Culture

EUGENE, Ore. - April 30, 2020 - Entrepreneurs launching a crowdfunding campaign to fund new product development benefit by reaching out early to engage with potential end-users, say business researchers from three universities.

Emerging companies that did so, tweaking their prototypes in an active and open exchange, reached their fundraising goals and drew media coverage more easily than those that didn't, said Alex Murray of the University of Oregon and lead author of a study published online ahead of print in Organization Science.

Most studies have explored how companies seek initial financial support with established professionals such as venture capitalists and angel investors. Studies of online fundraising, which is growing in use to attract broader support, Murray noted, have looked mostly at certain characteristics -- how many times a person smiles during a pitch, language used and geographic location.

"We all know creating a buzz matters, but how do you successfully do it?" said Murray, an assistant professor of management who teaches entrepreneurship in the UO's Lundquist College of Business. "We wanted to understand the processes, such as who you get involved and when, that help make it happen."

Murray and co-authors Suresh Kotha of the University of Washington and Greg Fisher of Indiana University compared the strategies of eight companies that used Kickstarter, the world's largest non-equity crowdfunding platform, between 2012 and 2014. To date, Murray said, Kickstarter has generated $4.8 billion in non-equity financing for more than 178,000 campaigns.

In the study, the eight unnamed early-stage companies were paired for comparison based on four prototype categories: household gadgets, board games, smartphone camera lenses and 3D printers.

Three key steps to success emerged: community building to establish psychological bonds with individuals who are knowledgeable about a product; engagement that fosters social identification among those individuals; and spanning that engagement to leverage proof points with others.

One successful company reached out to a National Geographic photographer for input about the prototype its new smartphone camera lens. After early interaction, the photographer took the prototype on a field trip and talked about the new lens with other photographers. That led to helpful feedback and photos that the company then used for its subsequent crowdfunding campaign.

Another company, the researchers noted, reached out to potential end-users, relying heavily on descriptions of its prototype's potential and responding privately to some emails. However, the company did not encourage and make use of the feedback. Its subsequent campaign was not as successful.

Companies that did poorly with their crowdfunding campaigns had innovative and creative products, but they depended on their own descriptions to generate interest rather than interacting with people in their domain, Murray said.

Companies that successfully established relationships with key stakeholders and incorporated their feedback into their prototypes, not only met their crowdfunding goals, but were also best equipped to attract news media coverage about their new products, another key step in the process, Murray said.

"Generating interest in the domain of an early prototype is critical," he said. "We found that when companies generate feedback and excitement early on, the people with whom they engage will, in turn, evangelize about the product in their networks and that will grow interest in it."

Sharing a prototype of a new product with others outside of a company, however, may be risky, requiring a high level of trust and sufficient protection of intellectual property, Murray said. In a follow-up study now under review for publication, he explores that issue.

Every now and then, scientists need to control the process of mixing liquids in vessels so small that the thinnest needle or even a hair wouldn't fit in there. At the same time, controlling the diffusion speed of molecules in the so-called microreactors is extremely important for the purposes of designing new drugs, conducting biological experiments and even to perform fast disease detection tests. Scientists from ITMO University and their colleagues from the Czech Academy of Sciences proposed to solve this problem by using the energy of light. Their research has been published in Advanced Science.

Nowadays, biologists, chemists and pharmacists make a wide use of microreactors, often integrated in miniaturized setups which are designed to perform several steps in the chemical synthesis of a specific product, the so-called lab-on-a-chip platforms . These minuscule containers with small grooves on their inside can range from several cubic millimeters to a few cubic centimeters in size - no larger than a matchbox. Nevertheless, they make possible to conduct blood analyses, mix microscopic doses of substances for the purpose of creating highly efficient drugs, and conduct experiments on cells.

Still, there's one issue associated with their operation: scientists have little to no control over the mixing speed, or, scientifically speaking, the diffusion of liquids and reagents inside such laboratories-on-a-chip. Scientists from ITMO University and their colleagues from the Czech Academy of Sciences proposed a method that can help solve this problem: they decided to use the so-called radiation pressure.

Back in the end of the 19th century, British scientist James Clerk Maxwell made the assumption that light can put pressure on physical objects. Before long, Russian scientist Pyotr Lebedev proved it possible. Still, the force of such interaction is very small, and at that time, no one found a use for it. Nowadays, there's a whole field of science called optomechanics that focuses on this phenomenon, and in 2018, professor Arthur Ashkin Nobel Prize for his pioneering works in this field. Light is being used to capture living cells and move miniscule particles of substances. Now it turns out that the same forces can be used for mixing liquids.

Based on the latest optomechanics discoveries, scientists from St. Petersburg developed a nanoantenna consisting of a miniscule silicon cube of about 200 nanometers in size. This device, invisible to the human eye, can efficiently manipulate light in a very particular way. "Our nanoantenna turns circularly polarized light into an optical vortex," explains Aleksandr Shalin, a professor at ITMO's Department of Physics, "the energy of light spirals around it."

Apart from nanoantennae, scientists proposed to also introduce gold nanoparticles into the liquid. The particles captured by an optical vortex begin spinning around the silicon cube, acting as a stirring "spoon" for mixing reagents. What's more, the size of such a system is so small that it can amplify the diffusion at one corner of a microreactor by hundreds of times while practically not affecting what happens in the other.

"Gold is a chemically inert material which doesn't react much", says Adria ?anos Valero, one of the main authors of the research. "It's also not toxic. What's more, it was necessary for us to design it so only spin forces and radiation pressure would affect the nanoparticles in a way that other forces do not cause them to be pulled towards the antenna (the silicon cube that we mentioned), otherwise the particles would just stick to it. This effect is observed for gold particles of a specific size if we illuminate the system with a common green laser. We've considered using other metals, but for silver, for instance, such an effect is observed in the UV band only, which is less handy but could be useful to increase the efficiency of some photochemically activated reactions."

By the way, this method can be applied not only for mixing liquids but also to sort gold nanoparticles: if scientists need to pick gold particles of some specific size, for example 30 nanometers, for an experiment. As of today, the system has been fully computed and there's a theoretical model designed for it. Conducting experiments will be the next step.

Researchers from the UPV/EHU, Cruces Hospital, the IVI Clinic Bilbao and Biocruces Bizkaia have discovered that the oocytes -immature ova- from obese and overweight women have lower concentrations of omega-3 fatty acids. A study of the lipid composition of 922 ova obtained during IVF treatment from 205 women of normal build and who were overweight or obese has found that the oocytes of both obese and overweight women have a very different lipid composition; the study was led by Roberto Matorras-Weinig, lecturer at the UPV/EHU's Faculty of Medicine and Nursing, and was published in the journal Fertility and Sterility.

Omega-3 fatty acids are essential in the human diet, in other words, they have to be ingested because the body cannot synthesise them. The intake of them tends to be low in the western diet. Moreover, as Dr Matorras of the Department of Medical and Surgical Specialties at the UPV/EHU points out, "omega-3 fatty acids compete metabolically with omega-6 ones, and the intake of the latter tends to be too high in the western diet. So the high intake of omega-6 fatty acids contributes towards low levels of omega-3 ones. Presumably this is the mechanism responsible for their low levels in the ova".

Childhood obesity could kick in before conception

Obesity is a well-known public health problem with numerous repercussions on different organs. "One of its implications in pregnancy is the birth of macrosomic babies (with a high weight), and the subsequent risk of childhood and adult obesity. Until now, this had been attributed to the effect of maternal obesity during pregnancy as well as to unsuitable diets during childhood. But these findings raise the possibility that the problems of these children may start even before conception, due to the poorer lipid composition of the ova which have generated them," said Matorras.

On another front, the researcher added that "obese patients tend to have poorer IVF outcomes, which have been attributed to a whole range of motives. This discovery highlights another possible cause of these poorer outcomes".

Neutron stars are among the densest objects in the universe. If our Sun, with its radius of 700,000 kilometres were a neutron star, its mass would be condensed into an almost perfect sphere with a radius of around 12 kilometres. When two neutron stars collide and merge into a hyper-massive neutron star, the matter in the core of the new object becomes incredibly hot and dense. According to physical calculations, these conditions could result in hadrons such as neutrons and protons, which are the particles normally found in our daily experience, dissolving into their components of quarks and gluons and thus producing a quark-gluon plasma.

In 2017 it was discovered for the first time that merging neutron stars send out a gravitational wave signal that can be detected on Earth. The signal not only provides information on the nature of gravity, but also on the behaviour of matter under extreme conditions. When these gravitational waves were first discovered in 2017, however, they were not recorded beyond the merging point.

This is where the work of the Frankfurt physicists begins. They simulated merging neutron stars and the product of the merger to explore the conditions under which a transition from hadrons to a quark-gluon plasma would take place and how this would affect the corresponding gravitational wave. The result: in a specific, late phase of the life of the merged object a phase transition to the quark-gluon plasma took place and left a clear and characteristic signature on the gravitational-wave signal.

Professor Luciano Rezzolla from Goethe University is convinced: "Compared to previous simulations, we have discovered a new signature in the gravitational waves that is significantly clearer to detect. If this signature occurs in the gravitational waves that we will receive from future neutron-star mergers, we would have a clear evidence for the creation of quark-gluon plasma in the present universe."

A study led by clinician scientists at RCSI University of Medicine and Health Sciences has found that Irish patients admitted to hospital with severe COVID-19 infection are experiencing abnormal blood clotting that contributes to death in some patients.

The study, carried out by the Irish Centre for Vascular Biology, RCSI and St James's Hospital, Dublin, is published in current edition of the British Journal of Haematology. (DOI: 10.1111/bjh.16749)

The authors found that abnormal blood clotting occurs in Irish patients with severe COVID-19 infection, causing micro-clots within the lungs. They also found that Irish patients with higher levels of blood clotting activity had a significantly worse prognosis and were more likely to require ICU admission.

"Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focussed within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19," said Professor James O'Donnell, Director of the Irish Centre for Vascular Biology, RCSI and Consultant Haematologist in the National Coagulation Centre in St James's Hospital, Dublin.

"In addition to pneumonia affecting the small air sacs within the lungs, we are also finding hundreds of small blood clots throughout the lungs. This scenario is not seen with other types of lung infection, and explains why blood oxygen levels fall dramatically in severe COVID-19 infection.

"Understanding how these micro-clots are being formed within the lung is critical so that we can develop more effective treatments for our patients, particularly those in high risk groups.

"Further studies will be required to investigate whether different blood thinning treatments may have a role in selected high risk patients in order to reduce the risk of clot formation," Professor O'Donnell said.

Emerging evidence also shows that the abnormal blood-clotting problem in COVID-19 results in a significantly increased risk of heart attacks and strokes.

(Philadelphia, PA) - Like power lines in an electrical grid, long wiry projections that grow outward from neurons - structures known as axons - form interconnected communication networks that run from the brain to all parts of the body. But unlike an outage in a power line, which can be fixed, a break in an axon is permanent. Each year thousands of patients confront this reality, facing life-long losses in sensation and motor function from spinal cord injury and related conditions in which axons are badly damaged or severed.

New research by scientists at the Lewis Katz School of Medicine Temple University (LKSOM) shows, however, that gains in functional recovery from these injuries may be possible, thanks to a molecule known as Lin28, which regulates cell growth. In a study published online in the journal Molecular Therapy, the Temple researchers describe the ability of Lin28 - when expressed above its usual levels - to fuel axon regrowth in mice with spinal cord injury or optic nerve injury, enabling repair of the body's communication grid.

"Our findings show that Lin28 is a major regulator of axon regeneration and a promising therapeutic target for central nervous system injuries," explained Shuxin Li, MD, PhD, Professor of Anatomy and Cell Biology and in the Shriners Hospitals Pediatric Research Center at the Lewis Katz School of Medicine at Temple University and senior investigator on the new study. The research is the first to demonstrate the regenerative ability of Lin28 upregulation in the injured spinal cord of animals.

"We became interested in Lin28 as a target for neuron regeneration because it acts as a gatekeeper of stem cell activity," said Dr. Li. "It controls the switch that maintains stem cells or allows them to differentiate and potentially contribute to activities such as axon regeneration."

To explore the effects of Lin28 on axon regrowth, Dr. Li and colleagues developed a mouse model in which animals expressed extra Lin28 in some of their tissues. When full-grown, the animals were divided into groups that sustained spinal cord injury or injury to the optic nerve tracts that connect to the retina in the eye.

Another set of adult mice, with normal Lin28 expression and similar injuries, were given injections of a viral vector (a type of carrier) for Lin28 to examine the molecule's direct effects on tissue repair.

Extra Lin28 stimulated long-distance axon regeneration in all instances, though the most dramatic effects were observed following post-injury injection of Lin28. In mice with spinal cord injury, Lin28 injection resulted in the growth of axons to more than three millimeters beyond the area of axon damage, while in animals with optic nerve injury, axons regrew the entire length of the optic nerve tract. Evaluation of walking and sensory abilities after Lin28 treatment revealed significant improvements in coordination and sensation.

"We observed a lot of axon regrowth, which could be very significant clinically, since there currently are no regenerative treatments for spinal cord injury or optic nerve injury," Dr. Li explained.

One of his goals in the near-term is to identify a safe and effective means of getting Lin28 to injured tissues in human patients. To do so, his team of researchers will need to develop a vector, or carrier system for Lin28, that can be injected systemically and then hone in on injured axons to deliver the therapy directly to multiple populations of damaged neurons.

Dr. Li further wants to decipher the molecular details of the Lin28 signaling pathway. "Lin28 associates closely with other growth signaling molecules, and we suspect it uses multiple pathways to regulate cell growth," he explained. These other molecules could potentially be packaged along with Lin28 to aid neuron repair.

WINSTON-SALEM, N.C. -- April 30, 2020 -- In an effort to rapidly provide specialized care for patients with coronavirus-like symptoms while protecting the safety of health care workers, doctors at Wake Forest Baptist Health created a special respiratory isolation unit from an existing 24-bed medical-surgical unit in the hospital in Winston-Salem.

The framework for this Person Under Investigation (PUI) unit was published in the April 13 issue of The Hospitalist, the official publication of the Society of Hospital Medicine.

"Given the novelty and seriousness of COVID-19 as well as the evolving guidelines, a lot of effort went into creating this unit quickly," said Padageshwar Sunkara, M.D., assistant professor of internal medicine at Wake Forest School of Medicine, part of Wake Forest Baptist Health.

"We wanted to move anyone suspected of having the virus directly to the isolation unit to minimize cross-contamination with other patients and staff."

To accommodate patients from all specialties, the rooms were retrofitted with additional features such as dialysis access.

In addition, specific medical teams were designated to provide patient care on the unit and trained in the proper ways to use and conserve personal protective equipment. Unit staff established a number of measures to minimize exposure risk to providers and other patients, such as limiting entry to patient rooms to only critical staff directly involved in patient care.

Sunkara, medical director for the PUI unit, said that staff members were able to get the unit established within one week, even before the first case was detected on March 24 at Wake Forest Baptist, and he hopes this model will be useful to other institutions.

An international team of researchers has outlined ways to manage different facets of life under the spread of the COVID-19 virus, ranging from how we can combat racially driven bias and fake news to how we can increase cooperation and better manage stress.

Its work, which appears in the journal Nature Human Behaviour, considers research stretching over the past half century to offer insights about how to address current circumstances.

"The COVID-19 pandemic represents a massive, global health crisis," observes Jay Van Bavel, an associate professor in New York University's Department of Psychology, who led the project with Stanford's Robb Willer. "Because the crisis requires large-scale behavior change and poses significant psychological burdens on individuals, insights from the social and behavioral sciences are likely going to be very helpful for optimizing pandemic response."

"This interdisciplinary review points to several ways in which research can be immediately applied to optimize response to this pandemic, but also points to several important gaps that researchers should move quickly to fill in the coming weeks and months," adds Willer, a sociologist.

The analysis, drawn from the expertise of over 40 researchers at more than 20 colleges and universities, focuses on phenomena linked to COVID-19, connecting existing scholarship to potential courses of action in several areas, including the following: "Group Threat," "Fake News and Misinformation," "Social Norms," and "Stress and Coping."

Group Threat

The authors, referring to recent attacks on ethnic Asians in predominantly white countries, note that "Europe's most deadly disease, the bubonic plague of the 14th century, unleashed massive violence, including the murder of Catalans in Sicily, clerics and beggars in some locations, and pogroms against Jews, with over a thousand communities eradicated."

However, they point to research that indicates pandemics may, in fact, present opportunities to reduce religious and ethnic prejudice: "coordinated efforts across individuals, communities, and governments to fight the spread of disease send strong signals of cooperation and shared values, which allow people to re-cast others who were previously considered out-group members as in-group members."

The authors recount cooperative acts currently unfolding: More than 20 countries donated medical supplies to China in February, and China has reciprocated. "Government officials can highlight events like these to improve out-group attitudes," they write, adding that other studies have shown that making people feel safer can reduce prejudice.

Fake News and Misinformation

Fake news and conspiracy theories about COVID-19 have undoubtedly proliferated on social media, but new research has explored social-science based solutions to counter the spread of fake news. Fact-checking and correction offer potential remedies, as does source expertise, bipartisanship in messaging, and messages from "unlikely sources"--those who benefit from the original misinformation.

But the researchers acknowledge that fact-checking and corrections may not keep up with the vast amount of false information produced in moments of crisis like a pandemic and that approaches beyond debunking are necessary.

In response, they offer what scholars term a "pre-bunking approach," which centers on psychological inoculation. Studies have found that preemptively exposing people to small doses of misinformation techniques (including scenarios about COVID-19) can reduce susceptibility to fake news. Another preventative approach involves subtle prompts that emphasize accuracy (for instance, asking users to judge the veracity of a single neutral headline). Such prompts have been found in prior work to improve the quality of the content users share and could be easily implemented by social media platforms.

"To effectively counter fake news about COVID-19 around the world, governments and social media companies must rigorously develop and test interventions in collaboration with independent behavioral scientists," the authors advocate. "This includes identifying treatments that effectively reduce belief in misinformation, while not undermining belief in accurate information--a particularly salient concern given evidence that most exposure to and sharing of fake news in the U.S. has been concentrated among relatively small sub-sections of the population."

Social Norms

"How much people change will be influenced by aspects of the social and cultural context," the researchers write. "The fact that people tend to follow social norms and cultural mores can sometimes have undesirable consequences. For example, continuous exposure to news examples of people going out might explain why it was difficult to convince Italians to stay at home after the COVID-19 lockdown of March 11." But they also report that "understanding these features of the social environment, such as social norms, social inequality, culture, and polarization, can help identify risk factors and successful messages and interventions."

Prior studies have found that our decisions are influenced by social norms--what we perceive others are doing or approve/disapprove of--and that "informational influence" occurs when people use others' behavior as input for reasonable interpretations and responses. Notably, this effect is stronger when people are uncertain and outcomes are important--as in during a pandemic.

However, the authors caution that although we are influenced by perceptions of norms, research has shown that our estimates of behavior are frequently inaccurate. For example, people can underestimate the frequency others engage in health-promoting behaviors (e.g., hand washing) and overestimate their unhealthy ones (e.g., not properly covering one's mouth when coughing). In order to most effectively change behaviors by correcting misperceptions, the authors point to the importance of public messages that reinforce health-promoting norms (e.g., social distancing and hand-washing) and not highlighting extreme or uncommon behaviors, such as panic buying or young adults gathering.

Stress and Coping

Public health experts have said that one of the most vital strategies for slowing the spread of COVID-19 is "social distancing"--a practice that, while beneficial, "clashes with the deep-seated human instinct to connect with others, especially during emotional times," the authors observe. Studies have shown social connection "helps people regulate affect, cope with stress, and remain resilient during difficult times" while other scholarship has revealed that "loneliness and social isolation worsen the burden of stress, and produce deleterious effects on mental, cardiovascular, and immune health."

However, the researchers list ways we can diminish the ill effects of isolation.

One, they advocate replacing the term "social distancing"--when possible--with "physical distancing." This change, they say, would "highlight the fact that deep social connection with a broader community is possible even when people are physically apart through the use of technology."

Two, they cite the value of online forums, which have long served as hubs for mutual support--in particular, among individuals with rare illnesses--and psychological well-being. Other technologies, such as FaceTime and Zoom, have been found to be valuable in generating empathy and connection.

Van Bavel and Willer recognize potential barriers to these tools for seniors.

"Special attention should be placed on helping older adults--who might be less familiar with these technologies--to learn and acclimate to the potential richness of digital connections. COVID-19 will leave many of us confused, anxious, and lonely," they write.

Conclusion

"Urgent action is needed to mitigate the potential devastation of COVID-19, and drawing from existing knowledge can help ensure we are taking constructive steps," Van Bavel says. "In addition, the lessons from past studies should be relevant to future pandemics and other public health crises. Whether policy makers are trying to increase vaccination rates or reduce the harm of climate change, they will be fundamentally facing many of the same issues in the future."

"By applying the knowledge gained from earlier research, we hope that public health experts will be better equipped to communicate effectively and drive behavior change in a manner that yields global benefits," adds Willer.

Journal

Nature Human Behaviour

DOI

10.1038/s41562-020-0884-z

PHARMACY experts at the University of Huddersfield are urging caution over claims that widely-available antimalarial drugs could be a "magic bullet" to prevent and cure CoVid-19. And the medicines can - if used rashly - have serious side effects.

Although there have been some encouraging signs from small-scale preliminary trials of the drugs chloroquine (CQ) and hydroxychloroquine (HCQ) when administered to coronavirus patients, the results are preliminary and should be treated with care, argue Dr Syed Shahzad Hasan and Dr Hamid Merchant.

They are co-authors - in collaboration with a pharmacist from Malaysia, Chia Siang Kow, of the International Medical University in Kuala Lumpur - of a new article in the British Journal of Pharmacy. It is freely available for all to read online.

The authors chart the excitement in press and social media over claims that CQ and HCQ could be effective CoViD-19 treatments. But they also report how this had led to hoarding and therefore shortages of the drugs - available over the counter in some countries.

There have been reports of deaths in some parts of the world because of inappropriate self-use of CQ. And while the drugs have a good safety record, they can have seriously adverse side-effects, including loss of vision and fatal cardiovascular problems.

"It is the duty of pharmacists and other healthcare professionals to monitor the proper usage of these antimalarial drugs," states the British Journal of Pharmacy article.

As the evidence currently stands, write the authors, CQ/HCQ cannot be used as a general treatment for all CoViD-19 patients.

"Its use should be restricted for the treatment of CoViD-19-associated pneumonia in severely-ill patients only under a trial or clinical supervision of a licenced practitioner and close cardiac monitoring."

The article - titled Is it worth the wait? Should Chloroquine or Hydroxychloroquine be allowed for immediate use in Covid-19? - includes a bullet point list of key points and recommendations.

It is stated that "there is no evidence to support the mass use of CQ/HCQ to prevent the infection in public at large, therefore these drugs cannot be recommended for general use by the public to protect from acquiring SARS-CoV-2 infection. Social isolation and quarantine measures are still appropriate to control the infection until a reliable preventive option becomes available, for instance a vaccine".

The authors also point out that there had been only limited use of CQ/HCQ in clinical settings and no conclusive, randomly-controlled trials are yet available.

It is argued that "there is a need for an open-access central repository where clinicians can record the use/outcomes of CQ/HCQ or other pharmacological interventions for the thorough scrutiny of the data by the global scientific community".

The warnings sounded in the British Journal of Pharmacy article have since been reinforced by the U.S. Food and Drug Administration in a webpage that cautions against use of hydroxychloroquine or chloroquine for CoViD-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems.

Meanwhile, Dr Merchant, who is the Subject Leader at the University of Huddersfield's Department of Pharmacy, and Dr Hasan, who is a Senior Research Fellow, continue to research and write about the latest developments in the coronavirus pandemic.

Analysis of potential treatments for CoViD-19

Another article by Dr Merchant published in the British Medical Journal analyses a World Health Organisation trial of four potential treatments for CoViD-19.

The article - also freely available online - is an 11-point analysis of the project. Dr Merchant acknowledges that "the launch of WHO's Solidarity Trial came as good news for many, the public in general and clinicians in particular who are at the frontline to manage these crises".

But he provides a detailed critique of the drugs that are and are not included in the WHO trial.

And he concludes that: "There are as many as seven variants of human coronavirus that have been reported and there have been reports of CoV-2 being further genetically evolving during the current CoViD-19 outbreak. If the global Solidarity Trial will not offer all drug options/combinations across the world in a single co-ordinated trial, we fear that the data from different countries may not be directly comparable to draw any meaningful comparison".

Many of the drugs and medicines that we rely on today are natural products taken from microbes like bacteria and fungi. Within these microbes, the drugs are made by tiny natural machines - mega-enzymes known as nonribosomal peptide synthetases (NRPSs). A research team led by McGill University has gained a better understanding of the structures of NRPSs and the processes by which they work. This improved understanding of NRPSs could potentially allow bacteria and fungi to be leveraged for the production of desired new compounds and lead to the creation of new potent antibiotics, immunosuppressants and other modern drugs.

"NRPSs are really fantastic enzymes that take small molecules like amino acids or other similar sized building blocks and assemble them into natural, biologically active, potent compounds, many of which are drugs," said Martin Schmeing, Associate Professor in the Department of Biochemistry at McGill University, and corresponding author on the article that was recently published in Nature Chemical Biology. "An NRPS works like a factory assembly line that consists of a series of robotic workstations. Each station has multi-step workflows and moving parts that allow it to add one building block substrate to the growing drug, elongating and modifying it, and then passing it off to the next little workstation, all on the same huge enzyme."

Ultra-intensive light beam allows scientists to see proteins

In their paper featured on the cover of the May 2020 issue of Nature Chemical Biology, the team reports visualizing an NRPS mechanical system by using the CMCF beamline at the Canadian Light Source (CLS). The CLS is a Canadian national lab that produces the ultra-intense beams of X-rays required to image proteins, as even mega-enzymes are too small to see with any light microscope.

"Scientists have long been excited about the potential of bioengineering NRPSs by identifying the order of building blocks and reorganizing the workstations in the enzyme to create new drugs, but the effort has rarely been successful," said Schmeing. "This is the first time anyone has seen how these enzymes transform keto acids into a building block that can be put into a peptide drug. This helps us understand how the NRPSs can use so very many building blocks to make the many different compounds and therapeutics."

Corporate social irresponsibility (CSI) and other questionable business practices that ultimately harm stakeholders occur frequently, drawing vastly different reactions from investors.

And, the extent to which investors punish firms for CSI -- or corporate events that may have a negative impact on stakeholders or the environment -- is associated with the proportion of top management executives in a firm who have a law degree, according to new research from the University of Notre Dame.

"Firms behaving badly? Investor reactions to corporate social irresponsibility" appears in the current issue of Business and Society Review from Vamsi Kanuri, assistant professor of marketing in Notre Dame's Mendoza College of Business, along with Michelle Andrews from Emory University and Reza Houston of Ball State University.

"A lot of attention has been paid to how investors react when firms 'do good,' Kanuri said. "Less attention has been paid to how and why investors react when firm actions may not be so good. Our research shows how investors react to news of CSI, including violations of environmental regulations and workforce reductions. We find if the percentage of top management with law degrees is too small or too large, punishment is more severe, while an average proportion with law degrees is associated with less or even no punishment. In our sample, we notice firms that had a proportion ranging from 6 percent to 9 percent realized the highest abnormal stock returns, whereas firms that had a proportion of less than 6 percent realized the lowest abnormal returns."

The team also finds this association depends on the size of the firm, amount of volatility in a firm's returns and competitiveness of a firm's industry of operation.

They collected data on the difference between actual and expected returns for 308 publicly traded S&P 500 firms shortly after the announcements of 629 CSI events. They also tracked the number of top management team (TMT) executives in each firm who had a law degree at the time of the announcement, comparing the proportion of executives with a law degree with how investors reacted to the announcement in terms of abnormal returns -- the difference between actual and expected returns.

"We hypothesize the proportion of board members and TMT executives with law degrees affects investor perceptions of firm foresight, and in turn, their judgment of blame and consequent punishment," Kanuri said, "and we show investors may punish firms based on whether they believe firms understood the potential ramifications of their actions."

For example, in early 2009, the study states, aircraft manufacturer Boeing announced plans to reduce its workforce by 4,500, representing cuts of more than 5 percent. Weeks later, construction equipment maker Caterpillar revealed plans to cut 20,000 workers, a slash equaling a tenth of its workforce. In the days following these announcements, Boeing incurred negative 3.8 percent cumulative abnormal returns, while Caterpillar accumulated 1.9 percent in positive returns. Varied investor reactions to reports of similar corporate events are not limited to such internal business concerns, but also manifest for external environmental concerns. For example, revelations in 2008 that confectioner Hershey's allegedly violated environmental regulations drew negative 1.2 percent cumulative abnormal returns, yet news that automotive parts manufacturer Johnson Controls paid environmental regulation fines yielded positive returns of 4.8 percent.

"We hypothesize and empirically illustrate that such findings can be explained by the proportion of top management executives in a firm who have a law degree," Kanuri said.

While it may not be surprising that the educational background of company executives can be associated with investor reactions to firm events, Kanuri is surprised to find that the proportion of corporate chiefs with a legal background matters. Investors naturally look to justify why unwelcome events occur and may scrutinize the experience of top management, including educational background, which can shape how decision-makers approach their decisions.

"Having the right proportion of law-trained executives on the senior leadership team can help," Kanuri said. "A law education can train business leaders to approach strategic decisions with a different lens and can signal to investors the extent to which firm leaders are capable of considering the ramifications of their actions.

"Our findings underscore how law degrees make an impact beyond the legal field and politics, and that proportion matters," he continued. "It's not just about having leaders with law degrees, but having the right balance. One way firms can reduce the likelihood of investor punishment is to assemble that right balance."

The accumulation of one particular protein in the brain is at the basis of three very different age-related conditions. Until recently, nobody understood how this was possible. Research by the Laboratory for Neurobiology and Gene Therapy (KU Leuven) now reveals that the shape of the protein determines the clinical picture.

The presence of α-synuclein protein deposits in the brain is characteristic for three different diseases: Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Although these disorders are part of the same family, they are clinically and pathologically very different.

Parkinson's disease affects around two percent of the population over 60. The condition manifests itself mainly in motor problems. Dementia with Lewy bodies is less common (0.4 percent of people over 65), but is still the second most common form of dementia, after Alzheimer's disease. Multiple system atrophy is a rare but extremely aggressive disease for which there is virtually no treatment. It causes a variety of health issues, including general pain, bladder problems and low blood pressure, as well as motor problems. Most patients succumb to the disease within five to ten years.

Simulating disease processes

In collaboration with their colleagues from the French National Centre for Scientific Research (CNRS) and Imperial College London, researchers of the KU Leuven Laboratory for Neurobiology and Gene Therapy isolated the α-synuclein protein from brain tissue of deceased PD, MSA and DLB patients. This protein was then multiplied and reproduced with a technique that was specifically designed for this purpose. The different protein shapes were carefully studied in the lab and introduced in lab animals to simulate the disease processes.

The researchers were able to identify two shapes of the protein: a helical one in MSA and Parkinson's disease, and a cylindrical one in DLB. The shape also determined the severity of the disease symptoms: in MSA the symptoms occurred more quickly and aggressively, while in DLB they were more moderate.

"Previously, it was a mystery why one and the same protein caused three different brain diseases," says research coordinator Dr Anke Van der Perren. "Now, for the first time, we've been able to identify different shapes of α-synuclein protein deposits in patients. Depending on the shape, a different disorder and, thus, a different clinical picture occurs."

Earlier and better diagnosis

The new insights on the origin and structure of the protein shapes may, in time, lead to an earlier and better diagnosis, says Professor Veerle Baekelandt. "To this day, it's very difficult to diagnose these three brain disorders. We want to further unravel the complex process of the protein deposits to gain a better understanding of how the diseases develop. In time, we hope that we'll be able to detect these harmful protein shapes and that a specific treatment can be found to slow down or even stop the disease process."

Use of sodium glucose cotransporter 2 (SGLT2) inhibitors to treat type 2 diabetes may help to lower the risk of serious kidney problems, finds a study published by The BMJ today.

The findings provide further support for the use of SGLT2 inhibitors in a broad range of patients with type 2 diabetes.

Type 2 diabetes is the leading cause of kidney failure. Clinical trials have shown that SGLT2 inhibitors protect kidney (renal) function among patients with type 2 diabetes, but their effect on serious renal events in patients in "real-world" clinical practice remains uncertain.

So an international team of researchers set out to assess the association between use of SGLT2 inhibitors and risk of serious renal events using data from routine clinical practice.

They used nationwide register data from Sweden, Denmark, and Norway from 2013-18 to compare use of SGLT2 inhibitors with another group of diabetes drugs called dipeptidyl peptidase-4 (DPP-4) inhibitors.

Prescription data was used to identify 29,887 new users of SGLT2 inhibitors and 29,887 new users of dipeptidyl peptidase-4 inhibitors (average age 61 years).

Hospital records and death statistics were used to track serious renal events for an average of two years. These included renal replacement therapy, death from renal causes, and hospital admission for renal events.

The researchers found that compared with DPP-4 inhibitors, use of SGLT2 inhibitors was associated with a reduced risk of serious renal events (2.6 events per 1000 person years versus 6.2 events per 1000 person years).

This equates to a difference of 3.6 fewer events per 1000 person-years or a 58% lower relative risk of serious renal events with SGLT2 inhibitors.

Further analysis found greater risk reduction in patients with underlying cardiovascular disease and chronic kidney disease (CKD).

This is an observational study, so can't establish cause, and the researchers point to some study limitations, such as relying on prescription data and hospital records, which may have affected the accuracy of their results.

What's more, because the study was conducted in Scandinavia, findings may not apply to other populations and healthcare systems.

However, they say that in this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with DPP-4 inhibitors, was associated with a significantly reduced risk of serious renal events.

These findings complement the results of previous randomised trials, suggesting that SGLT2 inhibitors may lower the risk of serious renal events in routine clinical practice, they conclude.

The results from this well designed study are consistent with previous research and add new evidence that SGLT2 inhibitors seem preferable to DPP-4 inhibitors in patients at risk of developing or worsening kidney disease, says Steven Smith at the University of Florida, in a linked editorial.

Despite this study's strengths there are some reasons for caution in interpreting the results, he writes.

Additional trials in real world settings and more diverse populations "could add further support for broader access to these drugs, not just in high income countries, but also in lower income countries where the burden of kidney disease is disproportionately high," he concludes.

In an analysis article also published today, researchers point out that SGLT2 inhibitors have received several serious safety warnings since approval, but the number, timeliness, and strength of these safety communications have differed between American, Australian, Canadian, and European regulators.

They call for greater transparency in decision making to help increase the accountability of both regulators and industry and allow more informed treatment choices to be made.

The hunt for an effective treatment for COVID-19 has led one team of researchers to find an improbable ally for their work: a llama named Winter. The team -- from The University of Texas at Austin, the National Institutes of Health and Ghent University in Belgium -- reports their findings about a potential avenue for a coronavirus treatment involving llamas on May 5 in the journal Cell. The paper is currently available online as a "pre-proof," meaning it is peer-reviewed but undergoing final formatting.

The researchers linked two copies of a special kind of antibody produced by llamas to create a new antibody that binds tightly to a key protein on the coronavirus that causes COVID-19. This protein, called the spike protein, allows the virus to break into host cells. Initial tests indicate that the antibody blocks viruses that display this spike protein from infecting cells in culture.

"This is one of the first antibodies known to neutralize SARS-CoV-2," said Jason McLellan, associate professor of molecular biosciences at UT Austin and co-senior author, referring to the virus that causes COVID-19.

The team is now preparing to conduct preclinical studies in animals such as hamsters or nonhuman primates, with the hopes of next testing in humans. The goal is to develop a treatment that would help people soon after infection with the virus.

"Vaccines have to be given a month or two before infection to provide protection," McLellan said. "With antibody therapies, you're directly giving somebody the protective antibodies and so, immediately after treatment, they should be protected. The antibodies could also be used to treat somebody who is already sick to lessen the severity of the disease."

This would be especially helpful for vulnerable groups such as elderly people, who mount a modest response to vaccines, which means that their protection may be incomplete. Health care workers and other people at increased risk of exposure to the virus can also benefit from immediate protection.

When llamas' immune systems detect foreign invaders such as bacteria and viruses, these animals (and other camelids such as alpacas) produce two types of antibodies: one that is similar to human antibodies and another that's only about a quarter of the size. These smaller ones, called single-domain antibodies or nanobodies, can be nebulized and used in an inhaler.

"That makes them potentially really interesting as a drug for a respiratory pathogen because you're delivering it right to the site of infection," said Daniel Wrapp, a graduate student in McLellan's lab and co-first author of the paper.

Meet Winter

Winter, the llama, is 4 years old and still living on a farm in the Belgian countryside along with approximately 130 other llamas and alpacas. Her part in the experiment happened in 2016 when she was about 9 months old and the researchers were studying two earlier coronaviruses: SARS-CoV-1 and MERS-CoV. In a process similar to humans getting shots to immunize them against a virus, she was injected with stabilized spike proteins from those viruses over the course of about six weeks.

Next, researchers collected a blood sample and isolated antibodies that bound to each version of the spike protein. One showed real promise in stopping a virus that displays spike proteins from SARS-CoV-1 from infecting cells in culture.

"That was exciting to me because I'd been working on this for years," Wrapp said. "But there wasn't a big need for a coronavirus treatment then. This was just basic research. Now, this can potentially have some translational implications, too."

The team engineered the new antibody that shows promise for treating the current SARS-CoV-2 by linking two copies of the llama antibody that worked against the earlier SARS virus. They demonstrated that the new antibody neutralizes viruses displaying spike proteins from SARS-CoV-2 in cell cultures. The scientists were able to complete this research and publish it in a top journal in a matter of weeks thanks to the years of work they'd already done on related coronaviruses.

McLellan also led the team that first mapped the spike protein of SARS-CoV-2, a critical step toward a vaccine. (Wrapp also co-authored that paper along with other authors on the current Cell paper, including UT Austin's Nianshuang Wang, and Kizzmekia S. Corbett and Barney Graham of the National Institute of Allergy and Infectious Diseases' Vaccine Research Center.) Besides Wrapp, the paper's other co-first author is Dorien De Vlieger, a postdoctoral scientist at Ghent University's Vlaams Institute for Biotechnology (VIB), and the other senior authors besides McLellan are Bert Schepens and Xavier Saelens, both at VIB.

This work was supported by the National Institute of Allergy and Infectious Diseases (U.S.), VIB, The Research Foundation-Flanders (Belgium), Flanders Innovation and Entrepreneurship (Belgium) and the Federal Ministry of Education and Research (Germany).

Backstory

The first antibodies the team identified in the initial SARS-CoV-1 and MERS-CoV tests included one called VHH-72, which bound tightly to spike proteins on SARS-CoV-1. In so doing, it prevented a pseudotyped virus -- a virus that can't make people sick and has been genetically engineered to display copies of the SARS-CoV-1 spike protein on its surface -- from infecting cells.

When SARS-CoV-2 emerged and triggered the COVID-19 pandemic, the team wondered whether the antibody they discovered for SARS-CoV-1 would also be effective against its viral cousin. They discovered that it did bind to SARS-CoV-2's spike protein too, albeit weakly. The engineering they did to make it bind more effectively involved linking two copies of VHH-72, which they then showed neutralizes a pseudotyped virus sporting spike proteins from SARS-CoV-2. This is the first known antibody that neutralizes both SARS-CoV-1 and SARS-CoV-2.

Four years ago, De Vlieger was developing antivirals against influenza A when Bert Schepens and Xavier Saelens asked whether she would be interested in helping to isolate antibodies against coronaviruses from llamas.

"I thought this would be a small side project," she said. "Now the scientific impact of this project became bigger than I could ever expect. It's amazing how unpredictable viruses can be."

ITHACA, N.Y. - Cornell scientists have developed a new technique for imaging a zebrafish's brain at all stages of its development, which could have implications for the study of human brain disorders, including autism.

Zebrafish are translucent when young, making them good models for live imaging, but they become opaque with age, which has prevented researchers from seeing into a live adult brain.

Now, an interdisciplinary team from Cornell Neurotech has developed a microscopy tool to use with adult zebrafish engineered with calcium sensors that light up to reveal when neurons are activated.

Since all vertebrate brains are fundamentally similar, the approach allows scientists to learn basic principles of brain structure and function that apply to all vertebrates, including humans.

"All vertebrate brains are, to a first approximation, the same, with nearly all brain regions [present] in nearly every vertebrate," said Joseph Fetcho, professor of neurobiology and behavior and director of Cornell Neurotech in the College of Arts and Sciences. "This is not surprising because they all, even the simplest ones, have to do the same things to survive and reproduce."

Fetcho is a co-senior author of the study, "Deep Three-Photon Imaging of the Brain in Intact Adult Zebrafish," which published April 27 in Nature Methods. The other senior author is Chris Xu, professor of applied engineering and physics in the College of Engineering and the Mong Family Foundation Director of Cornell Neurotech-Engineering.

When nerve cells activate, they flood with calcium. The fish used in Fetcho's studies are engineered with a protein that binds to the calcium in nerve cells. The protein also fluoresces when excited by laser light with a 480-nanometer wavelength, and the fluorescing cells can be imaged with a microscope.

The problem: When delivering that pulse of light, a single 480nm photon aimed through the top of the fish's head will excite other fluorescent proteins in the beam's path, blurring the image. The new technique works by delivering 1400nm wavelength photons to a focal point in the brain. This way, each individual photon has a wavelength that's too long to excite intermediary proteins, but three photons together will carry enough energy to excite a fluorescent protein when light is concentrated at the focal point.

The laser then scans repeatedly along a line in the brain. By repeatedly imaging, parallel lines add up to a two-dimensional cross section of a brain region. By repeating this process at different depths, the researchers attain a three-dimensional image of brain structures.

With the new tool, Fetcho said, researchers may now use fish that are engineered to develop a version of autism and other disorders, and watch how the disease progesses as the fish ages. These fish models could also be used to test potential treatments to see if they improve function, and how brain structure and function change if a condition improves.

"This is a step ... toward cures for some of the devastating brain disorders faced by humans," Fetcho said.

Xu's lab developed the imaging technology, while Fetcho's lab worked on the neurobiology and behavioral aspects of the study. Co-author Andrew Bass, the Horace White Professor of Neurobiology and Behavior in A&S, also provided a different fish model that is still in development, for a smaller relative of zebrafish, called Danionella dracula, which would be easier to image.