Culture

Scientists at Sanford Burnham Prebys have found a new way to kill pancreatic cancer cells by disrupting their pH equilibrium. The study, published in Cancer Discovery, reports how depleting an ion transport protein lowers the pH to a point that compromises pancreatic cancer cell growth.

Pancreatic cancer cells--like all cancer cells--have a constant need for energy to support their growth and expansion. To meet these energy needs, they boost metabolic pathways that normal cells don't use and, as a consequence, produce excess acid that needs to be expelled. Increasingly, scientists have focused on manipulating cancer cell pH as an approach to treat cancers lacking effective therapies.

"Our study suggests that interfering with cellular pH represents a new therapeutic avenue to treat pancreatic cancer, one of the deadliest cancers for which there is currently no effective treatment," says Cosimo Commisso, Ph.D., an assistant professor in Sanford Burnham Prebys' NCI-designated Cancer Center. "We have shown that a sodium-hydrogen exchanger called NHE7 plays a significant role in pancreatic tumors, and by suppressing it, we can promote cancer cell death."

Sodium-hydrogen exchange proteins

The NHE family of sodium-hydrogen exchangers are transport proteins that regulate the internal pH of cells and their organelles such as endosomes and the Golgi apparatus. They are located in membranes and work by exchanging hydrogen ions (H+) for sodium ions (Na+) and are essential for proper cell function.

"We hypothesized that the increased acid production that occurs in tumor cells could be harnessed as a therapeutic vulnerability, so we looked for a strategy to specifically target this," says Koen Galenkamp, Ph.D., a postdoctoral fellow in Commisso's lab and the first author of the study. "By mining a number of pancreatic cancer databases, we found that NHE7 levels were higher in tumors compared to normal pancreas, and highest in the tumors of patients with the poorest prognoses."

With this information, the research team set out to understand the role of NHE7 in pancreatic cancer cells. They found that it localizes to the Golgi where it imports hydrogen ions, creating an acidic Golgi and a corresponding alkaline cytoplasm that supports cancer cell metabolism.

"This led us to test if we could make pancreatic cells vulnerable by disabling or eliminating NHE7 to undermine the alkaline cytoplasmic pH they require to stay fit," adds Galenkamp.

Through a series of experiments in pancreatic cancer cells, the research team showed that suppressing NHE7 lowers the pH of the cell's cytoplasm, triggering cell death. Importantly, in mice transplanted with human tumors, getting rid of NHE7 caused tumors to shrink or completely stop their growth.

"Pancreatic cancer is predicted to soon become the second-leading cause of cancer-related deaths in the U.S.," says Commisso. "Given that the five-year survival rate for people newly diagnosed is less than 10%, it's crystal clear that we need better therapies--and finding new cancer targets can help us tailor treatments and possibly save the lives of many more patients."

Commisso adds, "This study illustrates the potential to target pH balance as an approach to combat pancreatic cancer. Our next step is to work with the Conrad Prebys Center for Chemical Genomics--the drug discovery facility at our Institute--to find ways to disable NHE7 and limit the Golgi's ability to sequester acid. If successful, cancer cells would be unable to maintain the proper pH that they need to grow."

A new method of evaluating and prioritising treatment for patients with suspected acute stroke, which has been used by the Stockholm health authority since 2017, has led to faster health interventions and better patient care, shows a new study from Karolinska Institutet published in the journal JAMA Neurology.

Stroke can be caused by a clot in the large arteries of the brain. For every minute that an artery is blocked, two million neurons die. Without acute intervention, only 10 percent of the patients return to normal function three months after their stroke. The most effective intervention is mechanical clot removal, or endovascular thrombectomy (EVT). The earlier the blood vessel is re-opened, the greater the number of brain cells that survive. However, there is commonly some delay before treatment, as most patients are taken by ambulance to the nearest hospital for examination, and then transferred to EVT-performing university hospitals, such as the Karolinska University Hospital in Solna.

"There has been a justification for this system, as patients who don't need EVT receive the best care at the stroke unit in their local A&E hospital," says the study's lead author Michael Mazya, consultant at Karolinska University Hospital and researcher at the Department of Clinical Neuroscience, Karolinska Institutet. "The challenge for ambulance staff has been to assess which patients may benefit from direct transport to a university hospital, and which can be taken to the nearest stroke unit as usual."

To reduce the time to EVT, a new triage system has been used in the Stockholm region since October 2017. The results have now been evaluated in a new study published in the scientific journal JAMA Neurology. In patients with suspected stroke, the triage involves two steps. First the ambulance nurse tests the degree of symptom severity using the A2L2 system (where A stands for arm, and L for leg). If the patient is unable to raise his or her arm for ten seconds and the leg for five, it generally indicates a severe stroke, which often requires EVT. The second step is a telephone call to a stroke physician, to exchange additional information and decide on the optimal destination.

"The telephone consultation allows the ambulance staff and stroke physician to discuss the preliminary diagnosis," Mazya says. "The doctor can read up on the patient's background and activate the stroke team. This really speeds up acute management and treatment decisions once the patient arrives at the hospital."

The results show that thanks to the A2L2 test and tele-consultation, 71 percent of patients in need of EVT are now taken directly to Karolinska University Hospital in Solna, as opposed to 28 percent before. The average time from stroke onset to EVT is now two hours and 15 minutes, which is 70 minutes faster than in the old system, 65 minutes faster than the Swedish national average, and a full 1 hour and 45 minutes faster than in international randomized studies of EVT.

Faster treatment delivery has resulted in 34 percent of EVT patients completely recovering their functional ability, compared with 24 percent in the old system, despite the fact that patients treated since the implementation of the new system have been older and had a higher average stroke severity.

"The results are very pleasing," says Christina Sjöstrand, senior consultant in charge of stroke care at Karolinska University Hospital and researcher at the Department of Clinical Neuroscience, Karolinska Institutet. "Much of the success is thanks to a close collaboration between key stroke professionals in all of the region's hospitals, and colleagues in pre-hospital care. We are continuing to use the new triage system throughout the Stockholm region and will be presenting more comprehensive data on patient outcomes at the World Stroke Conference in Vienna in November this year."

Joint research between Kobe University and Ushio Inc. has provided proof for the first time in the world that direct and repetitive illumination from 222nm ultraviolet radiation C (UVC), which is a powerful sterilizer, does not cause skin cancer. This suggests that 222nm UVC is also safe for human eyes and skin. This technology is expected to have a wide range of antibacterial and antiviral applications in medical facilities and daily life.

The research group consisted of members from the Division of Dermatology in the Department of Internal Related at Kobe University's Graduate School of Medicine (Professor NISHIGORI Chikako, Associate Professor KUNISADA Makoto, graduate student YAMANO Nozomi et al.) and Ushio Inc.

These research results were published online in Photochemistry & Photobiology on March 29 and Professor Nishigori is due to present this research at the 'American Society of Photobiology 2020 meeting' in Chicago on June 28.

Main Points

Provided proof for the first time in the world that 222nm ultraviolet radiation C (UVC) does not cause skin cancer.

These results indicated that UVC light is also safe for human skin and eyes.

In the animal experiments using a 222nm germicidal lamp, there were no signs of cataracts or cancer of the eyes or skin, even in mice with extreme weakness to ultraviolet radiation.

This could allow germicidal lamps to be shone directly on people's skin, enabling a wide range of antiviral and antibacterial applications in both medical fields and daily life.

Research Background

UVC emitted by the sun (with a wavelength of 280~200nm) does not reach the Earth's surface because it is absorbed by the Ozone layer. Germicide lamps that emit 254nm UVC have been developed and are utilized for sterilization because the wavelength can kill bacteria. So far these lamps are only utilized in places when people are not present because they are known to cause harmful side-effects such as skin cancer and cataracts.

The lamp used in this study has a smaller wavelength of 222nm. It is being developed in the hope that it can be utilized in the medical field. It has been shown that 222nm is comparable to 254nm, by the Division of Orthopaedic Surgery at Kobe University (Professor KURODA Ryosuke et.al.), in terms of ability to eradicate bacteria on human skin. However, if this technology is to be directly used on humans in a medical facility, it is necessary to prove that possible repeated exposure to 222nm UVC is safe and non-carcinogenic.

Research Methodology

To evaluate the safety of repeated eye and skin exposure to a 222nm germicide lamp, xeroderma pigmentosum (*2) group A model mice were used in this study. Compared to wild-type mice, these model mice have an increased sensitivity to ultraviolet radiation and an over 10,000 fold increased risk of developing skin cancer.

In the group that was exposed to UVB (280-315nm), the wavelength range equivalent to skin cancer caused by sunlight, all mice developed skin cancer and displayed adverse effects such as cataracts and cornea damage.

Conversely, mice in the 222nm germicide lamp group did not develop skin cancer at all. The effect on their eyes was investigated in cooperation with Shimane University's Department of Ophthalmology (Professor TANITO Masaki et al.). There were no abnormalities visible, even when examined under a microscope (Figure 1).

It was understood that 222nm produced no adverse effects due to the level of skin penetration. The 254nm UVC currently used in germicide lamps penetrates down to the basal cell layer, the bottommost layer of the skin, and damages the DNA of cells. On the other hand, it was shown that 222nm UVC doesn't damage the DNA of skin cells because it only travels as far as the stratum corneum, the outermost layer of the skin.

Further Research

These research results indicate that even though 222nm UVC is a powerful sterilizer, it can also be used directly on human skin. Beginning with hand sanitization in medical institutions, it is expected that this technology will have a wide range of antiviral and antibacterial applications in places that people enter, such as schools, welfare facilities, food factories, toilets and kitchens.

Washington, D.C., April 7, 2020 -- In states that have banned affirmative action, the share of underrepresented minorities among students admitted to and enrolling in public universities has steadily lost ground relative to changing demographic trends among those states' high school graduates, according to new research.

The study, by Mark Long at the University of Washington and Nicole Bateman at the Brookings Institution, was published today in Educational Evaluation and Policy Analysis, a peer-reviewed journal of the American Educational Research Association.

While prior research has looked at the immediate effects of affirmative action bans, this study evaluates the long-term changes, including the effects of admissions strategies that universities have implemented as alternatives. California, Texas, Washington, and Florida banned affirmative action in the late 1990s, and were followed later by Arizona, Georgia, Michigan, Nebraska, New Hampshire, and Oklahoma.

Long and Bateman analyzed trends in minority representation among applicants, admittees, and enrollees in 19 selected public universities in the states with affirmative action bans, from the time their bans went into effect through 2015. The researchers further evaluated a subset of those institutions that are considered flagship universities within their states and then those that are considered elite, based on their admissions criteria.

Averaging across the 19 universities studied, in the year prior to the affirmative action ban the share of underrepresented students (Black, Hispanic, and Native American students) among enrolled U.S. students was 15.7 percentage points below these students' share among high school graduates in the universities' states. However, this gap rose to 16.8 percentage points, on average, in the year immediately after the ban, and the gap increased in subsequent years to 17.9 percentage points.

Among the nine flagship universities in the study, the underrepresentation gap grew from 11.2 percentage points to 13.9 percentage points immediately after the ban and to 14.3 percentage points by 2015.

For the subset of 10 "elite" universities, the same pattern held, with the underrepresentation gap widening from 18.7 percentage points to 21.7 percentage points immediately following a ban and growing to 21.9 percent points by 2015.

Results from the study indicate that alternative policies--such as automatic admission for a certain top percentage of students from each high school (which leverages de facto racial and ethnic segregation of high schools), inclusion of socioeconomic factors in admission decisions, increased outreach and financial support for low-income students, and the elimination of admission preference for the children of alumni--have not been able to fully replace raced-based affirmative action.

"While the share of underrepresented minorities among enrolling undergraduate students has increased since the implementation of alternative policies, this growth is slower than the growth of underrepresented minorities in high schools," said Long, a professor of public policy and governance at the University of Washington. "When the changing demographics of state high schools are considered, the underrepresentation of Black, Hispanic, and Native American youth in the higher education system is worsening, not improving."

"Alternative policies and administrative decisions have, so far, been unable to fully replace race-based affirmative action," Long said.

The researchers note that improvement in many of the underlying conditions that generate underrepresentation in colleges--such as differences in household income, test scores, and incarceration rates--has occurred, but at a slow pace.

"The very slow rate of progress in these underlying conditions is surprising and concerning," Long said. "For example, if the past 20 years is a guide for future progress, it will take over a thousand years for the Black-White gap in median household income to close. It's clear that university leaders and state policymakers cannot rely on improvements in the underlying conditions to solve underrepresentation in higher education for many decades to come."

"University administrators need to rigorously evaluate their policies and be mindful of practices that show promise," said Long. "They should be challenged to do more and do better."

"But we should also recognize that many of the underlying conditions are outside of the control of these administrators," Long added. "If we expect flagship public universities to reflect the racial and ethnic diversity of their states, then policymakers must work harder and better to alleviate these pre-college disparities and improve college readiness for underrepresented students."

A team of international scientists has developed a suite of more than 200 new genetic techniques for using marine microbes to investigate a host of questions in biology. Published in Nature Methods, the new tools are an essential step forward in understanding the cellular instructions that underpin microbial life in the sea.

The vast resource created by the team comprises a major compilation of new techniques for performing genetic experiments on marine microbes. A persistent bottleneck in microbial oceanography is the lack of experimental model systems - well-studied organisms that can be genetically manipulated to reveal gene functions, as well as clarify how microbes contribute to ecosystem processes.

"There is an incredible diversity of microbes that we've never had the tools to truly explore, and it represents an untapped resource of knowledge and biotechnology potential," said José Antonio Fernández Robledo, a senior research scientist at Bigelow Laboratory for Ocean Sciences and one of the lead authors of the paper. "This project catalyzed development of the genetic tools that we need to interrogate these organisms, and it has opened the door for engineering them to provide new products for the biomedical and food supplement industry."

Funded by the Gordon and Betty Moore Foundation, the initiative supported development of genetic tools for a group of microbes called protists. These microscopic, single-celled organisms are among the most diverse yet least understood marine microbes. The tools created by Fernández Robledo and his coauthors set the stage for other researchers to develop protists as experimental model systems that can revealing the inner workings of the ocean and microbial life.

Fernández Robledo used advanced molecular techniques to develop a new approach to studying Crypthecodinium, a microalgae that produces a beneficial fatty acid used as food supplement. He developed a technique to insert DNA into the organism. This is the first essential step toward identifying the roles of individual Crypthecodinium genes, and ultimately being able to ask specific questions of its genome.

Fernández Robledo obtained Crypthecodinium samples from the National Center for Marine Algae and Microbiota at Bigelow Laboratory, and he was assisted by an undergraduate from Colby College as well as a master's student with this research. The protocols the team established, as well as all others described in the paper, are freely available online to help other scientists benefit from this effort.

"The process of tool development inherently includes failures as well as successes, and the challenge to secure funding for this type of work has previously restricted scientists from making progress in this area," Fernández Robledo said. "The Moore Foundation deserves a lot of credit for recognizing that the most interesting science happens at new frontiers, and that all results are valuable and sharing them helps to move the field forward."

In addition to Fernández Robledo, several other research teams succeeded in introducing DNA into marine protists. They are now working to employ genetic techniques such as CRISPR/Cas9 to interrogate these microbial genomes, a critical step that will allow scientists to identify the functions of specific genes and potentially harness them to develop beneficial applications.

The Nature Methods paper brings together 113 coauthors from 53 institutions across 14 countries, and it offers a wealth of methods for conducting genetic research in marine protists. The project efforts were accelerated by active communication and collaboration among the researchers, who have shared their protocols in a dedicated community group called Protist Research to Optimize Tools in Genetics (PROT-G) on the protocol-hosting website protocols.io.

"This paper is a landmark achievement after several years of hard work to solve numerous technical challenges in the laboratory," said Adam Jones, program officer at the Gordon and Betty Moore Foundation. "We look forward to seeing how the protocols and guidance offered by the scientists in this newly available resource accelerate genetic tool development in marine protists."

As COVID-19 spreads across the globe, a common question is, can infectious diseases be connected to environmental change? Yes, indicates a study published today from the University of California, Davis' One Health Institute.

Exploitation of wildlife by humans through hunting, trade, habitat degradation and urbanization facilitates close contact between wildlife and humans, which increases the risk of virus spillover, found a study published in the journal Proceedings of the Royal Society B. Many of these same activities also drive wildlife population declines and the risk of extinction.

The study provides new evidence for assessing spillover risk in animal species and highlights how the processes that create wildlife population declines also enable the transmission of animal viruses to humans.

"Spillover of viruses from animals is a direct result of our actions involving wildlife and their habitat," said lead author Christine Kreuder Johnson, project director of USAID PREDICT and director of the EpiCenter for Disease Dynamics at the One Health Institute, a program of the UC Davis School of Veterinary Medicine. "The consequence is they're sharing their viruses with us. These actions simultaneously threaten species survival and increase the risk of spillover. In an unfortunate convergence of many factors, this brings about the kind of mess we're in now."

THE COMMON AND THE RARE

For the study, the scientists assembled a large dataset of the 142 known viruses that spill over from animals to humans and the species that have been implicated as potential hosts. Using the IUCN Red List of Threatened Species, they examined patterns in those species' abundance, extinction risks and underlying causes for species declines.

The data show clear trends in spillover risk that highlight how people have interacted with animals throughout history.

Among the findings:

Domesticated animals, including livestock, have shared the highest number of viruses with humans, with eight times more zoonotic viruses compared to wild mammalian species. This is likely a result of our frequent close interactions with these species for centuries.

Wild animals that have increased in abundance and adapted well to human-dominated environments also share more viruses with people. These include some rodent, bat and primate species that live among people, near our homes, and around our farms and crops, making them high-risk for ongoing transmission of viruses to people.

At the other end of the spectrum are threatened and endangered species. These are animals whose population declines were connected to hunting, wildlife trade and decreases in habitat quality. These species were predicted to host twice as many zoonotic viruses compared to threatened species that had populations decreasing for other reasons.

Threatened and endangered species also tend to be highly managed and directly monitored by humans trying to bring about their population recovery, which also puts them into greater contact with people. Bats repeatedly have been implicated as a source of "high consequence" pathogens, including SARS, Nipah virus, Marburg virus and ebolaviruses, the study notes.

"We need to be really attentive to how we interact with wildlife and the activities that bring humans and wildlife together," Johnson said. "We obviously don't want pandemics of this scale. We need to find ways to co-exist safely with wildlife, as they have no shortages of viruses to give us."

GAINESVILLE, Fla. --- The bright chirp of the coquí frog, the national symbol of Puerto Rico, has likely resounded through Caribbean forests for at least 29 million years.

A new study published in Biology Letters describes a fragmented arm bone from a frog in the genus Eleutherodactylus, also known as rain frogs or coquís. The fossil is the oldest record of frogs in the Caribbean and, fittingly, was discovered on the island where coquís are most beloved.

"It's a national treasure," said David Blackburn, Florida Museum curator of herpetology and the study's lead author. "Not only is this the oldest evidence for a frog in the Caribbean, it also happens to be one of the frogs that are the pride of Puerto Rico and related to the large family Eleutherodactylidae, which includes Florida's invasive greenhouse frogs."

Jorge Velez-Juarbe, associate curator of marine mammals at the Natural History Museum of Los Angeles County, found the fossil on a river outcrop in the municipality of San Sebastian in northwestern Puerto Rico. Velez-Juarbe and his collaborators' previous collecting efforts at the site uncovered fossil seeds, sea cows, side-necked turtles and the oldest remains of gharials and rodents in the Caribbean, dating to the early Oligocene Epoch, about 29 million years ago.

Still, "there have been many visits from which I have come out empty-handed over the last 14 years," he said. "I've always kept my expectations not too high for this series of outcrops."

On this trip in 2012, he combed the deposits for half a day without much luck when a small bone, partially exposed in the sediment, caught his eye. He examined it with his hand lens.

"At the moment, I couldn't wrap my mind as to what it was," Velez-Juarbe said. "Then once I got back home, cleaned around it with a needle to see it better and checked some references, I knew I had found the oldest frog in the Caribbean."

The ancient coquí displaces an amber frog fossil discovered in the Dominican Republic in 1987 for the title of oldest Caribbean frog. While the amber fossil was originally estimated to be 40 million years old, scientists now date Dominican amber to about 20 million to 15 million years ago, Blackburn said.

Based on genetic data and family trees, scientists had hypothesized rain frogs lived in the Caribbean during the Oligocene, but lacked any fossil evidence. The small, lightweight bones of frogs often do not preserve well, especially when combined with the hot, humid climate of the tropics.

Matching a single bone fragment to a genus or species "is not always an easy process," Velez-Juarbe said. It can also depend on finding the right expert. His quest for help identifying the fossil turned up empty until a 2017 visit to the Florida Museum where he had once been a postdoctoral researcher.

"I got to talk with Dave about projects, and the rest is now history," he said.

Possibly first arriving in the Caribbean by rafting from South America, frogs in the genus Eleutherodactylus, which encompasses some 200 species, dominate the region today.

"This is the most diverse group by two orders of magnitude in the Caribbean," Blackburn said. "They've diversified into all these different specialists with various forms and body sizes. Several invasive species also happen to be from this genus. All this raises the question of how they got to be this way."

One partial arm bone may not tell the whole story of coquí evolution - but it's a start.

"I am thrilled that, little by little, we are learning about the wildlife that lived in Puerto Rico 29-27 million years ago," Velez-Juarbe said. "Finds like this help us unravel the origins of the animals we see in the Caribbean today."

Italy was the main origin of the individuals who first brought the novel coronavirus to Brazil, according to a study by Brazilian researchers in collaboration with colleagues in the United Kingdom, Canada and the United States.

The COVID-19 pandemic arrived in Brazil between February and early March.

"In contrast with China and other countries, where the outbreak began slowly with a small number of cases, it was started in Brazil by more than 300 people, most of whom came from Italy. The virus spread very quickly as a result," said Ester Sabino, one of the authors of the study. Sabino is a professor at the University of São Paulo's Medical School (FM-USP) and headed the university's Institute of Tropical Medicine (IMT-USP) between 2015 and 2019.

Most of these people came from Italy to São Paulo City, where the first cases of the disease in Brazil were notified, but some went to other destinations, including Rio de Janeiro, Porto Alegre, Salvador, Curitiba, Belo Horizonte, Fortaleza, Recife, Vitória and Florianópolis, contributing to the nationwide spread of the disease.

The study was supported by São Paulo Research Foundation - FAPESP under the aegis of the Brazil-UK Center for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE). The results are reported in an article published in the Journal of Travel Medicine.

The researchers estimated that 54.8% of all cases of COVID-19 imported into Brazil by March 5 derived from people infected in Italy, followed by passengers who flew in from China (9.3%) and France (8.3%).

They also estimated that 24.9% of all infected people flying to Brazil during the period traveled from Italy to São Paulo, and that Italy was the start of five of the ten main routes for infected travelers coming to Brazil (via China, France, Switzerland, South Korea and Spain).

To identify the main routes for the importation of COVID-19 to Brazil, the researchers analyzed February-March 2020 data for passengers traveling to any Brazilian airport from 29 countries with confirmed cases of the disease.

They estimated the proportion of infected travelers potentially arriving in Brazilian cities from each country and for each route based on the total number of passengers flying to any Brazilian airport during the period, country populations and the number of cases notified by these countries as of March 5, 2020.

The estimates were corroborated by the Brazilian Ministry of Health's official data on notified cases, showing that 14 of the first 29 patients diagnosed with COVID-19 in Brazil had just been to Italy. Six of them (23.1%) were notified in São Paulo.

"It was very clear that São Paulo would be the epicenter of the epidemic in Brazil because it was the final destination for the largest number of infected people coming mainly from Italy," Sabino said.

Focus on internal mobility

According to Sabino, who led the genome sequencing of the coronaviruses isolated from the first two confirmed cases of COVID-19 in Brazil, sustained community transmission of the disease now prevails and the authorities should focus on restricting internal mobility in order to contain the epidemic.

This means restricting the mobility of the inhabitants of São Paulo, where most of the confirmed cases in Brazil have been notified.

"São Paulo and to a lesser extent Rio de Janeiro will be the hubs from which the virus spreads to the rest of the country, so people should be prevented from leaving these two cities," she said.

Continuation of sequencing

The researchers led by Sabino continue to sequence SARS-CoV-2 isolated from Brazilians diagnosed with COVID-19. At one point they had to stop because some of their members were thought to have been infected.

"We had to shut down the lab, but we're back now and will analyze whether we can sequence a larger number of viral genomes," Sabino said.

The speed with which the disease spread around Brazil has disrupted the group's plans. "Transmission of the virus is proceeding so fast that the sequencing data can't help us understand how the epidemic is spreading as we planned," Sabino said.

The researchers expected to be able to sequence viruses as sporadic cases of the disease were notified in order to keep track of the transmission trajectory and contribute to the design of a containment strategy, but the number of cases arriving at the lab simultaneously turned out to be too high.

"It won't be possible to control the epidemic with sequencing alone. It's spreading very fast, and we can no longer track all the cases," Sabino said.

The number of genomes sequenced worldwide from infected patients has almost reached 800. These sequences are being made public, and can be used for research on primary resistance to help develop promising antiviral drugs against the virus, Sabino explained.

"When a candidate drug is found, a database of viral genome sequences will certainly be useful for this purpose," she said.

WASHINGTON, April 7, 2020 -- In recent years, chaos theory and other forms of computational modeling have sought to leverage findings in the social sciences to better describe -- and maybe one day predict -- how groups of people behave. One approach looks to update a widely used model to examine how changes in political opinions ripple through a group and how polarization can arise.

In this week's Chaos, from AIP Publishing, researchers at the University of Edinburgh and the University of Central Florida use a theoretical model for how political opinions evolve in a population to examine what effect those with more extreme views have on making the entire system more polarized. The group's network-based model extends a popular approach for studying opinion dynamics, called the Cobb model, and is based on the hypothesis that those with opinions farther from the middle of a political spectrum are also less influenced by others, a trait known to social scientists as "rigidity of the extreme."

"We have laws to understand gravity or chemical kinetics, but people don't always behave rationally, and the laws are much more difficult to pin down," said author Desmond Higham. "So, it's a fascinating but somewhat slippery area to try to work in. Anything that adds to our understanding with a simple model that captures behavior is worth pursuing."

In the simplest version of the model, members of a society are arranged in a line, each of whom can sway the two on either side of them. Each simulated person is assigned a starting number between 0 and 1 that describes how strongly they initially aligned to either end of a hypothetical political spectrum.

"These kinds of effects occur in patches in society and can be difficult to identify," said author Alexander Mantzaris. "They can evolve in segments that grow over time."

The simulations produced periods of what the researchers called bistability, where most members of a simulated society chose two extreme, competing opinions. In simulations that randomly connected individuals, the pair found the potential for taking extreme sides happened more rapidly.

The researchers believe their work can help inform other work on networks outside of political opinion, such as understanding how wealth affects handling finances, how international policymakers influence each other and even how we affect each other's music tastes.

They hope to expand the model by using new types of connectivity structures and to apply real-world data.

WASHINGTON, April 7, 2020 -- Bottle emptying is a phenomenon most of us have observed while pouring a beverage. Researchers from the Indian Institute of Technology Roorkee discovered how to make bottles empty faster, which has wide-ranging implications for many areas beyond the beverage industry.

Bubbles have been studied extensively for centuries, including early efforts by Leonardo da Vinci who famously noted the sinusoidal rise of bubbles within a pool. The growth dynamics of bubbles at the mouth of a bottle depend on the thermophysical properties of the fluid, the bottle geometry and its angle of inclination. These inextricably intertwined parameters have made bottle-emptying dynamics the next frontier for bubble physicists.

In this week's Physics of Fluids, from AIP Publishing, Lokesh Rohilla and Arup Kumar Das explore this bottle-emptying phenomenon from the perspective of bubble dynamics on a commercial bottle by using high-speed photography. Image analysis allowed them to conceptualize various parameters, such as liquid film thickness, bubble aspect ratio, rise velocity and bottle emptying modes.

"Bubble dynamics inside the bottle are too complex to study, so we divided the bubble interfacial growth into different stages to comprehend them," said Rohilla.

It's well known that a bottle's emptying time is faster if you increase its angle of inclination. This increases what's known as bubble pinch off frequency, and the relative increment depends upon the thermophysical properties of the fluid.

"Our experiments suggest there is a critical angle of inclination, after which any further increase in the inclination of the bottle won't lead to further reduction in the bottle emptying time," said Rohilla. "This occurs due to the saturation of the voidage, space occupied by air within liquid surrounding, at the bottle's mouth with the angle of inclination."

Two distinct bottle-emptying modes were identified. In one mode, the discharge rate is increased due to a high frequency pinch off of air bubbles inside the bottle. In the other mode, it is caused by an increase in volume of the pinched-off bubble at a comparatively lower frequency.

"We've also observed an encapsulated bubble while discharging fluid in a vertically upended bottle," Rohilla said. "Encapsulated bubbles have pinch off sites outside the bottle mouth, contrary to intuition. The presence of a violent ejector jet within inviscid fluids, in which liquid becomes thin due to almost no internal friction, and its complete absence within viscous fluids control the periodicity of the bubbles."

This work proves that bottle geometry and thermophysical properties play a role in reducing the time it takes for a bottle empty.

"We can manipulate the bottle discharge pattern by manipulating bottle geometry," said Das. "An intuitive product-specific bottle design will enable better control of its discharge rate."

The beverage industry and chemical plants are among the applications that will benefit from this better understanding of bottle geometry.

Creating new blood vessels, a process called angiogenesis, for tumors in lymph nodes is different than for tumors in other parts of the body, such as the colon or lung, a team from the Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC) reports in the journal Cancer Research. Scientists from the MDC labs of Dr. Armin Rehm, Dr. Uta Höpken and Professor Holger Gerhardt were involved in this project. The team identifies potentially more effective treatment targets to slow tumor growth for lymphoma patients.

Lymphoma is cancer of the lymphatic system, which includes the lymph nodes, spleen and bone marrow. Lymphoma patients with indicators of increased blood vessel development usually have lower chances of survival. They also don't respond well to treatments that have successfully inhibited blood vessel development in other cancer types.

"We hypothesized that tumors in lymph nodes are completely different from solid tumors because the lymph nodes provide such a supportive microenvironment for blood borne tumor cells," said Dr. Uta Höpken, who heads MDC's Microenvironmental Regulation in Autoimmunity and Cancer Lab. Still, it was "absolutely surprising that none of the usual suspects were involved," said Dr. Armin Rehm, who leads MDC's Translational Tumorimmunology Lab.

Eliminating suspects

Blood vessels in early lymphoma are unusually dense and irregular, with a lot more branching than observed in blood vessels of healthy lymph nodes. The pattern of branching has not been observed in solid tumors, in infected lymph nodes or in developing organs, which are typically other sites of neo-angiogenesis.

To uncover the unique signaling pathways that drive this development, the team ran analyses using transgenic mouse models that develop lymphoma, as well as mice implanted with lymphoma cancer cells. They looked at gene expression patterns to see which genes and proteins are most active in the initial phases of tumor development.

Culprits usually implicated in tumor angiogenesis - inflammation, low oxygen levels, and signaling between the base and tip of blood vessels, called Notch signaling - did not show up in the results.

Successful blocks

A group of proteins, called vascular endothelial growth factor (VEGF), are considered primary drivers of normal blood vessel development, as well as angiogenesis in tumors. In most solid mass tumors, VEGF-A is the protein mediating the process, in conjunction with its receptor, called VEGFR-2.

In the early stages of lymphoma, the team discovered VEGF-C is the most active protein. When they tried to block receptor VEGFR-2 to inhibit VEGF-C activity, nothing changed.

But when the researchers blocked a different receptor, VEGFR-3, blood vessel growth was significantly slowed. They also interrupted a receptor for a small protein called lymphotoxin, which is usually needed for normal lymph node development, also helped slow angiogenesis.

The team used two drugs that are already approved for clinical use in autoimmune disorders to inhibit the pathways. They confirmed the treatment also worked on human cells. While not clinicians themselves, the researchers hope the treatment can be taken up for clinical trials to investigate its effectiveness in human patients. "If a few cancer cells survive chemotherapy, it might be possible to prevent relapse by addressing these pathways with immunotherapy," Rehm said.

Watching from the start

A key feature of this study was the timing. The researchers traced angiogenesis in the first twelve days after cancer cells invaded lymph nodes. This gave them a unique opportunity to observe the early "crosstalk" or interaction between tumor cells and the lymph node microenvironment. Only five to ten per cent of lymph node cells were cancerous, and already the lymph node was being restructured. "The changes we saw occur very early and with a very low tumor burden," Höpken said.

Imaging these early changes in high-resolution presented a challenge that required a great deal of diligence. "Lymphoma cells are widely distributed cells within the highly compartmentalized lymph node," said Lutz Menzel, co-first author and post doc in the Translational Tumorimmunology Lab. "Finding lymphoma-induced remodeling of the stroma, when other areas of the lymph node remained unaffected, quite often became a search for a 'needle in the haystack' under the microscope."

The team underscored the importance of animals for this work. Such a study is not possible with human patients, because they are not yet showing symptoms. "Animals provide the advantage to see what is going on at the beginning of disease, rather than the end," Rehm said. "Organoids are simply not far enough developed to mimic the interaction between many different cell types in complex lymph node tissue."

The group plans to continue investigating the relationships between tumor cells and the lymph node microenvironment, and see if single-cell sequencing can reveal even more about the angiogenesis process.

Our brain is steadily engaged in soliloquies. These internal communications are usually also bombarded with external sensory events. Hence, the impact of the two neuronal processes need to be permanently fine-tuned to avoid their imbalance. A team of scientists at the Ruhr-Universität Bochum (RUB) revealed the role of the neurotransmitter Serotonin in this scenario. They discovered that distinct serotonergic receptor types control the gain of both streams of information in a separable manner. Their finding may facilitate new concepts of diagnosis and therapy of neuronal disorders related to malfunction of the serotonin system. The study is published online in the open access journal eLife on 7. April 2020.

Impacting on different streams of information in the brain

„The following everyday life example may sketch the task that the brain needs to solve", explains Dr. Dirk Jancke, Head of the Optical Imaging Group at the Institute of Neural Computation: „Imagine sitting with your family at dinner, a heated debate is going on how to properly organise some internal affairs. Suddenly the phone starts ringing; you are picking up while family discussion goes on. In order to understand the calling party correctly, the crowd in the back must speak lower or the caller needs to speak up. Thus, the loudness of each internal background conversation and external call need to be properly adjusted to ensure non-interfered - that means separable - information transfer." As in this anecdote, comparable brain processes involve serotonin.

Serotonin is a neurotransmitter of the central nervous system, in common parlance called „Happy hormone" because it contributes to changes in brain state and is often associated with effects on mood. The study of the RUB team now demonstrates that serotonin participates also in the scaling of current sensory input and ongoing brain signals.

Controlling neuronal release of serotonin with light

The RUB neuroscientists discovered the underlying mechanisms in experiments that investigated cortical processing of visual information. For their study, they used genetically modified mice in which the release of serotonin could be controlled by light. This mouse line was developed by the group of Professor Stefan Herlitze, Department of General Zoology and Neurobiology, to enable specific activation of serotonergic neurons by an implanted light fiber.

Combining this technique with optical imaging, the RUB team found that increasing levels of serotonin in the visual brain leads to concurrent suppression of ongoing activity and activity evoked by visual stimuli. Two types of receptors played a distinct major role here. "This was surprising to us, because both receptors are not only co-expressed in specific neurons but also widely distributed across different cell types in the brain", says Zohre Azimi, first author of the study. Separable action of these receptors allows distinct modulations of information carrying internal brain communication and evoked sensory signals. Low serotonin levels, as they typically occur during sleep at night, favor internal brain communication, and thus, may promote important functions of dreaming. "Dysfunction in the interplay of these receptors, on the other hand, harbor the risk of an overemphasis of either internally or externally driven information channels", says Jancke. For example, irregular 5-HT receptor distributions caused by genetic predisposition may become manifest in an imbalanced perception of inner and outside world, similar as seen in clinical pictures of depression and autism.

Facilitating understanding of serotonin effects

The scientists hope that their findings contribute to a better understanding of how serotonin affects fundamental brain processes. In turn, their study may trigger future research in developing receptor-specific drugs that benefit patients with serotonin-related psychiatric diseases.

The protein STING (Stimulator of Interferon Genes) is a critical component of the body's innate immune defence system, but can also contribute to chronic autoimmune and autoinflammatory diseases.

Monash Biomedicine Discovery Institute (BDI) researchers led by Dr Dominic De Nardo have discovered the mechanism behind one of two signalling arms involved in the cGAS-STING pathway. Their findings, published in Cell Reports today are important for the field and have significant implications for therapeutic targeting of this pathway.

Beyond being a major component of the host innate immune response to viral infection, the cGAS-STING pathway has also been implicated as a key player in a number of cellular and disease processes, including autoimmune disease (e.g. Aicardi-Goutières syndrome and forms of lupus), autoinflammatory conditions, neurodegenerative disorders and cancer.

It is being exploited in cancer immunotherapies, with research in preclinical models showing that STING activation primes the host's immune system to kill cancer cells.

Once activated, the cGAS-STING pathway has two major outcomes. One is the well-defined type I interferon (IFN) response, which helps combat viruses. The second outcome is a cytokine response, mediated by NF-kappaB, which is important for generating the inflammatory response that counteracts infection and helps the body get back to homeostasis.

"But no-one really knew exactly how these cytokines were being made," Dr De Nardo said.

Dr De Nardo, Group Leader in the Department of Anatomy and Developmental Biology, became curious after reading research papers on the STING interferon response that only briefly mentioned the cytokine response in "throwaway lines".

"As someone who very much likes to understand mechanisms thoroughly, I thought the work in the literature hadn't gone far enough," he said.

"It was an interesting 'unknown'; we thought we should fill in this knowledge gap".

The two signalling arms of the cGAS-STING pathway were thought to be mediated by a single upstream kinase, TANK binding kinase (TBK1). Using a new approach to knockout TBK1 from preclinical models, the researchers demonstrated that TBK1 was essential for the interferon response - consistent with what was known. However, they found that the absence of TBK1 did not affect cytokine production, which was still robust.

They then discovered that a closely related TBK1 homologue, I-kappa-B kinase epsilon (IKK-epsilon), when knocked out, also had no effect on cytokine production. However, knocking out both TBK1 and IKK-epsilon together resulted in the loss of both the interferon and the cytokine response.

"That basically told us that the mechanism that drives the second cytokine pathway depends on both proteins, but that they act redundantly - if one's missing the other one does the job," Dr De Nardo said.

"That was why other researchers hadn't worked this pathway out yet; they didn't delve as deeply as we did," he said.

"We basically described a new model for this pathway, which is exciting."

"What we've done is redefine the pathway that leads to cytokine production downstream of cGAS-STING," Dr De Nardo said.

"It's also significant from the perspective of treating people who might have diseases related to this protein."

The researchers are now examining the mechanisms involved in greater detail.

Dr De Nardo's PhD student, Katherine Balka, is first author on the paper.

"It has been really exciting to unravel some of the details surrounding STING signalling and I look forward to continue to expand on these findings," Ms Balka said.

Professor Benjamin Kile, Executive Dean of the Faculty of Health and Medical Sciences at the University of Adelaide, and Associate Professor Seth Masters from the Walter and Eliza Hall Institute of Medical Research were other senior authors who contributed to the study.

A pair of chemicals used by wallflowers and their kin to ward off predators have evolved to complement each other, with one targeting generalist herbivores and the other targeting specialised herbivores that have become resistant to the generalist defence.

Plants are engaged in an ongoing arms race with the creatures that eat them. They evolve defences to deter plant eaters, while their herbivores evolve counter-defences. The new study, published today in eLife, reveals details of the evolutionary chemical arms race in the wallflower genus Erysimum, a group of flowering plants in the mustard family Brassicaceae.

The first line of defence in all Brassicaceae plants are chemicals called glucosinolates, which are activated when predatory creatures nibble on the plants. More recently, wallflowers have developed a second line of defence by producing chemicals called cardenolides to deter plant-eating creatures that evolved defences to glucosinolates.

"Studying how these two defences evolved in this large genus can help scientists understand the trade-offs that the plants face as they try to defend themselves against multiple enemies," explains lead author Tobias Züst, PhD, Research Associate at the Institute of Plant Sciences, University of Bern, Switzerland.

To do this, Züst and his team sequenced the genome of the wormseed wallflower, a short-lived wild mustard. They next created a detailed family tree for this plant and 47 other wallflower species and compared the diversity and abundance of glucosinolates and cardenolides across these species. They found that the two defences varied independently of each other, and that closely related, geographically co-occurring species shared similar cardenolide traits, but not glucosinolate traits. This is likely a result of separate selective pressures acting on each defence.

"Even though most species co-expressed two different types of potentially costly chemical defences, there was no evidence of a trade-off between glucosinolates and cardenolides," Züst says. "Instead, these two types of chemicals appear to complement each other and do not serve redundant functions."

Züst adds that the emergence of cardenolides corresponds with an explosion in the number of wallflower species, which suggests this second complementary defence may have allowed these plants to succeed and diversify into new habitats.

"Further analysis of the wormseed wallflower genome will be needed to help scientists identify glucosinolate and cardenolide-producing genes in this species, as well as aid our understanding of the function of these chemicals in the evolution of Brassicaceae defences," concludes senior author Georg Jander, Professor at the Boyce Thompson Institute in Ithaca, New York, US.

Key Takeaways:

Researchers identify critical factors at each of three phases of crowdfunding: "friend funding", "getting crowded", and "races to the goal" and the characteristics of crowdfunders contributing to the successful fund raising.

Based on this understanding, fundraisers can maximize both the likelihood of successful fund raising and the amount of capital raised by optimizing fundraising goals, and crowdfunding platforms can optimize their targeting strategies in promotional campaigns and better predict which projects are likely to be successful.

CATONSVILLE, MD, April 6, 2020 - While the concept of crowdfunding is still in its early phases of development, a group of marketing researchers have conducted a study that reveals the most powerful drivers behind effective crowdfunding campaigns. According to the researchers, there are three primary mechanisms that serve as the major drivers of crowdfunding campaigns that yield results.

Crowdfunding is the process of raising capital from a crowd of investors through an online platform in order to produce new products or offer new services. Once a crowdfunding fundraising project reaches its goal, investors begin to receive returns on their investments.

In recent years, crowdfunding has been heralded as an untapped and vast new opportunity for entrepreneurs and start-ups who may have had challenges in obtaining funding from more traditional sources.

It's commonly understood in business fundraising that there are three phases: a "friend-funding" phase, where most funds are contributed by friends and family of the founders; a second phase known as the "getting crowded phase," where the process starts to build momentum beyond friends and family; and the "race to the goal phase," where the process gains momentum until the goal is achieved.

This study looked at this process and identified challenges and opportunities at each crowdfunding phase.

The research study, to be published in the INFORMS journal Marketing Science, is titled "Modeling Dynamics in Crowdfunding." It is authored by Chul Kim of the City University of New York; P.K. Kannan and Michael Trusov of the University of Maryland; and Andrea Ordanini of Bocconi University in Milan, Italy.

"In our research, we suggest three major drivers that lead to the dynamics in crowdfunding process: investors' forward-looking strategic behavior, social interactions among individual investors, and their expectations on the crowd's behavior" said Kim. "We found strong evidence for all three mechanisms and confirmed how they contribute to the dynamic patterns of crowdfunding".

"In the early stage (like the "friend-funding" phase), an individual crowdfunder expects that her investment will encourage other crowdfunders' participation. It can be a strong incentive for her to participate even at the early stage," said Kannan.

"In the middle stage where most of crowdfunding projects are likely to stagnate, it is very important to ignite the crowding process through social interactions among crowdfunders for successful goal completion," said Ordanini. "In the end, once the crowdfunding project gains momentum, investors sitting on the sides waiting for the opportunistic moment will jump in and follow."

"Based on these understandings on the crowdfunding dynamics, we identified for fundraisers the optimal goals that ensure intended results while raising the maximum capital," said Trusov. "For the crowdfunding platforms, we arrived at ways to optimize targeting of the right investors, identifying those crowdfunders who have the potential to contribute the most to the program's success. And, we have found ways to more accurately predict whether a crowdfunding campaign will succeed, and when it will succeed by observing early investment patterns."