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Tag: Washington University in St. Louis

  • ‘Long flu’ has emerged as a consequence similar to long COVID

    ‘Long flu’ has emerged as a consequence similar to long COVID

    BYLINE: Kristina Sauerwein

    Newswise — Since the COVID-19 pandemic began, extensive research has emerged detailing the virus’s ability to attack multiple organ systems, potentially resulting in a set of enduring and often disabling health problems known as long COVID. Now, new research from Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care System indicates that people hospitalized with seasonal influenza also can suffer long-term, negative health effects, especially involving their lungs and airways.

    The new study comparing the viruses that cause COVID-19 and the flu also revealed that in the 18 months after infection, patients hospitalized for either COVID-19 or seasonal influenza faced an increased risk of death, hospital readmission, and health problems in many organ systems. Further, the time of highest risk was 30 days or later after initial infection.

    “The study illustrates the high toll of death and loss of health following hospitalization with either COVID-19 or seasonal influenza,” said senior author Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University. “It’s critical to note that the health risks were higher after the first 30 days of infection. Many people think they’re over COVID-19 or the flu after being discharged from the hospital. That may be true for some people. But our research shows that both viruses can cause long-haul illness.”

    The findings are published Dec. 14 in The Lancet Infectious Diseases.

    The statistical analysis spanned up to 18 months post-infection and included a comparative evaluation of risks of death, hospital admissions and 94 adverse health outcomes involving the body’s major organ systems.

    “A review of past studies on COVID-19 versus the flu focused on a short-term and narrow set of health outcomes,” said Al-Aly, who treats patients within the VA St. Louis Health Care System and is an assistant professor of medicine at Washington University. “Our novel approach compared the long-term health effects of a vast array of conditions. Five years ago, it wouldn’t have occurred to me to examine the possibility of a ‘long flu.’ A major lesson we learned from SARS-CoV-2 is that an infection that initially was thought to only cause brief illness also can lead to chronic disease. This revelation motivated us to look at long-term outcomes of COVID-19 versus flu.

    “We wanted to know whether and to what degree people with flu also experience long-term health effects,” Al-Aly said. “The big answer is that both COVID-19 and the flu led to long-term health problems, and the big aha moment was the realization that the magnitude of long-term health loss eclipsed the problems that these patients endured in the early phase of the infection. Long COVID is much more of a health problem than COVID, and long flu is much more of a health problem than the flu.”

    However, the overall risk and occurrence of death, hospital admissions, and loss of health in many organ systems are substantially higher among COVID-19 patients than among those who have had seasonal influenza, Al-Aly said. “The one notable exception is that the flu poses higher risks to the pulmonary system than COVID-19,” he said. “This tells us the flu is truly more of a respiratory virus, like we’ve all thought for the past 100 years. By comparison, COVID-19 is more aggressive and indiscriminate in that it can attack the pulmonary system, but it can also strike any organ system and is more likely to cause fatal or severe conditions involving the heart, brain, kidneys and other organs.”

    The researchers analyzed de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation’s largest integrated health-care delivery system. They evaluated information involving 81,280 patients hospitalized for COVID-19 at some point from March 1, 2020, through June 30, 2022, as well as 10,985 patients hospitalized for seasonal influenza at some point from Oct. 1, 2015, through Feb. 28, 2019.

    Patients represented multiple ages, races and sexes.

    Regarding both viruses, patient vaccination status did not affect results. Those in the COVID-19 cohort were hospitalized during the pre-delta, delta and omicron eras.

    During the overall 18-month study period, patients who had COVID-19 faced a 50% higher risk of death than those with seasonal influenza. This corresponded to about eight more deaths per 100 persons in the COVID-19 group than among those with the flu.

    Although COVID-19 showed a greater risk of health loss than seasonal influenza, infection with either virus carried significant risk of disability and disease. The researchers found COVID-19 exhibited increased risk of 68% of health conditions examined across all organ systems (64 of the 94 adverse health outcomes studied), while the flu was associated with elevated risk of 6% of health conditions (six of the 94) – mostly in the respiratory system.

    Also, over 18 months, COVID-19 patients experienced an increased risk of hospital readmission as well as admission to an intensive care unit (ICU). For every 100 persons in each group, there were 20 more hospital admissions and nine more ICU admissions in COVID-19 than flu.

    “Our findings highlight the continued need to reduce the risk of hospitalization for these two viruses as a way to alleviate the overall burden of health loss in populations,” Al-Aly said. “For both COVID-19 and seasonal influenza, vaccinations can help prevent severe disease and reduce the risk of hospitalizations and death. Optimizing vaccination uptake must remain a priority for governments and health systems everywhere. This is especially important for vulnerable populations such as the elderly and people who are immunocompromised.”

    In both COVID-19 and the flu, more than half of death and disability occurred in the months after infection as opposed to the first 30 days, the latter of which is known as the acute phase.

    “The idea that COVID-19 or flu are just acute illnesses overlooks their larger long-term effects on human health,” Al-Aly said. “Before the pandemic, we tended to belittle most viral infections by regarding them as somewhat inconsequential: ‘You’ll get sick and get over it in a few days.’ But we’re discovering that is not everyone’s experience. Some people are ending up with serious long-term health issues. We need to wake up to this reality and stop trivializing viral infections and understand that they are major drivers of chronic diseases.”

    Washington University in St. Louis

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  • Separating out signals recorded at the seafloor

    Separating out signals recorded at the seafloor

    Newswise — Blame it on plate tectonics. The deep ocean is never preserved, but instead is lost to time as the seafloor is subducted. Geologists are mostly left with shallower rocks from closer to the shoreline to inform their studies of Earth history.

    “We have only a good record of the deep ocean for the last ~180 million years,” said David Fike, the Glassberg/Greensfelder Distinguished University Professor of Earth, Environmental, and Planetary Sciences in Arts & Sciences at Washington University in St. Louis. “Everything else is just shallow-water deposits. So it’s really important to understand the bias that might be present when we look at shallow-water deposits.”

    One of the ways that scientists like Fike use deposits from the seafloor is to reconstruct timelines of past ecological and environmental change. Researchers are keenly interested in how and when oxygen began to build up in the oceans and atmosphere, making Earth more hospitable to life as we know it.

    For decades they have relied on pyrite, the iron-sulfide mineral known as “fool’s gold,” as a sensitive recorder of conditions in the marine environment where it is formed. By measuring the bulk isotopic composition of sulfur in pyrite samples — the relative abundance of sulfur atoms with slightly different mass — scientists have tried to better understand ancient microbial activity and interpret global chemical cycles.

    But the outlook for pyrite is not so shiny anymore. In a pair of companion papers published Nov. 24 in the journal Science, Fike and his collaborators show that variations in pyrite sulfur isotopes may not represent the global processes that have made them such popular targets of analysis.

    Instead, Fike’s research demonstrates that pyritte responds predominantly to local processes that should not be taken as representative of the whole ocean. A new microanalysis approach developed at Washington University helped the researchers to separate out signals in pyrite that reveal the relative influence of microbes and that of local climate.

    For the first study, Fike worked with Roger Bryant, who completed his graduate studies at Washington University, to examine the grain-level distribution of pyrite sulfur isotope compositions in a sample of recent glacial-interglacial sediments. They developed and used a cutting-edge analytical technique with the secondary-ion mass spectrometer (SIMS) in Fike’s laboratory.

    “We analyzed every individual pyrite crystal that we could find and got isotopic values for each one,” Fike said. By considering the distribution of results from individual grains, rather than the average (or bulk) results, the scientists showed that it is possible to tease apart the role of the physical properties of the depositional environment, like the sedimentation rate and the porosity of the sediments, from the microbial activity in the seabed.

    “We found that even when bulk pyrite sulfur isotopes changed a lot between glacials and interglacials, the minima of our single grain pyrite distributions remained broadly constant,” Bryant said. “This told us that microbial activity did not drive the changes in bulk pyrite sulfur isotopes and refuted one of our major hypotheses.”

    “Using this framework, we’re able to go in and look at the separate roles of microbes and sediments in driving the signals,” Fike said. “That to me represents a huge step forward in being able to interpret what is recorded in these signals.”

    In the second paper, led by Itay Halevy of the Weizmann Institute of Science and co-authored by Fike and Bryant, the scientists developed and explored a computer model of marine sediments, complete with mathematical representations of the microorganisms that degrade organic matter and turn sulfate into sulfide and the processes that trap that sulfide in pyrite.

    “We found that variations in the isotopic composition of pyrite are mostly a function of the depositional environment in which the pyrite formed,” Halevy said. The new model shows that a range of parameters of the sedimentary environment affect the balance between sulfate and sulfide consumption and resupply, and that this balance is the major determinant of the sulfur isotope composition of pyrite.

    “The rate of sediment deposition on the seafloor, the proportion of organic matter in that sediment, the proportion of reactive iron particles, the density of packing of the sediment as it settles to the seafloor — all of these properties affect the isotopic composition of pyrite in ways that we can now understand,” he said.

    Importantly, none of these properties of the sedimentary environment are strongly linked to the global sulfur cycle, to the oxidation state of the global ocean, or essentially any other property that researchers have traditionally used pyrite sulfur isotopes to reconstruct, the scientists said.

    “The really exciting aspect of this new work is that it gives us a predictive model for how we think other pyrite records should behave,” Fike said. “For example, if we can interpret other records — and better understand that they are driven by things like local changes in sedimentation, rather than global parameters about ocean oxygen state or microbial activity — then we can try to use this data to refine our understanding of sea level change in the past.”

    Washington University in St. Louis

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  • Expert: Auto workers’ strike could impact future labor organizing

    Expert: Auto workers’ strike could impact future labor organizing

    In an unprecedented move, unionized auto workers from General Motors, Ford and Chrysler owner Stellantis have joined forces to pressure Detroit’s big three automakers into increasing wages and benefits.

    Even before the United Auto Workers (UAW) walked out Sept. 15, 2023 had already been unofficially named “the summer of strikes” for the unusually high level of labor activity. That’s because the persistently tight labor market combined with growing frustration over wage inequality has encouraged workers across industries to fight back and organize, according to Jake Rosenfeld, an expert on labor unions and a professor of sociology in Arts & Sciences at Washington University in St. Louis.

    Also fueling the trend: Support for unions is higher than it has been in nearly six decades. In a 2022 analysis for The Washington Post, Rosenfeld wrote, “The recent successes of organizing drives at Starbucks, Amazon, Trader Joe’s and elsewhere suggest unions are capitalizing on worker support and finding ways to overcome the barriers that have diminished their ranks in recent decades. The rising popularity of unions will probably bolster these efforts. After all, labor organizing is impossible if there is no support for unions.”

    With 13,000 auto workers in Missouri, Michigan and Ohio now on strike and others positioned to join them — including the union that represents autoworkers in Canada — the outcome of the UAW strike has the potential to impact future labor activity in the U.S., according to Rosenfeld, author of “You’re Paid What You’re Worth and Other Myths of the Modern Economy” and “What Unions No Longer Do.”

    “Past research has shown that successful strikes can prove contagious and spread to other industries,” he said. “But the strikes have to be successful. It’s important to keep in mind we have ongoing strikes out west in Los Angeles with writers, screen actors and hotel workers that unions are also watching closely. If these strikes fail, that could dampen enthusiasm for further action just as quickly as a successful strike could increase enthusiasm.”

    Below, Rosenfeld answers some of the common questions associated with the UAW strike.  

    Some have criticized the UAW’s demands as unreasonable. What’s your take?

    It’s hard to know without being privy to the inside negotiations which of the union’s demands are bargaining chips and which are non-negotiable. Certainly, they are asking for a lot, but the broader context here is important. For decades, the companies have eroded autoworkers’ contracts, claiming doing so was necessary to maintain competitiveness and — in the aftermath of the Great Recession — to stay afloat financially. The union is trying to claw back a lot that was lost during those lean years now that the companies are enjoying record profits.

    Do you think the current political environment has emboldened the auto workers?

    I think broader public sentiment certainly buttresses the union’s case here. But probably more importantly is the economic environment: You’ve got record-low unemployment combined with an auto sector that is thriving, making it the perfect opportunity for auto workers to ask for a share in the revenue.

    Will the work stoppage be long? What factors could affect that?

    Nobody wants a long strike, so certainly the incentives — and increasing pressures — are on both sides to find a deal. It does seem that both sides are actively negotiating, which hopefully indicates that they can find a solution in relatively short order.

    Last December, President Joe Biden and his administration played a role in preventing a railroad strike that would have devastated the economy. How might the Biden administration get involved in this strike?

    Whether or not the Biden administration gets involved likely depends on the duration of the strike and the broader devastation a long strike could play in key — politically speaking — state economies. But for now, what I’d expect is that the administration lets this play out while offering mediation as needed and requested by both sides.
     

    Washington University in St. Louis

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  • Here’s the Full Story of the Panda Express Postdoc

    Here’s the Full Story of the Panda Express Postdoc

    As soon as Twitter found the “Panda Express Postdoctoral Fellowship in Asian American Studies” at the University of Pennsylvania — posted on The Chronicle’s own job board — the jokes started rolling in.

    “Born too late to experience a good job market, too early to be a teen TikTok star,” lamented one Twitter user, a doctoral student studying Asian immigration. “Just in time to see the Panda Express postdoc.”

    Outrage soon followed. “IN NO UNIVERSE SHOULD A POSTDOC BE SPONSORED BY PANDA EXPRESS. The fact that it’s in Asian American studies is optically awful,” wrote another Twitter-using graduate student, who is not in an Asian American studies program.

    “Oh my god,” tweeted Ian Bogost, a professor of film and media studies at Washington University in St. Louis, contributing writer at The Atlantic, and Twitter user with 109,100 followers. (He later wrote he didn’t mean to judge. But he asked readers to “consider the lower-status postdoc whose CV will forever be an orange chicken ad.”)

    Completing the life cycle of a viral post on Twitter, people replied to Bogost’s tweet with outrage about his outrage. “What’s the problem here, Ian? … It’s a great Asian American immigrant-success story.” “This says everything about the snobbery of a certain sector of academics.” There was even a sprinkling of bad Chinese-food jokes that, in their cringiness, read as vaguely distasteful, if not racist. “Two writing samples? Is that like two sides, one lo mein, one rice?” Free hint with meal: Dad jokes don’t work if they’re about marginalized communities that are not your own.

    But the story of the Panda Express Postdoc is in many ways similar to those of more-solemn-sounding academic fellowships.

    There’s a big donor: Forbes estimates that Panda Express does $3.5 billion in sales annually. And there’s a personal connection: Andrea Cherng, daughter of the founders, Andrew and Peggy Cherng, and chief brand officer for the Panda Restaurant Group, graduated from the University of Pennsylvania in 1999 with a major in sociology and a minor in Asian American studies.

    In fact, Andrea Cherng was among the students who pushed for the creation of Penn’s Asian American studies program, which was established in 1996, said faculty members involved with it at the time. Nearly every Asian American studies program owes its existence to student activism, experts say, and Penn’s is no exception.

    “Panda and the Cherngs have always been avid supporters of the AAPI [Asian American/Pacific Islander] community and causes through philanthropy as well as brand and corporate initiatives,” read a written statement sent to The Chronicle by Jessica Chao, a spokesperson for the Panda Restaurant Group.

    Panda Express has pledged $450,000 to support five positions over the next three years. The scholars will be Penn’s first-ever postdoctoral researchers in Asian American studies. “It’s historic,” said David L. Eng, one of the program’s directors.

    A Good Name to Know

    Not everyone involved with the Asian American studies program’s founding at Penn knew of Andrea Cherng and her family’s background, but enough did. When the program celebrated its 25th anniversary in March 2022, with a series of events that drew hundreds of attendees, Eng and his co-director, Fariha I. Khan, kept hearing Andrea’s name. Alumni knew their beloved program was always seeking funding and a more stable future. Couldn’t Cherng be a source?

    Nearly every Asian American studies program owes its existence to student activism.

    The directors submitted a grant application last fall to the Panda CommUnity Fund, an effort created through a $10-million pledge that Panda Express made in 2021 to support nonprofits serving minority communities. Why didn’t the funders call the position something less eyebrow-raising, like the “Cherng Family Postdoc”? As one Twitter user wrote: “If this was the Richie Rockefeller IV postdoc, no one would bat an eye.” Chao explained that the fellowships are named after the restaurant, not the family, because the money comes from the corporate fund and not the family foundation.

    Staff members at the Cherng Family Trust reviewed the application, and Khan and Eng got the good news over email in February.

    Big Asian American donors aren’t new to supporting higher education, both within and outside of ethnic-studies programs. In 2017, the Cherngs themselves donated $30 million to what’s now called the Andrew and Peggy Cherng Department of Medical Engineering at the California Institute of Technology. But there’s been fresh interest in the study of Asian Americans and their roles in American culture and history since the onset of the pandemic.

    In the early days of the coronavirus’s spread in the United States, former President Donald J. Trump began calling it the “Chinese virus,” and the country saw a rise in hate incidents aimed at people of Asian descent. In response, Asian American activism of all kinds ramped up, and in 2021 two high-profile universities received major gifts related to Asian American studies and student life. Stanford University’s Asian American Activities Center got an endowed directorship, and Harvard University received more than $45 million from 10 alumni to expand the Asian American studies program.

    Meanwhile, Asian American student activists upped their demands for Asian- and Asian American-focused courses, hires, and student centers. There’s plenty of room for growth in the discipline. Outside of the western United States, Asian American studies departments are underdeveloped, experts say. Among Ivy League institutions, only Cornell University and the University of Pennsylvania have dedicated programs.

    Since the pandemic began, Duke University, Harvard, and Penn have all made cluster hires in the field. “This moment is transformative,” Khan said.

    Mass Appeal

    Early in the pandemic, the Cherng family, too, was disturbed by rising anti-Asian and anti-Chinese sentiment.

    Peggy Tsiang Cherng was born in Myanmar, Andrew in China. Both came to the United States for college in the mid-1960s, meeting as freshmen at Baker University, in Kansas. Profiles of the Panda Express business have attributed its success, in part, to the software that Peggy, who holds a doctorate in electrical engineering, wrote to track sales and inventory.

    Andrew opened the first Panda restaurant with his father, in Pasadena, Calif. (Peggy joined later.) Panda dishes have an authentic Chinese origin — Andrew’s father had trained in culinary school in southwest China — but they’ve been tweaked to appeal to the American masses, Andrea Cherng has said. “They took what they knew and they tailored it to an American audience, in order to have the volume of business they needed to provide,” she told The Splendid Table in 2017.

    Early in the pandemic, the chain suffered steep losses in certain regions, The Wall Street Journal reported. “Our stores and associates did experience xenophobia,” wrote Chao, the Panda Express spokesperson, but the company sought to regain public trust through health measures in the stores and donations to community Covid-relief efforts.

    Through Chao, Andrea declined interview requests from The Chronicle. She was quoted in the Penn student newspaper during her undergraduate days, advocating for more Asian American hires and raising awareness for ethnic-studies programs at the university. When the Asian American studies program was formally established, she became chair of its undergraduate advisory board.

    Rosane Rocher, professor emerita of South Asia studies and the program’s first director, recalled Andrea taking on secretarial tasks for the fledgling program, which had no dedicated staff members. “She was a dream,” Rocher said.

    After earning advanced degrees in law and business, Andrea worked elsewhere in the private sector before joining the family business.

    In a statement, Andrea wrote that she hopes Panda Express’s investment in the Asian American studies program will help students to “understand our collective history” and “learn from the past so that there could be greater belonging for those that may appear to have foreign faces.”

    Every program might hope to leave such a mark on its students that they remember it, three decades later, and that at least one of them has the means to turn that memory into major support for scholars and research. In return, the donors would typically get naming rights.

    Francie Diep

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  • Red flags indicate risk for early-onset colorectal cancer

    Red flags indicate risk for early-onset colorectal cancer

    Newswise — Researchers at Washington University School of Medicine in St. Louis have identified four important signs and symptoms that signal an elevated risk of early-onset colorectal cancer. These red flags may be key to earlier detection and diagnosis of early-onset colorectal cancer among younger adults. The number of young adults with colorectal cancer has nearly doubled in recent years.

    Studying de-identified health insurance data on more than 5,000 patients with early-onset colorectal cancer — cancer that occurs before a person turns 50 — the researchers found that in the period between three months and two years before diagnosis, abdominal pain, rectal bleeding, diarrhea and iron deficiency anemia each indicate an increased risk in those under age 50. They found that having a single one of the symptoms almost doubled the risk; having two symptoms increased risk by more than 3.5 times; and having three or more boosted the risk by more than 6.5 times.

    The study is published May 4 in the Journal of the National Cancer Institute.

    “Colorectal cancer is not simply a disease affecting older people; we want younger adults to be aware of and act on these potentially very telling signs and symptoms — particularly because people under 50 are considered to be at low risk, and they don’t receive routine colorectal cancer screening,” said senior investigator Yin Cao, ScD, an associate professor of surgery in the Public Health Sciences Division, and a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

    “It’s also crucial to spread awareness among primary care doctors, gastroenterologists and emergency medicine doctors,” Cao said. “To date, many early-onset colorectal cancers are detected in emergency rooms, and there often are significant diagnostic delays with this cancer.”

    Cao said two symptoms in particular — rectal bleeding and iron deficiency anemia, a condition in which there are not enough healthy red blood cells to carry oxygen — point to the need for timely endoscopy and follow-up.

    In this study, Cao, with first author Cassandra D. L. Fritz, MD, an assistant professor of medicine in the Division of Gastroenterology, and co-first author Ebunoluwa Otegbeye, MD, a general surgery resident, analyzed cases of early-onset colorectal cancer and matched controls using the IBM MarketScan Commercial Database, a big-data tool that provides longitudinal, de-identified information based on health insurance claims data from about 113 million insured adults ages 18 to 64.

    “It usually takes about three months to get a diagnosis from the time a person first goes to the doctor with one or more of the red-flag signs and symptoms we’ve identified,” Fritz said. “But in this analysis, we found that some young adults had symptoms for up to two years prior to their diagnoses. That may be part of the reason many of these younger patients had more advanced disease at the time of diagnosis than what we normally see in older people who get screened regularly.”

    Individuals born in 1990 have double the risk of colon cancer and four times the risk of rectal cancer compared with young adults born in 1950. That trend has prompted the National Cancer Institute, American Cancer Society, American Gastroenterological Association and other professional societies to prioritize research on identifying risk factors and improving early detection. In 2021, the U.S. Preventive Services Task Force lowered the recommended age for colorectal cancer screening from 50 to 45.

    Cao, also an associate professor of medicine, leads a research group focused on identifying risk factors and molecular variations in early-onset colorectal cancer. Her group is among the first to report that obesity, prolonged sitting, metabolic syndrome, diabetes, sugar-sweetened beverages and other risk factors may contribute to the rising incidence of early-onset colorectal cancer.

    According to the American Cancer Society, although the death rate from colorectal cancer has been dropping for several decades in older adults due to regular colonoscopies and improved treatment, more younger people are diagnosed with the disease at advanced stages, and many are dying of the disease.

    Such a shift suggests urgency in recognizing symptoms as early as possible.

    “Since the majority of early-onset colorectal cancer cases have been and will continue to be diagnosed after symptom presentation, it is crucial to recognize these red-flag signs and symptoms promptly and conduct a diagnostic work-up as soon as possible,” Cao said. “By doing so, we can diagnose the disease earlier, which in turn can reduce the need for more aggressive treatment and improve patients’ quality of life and survival rates.”

    Fritz, CDL. Otegbeye EE, Zong X, Demb J, Nickel KB, Olsen MA, Mutch M, Davidson NO, Gupta S, Cao Y. Red-flag signs and symptoms for earlier diagnosis of early-onset colorectal cancer. The Journal of the National Cancer Institute, May 4, 2023.

    The study was funded with support from the National Center for Advancing Translational Sciences, the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH). Grant numbers: UL1 TR002345, T32 DK007130, T32 CA009621, P30 DK52574 and R37 CA246175.

    About Washington University School of Medicine

    WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

    Washington University in St. Louis

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  • Small proteins in heart play big role

    Small proteins in heart play big role

    BYLINE: Beth Miller

    Newswise — A heartbeat is a carefully coordinated series of electrical signals led by sodium ion channels, which tell the heart when to contract and to relax. Any disruption to these signals may lead to cardiac diseases such as an irregular heartbeat, or arrhythmia. Two researchers at Washington University in St. Louis have taken a closer look at this process at the molecular level and have found what may provide new insights into different heart conditions and how to develop better therapies.

    Jonathan Silva, the Dennis & Barbara Kessler Career Development Associate Professor at the McKelvey School of Engineering, and Jeanne Nerbonne, Alumni Endowed Professor of Molecular Biology & Pharmacology in Medicine and Developmental Biology at the School of Medicine, and their labs found distinct effects of novel proteins, known as intracellular fibroblast growth factors (iFGF), on the regulation of the kinetics of cardiac sodium channel gating. Their results were published in the Journal of General Physiology March 21.

    Intracellular fibroblast growth factors are small proteins that are known to bind to sodium channels and to influence how these channels open and close, or “gate.” The gating properties of cardiac sodium channels affect how the electromechanical propagate through the heart. In addition, drugs interact differently with the sodium channels in different gating (i.e., open and closed) states, Silva said.

    The team sought to determine how one intracellular fibroblast growth factor, iFGF12, works in a healthy human heart by observing how the iFGFs change the sodium channel at the molecular level. Nerbonne’s lab generated a mouse model with iFGF12 to observe how it modulates the sodium channel in myocytes. Using electrophysiology methods, they found that it modulated the channel differently than the comparable iFGF in the mouse heart and changed the properties of the sodium current.

    “One of the reasons we want to define how the iFGFs and other sodium channel accessory proteins affect channel properties at the molecular level is that we know from previous work that the protein components of functional channels influence the pharmacology of these channels,” said Nerbonne, who also is the director of the Center for Cardiovascular Research. “These channels are potential therapeutic targets for people with arrhythmias.”

    Silva’s lab looked at how the iFGF affects channel function through methods they have developed to watch the voltage sensing domains.

    “We looked at how these subunits affect native cell electrophysiology, and that’s an exciting part of our collaboration with the Nerbonne lab,” Silva said. “We were able to determine how these subunits change the channel at the molecular level to cause those cell-level effects.”

    Going forward, the team plans to take a closer look at how different drugs interact with sodium channels that have different iFGF compositions.

    ***

    Originally published by the McKelvey School of Engineering.

    Angsutararux P, Dutta AK, Marras M, Abella C, Mellor RL, Shi J, Nerbonne JM, Silva JR. Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors. Journal of General Physiology, March 21, 2023. https://doi.org/10.1085/jgp.202213300

    This research was supported by the National Institutes of Health’s National Heart, Lung, and Blood Institute (R01 142520 and R01 HL150637); the NIH National Center for Research Resources (UL1 RR024992) and the Children’s Discovery Institute Pediatric Disease Mouse Models Core at Washington University.

    Washington University in St. Louis

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  • Adding antipsychotic med to antidepressant may help older adults with treatment-resistant depression

    Adding antipsychotic med to antidepressant may help older adults with treatment-resistant depression

    BYLINE: Jim Dryden

    Newswise — For older adults with clinical depression that has not responded to standard treatments, adding the drug aripiprazole (brand name Abilify) to an antidepressant they’re already taking is more effective than switching from one antidepressant to another, according to a new multicenter study led by Washington University School of Medicine in St. Louis.

    Aripiprazole originally was approved by the FDA in 2002 as a treatment for schizophrenia but also has been used in lower doses as an add-on treatment for clinical depression in younger patients who do not respond to antidepressants alone.

    The new findings are published March 3 in The New England Journal of Medicine and are to be presented that same day by Eric J. Lenze, MD — principal investigator and head of the Department of Psychiatry at Washington University — and colleagues at the annual meeting of the American Association for Geriatric Psychiatry in New Orleans.

    Many people with clinical depression don’t respond to medications used to treat the condition. Consequently, some doctors switch such patients to different antidepressants in the pursuit of finding one that works, while other physicians may prescribe another class of drugs to see if a combination of medications helps.

    Both strategies have been recommended by experts as options for older adults with treatment-resistant depression. However, the new study was designed to help determine which strategy is most effective. Augmenting an antidepressant with aripiprazole helped 30% of patients with treatment-resistant depression, compared to only 20% who were switched to another solo antidepressant, results of the study show.

    “Often, unless a patient responds to the first treatment prescribed for depression, physicians follow a pattern in which they try one treatment after another until they land on an effective medication,” said Lenze, the Wallace and Lucille Renard Professor and the study’s corresponding author. “It would be beneficial to have an evidence-based strategy we can rely on to help patients feel better as quickly as possible. We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being — which means how positive and satisfied patients felt — and this is good news. However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people.”

    Treatment-resistant depression is no more or less common in older people than younger people, but because it seems to accelerate cognitive decline, identifying more effective ways to treat it is very important.

    Lenze, along with colleagues at Columbia University, UCLA, the University of Pittsburgh and the University of Toronto, studied 742 people, ages 60 and older, with treatment-resistant depression, meaning their depression had not responded to at least two different antidepressant medications.

    The researchers evaluated strategies commonly used in clinical practice to help alleviate treatment-resistant depression in older patients and designed the study to have two distinct phases. In the first phase, 619 patients, each of whom was taking an antidepressant such as Prozac, Lexapro or Zoloft, were randomly divided into three groups. In the first group, patients remained on whatever antidepressant drug each already was taking but also received the drug aripiprazole (Abilify). A second group also continued taking antidepressants but added bupropion (brand names Wellbutrin or Zyban), and a third group tapered off of the antidepressant each had been taking and switched to bupropion entirely.

    Over the course of 10 weeks, the participants received biweekly phone calls or in-person visits with study clinicians. At these visits, the medications were adjusted according to the individual patient’s response and side effects. The researchers found that the group that experienced the best overall outcomes was the one in which patients continued with their original antidepressants but added aripiprazole.

    The researchers also anticipated that some people in the study wouldn’t respond to the various treatments, so they added a second phase that included 248 participants. In this phase, patients taking antidepressants such as Prozac, Lexapro and Zoloft were treated with lithium or nortriptyline — medications that were widely used before those other, newer antidepressants were approved more than two decades ago. Rates of alleviating depression in the study’s second phase were low, about 15%. And there was no clear winner when augmentation with lithium was compared with switching to nortriptyline.

    “Those older drugs also are a bit more complicated to use than newer treatments,” Lenze explained. “Lithium, for example, requires blood testing to ensure its safety, and it’s recommended that patients taking nortriptyline receive electrocardiograms periodically to monitor the heart’s electrical activity. Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases.”

    But even the best treatment strategy — adding aripiprazole to an antidepressant — was not markedly successful for many older patients with treatment-resistant depression.

    “This really highlights a continuing problem in our field,” said senior author Jordan F. Karp, MD, professor and chair of the Department of Psychiatry at the University of Arizona College of Medicine – Tuscon. “Any given treatment is likely to help only a subset of people, and ideally, we would like to know, in advance, who is most likely to be helped, but we still don’t know how to determine that.”

    Lenze emphasized that overall, antidepressants are highly helpful for the majority of people suffering from clinical depression. At least half of all people with depression feel much better after they begin taking the first medication they try. And almost half of the remainder not helped by a first drug improve when switched to a second drug, But that leaves a sizeable group with clinical depression that does not respond to two treatments.

    The problem is particularly difficult in older adults, many of whom already are taking several medications for other conditions such as high blood pressure, cardiac issues or diabetes,” Lenze said. “So switching to new antidepressants every few weeks or adding other psychiatric drugs can be complicated. In addition, because depression and anxiety in older adults may accelerate cognitive decline, there’s an urgency to find more effective treatment strategies.

    “There definitely is something that makes depression harder to treat in this population, a population that’s only going to keep getting larger as our society gets older,” he added.

    Lenze EJ, et al. Trial of antidepressant augmentation vs. switching in treatment-resistant geriatric depression. The New England Journal of Medicine, March 3, 2023.

    The study was funded by a grant from the Patient-Centered Outcomes Research Institute (PCORI), grant TRD-1511-33321. No in-kind support was received from pharmaceutical companies. Other funding was provided by the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine. Other support came from the National Center for Advancing Translational Sciences and the National Institute of Mental Health of the National Institutes of Health (NIH). Grant numbers: 5RO1 MH114980, K24 AT009198, R01 MH114981. Additional funding provided by the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto.

    About Washington University School of Medicine

    WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

    Washington University in St. Louis

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  • Commonly used police diversity training unlikely to change officers’ behavior, study finds

    Commonly used police diversity training unlikely to change officers’ behavior, study finds

    Newswise — Tyre Nichols, a 29-year-old Black man who died after a confrontation with police during a traffic stop earlier this month in Memphis, has become the latest face in a racial justice and police reform movement fueled by a string of similar cases in which Black men have died from injuries sustained while being taken into custody.

    While these cases have spurred calls for greater law enforcement investment in diversity training, new research from Washington University in St. Louis suggests that the day-long implicit bias-oriented training programs now common in most U.S. police departments are unlikely to reduce racial inequity in policing.

    “Our findings suggest that diversity training as it is currently practiced is unlikely to change police behavior,” said study lead author Calvin Lai, assistant professor of psychological and brain sciences in Arts & Sciences at Washington University in St. Louis.

    “Officers who took the training were more knowledgeable about bias and more motivated to address bias at work,” Lai said.” However, these effects were fleeting and appear to have little influence on actual policing behaviors just one month after the training session.”

    Published Feb. 3 in the journal Psychological Science, the study evaluates the experiences of 3,764 police officers from departments across the nation who participated in one-day bias training sessions provided by the non-profit Anti-Defamation League.

    The interactive workshops, which emphasize discussion and active learning over lecturing, were designed to help officers understand how their worldview is shaped by their identity and culture and to appreciate how these biases may affect their behavior.

    Lai’s evaluation of the program, which covered 251 training sessions held between July 2019 and January 2022, is based on police officers’ self-reported responses to surveys conducted before training, immediately after training and one month later.

    When officers were asked to describe their thoughts about the training, many reported that it was surprising and insightful. For instance, one officer wrote “it has opened my eyes to the bias we all have as human beings” and another said, “I really liked the course because it opened my eyes to implicit biases I never knew I had.”

    Officers participating in the study had an average of 15 years of service and most had been with their departments for more than five years. Most were below the rank of sergeant, 77% were male and 79% held a bachelor’s degree or higher. Among those who reported their race, 47% were white, 20% were Black, 27% were Hispanic/Latino and 2% were Asian.

    The final section of the training program focused on building skills to manage bias in policing. These strategies included mindfulness, such as intentionally bringing bias awareness to the present moment, and other interventions designed to help officers avoid perceptions based on negative stereotypes and see people as unique individuals with their own points of view.

    While the training produced an immediate and long-lasting understanding of bias, it delivered only a temporary bump in concerns about bias and in the motivation to use strategies to limit bias in law enforcement interactions.

    “Educating about implicit bias was effective for durably raising awareness about the existence of subtle or implicit biases, but little else,” Lai said. “Our study indicates that the current generation of diversity training programs are effective at changing minds but less consistent at changing behavior.”

    Lai, who is currently working with the U.S. Department of Justice’s Office of Community Oriented Policing Services to develop a new managing bias training course for law enforcement agencies, says it’s important to manage expectations about what can be accomplished in a single, standalone training session.

    His study documents shortcomings in the Anti-Defamation League’s Managing Bias program, which he considers to be one of the nation’s best available diversity training programs. The program is research-based, comes with an 80-page instruction manual and is delivered by two-person teams of highly trained facilitators.

    “The day-long training is more intensive than other diversity trainings, which are often only one to three hours,” Lai said. “And yet, we found little evidence for long-term efficacy.”

    Lai’s research suggests that police departments can boost the effectiveness of diversity training by showing a genuine, long-term commitment to program goals and ensuring that classroom bias training lessons are embedded with other organizational initiatives, reinforced by police managers and evaluated as a part of job performance.

    “Changing minds is hard, creating social change is difficult, but that doesn’t mean it isn’t worth doing,” Lai said. “We have to eliminate this all-or-none thinking about the effectiveness of implicit bias training and focus on specific changes that police departments can implement to make a real difference in outcomes.”

    This study was supported by grants from the Anti-Defamation League and the Russell Sage Foundation. Co-authors include Jacklyn Lisnek, a former lab manager in Lai’s lab now pursuing a doctoral degree in social psychology at the University of Virginia.

    Washington University in St. Louis

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  • When bugs swipe left

    When bugs swipe left

    Newswise — It’s almost Valentine’s Day, and love is in the air. Or in the waxy coating on your skin, if you are a vinegar fly. That’s where flies encounter pheromones that play an important role in regulating sexual attraction.

    Flies use pheromones to ensure that they court and mate with members of the same species. As new fly species split off from a common ancestor, but continue to share the same environment, they need a way to rapidly diversify their pheromones to suppress inter-species mating. When members of two related species stop finding each other attractive, this helps prevent interbreeding.

    But it’s more complicated than “she loves me, she loves me not.“

    Because the perception and production of pheromones are mediated by different tissues and cellular pathways, evolving new mating pheromones requires a coordinated evolution of both the genes responsible for sensing the pheromones as well as the genes that produce them.

    A new study in iScience led by Yehuda Ben-Shahar at Washington University in St. Louis identifies a link between the genetic instructions for the production and perception of sex pheromones. The research was conducted in collaboration with Jocelyn Millar from the University of California, Riverside.

    Researchers reported that a single protein called Gr8a is expressed in different organs in male and female flies and appears to play an inhibitory role in mating decision-making. The findings point to one of the ways that flies could put up behavioral barriers to protect against mating with the wrong kind of partner.

    “Mating pheromones often show rapid evolution,” said Ben-Shahar, a professor of biology in Arts & Sciences. “Because pheromonal communication requires a very robust and specific structural recognition of chemicals used as pheromones by the proteins that bind them in sensory neurons (chemoreceptors), it means that major molecular changes in either the receptor or the pheromone would reduce sexual attraction between males and females.”

    Ben-Shahar and his team found that Gr8a was expressed in tissues in fly mouthparts, including the proboscis, as well as in taste neurons in the forelegs of both males and females. They also found Gr8a in cells in the abdomens of males. This was important because it provided Ben-Shahar and his team the first hint that a gene that had been previously identified as a sensory chemoreceptor must also have non-neuronal functions.

    “Our findings provide a relatively simple molecular explanation for how signal production and perception are tied together in vinegar flies,” Ben-Shahar said. “A single pleiotropic protein can function as both a receptor for pheromones in sensory neurons, as well as contribute to their production in the pheromone-producing cells (oenocytes) of males, by way of a less-understood process.”

    In one of the experiments that Ben-Shahar and his team conducted, the scientists took flies that were mutant for the Gr8a receptor and reconstituted them using input from a different vinegar fly species. This experiment showed that introducing Gr8a from another species was enough to change the overall pheromone profile of the animal.

    The scientists still have not pinpointed exactly how the chemoreceptor affects the way the signal is produced, but they do know that it causes quantitative and qualitative differences in pheromones. And even small changes in pheromones could be enough to keep closely related flies from finding each other attractive — and change their mate choice behaviors.

    The question of how closely related species evolve and maintain behavioral mating barriers is one that has implications for several different basic and applied biological research fields.

    “Based on what we have observed, mutations in a single gene could provide a molecular path for a pheromonal communication system to evolve while still maintaining the functional coupling between a pheromone and its receptor,” Ben-Shahar said. “Our research uncovers a potential avenue for pheromonal systems to rapidly evolve when new species arise.”

    —

    This work was supported by National Science Foundation grants 1322783, 1754264 and 1707221, and National Institutes of Health (NIH) grant NS089834.

    Washington University in St. Louis

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  • Beyond the average cell

    Beyond the average cell

    Newswise — Nobody wants to be average.

    But for a long time, scientists have found it convenient to think of bacterial cells as just that: “average.”

    Researchers have traditionally relied on population-level strategies to understand fundamental aspects of bacterial physiology. These population-level approaches describe the behavior of idealized average cells, and they serve as the foundation for prevailing models of bacterial growth.

    Models based on an average cell are useful, but they may not accurately describe how individual cells really work. New possibilities opened up with the advent of single-cell live imaging technologies. Now it is possible to peer into the lives of individual cells. In a new paper in PLOS Genetics, a team of biologists and physicists from Washington University in St. Louis and Purdue University used actual single-cell data to create an updated framework for understanding the relationship between cell growth, DNA replication and division in a bacterial system.

    Petra Levin, the George William and Irene Koechig Freiberg Professor of Biology in Arts & Sciences at Washington University, an author of the new paper, has a keen interest in single-cell biology. In her research work, Levin has made seminal contributions to our understanding of bacterial cell growth.

    A chance encounter at the Aspen Center for Physics led to a collaboration with Srividya Iyer-Biswas, a physicist at Purdue University with expertise in both first-principles-based physics theory and high-precision single cell experiments.

    Taking advantage of the Zoom era brought on by the early days of the pandemic, Levin and Iyer-Biswas developed their virtual collaboration to revisit some of the “beautiful, classic models of the bacterial cell cycle,” as Levin describes them.

    They found exciting bits were missing.

    What was the problem? The models counted on the behavior of an “average” cell within a population. But using the average to infer what an actual cell does can be misleading.

    “Imagine each bacterium as singing its own whimsical tune, following its own rhythm,” Iyer-Biswas said. “The collective — a population of millions of cells — has its own music, where no single voice especially stands out, but a song nonetheless emerges. From hearing just the collective rendition, how could one possibly uncover what precisely an individual’s song might be? That is the problem we were faced with.”

    “What is true for the average cell is not necessarily true for the individual cell. Bacteria are just like us in this regard!” Levin added.

    For this new paper, Levin and Iyer-Biswas worked together with Sara Sanders, a postdoctoral scientist in the Levin lab who recently moved to the National Institutes of Health (NIH), and Kunaal Joshi, a PhD student in the Iyer-Biswas lab, to tackle one basic question.

    They wanted to figure out how these “whimsical” individual bacterial cells — or, as a more typical physicist might say, these stochastic cells — manage to exquisitely coordinate DNA replication with growth and division, so that overall events happen in the right sequence despite the “noisiness” of each process.

    To answer the question, the authors carefully looked at single-cell growth data from the model organism Escherichia coli collected by the Jun laboratory at the University of California, San Diego. They then constructed a minimal mathematical model that captured complex, stochastic behaviors of individual cells and accurately matched individual cell data.

    Based on average cell behavior, others had come to view the basic cell cycle steps of DNA replication and cell division as dependent on each other. But that wasn’t how Levin and Sanders saw it.

    “Decades of genetic and molecular studies indicate that although DNA replication and division are clearly coordinated, they are not dependent on one another,” Levin said. “As long as there are mechanisms to prevent division across uncopied chromosomes, or fix the situation in the unlikely event that does happen, everything is fine. E. coli does not have cell cycle checkpoints like eukaryotic cells do.”

    Meanwhile, Iyer-Biswas and Joshi realized that there was a simple way to understand the individual cell data. Each cell has three independent (stochastic) timers (equivalent to the whimsical tune from above) that start ticking each time DNA replication begins, and whose orchestration determines the sequence of cell cycle events.

    Starting from this simple idea, Joshi discovered he could predict the sequence of DNA replication initiation, the end of DNA replication and division based on when the three timers independently go off and reset. His predictions matched exquisitely with the extant data on individual cell DNA replication and cell division in many different growth conditions.

    By describing a stochastic, not deterministic, relationship between DNA replication and cell division, the authors have shifted how scientists understand a basic process in cell biology.

    “Our ultimate goal is to build a community around high-precision approaches in biology that seamlessly integrate theory and experiment,” Iyer-Biswas said. “A more immediate goal is to transcend system-specific details and provide a unifying framework also applicable to other bacterial species.”

    Washington University in St. Louis

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  • Nanoplastics unexpectedly produce reactive oxidizing species when exposed to light

    Nanoplastics unexpectedly produce reactive oxidizing species when exposed to light

    Newswise — Plastics are ubiquitous in our society, found in packaging and bottles as well as making up more than 18% of solid waste in landfills. Many of these plastics also make their way into the oceans, where they take up to hundreds of years to break down into pieces that can harm wildlife and the aquatic ecosystem.

    A team of researchers, led by Young-Shin Jun, professor of energy, environmental & chemical engineering in the McKelvey School of Engineering at Washington University in St. Louis, analyzed how light breaks down polystyrene, a nonbiodegradable plastic from which packing peanuts, DVD cases and disposable utensils are made. In addition, they found that nanoplastic particles can play active roles in environmental systems. In particular, when exposed to light, the nanoplastics derived from polystyrene unexpectedly facilitated the oxidation of aqueous manganese ions and formation of manganese oxide solids that can affect the fate and transport of organic contaminants in natural and engineering water systems.

    The research, published in ACS Nano Dec. 27, 2022, showed how the photochemical reaction of nanoplastics through light absorption generates peroxyl and superoxide radicals on nanoplastic surfaces, and initiates oxidation of manganese into manganese oxide solids.

    “As more plastic debris accumulates in the natural environment, there are increasing concerns about its adverse effects,” said Jun, who leads the Environmental Nanochemistry Laboratory. “However, in most cases, we have been concerned about the roles of the physical presence of nanoplastics rather than their active roles as reactants. We found that such small plastic particles that can more easily interact with neighboring substances, such as heavy metals and organic contaminants, and can be more reactive than we previously thought.”

    Jun and her former student, Zhenwei Gao, who earned a doctorate in environmental engineering at WashU in 2022 and is now a postdoctoral scholar at the University of Chicago, experimentally demonstrated that the different surface functional groups on polystyrene nanoplastics affected manganese oxidation rates by influencing the generation of the highly reactive radicals, peroxyl and superoxide radicals. The production of these reactive oxygen species from nanoplastics can endanger marine life and human health and potentially affects the mobility of the nanoplastics in the environment via redox reactions, which in turn might negatively impact their environmental remediation.

    The team also looked at the size effects of polystyrene nanoplastics on manganese oxidation, using 30 nanometer, 100 nanometer and 500 nanometer particles. The two larger-sized nanoparticles took longer to oxidize manganese than the smaller particles. Eventually, the nanoplastics will be surrounded by newly formed manganese oxide fibers, which can make them easily aggregated and can change their reactivities and transport.

    “The smaller particle size of the polystyrene nanoplastics may more easily decompose and release organic matter because of their larger surface area,” Jun said. “This dissolved organic matter may quickly produce reactive oxygen species in light and facilitate manganese oxidation.” 

    “This experimental work also provides useful insights into the heterogeneous nucleation and growth of manganese oxide solids on such organic substrates, which benefits our understanding of manganese oxide occurrences in the environment and engineered materials syntheses,” Jun said. “These manganese solids are excellent scavengers of redox-active species and heavy metals, further affecting geochemical element redox cycling, carbon mineralization and biological metabolisms in nature.”

    Jun’s team plans to study the breakdown of diverse common plastic sources that can release nanoplastics and reactive oxidizing species and to investigate their active roles in the oxidation of transition and heavy metal ions in the future.

    Gao Z, Chou P-I, Liu J, Zhu Y, Jun Y-S. Oxidative Roles of Polystyrene-Based Nanoplastics in Inducing Manganese Oxide Formation under Light Illumination. ACS Nano, Dec. 27, 2022. https://doi.org/10.1021/acsnano.2c05803. 

    Funding for this research was partially provided by the National Science Foundation (CHE-1905077) and the McDonnell International Scholars Academy at Washington University in St. Louis.

    The McKelvey School of Engineering at Washington University in St. Louis promotes independent inquiry and education with an emphasis on scientific excellence, innovation and collaboration without boundaries. McKelvey Engineering has top-ranked research and graduate programs across departments, particularly in biomedical engineering, environmental engineering and computing, and has one of the most selective undergraduate programs in the country. With 165 full-time faculty, 1,420 undergraduate students, 1,614 graduate students and 21,000 living alumni, we are working to solve some of society’s greatest challenges; to prepare students to become leaders and innovate throughout their careers; and to be a catalyst of economic development for the St. Louis region and beyond.

    Washington University in St. Louis

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  • Organelles grow in random bursts

    Organelles grow in random bursts

    Newswise — Eukaryotic cells — the ones that make up most life as we know it, including all animals, plants and fungi — are highly structured objects.

    These cells assemble and maintain their own smaller, internal bits: the membrane-bound organelles like nuclei, which store genetic information, or mitochondria, which produce chemical energy. But much remains to be learned about how they organize themselves into these spatial compartments.

    Physicists at Washington University in St. Louis conducted new experiments that show that eukaryotic cells can robustly control average fluctuations in organelle size. By demonstrating that organelle sizes obey a universal scaling relationship that the scientists predict theoretically, their new framework suggests that organelles grow in random bursts from a limiting pool of building blocks.

    The study was published Jan. 6 in Physical Review Letters.

    “In our work, we suggest that the steps by which organelles are grown — far from being an orderly ‘brick-by-brick’ assembly — occur in stochastic bursts,” said Shankar Mukherji, assistant professor of physics in Arts & Sciences.

    “Such bursts fundamentally limit the precision with which organelle size is controlled but also maintain noise in organelle size within a narrow window,” Mukherji said. “Burstlike growth provides a general biophysical mechanism by which cells can maintain, on average, reliable yet plastic organelle sizes.”

    Organelles must be flexible enough to allow cells to grow or shrink them as environments demand. Still, the size of organelles must be maintained within certain limits. Biologists have previously identified certain molecular factors that regulate organelle sizes, but this study provides new insights into the quantitative principles underlying organelle size control.

    While this study used budding yeast as a model organism, the team is excited to explore how these assembly mechanisms are utilized across different species and cell types. Mukherji said that they plan to examine what these patterns of robustness can teach us about how to harness organelle assembly for bioengineering applications and how to spot defects in organelle biogenesis in the context of disease.

    “The pattern of organelle size robustness is shared between budding yeast and human iPS cells,” Mukherji said. “The underlying molecular mechanisms producing these bursts are yet to be fully elucidated and are likely to be organelle-specific and potentially species-specific.”

    —

    Amiri KP, Kalish A and Mukherji S. Robustness and Universality in Organelle Size Control. Phys. Rev. Lett., Jan. 7, 2023. https://link.aps.org/doi/10.1103/PhysRevLett.130.018401

    Funding: This research was supported by the National Institutes of Health (NIH R35GM142704).

    Washington University in St. Louis

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  • Dry eye disease alters how the eye’s cornea heals itself after injury

    Dry eye disease alters how the eye’s cornea heals itself after injury

    Newswise — People with a condition known as dry eye disease are more likely than those with healthy eyes to suffer injuries to their corneas. Studying mice, researchers at Washington University School of Medicine in St. Louis have found that proteins made by stem cells that regenerate the cornea may be new targets for treating and preventing such injuries.

    The study is published online Jan. 2 in the Proceedings of the National Academy of Sciences.

    Dry eye disease occurs when the eye can’t provide adequate lubrication with natural tears. People with the common disorder use various types of drops to replace missing natural tears and keep the eyes lubricated, but when eyes are dry, the cornea is more susceptible to injury.

    “We have drugs, but they only work well in about 10% to 15% of patients,” said senior investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor in the John F. Hardesty, MD, Department of Ophthalmology & Visual Sciences. “In this study involving genes that are key to eye health, we identified potential targets for treatment that appear different in dry eyes than in healthy eyes. Tens of millions of people around the world — with an estimated 15 million in the United States alone — endure eye pain and blurred vision as a result of complications and injury associated with dry eye disease, and by targeting these proteins, we may be able to more successfully treat or even prevent those injuries.”

    The researchers analyzed genes expressed by the cornea in several mouse models — not only of dry eye disease, but also of diabetes and other conditions. They found that in mice with dry eye disease, the cornea activated expression of the gene SPARC. They also found that higher levels of SPARC protein were associated with better healing.

    “We conducted single-cell RNA sequencing to identify genes important to maintaining the health of the cornea, and we believe that a few of them, particularly SPARC, may provide potential therapeutic targets for treating dry eye disease and corneal injury,” said first author Joseph B. Lin, an MD/PhD student in Apte’s lab.

    “These stem cells are important and resilient and a key reason corneal transplantation works so well,” Apte explained. “If the proteins we’ve identified don’t pan out as therapies to activate these cells in people with dry eye syndrome, we may even be able to transplant engineered limbal stem cells to prevent corneal injury in patients with dry eyes.”

    Lin JB, Shen X, Pfeifer CW, Shiau F, Santeford A, Ruzycki PA, Clark BS, Liu Q, Huang AJW, Apte RS. Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis. Proceedings of the National Academy of Sciences, Jan. 2, 2023.

    The study was funded with support from the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences of the National Institutes of Health (NIH). Grant numbers: R01 EY019287, R01 EY027844, R01 EY024704, P30 EY02687, F30 DK130282, T32 GM07200 Additional funding provided by the Jeffrey T. Fort Innovation Fund, a Centene Corp. contract for the Washington University-Centene ARCH Personalized Medicine Initiative and Research to Prevent Blindness.

    About Washington University School of Medicine

    WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% in the last five years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,790 faculty physicians practicing at over 60 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

    Washington University in St. Louis

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  • Study reveals how chronic blood cancer transitions to aggressive disease

    Study reveals how chronic blood cancer transitions to aggressive disease

    Newswise — A type of chronic leukemia can simmer for many years. Some patients may need treatment to manage this type of blood cancer — called myeloproliferative neoplasms (MPN) — while others may go through long periods of watchful waiting. But for a small percentage of patients, the slower paced disease can transform into an aggressive cancer, called secondary acute myeloid leukemia, that has few effective treatment options. Little has been known about how this transformation takes place.

    But now, researchers at Washington University School of Medicine in St. Louis have identified an important transition point in the shift from chronic to aggressive leukemia. They have shown that blocking a key molecule in the transition pathway prevents this dangerous disease progression in mice with models of the disease and in mice with tumors sampled from human patients.

    The research appears Dec. 29 in the journal Nature Cancer.

    “Secondary acute myeloid leukemia has a grim prognosis,” said senior author Stephen T. Oh, MD, PhD, an associate professor of medicine and co-director of the Division of Hematology at the School of Medicine. “Almost every patient who develops acute leukemia after a history of myeloproliferative neoplasms will die from the disease. Therefore, a major focus of our research is to better understand this conversion from chronic to aggressive disease and to develop better therapies and, hopefully, prevention strategies for these patients.”

    The study suggests that inhibiting this key transition molecule — called DUSP6 — helps overcome the resistance that these cancers often develop to JAK2 inhibitors, the therapy typically used to treat them. JAK2 inhibitors are an anti-inflammatory therapy also used to treat rheumatoid arthritis.

    “These patients are commonly treated with JAK2 inhibitors, but their disease progresses despite that therapy, so we’re also trying to identify how the disease is able to worsen even in the setting of JAK2 inhibition,” said Oh, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

    The researchers conducted a deep dive into the genetics of these tumors, both during the slow chronic phase and after the disease had transformed into the aggressive form while patients were taking JAK2 inhibitors. The DUSP6 gene stood out as highly expressed in the 40 patients whose tumors were analyzed in this study.

    Using genetic techniques to delete the DUSP6 gene prevented the transition to aggressive disease in mice with models of this cancer. The researchers also tested a drug compound that inhibits DUSP6 and found that the compound — only available for animal research — stopped progression of the chronic disease to the aggressive disease in two different mouse models of the cancer and in mice with human tumors sampled from patients. Reducing DUSP6 levels both genetically and with a drug also reduced inflammation in these models.

    Since the drug that inhibits DUSP6 is not available for human clinical trials, Oh and his colleagues are interested in exploring treatments that inhibit another molecule that they found is activated downstream of DUSP6 and that they showed is also required to perpetuate the negative effects of DUSP6. There are drugs in clinical trials that inhibit this downstream molecule, known as RSK1. Oh’s team is interested in investigating these drugs for their potential to block the dangerous transition from chronic to aggressive disease and address resistance to JAK2 inhibition.

    “A future clinical trial might enroll myeloproliferative neoplasm patients who are taking JAK2 inhibitors and, despite that, show evidence of their disease worsening,” Oh said. “At that point, we might add the type of RSK inhibitor that’s now in trials to their therapy to see if that helps block progression of the disease into an aggressive secondary acute myeloid leukemia. A newly developed RKS inhibitor is in phase 1 clinical trials for patients with breast cancer, so we’re hopeful our work provides a promising foundation for developing a new treatment strategy for patients with this chronic blood cancer.”

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    This work was supported by the National Institutes of Health (NIH), grant numbers R01HL134952, T32HL007088 and R01HL147978; the Leukemia and Lymphoma Society Translational Research Program; the MPN Research Foundation; the When Everyone Survives Foundation; the Edward P. Evans Foundation; the Gabrielle’s Angel Foundation; the Leukemia and Lymphoma Society; a Canderel Rising Star Summer Studentship; a Canadian Research Chair in Functional Genomics; and Canadian Institutes of Health Research (CIHR) grants PJT-156233 and PJT-438303. Technical support was provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core Facility; the Biostatistics Shared Resource; the Flow Cytometry Core; Barnes-Jewish Hospital; the Institute of Clinical and Translational Sciences; and the Immunomonitoring Laboratory, which are supported by NCATS Clinical and Translational Sciences Award UL1 TR002345 and National Cancer Institute (NCI) Cancer Center Support Grant P30CA91842. Additional support was provided by the Barnard Cancer Institute. The Immunomonitoring Laboratory is also supported by the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs.

    Kong T, et al. DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression. Nature Cancer. Dec. 29, 2022.

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