Culture

When we make even simple decisions about how to interact with the world, we rely on computations performed by networks of neurons that span our brains. But what exactly are these neural networks computing?

Answering this question requires measuring the activity of lots of neurons throughout the brain as an animal makes a decision.

Now a team of Stanford researchers led by bioengineer Karl Deisseroth and electrical engineer Gordon Wetzstein - along with graduate student Isaac Kauvar and postdoctoral fellow Timothy Machado - has developed an optical technique that can simultaneously record the activity of neurons spread across the entire top surface of a mouse's cerebral cortex, a key part of the brain involved in making decisions. They published their findings in May in the journal Neuron.

Optical studies of the brain are not entirely new. Researchers already know how to track brain activity by using fluorescent dyes and proteins that emit light when a neuron fires. Until now, however, such optical techniques have not been able to record these faint flashes of light from many neurons, distributed across the curved surface of the cerebral cortex and working together to make a decision such as whether or not to take a drink of water.

To overcome this barrier, the Stanford researchers designed a bifocal microscope - analogous to bifocal eyeglasses - that allows them to keep the entire curved surface of the brain in focus.

The bifocal microscope uses a single camera to capture two movies of neural activity at the same time: one focused on the sides of the brain, and the other focused on the middle, to provide a side-by-side view shown in a video (available for download with this release). The researchers then computationally extract signals - reflecting the timing, intensity and duration of when neurons fire - from both of these movies to obtain a comprehensive measurement of neural activity across the whole surface.

The researchers call this system Cortical Observation by Synchronous Multifocal Optical Sampling, or COSMOS. In addition to studying motor control and decision making, the team is also using COSMOS to study sensory perception in animals and as a screening technique to develop better psychiatric drugs.

The prototype COSMOS system is relatively simple to build and costs less than $50,000, which is hundreds of thousands of dollars cheaper than other optical systems for recording neural population dynamics. To encourage further adoption and development of the technique, the authors have built a website with instructions to help other researchers build their own COSMOS systems.

Patients undergoing surgery after contracting coronavirus are at greatly increased risk of postoperative death, a new global study published in The Lancet reveals. Researchers found that amongst SARS-CoV-2 infected patients who underwent surgery, mortality rates approach those of the sickest patients admitted to intensive care after contracting the virus in the community.

Experts from different institutions including the University of Birmingham-led NIHR Global Research Health Unit on Global Surgery and the Department of Surgery at Massachusetts General Hospital have now published their findings that SARS-CoV-2 infected patients who undergo surgery experience substantially worse postoperative outcomes than would be expected for similar patients who do not have SARS-CoV-2 infection.

Researchers examined data for 1,128 patients from 235 hospitals. A total of 24 countries participated, predominantly in Europe, although hospitals in Africa, Asia, and North America also contributed.

Overall 30-day mortality in the study was 23.8%. Mortality was disproportionately high across all subgroups, including elective surgery (18.9%), emergency surgery (25.6%), minor surgery such as appendicectomy or hernia repair (16.3%), and major surgery such as hip surgery or colon cancer surgery (26.9%).

The study identified that mortality rates were higher in men (28.4%) versus women (18.2%), and in patients aged 70 years or over (33.7%) versus those aged under 70 years (13.9%). In addition to age and sex, risk factors for postoperative death included having severe pre-existing medical problems, undergoing cancer surgery, undergoing major procedures, and undergoing emergency surgery.

Patients undergoing surgery are a vulnerable group at risk of SARS-CoV-2 exposure in hospital. They may be particularly susceptible to subsequent pulmonary complications, due to inflammatory and immunosuppressive responses to surgery and mechanical ventilation.

The study found that overall in the 30 days following surgery 51% of patients developed a pneumonia, acute respiratory distress syndrome, or required unexpected ventilation. This may explain the high mortality, as most (81.7%) patients who died had experienced pulmonary complications.

"The decision in most hospitals to postpone elective surgery was made to both protect our patients as well as increase capacity to take care of the COVID-19 patients during the peak of the pandemic," says report co-author Haytham Kaafarani, MD, MPH, from the department of surgery at Massachusetts General Hospital and an associate professor of surgery at Harvard Medical School. "The high mortality and morbidity rates of the elective surgery patients in this study is proving that the decision was sound, as we would normally expect mortality for patients having minor or elective surgery to be under 1-3%."

"We recommend that thresholds for surgery during the SARS-CoV-2 pandemic should be raised compared to normal practice, says Aneel Bhangu, MD, PhD, Senior Lecturer in Surgery at the University of Birmingham, the co-author and overall study lead. "For example, men aged 70 years and over undergoing emergency surgery are at particularly high risk of mortality, so these patients may benefit from their procedures being postponed."

COLUMBUS, Ohio - Breast cancer survivors in romantic relationships who feel happy and satisfied with their partners may be at lower risk for a host of health problems, new research suggests.

The findings suggest that the relationship itself wasn't the cure-all, however. Women who were satisfied in their relationships also reported lower psychological stress - and these two factors were associated with lower markers for inflammation in their blood.

Keeping inflammation at bay is the key to promoting health generally, and especially in breast cancer survivors, researchers say. When we're sick or injured, inflammation promotes healing. But elevated inflammation over time increases survivors' risk for cancer recurrence and other illnesses.

"It's important for survivors, when they're going through this uncertain time, to feel comfortable with their partners and feel cared for and understood, and also for their partners to feel comfortable and share their own concerns," said Rosie Shrout, lead author of the study and a postdoctoral scholar in the Institute for Behavioral Medicine Research at The Ohio State University.

"Our findings suggest that this close partnership can boost their bond as a couple and also promote survivors' health even during a very stressful time, when they're dealing with cancer."

The research is published online in the journal Psychoneuroendocrinology.

Shrout is a relationship scientist working in the lab of Janice Kiecolt-Glaser, professor of psychiatry and psychology and director of the Institute for Behavioral Medicine Research. For this work, Shrout conducted a secondary analysis of data from a previous Kiecolt-Glaser study assessing fatigue and immune function in breast cancer survivors.

The 139 women with an average age of 55 completed self-report questionnaires and provided blood samples at three visits: upon recruitment within one to three months of their cancer diagnosis and during two follow-up visits six and 18 months after their cancer treatment ended.

One survey assessed relationship satisfaction by asking the women to report their degree of happiness, the level of warmth and comfort they felt with their partner, how rewarding the relationship was and their overall satisfaction. The other questionnaire was used to evaluate their level of perceived psychological stress over the previous week.

Researchers analyzed the blood samples for levels of four proteins that promote inflammation throughout the body even when there is no need for an immune response. This kind of chronic inflammation is linked to numerous health problems, including heart disease, Type 2 diabetes, arthritis and Alzheimer's disease, as well as the frailty and functional decline that can accompany aging.

The findings showed a clear trend in the women as a group: The more satisfied they felt about their romantic relationships, the lower their perceived stress and the lower their inflammation.

The design of the study allowed researchers to compare the group of women to each other and also gauge changes in each woman individually.

"This gave us a unique perspective - we found that when a woman was particularly satisfied with her relationship, she had lower stress and lower inflammation than usual - lower than her own average," Shrout said. "At a specific visit, if she was satisfied with her partner, her own inflammation was lower at that visit than at a different visit when she was less satisfied."

Shrout noted the study suggests that health professionals who care for breast cancer patients might want to keep an eye out for potential signs that their patients are struggling at home.

"The research shows the importance of fostering survivors' relationships. Some survivors might need help connecting with their partners during a stressful time, so that means it's important for part of their screening and treatment to take the relationship into account and include a reference to couples counseling when appropriate," she said. "Doing so could promote their health over the long run."

Though the findings in this study related to breast cancer survivors, Shrout said a strong romantic relationship would likely be helpful to people navigating the uncertainty associated with other serious illnesses by lowering their stress.

There are more sides to the relationship story: Previous work led by Kiecolt-Glaser, senior author of this study, has shown that marital conflict can have detrimental effects on health. And breast cancer survivors who are single may benefit from drawing on a network of family and friends for support.

"Some of the research would suggest it's better to be alone than in a troubled relationship," Kiecolt-Glaser said. "A good marriage offers good support, but the broader message for a breast cancer survivor who is not married is to seek support in other relationships.

"In general, one thing that happens when people are stressed is we tend to isolate ourselves, so seeking support when we're stressed is one of the more beneficial things that people can do."

Irvine, Calif., June 2, 2020 -- Octopuses, squids and other sea creatures can perform a disappearing act by using specialized tissues in their bodies to manipulate the transmission and reflection of light, and now researchers at the University of California, Irvine have engineered human cells to have similar transparent abilities.

In a paper published today in Nature Communications, the scientists described how they drew inspiration from cephalopod skin to endow mammalian cells with tunable transparency and light-scattering characteristics.

"For millennia, people have been fascinated by transparency and invisibility, which have inspired philosophical speculation, works of science fiction, and much academic research," said lead author Atrouli Chatterjee, a UCI doctoral student in chemical & biomolecular engineering. "Our project - which is decidedly in the realm of science - centers on designing and engineering cellular systems and tissues with controllable properties for transmitting, reflecting and absorbing light."

Chatterjee works in the laboratory of Alon Gorodetsky, UCI associate professor of chemical & biomolecular engineering, who has a long history of exploring how cephalopods' color-changing capabilities can be mimicked to develop unique technologies to benefit people. His team's bioinspired research has led to breakthrough developments in infrared camouflage and other advanced materials.

For this study, the group drew inspiration from the way female Doryteuthis opalescens squids can evade predators by dynamically switching a stripe on their mantle from nearly transparent to opaque white. The researchers then borrowed some of the intercellular protein-based particles involved in this biological cloaking technique and found a way to introduce them into human cells to test whether the light-scattering powers are transferable to other animals.

This species of squid has specialized reflective cells called leucophores which can alter the how they scatter light. Within these cells are leucosomes, membrane-bound particles which are composed of proteins known as reflectins, which can produce iridescent camouflage.

In their experiments, the researchers cultured human embryonic kidney cells and genetically engineered them to express reflectin. They found that the protein would assemble into particles in the cells' cytoplasm in a disordered arrangement. They also saw through optical microscopy and spectroscopy that the introduced reflectin-based structures caused the cells to change their scattering of light.

"We were amazed to find that the cells not only expressed reflectin but also packaged the protein in spheroidal nanostructures and distributed them throughout the cells' bodies," said Gorodetsky, a co-author on this study. "Through quantitative phase microscopy, we were able to determine that the protein structures had different optical characteristics when compared to the cytoplasm inside the cells; in other words, they optically behaved almost as they do in their native cephalopod leucophores."

In another important part of the study, the team tested whether the reflectance could potentially be toggled on and off through external stimuli. They sandwiched cells in between coated glass plates and applied different concentrations of sodium chloride. Measuring the amount of light that was transmitted by the cells, they found that the ones exposed to higher sodium levels scattered more light and stood out more from the surroundings.

"Our experiments showed that these effects appeared in the engineered cells but not in cells that lacked the reflectin particles, demonstrating a potential valuable method for tuning light-scattering properties in human cells," Chatterjee said.

While invisible humans are still firmly in the realm of science fiction, Gorodetsky said his group's research can offer some tangible benefits in the near term.

"This project showed that it's possible to develop human cells with stimuli-responsive optical properties inspired by leucophores in celphalopods, and it shows that these amazing reflectin proteins can maintain their properties in foreign cellular environments," he said.

He said the new knowledge also could open the possibility of using reflectins as a new type of biomolecular marker for medical and biological microscopy applications.

A University of Wyoming researcher led a study that showed Wyoming pronghorn exhibit little-to-no population genetic differentiation even though their range spans hundreds of kilometers, multiple mountain ranges and three major interstate highways.

While there are previously documented studies that show landscape features such as major highways restrict the daily and seasonal movements of pronghorn and increase mortality risk, Melanie LaCava says her research group found little, if any, evidence that these barriers affect genetic connectivity among Wyoming pronghorn.

"While there is ample evidence from previous research that pronghorn behavior is severely impacted by highways, roads, fencing and other forms of human development, there also is evidence that pronghorn exhibit flexible social and migratory behavior," says LaCava, a UW Ph.D. candidate in the Program in Ecology, from San Diego, Calif.

Pronghorn live in social groups. However, they do not necessarily stay in the same groups forever. Unlike some other Wyoming ungulates that live in social groups with animals to which they are related, pronghorn social structure is much more flexible, LaCava says. Seasonal migration behavior in pronghorn also is more flexible than other ungulates: Some pronghorn migrate every year; some migrate when they need to; and some stay residents in one area year-round.

"These flexible behaviors may lead to a lot of dispersal across the state, which could explain our findings of low genetic differentiation in Wyoming pronghorn," LaCava says.

LaCava was the lead author of a paper, titled "Pronghorn Population Genomics Show Connectivity in the Core of Their Range," that was published May 29 in the online version of the Journal of Mammalogy, an international scientific journal that promotes interest in mammals throughout the world. Papers published focus on mammalian behavior, conservation, ecology, genetics, morphology, physiology and taxonomy.

Holly Ernest, a UW professor of wildlife genomics and disease ecology, and the Wyoming Excellence Chair in Disease Ecology in the Department of Veterinary Sciences and the Program in Ecology, was the paper's senior and corresponding author. When Ernest moved her lab from the University of California-Davis to UW in August 2014, pronghorn was one of the species she was very excited to research for statewide genomic health. She then recruited LaCava as the lead Ph.D. student to work on the project.

Other contributors to the paper were Sierra Love Stowell, affiliated with Ernest's lab and a UW postdoctoral researcher from 2016-18; Roderick Gagne, a research scientist at Colorado State University and a UW postdoctoral researcher from 2015-17; Kyle Gustafson, an assistant professor of evolutionary ecology at Arkansas State University; Alex Buerkle, a UW professor of botany; and Lee Knox, a senior wildlife biologist at the Wyoming Game and Fish Department.

Wyoming is home to roughly half of North America's pronghorn population, which stands at approximately 750,000. The state continues to remain a stronghold for remaining pronghorn due to the presence of preferred sagebrush and grassland habitat, and lower density of human development compared to other parts of their range.

"We used multiple lines of genetic evidence to show that Wyoming pronghorn exhibit high levels of genetic connectivity across the state, and do not yet display any signs of barriers to gene flow," LaCava says.

The study, which included sample collection from 2014-18 and lab and data analysis from 2017-19, examined genetic data of 398 pronghorn across Wyoming, excluding Yellowstone and Grand Teton national parks. Researchers worked to equally represent male and female pronghorn to ensure that any differences in behavior between the sexes did not alter the findings.

According to the study, pronghorn at distances within 100 to 150 kilometers were slightly more genetically similar to one another than expected if the same individuals occurred at random locations.

"We were primarily interested in investigating statewide patterns of genetic connectivity to get a large-scale picture of what is going on with Wyoming pronghorn," LaCava explains. "When we did not find much genetic differentiation at the statewide level, we zoomed in on the Interstate 80 highway corridor because previous research has shown this is a significant barrier to pronghorn movement.

"We performed a rare variant analysis on samples close to I-80 to see if the most recent genetic mutations showed evidence that the highway corridor is inhibiting gene flow," she continues. "We found no evidence that I-80 is a genetic barrier, despite its impact on daily and seasonal behavior of pronghorn."

Although the study found no evidence that barriers to daily and seasonal movements of pronghorn impede gene flow, the researchers suggest periodic monitoring of genetic structure and diversity as part of management strategies to identify changes in connectivity. The goal is to prevent isolation and subsequent loss of genetic diversity.

"Maintaining connectivity among pronghorn populations is essential to the long-term sustainability of healthy pronghorn populations in Wyoming and throughout their range," LaCava says. "While we did not find any genetic evidence of barriers on the landscape, GPS tracking studies have demonstrated significant negative impacts of highways, roads, fencing and other forms of human development on the daily and seasonal behavior of pronghorn."

LaCava says many efforts are currently ongoing to maintain and improve habitat connectivity for pronghorn and other Wyoming wildlife, such as constructing highway overpasses or removing old, unused fencing from the landscape. Continuing and expanding these efforts will help sustain healthy pronghorn populations long into the future and, hopefully, prevent negative genetic impacts to this iconic sagebrush species, she says.

A new study from researchers at the University of Illinois at Chicago shows that high estrogen levels may make alcohol more rewarding to female mice.

The study, published in the Journal of Neuroscience, suggests that treatment for alcohol use disorder or binge drinking behavior may be more effective if sex differences are considered.

Amy Lasek, associate professor of psychiatry and anatomy and cell biology, led the research, which looked specifically at estrogen receptors in the brain to determine the mechanisms by which estrogen regulates alcohol sensitivity.

In one experiment, the researchers analyzed post-mortem brain tissue samples from female mice in two reproductive cycle phases -- one characterized by high estrogen levels and one characterized by low estrogen levels. They activated estrogen receptors and tracked how dopamine neurons responded to alcohol.

"We found that when one estrogen receptor was activated -- the alpha receptor -- dopamine neurons fired at increased rates in response to alcohol," said Lasek, who is part of UIC's Center for Alcohol Research in Epigenetics. "The effect was also greater in the tissues taken from mice in high-estrogen phases."

Lasek says that this increased neural activity could translate into a greater feeling of pleasure when drinking.

"This enhanced feeling of reward may make alcohol abuse, specifically binge drinking behavior, more likely," Lasek said.

In another experiment, the researchers blocked estrogen receptors located in the ventral tegmental area of the brain -- this is the region known to contain dopamine neurons and be associated with drug use -- and tracked the behaviors of both female and male mice in the presence of alcohol.

They found that reducing the number of estrogen receptors, like estrogen receptor alpha, led to decreased drinking behavior, but only in female mice.

"This is a novel finding that suggests there may be a sex-specific role of estrogen receptors in the ventral tegmental area when it comes to alcohol use," Lasek said.

"As we learn more about the role of estrogen in sensitizing the brain to the effects of alcohol, we may be able to develop more tailored treatments for alcohol use disorder or be able to provide better education to women on how drinking may affect them differently during various stages of their reproductive cycle.

"This is especially important because although more men are diagnosed with alcohol use disorder, around 5.3 million women in the U.S. also suffer from an alcohol use disorder," Lasek said. "There is evidence that women transition more rapidly from problematic alcohol drinking to having an alcohol use disorder and suffer from the negative health effects of alcohol, such as increased cancer risk, liver damage, heart disease and brain damage."

Researchers in Italy have melded the emerging science of convolutional neural networks (CNNs) with deep learning - a discipline within artificial intelligence - to achieve a system of market forecasting with the potential for greater gains and fewer losses than previous attempts to use AI methods to manage stock portfolios. The team, led by Prof. Silvio Barra at the University of Cagliari, published their findings on IEEE/CAA Journal of Automatica Sinica.

The University of Cagliari-based team set out to create an AI-managed "buy and hold" (B&H) strategy - a system of deciding whether to take one of three possible actions - a long action (buying a stock and selling it before the market closes), a short action (selling a stock, then buying it back before the market closes), and a hold (deciding not to invest in a stock that day). At the heart of their proposed system is an automated cycle of analyzing layered images generated from current and past market data. Older B&H systems based their decisions on machine learning, a discipline that leans heavily on predictions based on past performance.

By letting their proposed network analyze current data layered over past data, they are taking market forecasting a step further, allowing for a type of learning that more closely mirrors the intuition of a seasoned investor rather than a robot. Their proposed network can adjust its buy/sell thresholds based on what is happening both in the present moment and the past. Taking into account present-day factors increases the yield over both random guessing and trading algorithms not capable of real-time learning.

To train their CNN for the experiment, the research team used S&P 500 data from 2009 to 2016. The S&P 500 is widely regarded as a litmus test for the health of the overall global market.

At first, their proposed trading system predicted the market with about 50 percent accuracy, or about accurate enough to break even in a real-world situation. They discovered that short-term outliers, which unexpectedly over- or underperformed, generating a factor they called "randomness." Realizing this, they added threshold controls, which ended up greatly stabilizing their method.

"The mitigation of randomness yields two simple, but significant consequences," Prof. Barra said. "When we lose, we tend to lose very little, and when we win, we tend to win considerably."

Further enhancements will be needed, according to Prof. Barra, as other methods of automated trading already in use make markets more and more difficult to predict.

First review of all available evidence including 172 observational studies looking at how physical distancing, face masks, and eye protection affect the spread of COVID-19, SARS, and MERS in both community and healthcare settings across 16 countries.

Physical distancing of at least 1 metre lowers risk of COVID-19 transmission, but distances of 2 metres could be more effective.

Face coverings and masks might protect both healthcare workers and the general public against infection with COVID-19, and protective eye covering may also provide additional benefit--although the certainty of the evidence is low for both forms of protection.

Importantly, even when properly used and combined, none of these interventions offers complete protection and other basic protective measures (such as hand hygiene) are essential to reduce transmission.

Keeping at least one metre from other people as well as wearing face coverings and eye protection, in and outside of health-care settings, could be the best way to reduce the chance of viral infection or transmission of COVID-19, according to a systematic review and meta-analysis synthesising all the available evidence from the scientific literature, published in The Lancet.

However, none of these interventions, even when properly used and combined, give complete protection from infection, and the authors note that some of the findings, particularly around face masks and eye protection, are supported by low-certainty evidence [1], with no completed randomised trials addressing COVID-19 for these interventions (table 2).

The study, conducted to inform WHO guidance documents, is the first time researchers have systematically examined the optimum use of these protective measures in both community and healthcare settings for COVID-19. The authors say it has immediate and important implications for curtailing the current COVID-19 pandemic and future waves by informing disease models, and standardising the definition of who has been 'potentially exposed' (ie, within 2 metres) for contact tracing.

Many countries and regions have issued conflicting advice about physical distancing to reduce transmission of COVID-19, based on limited information. In addition, the questions of whether masks and eye coverings might reduce transmission of COVID-19 in the general population, and what the optimum use of masks in healthcare settings is, have been debated during the pandemic.

"Our findings are the first to synthesise all direct information on COVID-19, SARS, and MERS, and provide the currently best available evidence on the optimum use of these common and simple interventions to help "flatten the curve" and inform pandemic response efforts in the community", says Professor Holger Schünemann from McMaster University in Canada, who co-led the research. "Governments and the public health community can use our results to give clear advice for community settings and healthcare workers on these protective measures to reduce infection risk." [2]

The currently best available evidence suggests that COVID-19 is most commonly spread by respiratory droplets, especially when people cough and sneeze, entering through the eyes, nose, and mouth, either directly or by touching a contaminated surface. At the moment, although there is consensus that SARS-CoV-2 mainly spreads through large droplets and contact, debate continues about the role of aerosol spreading.

For the current analysis, an international team of researchers did a systematic review of 172 observational studies assessing distance measures, face masks, and eye protection to prevent transmission between patients with confirmed or probable COVID-19, SARS, or MERS infection and individuals close to them (eg, caregivers, family, healthcare workers), up to May 3, 2020.

Pooled estimates from 44 comparative studies involving 25,697 participants were included in the meta-analysis. Of these, 7 studies focused on COVID-19 (6,674 participants), 26 on SARS (15,928), and 11 on MERS (3,095).

The COVID-19 studies included in the analysis consistently reported a benefit for the three interventions and had similar findings to studies of SARS and MERS.

Analysis of data from nine studies (across SARS, MERS and COVID-19, including 7,782 participants) looking at physical distance and virus transmission found that keeping a distance of over one metre from other people was associated with a much lower risk of infection compared with less than one metre (risk of infection when individuals stand more than a metre away from the infected individual was 3% vs 13% if within a metre), however, the modelling suggests for every extra metre further away up to three metres, the risk of infection or transmission may halve (figure 3). The authors note that the certainty of their evidence on physical distancing is moderate [1] and that none of the studies quantitatively evaluated whether distances of more than 2 metres were more effective, although meta-analyses provided estimates of risk.

Thirteen studies (across all three viruses, including 3,713 participants) focusing on eye protection found that face shields, goggles, and glasses were associated with lower risk of infection, compared with no eye covering (risk of infection or transmission when wearing eye protection was 6% vs 16% when not wearing eye protection). The authors note that the certainty of the evidence for eye coverings is low [1].

Evidence from 10 studies (across all three viruses, including 2,647 participants) also found similar benefits for face masks in general (risk of infection or transmission when wearing a mask was 3% vs 17% when not wearing a mask). Evidence in the study was looking mainly at mask use within households and among contacts of cases, and was also based on evidence of low certainty [1].

For healthcare workers, N95 and other respirator-type masks might be associated with a greater protection from viral transmission than surgical masks or similar (eg, reusable 12-16 layer cotton or gauze masks). For the general public, face masks are also probably associated with protection, even in non-health-care settings, with either disposable surgical masks or reusable 12-16 layer cotton ones. However, the authors note that there are concerns that mass face mask use risks diverting supplies from health-care workers and other caregivers at highest risk for infection.

They also stress that policy makers will need to quickly address access issues for face masks to ensure that they are equally available for all. "With respirators such as N95s, surgical masks, and eye protection in short supply, and desperately needed by healthcare workers on the front lines of treating COVID-19 patients, increasing and repurposing of manufacturing capacity is urgently needed to overcome global shortages", says co-author Dr Derek Chu, Assistant Professor at McMaster University. "We also believe that solutions should be found for making face masks available to the general public. However, people must be clear that wearing a mask is not an alternative to physical distancing, eye protection or basic measures such as hand hygiene, but might add an extra layer of protection." [2]

The authors also stress the importance of using information about how acceptable, feasible, resource intense, and equally accessible to all the use of these interventions are when devising recommendations. "Across 24 studies of all three viruses including 50,566 individuals, most participants found these personal protection strategies acceptable, feasible, and reassuring, but noted harms and challenges including frequent discomfort and facial skin breakdown, increased difficulty communicating clearly, and perceived reduced empathy from care providers by those they were caring for", says Dr Sally Yaacoub from the American University of Beruit in Lebanon. [2]

According to co-author Karla Solo from McMaster University in Canada: "While our results provide moderate and low certainty evidence, this is the first study to synthesise all direct information from COVID-19 and, therefore, provides the currently best available evidence to inform optimum use of these common and simple interventions." [2]

Despite these important findings, the review has some limitations including that few studies assessed the effect of interventions in non-healthcare settings, and most evidence came from studies of SARS and MERS. Finally, the effect of duration of exposure on risk for transmission was not specifically examined.

Writing in a linked Comment, lead author Professor Raina MacIntyre (who was not involved in the study) from the Kirby Institute, University of New South Wales in Australia, describes the study as "an important milestone", and writes, "For health¬care workers on COVID¬19 wards, a respirator should be the minimum standard of care. This study by Chu and colleagues should prompt a review of all guidelines that recommend a medical mask for health workers caring for COVID¬19 patients. Although medical masks do protect, the occupational health and safety of health workers should be the highest priority and the precautionary principle applied."

She continues, "[They] also report that respirators and multilayer masks are more protective than are single layer masks. This finding is vital to inform the proliferation of home¬made cloth mask designs, many of which are single¬layered. A well designed cloth mask should have water¬resistant fabric, multiple layers, and good facial fit...Universal face mask use might enable safe lifting of restrictions in communities seeking to resume normal activities and could protect people in crowded public settings and within households."

Hamilton, ON (June 1, 2020) - A comprehensive review of existing evidence supports physical distancing of two metres or more to prevent person-to-person transmission of COVID-19, says an international team led by McMaster University and St. Joseph's Healthcare Hamilton.

Face masks and eye protection decrease the risk of infection, too.

The systematic review and meta-analysis was commissioned by the World Health Organization. The findings were published today in The Lancet.

"Physical distancing likely results in a large reduction of COVID-19," said lead author Holger Schünemann, professor of the departments of health research methods, evidence, and impact, and medicine at McMaster.

Schünemann is co-director of the World Health Organization (WHO) Collaborating Centre for Infectious Diseases, Research Methods and Recommendations. He also is director of Cochrane Canada and McMaster GRADE Centre.

"Although the direct evidence is limited, the use of masks in the community provides protection, and possibly N95 or similar respirators worn by health-care workers suggest greater protection than other face masks," Schünemann said. "Availability and feasibility and other contextual factors will probably influence recommendations that organizations develop about their use. Eye protection may provide additional benefits."

The systematic review was conducted by a large, international collaborative of researchers, front-line and specialist clinicians, epidemiologists, patients, public health and health policy experts of published and unpublished literature in any language.

They sought direct evidence on COVID-19 and indirect evidence on related coronaviruses causative of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The team used Cochrane methods and the Grading of Recommendations, Assessment, and Evaluation (GRADE) approach which is used world-wide to assess the certainty of evidence.

They identified no randomized control trials addressing the three coronaviruses but 44 relevant comparative studies in health-care and non-health-care (community) settings across 16 countries and six continents from inception to early May 2020.

The authors noted more global, collaborative, well-conducted studies of different personal protective strategies are needed. For masks, large randomized trials are underway and are urgently needed.

The scientific lead is Derek Chu, a clinician scientist in the departments of health research methods, evidence, and impact, and medicine at McMaster and an affiliate of the Research Institute of St. Joe's Hamilton.

"There is an urgent need for all caregivers in health-care settings and non-health-care settings to have equitable access to these simple personal protective measures, which means scaling up production and consideration about repurposing manufacturing," said Chu.

"However, although distancing, face masks, and eye protection were each highly protective, none made individuals totally impervious from infection and so, basic measures such as hand hygiene are also essential to curtail the current COVID-19 pandemic and future waves."

CHAPEL HILL, NC - June 1, 2020 - In a major scientific study published in the journal Cell, scientists at the UNC School of Medicine and the UNC Gillings School of Global Public Health have characterized the specific ways in which SARS-CoV-2 - the coronavirus that causes COVID-19 - infects the nasal cavity to a great degree - replicating specific cell types - and infects and replicates progressively less well in cells lower down the respiratory tract, including the lungs.

The findings suggest the virus tends to become firmly established first in the nasal cavity, but in some cases the virus is aspirated into the lungs, where it may cause more serious disease, including potentially fatal pneumonia.

"If the nose is the dominant initial site from which lung infections are seeded, then the widespread use of masks to protect the nasal passages, as well as any therapeutic strategies that reduce virus in the nose, such as nasal irrigation or antiviral nasal sprays, could be beneficial," said study co-senior author Richard Boucher, MD, the James C. Moeser Eminent Distinguished Professor of Medicine and Director of the Marsico Lung Institute at the UNC School of Medicine.

The other co-senior author of the study was Ralph Baric, PhD, the William R. Kenan Distinguished Professor of Epidemiology at the UNC Gillings School of Public Health.

"This is a landmark study that reveals new and unexpected insights into the mechanisms that regulate disease progression and severity following SARS-CoV-2 infection," said Baric, who also holds a microbiology faculty appointment at the UNC School of Medicine. "In addition, we describe a new reverse genetic platform for SARS-CoV-2 allowing us to produce key indicator viruses that will support national vaccine efforts designed to control the spread and severity of this terrible disease."

SARS-CoV-2 initially caused outbreaks in late 2019 in China and spread around the world, infecting nearly 6 million people and killing more than 350,000. The United States accounts for almost a third of those infections and deaths.

The UNC-Chapel Hill team in their study sought to understand better a number of things about the virus, including which cells in the airway it infects, and how it gets into the lungs in the patients who develop pneumonia.

In one set of laboratory experiments, the researchers used different isolates of SARS-CoV-2 to see how efficiently they could infect cultured cells from different parts of the human airway. They found a striking pattern of continuous variation, or gradient, from a relatively high infectivity of SARS-CoV-2 in cells lining the nasal passages, to less infectivity in cells lining the throat and bronchia, to relatively low infectivity in lung cells.

The scientists also found that ACE2 - the cell surface receptor that the virus uses to get into cells - was more abundant on nasal-lining cells and less abundant on the surface of lower airway cells. This difference could explain, at least in part, why upper airway nasal-lining cells were more susceptible to infection.

Other experiments focused on TMPRSS2 and furin, two protein-cleaving enzymes found on many human cells. It's thought that SARS-CoV-2 uses those two enzymes to re-shape key virus proteins and enter human cells. The experiments confirmed that when these human enzymes are more abundant, this particular coronavirus has an increased ability to infect cells and make copies of itself.

The researchers found that the virus can infect airway-lining cells called epithelial cells, and to a limited extent the all-important "pneumocyte" lung cells that help transfer inhaled oxygen into the bloodstream. But SARS-CoV-2 infects almost no other airway cells.

Intriguingly, the virus did not infect airway-lining cells called club cells, despite the fact that these cells express both ACE2 and TMPRSS2. Moreover, the same types of airway epithelial cells from different human donors, especially lower-airway epithelial cells, tended to vary significantly in their susceptibility to infection. Such findings suggest that there are undiscovered factors in airway cells that help determine the course of infection in individuals - a course known to vary widely from mild or no symptoms all the way to respiratory failure and death.

The team mapped the sites of coronavirus infection in the lungs of several people who had died from COVID-19, and found that these sites exhibited a sort of patchiness and other characteristics consistent with the hypothesis that these sites had originated from infection higher in the airway.

The hypothesis that aspiration of oral contents into the lung is a significant contributor to COVID-19 pneumonia is consistent with the observations that people at higher risk for severe lung disease - the elderly, obese, and diabetic - are more prone to aspiration, especially at night.

The team also found that previously described individual antibodies capable of neutralizing the original SARS coronavirus of 2002 and the MERS coronavirus, which has been spreading slowly in the Middle East since 2012, did not neutralize SARS-CoV-2. However, blood serum from two of five SARS 2002 patients showed a low level but significant capability to neutralize SARS-CoV-2 infectivity in cultured cells. These data suggests that people who have been exposed to other coronaviruses may carry some other types of antibodies in their blood that provide at least partial protection against SARS-CoV-2.

"These results, using some novel and innovative methodology, open new directions for future studies on SARS-C0V-2 that may guide therapeutic development and practices for reducing transmission and severity of COVID-19," said James Kiley, Director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.

Boucher, Baric, and colleagues note that their study, apart from its specific findings about SARS-CoV-2 infection in the airway, involved the development of key laboratory tools - including a version of SARS-CoV-2 re-engineered to carry a fluorescent beacon - that should be useful in future investigations of the virus.

Reperfusion therapy, the gold standard for stroke treatment, helps restore blood flow after a stroke caused by a clot, preventing loss of brain tissue. However, only about 10% of stroke patients qualify, in part because of reperfusion therapy's narrow treatment window.

A recent Medical University of South Carolina study suggests that this therapy could be both safer and more effective for both motor and cognitive recovery if administered with a specialized compound that blocks the immune response. The team's preclinical findings, reported in the cover article of the May 13 Journal of Neuroscience, suggest that reducing the immune response in the brain could be a strategy for improving cognitive recovery. It could also extend the treatment window for therapy, allowing stroke specialists to help many more stroke patients.

"With reperfusion therapy, we're restoring the blood flow, which is necessary to save the tissue, but there is an ongoing inflammatory response by the immune system that is not targeted by reperfusion," said Stephen Tomlinson, Ph.D., interim chair of the Department of Microbiology and Immunology at MUSC and senior author of the article.

This could explain why, though mechanical reperfusion has a success rate of 90% in returning blood flow to the brain, only about 40% of treated patients recover enough motor and reasoning skills within three months to tend to their daily needs independently. Even those who do recover motor function can still struggle with cognitive challenges months later.

"I've seen patients who have barely any motor deficits at follow-up, but they're really struggling in their daily life in terms of memory, behavioral consequences and language," said lead author Ali Alawieh, M.D., Ph.D., who completed his graduate studies at MUSC and is now a resident in neurosurgery at Emory University School of Medicine.

Tomlinson and Alawieh think the immune response in the brain is the culprit.

During a stroke, the oxygen and energy supply to the brain is cut off by a clot, causing brain tissue to become stressed and die rapidly.

Just as it is with a cut to the knee, the immune system is activated to heal the wound, which includes clearing the dead tissue.

A family of special immune proteins called complement proteins help to guide and promote this immune response in the damaged areas.

In a 2018 article in Science Translational Medicine, Tomlinson and Alawieh showed that these complement proteins flagged both dead tissue and stressed brain cells for removal.

The stressed brain cells were not yet dead, only damaged by lack of oxygen and energy. As the goal of stroke treatment is to save as much brain tissue as possible to lessen overall damage, this was a concerning result, as it meant salvageable tissue was being destroyed by the immune system.

Therefore, Tomlinson and his team developed a complement protein blocker, named B4Crry, which acts only at the site of stroke injury. This compound blinds the complement proteins to the signals of stressed brain cells, saving the stressed tissue and reducing overall brain damage in a preclinical stroke model.

In the current study, Tomlinson and Alawieh hypothesized that pairing reperfusion therapy and B4Crry would significantly improve stroke recovery beyond reperfusion therapy alone. In particular, they hypothesized this combination treatment would improve cognitive recovery.

As Tomlinson's team expected, reperfusion therapy alone did improve recovery of coordinated movements such as walking in a preclinical model of stroke. With the addition of B4Crry to treatment, coordinated movement improved even faster, with greater recovery seen as early as three days after the stroke.

The improvements to learning and memory were even greater than those seen with motor functions.

Reperfusion therapy alone was equal to no treatment at all for learning and memory recovery after stroke. However, when B4Crry was added to their treatments, mice had greatly improved cognitive recovery, making three times fewer errors on a learning and memory task.

Tomlinson's team further probed into why the addition of B4Crry, and the subsequent reduction of the brain's immune response, aided cognitive recovery so greatly.

They found that after stroke, brain immune cells called microglia began eating the connections between stressed brain cells. Immune system complement proteins were marking these connections for destruction because they displayed the stressed cell signal. Without these connections, brain cells cannot communicate efficiently, and overall brain function decreases.

B4Crry concealed the cells' stress signals from the complement proteins and thereby saved the connections between neurons. Preserving connectivity improved learning and memory brain function after stroke.

A complement inhibitor such as B4Crry might also help stroke specialists overcome the biggest hurdle for reperfusion therapy: the short treatment window.

Tomlinson's team showed that after clot removal adding B4Crry to reperfusion therapy reduced the potential for hemorrhage, or excessive bleeding, even with treatment given up to six hours after the stroke. These findings suggest that complement inhibition could not only make reperfusion therapy safer but extend its treatment window, making it available for many more stroke patients.

Alawieh is excited about the future use of complement inhibition in the clinic.

"Our next step is to see how complement inhibitors work with comorbidities, such as old age, smoking and diabetes, in a preclinical study," he explained. "Collectively, this information will help us design the best clinical trial when we move to humans."

Tomlinson's team at MUSC is also testing the potential for complement inhibitors in other brain injuries, such as traumatic brain injury.

"We have shown that we can administer complement inhibitors as far as two months after a traumatic brain injury and see improvements in cognitive recovery," said Tomlinson. "This is something I'm actually quite excited about. It means that months after an initial event, complement inhibitors could still be beneficial to cognitive recovery after brain injuries, including strokes."

Fluctuating estrogen levels may make alcohol more rewarding to female mice, according to new research in JNeurosci. Untangling the involved signaling pathways could unveil sex-based treatments for alcohol use disorders.

Recreational use of alcohol can escalate into something more dire such as excessive binge drinking or even an alcohol use disorder. Women are more susceptible than men to these negative effects of alcohol, potentially because of the sex hormone estrogen.

Vandegrift et al. activated estrogen receptors in mice and tracked how the activation influenced alcohol's effects on the brain. The research team targeted two subtypes of estrogen receptors in the ventral tegmental area (VTA), a brain region involved in drug reward and reinforcement. Activating the α estrogen receptor subtype caused neurons to fire even more than normal in response to alcohol. Increased neuron firing releases more dopamine and could translate to a greater feeling of reward when drinking, making abuse more likely when estrogen levels rise. The scientists then reduced the number of estrogen receptors in the VTA of both male and female mice. This decreased binge drinking behavior in female mice but had no effect on male mice -- even though they have estrogen in their brains, too.

What happens in the hippocampus even before people attempt to form memories may impact whether they remember.

A new study analyzed neuronal recordings from the brains of epilepsy patients while they committed a series of words to memory. When the firing rates of hippocampal neurons were already high before the patients saw a word, they were more successful in encoding that word and remembering it later.

The findings suggest that the hippocampus might have a "ready-to-encode" mode that facilitates remembering. The study, published in the Proceedings of the National Academy of Sciences with University of California San Diego researcher Zhisen Urgolites as first author, also suggests that when hippocampal neurons are not already spiking very much, novel information is more likely to be poorly encoded and later forgotten.

"A key question going forward is how to put our brains into 'encoding mode' when we wish to do so," said John Wixted, professor of psychology at UC San Diego, and one of the lead authors on the paper.

"'Encoding mode'," Wixted said, "is more than simply paying attention to the task at hand. It is paying attention to encoding, which selectively ramps up activity in the part of the brain that is the most important for making new memories: the hippocampus. Since we know, based on earlier research, that people can actively suppress memory formation, it might be possible for people to get their hippocampus ready to encode as well. But how one might go about doing that, we just don't know yet."

Neuronal recordings from the hippocampus, amygdala, anterior cingulate and prefrontal cortex were collected from 34 epilepsy patients while they underwent clinical monitoring at Barrow Neurological Institute. The experiments were originally performed in Peter Steinmetz's laboratory between 2007 and 2014 when he was at the institute. The data have since been maintained at the Neurtex Brain Research Institute, where Steinmetz is chief scientific officer, and the present research team is newly analyzing the data.

During the experiments, the patients either saw or listened to a steady stream of words and had to indicate whether each word was novel or a repeat. At first, all the words were novel, but after a while most words repeated.

The researchers calculated the average number of times a neuron fired in response to every word the study participants saw or heard. They also calculated the neuronal firing rates immediately preceding each word. Only the average firing rate in the hippocampus approximately one second before seeing or hearing a word for the first time was important: That neuronal activity predicted whether the participants remembered or forgot the word when it was repeated later on.

"If a person's hippocampal neurons were already firing above baseline when they saw or heard a word, their brain was more likely to successfully remember that word later," said Stephen Goldinger, professor of psychology at Arizona State University.

The neuronal activity measured in the amygdala, anterior cingulate, and prefrontal cortex did not predict task performance.

"We think new memories are created by sparse collections of active neurons, and these neurons get bundled together into a memory. This work suggests that when a lot of neurons are already firing at high levels, the neuronal selection process during memory formation works better," Goldinger said.

Climate engineering provides solutions that directly affect the incoming radiation from the sun and are able to rapidly offset the temperature increase. These technologies open new scenarios on the management of the risks related to climate change, on the need to contain the warming of the planet within two degrees Celsius as defined by international agreements, on the strategies that individual states, or coalitions of states, can put in place to avoid negative impacts related to climate.

An international team of scientists conducted the first-of-its-kind laboratory experiment to test how behavioural and strategic factors shape the economic outcomes of climate geoengineering.

Belonging to different research groups in Italy (RFF-CMCC European Institute of the Economics and the Environment, Fondazione Centro Euro-Mediterraneo sui Cambiamenti Climatici, Università Bocconi, Università di Bologna, University of Milano-Bicocca, and Politecnico di Milano), researchers have taken into consideration the governance challenges arising from the prospects opened by geoengineering, and the results are reported in the article "Solar geoengineering may lead to excessive cooling and high strategic uncertainty", recently published in the journal PNAS (Proceedings of the National Academy of Science of the United States).

Based on a geoengineering model, the experiment conducted by the research group showed that countries wanting a cooler climate employ geoengineering to reach it even if by doing so they impose it on others who would prefer a warmer climate - an outcome called 'free driving'. This strategic, rational behaviour leads to too much geo-engineering, and results in increased inequalities and economic losses. The experiment also studied the possibility of retaliation through counter-geoengineering solutions. Here, results how behavioural motives lead to high variability in geoengineering outcomes, with detrimental economic and equity consequences.

"Miscoordination among countries increases under counter-geoengineering," says Anna Abatayo, research fellow at Bocconi University.

Riccardo Ghidoni, Assistant Professor at the University Milano-Bicocca, says: "We find that retaliation through counter-geoengineering is particularly risky when there are many decision makers. This is relevant for international negotations with multiple parties".

"Solar geoengineering brings us into uncharted territory", says Marco Casari, Professor of Economics at Bologna University, "and our experiment can shed light on what to expect in those new situations. If major issues emerge, the rules of governance could be corrected before field implementation. I like the analogy with aeronautical engineering: prototypes of new airplanes go first in 'wind tunnels' to identify and remove design flows. Our experiments serve a similar purpose in the realm of the social sciences".

"This paper shows the relevance of the human factor -both rational and irrational- for climate decision making in general not just climate engineering", says Massimo Tavoni, director of the RFF-CMCC European Institute of the Economics and the Environment and Professor at Politecnico di Milano. "It highlights the necessity of strong institutions to solve global environmental challenges".

CAMBRIDGE, MA -- One promising strategy to treat cancer is stimulating the body's own immune system to attack tumors. However, tumors are very good at suppressing the immune system, so these types of treatments don't work for all patients.

MIT engineers have now come up with a way to boost the effectiveness of one type of cancer immunotherapy. They showed that if they treated mice with existing drugs called checkpoint inhibitors, along with new nanoparticles that further stimulate the immune system, the therapy became more powerful than checkpoint inhibitors given alone. This approach could allow cancer immunotherapy to benefit a greater percentage of patients, the researchers say.

"These therapies work really well in a small portion of patients, and in other patients they don't work at all. It's not entirely understood at this point why that discrepancy exists," says Colin Buss PhD '20, the lead author of the new study.

The MIT team devised a way to package and deliver small pieces of DNA that crank up the immune response to tumors, creating a synergistic effect that makes the checkpoint inhibitors more effective. In studies in mice, they showed that the dual treatment halted tumor growth, and in some cases, also stopped the growth of tumors elsewhere in the body.

Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, and a member of MIT's Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science, is the senior author of the paper, which appears this week in the Proceedings of the National Academy of Sciences.

Removing the brakes

The human immune system is tuned to recognize and destroy abnormal cells such as cancer cells. However, many tumors secrete molecules that suppress the immune system in the environment surrounding the tumor, rendering the T cell attack useless.

The idea behind checkpoint inhibitors is that they can remove this "brake" on the immune system and restore T cells' ability to attack tumors. Several of these inhibitors, which target checkpoint proteins such as CTLA-4, PD-1, and PD-L1, have been approved to treat a variety of cancers. These drugs work by turning off checkpoint proteins that prevent T cells from being activated.

"They work incredibly well in some patients, and they've given what some would call cures, for about 15 to 20 percent of patients with particular cancers," Bhatia says. "However, there's still a lot more to do to open up the possibility of using this approach for more patients."

Some studies have found that combining checkpoint inhibitors with radiation therapy can make them more effective. Another approach that researchers have tried is combining them with immunostimulatory drugs. One such class of drugs is oligonucleotides -- specific sequences of DNA or RNA that the immune system recognizes as foreign.

However, clinical trials of these immunostimulatory drugs have not been successful, and one possible reason is that the drugs are not reaching their intended targets. The MIT team set out to find a way to achieve more targeted delivery of these immunostimulatory drugs, allowing them to accumulate at tumor sites.

To do that, they packaged oligonucleotides into tumor-penetrating peptides that they had previously developed for delivering RNA to silence cancerous genes. These peptides can interact with proteins found on the surfaces of cancer cells, helping them to specifically target tumors. The peptides also include positively charged segments that help them penetrate cell membranes once they reach the tumor.

The oligonucleotides that Bhatia and Buss decided to use for this study contain a specific DNA sequence that often occurs in bacteria but not in human cells, so that the human immune system can recognize it and respond. These oligonucleotides specifically activate immune cell receptors called toll-like receptors, which detect microbial invaders.

"These receptors evolved to allow cells to recognize the presence of pathogens like bacteria," Buss says. "That tells the immune system that there's something dangerous here: Turn on and kill it."

A synergistic effect

After creating their nanoparticles, the researchers tested them in several different mouse models of cancer. They tested the oligonucleotide nanoparticles on their own, the checkpoint inhibitors on their own, and the two treatments together. The two treatments together produced the best results, by far.

"When we combined the particles with the checkpoint inhibitor antibody, we saw a vastly improved response relative to either the particles alone or the checkpoint inhibitor alone," Buss says. "When we treat these mice with particles and the checkpoint inhibitor, we can stop their cancer from progressing."

The researchers also wondered whether they could stimulate the immune system to target tumors that had already spread through the body. To explore that possibility, they implanted mice with two tumors, one on each side of the body. They gave the mice the checkpoint inhibitor treatment throughout the entire body but injected the nanoparticles into only one tumor. They found that once T cells had been activated by the treatment combination, they could also attack the second tumor.

"We saw some signs that you could stimulate in one location and then get a systemic response, which was encouraging," Bhatia says.

The researchers now plan to perform safety testing of the particles, in hopes of further developing them to treat patients whose tumors don't respond to checkpoint inhibitor drugs on their own. To that end, they are working with Errki Ruoslahti of the Sanford Burnham Prebys Medical Discovery Institute, who originally discovered the tumor-penetrating peptides. A company that Ruoslahti founded has already taken other versions of the tumor-penetrating peptides into human clinical trials to treat pancreatic cancer.

"That makes us optimistic about the potential to scale up, manufacture them, and advance them to help patients," Bhatia says.