address before, particularly in plants which have a really wide diversity of these sorts of weird genomes," Sackton said.

The project dates back to 2004. It involved extensive fieldwork in Thailand and Malaysia and careful logistics to transport the plants. In the lab, the researchers dissected the plants and extracted their genetic materials. This involved its own slew of sensitive protocols, like making sure not to cross-contaminate genes from the parasite with those of the host. Researchers said putting together the genome was like assembling a puzzle that had millions of pieces.

When it comes to parasites, Rafflesiaceae are the stuff of nightmares. They have no roots, stems, or leaves of their own. Instead, they are invisible for most of their life, living only as a small necklace of cells inside the woody vines of their host until without warning -- like the creature in the movie "Alien" -- they burst out to bloom some of the largest flowers in the world. Their pungent smell of rotting meat or fruit attracts carrion flies who help pollinate these plants, allowing them to produce seeds and spread to another unsuspecting host, restarting the whole cycle.

Rafflesiaceae represent the most extreme form of parasitism known as endoparasitism. To those who study these plants, it's one of the many things that makes them so remarkable.

"These are easily the most charismatic and strange of all flowering plants," said Davis. "They're just so bizarre."

In a new study published in Journal of Extracellular Vesicles, Chen-Yu Zhang's group at Nanjing University, School of Life Sciences, and Antonio Vidal-Puig's group at University of Cambridge report that pancreatic β cells secrete miR-29 family members (miR-29s) via exosomes in response to high levels of free fatty acids (FFAs). Theses β cell-derived exosomal miR-29s regulate glucose homeostasis through their manipulations on glucose output in liver.

Previously, Chen-Yu Zhang’s group identified extracellular miRNA as a new form of cell-to-cell communication. They are among the first that reported the selective secretion of miRNAs under different physiological or pathological states; also, the uptake and function of secreted miRNAs in recipient cells. In the past decade, intensive studies have revealed the role of extracellular miRNAs in a range of biological processes. Thus, as a newly-emerged secretory factor, more insightful studies are needed to further reveal its relevance to more physiological progresses and diseases. Pancreatic islet has long been identified as critical secretory tissue in term of its role on maintaining glucose homeostasis by releasing conventional hormones, such as glucagon and insulin. Since pancreatic islet is a classic secretory organ, study to identify its secreted miRNAs and their functional implications in the regulation of glucose homeostasis is very needed.

In the current study, they show that high levels of FFAs can selectively induce the secretion of miR-29s from cultured pancreatic β cells. In vivo study revealed both physiological (fasting)-and pathological (obese)-associated high levels of FFAs induce the secretion of miR-29s from pancreatic β cells. Likewise, miR-29s are also increased in the plasma of obese human compared to normal human. Intriguingly, they discovered that exosomal miR-29s administrated intravenously can cause impaired insulin sensitivity. Next, they used a combination of genetic modification animals to further confirm the functional role of secreted miR-29s. First, mice overexpressed miR-29s in β cells show insulin resistance and an enhanced hepatic glucose output, indicating β cell-derived miR-29s may target liver and impact hepatic insulin action. To confirm this, a distinguishable mutant miR-29a (with four nucleotides mutated in non-seed region) was overexpressed in pancreatic β cells of mice. Consistently, these mice show impaired insulin sensitivity. By tracking the distribution of mutant miR-29a, they found β cell-derived mutant miR-29a can be taken up by liver. Mechanism dissections revealed that β cell-derived miR-29s negatively regulate insulin signalling pathway via targeting p85 α (regulatory subunit of PI3K), and subsequently attenuate the suppression of insulin on glucose output. Finally, miR-29s deficiency in β cell significantly improves the insulin sensitivity in mice fed on HFD. This study not only identifies a new secretory factor from pancreatic β cells, but also elucidates an alternative mechanism that underlies β cell-controlled glucose homeostasis.

This work is important for the following reasons:

This study demonstrates pancreatic islets secrete not only canonical hormones, but also exosomal miRNAs, which is largely extended our understanding of islet function;

This study also identifies new secretory factors that play a role in regulation of glucose homeostasis;

This study reveals a new mechanism underlying obesity/FFAs-induced insulin resistance and type 2 diabetes. Obesity or high levels of FFAs may not only directly affect liver, skeletal muscle and white adipose tissue and cause insulin resistance, but also regulate exogenous secreted miRNAs to indirectly result in pathophysiology as well. More importantly, the secreted miR-29s are increased prior to the onset of insulin resistance in ob/ob or DIO mice, indicating secreted miR-29s may be the factors that initiate the development of insulin resistance;

Finally, this study provides further evidence for the selectivity of secreted miRNAs under certain physiological or pathological context

A new algorithm may reduce the need for expensive, time-consuming whole-genome sequencing computations to understand how a microbiome functions. A team led by JING Gongchao of the Qingdao Institute of BioEnergy and Bioprocess Technology (QIBEBT) of the Chinese Academy of Sciences (CAS) and SU Xiaoquan of Qingdao University, published their approach, called Meta-Apo, on Jan. 6 in BMC Genomics.

Researchers routinely sequence samples of microbial communities found on human skin, in human guts, and in the environment to understand what genes they contain with the ultimate goal of understanding how they function.

According to JING, the first author of the study, two main approaches exist: shotgun whole-genome sequencing and 16S rRNA gene amplicons. Whole-genome sequencing requires significant sequencing cost as well as computing power to determine all of the genes and their functions in a single sample, while 16S rRNA gene amplicons can quickly tease out a sample's specific gene for taxonomy information and thus predict how they function.

"However, due to the potential biases in how the amplicons are prepared and gene profile variation among genomes, functional profiles predicted from 16S amplicons may deviate from whole-genome sequencing ones, resulting in misleading results," said JING. "Our approach, Meta-Apo, greatly reduces or even eliminates such deviation, deducing more consistent diversity patterns between the two approaches."

Meta-Apo matches pairs of data from whole-genome sequencing and 16S amplicons - each pair is sequenced via both methods - to teach new 16S amplicon samples to better recognize gene function. The results are much more consistent with the whole-genome sequencing results.

"Tests of Meta-Apo on more than 5,000 16S amplicon human microbiome samples from four body sites showed the deviation between the two strategies is significantly reduced by using only 15 training sample pairs," JING added. "Moreover, Meta-Apo enables cross-platform functional comparison between whole-genome sequencing and amplicon samples, greatly improving 16S-based microbiome diagnoses."

To test this experimentally, the researchers were able to improve the accuracy of a gingivitis diagnosis from 65% to 95% percent using the 16S-derived functional profiles, produced by training the whole-genome sequencing pairs.

"With the low cost of 16S-amplicon sequencing, Meta-Apo can produce a reliable, high-resolution view of microbiome function equivalent to that offered by shotgun whole-genome sequencing," SU, senior author of the study, explained.