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A Person’s Race Influences Question Asking as Much as Their Stroke History
DURHAM, NC — Strokes that occur on the right side of the brain can sometimes subtly impair social communication, which can be difficult for clinicians to assess.
But these impairments are a lot less subtle for the patients and their families, who often have their lives and livelihood upended, leading to significant life changes such as job loss and divorce.
Clinical researchers have developed a few diagnostic tools for right side, (right hemisphere) stroke survivors, but the tools have been largely based on data from White patients.
And that’s a problem, according to Duke speech pathologist and assistant professor Jamila Minga, Ph.D., CCC-SLP, because the few diagnostic tools available may be biased against the people most affected by stroke. Black men and women are twice as likely to have a stroke compared to White adults, and a person’s linguistic tendencies can vary based on their race and gender.
A new study from Duke and North Carolina Central University (NCCU) that Minga led verifies the suspicion that race changes how communication impairments present themselves.
Minga has found that some right brain stroke survivors ask fewer questions. But this new study also found that a person’s race – independent of brain injury – affects their inclination to ask questions.
The research appears on January 10 in the Journal of Speech, Language, and Hearing Research.
While a stroke is just as likely to occur within the left or right side of the brain, research on stroke-related communication deficits has mostly focused on people who have survived a left hemisphere stroke.
“That's largely because communication impairments after a left hemisphere stroke are more overt,” said Minga, who recently joined Duke as an assistant professor in the department of head and neck surgery & communication sciences.
Instead, right hemisphere stroke survivors have what clinicians call apragmatism — a difficulty understanding and producing language that is appropriate for different settings and situation. For example, Minga recalled the time she visited a patient’s room for a speech assessment and while his wife sat in a chair beside him, the patient asked Minga to join him in his hospital bed. He wasn’t joking or being deliberately crass.
“He could produce language. He was completely intelligible. His sentence structure, grammar and morphology were all fine,” Minga said. “The appropriateness? Not so much.”
It’s this subtlety in speech and social conventions that makes communication impairments so hard to pinpoint in right hemisphere stroke survivors, which leaves many undiagnosed and without assistance, Minga said.
Another study by Minga found that right hemisphere stroke participants asked fewer questions when getting to know a new person, inspiring her and others to measure the quantity and quality of question asking as a potential diagnostic tool.
“Everyone recognizes what a question is, no matter what language you speak,” Minga said. “It’s easily quantifiable. And questions are used to initiate, maintain and dissolve relationships. They're key to social communication.”
To address whether race affected a stroke survivor’s question-asking habits, Minga analyzed five-minute snippets of conversation from 32 women who had participated in a prior study and measured how many questions they asked while getting to know someone new. The participant pool consisted of an equal number of Black and White women, half of whom had sustained a right hemisphere stroke.
As Minga had found before, right hemisphere stroke participants asked fewer questions than their non-stroke counterparts no matter their race during the get-to-know-you chat with an unfamiliar person (a female speech pathology graduate student).
However, when Minga and her team analyzed the results by race, they discovered that no matter the stroke condition, Black women asked half as many questions as White participants, about 20 on average.
“White participants without stroke had the highest frequency of question-asking, followed by White participants who had a right hemisphere stroke,” Minga said. “Then the Black participants who did not have a stroke, and the lowest numbers seen were with Black participants who had experienced a right hemisphere stroke.”
The results highlight how diagnosing communication impairments resulting from a right hemisphere stroke may need to be adjusted based on race.
The research team is following up on this study to see whether pairing Black participants with a Black conversation partner changes the nature of question asking. (The vast majority of speech pathologists are White; only 4% identify as Black).
Minga hopes this work motivates clinicians to consider providing more information to patients rather than assuming someone’s reservedness is due to a lack of curiosity. Especially for Black women.
“For Black women who survive a stroke, the functional consequences of a communication impairment are significant,” Minga and her team write in their report. “It can impact financial stability, child rearing and daily socializing, which are all important for good health and well-being.”
Support for the research came from the U.S. National Institute on Deafness and Other Communication Disorders (3R01-DC008524-11S1, L60 DC019755), the U.S. National Institutes of Health Office of Research on Women’s Health (2K12-HD043446-16), the U.S. National Institute on Minority Health and Health Disparities (5U54MD012392-03), and the Duke University School of Medicine.
CITATION: “Intersectionality of Race and Question-Asking in Women After Right Hemisphere Brain Damage,” Danai K. Fannin, Jada Elleby, Maria Tackett, Jamila Minga. Journal of Speech, Language and Hearing Research, Jan. 10, 2023. DOI: 10.1044/2022_JSLHR-22-00327.
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Gene Therapy for Heart Attacks in Mice Just Got More Precise
DURHAM, N.C. — If humans are ever going to be able to regrow damaged tissues the way lizards and fish routinely do, it will require the precise control of gene expression in time and place – otherwise you might end up with random cells growing everywhere or a new body part that never quits growing. That is, stopping the process just as important as starting it.
A team of Duke scientists studying how other animals regrow damaged tissues has made an important step toward controlling at least one part of the regenerative machinery with that kind of precision. They used the mechanisms zebrafish rely on to repair damage to their hearts combined with viral vectors used for gene therapy in humans.
In a new paper appearing online Dec. 13 in Cell Stem Cell, the researchers demonstrate the ability to control gene activity in response to injury, limiting it to a specific region of tissue and during a defined time window, rather than being continuously active in the entire organ.
They borrowed a segment of fish DNA that they call a TREE, tissue regeneration enhancer element. TREEs are a family of gene enhancers included in the genome that are responsible for sensing an injury and orchestrating the activity of repair-related genes for reconstruction in a specific place. These enhancers also can shut off gene activity as healing is completed. These regulatory elements have been found in fruit flies, worms, and mice as well as the zebrafish.
“We probably have them too,” said Ken Poss, Ph.D, the James B. Duke Distinguished Professor of Regenerative Biology in the Duke School of Medicine, who discovered heart regeneration in zebrafish two decades ago and has been studying it since. “But it’s just easier for us to find them in zebrafish and ask if they work in mammals.”
About 1,000 nucleotides long, these enhancer sequences are bristling with recognition sites for different factors and stimuli to attach and change gene activity. “We don’t fully understand how they do this and what they’re truly responding to,” Poss said.
Different cell types within an animal also have different types of these enhancers, Poss said. “Some of them are responsive in multiple tissues — those are the ones we use here. But when we profile regenerating spinal cord or fins in fish, we get different sequences.” There may be tens of thousands of these types of enhancers in the human genome, he added.
As a first step in this 6-year research project, the researchers incorporated several different kinds of zebrafish TREEs into the genomes of embryonic mice. Using a visible marker to indicate gene activity, they found that about half of the enhancers worked as intended and turned tissue blue when and where they sensed tissue injury in the transgenic mammals.
Then they wanted to know if they could selectively incorporate the enhancer elements into an adult mouse using adeno-associated virus, a familiar gene therapy tool for introducing gene sequences into cells. The virus introduced DNA containing an enhancer to all tissues, but the hope was that the TREEs would only become active in response to an injury.
A series of experiments in heart attack models of mice showed that viruses containing a TREE could be infused a week before injury and then the enhancer would jump into action when it detected injury. But they found it also worked when introduced to the animal a day or two after the heart attack. “All three TREEs that we tested could be effective if delivered one day or sometimes longer after the injury — they could still target expression to the injury,” Poss said.
“Is this method of delivering a TREE and a gene going to allow us to deliver a molecular cargo to the right place at the right time? We found that it does in mice,” Poss said.
They also virally delivered a TREE and a fluorescent marker gene in pigs, which have a much larger heart with a more human-like heart rate. They infused viruses into the pig hearts through the coronary arteries either before or after a heart attack and again, the marker only glowed at the site of the injury.
Then, to see if this system could actually repair damage, rather than just sensing damage and turning on a gene that lights up tissue, they delivered a hyperactivated form of YAP, a powerful tissue growth gene that is implicated in cancer. The key question was whether this “really potent hammer” that can make cell division run amok could be lassoed into working only in the right time and place.
They used a mutated YAP controlled by a TREE to see whether they could have safe growth of muscle after a heart attack in mice. “The TREE turned on a mutated YAP for a few weeks, just in the injury site, and then it naturally shut down expression,” Poss said. The treatment caused muscle cells to begin to divide and the mouse’s heart returned to near normal function after several weeks, though not without some scarring.
“You really wouldn’t want to express YAP at full blast, that can cause problems like excessive growth, but what we found is that we could direct it,” Poss said. “The whole animal gets the gene therapy, but the YAP cargo only gets expressed at measurable levels when and where you injure the heart,” Poss said. “We think we can use these methods to control genes in a certain time and certain space, and that includes shutting them off.”
The next task for the researchers will be understanding better what molecules bind to the enhancers, what controls their functions, and where they are located in the human genome, in addition to improving their targeting abilities.
“These control elements are what’s important,” Poss said. “Zebrafish have largely the same genes that we do, but their ability to regenerate the heart is a function of how they control those genes after a massive injury.”
“And what about other injury models?” Poss wonders. “Can this work for traumatic brain injury or spinal cord injury?”
Ruorong Yan and Valentina Cigliola were the lead authors for this research, which was supported by Translating Duke Health; the National Institutes of Health (F31-HL162460, R01-HL151522, P30-AG028716, R21-AG067245, R01-HL157277, U01-AI146356, UM1-HG013053, RM1-HG011123, R33-DA041878, U01-HL134764, R01-HL126524, R01-HL146366, R01-DK119621, R35-HL150713, R01-HL136182); National Science Foundation (EFMA-1830957); American Heart Association (AHA) (17POST33660087, 903369, AHA16SDG30020001, AHA117SDG33660922); Swiss National Science Foundation (P2GEP3_175016, P400PM_186709); and Fondation Leducq.
CITATION: “An Enhancer-Based Gene Therapy Strategy for Spatiotemporal Control of Cargoes During Tissue Repair,” Ruorong Yan, Valentina Cigliola, Kelsey A. Oonk, Zachary Petrover, Sophia DeLuca, David W. Wolfson, Andrew Vekstein, Michelle A. Mendiola, Garth Devlin, Muath Bishawi, Matthew P. Gemberling, Tanvi Sinha, Michelle A. Sargent, Allen J. York, Avraham Shakked, Paige DeBenedittis, David C. Wendell, Jianhong Ou, Junsu Kang, Joseph A. Goldman, Gurpreet S. Baht, Ravi Karra, Adam R. Williams, Dawn E. Bowles, Aravind Asokan, Eldad Tzahor, Charles A. Gersbach, Jeffery D. Molkentin, Nenad Bursac, Brian L. Black, and Kenneth D. Poss. Cell Stem Cell, Jan. 5, 2023. (Online Dec. 13, 2022) DOI: 10.1016/j.stem.2022.11.012
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Mom’s Dietary Fat Rewires Male And Female Brains Differently
DURHAM, NC — More than half of all women in the United States are overweight or obese when they become pregnant. While being or becoming overweight during pregnancy can have potential health risks for moms, there are also hints that it may tip the scales for their kids to develop psychiatric disorders like autism or depression, which often affects one gender more than the other.
What hasn’t been understood however is how the accumulation of fat tissue in mom might signal through the placenta in a sex-specific way and rearrange the developing offspring’s brain.
To fill this gap, Duke postdoctoral researcher Alexis Ceasrine, Ph.D., and her team in the lab of Duke psychology & neuroscience professor Staci Bilbo, Ph.D., studied pregnant mice on a high-fat diet. In findings appearing November 28 in the journal Nature Metabolism, they found that mom’s high-fat diet triggers immune cells in the developing brains of male but not female mouse pups to overconsume the mood-influencing brain chemical serotonin, leading to depressed-like behavior.
The researchers said a similar thing may be happening in humans, too.
People with mood disorders like depression often lose interest in pleasurable activities. For mice, one innately pleasurable activity is drinking sugar water. Since mice preferentially sip sugar water over plain tap when given the choice, Ceasrine measured their drink preference as an estimate for depression. Males, but not females, born by moms on a high-fat diet lacked a preference for simple syrup over tap water. This rodent-like depression suggested to Ceasrine that mom’s nutrition while pregnant must have changed their male offspring’s brain during development.
One immediate suspect was serotonin. Often called the “happy” chemical, serotonin is a molecular brain messenger that’s typically reduced in people with depression.
Ceasrine and her team found that depressed-like male mice from high-fat diet moms had less serotonin in their brain both in the womb and as adults, suggesting these early impacts have lifelong consequences. Supplementing mom’s high-fat rodent chow with tryptophan, the chemical precursor to serotonin, restored males’ preference for sugar water and brain serotonin levels. Still, it was unclear how fat accumulation in mom lowered serotonin in their offspring.
To get at this, the team investigated the resident immune cells of the brain: microglia.
Microglia are the understudied Swiss Army knives of the brain. Their jobs include serving as a security monitor for pathogens as well as a hearse to haul away dead nerve cells. Microglia also have ample space and appetites to consume healthy brain cells whole.
To see if microglia were overindulging in serotonin, Ceasrine analyzed the contents of their cellular “stomach”, the phagosome, with 3D imaging, and found that males born by moms on high-fat diets had microglia packed with more serotonin than those born to moms on a typical diet. This indicated that elevated fat accumulation during pregnancy somehow signals through the male but not female placenta to microglia and instructs them to overeat serotonin cells. How fat can signal through the placental barrier remained a mystery, though.
One thought was that bacteria were to blame.
“There's a lot of evidence that when you eat a high fat diet, you actually end up with endotoxemia,” Ceasrine said. “It basically means that you have an increase in circulating bacteria in your blood, or endotoxins, which are just parts of bacteria.”
To test if endotoxins could be the critical messenger from mom to enwombed males, the team measured their presence and found that, indeed, high-fat diets during pregnancy beefed up endotoxin levels in the placenta and their offspring’s developing brain. Ceasrine said this may explain how fat accumulation triggers an immune response from microglia by increasing the presence of bacteria, resulting in overconsumed brain cells in male mice.
To see whether this may be true of humans as well, Ceasrine teamed up with Susan Murphy, Ph.D., a Duke School of Medicine associate professor in obstetrics and gynecology, who provided placental and fetal brain tissue from a previous study. Just as the researchers observed in mice, they found that the more fat measured in human placental tissue, the less serotonin was detected in the brains of males but not females.
Bilbo and Ceasrine are now starting to work out how and why female offspring are impacted differently when mom amasses high levels of fat during pregnancy. Fat doesn’t lead to depression in female mice, but it does make them less social, perhaps due to an overconsumption of the pro-social hormone oxytocin, instead of serotonin.
For now, this research highlights that not all placentas are created equally. This work may one day help guide clinicians and parents in better understanding and possible treatment or prevention of the origins of some mood disorders by considering early environmental factors, like fat accumulation during gestation.
So, why would the placenta treat male and female fetuses differently? Ceasrine was initially stumped when a student asked a similar question after a talk she gave to Bilbo’s class. Bilbo laughed and reiterated the question. But now they think they have it figured out.
“I was hugely pregnant at the time, and I was like, ‘Oh, wait. Pregnancy!’” Ceasrine recalled. “Men never have to carry a fetus, so they never have to worry about the kind of immune response of self versus non-self that you have to do when you're a woman and you carry a baby.”
Support for the research came from the US National Institutes of Health (F32HD104430, R01ES025549), the Robert and Donna Landreth Family Foundation, and the Charles Lafitte Foundation.
CITATION: “Maternal Diet Disrupts the Placenta-Brain Axis in a Sex-Specific Manner,” Alexis M. Ceasrine, Benjamin A. Devlin, Jessica L. Bolton, Lauren A. Green, Young Chan Jo, Carolyn Huynh, Bailey Patrick, Kamryn Washington, Cristina L. Sanchez, Faith Joo, A. Brayan Campos-Salazar, Elana R. Lockshin, Cynthia Kuhn, Susan K. Murphy, Leigh Ann Simmons, Staci D. Bilbo. Nature Metabolism, Nov. 28, 2022. DOI: 10.1038/s42255-022-00693-8
Human Evolution Wasn’t Just the Sheet Music, But How it Was Played
DURHAM, N.C. — A team of Duke researchers has identified a group of human DNA sequences driving changes in brain development, digestion and immunity that seem to have evolved rapidly after our family line split from that of the chimpanzees, but before we split with the Neanderthals.
Our brains are bigger, and are guts are shorter than our ape peers.
“A lot of the traits that we think of as uniquely human, and human-specific, probably appear during that time period,” in the 7.5 million years since the split with the common ancestor we share with the chimpanzee, said Craig Lowe, Ph.D., an assistant professor of molecular genetics and microbiology in the Duke School of Medicine.
Specifically, the DNA sequences in question, which the researchers have dubbed Human Ancestor Quickly Evolved Regions (HAQERS), pronounced like hackers, regulate genes. They are the switches that tell nearby genes when to turn on and off. The findings appear Nov.23 in the journal CELL.
The rapid evolution of these regions of the genome seems to have served as a fine-tuning of regulatory control, Lowe said. More switches were added to the human operating system as sequences developed into regulatory regions, and they were more finely tuned to adapt to environmental or developmental cues. By and large, those changes were advantageous to our species.
“They seem especially specific in causing genes to turn on, we think just in certain cell types at certain times of development, or even genes that turn on when the environment changes in some way,” Lowe said.
A lot of this genomic innovation was found in brain development and the GI tract. “We see lots of regulatory elements that are turning on in these tissues,” Lowe said. “These are the tissues where humans are refining which genes are expressed and at what level.”
Today, our brains are larger than other apes, and our guts are shorter. “People have hypothesized that those two are even linked, because they are two really expensive metabolic tissues to have around,” Lowe said. “I think what we’re seeing is that there wasn’t really one mutation that gave you a large brain and one mutation that really struck the gut, it was probably many of these small changes over time.”
To produce the new findings, Lowe’s lab collaborated with Duke colleagues Tim Reddy, an associate professor of biostatistics and bioinformatics, and Debra Silver, an associate professor of molecular genetics and microbiology to tap their expertise. Reddy’s lab is capable of looking at millions of genetic switches at once and Silver is watching switches in action in developing mouse brains.
“Our contribution was, if we could bring both of those technologies together, then we could look at hundreds of switches in this sort of complex developing tissue, which you can't really get from a cell line,” Lowe said.
“We wanted to identify switches that were totally new in humans,” Lowe said. Computationally, they were able to infer what the human-chimp ancestor’s DNA would have been like, as well as the extinct Neanderthal and Denisovan lineages. The researchers were able to compare the genome sequences of these other post-chimpanzee relatives thanks to databases created from the pioneering work of 2022 Nobel laureate Svante Pääbo.
“So, we know the Neanderthal sequence, but let's test that Neanderthal sequence and see if it can really turn on genes or not,” which they did dozens of times.
“And we showed that, whoa, this really is a switch that turns on and off genes,” Lowe said. “It was really fun to see that new gene regulation came from totally new switches, rather than just sort of rewiring switches that already existed.”
Along with the positive traits that HAQERs gave humans, they can also be implicated in some diseases.
Most of us have remarkably similar HAQER sequences, but there are some variances, “and we were able to show that those variants tend to correlate with certain diseases,” Lowe said, namely hypertension, neuroblastoma, unipolar depression, bipolar depression and schizophrenia. The mechanisms of action aren’t known yet, and more research will have to be done in these areas, Lowe said.
“Maybe human-specific diseases or human-specific susceptibilities to these diseases are going to be preferentially mapped back to these new genetic switches that only exist in humans,” Lowe said.
Support for the research came from National Human Genome Research Institute – NIH (R35-HG011332), North Carolina Biotechnology Center (2016-IDG-1013, 2020-IIG-2109), Sigma Xi, The Triangle Center for Evolutionary Medicine and the Duke Whitehead Scholarship.
CITATION: "Adaptive Sequence Divergence Forged New Neurodevelopmental Enhancers in Humans," Riley J. Mangan, Fernando C. Alsina, Federica Mosti, Jesus Emiliano Sotelo-Fonseca, Daniel A. Snellings, Eric H. Au, Juliana Carvalho, Laya Sathyan, Graham D. Johnson, Timothy E. Reddy, Debra L. Silver, Craig B. Lowe. CELL, Nov. 23, 2022. DOI: 10.1016/j.cell.2022.10.016
Duke Senior Awarded George J. Mitchell Scholarship To Study In Ireland
DURHAM, N.C. — Duke University senior Alexandra Bennion of Tampa, Florida, is one of 12 Americans selected this weekend to receive the George J. Mitchell Scholarship for a year of graduate study in Ireland.
This year, 306 students applied for the scholarship, named in honor of Sen. George Mitchell’s contributions to the Northern Ireland peace process. Recipients are chosen on the basis of academic distinction, leadership, and service.
A Nakayama Public Service Scholar, Bennion is a prolific researcher in the field of cancer biology. As a SPIRE Fellow, which supports underrepresented students pursuing degrees in the STEM fields, Bennion will graduate this spring with a degree in biology.
She studies inflammatory breast cancer — a rare and aggressive cancer — in the Devi Lab in the Duke School of Medicine’s Department of Surgery. She is working on her senior thesis, which investigates ways to enhance immune responses to chemotherapeutics.
“I am delighted to congratulate Alexandra Bennion on receiving the Mitchell Scholarship, the culmination of her extraordinary accomplishments as an undergraduate,” said Duke University President Vincent E. Price. “I wish her well as she pursues a master’s degree in translational oncology at Trinity College Dublin, and I am excited about what lies ahead for her very bright future.”
Bennion has supported research projects at an impressive nine different labs and clinics, and has co-authored papers and presented at numerous professional conferences alongside leaders in the field.
She has conducted research at Memorial Sloan Kettering Cancer Center as a 2020 American Physician Scientists Association Summer Scholar, and was selected as a 2020 Scholar in Marine Medicine. Bennion has participated in Bass Connections and DukeEngage, and is a co-founder of Duke Clever Endeavor, a mentorship program for fourth- and fifth-grade students in Durham and Chapel Hill.
She will pursue a master’s degree in translational oncology at Trinity College of Dublin. Bennion then plans to earn an MD/Ph.D. and embark on a career as a physician-scientist, conducting cancer research.
“I am so honored and humbled to have been chosen for the Mitchell Scholarship, and I look forward to taking this next step in studying global cancer research and care,” she said. “This opportunity would not have been possible without the support of the Duke community. I am incredibly thankful to all of my professors, mentors, peers and all who have guided me throughout my college years.”
Bennion will begin her studies in Ireland in September 2023.
For more information, visit the George J. Mitchell Scholarship Program website.
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