Culture

Is the basic research that goes into the development of new drugs more efficiently conducted by public-sector scientists, pharmaceutical firms, or independent private laboratories? What role do each of these groups play in determining prices of innovative pharmaceuticals, which have risen steeply over the last years? To answer these questions, economists Francesca Barigozzi, of the University of Bologna, and Izabela Jelovac, of the CNRS,* designed and studied a model inspired by game theory.** In an article recently published in Health Economics, they demonstrate that basic research is most cost-effective when carried out either in a public research laboratory or a pharmaceutical firm. If basic and applied research are highly complementary--where improving the quality of one benefits the other--public research units outperform pharmaceutical companies in the conduct of basic research. Furthermore, the price of new drugs is lowest when basic research takes place in public labs. These findings therefore condition the validity of the economic assumption that greater efficiency in research necessarily results in a more expensive end product.*** In some cases, public-sector basic research is the most efficient and leads to the lowest drug prices.

New research indicates that significant enhancement of secondary aerosol formed in the atmosphere via gas-to-particle conversion, together with long-lasting regional transport, may be the cause of severe haze over China despite a dramatic reduction in emissions during the COVID-19 shutdown. The findings are published in Geophysical Research Letters.

During the Chinese Lunar New Year holiday between January 24 and February 10, 2020, China was in an unprecedented state of shutdown because of COVID-19, with mobility, energy demands, and industrial pollution emissions remaining far below their normal levels. Nevertheless, a high and widespread haze pollution was observed over Eastern China.

To investigate this puzzling occurrence, Yunhua Chang, Professor, of the Nanjing University of Information Science & Technology, Ru-Jin Huang, Professor, of the Chinese Academy of Sciences, and their colleagues analyzed the chemical components of the air in and out of Shanghai before, during, and after the Chinese New Year holidays in 2019 and 2020, and they performed atmospheric transport modeling, a method to track particles and trace gases that are dispersed by atmospheric winds.

The team found that secondary aerosol formation that interacts with long-range transport likely caused the long-lasting haze during the COVID-19 pandemic.

The results highlight the need for joint management efforts and control strategies across large areas to effectively clear China's air.

"We hope our findings can inform future regulatory policies to mitigate China's haze-associated problems," said Dr. Chang.

"Additional studies are needed to pinpoint the role of atmospheric oxidation capacity--which is affected by emission reductions of air pollutants--in the formation of secondary aerosols," added Dr. Huang.

This paper is part of an ongoing special collection of research in AGU journals related to the current pandemic.

Biophysicists from the Moscow Institute of Physics and Technology and their colleagues have proposed a simple way to observe the heart tissue. Besides being relatively uncomplicated, the new method is cheaper and produces results that are more independent, compared with the analogues currently in use. The study came out in Annals of Biomedical Engineering.

The heart tissue is a special kind of muscle. When excitation waves propagate through it, this causes the constituent fibers to contract. The excitation waves coordinate the work of the heart compartments to ensure the organ functions correctly.

Many heart diseases, among them arrhythmias, are associated with disruptions in excitation wave conduction or with some peculiar propagation regimes taking over. This is why fundamental research into the mechanisms of excitation wave propagation in the heart is important. Such studies provide insights into how the heart functions, how arrhythmias arise, and how various drugs and substances affect the processes in the cardiac tissue.

One of the staple methods for observing excitation waves is optical mapping. It involves the use of fluorescent dyes to visualize the propagation of excitations in the heart tissue. The process is monitored with sensitive video cameras, and the resulting data are then subjected to analysis.

Optical mapping has certain drawbacks. For one thing, the dyes and cameras suitable for the technique are fairly expensive. Another disadvantage is that the dye may interact with drugs and thus disturb the experiment. The dyes also affect the cells in the heart tissue sample, reducing their lifetimes.

"We found that if you grow the cardiac tissue culture on an elastic substrate made of polydimethylsiloxane, it is possible to observe wave propagation with a microscope, and no dyes are needed," said Konstantin Guria, a senior researcher at the MIPT Laboratory of the Biophysics of Excitable Systems.

This idea laid the foundation for the new method. In it the heart tissue is cultivated on an elastic substrate. As a result, when an excitation wave propagates across the sample in the experiment, the substrate deforms. This process can be optically registered via oblique illumination. The technique eases camera requirements, because even a GoPro provides sufficient quality.

"We have proposed a method that is simpler and cheaper than conventional mapping. That said, an even greater competitive advantage is being sure that the analyzed substance does not interact with a dye, since it becomes redundant for visualization," commented Konstantin Agladze, who heads the Laboratory of the Biophysics of Excitable Systems at MIPT.

The new method can be used for affordable testing of various processes on tissue cultures grown from stem cells. The process lends itself to automation and is suitable for longer observations than those that rely on regular mapping.

In addition to MIPT staff, this study involved researchers from Vladimirsky Moscow Regional Research and Clinical Institute and the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences.

The Laboratory of the Biophysics of Excitable Systems is part of the Phystech School of Biological and Medical Physics at MIPT. It uses human cardiac tissue models to conduct experimental research into the fundamental mechanisms behind heart arrhythmias. The head of the laboratory is Konstantin Agladze. You can reach the lab by contacting the secretary, Irina Egorova, at egorova.ia@mipt.ru or by dialing +7 (495) 408-46-45.

New research has shown that Drax power station in North Yorkshire is the optimal site for the carbon capture and storage facilities that will be needed reduce carbon emissions and achieve the targets of 2016 Paris Climate Agreement.

There has been a growing interest in the use of bioenergy with carbon capture and storage (BECCS) to achieve a net reduction in greenhouse gases. BECCS involves the combustion of biomass to generate energy, using trees and grasses grown on both agricultural land and marginal land unsuitable for food crops. The resulting CO2 emissions are captured, compressed, and transported to suitable underground storage sites. BECCS is an example of a Negative Emission Technology (NET), with others including the direct capture of CO­2 from the air, afforestation and carbon capture by trees, and pulverisation of rocks to enhance the natural weathering process and CO2 uptake. These are controversial technologies because they are largely untested at scale and because we have limited understanding of their wider impacts on society and the environment.

The new study, led by the University of Southampton and published in the journal GCB Bioenergy, looked at six potential locations for BECCS power plants across the UK. Each site was assessed on a number of criteria including proximity to CO2 storage sites, costs of transporting biocrops as well as the potential for soil sequestration (the process by which crops remove CO2 from the atmosphere) and flood mitigation. The researchers also calculated welfare value by integrated the costs and the potential for environmental benefits.

Drax was identified as one of the most positive UK sites for the delivery of ecosystem service benefits. However, these benefits decline with size with 1 GW BECCS being significantly less beneficial to the environment than 500 MW, suggesting that future BECCS requires site-specific ecosystem service valuations to assess trade-offs and co-benefits of this NET and that smaller power plants are preferred over large infrastructures.

Achieving the Paris Agreement targets requires net zero emissions and the UK, along with other nations, plans to deploy NETs to achieve a net zero economy by 2050. BECCS features heavily in the net zero energy scenarios, estimated to be as high as 15 GW (capturing 67 Mt of CO2 per year) by the UK Committee on Climate Change. However, models currently used to generate BECCS scenarios don't quantify the environmental and social implications of BECCS and rarely consider the environment. The researchers believe they have addressed this limitation with their new model.

Professor Gail Taylor of the University of Southampton and University of California Davis who led the research said: "The novelty of this study is that for the first time we have managed to quantify the impact of BECCS at a regional scale, on the environment - showing perhaps surprisingly that BECCS can have significant positive impacts because long-lived trees are good for soil carbon and flood protection. However, this net benefit depends very much on where the BECCS power station is sited and consistently, in our study, declined as the capacity of the power station increased. These are very significant findings for policy makers if BECCS, as predicted, is to play a big role in the UK strategy to get to net zero by 2050".

SALT LAKE CITY - An overactive defense response may lead to increased blood clotting, disease severity, and death from COVID-19. A phenomenon called NETosis--in which infection-fighting cells emit a web-like substance to trap invading viruses--is part of an immune response that becomes increasingly hyperactive in people on ventilators and people who die from the disease.

A team led by University of Utah Health and PEEL Therapeutics, in collaboration with Cold Spring Harbor Laboratory and Weill Cornell Medicine, report the findings in a new study published in the journal, Blood.

"This study tells us about a potential mechanism for lung injury in COVID-19 that had not previously been recognized as a possible target for treatment," says Elizabeth Middleton, M.D., the study's first author and a critical care specialist at U of U Health.

The investigation also reports that a naturally occurring protein--originally found in umbilical cord blood--quiets this NET immune response in laboratory experiments, potentially opening new avenues for treatment.

It is estimated that up to 10% of people with COVID-19 become critically ill with respiratory distress. Causes of lung damage are a subject of intense investigation, and increasing evidence demonstrates that increased blood clotting may lead to complications caused by the disease.

Middleton, U of U Health physician-scientists and co-senior authors Christian Con Yost, M.D. and Joshua Schiffman, M.D., and colleagues, took a closer look to see if a specific immune response, called NETosis, could be involved.

As part of an immune response, white blood cells release web-like Neutrophil Extracellular Traps (NETs) to capture and kill pathogens. While typically beneficial, Yost had previously shown that overactive NETs exacerbate certain illnesses. In conditions such as overwhelming infection, NETs can clog blood vessels and lead to inflammatory tissue damage.

To determine whether NETs could be responsible for complications seen in COVID-19, the team examined plasma from 33 patients, along with tracheal aspirates from the lungs. They found that NET activity correlated with disease severity.

Patients on life support and those who died from COVID-19 had significantly more signs of NET activation than patients who were not as sick or who went on to recover. The NET immune response was lower still in healthy people. NET levels also tracked with a marker for blood-oxygen levels, an independent indicator of disease severity.

Similarly, plasma from sick patients was primed to launch the NET response. When examined in laboratory experiments, plasma from COVID-19 patients triggered white blood cells from healthy patients to shoot out 50 times as many NETs as cells exposed to plasma from otherwise healthy adults.

"This study may tell us that NET levels in the blood could potentially help predict disease severity and mortality in COVID-19," says Yost, a physician-scientist at U of U Health. "Additional information is urgently needed in this pandemic regarding how to know which patient will fare better or worse." Larger studies will need to be done to determine whether NETs could become a biomarker for COVID-19 severity. "Importantly, we think exaggerated NETs could be a cause of morbidity and mortality in COVID-19," Yost says.

In support of the idea, collaborators at Cold Spring Harbor Laboratory showed that blood vessels in the lungs of deceased COVID-19 patients were dotted with clumps of NET-producing cells and a critical type of blood cell for clotting, the platelets. Another recent study from U of U Health showed that platelets become hyperactive during the disease. Investigations are now underway to determine whether NETs and platelets increase the risk for blood clotting and other clinical manifestations of COVID-19.

"In COVID-19, thrombosis is a major cause of death. So, our findings tell us that we should focus on understanding more about NETs' role in clotting in COVID-19," Mikala Egeblad, Ph.D., a cancer researcher from Cold Spring Harbor Laboratory, says. "Thrombosis is also a major cause of death in late stage cancer, where there also can be elevated NETs in the blood. Therefore, I think that what we learn from COVID-19 will help us with other diseases, including cancer."

Additionally, laboratory experiments showed that a small protein found in umbilical cord blood of newborn babies, called neonatal NET Inhibitory Factor (nNIF), quiets the hyperactive NET response in white blood cells treated with COVID-19 patient plasma. This peptide is thought to protect babies from harmful inflammation early in life, explains Schiffman, CEO of PEEL Therapeutics. His company is now evaluating whether the protein could become the basis for a clinical treatment.

"Newborns babies have a natural therapeutic in their blood to protect against these same inflammatory events that we think could be killing COVID-19 patients," Schiffman says. "This targeted approach to stopping NETs may be more effective with less side effects than some other drugs being tested now in COVID-19 patients that block the entire immune system¬¬¬¬."

A protein derived from the saliva of the tick Amblyomma sculptum has been successfully used by researchers at the Butantan Institute in São Paulo, Brazil, to treat skin cancer (melanoma) in horses. The results of the study are described in the journal Scientific Reports.

The principal investigator for the project is Ana Marisa Chudzinski-Tavassi, who leads the Center of Excellence in New Target Discovery (CENTD), an Engineering Research Center (ERC) established at the Butantan Institute by São Paulo Research Foundation - FAPESP and GlaxoSmithKline.

CENTD's mission is to discover and validate molecular targets to treat inflammatory diseases for the purpose of developing new drugs.

The protein is Amblyomin-X, which has been studied at the Butantan Institute for more than ten years and evidences significant antitumor potential in the laboratory and in vivo and has already been approved in preclinical toxicity testing.

The researchers used "omics" tools (genomics, transcriptomics, proteomics and metabolomics) to analyze the signaling pathways and proteins affected by the treatment of horse melanoma with Amblyomin-X.

Roger Chammas, a researcher at the São Paulo State Cancer Institute (ICESP), collaborated with CENTD scientists on the project.

Immune mechanisms

Equine melanomas are spontaneous tumors. Unlike cutaneous melanomas in humans, in horses, they are encapsulated and locally confined, rarely giving rise to metastasis. However, in both humans and horses, these tumors are potentially immunogenic, i.e., capable of producing an immune response, and can serve as a model for the investigation of the immune mechanisms involved in tumor regression induced by therapeutic molecules.

In the first phase of the study, spontaneous tumors in five horses were treated for 30 days with intratumoral injections of Amblyomin-X. The treatment took place at the Butantan Institute's farm in Araçariguama, state of São Paulo. The animals were monitored throughout the period by means of clinical examinations, blood work, and biochemical laboratory tests.

The results were promising. Control tumors (not treated with the compound) maintained their shape and grew in size, whereas tumors treated with Amblyomin-X shrank and, in some cases, even reached remission up to two months after the treatment ended.

None of the five treated animals developed any adverse reactions. At the end of the treatment, the tumors were surgically removed for histopathological analysis. The researchers found no trace of tumoral characteristics.

The second phase of the study consisted of experiments in transcriptomics (analyzing messenger RNA expression) and interactomics (analyzing the interaction between tumor cell proteins and Amblyomin-X) to see how signaling pathways were modulated by the treatment and, especially, to obtain molecular confirmation of previous findings from in vitro and in vivo experiments conducted by Chudzinski-Tavassi and her team. The results published by the group between 2010 and 2017 suggested that the antitumor action of Amblyomin-X occurred via the modulation of the endoplasmic reticulum and mitochondrial stress and apoptotic and proteasomic pathways, among others.

The transcriptome study was expected to confirm activation of these pathways and show whether others were affected by the treatment. The researchers also deployed next-generation sequencing and analysis based on bioinformatics and systems biology to map the initial mechanisms of the response triggered by Amblyomin-X, which culminated in tumor regression.

Among the findings of the transcriptomic analysis was the discovery that the innate immune system's rapid response (six hours after the injections) involved the modulation of four different pathways: TLR (toll-like receptor), RIG-I (viral invasion sensors), OAS (2',5'- oligoadenylate synthetase and RNase L) and oncostatin-M (corresponding to the interleukin-6 family inflammation pathway). These findings described the first steps in the activation of a defense response that culminated in tumor regression, pointing to potential candidate targets for adjuvant therapies against tumors.

PHILADELPHIA -- After one consumes food or a beverage containing fructose, the gastrointestinal system, or gut, helps to shield the liver from damage by breaking down the sugar before it reaches the liver, according to a new multi-center study led by researchers in the Perelman School of Medicine at the University of Pennsylvania. However, the consumption of too much fructose--particularly in a short period of time--can overwhelm the gut, causing fructose to "spill over" into the liver, where it wreaks havoc and causes fatty liver, researchers discovered.

The findings, in mice, help to unravel longstanding questions about how the body metabolizes fructose--a form of sugar often found in fruits, vegetables, and honey, as well as most processed foods in the form of high fructose corn syrup. Consumption of fructose has increased 100-fold over the last century, even as studies have shown that excessive consumption, particularly sweet drinks, are linked to non-alcoholic fatty liver disease, obesity and diabetes. The findings were published in Nature Metabolism.

"What we discovered and show here is that, after you eat or drink fructose, the gut actually consumes the fructose first--helping to protect the liver from fructose-induced damage," said the study's corresponding author Zoltan Arany, MD, PhD, a professor of Cardiovascular Medicine at Penn. "Importantly, we also show that consuming the food or beverage slowly over a long meal, rather than in one gulp, can mitigate the adverse consequences."

Studies have shown that the excessive consumption of fructose can be toxic to the liver. When large quantities of fructose reach the liver, the liver uses excess fructose to create fat, a process called lipogenesis. Eventually, people who consume too much fructose can develop nonalcoholic fatty liver disease, a condition in which too much fat is stored in the liver cells.

Until now, it hasn't been clear whether the gut's role in processing the fructose prevents or contributes to fructose-induced lipogenesis and the development of liver diseases. For this study, the team of researchers, including Princeton University's Joshua Rabinowitz, MD, PhD, studied a key enzyme, called ketohexokinase, that controls how fast fructose is consumed. They showed, by genetically engineering mice, that lowering the levels of this enzyme in the gut led to fatty livers in the mice. Conversely, the team showed that increasing the level of ketohexokinase in the gut protected from fatty liver. Thus, the researchers found the breakdown of fructose in the gut mitigates the development of extra fat in liver cells in mice. They discovered that the rate at which the intestine can clear fructose determines the rate at which fructose can be safely ingested.

In addition, the team showed the same amount of fructose is more likely to result in the development of fatty liver when its consumed via a beverage versus food. Similarly, one faces an increased likelihood of developing fatty liver when consuming fructose in a single setting compared to several doses spread over 45 minutes.

"Collectively, our findings show fructose induces lipogenesis when the intake rate exceeds the gut's capacity to process fructose and protect the liver," Arany said. "In the modern context of excessive availability and consumption of processed foods, it is easy to see how the resulting fructose spillover would drive metabolic syndrome."

Scientists have new evidence that overactive neutrophils--a common type of circulating immune cell--may drive the life-threatening blood clots and inflammation that occur in some patients with COVID-19. High levels of the sticky, pathogen-trapping webs produced by the cells were associated with the most severe cases of COVID-19 in a study reported online in the journal Blood.

Neutrophil extracellular traps (NETs) are a type of defense that the immune system deploys against certain pathogens--webs of DNA and toxins that ensnare and destroy viruses and bacteria. When too many of these NETs accumulate during a persistent infection, they can lead to acute respiratory distress syndrome, which leads many patients with COVID-19 to require intensive care.

Researchers at Cold Spring Harbor Laboratory (CSHL), University of Utah Health, PEEL Therapeutics and Weill Cornell Medicine collaborated to investigate NETs suspected role in COVID-19, collecting blood samples from 33 hospitalized patients, as well as autopsy tissue. They found that biomarkers of NET formation were more abundant in patients who required ventilation, and highest in the three study participants who eventually died from COVID-19.

When the team examined the lungs of the patients who died, they found tiny clots of tangled NETs and blood platelets known as microthrombi scattered through the tissue. "It will be important to investigate NETs role in clot formation (thrombosis) not only in light of the COVID-19 pandemic, but also to understand their broader role in disease," says CSHL Associate Professor Mikala Egeblad.

"Excess NETs are formed in other viral diseases," she says. "We also know that clotting is a major cause of death in people with end-stage cancer, so what we are learning in COVID-19 may help us understand basic properties in cancer and other diseases."

In the laboratory, neutrophils from patients with COVID-19 churned out exceptionally high levels of NETs, and the researchers found healthy neutrophils behaved the same way when they were exposed to plasma from patients with the illness. They could stop NET production, however, by exposing cells to neonatal NET-Inhibitory Factor (nNIF), an anti-inflammatory peptide from umbilical cord blood that protects newborn babies.

Several therapeutic strategies for dismantling NETs or preventing their formation are currently under investigation. These include the nNIF peptide, which is in pre-clinical development by PEEL Therapeutics. "Although further studies will be required, the NET-inhibitory protein may block exaggerated NET formation in COVID-19 patients," says Christian Con Yost, whose laboratory at University of Utah Health discovered nNIF in 2016.

Neurons that regularly remodel are more prone to Alzheimer’s disease and die when that remodeling goes awry, a new study suggests. The work is the first to track the progression of Alzheimer’s at the genetic and molecular levels within neurons vulnerable to the disease.

“Identifying the molecular characteristics of neurons that are especially vulnerable to neurodegeneration is important both for the basic understanding of Alzheimer’s and for future development of better diagnostic and treatment options,” says study co-author Olga Troyanskaya, deputy director for genomics at the Flatiron Institute’s Center for Computational Biology in New York City and a professor at Princeton University.

Using a machine learning framework that integrated neuron type-specific mouse experiments with human studies, the researchers compared two types of neurons susceptible to Alzheimer’s with five resistant types. The most significant difference was that the vulnerable neurons were enriched with processes related to remodeling connections with adjacent neurons.

The findings suggest that aging and the accumulation of a protein fragment called amyloid-beta can cause the remodeling process to go haywire, creating tangles of tau proteins that lead to neuron death. The work is the first to link amyloid-beta and tau proteins — two previously proposed prime suspects in Alzheimer’s progression — at the genetic and molecular levels.

“By understanding what makes these neurons extra vulnerable, we can understand what makes Alzheimer’s start killing neurons,” says study co-lead author Vicky Yao, an assistant professor of computer science at Rice University in Houston who started the project while working in Troyanskaya’s group at Princeton. “The question now is whether we can somehow make these neurons more resistant.”

Yao led the work along with Jean-Pierre Roussarie, a senior research associate at the Fisher Center for Alzheimer’s Disease Research at Rockefeller University in New York City. The researchers present their findings June 29 in Neuron.

Alzheimer’s is a progressive disorder that causes brain cells to waste away and die. The disease first targets neurons related to memory and navigation. Over time, the disease spreads to other neurons. In the United States, Alzheimer’s is the sixth-leading cause of death and the fifth-leading cause of death for Americans age 65 and older.

The cause of the disease remains unclear. Previous studies identified genes that elevate Alzheimer’s risk, but scientists still don’t know why the disease starts attacking neurons. One challenge to studying the disease is that the brain quickly starts deteriorating after death, distorting any potential postmortem findings.

For the new study, Roussarie and his colleagues generated genetic lines of mice tailor-made for studying neurons. Each line focuses on a single neuron type, with genetic changes to make gene transcription in those neurons easier to track (including the addition of a green fluorescent protein). The researchers developed mice lines targeting neurons resilient to Alzheimer’s and others targeting neurons vulnerable to the disease.

In the new paper, the researchers show that the human and mouse neurons were nearly identical at the molecular level, making the rodents superb stand-ins for studying Alzheimer’s.

The researchers combined experimental data from Roussarie’s mice with Yao’s computational models of human genetics, which show when and where genes related to Alzheimer’s-related processes are expressed in the brain and how those genes interact with other genes. Together, the two data sources produced a profile of what characteristics make neurons vulnerable to Alzheimer’s.

The profile turned up two of the usual suspects in Alzheimer’s: amyloid-beta and tau. Amyloid-beta is a protein fragment that can aggregate, forming plaques that fill the gaps between nerve cells. Tau proteins — the top candidate in the profile — stabilize microtubules, molecular rods that give neurons their shape and form the backbone of connections between neighboring neurons. When tau proteins are misfolded, they can create tangled threads that block a neuron’s transport system, preventing neurons from functioning properly.

“When I first did the predictions, I actually went back and double-checked because I thought that this was too good to be true,” Yao says. “These were things we had already known were related to Alzheimer’s, and we were able to link them together. It was verification that we were on the right track.”

Scientists have long debated which process — involving amyloid-beta or tau — is responsible for the onset of Alzheimer’s, but the new findings suggest that the two are connected. The work strongly linked PTB, a gene that regulates the formation of the several flavors of the tau protein, to Alzheimer’s. If PTB is dysregulated, the ratio of tau proteins is thrown off. This imbalance causes the tau proteins to start aggregating, forming the tangled threads. The researchers propose that age and amyloid-beta accumulation boost the risk of this dysregulation.

The researchers plan to continue their research by looking for other characteristics that make neurons vulnerable to the disease. Gathering more information about the onset of Alzheimer’s will aid the development of potential treatments that prevent the disease from taking root in the first place, Yao says.

Journal

Neuron

DOI

10.1016/j.neuron.2020.06.010

LA JOLLA--A new study from researchers at La Jolla Institute for Immunology (LJI) and Erasmus University Medical Center (Erasmus MC) shows that even the sickest COVID-19 patients produce T cells that help fight the virus. The study offers further evidence that a COVID-19 vaccine will need to elicit T cells to work alongside antibodies.

The research, published June 26, 2020 in Science Immunology, also reveals that both Dutch and American patients have similar responses to the virus. "This is key to understanding how the immune response fights the virus," says LJI Professor Alessandro Sette, Dr. Biol. Sci., who co-led the study with Erasmus MC Virologist Rory de Vries, Ph.D. "You want vaccine approaches to be grounded in observations from rather diverse settings to ensure that the results are generally applicable."

For the study, the researchers followed ten COVID-19 patients with the most severe disease symptoms. All ten were admitted to the ICU at Erasmus University Medical Center, in the Netherlands, and put on ventilators as part of their care. Two of the patients eventually died of the disease. An in-depth look at their immune system responses showed that all ten patients produced T cells that targeted the SARS-CoV-2 virus. These T cells worked alongside antibodies to try to clear the virus and stop the infection.

"Activating these cells appears to be at least as important as the production of antibodies," says Erasmus MC Virologist Rory de Vries, Ph.D., who co-led the study with Sette.

These findings are in line with a recent Cell study from Sette, LJI Professor Shane Crotty, Ph.D., and LJI colleagues that showed a robust T cell response in individuals with moderate cases of COVID-19. In both studies, the T cells in these patients prominently targeted the "spike" protein on SARS-CoV-2. The virus uses the spike protein to enter host cells, and many vaccine efforts around the world are aimed at getting the immune system to recognize and attack this protein. The new study offers further evidence that the spike protein is a promising target and confirms that the immune system can also mount strong responses to other targets on the virus.

"This is good news for those making a vaccine using spike, and it also suggests new avenues to potentially increase vaccine potency," says Daniela Weiskopf, Ph.D., research assistant professor at LJI and first author of the new study.

The collaboration between scientists in La Jolla and the Netherlands is also a part of a larger picture, and emphasizes the highly collaborative philosophy adopted by the LJI group. Sette is a world leader in understanding what specific pieces (or epitopes) the immune system recognizes when it encounters a new microbe. The Sette lab's work in defining epitope sets to allow to measure SARS-CoV-2 T cell responses was a key element of the study.

In fact, LJI has become a hub for COVID-19 T cell studies, and Sette has sent out reagents to more than 60 labs around the world. "The study is also highly significant because it illustrates how science has no frontiers," says Sette. "To truly understand a global pandemic, our approach needs to be global, and we need to study effective immune response in people with different genetic backgrounds, living in different environments."

While the Cell paper followed San Diego residents, the new paper follows Dutch patients--and the T cell responses were consistent in both populations. "This study is important because it shows this immune response in patients thousands of miles apart," says Weiskopf. "The same observation has now been strongly reproduced in different continents and different studies."

A new, first-of-its-kind Boston University School of Public Health (BUSPH) study finds that 48% of 12-18-year-olds who have been in a relationship have been stalked or harassed by a partner, and 42% have stalked or harassed a partner.

Published in the journal Youth & Society, the analysis is part of the first nationally-representative study of non-physical youth dating abuse.

"These victimization and perpetration numbers are unacceptably high," says study lead author Dr. Emily Rothman, professor of community health sciences at BUSPH. "Unfortunately, they are in line with estimates of similar problems like dating and sexual violence victimization, so they are both shocking and unsurprising at the same time."

Previous research shows that harassing and stalking behaviors, including destroying belongings or going through social media accounts, can lead to physical violence, Rothman says.

But perhaps especially in the time of COVID, non-physical dating abuse needs to be recognized as real and harmful in its own right, she says.

"Adolescents have already been fully aware of how harmful online forms of abuse can be--that it's valid to be interested in that and to try to address it," Rothman says. "COVID has in some ways made parents, teachers, and other adults more willing to see, right now, that what we do online matters and is fully part of our real lives."

Rothman and colleagues from NORC at the University of Chicago used data from the ongoing Survey on Teen Relationships and Intimate Violence (STRiV) study to look at responses from 148 boys and 172 girls who were currently in relationships or had been in relationships in the past year. The survey asked teens if a partner had ever followed or spied on them, damaged something that belonged to them, or gone through their online accounts. The survey also asked the teens if they had ever done any of these things to a partner.

They found that rates of perpetration and victimization were similar for boys and girls: 46.5% of boys and 50.6% of girls reported stalking or harassing a partner, and 44.6% of boys and 51.1% of girls reported a partner doing these things to them.

The researchers analyzed and controlled for a range of other factors to better understand why particular teens may be at higher risk of perpetration, victimization, or both.

Among boys, having worse relationships with parents and living in neighborhoods with higher rates of violent crime were both associated with higher risk of perpetration. Among girls, being in relationships at younger age, living in neighborhoods with higher rates of violent crime, using marijuana, and using alcohol were associated with higher risk of victimization and perpetration. By race/ethnicity, the researchers found that Latino boys and Black girls faced higher risk of both victimization and perpetration.

Further research will need to untangle these associations, but Rothman says the findings show that dating abuse is shaped by forces larger than the individual.

"We know from intervention research that the way to prevent stalking and harassment, or sexual and dating violence, is partly about addressing how young people think about relationships, gender norms, and improving their social-emotional skills, but these are also influenced by the context in which they are operating," she says.

"So, addressing racism, poverty, homophobia, misogyny, and disability-related discrimination is part of the solution, too."

Cholera can kill within hours if left untreated, and it sickens as many as 4 million people a year. In a new article in the journal Cell, researchers describe how gut bacteria helps people resist the disease.

Bacteria live everywhere on the planet — even inside the human body. UCR microbiologist Ansel Hsiao studies whether the bacteria living in our bodies, collectively known as the human microbiome, can protect people from diseases caused by external bacteria such as Vibrio cholerae, which lives in waterways and causes cholera.

Hsiao’s team examined the gut microbiomes from people in Bangladesh, where many suffer from cholera as a result of contaminated food, water and poor sanitation infrastructure. “When people get sick, the diarrhea gets flushed into water systems that people drink from, and it’s a negative cycle,” Hsiao explained.

His team wanted to see whether prior infections or other stresses, like malnutrition, make people more vulnerable, as compared to Americans who don’t face these same pressures.

The findings surprised the group, which expected stressed Bangladeshi microbiomes would allow for higher rates of infection. Instead, they saw infection rates varied greatly among individuals in both populations, suggesting susceptibility is based on a person’s unique microbiome composition — not the place they’re from.

Vibrio cholerae spends most of its time outside of humans in aquatic environments. It doesn’t usually encounter bile, which mammals produce to help digest fats after a meal.

“Because bile is specific to the intestines of humans and animals, many microorganisms, including cholerae, have evolved ways to deal with it,” Hsiao said.

Once Vibrio cholerae enters a body, the presence of bile and lack of oxygen in the gut triggers previously dormant genes that enable it to survive in its human host. These genes are responsible for cholera’s virulence, helping Vibrio cholerae attach to intestinal walls and cause diarrhea.

Hsiao’s team identified one bacterium in the human microbiome, Blautia obeum, that can deactivate the cholera bacterium’s disease-causing mechanisms, preventing it from colonizing the intestines. They also figured out how this feat is accomplished.

Blautia obeum produces an enzyme that degrades salts in bile, which Vibrio cholerae uses as signals to control gene activity. When these bile salts are corrupted, the cholera-causing bacteria does not receive the signal to activate the dormant genes that cause infection.

Since it’s become clear that more Blautia obeum makes people less susceptible to cholera, a focus of future studies will be how to increase its presence in the gut. “We are extremely interested now in learning which environmental factors, such as diet, can boost levels of obeum,” Hsiao said.

Similar studies are also underway with regard to the virus causing another global pandemic — SARS-CoV-2. Hsiao is collaborating with several groups trying to understand how the microbiome changes with COVID-19 infection.

“One day, we may also understand whether and how the microbiome affects COVID-19 and makes people resistant to other illnesses we don’t currently have treatments for,” Hsiao said.

Journal

Cell

DOI

10.1016/j.cell.2020.05.036

Millions of websites, including some of the largest Internet companies (e.g., Google, Yahoo), depend on advertising as their main source of revenue, allowing them to offer their content for free. The use of software that blocks ads has surged in recent years, presenting a challenge to platforms that depend on ad revenue. A new study sought to determine the effect of ad blockers on websites' ability to generate revenue and on users' experiences. The study found that contrary to common assumptions, ad blockers may offer some benefits to companies, users, and the market at large. The findings have implications for how online platforms make decisions about advertising.

The study, by researchers at Carnegie Mellon University and the City University of Hong Kong, appears in Management Science.

"While most speculations point to a grim outlook for advertisers and platforms as a result of ad blockers, the results of our study offer a glimmer of hope by arguing that ad blockers could actually benefit companies," suggests Kannan Srinivasan, Professor of Management, Marketing, and Business Technologies at Carnegie Mellon University's Tepper School of Business, who coauthored the study.

An ad blocker is a type of software, usually added by a user as an extension to an Internet browser, that prevents ads from appearing on the browsed webpages. When a user with an ad blocker visits a website with ads, the blocker identifies the ad content and prevents it from loading--as a result, the website does not receive ad revenue for that user.

Researchers devised an analytical model to assess the effects of ad blockers by modeling competition, the rate of advertising, and users' sensitivity to advertising. The authors identified two classes of users: one that is more sensitive to ads and uses ad blockers and one that does not use ad blockers. Based on the prevailing conditions, each platform had three options to manage the potential use of ad blockers by some users:

1. Ban ad blocking: Continue displaying ads and ban ad blocking. If a viewer used an ad blocker, he or she has to disable it to gain access to the site.

2. Allow ad blocking: Continue to display ads and allow ad-blocking software by any user who installs it.

3. Charge fees for ad blocking: Stop displaying ads and offer only an ad-free site with a subscription fee.

Based on their work, the researchers concluded that ad blockers may be helpful in one of four ways:

They can make the market more efficient by filtering users who are sensitive to general ads, allowing websites to target more intense ads to the rest of the users.

They benefit users by allowing the removal of ads that annoy them.

They help regulate the ad industry by motivating the advertising platform to pay a fee to the ad-blocking company to include it in a list of ads that are allowed past the blocker.

A more efficient market can boost the quality of websites' content, which also benefits users.

"Our study has implications for platforms dependent on ad revenue, providing general guidelines regarding how they should proceed with decisions about advertising," according to Stylianos Despotakis, Assistant Professor of Marketing at the City University of Hong Kong, who coauthored the study. "For example, if a website has users who are generally sensitive to ads, then its platform cannot expect to receive a lot of ad revenue, even when it prevents the use of ad blockers. By allowing ad blockers, both the platform and the users can benefit."

R. Ravi, Professor of Operations Research and Computer Science at Carnegie Mellon University's Tepper School of Business and a coauthor of the study, adds: "To estimate users' ad sensitivities, platforms can do tests under differing conditions to decide the ideal course of action to manage ad blocking."

In their efforts to better understand ongoing wildlife trafficking and the dynamics of unsustainable bear product use by consumers in Cambodia, a team of researchers led by San Diego Zoo Global made an unexpected discovery: the use of bear bile and body parts in traditional remedies consumed by new and pregnant mothers. The use of traditional medicines derived from bear bile and gallbladders by young and expecting mothers for ailments related to pregnancy had not been previously documented. With populations of wildlife--including bears--in decline across Southeast Asia, understanding this large consumer base could inform conservation efforts in the region, the researchers wrote in a study published recently in the Journal of Ethnobiology and Ethnomedicine.

"To effectively conserve bear populations, we must reduce poaching of bears through reducing demand pressures such as use of bear bile for maternal health," said Elizabeth Oneita Davis, Ph.D., the study's lead author, a postdoctoral associate in Community Engagement at San Diego Zoo Global. "In Cambodia, we are currently working in a rural community to encourage older women to support expecting mothers by accompanying them to the doctor and advising them to take biomedicine."

For this study, the researchers interviewed 122 women in seven Cambodian provinces, each with its own ethnic makeup and level of development, from 2016 to 2019. They found that pregnant women and new mothers used bear products for pregnancy and post-partum-related ailments, including headaches, abdominal cramps, diarrhea and symptoms that may be described as post-partum depression.

Though Western medicine is widely accepted in Cambodia, it exists alongside traditional medicine practices similar to those found in China and Vietnam, with treatments derived from plants and animals--including rhinoceroses, slow lorises and bears. Currently, researchers do not have a deep understanding of when and why traditional medicine is used instead of Western treatments. The researchers have previously estimated that up to 15% of Cambodians use bear products, but that percentage could rise if women continue or increase their current usage for maternal health reasons.

"Beyond bear bile, there is a lack of data around other illegal wildlife products, which may also be used for uterine issues, with the same possible implications of pressure on wildlife populations," Davis said. "In general, the role of women in wildlife trade is largely neglected in research."

In the case of new and expectant mothers, bear products are often taken at the urging of women in their "kinship networks," who care for one another during and after pregnancy, the researchers found. The authors said the study could help shape how Khmer women can promote their reproductive health while protecting bear populations in Cambodia. Older, influential women should be encouraged to promote Western medicine or non-wildlife-based traditional medicine for their young, pregnant kin, they suggested.

When work meetings shifted online this spring, some may have noticed new standouts among their colleagues. According to new research, members of virtual teams identify leaders in significantly different ways compared to members of in-person teams.

The brand new study looked at "emergent leaders"--those who lack formal authority but are recognized as leaders by team members--in teams with varying levels of virtual interaction. Researchers found that in face-to-face gatherings, team members value those with "classic" leadership characteristics, such as extroversion and intelligence, but in virtual settings, those qualities take a backseat.

Online, perhaps because there are fewer cues available for human interaction and more opportunities for miscommunication, team members gravitate toward those who take concrete steps to ensure achievement, rather than toward those with charismatic personalities.

"On a virtual team, it's more important than in a face-to-face meeting to stand out as the one who helps others," said study coauthor Cody Reeves, an assistant professor at the Marriott School of Business at Brigham Young University. "Those who take the time to pause and assist others with tasks are more likely to be viewed as leaders."

Perceived differences between virtual and in-person leaders were "stark," according to Reeves. While it remained essential for leaders in virtual teams to connect socially, successful leadership online was driven primarily by small actions like monitoring timelines, providing feedback, and coordinating teamwork.

For the study, researchers observed 220 student teams at two Midwestern universities who met to work on assigned projects mostly virtually, mostly in person or in a mix of the two. The students completed surveys about their own and their team members' characteristics and behaviors, as well as whom they considered to be team leaders. Combining that data with transcripts of the students' virtual interactions, the researchers identified patterns in how leaders emerge across the spectrum of virtual to in-person teams.

As virtual work becomes more common for organizations, managers and team members alike would benefit from understanding that leadership traits and behaviors impact leadership perceptions differently in different virtual contexts, authors said. For example, organizations should not automatically promote individuals who have distinguished themselves as emergent leaders from a more in-person (and low virtual) context to leadership roles in a highly virtual context.

"In virtual environments, our actions speak loudly," said fellow study author Steven Charlier, a professor of management at Georgia Southern University. "The 'soft' skills that traditional managers rely on might not translate easily to a virtual environment."

Reeves agreed, noting that "a 'natural leader' who doesn't usually engage in these specific leader-like behaviors but always kind of 'has it' needs to be extra careful--because those are the types that are at the highest risk of no longer being viewed as a leader in virtual contexts."

With the "new normal" of work online, "now is the time for organizations and employees to gain virtual leadership competencies," said study lead author Radostina Purvanova of Drake University. "These are the skills of the future. Those companies that have already embraced virtuality are now reaping the benefits -- and the rest of us must catch up quickly, or else we will simply be left behind."