Physicians at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis have been awarded a six-year, $7.8 million grant from the National Cancer Institute (NCI) to play a leading role in designing, conducting and enrolling patients in clinical trials through the NCI’s National Clinical Trials Network.

The funding acknowledges Siteman’s continued role as a Lead Academic Participating Site in the National Clinical Trials Network (NCTN). This designation recognizes Siteman’s ability to enroll large numbers of patients in NCI network trials and its scientific leadership in designing and carrying out cancer clinical trials.

Across the United States and Canada, about 20,000 patients are enrolled annually in NCTN trials, including hundreds at Siteman. The network is made up of four collaborative groups that conduct cancer clinical trials in adults, one group that conducts cancer clinical trials in children and a Canadian group. The network integrates and streamlines the development of cancer clinical trials. By collaborating, the network groups can enroll significant numbers of patients in trials, even for rare cancers, and share resources, which reduces the costs of conducting trials.

With the new funding, Siteman will be one of 32 U.S. institutions – most of them NCI-designated cancer centers – to be named a Lead Academic Participating Site in the NCI trials network, and the only such site in Missouri, Kansas and southern Illinois. Siteman was first selected as an inaugural lead academic site in 2014, when NCI reorganized its clinical trials network.

“Siteman Cancer Center has a strong reputation – regionally and nationally – for cancer clinical trials,” said lead investigator and Washington University medical oncologist Nancy Bartlett, MD, who specializes in treating blood cancers. “As a Lead Academic Participating Site, Washington University physicians will have a leadership role in designing and conducting innovative clinical trials that will help shape the future of cancer care. For patients, this means Siteman offers access to National Clinical Trials Network trials led by Siteman and other leading cancer centers across the U.S. and Canada.”

In addition to Bartlett, the Komen Professor of Medical Oncology in Medicine, co-lead investigators on the grant include Washington University thoracic oncologist Benjamin D. Kozower, MD, a professor of surgery; gynecologic oncologist David G. Mutch, MD, the Ira C. and Judith Gall Professor of Obstetrics and Gynecology; radiation oncologist Clifford G. Robinson, MD, an associate professor of radiation oncology; and radiologist Barry A. Siegel, MD, a professor of radiology.

The new funding also is designed to help speed the pace of research as promising findings move from the laboratory into clinical trials. The trials offered through the network are typically late-phase trials that address critical questions related to the diagnosis or treatment of cancer and require the enrollment of patients from multiple sites. The results of such trials often are published in high-impact journals, helping to set the standard of cancer care across North America and around the world.

Among the trials now underway through the network are those evaluating immunotherapies for a variety of cancer types, molecular approaches to diagnosing and treating cancer, and innovative therapies aimed at treating rare cancers.

“Our role in the NCTN gives our researchers and patients access to clinical trials that are on the forefront of cancer research,” Bartlett added. “Through the network’s cooperative groups, Washington University researchers at Siteman attend twice-yearly meetings of specialized cancer experts from across the country to brainstorm about how best to utilize the NCTN to conduct trials that reflect the needs of our patients and are designed to answer potentially practice-changing questions. We have a number of researchers engaged in nearly every disease site committee in the NCTN, taking ideas to the meetings to suggest new clinical trials and important correlative studies.”

This means more trials available for Siteman researchers to enroll their patients in, which is critical in this age of more personalized medicine and specialized treatments; a broader menu of trials makes it more likely there will be one to fit the special circumstances of individual patients, Bartlett added.

Siteman – an NCI-designated Comprehensive Cancer Center – is part of Barnes-Jewish Hospital and Washington University School of Medicine. While its main location is on the Washington University Medical Campus, the center also has five satellite locations across the St. Louis region. Cancer clinical trials are offered at all Siteman locations.

Learn more by visiting Siteman’s Find a Clinical Trial website.

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Medicare Part D is a rock star in the policy world. The prescription drug plan is considered a role model for publicly financed, privately provided social insurance programs.

The idea: Leverage competition to provide high-quality services at low costs to consumers and to the government. Doing so requires the government to subsidize costs. Yet how efficient is Part D’s design for setting those subsidies?

In a new study, Stephen P. Ryan, professor of economics at Washington University in St. Louis’ Olin Business School, and co-researchers discovered something they say surprised them: Part D’s setup actually inhibits insurers from seeking higher subsidies from the government. It keeps subsidies in check by virtue of the way it’s designed, although that may have been a happy accident.

More on that in a bit.

The researchers report their findings in “Subsidy design in privately-provided social insurance: Lessons from Medicare Part D,” forthcoming in the Journal of Political Economy.

They first set out to understand how the market works.

“What is the interaction between the rules of the subsidy mechanism, insurer behavior and consumer demand?” Ryan asked. “That’s basically the triangle that we were interested in.”

If people enrolled in Medicare decide they want coverage for prescription costs excluded from their plan, they can buy a policy under Part D. Or they can opt out of traditional Medicare and switch to a private Medicare Advantage (MA) plan for bundled coverage — including prescriptions. MA plans are privately run, publicly financed alternatives to government-run Medicare.

The government launched Part D in 2006. Medicare contracts with private firms to sell the coverage, and it regulates and subsidizes those firms. To get the coverage, which is optional, beneficiaries must buy a policy.

Part D is a rapidly growing market that accounts for about one-fifth of federal spending on Medicare, or about $100 billion a year. Consumers bear a fraction of the cost, about 15 percent, because of premium subsidies and risk-equalization programs.

Works like a voucher, despite ‘convoluted structure’

The researchers chose Medicare Part D as their laboratory for a couple of reasons. It has clear rules that allowed them to model a variety of experimental scenarios for insurance firms. Plus, it has strong data on potential customers and the choices available to them.

Through testing different structures, they learned that “the present program, despite its convoluted structure, actually works very much like a flat voucher program,” Ryan said.

Vouchers often perform better than proportional subsidies. That’s mostly because they preserve some elasticity of demand while still allowing policymakers to sort between prescription drug plans, Ryan and his co-researchers report.

Demand elasticity is important because it helps firms model potential change in demand due to changes in the price of a good, the effect of changes in prices of other goods, and many other market factors. If the demand for a good is more elastic, in response to changes in other economic factors, companies must use caution when raising prices.

This, in turn, leads insurance firms who sell Part D plans to keep their bids competitive, minimizing the cost to taxpayers.

Broad implications

The researchers’ findings have broad implications for the design of privately provisioned, publicly subsidized social insurance programs. Traditionally, the U.S. government has provided social insurance programs directly to Americans. But in the past 20 years, efforts have accelerated to move such programs to private markets.

Part D’s design “mutes,” or inhibits, insurers’ efforts to get higher government subsidies because of the complex way it ties together prices for numerous, distinct parts of the program into one “subsidy mechanism.” (That mechanism sets the public funding to private insurance firms.)

“The current mechanism actually did a pretty good job,” Ryan said. “But it is probably not entirely by design, as the subsidy could have been too high or low relative to optimal. It turns out that a combination of all the forces come together to produce something actually not too far from an optimal voucher. It was surprising when we computed that.”

The researchers also learned that insurers’ competition for low-income enrollees kept incentives low for insurers to seek higher subsidies. In addition, tying the subsidy to prices in the related Medicare Advantage prescription drug market — where premiums are typically zero — also kept subsidies stable.

Consumer demand depends on high subsidies

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Violence at the hands of police is a leading cause of death for young men in the United States, finds a new study involving Washington University in St. Louis.

“Over the life course, about 1 in every 1,000 black men can expect to be killed by police,” said Hedwig (Hedy) Lee, professor of sociology in Arts & Sciences and associate director of the Center for the Study of Race, Ethnicity & Equity.

Lee is co-author of the new study, “Risk of Being Killed by Police Use of Force in the United States by Age, Race–ethnicity, and Sex,” published Aug. 5 in the journal PNAS.

Risk of being killed by police peaks between the ages 20 and 35 for men and women and for all racial and ethnic groups, the study found. Black women and men and American Indian and Alaska Native women and men are significantly more likely than white women and men to be killed by police. Latino men also are more likely to be killed by police than are white men.

“I think that our results really underscore that police killings are a lot more common than we might have imagined,” Lee said. “Our work also provides more evidence that people of color, particularly African American men and women, but also American/Indian Alaska Native women are at risk. The next task for researchers is to get a better understanding of what is driving these patterns now that we have documented them.”

Frank Edwards of Rutgers University and Michael Esposito of University of Michigan were co-authors on the study.

“What we found maps to the racial/ethnic disparities that others have found in regards to criminal justice contact and police-involved harms,” Lee said. “The results were, nonetheless, sobering. We found quite stark disparities in risk of being killed by the police in the U.S. That police violence is the sixth-leading cause of death for African American, American Indian/Alaska Native, and Latino men between the ages of 20 and 24 should give us pause.”

The study found that black men face about a 1-in-1,000 chance of being killed by police over the life course. The average lifetime odds of being killed by police are about 1 in 2,000 for men and 1 in 33,000 for women.

“We try to provide comprehensive estimates of the risk of being killed by police in the U.S. by race/ethnicity, sex and age,” Lee said. “Our hope was to provide a more detailed and nuanced understanding of the patterning of deaths and also produce estimates of lifetime risk. Despite all the great work folks have done on disparities in police-related homicides, there hasn’t been much that’s looked at how intersecting social conditions structure risk.

The researchers used both “official” and “unofficial data” on police-involved killing.

“Our ‘official’ data come from National Vital Statistics System (NVSS), which provides the most comprehensive data on police-involved killings in the U.S.,” Lee said. “Our ‘unofficial’ data come from Fatal Encounters (FE), a journalist-led effort to document deaths involving police using crowdsourcing. Cases are identified via online media reporting and public records.”

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Most people with a medical condition called long QT syndrome have a mutation in a gene that causes bouts of fast, chaotic heartbeats. They also experience fainting spells and seizures. The clinical approach has largely assumed that when the heart beats erratically, the brain eventually does not get enough oxygen — which in turn causes the seizures.

Research from Washington University in St. Louis finds that mutations of a gene implicated in long QT syndrome in humans may trigger seizures because of their direct effects on certain classes of neurons in the brain — independent from what the genetic mutations do to heart function. The new work from Arts & Sciences was conducted with fruit flies and is published Aug. 8 in PLOS Genetics.

“This gene seems to be a key factor in the physiological process that protects neurons from starting to fire uncontrollably in response to a rapid increase in temperature, which could lead to paralysis and death,” said Yehuda Ben-Shahar, associate professor of biology in Arts & Sciences.

Alexis Hill, recently a postdoctoral fellow in the Ben-Shahar laboratory, discovered this unexpected relationship as she probed the nervous system response to acute environmental stress.

Heat in general causes neurons to start firing faster, so the brain is particularly sensitive to overheating. Mammals and other large animals have ways to maintain their internal temperature and protect their brains from heat. But not the fruit fly. With no extra bulk in his tiny body, the only thing a fly can do to regulate temperature is to move from an uncomfortable spot to a comfortable one.

Ben-Shahar had previously published work showing flies that lack a gene called sei could not act to save themselves at temperatures above 25 degrees Celsius (77 Fahrenheit). They had no ability to buffer heat stress, and started having seizures as temperatures increased.

This gene sei — named by other researchers who had previously discovered its role in seizure activity — shows up in lots of places in fruit flies: in the neurons responsible for primary communication of both excitatory and inhibitory signals, in the glia cells of the nervous system that support neurons in various ways, and in the heart.

In their new work, Hill and Ben-Shahar were able to show that sei protects against heat-induced hyperexcitability only when it is expressed in a few particular classes of neurons and glia. Knocking down the gene in the heart had no effect on seizure activity.

“The ability of flies to resist the heat is in neurons that release neurotransmitters that make other neurons fire faster, the ones that excite neurons,” Ben-Shahar said.

Surprisingly, the study also uncovered a protective role for sei in glia, the other primary cell of the nervous system. Glia have traditionally been overshadowed by the importance of neurons, but in recent years they have been emerging as equally important in maintaining healthy brain functions. The fact that this work identifies a protective role of an ion channel in glia further supports the idea that glia have much broader physiological functions in the nervous system and how it might respond to environmental challenges, the researchers said.

A careful look through the scientific literature reveals many references to seizure associated with long QT syndrome, which afflicts human beings with a genetic mutation to a sei-comparable gene called hERG.

But most clinical practitioners assume that these seizures are a secondary outcome of cardiovascular disease. Ben-Shahar hopes this soon will change.

“If you look at population statistics, there is a much higher incidence of seizures in long QT patients than in the general population,” he said. “Because cardiovascular dysfunction can cause all kinds of problems, in the literature right now it is assumed that the seizures are secondary — that because the people have a sick heart they end up developing seizures and other things.

“It’s possible, based on our data, that it’s two independent effects. Because if the mutation is affecting the function of the gene in the heart, it will affect the function in the neurons.

“And in flies, it’s not going to kill neurons,” Ben-Shahar said. “We know that we can completely eliminate this gene from the fly genome — and flies will develop normally, mostly. Yet they become extremely sensitive to environmental (conditions). It’s possible that that’s exactly what’s happening in people — that it’s completely independent.”

Wild type control flies (left) and flies that carry a mutation in the sei gene (right) respond differently to an acute increase in temperature. In contrast to wild type flies, which are relatively resistant to heat stress, mutant flies exhibit rapid development of seizures followed by paralysis. (Video courtesy of Ben-Shahar laboratory)

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When the Washington University in St. Louis Class of 2023 arrives Aug. 17, a Saturday, they will experience a nine-day Bear Beginnings orientation program that is more inclusive, more fun and, yes, more days. 

Traditions such as Convocation, SUp All Night and the Common Reading Program discussion will continue. But Bear Beginnings also will include new programs such as immersive experiences in St. Louis, a residential life block party and “Dialogue Across Difference,” a workshop introducing students to university values of free expression and inclusion. 

“Orientation has always been a terrific introduction to WashU, but we hope the new Bear Beginnings will provide students an opportunity to make stronger connections to their school, the St. Louis community and, most importantly, to each other,” said Katharine Pei, director of the First Year Center. 

Students will arrive Aug. 17. To prevent traffic jams, students will be assigned a time slot during which to arrive. More than 300 students and staff will be on hand to haul mini fridges and comforters into the residential colleges. 

As in years past, Convocation will take place that evening at the Athletic Complex. This will be Chancellor Andrew D. Martin’s first Convocation, and he has some surprises planned for the ceremony and the following party, which will take place in the newly completed Ann and Andrew Tisch Park.

Pei said the move to Saturday will enable more parents to participate in move in and Convocation.

“For many parents, it is difficult to miss  work during the week,” Pei said. “The new schedule will better serve their needs. After all, this is a big day for parents, too.”

Another change is the elimination of pre-orientation programs, which were popular but not accessible to all students, even after the university waived the fees for low-income students.

“We wanted to give everyone the same excellent welcome into the university,” said Rob Wild, associate vice chancellor for student affairs. “Before, you had a significant fraction of students who had the opportunity to make friends and connections through pre-o and the rest who arrived and didn’t know anybody. It was a priority to fix that while still giving students the benefit of smaller group experiences.”

Those group experiences will take place Aug. 19-24. Students will first participate in three days of academic experiences programmed by their respective schools, followed by a three-day “immersive experience” in either the arts, community engagement, entrepreneurship or leadership. 

Colleen Smyth of the Gephardt Institute for Civic and Community Engagement said the immersive programs will introduce students to campus resources and the St. Louis community. She is organizing Engage STL, an immersive experience that will feature visits to St. Louis neighborhoods, the Griot Museum of Black History and the Festival of Nations as well as a service project at the Greenwood Cemetery.

“As a new college student, it’s easy to see campus as your home,” Smyth said. “But St. Louis — its people, its history and its assets and challenges — also is part of the Washington University experience.” 

As in prior years, all students will participate in a Common Reading Program discussion with their floor. This year’s book is “Hate: Why We Should Resist It with Free Speech, Not Censorship,” by Nadine Strossen, a law professor and past president of the American Civil Liberties Union.

Students also will attend “The Date,” a sexual violence prevention program, and “Our Names, Our Stories,” which explores Washington University’s diverse and inclusive community. Both productions are written and performed by students.

New this year: “Dialogue Across Difference,” a workshop that explores the meaning and practice of freedom of expression and inclusion. Lori White, vice chancellor for student affairs, launched the program to provide students with strategies for having meaningful conversations. 

“At Washington University, we strive to educate a generation of students who can lead our diverse society,” White said. “But to lead, we must be able to talk to one another. That’s not always easy for students, many of whom come to us from relatively homogeneous neighborhoods. By exploring the values of freedom of expression and inclusion and providing tools students can use in their daily conversations, we hope this program helps them better engage with people who are different from them.” 

In the evenings, students may choose to attend various events, such as a men’s football or women’s soccer scrimmage, open house for various cultural groups, on-campus performances and a trip to the City Museum. The fun wraps up Aug. 25, the day before classes begin, with a pep rally, class photo and Ted Drewes frozen custard.

Wild said the mix of programming — some mandatory, some not; some academic, some social — provides breathing room and balance. Bear Beginnings is longer than its previous four-day incarnation, but not by much, considering that pre-orientation participants arrived eight days before classes began. 

“We were hearing that there was too much to do in those four days, so by the time students got to class, they were stressed out,” Wild said, noting that many peer institutions also have extended orientation. “The new schedule allows our students to ease into life at the university.” 

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Antibiotics are known to upset the balance of bacteria in the intestinal tract. In some cases, antibiotics can cause the bacterium Clostridium difficile (C. difficile) to overgrow wildly, causing diarrhea and, in severe cases, life-threatening intestinal inflammation.

Researchers at Washington University School of Medicine in St. Louis have found the molecular signature of a healthy gut microbial community, or microbiome – the kind of community that keeps C. difficile in check even in the aftermath of antibiotic treatment. They also have identified a specific molecule produced when C. difficile is not lying dormant but is active and making toxins. Together, the findings outline a set of molecular signs that indicate a person has – or is at risk for – diarrhea caused by C. difficile.

“Right now, we just accept that taking antibiotics raises the risk of C. diff infection,” said senior author Jeffrey P. Henderson, MD, PhD, an associate professor of medicine and of molecular microbiology. “By analyzing the small molecules produced by the microbiome, we may be able to identify people at high risk for developing C. diff diarrhea. We also may be able to use this type of analysis to screen potential donors for fecal transplants and make sure they are donating the kind of microbiome that can help keep C. diff under control.”

The findings are published Aug. 12 in The Journal of Clinical Investigation.

Every year, there are about 450,000 cases of C. difficile diarrhea in the U.S., and 29,000 deaths. Henderson and colleagues – including first author and postdoctoral researcher John Robinson, PhD, and co-author Erik Dubberke, MD, a professor of medicine, both at Washington University; as well as co-author Peter Mucha, PhD, a professor of mathematics at the University of North Carolina at Chapel Hill – studied the microbiomes of people with and without C. difficile disease by analyzing their metabolomes, or the chemical compounds produced in the gut as human intestinal cells and microbes eat, breathe and interact with each other. They were searching for a molecular signature that distinguishes a healthy gut from one prone to C. difficile disease.

The search was complicated by the fact that some people carry C. difficile in their gastrointestinal tracts with no ill effects. But the bacteria also can produce two toxins that cause diarrhea and inflammation. In the absence of these toxins, the bacteria are mostly harmless.

The researchers studied 186 hospitalized people with diarrhea, divided into three groups: a group with no C. difficile; a group with C. difficile but without toxins, which means they carried the bacteria but their symptoms were caused by something else; and a group with C. difficile and toxins, all of whom had C. difficile infections.

Using mass spectrometry, the researchers analyzed thousands of metabolic byproducts in stool samples from patients in all three groups. In particular, they found high levels of a fatty acid called 4-methylpentanoic acid in the stool of people with C. difficile disease. The fatty acid is produced when proteins are broken down for fuel using an unusual metabolic process. Human cells don’t produce the fatty acid, and neither do most of the bacteria in the normal microbiome – except for C. difficile. The presence or absence of the fatty acid in stool identified people with C. difficile disease with 92.8 percent accuracy.

Further, the researchers uncovered a pattern of molecules related to bile acid metabolism that was linked to protection against C. difficile disease. Bile acids are produced by the liver to help with fat digestion, then absorbed into the intestine, where members of the microbiome chemically modify them. The researchers identified a set of modified bile acids in people who did not carry the bacterium, or who carried it harmlessly, that was absent from people with C. difficile infections.

“These unusual bile acids may be fingerprints of people who are more resistant to C. difficile infection,” Henderson said. “There seems to be a difference in the metabolism of bile acids by the microbiome that affects how likely people are to develop disease.”

The researchers now are working on identifying which bacteria in the microbiome are involved in producing the protective bile acids, and how a healthy microbiome keeps C. difficile restrained.

“We know that disruptions to the microbiome predispose some people to getting C. diff disease, but until now we haven’t known much about what these changes are and why they’re harmful,” Henderson said. “Small molecules give us a direct readout of what the microbiome is doing. This study provides some big clues as to how these antibiotic-resistant bacteria make people sick, and that could lead to better ways to identify, prevent or treat C. diff infections.”

Robinson JI, Weir WH, Crowley JR, Hink T, Reske KA, Kwon JH, Burnham CAD, Dubberke ER, Mucha PJ, Henderson JP. Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infections. The Journal of Clinical Investigation. August 12, 2019.DOI: 10.1172/JCI126905

This study was supported by the Centers for Disease Control and Prevention, award numbers 200-2016-91939 and CU54 CK 000162; the Washington University Institute of Clinical and Translational Sciences, grant number UL1TR000448; and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH), grant number KL2TR000450.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Originally published by the School of Medicine

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On any given day, a news story might list a city in India as “most polluted.” In another story, a city in China may have held the distinction. Then again, maybe Iran hosts the most polluted city in the world, as a recent news report indicated.

The truth, however, is that no one knows what city has the highest level of pollution.

“I often see rankings of the most polluted city in the world,’” said Randall Martin, professor in the Department of Energy, Environmental ＆ Chemical Engineering in the McKelvey School of Engineering at Washington University in St. Louis.

“These rankings are misleading,” he said, “because there is insufficient information to know.” 

In a paper recently published in Atmospheric Environment: X, Martin outlines the extent of the gap between what researchers know and don’t know about on-the-ground levels of fine particulate matter, also known as PM_2.5.

The number refers to the size of certain particulates in the air that constitute pollution — they are 2.5 microns and smaller; for scale, a human hair is about 70 microns in diameter. These particles can be composed of anything from dust to industry byproducts. Because of their size, they can travel through the body’s respiratory tract and deposit in the lungs. 

The health impacts of PM_2.5 start with cardiovascular damage and get worse from there. The Organisation for Economic Co-operation and Development estimates worldwide, the cost associated with premature deaths from pollution will rise from $3 trillion in 2015 to $18-25 trillion by 2060.

Understanding the amount of pollution in the air requires on-the-ground monitoring, but many cities — ostensibly some with high PM_2.5 levels — have no monitoring at all. In India, for example, there is just one monitor for every 6.8 million people. Such sparse monitoring fails to represent pollution variability.

Martin and colleagues found that just about nine percent of the world’s population lives in areas that have more than three monitors per million people. About 18 percent of the population live in areas without monitoring.

“Although the health effects of PM_2.5 are valued at a few percent of global GDP, PM_2.5 is grossly under-monitored,” Martin said. “The difference between the importance of this measure and the level of ground-based monitoring is shocking.”

Beyond mitigating health concerns, a better understanding of pollution on the ground is important for several reasons. For Martin, whose research sits at the intersection of remote sensing and global modeling, having accurate data is the only way to develop accurate models. 

“Part of our analysis involves relating what satellites measure to ground-level PM_2.5,” he said. “If we relied only on ground-based monitors, we would have insufficient information.”

In order to improve the ground-level data, Martin and colleagues propose a robust “integrated monitoring framework” composed of different types of monitoring equipment focused on the most densely populated areas, or even on those most prone to variability. They calculate that in order to achieve a goal of one monitor per million people, thousands of new monitors will need to come online. 

In addition, Martin and colleagues suggests this framework should include ground-based aerosol measurements, innovative low-cost monitors, mobile monitoring and measurements at different points along the vertical (by aircraft, for example). Integrating these systems would not only help researchers gain a more comprehensive picture of the PM_2.5 levels on the ground, but would assist with air quality forecasting and help to improve atmospheric models.

 “The ability to identify the location of the most polluted city in an indicator of scientific progress,” Martin said. “It is important to be able to answer basic questions about something this important. The drive to overcome this challenge, speaks to something fundamental about our knowledge of the world around us.”

The McKelvey School of Engineering at Washington University in St. Louis focuses intellectual efforts through a new convergence paradigm and builds on strengths, particularly as applied to medicine and health, energy and environment, entrepreneurship and security. With 96.5 tenured/tenure-track and 33 additional full-time faculty, 1,361 undergraduate students, 1,291 graduate students and 21,000 alumni, we are working to leverage our partnerships with academic and industry partners — across disciplines and across the world — to contribute to solving the greatest global challenges of the 21st century.

This work was supported by the Natural Sciences and Engineering Research Council of Canada.

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Real-time video of YFP-ARF19 in a cell from the upper portion of the root. (Source: Strader Lab)

Depending on the temperature, a plant may synthesize the hormone auxin. Depending on the pathogens present, a plant may synthesize auxin. Depending on the available nutrients, water, stressors or development cues: auxin.

When a plant bends toward the light as it grows, the underlying chemical that regulates that movement?

Auxin.

Depending on the situation, the presence of this hormone can be a signal that kicks DNA transcription into gear, promoting growth and development, or it can keep transcription from happening.

An interdisciplinary team comprising members of Arts & Sciences and the McKelvey School of Engineering at Washington University in St. Louis has recently uncovered a mechanism by which a plant can be affected in a myriad of ways based on the presence of the same hormone.

The research was published Aug. 14 in the journal Molecular Cell.

“You can have any cue,” said lead researcher Lucia Strader, associate professor of biology in Arts & Sciences and associate director of the Center for Science & Engineering of Living Systems. “Light, temperature, different nutrients … the plant makes auxin in response to all of these things.” What follows as a result of that auxin release can also vary, from stress responses to leaf development to changes in the root system architecture.

Those responses are all results of Auxin Response Factors (ARFs), proteins which bind to DNA in a cell’s nucleus to facilitate growth and development in one way, or another.

The question Strader’s lab was investigating: how can ARFs do the right thing, in the right place, at the right time while at the same time preventing inappropriate responses? 

The answer began with an updated understanding of the fundamental nature of ARFs.

They are always present in a plant, but ARFs are often impotent because they are bound by Aux/IAA repressor proteins, which keep the ARFs inactive, until auxin chemically uncouples them. A new understanding of the structure of the ARFs led to a new understanding about the way they connect.

The change centered on the PB1 domain, on the opposite end of the ARF protein from the DNA binding domain (where the ARF, once in the nucleus of a cell, will bind to DNA during the transcription process).

As opposed to being bound to repressor or ARF proteins in pairs, “ARF PB1 domains are like miniature bar magnets, with a plus side and a minus side, free on two ends to pair with other proteins,” Strader said. “There’s the potential for them to grow into long chains.”

Outliers in the cytoplasm

It turns out that ARF PB1 domain chain formation plays an unexpected role.

While researching ARFs, Samantha Powers, a graduate student in the lab, was tasked with tagging one of the 23 Arabidopsis ARFs as part of her research. The image she came back with was unusual. Instead of finding the ARFs in the nuclei of plant cells, they were showing up in the cytoplasm, the gel-like substance that surrounds the nucleus. “Which is weird,” Strader said. 

Looking in the literature for studies showing the location of ARFs in plant cells, the team found one. Just one. And it looked much different than what Powers saw in her research: the ARFs were mostly where they “should” be, in the nuclei of the cells, with a couple of outliers in the cytoplasm.

Powers, it turned out, had been looking at ARFs in the plant’s mature root, while the study they found had looked at the meristematic root tip, the area where young cells divide. 

“The beautiful thing about plants as a developmental model is that in a single individual, at a single time point, you have every stage of development present,” Strader said. The youngest cells are at the beginning of the root system and since plant cells don’t move, they simply divide upward, building upon each other; the cells get older the farther away they are from the tip. 

Powers’s finding, then, was a clue: In the younger cells, ARFs were in the nucleus, transcribing mRNA, but in the older cells, they were stuck in the cytoplasm, not doing much of anything. And in the intermediate regions, there was a mix.

Strader discussed these findings at a biophysics seminar, after which Alex Holehouse — then a PhD student working in the lab of Rohit Pappu, the Edwin H. Murty Professor of Engineering in the McKelvey School of Engineering — approached her with a specific proposal. 

“He said, ‘While you were giving the talk, I downloaded the sequences of all 23 ARFs and analyzed them. I have data for you,’” Strader said. 

Holehouse is currently a postdoctoral fellow in the Pappu lab and is slated to start his own lab in the Department of Biochemistry & Molecular Biophysics in early 2020. He proposed that the ARFs that Powers and Strader were seeing in the cytoplasm were in fact protein condensates driven, in part by the “intrinsically disordered regions” of ARF proteins, the regions that lie between the DNA binding and the PB1 domains.

Holehouse postulated that the ARF proteins were transitioning from dispersed to condensed states to accumulate in the cytoplasm; similar to the way water molecules condense to form droplets.

“Conventional wisdom says that proteins have to adopt specific three-dimensional shapes to recognize their molecular targets; IDRs are different in that they are shape shifters,” Pappu said. “They can adopt different shapes depending on their contexts and these features make them ideal drivers of condensates providing they have the requisite sticky regions.

“Alex analyzed the sequences and found a very clear compositional distinction,” Pappu said.

The IDRs (intrinsically disordered regions) of particular ARFs had all the features of molecules that readily stick to themselves. Coupled with the ability for the ARFs to connect and form repeating structures — or oligomerize — via the PB1 domain, ARFs in the older cells condensed into assemblies that ensure that they remain stuck in the cytoplasm. 

And when ARFs are stuck in the cytoplasm, they cannot initiate DNA transcription. “It is that simple,” Pappu said.

“We think this is a way of keeping that pathway from being active in a certain cell type without turning it off completely,” Strader said.

Plants as model systems

Guided by Holehouse’s detective work, Powers went on to mutate certain ARFs so they would all make their way into the nucleus. They found that, as long as the ARFs can make it into the nucleus to bind DNA, when auxin is present, transcription will occur, no matter the cell type.

“It’s really exciting because we have shown that forming condensates in the cytoplasm is a way of attenuating auxins,” Strader said. “Every cell is responsive to auxin when there is an ARF variant that’s constitutively nuclear, whereas unresponsive cells sequester ARFs in their cytoplasm.” A constitutively nuclear variant be able to activate genes in all cell types.

“Engineers routinely try to design biomaterials that can form depots within cells so as to control the release of material that gets tied up in the depots,” Pappu said. “What is fascinating is the level of control afforded to the localization of ARF proteins by making cytoplasmic depots, the condensates, via sticky IDRs in older cells. The depot making apparatus, comprising of molecules with sticky IDRs can tell older from younger cells. Being able to replicate this type of molecular control to make active matter would be a dream for bioengineers.”

The continuing collaboration between the Strader and Pappu labs is focused on adapting plants as model systems to study molecular and cellular processes that are tied to neurodegeneration.

That’s because this research shows a strong, positive biological role for protein condensation which, Strader pointed out, is the same process often associated with disease such as Alzheimer’s , ALS, and other prion-related disorders.

For plants, this research illustrates how condensation is a mechanism that can prevent them from transcribing genes by keeping transcription factors out of the nucleus in certain contexts, ensuring auxin does the right thing, at the right time, in the right place.

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An international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer’s disease.

Most genes implicated thus far in Alzheimer’s affect neurons that transmit messages, allowing different regions of the brain to communicate with one another. But the newly identified genes affect an entirely different population of cells: the brain’s immune cells. The findings, published online Aug. 14 in the journal Science Translational Medicine, could provide scientists with new targets and a strategy for delaying the onset of Alzheimer’s symptoms.

The genes — known as MS4A4A and TREM2 — operate in the microglia, the brain’s immune cells. They influence Alzheimer’s risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer’s proteins amyloid and tau from the brain.

“The findings point to a new therapeutic strategy,” said co-senior investigator Carlos Cruchaga, professor of psychiatry and director of the NeuroGenomics and Informatics Group. “If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer’s disease or slow its development.”

In this study, the researchers measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer’s disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment. They also analyzed the participants’ DNA, conducting genomewide association studies to look for regions of the genome that may influence TREM2 levels in the cerebrospinal fluid.

Although variants in TREM2 are found in a very small percentage of patients with Alzheimer’s disease, the gene previously had been linked to the disorder. People who carried those previously identified risk mutations were excluded from the study. Common variants in the MS4A4A gene also had been associated with risk for Alzheimer’s, but this study connects those genes.

“We observed TREM2 risk variants more often in people who had Alzheimer’s or were mildly cognitively impaired, compared with those who were cognitively normal,” said co-senior investigator Celeste Karch, assistant professor in the Department of Psychiatry. “It turns out that about 30 percent of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer’s disease. Some variants protected people from Alzheimer’s or made them more resilient while others increased their risk.”

When the researchers dug further, they noted that variants in the MS4A4A gene cluster linked to an increase in risk for developing Alzheimer’s disease are associated with lower levels of soluble TREM2 protein. The other variant, associated with higher levels of TREM2 in the cerebrospinal fluid, seemed to protect against Alzheimer’s.

The research team validated its results in DNA from another 580 older adults. Once again, they found that higher soluble TREM2 levels in the cerebrospinal fluid seemed protective, while lower levels increased risk. And those protein levels — whether high or low — were linked to variants in the MS4A4A gene.

“For the past several years, we’ve been looking at TREM2 and increasing our focus on the involvement of the brain’s immune cells in Alzheimer’s disease” said another co-senior author, Bruno A. Benitez, MD, assistant professor of psychiatry. “These findings give us a new therapeutic strategy to pursue, one focusing not only on neurons but on how the microglia may be involved in helping to clear damaging proteins, such as beta amyloid and tau, that are linked to Alzheimer’s disease.”

Those gene variants also may play a role in other diseases of the central nervous system, according to Laura Piccio, MD, PhD, associate professor of neurology and another co-senior author.

“By combining large genetic and spinal fluid analyses with laboratory work, we have provided strong evidence of a biological link between TREM2 and proteins in the MS4A gene cluster, both of which previously had been associated with Alzheimer’s disease,” Piccio said. “We are beginning to elucidate a molecular pathway in microglia that could be critical not only in Alzheimer’s disease but also in other neurodegenerative and inflammatory diseases in the central nervous system.”

Deming Y, et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer disease risk. Science Translational Medicine, published online Aug 14, 2019.

This work was supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute and the National Institute of Mental Health of the National Institutes of Health (NIH). Grant numbers R01 AG044546, P01 AG003991, RF1 AG053303, R01 AG058501, U01 AG058922, K01 AG046374, P50 AG05681, P01 AG026276, R01 HL119813 and T32 MH014877. Additional funding was provided by the Alzheimer’s Association; the Fondazione Italiana Sclerosi Multipla; the National Multiple Sclerosis Society; a Fondazione Veronesi fellowship; the Hope Center for Neurological Disorders and the Danforth Foundation Challenge at Washington University; the Swedish Alzheimer Foundation; the Research Council, Sweden; Hjarnfonden, Sweden; the LUA/ALF project, Vastra Gotalandsregionen, Sweden; the Swedish and European Research Councils; and the UK Dementia Research Institute.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Originally published by the School of Medicine

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The School of Law at Washington University in St. Louis has launched a new First Amendment Clinic, aimed at allowing students to gain experience by providing legal assistance to organizations, students, journalists and citizens.

“The clinic has two major goals,” said Lisa Hoppenjans, assistant professor of practice and director of the clinic. “To defend and advance freedom of speech, press and assembly by providing pro bono legal services to individuals and organizations in matters raising First Amendment issues; and to educate law students to become leaders on First Amendment issues through real-world practice experience.”

The clinic is believed to be the first in Missouri to focus on the First Amendment. It is funded by a grant from the Stanton Foundation.

It will include six students in the fall semester and eight in the spring.

Clients will include media organizations, journalists, students and other individuals with First Amendment claims, and the focus will be on local and regional matters, Hoppenjans said.

“The matters we may handle could include, for example, a motion to unseal court records for a news organization or bringing claim on behalf of an individual who was excluded from a government meeting for criticizing local officials,” she said.

One of the advantages of having the clinic at the university is that “the law school has several outstanding First Amendment scholars whose courses have really sparked a deeper interest in First Amendment law among a number of students,” Hoppenjans said. “Those students will now have the opportunity to take the passion and knowledge developed through their coursework and apply it to real cases.  And even though most of the clinic’s students may not end up practicing First Amendment law, the skills that they learn will be transferable to all kinds of litigation.”

Protecting free speech and vigorous public debate is foundational to our democracy, Hoppenjans said.

“But over the last few years, both nationally and here in St. Louis, we’ve seen government actors try to exclude, silence or punish individuals for exercising their First Amendment rights. The clinic will give students the opportunity defend critically important rights at a challenging time.”

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At city parks, local forests and even on the grounds of the Gateway Arch National Park, the creatures come out at night. And sometimes during the day, too.

To catalogue the animal residents of urban green spaces without disturbing them, researchers have set up 34 motion-activated cameras from the densely urbanized St. Louis riverfront to the wilds of Route 66 State Park in Eureka, Mo. Four times a year, these camera traps are opened up to snap pictures of wildlife living along the Henry Shaw Ozark Corridor.

The St. Louis Wildlife Project is a collaboration between St. Louis College of Pharmacy and the Tyson Research Center at Washington University in St. Louis. The project aims to quantify biodiversity and improve the understanding of wildlife ecology in the greater St. Louis area. Through this project, St. Louis serves as a partner city in the Urban Wildlife Information Network, an initiative based at the Lincoln Park Zoo in Chicago that includes partner cities across North America.

“Currently, more than half of the global population lives in cities, and this portion is expected to rise,” said Solny Adalsteinsson, staff scientist at Tyson Research Center. “If we are to conserve biodiversity, we need to understand how we can better plan these cities to benefit wildlife and create more sustainable cities,” she said.

One of the greatest threats to biodiversity is urbanization. However, metropolitan areas such as St. Louis can play an important role in maintaining biodiversity. Habitat patches and green spaces can support species and protect diversity in urban areas. Understanding how wildlife utilize these habitats, and interact with each other and humans in an urban environment, is essential for minimizing human-wildlife conflict.

“St. Louis is unique because we have three rivers  in this region — the Mississippi, the Missouri and the Meramec,” said Whitney Anthonysamy, assistant professor of biology at St. Louis College of Pharmacy. “There’s already a lot of urban green space, and not far out of the city you immediately get into some Ozark habitats , which are also known for having a lot of species biodiversity.”

By studying how unique features of the St. Louis landscape — including rivers and parks — affect diversity and abundance of wildlife in the region, researchers can identify important elements that promote biodiversity and the coexistence of humans and wildlife.

These elements can be incorporated into sustainable design and planning for St. Louis while also informing a broader understanding of urban ecology and how best to conserve biodiversity through data-driven urban planning and development.

Students review the photos and identify the species caught on camera. So far, they have spotted squirrels, raccoons, opossums and deer — and even less common animals such as red foxes, turkeys, bobcats, river otters, skunks and armadillos.

Interested community members can volunteer for the St. Louis Wildlife Project.

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Key leaders from some of the United States’ largest financial-adviser firms are featured speakers at the fourth annual Wealth and Asset Management Research Conference Aug. 22 and 23 at Knight Hall’s Emerson Auditorium on the Washington University in St. Louis campus.

The speakers represent roughly one of every six advisers in the country, and some hail from firms partially founded or based in St. Louis. Register here for the conference, subtitled “Finance: Today, Tomorrow and in the Future.”

The event kicks off the academic year for students in Olin Business School’s master’s program for wealth and asset management (WAM). It includes leading academics discussing their research; panel discussions with industry experts; and a candid conversation with David Booth, who in 1981 with Rex Sinquefield founded Dimensional Fund Advisors, which today manages $500 billion-plus in assets.

The headline speakers and panelists are:

• Aug. 22: A panel discussion with Peter J. deSilva, president of retail at TD Ameritrade; Penny Pennington, managing partner at Edward Jones; Ronald J. Kruszewski, Stifel board chairman and CEO; and John Alexander, head of integrated brokerage at Wells Fargo Advisors.
• Aug. 23: A conversation between Booth, executive chairman of Dimensional Fund Advisors, and Dean Mark Taylor.

“WashU, Olin and our students are very fortunate that this year’s WAM Research Conference has attracted such a great lineup of academics and practitioners,” said conference chair Rich Ryffel, professor of finance practice, market manager for J.P. Morgan Private Bank and founder of the WAM master’s track at Olin. “David Booth is a luminary in the asset management world. And to gather the leaders of four of the biggest wealth management firms in America, all with deep roots in St. Louis, and put them on the same stage at once is a rare and notable occurrence.

“In its fourth year, to see both the WAM program and the conference grow in size and prominence the way it has, speaks volumes about the ability of Olin to serve as a convener of industry and academic leaders.”

Read more on the Olin Blog.

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World War II was, by any measure, a massive undertaking that involved huge loss and suffering.  The countries involved — Allied and Axis — committed substantial resources and sacrificed an astounding number of human lives. 

No matter how much a particular country contributed however, the sum total of all losses cannot equal more than 100%. Nonetheless, in a survey of people from countries on both sides of the war, researchers from Washington University in St. Louis show that across the board, people ascribe an inflated weight to their country’s contribution to the war effort.

The results were published this week in Proceedings of the National Academy of Sciences.

There was another interesting finding. “Russians view World War II very differently than, basically, people from every other country in our study,” said lead author Henry Roediger, the James S. McDonnell Distinguished University Professor in Arts & Sciences. “When you ask people to list the top 10 important events, people from China and Australia, and everyone else, they all list Pearl Harbor and D-Day. Russians don’t.

“Well they do list D-Day,” Roediger said, “but they call it the ‘Opening of the Second Front,’ and they see it as relieving some of the pressure on Soviet forces who then drove to Berlin.” 

In the first part of the study, researchers surveyed 1,338 people, 18 and older, from 11 countries. They received at least 100 usable surveys from natives of eight of the former Allied powers — Australia, Canada, France, New Zealand, Russia (as a proxy for the former Soviet Union), the United Kingdom and the United States — and three former Axis powers, Germany, Italy and Japan.

The study was designed to gauge how important people thought their country’s contribution was in the war effort. Participants from the Allied countries were asked, “In terms of percentage, what do you think was (your country’s) contribution to the victory in World War II?”

Among just three Allied countries, Russia, the U.K. and the U.S., participants claimed their countries contributed 180%. Russians claimed 75%, the UK respondents claimed 51%, and those from the U.S. 54%. Across all eight Allied countries, the total effort amounted to about 300%.

And that’s only eight of the dozens of countries that signed onto the Declaration of the United Nations before the end of the war. According to the National World War II Museum website in New Orleans, 12 additional countries had at least 1,000 military deaths during the war.

“Collective memory refers to the way people remember history, what they believe about it, and these beliefs arise from your background, your society, your education and your media,” Roediger said. “And, of course, all these influences create the memories about your country as it was involved in World War II.”

Even when the question was changed to require respondents to provide estimates for all eight Allied countries as well as other countries, so that their totals had to equal 100% (or less, if they were considering some of the countries not included in the survey), adding the scores that people in a given country gave their own country still totaled more than 191%. 

National narcissism

Overestimating one’s contribution is not just a feature of the “winning” side. Residents of former Axis countries were asked what percentage of the war effort their country contributed. The German respondents claimed 64%, Japanese 47% and Italians 29% for a total of 140%.

The results of the study illustrate what Roediger terms national narcissism, borrowing the term from the personality disorder in individuals. Although such results may seem esoteric, they have real consequences that we can see all around us. 

Take Russia. In this second framing of the question, when respondents were forced to look at answers for their country alongside other the other seven countries, most people did rate their country’s contribution much lower than in the first question. 

Except Russia. Its respondents lowered their estimates just 11%, from 75% to 64%. “They may be right,” Roediger said, “at least for the war in Europe.”

Estimates put the loss of Soviet Union soldiers between 8 million and 11 million. In stark contrast to Time Magazine’s coverage of D-Day as “24 Hours That Saved the World,” many historians would argue that the Soviet Union played the most important role in the outcome of the war in Europe. Overall, the Soviet Union lost between 22 million and 28 million people in the war, or roughly 14% of its population.

But most students in the U.S. learn the Time Magazine version of the war, both in school and through cultural representations, where the U.S. played the leading role. 

“The Russian story is told in practically none of our movies, none of our novels,” Roediger said. “It’s all about us. 

“But we can understand how the Soviet Union, now Russia, always sees itself as embattled,” Roediger said. “We see them as aggressive, but they often see themselves in terms of this narrative going back hundreds of years: Russia is minding its own business, it is viciously attacked and looks like it’s going to lose everything, but they come together, against all odds, and win. My co-author, Jim Wertsch, refers to this script as the Russian narrative template.”

Today, the Russians may see the United States in that same context.

“Now, we have NATO countries that surround them,” Roediger said. “The idea is that if you can understand the historical memory of a people, you can be more successful in understanding their viewpoint and in your negotiations with them.”

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Impact events are relatively common. The objects known as shooting stars are actually small meteors burning up as they pass through Earth’s atmosphere. If a meteor is large enough, some part of it may reach Earth as a meteorite. These small impacts don’t form big craters, even if they might be large enough to devastate urban areas.

In its long history, Earth has experienced several meteor-impact events large enough to melt terrestrial rock and send it flying for hundreds or even thousands of miles. Following these impact events, the melted rock cooled to form materials known as tektites, which can now be found in several large areas, or “strewn fields,” around the world.

Understanding the impact process for tektite-forming events on Earth can lead to insights into the giant impact event that is believed to have formed the moon billions of years ago. That’s one result of new research from Washington University in St. Louis focusing on volatile elements, “Implications of K, Cu, and Zn isotopes for the formation of tektites.” The research was published Aug. 15 in the journal Geochimica et Cosmochimica Acta.

“We’re comparing tektites with the source of tektites, which is the upper continental crust, to see what changed during the impact,” said co-author Kun Wang, assistant professor of earth and planetary sciences in Arts & Sciences.

By establishing the expected pattern for volatile losses during impact events, Wang and his fellow researchers will be able to work backward from the products of impact events —tektites and lunar rocks alike — to learn about pre-impact conditions.

Read more about this research on the Arts & Sciences website. 

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A new study from Washington University School of Medicine in St. Louis supports evidence that children with mild asthma can effectively manage the condition by using their two inhalers — one a steroid and the other a bronchodilator — when symptoms occur. This is in contrast to the traditional method of using the steroid daily, regardless of symptoms, and the bronchodilator when symptoms occur. The as-needed use of both inhalers is just as effective for mild asthma as the traditional protocol, according to the investigators.

The steroid inhaler lowers inflammation, and the bronchodilator — also known as a rescue inhaler — relaxes the airway during an asthma attack to quickly make breathing easier.

The research focused on African American children, who are disproportionately affected by asthma. The study appears in The Journal of Allergy and Clinical Immunology: In Practice.

“We were pleased to find that as-needed treatment based on symptoms can deliver similar asthma control with less medication,” said first author Kaharu Sumino, MD, an associate professor of medicine. “Patients in the group that used both inhalers as needed used about one-fourth the steroid dose of the group that inhaled a prescribed daily amount. We also were pleased to see that the patients and families felt that they had more ownership over their asthma management when practicing as-needed treatment.”

In the U.S., about 6.2 million children under age 18 have asthma. Among white children, about 7.4 percent have asthma. Among African American children, that statistic is almost double, at 13.4 percent. According to the Allergy and Asthma Foundation of America, asthma attacks account for 1.8 million emergency room visits per year, and African Americans are three times more likely than average to be hospitalized due to asthma.

The study was conducted by primary care doctors at multiple pediatric practices throughout the St. Louis area, suggesting the strategy is widely applicable in a primary care setting and not just effective when implemented by researchers at a single academic medical center.

Past clinical trials conducted in the highly controlled settings of academic medical centers had suggested that the medication-as-needed approach worked just as well as a traditional strategy of daily scheduled steroid treatments with a rescue inhaler as needed. But how well that strategy might transfer to individual community medical practices had been an open question. Not only is this alternative, as-needed, symptom-based strategy effective when administered by the children’s primary care doctors, the researchers found that approach reduced the amount of steroid medication the children took monthly by almost 75 percent.

The study included 206 African American children 6 to 17 years of age with mild asthma that was adequately controlled with asthma controller steroid medication. Participants saw their own pediatricians at 12 primary care providers throughout St. Louis. The patients were randomly assigned to one of two groups. Each participant in one group was advised to take a dose from an inhaler containing the steroid beclomethasone as needed when symptoms arose, along with the rescue bronchodilator albuterol. Symptoms that might prompt the use of medication include shortness of breath, tightness in the chest, coughing, wheezing and difficulty performing physical activities.

Each participant in the second group was advised to take a specific inhaled dose of the steroid beclomethasone daily, regardless of symptoms, plus the rescue bronchodilator as needed in response to symptoms, as has been the standard recommendation for almost 30 years by the Global Initiative for Asthma guidelines.

At the end of the one-year study, the researchers found no differences between groups in surveys of how well the patients’ asthma was controlled, as well as no differences in breathing tests that measure lung function. There also were no differences in the number of participants who sought extra medical care — such as office or emergency room visits — for asthma attacks.

As might be expected, the group taking daily beclomethasone, an inhaled corticosteroid, used more of the medication per month than those in the symptom-based group. On average, children in the daily-use group used 1,961 micrograms per month, while the symptom-based group used 526 micrograms per month, cutting the amount of this medication by almost three-fourths. The reduced amount is desirable, according to the investigators, because steroids have side effects that include stunted growth.

“Many families are concerned about the cost of this medication as well as the growth-related side effects, and stop taking their steroid medicine altogether. So it’s nice to show that less medication — used as needed — is just as effective,” Sumino said. “This as-needed steroid plus rescue albuterol strategy is now recommended in the Global Initiative for Asthma guidelines as one of the options for the treatment of mild asthma. Given the result of our study and others, primary care doctors may tell their patients with mild asthma that they have an alternative effective strategy other than taking the inhaled steroid every day, if they prefer not to do so.”

The researchers also noted that children and caregivers in the group taking medication as needed reported that they felt they were actively managing their asthma care rather than passively relying on doctors’ orders. The symptom-based strategy, in other words, gave them a sense of ownership over their asthma management, which is important in the long-term control of the disease, according to the Sumino and her colleagues.

This work was supported by a Patient Centered Outcomes Research Institute (PCORI) Award, number AS-1307-05588.

Sumino K, Bacharier LB, Taylor J, Chadwick-Mansker K, Curtis V, Nash A, Jackson-Triggs S, Moen J, Schechtman KB, Garbutt J, Castro M. A pragmatic trial of symptom-based inhaled corticosteroid use in African American children with mild asthma. The Journal of Allergy and Clinical Immunology: In Practice. July 30, 2019.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Originally published by the School of Medicine

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Filing into the Athletic Complex for Convocation on Aug. 17, the 1,736 members of the Washington University in St. Louis Class of 2023 were excited, nervous and eager to make new friends.

Chancellor Andrew D. Martin could relate.

“I feel like a first-year student myself,” said Martin, who started his term as Washington University’s 15th chancellor in June. “All summer, we’ve been waiting for these students to arrive. Now that they are here, I can’t wait to get to know them.” 

The Class of 2023 was chosen from a field of 25,426 applicants and is both diverse and academically gifted. Its members boasted an average SAT score of 1510 and hail from 19 countries and 47 states, Puerto Rico and the District of Columbia. Eight percent are from St. Louis, 15 percent are Pell grant-eligible and 9 percent are first in their families to attend college. Twenty percent of the class is Asian, 11 percent identifies as black and 10 percent is Hispanic.

In coming days, they will participate in the new, expanded Bear Beginnings orientation programs before the first day of classes Aug. 26. 

But this moment was for reflection and celebration. As the students shouted their residential college cheers, Martin took the Convocation stage, joined by deans and faculty fellows as well as speakers Marion Craig, interim provost; Lori White, vice chancellor for student affairs; and student speaker Chibueze Agwu, a senior majoring in  philosophy-neuroscience-psychology in Arts & Sciences. 

Martin told the students he knew the many questions running through their minds: Why aren’t the residence halls named Gryfindor or Slytherin? What’s in provel cheese? And will their parents ever actually leave? Parents, likewise, had their own questions, like what color to paint their child’s room now that it will be an office. 

And then there is the biggie. 

“You’re looking around and wondering if you made the right choice to come to WashU,” said Martin, who has chosen Washington University three times — first as a PhD student, then as a department chair and vice dean and, now, as chancellor. “Indeed, you have a host of thoughts, questions and, yes, even feelings about today, about tomorrow and about the years ahead. And the bottom line is that all of you had a choice to make when it came to college. In the end, you chose WashU. 

“Likewise, we also chose you — and for a reason. We chose you because we saw something about you that goes way beyond your academic achievements, your test scores or your impressive extracurricular resume. And with that, I want each and every one of you to know that we chose you because you belong here, and that we are committed to ensuring this is a place where each of you will thrive both intellectually and personally. We also chose you because we saw potential — the potential for you to become future leaders in your fields and industries.”

Martin acknowledged the work will be hard but assured students they will come to cherish the people and customs they experience along the way. To that end, Martin introduced a new tradition  — a class coin. As students made their way into the newly completed Tisch Park for a post-Convocation party, each received a silver coin stamped with Brookings Hall and the university motto, ‘per veritatem vis’  or strength through truth. 

“This coin represents WashU’s investment in you,” Martin said. “I hope you will carry this coin proudly as you consider the remarkable journey you are beginning as a member of this community.”

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Holden Thorp, the Rita Levi-Montalcini Distinguished University Professor at Washington University in St. Louis, has been named editor-in-chief of the Science family of journals, widely recognized as being among the world’s most prestigious publications dedicated to research and science. He will assume his new role Oct. 28 and will remain on the Washington University faculty as the Rita Levi-Montalcini Distinguished University Professor. He will be on leave while serving as editor-in-chief.

“I am truly delighted we have been able to recruit Holden Thorp as the new editor-in-chief of the Science family of journals,” said Alan Leshner, interim chief executive officer of the American Association for the Advancement of Science (AAAS) and executive publisher of Science. “He is a distinguished scientist and administrator with a remarkable breadth of expertise.”

As editor-in-chief, Thorp will oversee a staff of PhD-level editors and award-winning writers for the family of journals including Science, which has the largest paid circulation of any peer-reviewed general science journal in the world. Published by AAAS, Science reaches approximately 1 million readers weekly.

“While we all will certainly miss Holden’s regular presence here at Washington University, we are thrilled for him to have been selected for this distinguished position,” said Chancellor Andrew D. Martin. “Not only is it a terrific honor for him, it also is a wonderful choice for the scientific community, which will no doubt benefit greatly from his leadership and expertise. I wish him all the best.”

Thorp, who holds faculty appointments in both chemistry and medicine, served as Washington University’s provost from 2013 until concluding his term last month. During his tenure as provost, he led the university’s academic enterprise through a period of tremendous growth in several key areas, including efforts to increase socioeconomic diversity and changes to the undergraduate admissions process, all of which led to an academically stronger and more diverse student body. He also was instrumental in furthering the university’s prominence as an institution that drives innovation and entrepreneurship, particularly in the St. Louis region.

“This is an extraordinary opportunity to serve the scientific community and advocate for the importance of science in Washington and throughout the world,” Thorp said. “Going from Washington University to Washington, D.C., will be a big change, but one thing that will remain a steady presence is the community of scientists and researchers who are working every day, all around the world, to make the discoveries that elucidate nature and change lives.”

Before coming to Washington University, Thorp served for three decades at the University of North Carolina at Chapel Hill, where he served as the 10th chancellor from 2008 through 2013. He earned a doctorate in chemistry in 1989 at the California Institute of Technology and completed postdoctoral work at Yale University. An inventor and entrepreneur, he developed technology for electronic DNA chips, and is the co-founder of Viamet Pharmaceuticals, which developed oteseconazole, now in Phase 3 clinical trials for fungal disease.

“I am delighted that AAAS has chosen Holden Thorp as editor-in-chief of the Science family of journals,” said Barbara A. Schaal, dean of the faculty of Arts & Sciences, the Mary-Dell Chilton Distinguished Professor of Biology, and a former president of AAAS. “As editor-in-chief, he will be one of the most significant voices in the global conversation about research and scientific discovery. Championing the value of science has never been more important, and I look forward to following along as he takes on this vital work.”

AAAS is the world’s largest general scientific society and publishes Science, as well as Science Translational Medicine; Science Signaling; a digital, open-access journal, Science Advances; Science Immunology; and Science Robotics. AAAS was founded in 1848 and includes more than 250 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world. The nonprofit AAAS is open to all and fulfills its mission to “advance science and serve society” through initiatives in science policy, international programs, science education, public engagement and more.

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Investigative journalist Carey Gillam will deliver the first talk of the fall 2019 Agri-Food Workshop lecture series, “Monsanto Trials and Monsanto Papers,” casting a critical eye on industry influence and pesticide science.

The talk, hosted by the Department of Anthropology in Arts & Sciences and the Institute for Public Health, will take place at 1 p.m. Aug. 30 in Seigle Hall, Room 204, on the Danforth Campus of Washington University in St. Louis. It is free and open to the public.

Gillam is a veteran journalist, researcher and writer with more than 25 years of experience in the news industry covering corporate America. Since 1998, Gillam’s work has focused on digging into the big business of food and agriculture.

A former senior correspondent for Reuters international news service, she is currently research director for consumer group U.S. Right to Know. Gillam said that she specializes in finding the story behind the spin, uncovering both the risks and rewards of the evolving new age of agriculture.

Gillam’s areas of expertise include biotech crop technology; agrichemicals and pesticide product development; and the environmental impacts of American food production. Gillam has been recognized as one of the top journalists in the country covering these issues.

Gillam is author of the 2017 book “Whitewash: The Story of a Weed Killer, Cancer, and the Corruption of Science.” The book won the 2018 Society of Environmental Journalists’ Rachel Carson Environmental Book Award.

Other upcoming talks in the Agri-Food Workshop lecture series include:

• Crops of the past and future: Natalie Mueller, assistant professor of anthropology in Arts & Sciences, on reconstructing the agroecology of lost crops; and Allison Miller, of Saint Louis University, on perennial crops and the future of agriculture. 1 p.m. Sept. 30 (location to be announced later).
• Fieldnotes on the Future of Food Production: Bradley Jones on learning processes among alternative farmers and James Babbitt on robotic dairies. Both speakers are PhD candidates in anthropology in Arts & Sciences. 1 p.m. Oct. 18 (location to be announced later).

For more information, visit the Agriculture and Food Studies website or contact Bradley Jones at 314-935-5346 or bradleyjones@wustl.edu or Glenn Stone at 314-935-5252 or stone@wustl.edu.

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More than 60% of women will experience a urinary tract infection (UTI) at some point in their lives, and about a quarter will get a second such infection within six months, for reasons that have been unclear to health experts.

Now, researchers at Washington University School of Medicine in St. Louis have discovered that an initial infection can set the tone for subsequent infections. In mouse studies, the researchers found that a transient infection triggers a short-lived inflammatory response that rapidly eliminates the bacteria. But if the initial infection lingers for weeks, the inflammation also persists, leading to long-lasting changes to the bladder that prime the immune system to overreact the next time bacteria find their way into the urinary tract, worsening the infection.

The findings, published Aug. 20 in eLife, suggest that reversing such changes to the bladder may help prevent or mitigate future UTIs.

“Millions of women suffer from recurrent bladder infections, and it can really take a toll on their quality of life,” said co-senior author Thomas J. Hannan, DVM, PhD, an instructor in pathology and immunology. “In the process of fighting these infections, the immune system sometimes does more harm to the bladder than to the bacteria. If we could fine-tune the immune response to keep the body focused on eliminating infecting bacteria, we might be able to reduce the severity of these infections.”

To understand why some people are more prone to severe, recurrent infections than others, Hannan and co-senior author Scott J. Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology – along with co-first authors Lu Yu and Valerie O’Brien, both graduate students who have since earned PhDs when the work was conducted – infected a strain of genetically identical mice with E. coli, the most common cause of UTIs in people. The strain can have widely divergent responses to bacterial bladder infections. Some eliminate the bacteria within a few days; others develop chronic infections that last for weeks.

The researchers infected these mice with E. coli, monitored them for signs of infection in their urine for four weeks, and then gave them antibiotics. After giving the mice a month to heal, the researchers infected them again. For comparison, they also infected a separate group of mice for the first time.

All the previously infected mice mounted immune responses more rapidly than the mice infected for the first time. The ones that had cleared the infection on their own the first time around did so again, eliminating the bacteria even faster than before. But the mice that failed to clear the infection the first time did much worse, despite the speed of their immune responses. A day after infection, 11 out of 14 had more bacteria in their bladders than they had started with, and many went on to again develop chronic infections that lasted at least four weeks.

The difference lay in an immune molecule called TNF-alpha that coordinates a powerful inflammatory response to infection, the researchers discovered. Both sets of mice turned on TNF-alpha within six hours of infection. But the mice that controlled the infection turned off TNF-alpha again within 24 hours, allowing the inflammation to resolve. In the mice with prolonged initial infections, TNF-alpha stayed on, driving persistent inflammation and triggering a change to the patterns of gene activity in immune cells and the cells of the bladder wall.

“After a chronic infection, even though the bacteria have been eliminated with antibiotics and the bladder lining has healed, the behavior of cells lining the bladder do not revert back to normal even after the inflammation is finally resolved,” Hannan said. “The bladder becomes trained to respond to infecting bacteria too harshly, causing tissue damage that predisposes to recurrent infection. So then the question becomes, ‘Can we retrain these bladders to be more predisposed to resolving inflammation quickly?’”

To find out, the researchers took mice that had recovered from initial prolonged UTIs and depleted their TNF-alpha before re-infecting them with bacteria. Without TNF-alpha driving excessive inflammation, the mice fared better, significantly reducing the number of bacteria in their bladders within a day of infection.

The findings suggest that targeting TNF-alpha or another aspect of the inflammatory response that causes bladder tissue damage during acute infection may help prevent or alleviate recurrent UTIs, the researchers said.

“Improving our understanding of this underlying biological process will be essential for developing new therapies that target inflammation as an alternative strategy against rapidly increasing antimicrobial resistance,” Hultgren said.

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Ai Weiwei is among the most rigorous, challenging and outspoken artists in the world today. This fall, the renowned Chinese dissident will discuss his wide-ranging practice as part of a public Q&A at Washington University in St. Louis.

The talk, which will take place Sept. 26, is presented as part of the Sam Fox School of Design & Visual Arts’ fall Public Lecture Series. In all, the series will feature eight presentations by internationally renowned artists, architects, art historians and designers.

Events begin Sept. 19 with Swiss architect Patrick Gmür, founding partner of Gmür & Geschwentner and a former director of urban planning for the City of Zurich, who is serving as the Sam Fox School’s Ruth and Norman Moore Visiting Professor this fall. The winner of numerous architectural competitions, Gmür is internationally renowned for his housing developments and school buildings. Major projects in Zurich include the James and Paul Clairmont housing development, the Hard Turm Park high rise and the Scherr schoolhouse renovation and extension.

Sabine Eckmann, the William T. Kemper Director and chief curator of Washington University’s Mildred Lane Kemper Art Museum, will host the Sept. 26 Q&A with Ai. Co-sponsored by the Assembly Series, the event will explore the artist’s ongoing engagement with human rights issues and with Chinese culture past and present. It comes in conjunction with the exhibition “Ai Weiwei: Bare Life,” a major survey debuting at the newly expanded Kemper Art Museum Sept. 27 and 28.

The series will continue Oct. 23 with art historian John Curley, followed on Oct. 24 by Yvonne Farrell, founder of Dublin-based Grafton Architects. The “Decoys & Depictions” symposium, which explores the role of digital images in contemporary art and architecture, will feature keynote addresses by Nader Tehrani, dean of architecture at The Cooper Union (Oct. 25), and Brett Steele, dean of UCLA Arts (Oct. 26).

Native American artist Duane Slick will present the Arthur L. and Sheila Prensky Island Press Visiting Lecture Nov 4. Rounding out the series will be Dave Hullfish Bailey, who will present the Henry L. And Natalie E. Freund Teaching Fellow Lecture Nov. 17 at the Saint Louis Art Museum, in conjunction with his fall Currents exhibition.

All events are free and open to the public, though tickets are required for the Q&A with Ai. See here for details. Unless otherwise noted, all events will begin at 6 p.m. in Steinberg Hall Auditorium and will be preceded by a reception at 5:30 p.m.

Steinberg Hall is located on the east end of Washington University’s Danforth Campus, near the intersection of Skinker and Forsyth boulevards and immediately adjacent to the Kemper Art Museum. For more information, call 314-935-9300 or visit samfoxschool.wustl.edu.

Fall 2019 events

Sept. 19
Patrick Gmür
Founding partner, Gmür & Geschwentner Architekten
Ruth & Norman Moore Visiting Professor Lecture

Sept. 26
Ai Weiwei
Artist
Bunny & Charles Burson Visiting Artist Lecture
Q&A with Sabine Eckmann
5:30 p.m. in Edison Theatre. Livestream in Steinberg Auditorium.

Oct. 23
John Curley
Associate professor, modern and contemporary art
Wake Forest University
“Ai Weiwei: Between Mao and Warhol”
6:30 p.m. in the Kemper Art Museum Lobby

Oct. 24
Yvonne Farrell
Founding director, Grafton Architects
Ruth Kahn Lynford Lecture

Oct. 25
Nader Tehrani
Dean of architecture, The Cooper Union
AIA St. Louis Scholarship Fund Lecture
Keynote address, “Decoys & Depictions: Images of the Digital Symposium”
5:30 p.m. in the Kuehner Family Court, Weil Hall

Oct. 26
Brett Steele
Dean, UCLA School of the Arts and Architecture
Abend Family Lecture
Keynote address, “Decoys & Depictions: Images of the Digital Symposium”
5:30 p.m. in the Kuehner Family Court, Weil Hall

Nov. 4
Duane Slick
Professor of painting, Rhode Island School of Design
Arthur L. and Sheila Prensky Island Press Visiting Artist Lecture

Nov. 17
Dave Hullfish Bailey
Henry L. And Natalie E. Freund Teaching Fellow Lecture
2 p.m. at the Saint Louis Art Museum

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