Carolina Scientific Fall 23

Carolina

scıentific FALL 2023 | Volume 18 | Issue 1

—HOW PLATELET FUNCTION CAN GO AWRY— full story on page 8 1

PAST EDITIONS OF CAROLINA SCIENTIFIC

Check out all of our previous issues at issuu.com/uncsci.

As the organization continues to grow, we would like to thank our Faculty Advisor, Dr. Lillian Zwemer, for her continued support and mentorship.

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PAST EDITIONS OF CAROLINA SCIENTIFIC

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Carolina

scıentific

Executive Board

Mission Statement:

Founded in Spring 2008, Carolina Scientific serves to educate undergraduates by focusing on the exciting innovations in science and current research that are taking place at UNC-Chapel Hill. Carolina Scientific strives to provide a way for students to discover and express their knowledge of new scientific advances, to encourage students to explore and report on the latest scientific research at UNC-Chapel Hill, and to educate and inform readers while promoting interest in science and research.

Editors-in-Chiefs Sarah Giang Isaac Hwang Design Editor Cassie Wan Copy Editor Corinne Drabenscott Managing Editor Meitra Kazemi Treasurer Ambika Bhatt Secretary Natalie Druffner Publicity Chair Heidi Cao Fundraising Chair Hari Patel Associate Editors Esha Agarwal Kruti Bhargav Julia Boltz Sprihaa Kolanukuduru Andrew Phan Jasmeet Singh Online Content Manager Sreya Upputuri Faculty Advisor Lillian Zwemer, Ph.D.

Letter from the Editors:

Navigating the complexities of being a student is never easy. Most especially for our Carolina community this semester, as we collectively experienced a profound tragedy. Though, in the face of adversity, our community’s shared commitment to scholarly pursuits shines brightly.

Carolina Scientific continues to highlight any and all advancements at our university by enhancing the accessibility of scientific knowledge for the entire student body. Through this process, we aim to encourage and foster the growth of future generations of scientists, designers, and writers. Every issue of our magazine is only made possible through the collaborative effort of University of North Carolina at Chapel Hill students. As you immerse yourself in the pagesof this journal, we hope that you appreciate our semester-long endeavor.

- Sarah Giang & Isaac Hwang

Contributors

on the cover Platelets are critical to driving hemostasis.

Learn about the platelet aggregation response and its relevance to cancer patients.

Full story on page 8.

Illustration by Tanisha Choudhury

carolina_scientific@unc.edu carolinascientific.org instagram: @carolinascientific facebook.com/CarolinaScientific 4

Staff Writers

Copy Staff

Amil Agarwal Simran Bhatia Samantha Breen Grayson Coleman Quinten Curtis Daniela Danilova Anooshka Deshpande Masha Dixon Reagan Gulledge Zehra Gundogdu Keeshant Hoogar Sai Satvik Kolla Shreya Kusumanchi Jinghan Li Nik Li Simran Malik Baylee Materia Isha Mistry Jordan Moseley Aldrin Mosqueda Ria Patel Tara Penman Lucas Ralls Ellie Rogers Arora Rohrbach Morcos Saeed Ruhi Saldanha Julia Sallean Vina Senthil Blake Siegler Preston Szczesniak Natalie Travis Anna Vu Catherine Wiles Karen Zhu

Yasmine Ackall Sneha Adayapalam Suhan Asaigoli Sara Boburka Nicholas Boyer Ciara Daly Daniela Danilova Aditi Deshpande Sofia Domenech Corinne Drabenstott Natalie Druffner Qiling Geng Emily Harper Nastia Hnatov Lillian Hohn Sophia Huang Janessa Jackson Alexander Kinrade Sai Satvik Kolla Sabrina Kolls Cindy Lam Emma Lau Raife Levy Angela (Yanning) Liu Keerthana Mariappan Alacia McClary Isabelle Min Alejandra Ramirez Susan Ran Madison Reavis Morcos Saeed Khadeejah Saleem Blake Seigler Arushi Vaish Gayatri Venkatesan Sophia Vona Joselyn Yoo Kelly Yun

Designers and Illustrators Sara Boburka Estella Calcaterra Heidi Cao Tanisha Choudhury Reem Fayyad Srinithi Gali Noha Goumaa Jessica Hoyt Cindy Lam Clara Lord Spoorthi Marada Katrina Murch Jacqueline Nguyen Caroline Norland Emily Ormond Skyler Peterson Matthew Rodzen Heidi Segars Amelia Spell Arushi Vaish Cassie Wan Sharon Wang Abigail Wells Kelly Yun

Life Sciences Cell Cycle - More than Just a Ring 6 The Daniela Danilova Platelet Function Can Go Awry 8 How Anooshka Deshpande Peek into Water Quality 10 AMasha Dixon

contents

Medicine & Public Health

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Aftermath: The State of Telemedicine in the PostPandemic Era Grayson Coleman and Ruhi Saldanha

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Ubiquitination: The Ubiquitous Process that Might Ease Breast Cancer Treatment Quinten Curtis

Gray Skies to Green Waters 12 From Reagan Gulledge

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Can We Undo Peanut Allergies with Peanuts?

“Emergent” Field Possibly Guides the 14 An Future of Cell Engineering

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A Super-Suit for the Heart

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Addressing the Inevitable Diagnosis with a Censored Covariate

Jinghan Li

it to the Equator: Ecological Case 16 Taking Studies in Ecuador Jordan Moseley

Triglycerides: LPL’s Crucial Role in 18 Tackling Health Ellie Rogers

of Smooth Muscle Cells: An Insight 20 Mysteries from the Wirka Lab Morcos Saeed

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The Stratified Epithelium: A Dynamic Structural Player Vina Senthil

in Protection for Migratory 24 Advancements Sharks in Galapagos Islands

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26 Karen Zhu

Physical Sciences

Molecular Machines for the Reversal 28 Catalytic of Reactions Amil Agarwal

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Reshaping the Future of Plastic Recycling Lucas Ralls

Bright Future for Perovskite 32 ABlake Siegler

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Looking into the Crystal Ball: Using Technology to Predict Photoreactions Anna Vu

Social Sciences

Sai Satvik Kolla

Shreya Kusumanchi

Breaking Barriers, Building Health: Innovative Paths to Chronic Disease Prevention in Minority Communities Simran Malik

the Untreatable: The Fight Against 52 Treating Recurrent Ovarian Cancer Baylee Materia

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A Misguided Intestinal Immune Response

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Fighting Malnutrition Before Conception

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SNAP Decisions: How Federal Assistance Impacts Population Health

Preston Szczesniak

Haunting Stress

Keeshant Hoogar

Isha Mistry Ria Patel

Arora Rohrbach

Psychology & Neuroscience

Human Choices: The Power of 60 Deciphering Discounting Theory Simran Bhatia

Power of Sleep: Synaptic Magic and Memory 62 The Samantha Breen for Stress: A Neurological Perspective 64 Wired Zehra Gundogdu Cognitive Ability from the Insult of 66 Restoring Intermittent Adolescent Binge Drinking Aldrin Mosqueda

Psychedelics to Antidotes: Developments In 68 From Treatments for Depression Nik Li

the Reach of Research: The South 36 Widening Asian Body Image Study

70 Rats, Lobsters, and MRIs: A Non-Invasive Way to Study

38 Society as an Experiment: The Ancient Past

Obesity Epidemic: Is the Brain to Blame?

72 The Julia Sallean

Natalie Travis

and our Uncertain Future Catherine Wiles

the Brain in Animals Tara Penman

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life sciences

The Cell Cycle – More than Just a Ring

By Daniela Danilova

Image courtesy of UBC Learning Commons, CC BY 2.0.

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s one flips through an introductory biology textbook, they are bound to come across a ubiquitous ring-shaped diagram – the common cell cycle (Fig. 1). Although a fair simplification, reality reveals a more malleable picture.

Depending on a cell’s purpose within the body, the blueprint for how it grows and divides may look different. This flexibility, or “plasticity”, of the cell cycle is the research focus of Dr. Jeremy Purvis, associate professor at UNC School of Medicine’s Department of Genetics, and his team at the Purvis Lab. Around the time he was beginning his own research journey, the human genome was finally sequenced; he recalls the “explosion of enthusiasm”1 that followed for unlocking its secrets, particularly via mathematical approaches. With an analytical mind and a

knack for programming, Dr. Purvis found his calling in the field of computational biology. Using computational modeling and microscopy, his goal is to understand the human cell cycle as a basic biological process as well as in the context of diseases and developmental disorders to see how the cycle adjusts to various physiological conditions.

A cell fate decision occurs every time a cell makes a significant change in its outcome. Decisions seem to be inherently human concepts, requiring periods of ponder to consider all available options, but Dr. Purvis finds this definition to be suitable for cells as well: Based on its environment, a cell may alter its progression through the cell cycle (Fig. 2). A stem cell, for instance, may choose to differentiate, assuming a new identity. It may even exit the cell cycle entirely, arresting its development. The real question lies with how a cell processes incoming signals to decide exactly what to do next. To give an example, an embryo early in development will exhibit a cell cycle much faster than that of a fully-grown hair follicle or neuron. The mystery is in how these cell cycles share many of the same parts and yet behave differently to better adapt to their unique contexts.

Although cells are individually programmed to carry out their tasks, together, they give rise to patterns known as emergent behaviors. Despite a cell being oblivious to the activities of its neighbor, they can engage in a “sophisticated dance”1 to create familiar sights like stripes and spots on the organism. The field of study concerned with such interactions is called synthetic biology. Researchers in this discipline attempt to engineer cells to coordinate and generate recognizable structures, trying to understand what molecular interactions between groups of cells make them possible. While this area is outside Dr. Purvis’s purview, he has a strong appreciation for it nonetheless, “It’s amazing how biology has designed and put [everything] together so it works.”1 A common method used in his lab is the single-cell approach. Exactly as it sounds, single-cell approaches focus

Figure 1. The simplified cell cycle. Figure courtesy of the National Human Genome Research Institute.

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life sciences on isolating, probing, and measuring one cell at a time, a practice that became possible only around a decade ago. Before then, cells had to be taken as a batch and ground up for their insides to be analyzed, missing the granularity required for understanding individual decisions. Reflecting the “fuzziness” of these measurements, Dr. Purvis equates the scenario to a familiar process, “It would be like trying to understand how individual people vote by gathering a group of a million and asking for one indicator to determine individual voting preferences.”1 Next comes a lab favorite: single-cell microscopy. One version uses live cells cultured directly under the microscope to view growth, division, and signaling in real time. For example, to track a particular protein, a fluorescent reporter can be used to bind to the protein’s surface, illuminating it so that its abundance can be measured. Periodic snapshots of the cells can be merged into a “movie,” showing gradual changes in cell structures and protein locations. Gathered data can be interpreted to infer when a cell seems to have made the decision to change states, and what events led up to that shift. Individual cells can also be imaged in a fixed state. Although their motion is arrested, the cells can be stained with fluorescent antibodies specific to certain proteins. In fact, following application, the antibody layer can be stripped, allowing a new antibody to stain the cells. The result is nearly sixty protein markers visualized over tens of thousands of cells, something that would be impossible with live imaging.

Although the latter approach loses molecular dynamics, it is far superior in clarity and detail.

on their location in the wound yet still contributing to the main task. Dr. Purvis’s work is also supplemented with computational simulations, such as those used by meteorologists to track storms, to help predict what will happen over the lifetimes of these cells.

The curiosity-driven Purvis Lab is currently engaged in some of their most exciting work. In collaboration with surgical oncologist Dr. Philip Spanheimer, they have Dr. Jeremy Purvis been implementing their imaging techniques on live tumor specimens resected from patients.3 The goal is to understand an individual’s one-of-a-kind cell cycle and how it will respond to chemotherapy in its specific manner.

Another project focuses on cell fate decisions in the early embryo using human pluripotent stem cells. Cells like these are akin to “blank Scrabble pieces”,1 capable of differentiating into many different types. Still, they make a distinct choice to become part of one of the three germ layers, the primary layers of cells that form during embryonic development. Hopefully, the findings can be used to make progress in regenerative medicine.

A person’s stem cells could one day be reprogrammed into functional, differentiated tissues for replacement of damaged sections of the body. While these prospects will require further work, Dr. Purvis believes that the sturdiest path towards such a future involves getting a solid grasp on the basics of cell fate.

Dr. Purvis oversees a versatile team, always pushing them to be interdisciplinary and to keep learning. He hopes his outreach to local schools will inspire the next generation of scientists to follow in his footsteps. The past decade working at UNC-Chapel Hill has been enjoyable, albeit not without a great deal of trial and error. When asked what qualities he looks for in his lab, Dr. Purvis mentioned several, ranging from inquisitiveness to attention to detail. However, he concluded by stating, “The best scientists are great communicators.”1 At the heart of his meticulous craft lies the ability to inspire and excite about the magic of science.

References

1. Interview with Jeremy Purvis, PhD. 09/19/2023.

2. Stallaert, Wayne et al. “The structure of the human cell cycle.” Cell systems vol. 13,3 (2022): 230-240.e3. doi:10.1016/j. cels.2021.10.007 3. Zikry, Tarek M., et al. “Cell Cycle Plasticity Underlies Fractional Resistance to Palbociclib in ER+/HER2- Breast Tumor Cells.” bioRxiv, Cold Spring Harbor Laboratory, 1 Jan. 2023, www.biorxiv.org/content/10.1101/2023.05.22.541831v1. full.pdf+html.

4. “Cell Cycle.” Genome.Gov, National Human Genome Research Institute, www.genome.gov/genetics-glossary/CellCycle. Accessed 20 Oct. 2023.

Figure 2. A breakdown of human cell cycle phases; each dot is an individual cell. Figure courtesy of Stallaert, Wayne et al.

The method of single-cell isolation is good, but not perfect. Observing individual cells can provide invaluable insight into how differently each may behave despite having proximity to others, but the technique does not involve observing a cell group to see how its members function together and create an emergent property. While tricky to accomplish, the latter scenarios are of medical importance and may be a future direction for the lab. Wound repair, for one, is a collective behavior of millions of cells performing varying actions based

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life sciences

Illustration by Tanisha Choudhury

How Platelet Function Can Go Awry By: Anooshka Deshpande

How Platelet Function Can Go Awry

By Anooshka Deshpande

W

e all have sustained injuries at some point in our lives ranging from a paper cut to a knee bruise. Eventually, we stop bleeding because blood ceases to leak out of the broken blood vessel. Platelets, tiny cells that are circulating in our blood, prevent blood from incessantly leaking out of our blood vessels. They clump together to form an aggregate at the site of a vessel injury in a process called hemostasis. In some patients, platelet function can go awry. In thrombosis, platelets become activated and form blood clots in the absence of a vessel injury, obstructing the vessel and hindering blood flow to organs. On the other hand, platelets can

Dr. Wolfgang Bergmeier

remain quiescent even when a blood vessel wall is damaged and blood is leaking out, leading to bleeding disorders.

Thousands of individuals suffer from platelet disorders in the United States, yet treatment options remain limited. Dr. Wolfgang Bergmeier, a researcher in the UNC Department of Biochemistry and Biophysics, is studying the intracellular machinery that platelets use to adhere to vascular injury sites. His objective is to develop treatments for patients with bleeding or thrombotic complications.

Platelets lack a cell nucleus; instead, they are packed with sacs called granules that release enzymes and clotting factors when a blood vessel is damaged. Platelets normally circulate through the blood in a quiescent, inactivated state. As soon as platelets are activated following an injury, biochemical changes alter their morphology. This increases their surface area and facilitates their contact with each other. Before platelets can release their granules, they must detect and contact the damaged vessel wall. They contain receptors on their membrane called integrins, which help them bind to each other and to the broken vessel’s exposed extracellular matrix. Then, they release various enzymes and clotting factors that

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provide feedback activation required for a robust platelet aggregation response.

Two techniques can be used to observe the platelet aggregation response: light transmission aggregometry and flow cytometry.

In light transmission aggregometry, a sample of a patient’s platelet-rich plasma is put into a tube called a cuvette. Then, light is shone through the cuvette. High light transmission through the sample is a sign of increased platelet aggregation because the platelets are stuck to each other, maximizing the room available for light to pass through other regions of the sample. On the other hand, low light transmission is a sign of decreased platelet aggregation because the platelets are scattered throughout the sample and absorb most of the incoming light. Light transmission aggregometry can also reflect the activation state of integrin receptors; increased integrin activation corresponds to increased platelet aggregation and thus correlates with light transmission. In flow cytometry, a laser beam is shone on each platelet in the sample and specific probes are used to detect agonist-induced changes inside the platelets as well as on the cell surface.

This enables scientists to observe how

life sciences each platelet’s activity changes during an aggregation response.1 Due to the similar proteins that mice and humans express, platelet aggregation has been widely studied in mice. Mice can be easily manipulated and bred for a variety of genotypes, which is why they are convenient to use. In the tail transection model, researchers study hemostasis and bleeding time by cutting open a blood vessel in the tail of the mouse because the tail is easily accessible and involves no invasive surgery.1 Cancer patients tend to experience increased bleeding and thrombosis due to inappropriate activation of platelets.

The Bergmeier lab investigates the effects of cancer cells on platelet function in collaboration with other investigators at the UNC Blood Research Center, including Drs. Nigel Mackman and Yohei Hisada. In a recently published study, BxPC-3 pancreatic cancer cells were injected into immunocompromised mice, i.e. mice that do not mount an immune response against the tumor cells. In the control group, mice received phosphatebuffered saline, a benign salt solution, instead of BxPC-3 tumor cells. After the tumors grew and weighed between 2.0 and 3.2 grams, thrombosis was induced in the carotid artery by exposing the artery wall to ferric chloride. Then, a tail transection model was used to observe the hemostatic response. Lastly, the lab used flow cytometry and light transmission aggregometry to observe markers of platelet activation.2 The research team observed that experimental mice bled longer and had

a lower platelet count. Experimental mice also had a higher amount of reticulated platelets in circulation. Reticulated platelets are immature platelets that signify the rate of platelet formation from megakaryocytes, their precursor cell.

These results highlight that experimental mice experienced higher platelet turnover; their platelets were destroyed and replenished faster. Compared to controls, platelets isolated from tumorbearing mice exhibited functional changes, such as a lower expression of an important adhesion receptor, called GPIbα, and impaired activation of the main platelet integrin, αIIbβ3. Overall, the findings suggest that mice injected with pancreatic cancer experienced chronic platelet activation, which is when

long road to breakthrough discoveries, but when it happens it is one of the best feelings one can have.”1 Treatments for platelet disorders will undoubtedly save myriad lives.

“The study may hint at why cancer patients experience excessive bleeding."

platelets are repeatedly activated and cleared from circulation. This leads to thrombocytopenia, platelet exhaustion, and excessive bleeding.2 In other projects performed in collaboration with engineers and clinicians, the Bergmeier lab investigates nanoparticles that can serve as clot busters or as procoagulant agents, how to optimize treatment protocols for patients with bleeding disorders, and how genetic variations can impact platelet function.

His lab continues to investigate platelet signaling mechanisms to better understand how platelets respond to changes in their environment and whether platelet function is regulated differently in the context of inflammation, where these cells are one of the first lines of defense against bacterial infections.

Dr. Bergmeier is very enthusiastic about the different projects going on in his lab, and the many collaborations they have with investigators at UNC and other institutions. “We will continue to work on these Figure 1. Platelet formation. Platelets store granules exciting projects, with the hope that contain enzymes and blood clotting factors. Image that some of our findings will courtesy of Wikimedia Commons. change clinical practice. It is a

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References

1. Interview with Wolfgang Bergmeier, PhD, 9/26/2023.

2. Tomohiro Kawano, Yohei Hisada, Steven P Grover, Wyatt Schug, David Paul, Wolfgang Bergmeier, Nigel Mackman; Decreased Platelet Reactivity and Function in a Mouse Model of Pancreatic Cancer. Blood 2022; 140 (Supplement 1): 5533. doi: https://doi.org/10.1182/ blood-2022-163420

life sciences

A Peek into Water Quality

By Masha Dixon

Image courtesy of morroelsie, CC BY-NC 2.0.

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icknamed the “nurseries of the sea” and serving as a bridge between the salty ocean and freshwater rivers, estuaries are necessary components of healthy ecosystems. Estuaries provide habitats for hundreds of different aquatic and terrestrial species, and they reflect change in climate and wildlife health.

North Carolina hosts one of the largest estuarine systems in the Eastern United States – the Pamlico Sound. The Neuse River Estuary, a 40 -mile- long tidal estuary that feeds into the Pamlico Sound,1 has one of the longest prevailing estuarine datasets: encompassing around 30 years of water quality data.

The Neuse River Estuary is also a large fishing and leisure hub, so it is a vital part of the economy and recreation of North Carolina.

Understanding estuarine water quality patterns is essential for wildlife conservation, pollution mitigation, and human health.

Dr. Nathan Hall is a Research Assistant Professor at the University of North Carolina at Chapel Hill Institute of Marine Sciences in Morehead City, North Carolina.2 He currently acts as the Co-Principal Investigator of the ModMon project – the organization responsible for the 30 yearlong dataset monitoring the Neuse River Estuary.

Dr. Hall stated that to understand the ModMon project, it is “best to start with some history.”2 In the early 1990’s the Neuse River Estuary had a huge problem with fish kills – aquatic events where numerous dead fish are observed in a body of

Figure 1. Dr. Hall showing students how to measure water clarity. Image courtesy of Dr. Hall.

water. Fish kills are caused by problems in water quality, such as low dissolved oxygen, nutrient depletion, algal blooms, and pesticide toxicity. These events soon got the attention of the state, which launched an investigation into the water quality of the Neuse Estuary.1 This is where Dr. Hans Paerl, a Kenan Distinguished Professor and aquatic ecologist, Dr. Nathan Hall became involved. His lab, the Paerl Lab, researches nutrient and algal production dynamics and water quality of local estuarine systems. In 1994, he launched the ModMon project, which was an expansion of these state funded estuarine projects. Since the 90’s, ModMon has been collecting data about water quality in the estuary to understand the factors that make algae grow and impact fish health.

As a grad student, Dr. Hall worked with Dr. Hans Paerl and used ModMon data for his dissertation around macroplanktonic algae that floated on the surface of North Carolina’s water systems. Dr. Hall is primarily responsible for ModMon’s outreach; he focuses on getting ModMon data out to the public in an easily digestible format. He writes summaries of changes in data or any concerns around water quality in the Neuse River Estuary and sends it out to the State Division of Water Resources and nonprofits such as the Coastal Federation, Sierra Club, River Keepers Association, and other educator programs. Dr. Hall stated that the most exciting thing about working on the ModMon project is that “you can see change” which is normally difficult, as “estuaries are dynamic; and are so responsive to weather events so long data sets are necessary to see longterm patterns.”2 With ModMon’s extensive collection of data, it is easier to make predictions surrounding water quality and improve estuarine conditions.

ModMon has eleven stations in the Neuse River Estuary and nine in the Southwest Pamlico Sound River.2 Every other week, two technicians visit these stations to collect physical data samples. One scientist measures water conditions using a Water Quality Sonde – a water measuring tool containing probes that measure temperature, salinity, dissolved oxygen content, and acidity/pH. The sonde starts logging at the surface and is slowly lowered into the water, stopping every half a meter until hitting

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life sciences the bottom. Another scientist collects 4-liter water samples with a pump which are taken back to the lab and analyzed.

Water quality parameters such as such as dissolved nutrient levels (nitrate, ammonia, phosphate) and turbidity (how cloudy the water is) impact fish health and native seagrass growth. Seagrass is an important habitat for fish and stabilizes sediment. Loss of seagrass negatively affects both fish communities and water quality.

Measuring these Figure 3. Map of the ModMon sampling stations on the Neuse River. Figure courtesy of ModMon/Dr. Hall. factors can help scientists better understand the health of the estuary. understand factors that affect the growth of native seagrasses.2 Water sampling influences state regulations around This project is going directly to the state, which is actively water quality standards. Dr. Hall believes that the biggest impact adapting water quality standards to protect seagrass. This is of water quality data is “understanding what we are sending exciting for Dr. Hall since it is “as much of a direct linkage to downstream [to our estuaries]”, which is where predictions play [his] science and rulemaking that [he’s] ever had.” The next a role.2 Dr. Hall listed an example of how water quality data steps for ModMon, however, are ongoing: Dr. Hall believes that influenced the city of Raleigh to reduce their nutrient output. maintaining the ModMon project is a “long-term goal, but an In the 90s, ModMon data helped determine that to improve extremely important goal” and that there are constantly new estuarine conditions the excess nutrient levels had to decrease findings surrounding the data ModMon collects.2 by 30%. Raleigh – which was one of the main sources of runoff The Neuse River Estuary is an important pillar of North and excess nutrients in the Neuse River – has kept their nutrient Carolina’s ecosystem. Pivotal datasets - like ModMon – allow levels constant, despite their population doubling over the scientists to monitor and understand estuarine health, which years.2 in turn, allows the estuary to continue providing a habitat for Currently, Dr. Hall is working with the Albemarle-Pamlico hundreds of organisms and being a source of enjoyment for National Estuary Partnership and with ModMon data to hikers and boaters alike.

References Figure 2. A microscope photo (photomicrogram) of an algal bloom in the Neuse River estuary. Image courtesy of Dr. Hall.

1. Neuse River Basin. https://www.eenorthcarolina.org/documents/files/neuse-river-basin (accessed September 12th, 2023).

2. Interview with Nathan Hall, Ph. D. 09/12/23.

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life sciences

From Gray Skies to Green Waters

By Reagan Gulledge Illustration by Bhavika Chirumamilla

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lgae blooms are probably not the first thing to come to mind for many people when watching the television for the latest hurricane updates. Many people don’t consider algae blooms a major consequence when the powerful hurricanes finally impact their shores, nor the impacts it will have on water quality. The torrential downpours resulting from hurricanes cause extensive flooding, which ultimately brings large amounts of nutrient laden runoff to downstream waters.

Excess storm-driven nutrient loads entering our nutrientsensitive waters can promote the proliferation of harmful algae blooms (HABs) throughout the freshwater to marine continuum characterizing North Carolina’s coastal zone.

Dr. Hans Paerl and his colleagues at University of North Carolina at Chapel Hill’s Institute of Marine Sciences, in Morehead City, are engaged in collecting and analyzing water samples in these waters through their “FerryMon” project. Dr. Paerl first became inspired to learn more about environmental causes and impacts of HABs while working on research in Finland. There, the team learned about ships traveling over the Baltic Sea, which autonomously collected water samples, and recorded data on water quality during Dr. Hans Paerl their transits. The

opportunity to incorporate this idea into North Carolina waters arose after Hurricane Floyd in 1999, one of the largest hurricanes in recent memory that impacted eastern North Carolina.1 The hurricane resulted in major changes in water quality for the Pamlico Sound because of intense flooding, accompanied by sediment and nutrient loading, causing Dr. Paerl to seek out a better understanding of impacts on water quality in this large and important water body, including intense potentially toxic HABs, accompanied by low dissolved oxygen conditions, and pH changes. Thus, in 2000, FerryMon was officially born.

The decline of the Pamlico Sound’s water quality after hurricane Floyd gave Dr. Paerl the opportunity to officially initiate his research. As Dr. Paerl stated, “It’s interesting how catastrophes often lead to opportunities.”1 In this case, that opportunity was “FerryMon”. FerryMon, or Ferry-Based Water Quality Monitoring, using a flow-through system that is located in ferries to conduct automated, continuous water quality monitoring. FerryMon has two currently operating ferries, with one located in the western Pamlico Sound and the other in the Neuse River estuary. The ferries this serve as ships of opportunity—because the ferries operate almost every day, the research project was cost-efficient in its inception.

FerryMon’s equipment is located below deck of the ferries.

The ferries take in water that travels through the bough, or front, of the boat, some of which is split between AC system and FerryMon’s plenum. The plenum is a large tank in the ferry boat that has sensors inside to measure the different water quality parameters. There is also an in-line carousel-type system that allows water to be collected at certain intervals, which facilitates

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life sciences

Figure 1. Dr. Paerl is in the Paerl Labs running parameter analyses on the collected water samples. Image provided by Dr. Hans Paerl. water collection throughout the entire estuary. The plenum has a sensor unit placed in it that measures some of the standard water quality parameters: dissolved oxygen, pH, temperature, salinity, and chlorophyll.1 Once collected, the data are sent to the Paerl Labs via the internet so it can be further analyzed for quality control and compiled into graphs. Additionally, the water that is collected by the carousel is periodically loaded off the ferry and sent to the lab to obtain more sophisticated chemical and molecular analyses. Some of the relevant parameters include pigment analysis of algae, indicators of pathogens, organic pollutants, nutrients, and chemical constituents.1 Another key component of the FerryMon project is the Digital Global Positioning System (GPS). When the ferry boats are on the water, the water quality parameters are measured every minute of the trip, and each data point collected has a GPS location attached to it.2 These GPS points are essential in determining water quality patterns, such as the location, travel, and growing patterns of large algae blooms. These data points are converted into graphs, so that agencies such as the NC Dept. of Environmental Quality, NC Division of Marine Fisheries, EPA, and NOAA can use this information to make management decisions to help protect vulnerable finfish and shellfish species and formulate allowable fish catches.

Algae blooms can form in the freshwater to marine continuum representing our estuarine and coastal waters and are especially prominent after major storms such as Hurricane Floyd in 1999. However, some people may not realize that in addition being unsightly, algae blooms can be toxic to finfish and shellfish, as well as other marine life, and humans.3 Algae blooms do not grow in uniformity and can even be growing while invisible to the naked eye. “They are what I call raisin cookies: You get some dense areas of bloom and some not dense areas,” described Dr. Paerl.1 Salinity and temperature are important factors that determine the growth rate of algae, and both parameters fluctuate considerably in the presence of storms, especially in the large Pamlico Sound. The Pamlico Sound is also connected to coastal waters, so the salinity and temperature fluctuations can vary depending on how much freshwater is coming in compared to the coastal water exchange.2 Changes in the wind direction, speed of water currents, and river elevation can also cause water to build up on one side of the estuary, which leads to algae blooms growing and accumulating in

specific areas. Climate change (warming and more extreme rainfall events) is increasingly affecting ecologically sensitive local bodies of water.

Record-breaking storms are now a common occurrence, and it is important to observe the impact of such storms on the marine environment and water quality parameters. Dr. Paerl and his research team are working on making portable sensing systems that can be loaded onto any convenient ferry, allowing for more geographic flexibility in the research opportunities.

“It’s a program for all times and all seasons,” stated Dr. Paerl.1 The future of FerryMon is only expanding, promising to provide new data about the future of our water quality. With the help of Dr. Paerl and his research, FerryMon will continue to be integral in the search for the right solution to combat human and climatically driven change in our ecologically and economically important water bodies. FerryMon is essential in learning about the future of our water quality, and it aids scientists in finding the right management solutions and mitigation steps to ensure acceptable water quality.

Figure 2. Dr. Paerl is collecting a water sample to analyze the algae levels. Image provided by Dr. Hans Paerl.

References

1. Interview with Hans Paerl, 09/14/2023.

2. The Paerl Lab. https://paerllab.web.unc.edu/ 3. Paerl, H. Biogeochemistry. 2018, 141: 307-332.

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life sciences

An “Emergent” Field Possibly Guides the Future of Cell Engineering

by Jinghan Li Image courtesy of cloning girl, CC BY-NC-SA 2.0.

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articles bouncing off a surface, altering their direction of movement; electric fields acting on charges; mass continuing its motion after a push. These are the basic physical properties many are intimately familiar with, yet the laws underpinning them— those of quantum mechanics—are far less intuitive. More importantly, these physical properties interact on a larger scale and constitute observations in daily lives, once again eluding intuition.

Cells also contain similar mysteries.

On one hand, the genomes—guides to the creation of raw materials for the mansion of organisms—of various species, including humans, have been accurately sequenced since the 1990s.

One notable example is the yeast cell that was sequenced in 1996. This was the first eukaryote, which has linear DNA capable of highly complicated coiling, to be sequenced. On the other hand,

Figure 1. Photo of mounds of cathedral termites. Image coutesy of Brian Voon Yee Yap.

biologists have had little insight into how to construct the intricate machinery of cells—holding every single building block in their hands—without a guidebook of how to put those blocks together.

The ambition of Dr. Kerry Bloom in the Department of Biology at the University of North Carolina at Chapel Hill, along with his lab members, is to contribute to writing this guidebook, specifically regarding DNA. “Change is our one constant,” remarked Dr. Bloom when discussing the path of exploration undertaken by his lab.

Introducing new perspectives and ways of thinking has enabled the Bloom Lab to continuously make new discoveries, with the focus of research constantly shifting based on recent findings.

Dr. Bloom’s most recent study, “The Power of Weak, Transient Interactions Across Biology: A Paradigm of Emergent Behavior,” sheds light on a significant concept to understanding the behavior of DNA in eukaryotes, wherein the contributions of microscopic molecular interactions to overall patterns are emphasized.

Emergent behavior occurs when individual components of a system possess simple properties that enable them to interact with significant complexity and form patterns. Emergent behavior is the basis for many astonishing natural marvels. Underlying the intricate design of snowflakes is the property of single water molecules to arrange themselves in particular ways; meterhigh “termite cathedrals (Figure 2)” stand as feats of millions of single termites less than 3mm in height, performing simple functions with individual logic, all without any awareness of their collective

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Figure 2. DNA coils into even more complex structures—by themselves.

Image courtesy of WillowW. accomplishments. Similarly, perplexing phenomena occur within cells, where strands of DNA coil up, like threads coiling into a ball—though they embody a far more complex structure, all without a “hand” creating the mechanical force that facilitates the wrapping. Instead, the molecular interactions within DNA itself, governed by its molecular properties and influenced by other cellular factors, contribute to the “spontaneous” coiling of DNA, a manifestation of emergent behavior. These microscopic interactions also contribute to the spatial organization of DNA movement, which relates to the accessibility of DNA information and influences cellular functioning.

In the study, DNA movements were recorded in live yeast cells with DNA labeled with green fluorescent protein (GFP). The observations of the movements are then compared with the results from computer models of DNA movement within the cell—specifically, bead-string polymeric models (Figure 3)—where the DNA moves in programmed patterns according to the physical laws believed to underlie DNA movement, including drag force, spring force, excluded

life sciences volume (preventing beads to overlap in position), etc. The results of the study suggest that the computer model successfully predicted the behavior of DNA under numerous conditions.

Additionally, the study also modeled the activity of mucus—the slimy fluid found in various parts of our bodies, including the nose, throat, and lungs— and identified similar roles of weak molecular interactions. This leads to the conclusion that weak, simple, and transient interactions at the molecular level do indeed provide a plausible explanation for life, from the genetic level to the organismal level, offering Figure 3. Bead-string polymeric models used to simulate DNA activity. Figure courtesy of Dr. Bloom. a reference for subsequent researchers in predicting bodily functions specializing in different fields, terms into crafting a self-serving narrative. as well as DNA behavior—a central part carried different meanings for different Meanwhile, intuition frequently asks of cellular function—within natural and people based on their knowledge and simple choice questions, in search for backgrounds. For example, saying “stress” immediate, simple answers. engineered cells.

The study represented a meticulous alone could be problematic, as it relates As researchers, scholars, analysts, and interdisciplinary endeavor, from to specific formulas for physicists, while “it is naïve to think, when you ask a good creating computer models to recording it is commonly used in various contexts. question, that there will be a yes or no corresponding activities within live When communicating with others, team answer”.1 This dogma elicited from the cells. Experts from fields ranging from members had to remain constantly aware studies of the Bloom Lab constantly computer science, physics, and biology of how each other interpreted their reminds us of how far feelings may digress worked cohesively to reach a conclusion. words. In this sense, the team worked from facts, and how people’s prospective, Interestingly, Dr. Bloom described hard to be sympathetic and sensitive— exciting, and insightful endeavors may the most significant hurdle for the team to on a different, scientific scale. end up being fallacies. Yet it is precisely Indeed, Dr. Bloom’s study of this state of ignorance, insolence, and be finding the best way to communicate with team members. Having to use emergent behavior not only illuminates innocence that fuels the insatiable quest advanced computer models to predict a novel way of considering organisms, for the deceptive, unfathomable, yet in-depth processes in biology, the but also invites people to ponder on omnipresent truth. researchers had their own “jargon” that approaches for broader challenges.

An important philosophy of needed to be explained and understood within the team. In the face of experts emergent behaviors is that the whole looks different when the individual parts are put together. Unless one precisely comprehends the individual parts— from their fundamental organization to their higher-order interactions—prior to assembly, the resulting complexities begin to elude the intuition, pushing it beyond its capacity for quick, albeit superficial, explanations. Bound by its References very nature, intuition renders a definitive 1. Interview with Kerry S. Bloom, Ph.D. judgment grounded solely in one’s 9/13/2023. limited knowledge—a blend of bulks 2. Vasquez P A, Walker B, Bloom K, et of ignorance and tiny grains of truth al. Phys. D: Nonlinear Phenom. 2023, and fiction, often leading people astray 454: 133866.

Dr. Kerry Bloom (left)

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life sciences

Taking it to the Equator: Ecological Case Studies in

By Jordan Moseley Ecuador

Figure 3. Mount Chimborazo, Riobamba, Ecuador. Image courtesy of Jordan Negrón Moseley.

Agriculture’s Dangerous yet Unintended Side Effects

I

f one were to visit Ecuador, they would find snow-covered mountains, coastal areas filled with iguanas and penguins, and dense rainforests surrounding the Amazon River. Such a broad range of biodiversity in a small geographic area is rare, which results in many researchers hoping to visit the region for the sole purpose of studying ecology and environmental science.1 Dr. Diego Riveros-Iregui, a professor at the University of North Carolina at Chapel Hill, works in the geography department and studies these topics year-round. Microbiologists and ecologists collaborate with him to understand the carbon and nitrogen cycles across Latin America, but more importantly, how to repair them.2 Ecuador’s Andes páramos and the Galápagos Islands are their main focal points. “Páramo” is a broad term for many types of ecosystems found in the Andean mountains, and Dr. Riveros-Iregui studies peat, a type of soil found in places called peatlands. Peatlands are an ecosystem known for having relatively flat surfaces and amazing soil fertility, which make them ideal hotspots for agricultural activity.2 Due to the human activity of converting natural peat and island land into agricultural land, these areas have been damaged and release an excessive amount of carbon dioxide (CO2) and methane (CH4) into the atmosphere.3 In the Galápagos Islands, the rapid growth of invasive plants due to agricultural Diego Riveros-Iregui, Ph.D. cultivation has led to

nitrogen depletion in the soil. Excessive carbon and insufficient nitrogen in the ecosystem cause a disruption within plant and animal communities. These declines directly increase global warming and climate change. Dr. Riveros-Iregui hopes to undo the process of agricultural irrigation, which would help prevent further damage and repair some of the land.2 If páramo lands have proper water drainage, then the lagoons can properly store carbon in the waters instead of in the atmosphere. For the Galápagos, healing the land by planting native plants instead of invasive ones will help restore nitrogen levels in the soil. 4

Andean Páramos

The páramos are found in the Andean Mountains of northwestern South America. They are almost exclusively found in high altitudes—some exceeding heights of 14,000 feet.2 They capture substantial amounts of carbon by storing it in their waterways and plant roots.3 Páramos receive carbon from plants and the atmosphere so they can deliver it to land that the waterways run through. Páramos also serve as a medium to provide carbon in the form of CO2 and CH4 back into the atmosphere. These are important steps in the carbon cycle so that other parts of the world can give and receive carbon.3 Waterways inside the páramos are vital for maintaining large amounts of carbon to facilitate the carbon cycle. Dr. RiverosIregui’s work consists of measuring the amount of CO2 and CH4 that the páramos receive and release back into the atmosphere, which is known as taking flux measurements. They expect that lagoons with the most human activity have the most increases in CO2 and CH4 measurements. Dr. Riveros-Iregui’s main goal for the páramos is to find methods of restoring the land back to its natural state in order for carbon to be regularly cycled again. Reversing the effects of agricultural conversion will help balance out the carbon that is already in the atmosphere and allow waterways in the páramos to store it correctly, which will reduce global warming and climate change worldwide.

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life sciences

Figure 1. Photo of Samanga in Parque Nacional Cayambe Coca. Image courtesy of Jordan Negrón Moseley.

The Galápagos Islands

Dr. Riveros-Iregui’s next region of investigation is La Isla San Cristobal in the Galápagos Islands. One of the main concerns for the Galápagos Islands are the microbial communities that live there, as they catch and release nitrogen in the ecosystem.4 For him and his team, they aim to study why invasive plants are uptaking more nitrogen in their roots.4 Dr. Riveros-Iregui and his team are currently studying one

invasive species in the Galápagos: Psidium guajava, commonly known as the guava plant. His group wants to research if invasive plants like the guava plant have different bacterial and fungal communities than native-grown plants, which would affect the nitrogen cycle.4 They collected samples of guava soil and soil from the Galápagos native plant scalesia, a type of daisy tree, to compare their rates of nitrogen consumption.4 They found that guava soil significantly and negatively impacts the nitrogen cycle. Guava soil stores more nitrogen, which can hinder the element from cycling throughout the rest of the environment.4 This is similar to the carbon issues found in the páramos.

Nitrogen overconsumption is a concern for the Galápagos Islands because few invasive plants overconsuming nitrogen will disrupt the elemental cycle in multiple regions outside of South America. In areas where there is less nitrogen than usual, there is less plant growth.4 For Dr. Riveros-Iregui and his research group, they want to emphasize the importance of considering multiple factors simultaneously by gathering a variety of evidence to see which factors are influencing the environment the most. Since Ecuador is a country that contains diverse habitats and biomes, they can complete this task without having to go to another country.

Dr. Riveros-Iregui’s research will continue to explore important parts of Ecuador and Latin America that experience high atmospheric disturbances, and he will continue to collaborate with other researchers to find solutions for healing the carbon and nitrogen cycles. Ultimately, this research will work to prevent further damage from occurring in these regions, and more broadly, the entire globe.

References

Figure 2. Photo of Laguna de los amantes (Lover’s Lake) in Parque Nacional - Cayambe Coca, Ecuador. Image courtesy of Jordan Negrón Moseley.

1. MacLeod, M. J., & Knapp, G. W. (2019). Ecuador | History, Geography, & Culture. In Encyclopædia Britannica. https:// www.britannica.com/place/Ecuador 2. Interview with Diego Riveros-Iregui. (2023, September 5).

3. Marx, A., Dusek, J., Jankovec, J., Sanda, M., Vogel, T., van Geldern, R., Hartmann, J., & Barth, J. A. C. (2017). A review of CO2and associated carbon dynamics in headwater streams: A global perspective. Reviews of Geophysics, 55(2), 560–585. https://doi.org/10.1002/2016rg000547 4. Schoenborn, A. A., Yannarell, S. M., MacVicar, C. T., Barriga-Medina, N., Bonham, K. S., León-Reyes, A., RiverosIregui, D. A., Vanja Klepac‐Ceraj, & Shank, E. A. (2023).

Microclimate is a strong predictor of the native and invasive plant‐associated soil microbiome on San Cristóbal Island, Galápagos archipelago. Environmental Microbiology, 25(8), 1377–1392. https://doi.org/10.1111/1462-2920.16361

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life sciences

Tackling Triglycerides: LPL’s Crucial Role in Health Examining LPL’s Different Structures and Functions

By Ellie Rogers Figure 1. Kathryn Gunn, a postdoctoral research fellow in the Neher Lab, conducting research under a microscope. Photo by Anna Wheless courtesy of Dr. Saskia Neher.

F

eeling a familiar pang of hunger, you find yourself reaching for a bag of your beloved potato chips. However, within minutes of savoring those crunchy crisps, greasy gratification transforms into an onslaught of affliction—a surge of nausea, unsettling abdominal discomfort, and a startling metamorphosis that makes you regret your choice instantly.

Fortunately, most people will never find themselves in this hyperbolic ordeal following a mere bag of chips due to our body’s capacity to break down fats—an essential element of our diets.¹ However, like many substances coursing through the bloodstream, fats are not meant to permanently reside there.

Insufficient breakdown of triglycerides, the body’s predominant fat, leads to dire consequences as they accumulate (Figure 4).

This perilous buildup, termed hypertriglyceridemia, underlies conditions ranging from rare pancreatitis to the world’s foremost cause of mortality, cardiovascular disease.² To combat hypertriglyceridemia, a formidable guardian exists within the intricate tapestry of human physiology: lipoprotein lipase (LPL), an enzyme that breaks triglycerides into smaller fatty acids for storage or energy.³ Dr. Saskia Neher, a researcher in the University of North Carolina at Chapel Hill’s department of Biochemistry, seeks to understand the precise mechanisms of LPL and its potential in combating hypertriglyceridemia and related health conditions.

LPL is no ordinary enzyme; stationed at the border between two worlds— the hydrophilic realm of water and the hydrophobic Figure 2. Visualization of territory of lipids in our the inactive LPL helix. Photo body—LPL’s calling lies in courtesy of Dr. Saskia Neher. navigating this boundary,

Figure 3. Visualization of the active LPL dimer. Photo courtesy of Dr. Saskia Neher. distinguishing it from most enzymes that reside in our biological fluids. Furthermore, LPL does not settle for a single identity, dynamically altering its structure to adapt to the body’s needs. These changes allow it to undertake various functions, ensuring proper triglyceride breakdown or storage. Given its complexities, understanding how LPL accomplishes its role has come with challenges. “LPL is a very unstable protein,” Dr. Neher admits, “and it does have a propensity to aggregate, so some of the structure studies were quite challenging…but I like the proteins that are kind of a challenge.”⁴ Dr. Neher and her lab employ a powerful tool to understand the structural and functional changes of LPL: cryoelectron microscopy (cryoEM). “[One is] able to image hundreds of thousands of individual particles of [the] protein,” she explains, “and because the detectors are very good, [one] can put those images together and rebuild the structure.” This revolutionary technique allows researchers to decipher the three-dimensional structures of proteins without the need for crystallization, a complex stabilization process. Instead, the protein is frozen on a grid at low temperatures, allowing the capture and assembly of numerous images to rebuild a structure

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life sciences that shows the elaborate folds and shapes of proteins in their natural biologically relevant states.⁴ CryoEM has unveiled two novel oligomeric forms of LPL, providing remarkable insights into the enzyme’s structure and function. Dr. Neher explains,“One was a helix, and in this form, the LPL circles up, and in this circled up form, the lipase is not active, and we think that’s how it’s stored”⁴ (Figure 2).

Dr. Saskia Neher LPL remains dormant in this helical structure until it is needed by the body. Dr. Neher illustrates that, “The lipase is made before [one] need[s] it, and then when [one] eat[s], insulin will signal that [one] need[s] to put some lipase into the blood so [that it] can break down the food that you ate.” She further explains that “[lipase] needs to sit in the cells until that signal comes.” This mechanism allows the body to store ample LPL in a tiny space, primed for deployment when necessary.⁴ Dr. Neher made another discovery when she observed LPL in action at the air-water interface. “We believe that the lipase recognizes that interface just like it would a substrate,” Dr. Neher discusses, “and so we believe that we caught an active form of it just as if it were sitting on a substrate when it was sitting on the air-water interface” (Figure 3).⁴ This revelation unveiled a hidden pore within LPL, a potential gateway for extracting triglycerides. Dr. Neher details, “It would be a very efficient way to utilize substrate because it would be able to extract a triglyceride, and then the free fatty acid would be able to exit from the pore.” This insight into LPL’s structure prompts further exploration. “We’re still studying the pore,” Dr. Neher explains, adding on that “we haven’t proven that it is the exit tunnel, but we believe that it is a good model.”

Additionally, the potential for exploration widens. “We are very interested in if this lipase exit tunnel is common to other lipases,” she states, offering a glimpse into her lab’s future research.⁴ LPL’s role in the body extends beyond lipid metabolism, intersecting with another group of proteins. “There are known inhibitors of the lipase,” Dr. Neher elaborates, “...called the angiopoietin-like proteins…they block LPL activity at specific times and locations in the body.” Understanding these inhibitors’ interactions with LPL may hold the promise of unlocking healthier hearts.

“Individuals who lack the inhibitors have lower triglycerides and healthier hearts,” she reveals.

Additionally, unraveling the secrets of LPL entails a deep exploration of cellular trafficking, the way substances move within cells. “The secretion of LPL Figure 4. A triglyceride. Photo in response to insulin is an courtesy of WikiMedia Commons. important way to keep our

triglycerides down,” Dr. Neher notes, “and really understanding the trafficking of LPL throughout the cell is an important factor not only for heart disease and diabetes…it helps us understand that basic trafficking pattern and where it goes wrong.”⁴ In the context of disease, understanding LPL’s mechanisms stands as a medically pertinent endeavor for future disease management and treatment. Dr. Neher emphasizes this importance, adding “You want your work to have an impact if possible, and so I do like working on an enzyme that has such a high medical relevance.”⁴ Dr. Neher’s dedication to the ongoing exploration of disease and molecular mysteries has illuminated this uniquely multifaceted enzyme, offering incredible insights into critical health conditions. So the next time you savor the crunch of your potato chips, relish the role of LPL, for within its depths lie a taste of scientific wonder promising a healthier future.

Figure 5. Blood sample of an individual with hypertriglyceridemia. Photo courtesy of WikiMedia Commons.

References

1. Field CJ, Robinson L. Dietary Fats. Adv Nutr. 2019 Jul 1;10(4):722-724. doi: 10.1093/advances/nmz052. PMID: 31147674; PMCID: PMC6628852. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628852/ 2. U.S. Department of Health and Human Services. (n.d.).

High blood triglycerides. National Heart Lung and Blood Institute. https://www.nhlbi.nih.gov/health/high-blood-triglycerides#:~:text=Triglycerides%20come%20from%20 foods%2C%20especially,does%20not%20need%20right%20 away.

3. Gunn KH, Neher SB. Structure of dimeric lipoprotein lipase reveals a pore adjacent to the active site. Nat Commun. 2023 May 4;14(1):2569. doi: 10.1038/s41467-023-38243-9.

PMID: 37142573; PMCID: PMC10160067. https://pubmed.ncbi.nlm.nih.gov/37142573/.

4. Interview with Dr. Saskia Neher, PhD, 9/26/2023.

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life sciences

Mysteries of Smooth Muscle Cells: An Insight from the Wirka Lab

By Morcos Saeed

Photo by Pawel Czerwinski Unsplash Image

by SIUvia University

A

therosclerosis is a complex and pervasive disease, often referred to as the “silent killer.” It lurks within our arteries, gradually narrowing them, and is a leading cause of heart attacks and strokes. But beneath this seemingly silent assassin, there’s a fascinating world of cellular activity that scientists are just beginning to unravel. This article delves into the groundbreaking research of Dr. Robert C. Wirka—a cardiologist and researcher at UNC’s department of cardiology- and his team at the Wirka lab shed light on the role of vascular smooth muscle cells in atherosclerosis.

Vascular smooth muscle cells (VSMCs) are the unsung heroes of our arteries. These cells play a vital role in regulating blood flow, maintaining vascular integrity, and responding to injury.

Dr Robert C. Wirka

However it will be more realistic to think of them as the construction workers of the blood vessels. In atherosclerosis, these cells can transform from diligent builders to destructive agents.

They accumulate cholesterol and other fatty substances, gradually creating plaque that clogs Figure 1. Basic design of high fat diet mice experiments used by arteries.

This the Wirka lab. Image by Wirka et al. transformation from a healthy, contractile state to a synthetic, treatment and prevention. proliferative state contributes to the As it stands, most widely adopted narrowing of arteries and sets the stage for treatments to CAD amount to targeting heart disease. lipids, which, while it reduces the symptoms When it comes to cardiovascular of CADs, does not affect the actual disease (CAD), VSMCs have been shown to mechanisms caused by VSMCs that lead to play both the roles of protective cells and the phenomena. contributors to disease like atherosclerosis; “We are not starting with a biological a disease characterized by the accumulation phenomenon that we find interesting and of plaques in arteries which leads to their hoping it has relevance to a human disease. gradual narrowing. Think of these VSMCs What we are doing is, we are starting with as shapeshifters. Even though some are signals that are saying “hey, these few already specialized, they can revert to a things are literally the most important more primitive state, where they multiply things that are driving human disease and excessively. This “reprogramming” is a key we are trying to figure out how that works player in the formation of the plaque that “……we’re really just starting at the most narrows arteries. Understanding how and systemically important things and digging why this happens could open new doors for out and trying to figure out the mechanism.”

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life sciences to resist transformation into plaque-forming cells. These “good” VSMCs help protect arteries from blockages.

The TCF21 gene plays a significant role in this protective process.

Dr. Wirka believes that over time, with enough understanding of the mechanism behind each of the markers, a complete connection between this mechanism is hoped to be achieved which can lead to a Figure 2. Schematic summarization of the current total understanding of knowledge of the identity and origins of vascular smooth how and why CADs— muscle cells (VSMCs). Image by Bennett et al. which are the leading This is how Dr.Wirka summarized the cause of death in US—occur and how can basics of his research. The Wirka lab focuses they be stopped. on the underlying molecular mechanism The Wirka lab utilizes mouse models that leads to changes in the blood vessel to study the molecular mechanisms of CADs. tissue that leads to CADs like atherosclerosis. APOE, a gene related to atherosclerosis Dr. Wirka explained that a very small amount is modified to be inactive in the mice. The VSMCs tend to uncontrollably reproduce at mice are fed a high fat diet (HFD) for 8 a relatively large scale which might sound weeks. After the process, the cardiovascular similar for people familiar with how cancer tissue is harvested from the mice analyzed. cells proliferate. By studying certain genetic A key component of the lab’s study is the markers, the Wirka lab can understand the use of single molecular analysis which mechanism through which the mentioned basically can be described as the ability to proliferation occurs. By analyzing individual isolate and focus on one single molecule genes, they gain a multicellular “Instead of finding VSMCs as in insights into the environment such only “the villains”, Dr. Wirka’s as cardiovascular mechanisms underlying CADs. This allows team investigated their potential tissue.

This research, the researchers though not as “heroes” in the battle against to focus on one directly related variable at a time— atherosclerosis.” to atherosclerosis like the previously alone, aims to understand the versatility of mentioned TCF21—with the hope of VSMC studies and their potential impact on understanding their molecular mechanism various cardiovascular diseases. For example, through genetic analysis and staining that one of the genes the Wirka lab investigated shows where certain cells and genes tend was a gene called TCF21. Instead of finding to proliferate and demonstrate increased VSMCs as only “the villains”, Dr. Wirka’s team expression. investigated their potential as “heroes” in the Atherosclerosis remains a formidable battle against atherosclerosis. They found foe, but thanks to the pioneering work of that some VSMCs possess a unique ability researchers like Dr. Wirka and his team,

Figure 3. The RNA staining of the aortas of 8 week high fat diet mice that are used to understand the molecular mechanisms of VSMCs. Image by Wirka et al.

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science is gaining valuable insights into the role of vascular smooth muscle cells in this disease. The cellular world within arteries is a dynamic and complex one, where VSMCs can be both the architects of health and the architects of disease. By deciphering the mechanisms that govern their behavior, The research community inches closer to new strategies for prevention and treatment, potentially saving countless lives. So, as the battle against this silent killer rages on, let’s not forget the marvels that lie within, waiting to be understood and harnessed for human benefit.

References

1. Interview with Robert C. Wirka MD, 02/19/2023 2.Bennett, M. R., Sinha, S., & Owens, G. K. (2016). Vascular Smooth Muscle Cells in Atherosclerosis. https://pubmed. ncbi.nlm.nih.gov/26892967/ 3. Chappell, J., Harman, J. L., Narasimhan, V. M., Yu, H., Foote, K., Simons, B. D., Bennett, M. R., & Jørgensen, H. F. (Year of publication).

Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models. Title of Journal, Volume number. doi:10.1161/ CIRCRESAHA.116.309799 https:// pubmed.ncbi.nlm.nih.gov/27682618/ 4. Wirka, R.C., Wagh, D., Paik, D.T. et al. Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat Med 25, 1280– 1289 (2019). https://doi.org/10.1038/ s41591-019-0512-5

life sciences

The Stratified Epithlium: A Dynamic Structural Player

By Vina Senthil Figure 2. With about 1 in every 1,700 babies born with cleft palate (CP) in the U.S. and about 1 in 700 babies born with CP in the world annually, CP is one of the most common birth defects. Courtesy of Kita, Natalie.

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hile stratified squamous epithelia are the most Asymmetric cell division abundant epithelial tissues in the human body, they refers to cells dividing are nothing short of complex. A stratified epithelium is perpendicular to the a type of multi-layered epithelial tissue, or a tissue that lines all plane of the epithelium surfaces of the body, internal and external. Due to their relative via the 90° rotation of the thickness, stratified epithelia are found in areas of the body that mitotic spindle. During are regularly subjected to considerable mechanical force, such cell division, the mitotic as the oral cavity and skin. spindle facilitates the While the skin is the most obvious form of stratified separation of parent epithelia, Dr. Scott Williams, a cell, developmental, and cancer cell DNA into the two biologist at the University of North Carolina at Chapel Hill’s daughter cells. The 90° School of Medicine, says the stratified epithelia of the oral cavity rotation of the mitotic is a research focus in his lab because it is often overlooked. “The spindle produces one Dr. Scott Williams oral epithelia heal very quickly, very efficiently, and without daughter cell that remains scarring, and we don’t fully understand a stem cell, while the apical daughter why they [the oral epithelia and skin] cell (a cell that undergoes division heal differently,” said Dr. Williams.1 repeatedly) is displaced into the layers of In the Williams Lab, stratified cells above, becoming a differentiating epithelia are an overarching research cell. The Williams lab is interested in interest encompassing smaller, in-depth the underlying processes dictating projects investigating various interests whether a cell divides symmetrically or related to it. One interest is division asymmetrically, as well as whether cellorientation, a mechanism of epithelial extrinsic factors, such as the activity stratification that occurs during human of neighboring cells, affect division embryonic development.

During orientation.1 development, embryonic cells undergo While key differences exist differentiation, a process during which between the epithelia of the skin and stem cells become specialized cells. the oral cavity, Dr. Williams says there While differentiating, cells divide in a is inherent heterogeneity within oral specific orientation, either symmetric or epithelia itself. Epithelia in the buccal asymmetric cell division. These processes area (cheeks) form thicker layers than are types of oriented cell division. in the roof (palate) and floor of the Symmetric cell division refers mouth. They are also made of mucosal to cells dividing within the plane of membranes, whereas palatal epithelial the epithelium, creating two daughter Figure 1. During cell division of epithelial tissue is keratinized, or has a layer of cells oriented adjacent to each other. cells, the mitotic spindle can exhibit different dead cells that periodically sheds. In Dr. Williams calls this a “self-renewing orientations to produce symmetric or studying this heterogeneity, the lab division,” because the two daughter cells asymmetric cell division. Courtesy of Nestor- investigated differences in division are stem cells, just like the parent cell.1 Bergmann et al. orientation between areas. Among other

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life sciences information on specific genes implicated in different human disease phenotypes. The group discovered that while AFDN itself is not associated with CP formation, likely Figure 3. During palatogenesis, the secondary palatal shelves (pictured in purple) undergo because it is an essential distinct stages. Courtesy of Lough et al. gene, or a gene required for survival, it is required for findings, they discovered that the filiform papillae on the back the functioning of nectin proteins—two of which are heavily of the tongue exhibit a completely different pattern of division correlated with CP, Nectin1 and Nectin4. After AFDN expression orientation in comparison with other structures of the oral had been knocked out in mice epithelial cells, all the subjects were found to exhibit CP. This served as evidence that players in cavity.1 The Williams Lab also studies division orientation of the Afadin-Nectin pathway could be contributing factors to CP adult stem cells in oral epithelial tissue to better understand its formation.1 From a developmental biology perspective, the regenerative properties, or its abilities to aid in wound healing.

Another project investigates how the balance between Williams Lab’s investigation into CP formation has potential self-renewal and differentiation resulting from division clinical applications, too. “Most human disease is rooted in a orientation during cell division affects oral cancer growth. The developmental process that has gone awry,” said Dr. Williams.1 project was started to better understand oral cancer, a serious According to him, the group’s research may provide a basis for public health issue stemming from tobacco and alcohol use, as creating gene therapies that could prevent CP formation in-utero.

Such therapies would offer a more cost-effective, accessible, well as diseases such as HPV.2 Dr. Williams describes his lab’s project studying cleft and safe treatment of CP, as opposed to reconstructive surgery palate formation (CP), the most common birth defect in humans immediately following birth.3 This would be especially crucial after heart defects, as a “happy accident.”1 The group first took for the outlook of CP patients in developing countries, where interest in the AFDN gene because of its connection to a mitotic access to corrective care of the condition threatens the survival spindle orientation gene, LGN. The AFDN gene produces afadin, of patients. In hopes of pursuing translational outcomes, the an actin-binding protein that binds to nectin receptors. Nectin Williams lab will continue to elucidate the genetic underpinnings receptors are proteins that facilitate cell-cell adhesion. The initial of CP formation. hypothesis was that AFDN played a role in regulating oriented cell divisions, and that it was doing so through interactions with LGN. After conducting an experiment where they knocked out AFDN expression in the skin of mice, the group discovered that AFDN did affect spindle orientation. It caused random division orientation of epithelial stem cells, as opposed to approximately half of cells undergoing symmetric cell division and the other half undergoing asymmetric cell division. In this context, random division orientation of cells refers to cells dividing at an oblique angle as opposed to parallel or perpendicular to each other.1 AFDN’s connection to CP became apparent when the lab began investigating possible disease phenotypes that could result from a change in AFDN expression in epithelia using the Online Mendelian Inheritance in Man (OMIM), an online catalog of human genes and genetic disorders and traits. OMIM provides

References

1. Interview with Scott Williams, Ph.D. 09/21/23 2. Williams Lab. https://www.scottwilliamslab.com/ (accessed Oct 6th, 2023) 3. Kendall J. Lough, Danielle C. Spitzer, Abby J. Bergman, Jessica J. Wu, Kevin M. Byrd, Scott E. Williams, Sally Dunwoodie, John Wallingford; Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1. Development 1 November 2020; 147 (21): dev189241. doi: https://doi.

Figure 4. CP formation occurred in mice with the Nectin1/ Nectin4 knockdown, signified in the image above as the Nectin14402 and Nectin42589 mutants, respectively. Courtesy of Lough et al.

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life sciences

Advancements in Protection for Migratory Sharks in Galapagos Islands

By Peter Szczesniak

Illustration by Jessica Hoyt

I

magine a person is SCUBA diving underwater along a reef ecosystem, when suddenly, they see a channel filled with shivers of sharks. The sharks all appear to be moving through a current, as if they all have a motivation to head toward another place in the ocean. Dr. Alex Hearn spearheads the answer to the question of where the sharks are going

Dr. Alex Hearn

in the Galapagos Islands, aiming to find an explanation for this puzzling query.

Dr. Alex Hearn is currently studying the movement, ecology, and behavior of shark species in the Galapagos Islands.1 He is an adjunct professor at the University of North Figure 1. Movement of silky, hammerhead, Galapagos, Carolina at Chapel Hill and blacktip shark species tracked by satellite imagery and in the Department of acoustic detectors. Figure courtesy of Hearn et al.

Biology. He studied at the University of Southampton in the leaders of the Shark Research Program for United Kingdom to obtain a Bachelor the Galapagos Marine Reserve, which he of Science in both Oceanography and continues to lead today.

Dr. Alex Hearn tracks shark Marine Biology, and he then went on to Heriot-Watt University in the Orkney movements by taking satellite images Islands to obtain his Master of Science and capturing their paths with tags and Ph.D. In 2002, he began working in placed onto the sharks in the research the Galapagos Islands. Since starting in project. He is also looking at the health 2006, he has been one of the instrumental of various shark nursery grounds in the

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life sciences hammerhead, and whale shark species.

SPOT tags were used to send information to a network of satellites, transmitting information back to scientists, enabling detection and tracking of the tagged sharks.

Placing the ultrasonic tags on the five different shark species studied by the scientists Figure 2 . Movement of whale sharks tracked by in the Galapagos ensured satellite imagery and acoustic detectors. Figure courtesy that the movements of the of Hearn et al. sharks would be detected Galapagos Marine Reserve. “Basically, by the underwater receivers. Additionally, a lot of these species that I study are the sharks were detected by satellites to threatened or endangered, or even provide information on where the sharks critically endangered, as is the case for were moving, allowing the scientists to the scalloped hammerhead shark,” says see a visual map of the movements of the Dr. Alex Hearn. “Even though we’ve got shark species, from which they analyzed a marine reserve around the Galapagos the data.

Islands, the question [is] ‘Do these highly At the end of the research project, mobile, or migratory, animals actually Dr. Alex Hearn and the researchers get much protection from a fixed marine learned that hammerhead sharks tended reserve?’ And so, my questions related to be around the Darwin and Wolf Islands to these species are about how they use during the day but moved away from the space.”2 islands and swam out into the open ocean In his paper “Ten Years of Tracking at night; blacktip sharks tended to move Shark Movements Highlight the Ecological monthly between the Darwin and Wolf Importance of the Northern Islands: Islands; and silky sharks mostly stayed Darwin and Wolf,” Dr. Hearn investigated at the islands they were at when they the importance of the Darwin and Wolf were tagged, either Darwin or Wolf, and Islands to shark populations and shark rarely travelled to the other island. While migratory paths in the Galapagos Islands.3 most Galapagos sharks moved between He says that the research contributes to Darwin and Wolf and stayed primarily in “…a larger question of what is the role of nearby reef ecosystems, the sharks also Galapagos regionally for the protection spent much time in the open ocean away of these migratory species…[H]ow can from these islands. we design perhaps an effective network of MPAs [marine protected areas] across the region?”

To answer this question, Dr. Hearn and his colleagues placed ultrasonic tags on the sharks either by diving into a school of sharks and using pole spears to dart the sharks, or by tagging the inside of sharks through capture and Figure 3. Based on the migratory routes of marine species, then brief surgery. including some of the shark species that were investigated The study focused by Dr. Alex Hearn and his colleagues, the marine protected on the Galapagos, area of the Galapagos Islands must encompass more of their silky, blacktip, movement ranges. Figure courtesy of Hearn et al.

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The behavior of whale sharks is different since the species are not native to the Galapagos. Young males tended to gather around the Galapagos islands to feed on plankton, and whale sharks at Darwin tended to be pregnant females also feeding on plankton. The sharks tended to move to the Equatorial Front in July, towards Darwin in September, but further to the coasts of Ecuador and Peru and to the island of Isabela from March through June.

Dr. Alex Hearn and his colleagues believe that the next steps of the project are to “provide technical advice on the design and management of marine protected areas, and on the adoption of national and international legislation to protect sharks.”3 To do this, the team is currently supporting methods to help ensure that marine areas can be protected. Such methods take the form of the inclusion of silky sharks in the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) and improving enforcement of conservation efforts in the Galapagos Marine Reserve and other marine protected areas. Additionally, the team is hoping there will be expansion of the marine protected areas based on accompanying expanded movements of the studied shark species (especially hammerhead sharks) and other marine species to ensure that such areas are also covered for protection. Through these initiatives, Dr. Alex Hearn and his colleagues hope to ensure that the conservation and protection of some of the most cherished marine life that thrive in this hotspot for aquatic biodiversity stays.

References

1. Universidad San Fransisco de Quito.

Alexander Rafael Hearn. https://www. usfq.edu.ec/en/profiles/alexanderrafael-hearn (accessed September 30, 2023).

2. Interview with Dr. Alex Hearn, Ph.D. 09/26/2023 3. Hearn A, E Espinoza, J Ketchum, et. al. 2017. Ten years of tracking shark movements highlight the ecological importance of the northern islands: Darwin and Wolf. Pp. 130-139. In: Galapagos Report 2015-2016. GNPD, GCREG, CDF and GC. Puerto Ayora, Galapagos, Ecuador.

life sciences

Haunting Stress

By Karen Zhu

Figure 4. Fluorescent zebrafish. Image courtesy of Dr. Christina Graves

S

tress wears down the body and the mind. It exists in a myriad of forms. Stress may come from battling an illness, trying to recover from an injury, coping with trauma, or the sorrow of bereavement. On a lighter note, stress may come from a deadline to catch or an interview for a dream job. People proceed on with life attempting to overcome one stress factor after another. However, stress does not necessarily go away even after enduring the full brunt of its affliction. It has a lasting negative impact on health. The physiological repercussions of stress are a focal research interest of the Graves Lab at the University of North Carolina at Chapel Hill.

Dr. Christina Graves is a professor of biomedical science at UNC-Chapel Hill, specializing in neuroimmune and gut biology.

Her lab uses zebrafish as model organisms to study the effects of early life stress (ELS) on gut and neuroimmune gene expression and cell function. In her study, she chronically stressed zebrafish by exposing them to water turbulence, chasing them with a small transfer pipette, and flashing them with a strobe light. The

Figure 1. Bottom tank dwell time and top tank dwell time of control group and ELS group

fishes were exposed to these stressors beginning 6 days post fertilization (dpf ) until 1 week or 30 dpf, during which the fish larvae developed. A control group of zebrafish not subjected to stress was raised alongside the stressed fishes.

After the completion of stress exposure, the zebrafish were filmed for behavioral analysis. The behavior of interest is the fish’s dwell time in the top half of the fish tank and the bottom half of the fish tank. The stressed group spent significantly more time in the bottom half of the tank Dr. Christina Graves than the control group. Longer dwell time in the tank bottom is an anxiety-like behavior. Bottomtank preference persisted after stress exposure terminated, suggesting that ELS leaves behind enduring anxiety-behavior.

Morphologically, fishes exposed to stress for 30 dpf were smaller in size than the control group, with an observed 10% growth deficit.

The zebrafish were euthanized for gut and brain resection.

Tissues and RNA were extracted from the guts and brain. The extracted tissues went through immunostaining and imaging to quantify enteric neurons per unit area, that is, neuron density.

The stressed group had a lower neuron density than the control group. Decreased enteric neuron density suggests that ELS impairs gut function and development. A transit assay revealed

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life sciences that stressed fishes took a longer she attended when she was time to clear content from still a student. She said it was their gut. Decrease in enteric remarkable that a lot of people neuron density and delayed gut at the patient conferences had clearance also persisted after interests in “modulating their stress withdrawal. Extracted symptoms in real time through RNA was quantified using light things like diet and meditation spectroscopy. RNA quantity is and some of the more proportional to gene expression; nontraditional pharmacological therefore, knowing how much options.”2 The use of diet and RNA there is determines how meditation illustrates how much of a gene of interest was environmental factors influence expressed. Dr. Graves chose to health. During her PhD years, she study genes that are known asked questions such as “how do or suspected targets of stress we learn what our environment signaling response in the brain is over time through the lens of and gut. The stressed fishes infectious stress?” and “do you exhibited increased expression even need an infectious trigger of genes associated with neuron or will the body’s perception of damage and gut inflammation. stress alone kind of drive tissue Genes of increased expression responses?”2 Existing studies included casp3a, a common have already shown that the marker for cell death, and human body does remember nfkb2, the zebrafish homolog how much stress it has endured. to the NK-kβ gene in humans “We know that people and associated with post-traumatic especially children that have Figure 2. Logarithmic normalized expression of nfkb2 and stress disorder (PTSD). experiences of chronic stress are Dr. Graves’ research bears casp3a expression following 1 week stress exposure and 30 predisposed to immune system implications of how ELS in day stress exposure (30d-g represents gene expression in the dysfunction and nervous humans can imprint devastating gut and 30d-b represents gene expression in the brain). Blue system dysfunction later in life, effects that carries throughout bar is the control group and gray bar is the ELS group. Figure but we’re still answering the later life. Although there are courtesy of Graves et al. question mechanistically and existing studies on the effects of stress on long-term health, few biologically how does the body keep the scores,” Dr. Graves said.2 go beyond a seven-day stress period. Thus Dr. Graves’s chronic stress experiment on zebrafish establishes a more robust model in studying the connections between stress and health. The results from this zebrafish model points to questions about the biological mechanisms that caused the observed changes.2 Specifically, Dr. Graves’ is looking into the mechanism of DNA methylation related to changes in gene expression.2 Another aspect to investigate is whether the effects of stress are carried into the offspring of the stressed fish.2 Inquiries about stress and health fall under the research realm of interactions between the environment and the body.

Dr. Graves is interested in how the human body responds dynamically to environmental factors, and stress is one such example. Her interest traces back to the patient conferences

References

Figure 3. Imaging and bar graph comparing enteric neuron density between control and ELS. Figure courtesy of Graves et al.

1. Graves CL, Norloff E, Thompson D, Kosyk O, Sang Y, Chen A, Zannas AS, Wallet SM. Chronic early life stress alters the neuroimmune profile and functioning of the developing zebrafish gut. Brain Behav Immun Health. 2023 Jun 17;31:100655. doi: 10.1016/j.bbih.2023.100655. PMID: 37449287; PMCID: PMC10336164.

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physical sciences

Catalytic Molecular Machines for the Reversal of Reactions

By Amil Agarwal

Image courtesy of Wikimedia Commons

C

atalysts have played a crucial part in life and the chemical catalytic energy rectification, the Mpemba effect, information industry because they allow slow chemical reactions transduction via biological sensors, and the “intelligence” of to occur at a much faster speed. Examples of catalyzed single-molecule computers. Although Dr. Lu’s group is based reactions include the conversion of starch to simple sugars by on theory and math, his group strives to come up with intuitive an enzyme in saliva. The speed of a chemical reaction is typically theory and practical design principles that can be directly tested dictated by the height of the energy barrier that the reaction and used in wet-lab experimental research groups. needs to be overcome. Catalytic processes speed up reactions by Dr. Lu’s group recently developed a general theory to reducing the barriers’ heights. Even though catalysts participate explain the inversion of catalytic reactions under oscillation of in chemical reactions, they are not consumed as the catalysts environmental conditions. The main difficulty of obtaining a return to their initial form at the completion of the reaction. As general theory lies in the diversity of catalysts and their response a result, catalytic reactions form cycles that can be described to different environmental conditions. Specifically, each catalyst

by Markov state models (Figure 1).1 In the cycle, the catalyst may involve different reaction rates and their rates could be reacts with the reactants through multiple intermediate steps, altered by various environmental factors including the substrate eventually creating the products while the catalyst returns to its concentration, pH, temperature, and enzyme concentration, initial state. Each product has an overall lower energy than the which are crucial to biological functions.2 However, such difficulty previous intermediates and reactants, resulting in the formation can be circumvented by utilizing languages of geometry. of compounds that sequentially decrease in energy.3 At the heart of Dr. Lu’s groundbreaking research is a It is taught in introductory chemistry that catalysts geometric argument that offers a fresh perspective on how can only speed up the reaction and are unable to invert the catalysts operate under environmental oscillation. This argument spontaneous reaction’s direction unless an external hinges on the idea of “rate vectors”2,3 – points in a energy resource is supplied. Physical Chemists have high-dimensional space that represent the reaction been arguing that, if the environment oscillates, rates for every step of a catalytic cycle. Given a rate certain catalysts can invert the spontaneous vector, the performance of the catalyst, including direction of the reaction.4 However, researchers aspects like directionality, selectivity, and turnover had not developed a universal theory and intuitive frequency, becomes predictable. Traditionally, explanation – until now.1,2,3 catalyst behavior has been understood in the In 2019, Dr. Zhiyue Lu started his theoretical context of stationary environmental conditions. physical chemistry group at the University of However, when environmental parameters such as North Carolina at Chapel Hill. This group studies temperature, substrate concentration, or pH value the theories behind various non-equilibrium oscillate, the catalyst’s rate vector does not remain thermodynamics phenomena, including static. Instead, it sweeps out a bent curve in the rate Dr. Zhiyue Lu

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physical sciences

Figure 1. This figure depicts the Markov model of the cyclic pathway for a catalytic reaction, and this is the most basic form of a cyclic pathway. Figure courtesy of Zhang et al. space, representing a family of rates that a catalyst exhibits at any given environmental condition.

Under the traditional stationary perspective, the range of performances achievable by all possible choices of catalysts under all possible environmental conditions has been limited by the laws of physics. Figure 2a shows an iso-performance hyperspace depicting all combinations of catalysts and their effects for a specific system. For instance, no matter the catalyst, the spontaneous direction of a reaction was deemed irreversible.

However, Dr. Lu’s geometric theory challenges this notion. By rapidly oscillating environmental conditions, the rate vector of a catalyst moves over its corresponding bent curve. This rapid oscillation results in a set of effective rate vectors that lie beyond this curve. Depending on the oscillation protocol, a multitude

(a)

(b)

(c)

of new rate vectors can emerge, forming what is termed the “convex hull” of the curve. If this convex hull extends beyond the traditional boundary of achievable performances, the previously forbidden outcomes become possible.3 Various isoperformance spaces can be obtained for a specific change in environment and can be seen in Figure 2b. A concave curve is best suited for this, as it allows for a reversible process with an oscillation between most values.3 One direct application of the geometric theory is the inversion of a reaction’s direction under an oscillatory environment, which bears mathematical similarities to Parrondo’s Paradox. This paradox states that if the environmental parameters are fluctuated, it could drive the system in the reverse direction. Furthermore, it can be simplified to state that two losing scenarios can be used to create a winning strategy.1 Parrondo’s Paradox has been studied heavily for its use in catalytic cycles by researchers such as Dauenhauer, Astumian, Rahav, Esposito, and others during the 2010s. Depicted in Figure 2c, this paradox has inspired the discovery of thermal ratchets as well as catalysts that harness energy from the periodic switching of environmental parameters. When the new geometric argument is applied to Parrondo’s paradox, it can serve as a design rule, guiding researchers in designing thermal ratchets with optimal strength.

The geometric principle introduced by Dr. Lu’s group holds immense practical potential. Firstly, it allows for general predictions about the feasibility of achieving certain performances through environmental oscillation without even specifying a particular catalyst. The geometric properties of the curves, which depend on the nature of the catalytic reaction, can indicate whether environmental oscillation will enhance or diminish a desired performance.1 Secondly, these geometric properties can be harnessed to derive optimal design objective functions. These functions can predict the best energy landscape for a catalytic cycle to achieve a specific performance. Moreover, the geometry can guide researchers in determining the optimal environmental oscillation protocol to drive a catalyst toward a desired outcome.2 Dr. Zhiyue Lu and his team are redefining the boundaries of what’s possible in the realm of catalysis. By merging geometric principles with the dynamic world of chemical reactions, they’re paving the way for innovations that could revolutionize industries ranging from pharmaceuticals to sustainable energy.

As research progresses, the future of catalysis promises to be as dynamic and oscillating as the environments that drive these groundbreaking reactions.

References

Figure 2. a) This graph depicts the curve for the hyper-surface of interest. b) These graphs depict all three different forms of the hyper-surface which can exist. c) This graph depicts what the environment would look like when the environmental parameters were oscillated between two points which would produce a reverse catalytic cycle. Figures courtesy of Dr. Lu and group.

1. Zhang, Z.; Du, V.; Lu, Z. Energy Landscape Design Principle for Optimal Energy Harnessing by Catalytic Molecular Machines. Physical review 2023, 107 (1). https://doi.org/10.1103/ physreve.107.l012102.

2. Zhang, Z.; Lu, Z. Nonequilibrium Theoretical Framework and Universal Design Principles of Oscillation-Driven Catalysis. Journal of Physical Chemistry Letters 2023, 14 (33), 7541–7548. https://doi. org/10.1021/acs.jpclett.3c01677.

3. Interview with Dr. Zhiyue Lu, 9/18/2023 4. Berthoumieux, H.; Antoine, C.; Jullien, L.; Lemarchand, A. Resonant response to temperature modulation for enzymatic dynamics characterization. Physical Review 2009, 79, 021906. DOI: 10.1103/PhysRevE.79.021906

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physical sciences

Reshaping the Future of Plastic Recycling

By Lucas Ralls

Image by Richmond Waste

E

very single day, the world produces enough plastic to fill up the Houston Texans’ stadium to the brim.1 Moreover, much of this plastic is disposed of improperly and recycled inefficiently, resulting in large-scale pollution. In fact, only around 10% of plastic waste recycled actually gets recirculated into the economy in the United States.2 However, Dr. Frank Leibfarth, a Chemistry professor at the University of North Carolina at Chapel Hill, has pioneered a groundbreaking method to prolong the lifespan of single-use plastic waste, promoting upcycling and enhancing its value within the existing recycling infrastructure.

byproducts were solidified for more sustainable disposal.

The solidified waste products, referred to as polyolefins, were discovered to be easily molded to desired shapes and produced inexpensively. Fast forward to 2023, and more than half of all plastics produced are these polyolefins, as they make up everything from plastic bags to milk jugs.

The Challenge of Recycling

As Dr. Leibfarth puts it, “It’s very clear plastics are amazing materials that enable our modern way of life - the problem is how do we deal with them in a responsible manner.”1 The issue lies in the economic viability of regenerating plastic waste. The current recycling process in the United States, which involves melting down and reshaping ‘thermoplastics,’ often weakens the plastic through the heating and grinding process, making it more susceptible to breakage and causing discoloration. It’s more of a ‘downcycling’ process, where the original quality of the plastic deteriorates.

A New Path: Upcycling

Dr. Frank Leibfarth

The Plastic Revolution

Plastics are typically the main byproduct created when crude oil is refined to make gasoline. During this distillation process, gases, known as olefins, are produced as a byproduct.

Originally considered harmful to the atmosphere, these gaseous

To combat this issue, research efforts by the Leibfarth Group have unlocked new potential applications in the recycling of waste plastics. By modifying the chemical properties of polyolefins, Dr. Frank Leibfarth hopes to employ the process of upcycling. In chemical terms, upcycling involves adding chemical groups or reagents to increase the value and application of waste plastics.

The inspiration behind the chemistry for the Leibfarth Group’s project stems from the process of late-stage functionalization, which is often used in pharmaceutical chemistry to modify potential drugs that are not efficient enough for large-scale use. This approach allows for the addition of new properties without starting from scratch. Collaborating

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physical sciences could react with polyolefins. The first component of the “magic” reagent is a functional group, known as an amide.1 When heated, the amide becomes an amidyl radical, which is highly reactive and capable of breaking the C-H bond in waste plastics by removing a hydrogen molecule. The second component of the ‘magic’ reagent is a “trap” for the broken C-H bond.1 Adding this trap that can be eventually converted into a cation, places a hydrophilic, or water-loving component, to a sea of hydrophobic carbon and hydrogen bonds. Thus, creating a dynamic push and pull within the plastic, causing it to lose its rigidity and become malleable.1

Unlocking the Potential Figure 1. Dr. Frank Leibfarth and Dr. Eric Alexanian observe a newly designed polymer at the University of North Carolina at Chapel Hill. Photo by Jon Gardiner. with Dr. Erik Alexanian, a UNC Associate Professor focusing on pharmaceutical chemical synthesis, has been instrumental in the project’s success.

Breaking Strong Bonds

Using late-stage functionalization provides a ‘toolbox’ for chemists to add new chemical groups to different parts of an existing molecule, laying the theoretical framework for the project. The group needed to determine what reagent would react well with the incredibly strong carbon-hydrogen bonds in polyolefins. Carbon-hydrogen bonds are some of the most common and strongest bonds found in nature, therefore making them some of the most difficult to break. Dr. Leibfarth describes this as a “fun scientific challenge” – finding a way to react with bonds evolved not to react with anything.1 By modifying these strong bonds, Dr. Leibfarth’s lab was able to add chemical properties that improve the quality and scope of use of these cheaply produced plastics.

Through trial and error, the lab developed a reagent that

Through this C-H functionalization of polyolefins, the Leibfarth group was able to add properties to waste plastics that resemble the plastic, SurlynTM, commonly found in highend packaging and golf balls. This innovative approach allows Dr. Leibfarth’s lab to increase the lifespan and value of simple plastics that are often discarded without a second thought, thereby generating a more circular economy for plastic.

“From a chemistry standpoint it works,” Dr. Leibfarth explained as he discussed the viability of employing this method in recycling plants.1 On top of improving the chemical properties of polyolefins for upcycling and repurposing, Dr. Leibfarth’s research demonstrated this could all be done using pre-existing infrastructure. While the lab continues to explore ways to reduce the cost of producing the ‘magical’ reagent and ensuring the safety of the molecule in practice, the reagent utilizes the heating process already used in polymer repurposing plants to drive the chemical reaction. Therefore, increasing the economic incentive of employing this novel recycling method by not requiring significant investments into new recycling technologies.

The Future of Plastic Recycling

Dr. Leibfarth’s research offers a promising solution to the plastic waste crisis. By transforming waste plastics into valuable materials, it changes the way we view polymers previously considered single-use plastics. Dr. Frank Leibfarth’s research is not only about upcycling plastics; it’s about upcycling our approach to sustainability. By finding innovative ways to extend the lifespan and value of plastics, we can reduce waste and its environmental impact. It’s time to shift our perspective on plastics and embrace a circular economy that benefits both the planet and our modern way of life.

References

Figure 2. Dr. Leibfarth’s method of C-H functionalization has shown the ability to modify the properties of certain polymers and promote the upcycling of specific plastics. Image courtesy of Jill B. Williamson.

1. Interview with Frank A. Leibfarth, P.H.D. 10/04/2023.

2. McConnell, B. On Air Today: Frank Leibfarth of UNC’s 2.

Chemistry Department. Chapelboro.com. https://chapelboro.com/news-on-the-hill-with-andrew-stuckey/on-air-today-news-on-the-hill/on-air-today-frank-leibfarth-of-uncschemistry-department (accessed 2023-11-16).

3. Alexanian and Leibfarth Groups: Creating a Better Plastic. https://chem.unc.edu/news/alexanian-and-leibfarth-groups-creating-a-better-plastic/ (accessed 2023-11-16).

4. Williamson, Jill B.; Lewis, Sally E.; Johnson, Robert R.; Manning, Irene M.; Leibfarth, Frank A. C−H Functionalization of Commodity Polymers. Angewandte Chemie International Edition 2018, 58 (26), 8654–8668. https://doi. org/10.1002/anie.201810970.

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physical sciences

A Bright Future for Perovskite

By Blake Seigler

Image via Wikimedia Commons

T

he world is rapidly burning with us on it. The summer of 2023 was the hottest on record at 0.41 degrees Fahrenheit hotter than any previous summer.1 With carbon emissions driving record temperatures, searing wildfires, and monstrous hurricanes, a replacement for fossil fuels is desperately needed. Although renewable energy sources exist, many are still expensive or rely on geographic privileges that may not be accessible to the wider world. One of the most prominent renewable sources is solar energy because of the vast amount of sunlight that hits the earth each year (Figure 1). This light can be captured by the photovoltaic (PV) cells and converted into electricity. Many of these solar cells, however, are either very costly to manufacture or not efficient enough to be used as a viable substitute. Perfecting the technologies used for generating solar energy will be an essential step in fighting against the shadow of global warming that looms over.

Figure 1. A comparison of available energy sources. Each energy source can be seen typed out with a description of the available energy in terawatts (TW) and represented by a colored circle of proportional size. The world energy consumption is also included for scale. Figure courtesy of Wikimedia Commons.

Solving global crises, however, was not on Dr. Huang’s mind when he began his research. Originally, he was interested in the possibility of charging devices on the go without the need for external sources of power. “I started with research in organic solar cells which basically use organic semiconductors for solar cells to make them cheaper and more flexible.” He explains that “if you had no other power source you could simply unfold the flexible solar cell and charge your device.”2 As global warming became a hot topic on the global stage, he realized the urgency of his research. Eventually, Dr. Huang found his way to UNC

Figure 2. Jinsong Huang and PhD student Mengru Wang.

Image courtesy of Jinsong Huang. because of their Applied Science Department where his lab now works on developing technologies with materials known as perovskites. Perovskites are materials with crystal structures identical to that of the mineral Perovskite. These materials have incredible optical properties, which the Huang Lab have utilized to develop state of the art solar panels and X-ray detectors.

Dr. Huang’s lab has even made several notable advancements in using perovskite to detect X-rays for medical purposes and he has since become one of the top perovskite researchers in the field. The lab’s discoveries have allowed ever more precise detection of X-rays and could reduce the radiation necessary during screenings, lowering potential health risks for those already burdened with the costs of medical care.2 Dr. Huang’s recent research has been centered around the challenges perovskite solar cells face to achieve commercialization.

Dr. Huang and his lab work with perovskite to develop Generation III solar cells and prepare the technology for commercialization (Figure 3). Generation III solar cells are technologies that have shown promise in the lab but have yet to become viable commercially. This is opposed to Generation I and II which have shown to work commercially but may not be the best possible technology. Cells made from perovskite can generate electricity with efficiency comparable to commercialized silicon-based cells but at a dramatically lower cost due to the unique manufacturing capabilities provided by the perovskite cells. Typical silicon solar cells are made by cutting silicon into wafers, adding imperfections, and then using a process known as etching to put the connections into the modules for the electricity to flow.3 For perovskite cells however, the low melting point of perovskite allows it to be printed onto the surface of a substrate directly rather than having to undergo

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physical sciences the extensive and expensive process. At the same time, they are still able to generate power and be more efficient.4 Imagine being able to simply print all the solar panels we needed to meet global demand!

One of his recent Figure 3. Nine Perovskite solar studies, in joint with modules displayed in a 3x3 grid. the National Renewable Image courtesy of Jinsong Huang.

Energy Laboratory and the University of Toledo, examines the flaws in modeling power output and efficiency because of how solar panels are affected as the day progresses.5 Proper modeling of the panels has a major impact on effectively determining the lifetime power output of the panels. A better understanding of the power output can help researchers to provide more accurate estimates of the cost per watt that the panels provide. To test the extent that the panels are impacted, the group of researchers deployed three photovoltaic modules in Golden, Colorado. One of the modules was composed of crystalline silicon, identical to what can be found on the market today. The other two, however, were specially made perovskite solar modules. These modules were set out in the sun where the voltage and current were recorded every 30 seconds for 52 days to measure the power output. A current-voltage graph was also generated every hour and each module had its back panel surface temperature monitored. As the day goes on, the intensity of sunlight rises and peaks in the middle of the day until slowly dropping until the sun goes down.

To control for this effect, readings were taken in the morning and afternoon when the intensity was similar.

After all the data was analyzed, Dr. Huang and his coauthors found that as the day progresses, the efficiency of the cells increases. This means that as the day goes on, the cells capture a higher percentage of sunlight that hits them, thus generating even more power to be used.

Research at UNC is not the only way Dr. Huang works to commercialize new technologies. As of 2018, he founded Perotech, a semiconductor startup with a mission of developing perovskite solar cells and x-ray imaging technology.6 “We are the first group to show perovskite could make a viable x-ray photodetector and it has big potential to make x-rays much safer.

So, we had been waiting for someone to come along and license our patents, Dr. Jinsong Huang but nobody came.”

This was because as Dr. Huang notes, trying to go from research to a commercially viable product is “a huge gap to breach”, one that is “not always a good fit for a university or big companies.”2 Taking the initiative upon himself, he and his lab teamed up with Carolina Kickstart, a service of the UNC Department of Innovation, Entrepreneurship, and Economic Development, to create Perotech to breach this gap.7 When asked about the direction he believes his research will take going forward, Dr. Huang explains, “There are also new challenges, like someone may not want toxic elements in their devices, so we have to use nontoxic or lead-free materials while still maintaining a high performance.” Overall, though, he notes that even though they may face setbacks it is important to trust the process and continue to support fields such as perovskite research. “Research is a lot of times not manufactured and is something not well predictable,” he says.2 The importance of research into fields like photovoltaics, may have dramatic implications for our lives moving forward. Especially with problems on our horizon as significant as climate change. The world is rapidly burning with us on it. The summer of 2023 was the hottest on record at 0.41 degrees Fahrenheit hotter than any previous summer.1 With carbon emissions driving record temperatures, searing wildfires, and monstrous hurricanes, a replacement for fossil fuels is desperately needed. Although renewable energy sources exist, many are still expensive or rely on geographic privileges that may not be accessible to the wider world. One of the most prominent renewable sources is solar energy because of the vast amount of sunlight that hits the earth each year (Figure 1). This light can be captured by the photovoltaic (PV) cells and converted into electricity. Many of these solar cells, however, are either very costly to manufacture or not efficient enough to be used as a viable substitute.

Perfecting the technologies used for generating solar energy will be an essential step in fighting against the shadow of global warming that looms over.

References

1. “NASA Announces Summer 2023 Hottest on Record – Climate Change: Vital Signs of the Planet.” NASA, NASA, 14 Sept. 2023, climate.nasa.gov/news/3282/nasa-announcessummer-2023-hottest-on-record/#:~:text=Summer%20of%20 2023%20was%20Earth’s,(GISS)%20in%20New%20York.

2. Interview with Jinsong Huang, Ph.D. 9/21/2023 3. Almerini, Ana. “How Are Solar Panels Made?” Solar Reviews, Solar Reviews, 19 Feb. 2021, www.solarreviews.com/ blog/how-are-solar-panels-made.

4. “Picture This: Making Perovskite Solar Cells with Kodak Printers.” Energy.Gov, www.energy.gov/eere/solar/articles/ picture-making-perovskite-solar-cells-kodak-printers.

Accessed 3 Oct. 2023.

5. Silverman, Timothy J, et al. “Daily performance changes in metal halide perovskite PV modules.” IEEE Journal of Photovoltaics, vol. 13, no. 5, 2023, pp. 740–742, https://doi. org/10.1109/jphotov.2023.3289576.

6. “Perovskite Solar Cells: Perovskite X-Ray Detectors: Perotech Inc..” New Perotech Site, www.perotech.org/.

Accessed 3 Oct. 2023.

7. “UNC Innovation and Entrepreneurship.” Innovate Carolina, 18 July 2023, innovate.unc.edu/.

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physical sciences

Looking into the Crystal Ball:

Using Technology to Predict Photoreactions

By Anna Vu

Figure 1. Illustration of a molecule absorbing light energy and forming possible products as a result. Photo by Elisa Pieri.

H

umans have always wished to know what their futures rays and enters its excited state, which is a higher energy state. would be like. With the emerging field of computational To imagine a molecule going through a photoreaction, picture a science, this wish has turned into a reality as technology ball rolling on a hilly landscape – this represents its ground state. is utilized to predict and answer any questions one may have When the ball absorbs a photon, it is immediately projected about the universe. up on a new hilly landscape that lives above the first one. In Computational science consists this new state, the molecule starts roaming “The NANR workflow around full of energy and searches for a way of “using computing systems to apply mathematical models” to solve complex to go back to the cozy, lower-energy ground is a culmination of scientific questions.1 With the addition state. During its exploration of the excited intricate theories, of computational science to traditional state, the molecule likely encounters conical theoretical (developing a theory based (CI), which are funnel-like shaped equations, and models intersections on observations and calculations) and portals that the molecule can cross to roll back that create a map of experimental practices (testing out that to the ground state and form some products. theory in the laboratory), the entire are an infinite number of CIs a molecule an excited molecule’s There body of a scientific concept could can go through, leading to many different journey." be fully understood. Computational products that a molecule can form. If there was science is especially useful in the field of a way to know which CI the molecule would photochemistry, where there can be several outcomes for the go through, one could predict which products it would form. events triggered by photon absorption.

However, since excited molecules have a lot of energy and it can Photochemistry is a branch of chemistry surrounding be hard to predict what conical intersection they will encounter, the chemical processes of light-based reactions. When light how do we know what type of photoproduct will be formed? is shined on a molecule in its ground state, which is its lowest Dr. Elisa Pieri shines light on the uncertainties of these products energy state, that molecule absorbs the photons from the light through her implementation of the nonadiabatic nanoreactor

34

physical sciences (NANR) workflow, which is a method “that aims at modeling photoreactions with no prior chemical knowledge.”2 The NANR workflow is a culmination of intricate theories, equations, and models that create a map of an excited molecule’s journey. It is a tool that “systematically finds all the possible types of CIs and then link them to all the possible photoproducts” that can be formed.3 In Dr. Pieri’s words, “It tells me, if I shine light on this molecule, what could happen.” The way the NANR operates is that it forces the molecule to find the intersection seam, which is the multidimensional space composed of all the possible CIs, and move along it to characterize as many different types of CIs as possible. The result of this model is a movie of the molecule crossing the seam through different CIs multiple times. For each CI, arbitrary points are randomly distributed on an area close to the CI called a branching plane. The points are then “relaxed” and travel down to the ground state, and into the pits of photoproducts (P1, P2, P3) represented in Figure 2 to find out which products can be formed from that CI. The more points that are in a photoproduct hole, the more probable that photoproduct will be made when entering through that specific CI. The NANR workflow can predict all the potential photoproducts and then estimate the probability of the types of photoproducts, showing which is more likely to be formed.

The process is then repeated with every CI, resulting in a full database of infinite possibilities.2 A limit of the tool is the sheer number of CIs that the NANR must measure. The intersection seam is multidimensional, and the number of dimensions it contains is proportional to 3N-8 , where N represents the number of atoms in a molecule. For example, take a glucose (C6H12O6), a type of sugar molecule that has 24 atoms: this makes the number of existing dimensions in the intersection seam for glucose is 64! Can you imagine a 64-D space? With even larger molecules like proteins, a complex group of molecules in cells that serve many important functions for the body, the number of dimensions would be prohibitively high. Furthermore, every point on the intersection seam is a conical intersection, so accurately modeling all accessible conical intersections and their corresponding products would be expensive computationally, or extremely time consuming.

The NANR workflow currently works for small molecules in the gas phase, but Dr. Pieri plans to adapt it to simulate larger

molecules and molecules in the liquid or solid phase.3 The usage of computational chemistry in photochemistry has revolutionized the field. There are many applications to photochemistry, ranging from selectively activating neurons in the brain with light through optogenetics, where shining two different colors of light could cause a cell to switch between an alive or dead state, to in-vivo bioimaging using engineered fluorescent proteins.

With the NANR workflow and other Dr. Elisa Pieri computational techniques, molecules with photochemical properties that are harder to test in a laboratory setting can now be computationally discovered and improved upon. The predictions of their behavior can then be tested, verified, and replicated experimentally in the laboratory setting to streamline the scientific process more efficiently.3 Implementing computational science into an experimental setting can allow researchers and scientists to solve the most difficult queries of science, and uncover the answer to anything imaginable.

References

Figure 2. Simulation of random points on the branching plane relaxing down into the ground states and landing in different photoproducts (P1, P2, P3). Photo by Elisa Pieri.

1. Nambiar, Kavya. “Computational Science - Everything you need to know” (accessed October 10th, 2023) https:// www.analyticssteps.com/blogs/computational-scienceeverything-you-need-know 2. Pieri, E.; Lahana, D.; Chang, A. M.; Aldaz, C. R.; Thompson, K. C.; Martínez, T. J. The Non-Adiabatic Nanoreactor: Towards the Automated Discovery of Photochemistry. Chem. Sci. 2021, 12 (21), 7294–7307. https:// doi.org/10.1039/D1SC00775K. 3. Interview with Elisa Pieri, Ph.D. 09/19/23

35

social sciences

Widening the Reach of Research: The South Asian Body Image Study

By Natalie Travis

Image courtesy of Lowell So Via Unsplash

A

lthough we are all human, it is important for research to acknowledge how different life and cultural experiences shape our thoughts, feelings, and behaviors. For a long time, it was thought that only rich white females were at risk for eating disorders; however, every race and gender experiences eating disorders to different degrees with various cultural influences. In particular, South Asian people are a majorly understudied population in research on body image and disordered eating. The Bardone-Cone Lab at UNC Chapel Hill, run

by Dr. Anna Bardone-Cone,1 is working to fill this gap in research with the South Asian Body Image (SABI) study. Dr. Bardone-Cone discovered her intrigue with eating disorders while in graduate school at the University of Wisconsin-Madison. She states that almost every woman she knows struggles with body image and eating. In fact, there is even a term for this phenomenon: “normative discontent,” meaning that for most people, it is very normal not to feel very good about their bodies. Inspired by the

Figure 1. Woman holding hand mirror in bathroom at home.

Figure courtesy of Wavebreakmedia.

body image issues she saw in the people around her, Dr. Bardone-Cone has researched eating disorders in various understudied populations including Asian, Black, Latina, and older women.

The SABI Study is the Bardone-Cone Lab’s next step in diversifying psychology. For the purposes of the study, the term “South Asian” describes people with an ethnic background from Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Dr. Anna Bardone-Cone Sri Lanka.3 Additionally, body image is defined as how one perceives their body. Cognitively, body image is about how one thinks their own body looks and how accurate that is to how they actually look.2 Emotionally, it is about body satisfaction—how positively or negatively one feels about their own body. A key distinction in the SABI Study that is different from other attempts to diversify research is the choice not to compare the results to a sample of white people. Often in research, the experiences of white people are considered the norm—an assumption that is biased and inaccurate. Furthermore, most research on body image in Asian people represents East Asians but East and South Asian cultures are different. For example, in a 2012 survey of Chinese and Indian parents, both cultures highly valued hard work but Indian parents were more likely to prioritize religious faith when raising their children.4 This among other differences highlights the need for research on specifically South Asian people.

The method of data collection for the SABI Study is a 25-35

36

social sciences American culture—influences body image and disordered eating. Acculturation can be a stressful experience, especially for South Asian Americans who may be trying to navigate two cultures at once. Dr. Bardone-Cone suggests that stress from acculturation may increase body dissatisfaction and disordered eating. Analyzing all of these factors will provide a large breadth of information about South Asian body image that Dr. BardoneCone and future researchers can examine in depth.

The SABI study is only part of the work that still needs to be done to continue diversifying psychological research. Dr. Bardone-Cone plans to continue expanding on the SABI study.

After the study is completed, the Bardone-Cone lab will spread the results to healthcare providers and communities, especially in areas with high South Asian populations. Next, the lab plans to reach out to participants who have indicated that they would like to be contacted for follow-up interviews. Dr. Bardone-Cone hopes this will eventually produce a longitudinal study—an investigation of changes in participants over prolonged periods of time—as this is a gap in research on South Asian body image.

Psychology is the study of human thought, behavior, and emotion and Dr. Bardone-Cone’s SABI study is just one step in the direction of understanding all types of people.

Figure 2. Map of South Asia. Figure courtesy of Macky. minute survey that participants can pause as needed and return to later. The Bardone-Cone lab mulled over whether or not to shorten the survey time but decided that the large breadth of the questions would help to fill the extreme lack of research in the area. The only requirements are that participants must be 18 or older, of South Asian descent, and American. As recruitment is ongoing, Dr. Bardone-Cone hopes to reach at least 400 people with various gender identities, South Asian backgrounds, and ages. Recruitment thus far has been focused on South Asian groups in universities around the nation and the lab will soon be reaching out to nursing homes, religious organizations, gyms, and other places where non-college-aged South Asian people may be. In the later stages of recruitment, the Bardone-Cone Lab will provide in-person presentations on the SABI Study in local NC Triangle area facilities and Zoom presentations to other organizations in the United States.

The study will examine many possible influences on body image specific to South Asian Americans. Such variables include navigating American and South Asian culture, ethnic identity, family dynamics, colorism (discrimination against dark skin tones), and more. Dr. Bardone-Cone predicts that the data will show that South Asian Americans report similarly high rates of body dissatisfaction and disordered eating to other populations.

Furthermore, she has used previous literature on body image to predict that ethnic identity will be a buffer against negative body image and that opinions of family members will influence body image. For example, a South Asian American who is very connected to their ethnic identity and is involved with their culture may have a more positive body image than others with low ethnic identities. Additionally, extended family is usually highly valued in South Asian cultures and pressures from family to look or eat a certain way may influence body image.4 Another variable Dr. Bardone-Cone is interested in is how acculturation— the process of assimilating to another culture, in this case,

Figure 3. A South Asian family eating together Figure courtesy of Rawpixel.

References

1. Interview with Dr. Anna Bardone-Cone 9/29/2023 2. Rawpixel. (n.d.-a). Family having Indian Food. iStock. https://www.istockphoto.com/photo/family-having-indianfood-gm907578902-250019448?phrase=south%2Basian%2Bfa mily%2Beating&searchscope=image%2Cfilm 3. Macky, I. (n.d.). Public domain maps of South Asia. South Asia · public domain maps by Pat, the free, open source, Portable Atlas. https://ian.macky.net/pat/map/sasa/sasa. html 4. Skelton, C. (2012, July 5). Chinese vs. Indian parents: How do they differ?. Vancouver Sun. https://vancouversun.com/ news/staff-blogs/chinese-vs-indian-parents-how-do-theydiffer 5. Wavebreakmedia. (n.d.). Woman Holding Hand Mirror in bathroom at home. iStock. https://www.istockphoto.com/ photo/woman-holding-hand-mirror-gm838282450-136432527

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social sciences

Society as an Experiment: The Ancient Past and our Uncertain Future

by Catherine Wiles

F

or hundreds of years, human societies have experimented with different ways of life. According to some in the archaeology field, the ingredients for adaptation to modern challenges might just lie in ancient “failed” states. Dr. Patricia McAnany is a Kenan Eminent Professor of Anthropology at the University of North Carolina at Chapel Hill. As a specialist in indigenous identity, her academic background consists of field research and leading cultural heritage programs in the Maya region of Central America, which includes southern Mexico, Guatemala, Belize, and western Honduras.1 In her own research and as a founder of InHerit, McAnany is an advocate for participatory research with indigenous communities.2 She believes that allowing local voices to tell their own stories brings greater value to both the academic work itself and the communities it addresses.2 In her paper “Experimenting with Large Group Aggregation,” with Dr. Nam Kim from the University of Wisconsin-Madison, Dr. McAnany argues that discounting the diversity of ancient political systems and methods of interaction with the natural world risks missing out on lessons vital to

Photo by Fred Rockwood via Flickr, CC-By-SA 2.0. solving modern challenges, particularly climate change.3 While working with an Arizonabased research group called the Amerind Foundation, Dr. McAnany encountered a number of other archaeologists who worked with so-called “anomalous sites,” which are - archaeological sites that don’t fit neatly into archaeological categories.2 Anomalous sites, scattered across the planet, are distinguished by a lack of clear signs of social stratification, such as royal palaces or hierarchical housing.3 These include the Ukrainian settlement of Trypillia, Great Zimbabwe, and the widespread settlement that originally surrounded Stonehenge.3 When V. Gordon Childe first standardized the definition of a ‘city’ in 1950, he found that his definition excluded many of the large settlements of the Americas despite their complexity.3 Even so, this standard has persisted for decades, creating a blind spot in the archaeological understanding of how advanced societies can organize themselves. By willfully ignoring the diversity of ways in which ancient societies have arranged themselves, there is a risk of missing out on lessons that show how

38

ancient people reacted to climate change and other challenges.

For Dr. McAnany, society is an everevolving experiment. Rather than failures, the paper frames ancient societies as a series of attempts to craft a cohesive identity in a changing world.3 Just like the experiments in the sciences, attempts that have ‘failed’ to last forever have something to offer.2 Ancient societies were a series of experiments in social organization in which humans attempted to adapt and thrive in their unique social and environmental conditions.3 In other words, the flexibility

Dr. Patricia McAnany

social sciences hopeful, that it is worth pointing out that things can be different,” Dr. McAnany says.2 There is much to be learned from ancient societies, but that can only be done if archaeologists look deeper into the past.

Figure 1. Great Zimbabwe is one example of an “anomalous site,” where large populations were housed not in a high-density area with high social stratification, but in a more dispersed territory. Figure 1 taken by Richard Pluck via Flickr, CC-byNC-ND 2.0 of human social structures is key to either a more people-driven, equitable adaptability in the face of change. approach, where decisions are made with Throughout history, and even pre- respect to the environment and collective history, archaeologists can see the signs well-being, or an authoritarian approach of radical social experimentation: the rise where risk is managed by centralized and fall of cities and mass migrations, control.3 Attitudes about our place in the the realignment of political structures world also play a role.3 Many indigenous and societal societies, for norms.3 According example, see to the paper, one humans not as view expressed controllers of

by Graeber and nature but as Wengrow argues part of it.2 In this that we need worldview, there “another urban is less space for evolution” in order a destructive to create more equitable and sustainable relationship with the surrounding population centers that are structurally environment. The paper argues that and economically resilient to climate some valuable insights could be gained change.3 through careful study of archaeological According to the paper, past sites.3 societies represent a “cornucopia” Humans are an incredibly from which valuable strategies can be adaptable species. While today’s manobtained to reconfigure cities in the made climate change is unprecedented, face of climate change when combined change is not. The past may well hold with modern technology.2 For example, valuable insights for today’s challenges. archaeological sites can provide a glimpse However, this can only be done if the true into the ancient methods of arranging diversity of societies throughout time is infrastructure and food systems to considered. Dr. McAnany hopes that the feed large populations in unfavorable paper’s reframing of ancient societies conditions.2 Social organization, is also as experiments in human sociality will an important factor in determining provide a more positive perspective on the resilience of a society in the face of human adaptability and climate change. change, with two potential approaches: “I hope that the takeaway is something

“I think maybe the issue of control is a big one, that we always try to control everything."

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References

1. Patricia A. McAnany | Department of Anthropology. https://anthropology. unc.edu/person/patricia-a-mcanany/ (accessed 2023-10-02).

2. Interview with Patricia 3. Kim, N. C.; McAnany, P. A. Experimenting with Large-Group Aggregation. Journal of Urban Archaeology 2023, 7, 17–30. https://doi.org/10.1484/j. jua.5.133448.

medicine and public health

Aftermath:

The State of Telemedicine in the Post-Pandemic Era

by Grayson Coleman and Ruhi Saldanha

Image by macrovector on Freepik

T

he SARS-CoV-2 pandemic wreaked international havoc for nearly three years and catalyzed unprecedented changes in every facet of life. Among the most profound transformations was the widespread adoption of telehealth, a trend that promised to revolutionize healthcare accessibility and delivery. Telehealth technology enabled physicians to remotely diagnose and treat patients despite social distancing mandates instituted during the pandemic. This unexpected pilot of the potential future for medicine was extraordinary but disappeared almost as quickly as it initiated. As the pandemic subsided and the world began its path towards recovery, many telehealth policies reverted to pre-2020 norms, making its accessibility to patients and feasibility for physicians impractical. The need for sustained efforts to make telemedicine more equitable and efficient is of incredible urgency. Dr. Saif Khairat has made it his career to investigate how to make telehealth a reality both in its efficiency and in its accessibility. Dr. Khairat became involved in telemedicine ten years prior to being named lead investigator of the Center for Virtual Care Value and Equity (ViVE) while teaching at the University of Minnesota. He has since led multiple projects Dr. Saif Khairat, lead to enhance existing healthcare services and research. His investigator of UNC Chapel research focuses primarily on Hill’s Center for Virtual Care Value and Equity utilizing telemedicine to support

health equity and leveraging technology to improve patient safety.1 Before the pandemic, telehealth visits were limited primarily to established patients who had previously seen a healthcare provider in person. The sudden and widespread shutdown of healthcare systems in 2020, though, posed significant challenges to this status quo. Providers became increasingly difficult to access, and the prior-patients-only policy made it near impossible for thousands of Americans to access healthcare resources. Within the first six months of the nationwide lockdown, clinics faced an overwhelming influx of patients, which they were often ill-prepared to handle using traditional in-person care models. This allowed the emergence of telehealth as a vital tool in providing care to dictate public policy in relaxing government restrictions that limited physicians’ ability to use technology. Patients and healthcare providers alike embraced telehealth to bridge the gap during a period of uncertainty. As the pandemic eased, however, the policies that allowed this renaissance reverted back to their original state.

The relaxed restrictions that had facilitated telehealth during the crisis were rolled back, and healthcare systems returned to their pre-COVID practices. This abrupt shift highlighted the need to establish a more enduring foundation for telemedicine in the healthcare landscape.

While telemedicine holds the potential to increase healthcare accessibility, it also brings to the forefront various challenges that must be addressed to fulfill its promises.

One of the most significant challenges is the digital divide, which became glaringly evident during the pandemic. Many underserved populations, particularly those in low-income communities, lacked access to the technology required for virtual care. Additionally, financial instability among these

40

medicine and public health patient access, enhancing clinical effectiveness, and connecting patients with healthcare providers. “We need to create datadriven evidence that drives policies,” Dr. Khairat urges.1 As technology continues to evolve, the future of healthcare may indeed be shaped by the innovative combination of telemedicine and artificial intelligence, ultimately providing greater healthcare accessibility and equity for all. While we have made significant strides in the field of telemedicine, the journey toward a more equitable and efficient healthcare system is far from over. Dr. Khairat’s dedication and vision serve as a beacon of hope, lighting the path toward a future where healthcare is truly accessible to all, regardless of barriers.

Figure 1. COVID Curfew illustration during the peak of the Pandemic. Image by Freepik. populations further hindered their ability to embrace telehealth.

Moreover, patient acceptance of virtual care varied widely. While some patients readily embraced telemedicine as a convenient and effective way to receive healthcare services, others were skeptical or resistant to this mode of care delivery. Overcoming these barriers to acceptance and ensuring that telemedicine serves as a viable option for all patients remains a complex challenge.

Dr. Khairat and the Center for Virtual Care Value and Equity (ViVE) are at the forefront of addressing these challenges.

Following a $3.7 million endowment from the National Institutes of Health’s National Center for Advancing Translational Sciences, University of North Carolina at Chapel Hill established the Center for Virtual Care Value and Equity (ViVE).2 Dr. Khairat, a distinguished scholar in healthcare informatics, leads this groundbreaking initiative, which seeks to advance the quality and accessibility of healthcare through research and innovation.

“The Center for ViVE will foster expertise in virtual care data and create workforce development opportunities with its partners throughout North Carolina and the nation,” Dr. Khairat explained with pride.”1 Dr. Khairat envisions a future where telemedicine, supported by artificial intelligence and emerging technologies, can efficiently and accurately serve patients on a global scale.1 While this vision may evoke images of robot doctors and fully automated healthcare, Dr. Khairat emphasizes that the integration of artificial intelligence does not seek to replace healthcare providers. Instead, it aims to enhance care delivery by leveraging technology to its fullest potential.1 One of the most intriguing possibilities lies in the use of artificial intelligence (AI) for diagnosis and care coordination. In this future reality, AIpowered systems could analyze medical images or patient data, allowing for faster and more accurate diagnoses. Additionally, easily accessible chatbots could assist patients in navigating their healthcare journey, answering questions, and providing guidance. These innovations have the potential to revolutionize healthcare by improving efficiency, reducing costs, and increasing accessibility.

The COVID-19 pandemic accelerated the adoption of telemedicine, revealing both its potential and challenges. Dr. Khairat’s pioneering work at the ViVE initiative aims to bridge these gaps by advancing telemedicine research, improving

Figure 2. A “Khairatian” future where medicine is harmonious with technology in aiding patients. Image by fatmawatilauda Freepik.

References

1. Interview with Dr. Saif Khairat, Ph.D., MPH on 09/26/2023.

2. Gabryel, C. $3.7M in NIH funding will establish first-of-itskind virtual care center at Carolina. UNC Research. https:// research.unc.edu/2023/08/08/3-7m-in-nih-funding-willestablish-first-of-its-kind-virtual-care-center-at-carolina/ (accessed 2023-09-28).

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medicine and public health

Ubiquitination: The Ubiquitous Process that Might Ease Breast Cancer Treatment

By Quinten Curtis

Illustration by Caroline Norland

C

ancer is an incredibly complicated disease to treat; it can affect any part of the body, and survival and cell growth rates vary widely across types of cancer. About 300,000 people in the United States are diagnosed with breast cancer every year. Triple-negative breast cancer is the most aggressive type of breast cancer, affecting about 15% of all patients, with a 5-year survival rate of 77%.1 Of these diagnoses, basal-like breast cancer (BLBC) is the most common subtype.

The key factor in the cancer development involves dysfunctions in the cell cycle that cause frequent and uncontrolled cell divisions. Simply put, in all cancers, the cell cycle is overactive. The lab of Michael Emanuele at the University of North Carolina at Chapel Hill studies how the cell cycle is regulated, especially in cancer.

Dr. Emanuele began researching cell division as a Ph.D. candidate at the University of Virginia. Later, as a postdoctoral fellow at Harvard Medical School, he began studying how the ubiquitin protein signals the degradation of other proteins. In 2013, Dr. Emanuele became an assistant professor at UNC-Chapel Hill’s Department of Pharmacology, where he is now a full professor with tenure. Since coming

to UNC, Dr. Emanuele has merged his graduate school research with his postdoctoral research, as he currently studies the effects of ubiquitin and deubiquitinating enzymes (DUBs) such as USP21 on cell division.2 Dr. Emanuele’s lab has conducted research into the roles of specific proteins as cell cycle regulators in BLBC: the forkhead box M1 protein (FOXM1), the

Dr. Michael J. Emanuele

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ubiquitin protein, and the ubiquitinspecific peptidase 21 (USP21) enzyme.

FOXM1 is a protein that helps the cell progress into mitosis (a type of cell division—see Figure 1); therefore, an excess of FOXM1 is associated with cancer.

Ubiquitin, a protein found in all plants and animals, is essential to eukaryote survival. Its most common function is ubiquitination, in which multiple ubiquitin proteins attach to other proteins and target them for destruction. For example, if FOXM1 were ubiquitinated, it would be targeted for destruction, interrupting the cell’s progression into mitosis. Deubiquitination is the opposite of this process, wherein ubiquitin is removed from a protein to prevent it from being destroyed. USP21 is an enzyme that removes ubiquitin from FOXM1, protecting it from degradation.

In cancerous cell division influenced

by FOXM1, having more USP21 is like “pouring more gas into an engine,” according to Dr. Emanuele.2 Conversely, lower amounts of USP21 would reduce cell division by allowing for the degradation of FOXM1. Since FOXM1, ubiquitin, and USP21 regulate the cell’s progression into mitosis, these proteins show promising results for treating cancers like BLBC.3 Dr. Emanuele’s lab discovered that USP21 contributes to cell division and cancer

medicine and public health growth by increasing amounts of FOXM1.

The same study also showed that FOXM1 and USP21 are present in high amounts in BLBC cells. The Emanuele Lab further examined the relationship between FOXM1 and USP21 in BLBC cells to discover how it is affected by paclitaxel, a common drug used in breast cancer treatment. High FOXM1 expression often hinders the drug’s effectiveness in preventing cancerous cell division.

Since USP21 promotes FOXM1 expression, Dr. Emanuele’s lab sought to understand if restricting USP21 could aid the function of paclitaxel, which would inhibit cell division. For this experiment, the Emanuele Lab used RNA interference (RNAi) to create cell lines with low levels of FOXM1 and of USP21. To generate these cell lines, the lab used short interfering RNA (siRNA) to cut a piece of mRNA before it could be translated into a protein.3 The lab used three groups of cancer cells in their experiment: one with depleted FOXM1, one with depleted USP21, and a control group without depleted gene expression. Each group was treated separately with paclitaxel and a control chemical called DMSO.3 The lab’s main finding in this experiment was that, when treated with

Figure 1. Photo of a cell going through anaphase in mitosis. Image courtesy of Dr. Christine Allie Mills.

paclitaxel, the group with depleted FOXM1 and USP21 showed significantly less viability than when treated with DMSO. While lower amounts of USP21 cause a decline in cell division due to decreased FOXM1, treating the cells with paclitaxel causes cell division to decline even further. This experiment shows promise for combining a reduction in USP21 expression with paclitaxel treatment as a potential treatment for BLBC and similar cancers.3 According to Dr. Emanuele, the problem with paclitaxel and other chemotherapy drugs is that “we’re giving the patient basically as much as they can handle, and a lot of times, patients don’t finish rounds of chemotherapy because they’re so sick.”2 This issue could be fixed by targeting USP21 to reduce the burden of chemotherapy drugs on the body.

Such a drug could lower the amount of paclitaxel cancer patients have to take, and therefore reduce the side effects of chemotherapy.

In the future, pharmaceutical companies could create a drug that blocks USP21’s active site, the area that binds to ubiquitin on FOXM1. This action would prevent USP21 from removing the ubiquitin from FOXM1, ultimately inhibiting cell division. Such a drug could lower the amount of paclitaxel cancer patients need to take and, therefore, reduce the side effects of chemotherapy.

One issue with this proposal is that the importance and functionality of USP21 are not yet understood well enough.

Depending on the role USP21 has in other cellular processes, a drug that binds to it might have significant adverse effects on patients. According to Dr. Emanuele, “one of the tricky things with [DUBs] is that once you take them out of the native state of the cell, they can be very nonselective.”2 This means that when cells are isolated from the main organism (or in vitro), DUBs bind to many proteins they would not bind to when the cells are part of the main organism (or in vivo).

This issue can make results difficult to interpret in studies done with cells in vitro. Since DUBs can bind to so many different proteins, Dr. Emanuele and other researchers aim to figure out which

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molecules specific DUBs can bind to and which of these molecules are involved in certain cellular processes like mitosis.

In the future, more experimentation is needed to understand DUBs like USP21 and how they work in vitro and in vivo.

Uncovering how deubiquitinating enzymes function and bind to certain molecules like FOXM1 can reveal critical mechanisms in cell biology, especially those relating to cell division and cancer.

Although more research on DUBs is needed, they show promise as a target for cancer treatment. In the past few years, clinical trials have begun to assess the effectiveness of targeting DUBs like USP21. This research suggests significant potential for DUB inhibition in combination with paclitaxel as a treatment for cancers like BLBC.4 Inhibiting these enzymes could make the standard chemotherapy regimen more manageable and effective.

References

1. Triple-negative Breast Cancer. https://www.cancer.org/cancer/types/ breast-cancer/about/types-of-breastcancer/triple-negative.html (accessed October 1, 2023).

2. Interview with Michael Emanuele, Ph.D. 09/19/23.

3. Arceci, A.; Bonacci, T.; Wang, X.; Stewart, K.; Damrauer J.S.; Hoadley, K.A.; Enamuele, M.J.; Cell Reports 2019, 26, 3076-3086.

4. Antao, A.M.; Tyagi, A.; Kim, K.; Ramakrishna, S.; Cancers 2020, 12.

medicine and public health

Image courtesy of Pexels Stock Image

Y

ears ago, there was a king who was so desperate, so fearful of being poisoned, that he poisoned himself.

Little by little, every day, he would give himself a little more so that one day he would have built up such a tolerance that no assassin could harm him. This idea of treating patients with the very thing that could trigger an intense biological response is what has inspired modernday allergy treatments.¹ Between one and two percent of all children suffer from peanut allergies, leading them to be one of the most common reasons behind anaphylaxis cases in the ER and the most common cause of fatal food-allergic reactions.

Only recently have there been any FDAapproved preventative treatments for peanut allergies, with Palforzia, one such treatment, receiving the green light in 2020. With these treatments, the goal is to achieve desensitization by exposing patients to allergens in incremental amounts, ultimately leading the immune system to build up a tolerance to what would have been an otherwise serious threat. There are three such desensitization methods currently under research: Oral Immunotherapy (OIT), Sublingual Immunotherapy (SLIT) and Epicutaneous Immunotherapy (EPIT). In OIT, treatment is usually in the form of a powder, which must be mixed into a drink or food item. With SLIT, the allergen

is often administered in liquid form, through droppers or sprays, and is meant to be held under the tongue for several minutes and then swallowed. EPIT does not require ingestion of any allergen, but instead involves attaching a round BandAid-like device to a body part, usually the back, allowing the allergen to be absorbed through the skin.¹ One particular study, Open-label study of the efficacy, safety, and durability of peanut sublingual immunotherapy in peanut-allergic children, looks into key characteristics of SLIT and compares them to those of OIT, the premier treatment available. The research itself was conducted by a group of researchers based primarily out of the UNC Pediatric Allergy & Immunology department, and was supported by grants from the National Institutes of Health. Dr. Edwin Kim, a member of the former and a head researcher on this project, was interviewed for his thoughts on this nuanced topic. Dr. Kim is a specialist in this field, and focuses primarily on the safety and tolerability of immunotherapy, alongside formulating successful treatments and examining their lasting benefits. He has researched all three modes of treatment previously listed and is a parent of children with food allergies as well.¹ Here is an overview of the study: Eligible children (those who met certain technical criteria and safety benchmarks,

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in addition to having a peanut allergy) between the ages of 1 and 11 were treated with a liquid dose of 4 mg peanut SLIT for up to 48 months. In a novel form of testing to determine the durability of the treatment’s protective effects, the participants were also subjected to randomly assigned avoidance periods in which they stopped treatment altogether for up to 17 weeks. After the avoidance periods, participants were submitted to a double-blind, placebo-controlled food challenge in which they were given a dosage of peanut proteins up to 5000 mg. Afterwards, they were tested through skin pricks, and researchers evaluated

Dr. Edwin H. Kim

medicine and public health

Figure 1. Peanut SLIT Treatment Protocol. Figure courtesy of Kim et al. their immunoglobulin levels, basophil activation test results, and TH1, TH2, and IL-10 cytokine readings. In total, 47 participants underwent the full process, demonstrating a mean successfully consumed dose (SCD) of 2723 mg of peanut proteins, with 37% of participants able to tolerate the full 5000 mg. Median time to loss of desensitization was 22 weeks.² It is important to contextualize the numbers provided, specifically those regarding administered doses and SCD. An individual peanut is similar to a 300 mg dose, a serving of peanuts is approximately 5000 mg, and most kids, without any treatment, tend to react when exposed to only 100 mg. This study, through the administration of a dose equivalent to that of a hundredth of a peanut daily, was able to establish a tolerance of nearly 3000 mg— around 10 peanuts’ worth.¹ When comparing the three forms of immunotherapy, efficacy, safety, and ease of use are important points to consider.

With regards to safety, OIT tends to perform the worst amongst the three, given its extremely high dosage; the FDA approved dosage for OIT is around 300 mg, while doses up to 4000 mg have been researched in clinical settings. The sheer volume of peanut being consumed at a given time often contributes to gastrointestinal issues, and it poses heightened risk to allergic reaction in

specific scenarios. Examples included an increased risk when performing physical activity soon after taking the treatment, and when sick or feverish. SLIT, while it (albeit at reduced rates) may also induce some stomach pain or GI issues, has no such instances of heightened risk and has a comparatively tiny dosage, with 4 mg currently being the highest tested dosage.

EPIT, given its mode of treatment, often induces uncomfortable or painful skin rashes or sensitivity, triggering a miniature allergic reaction of sorts if the patient’s tolerance is low enough. This brings up the topic of ease of use as well; OIT, yet again, due to its larger dosage and flourlike form factor, tends to cause a natural aversion in many people due to the taste, smell, or texture of the treatment. EPIT is by far the easiest to use, as it is a simple patch which can be applied and forgotten about.

SLIT is a mixed bag— while not unpalatable, the act of holding the medication under the tongue for several minutes on a daily basis calls into question both children’s ability to reliably perform the task repeatedly and to adhere to the program over a long period of time.

While the research acknowledges these limitations and factors them into the final calculations, this study still revealed extremely promising data for the efficacy of peanut SLIT.¹ Dr. Kim believes that each of these treatments holds incredible potential and has the capacity to help families

“Dr. Kim believes that each of these treatments hold incredible potential and may help specific families with specific needs”

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on a case-by-case basis. Each of the treatments provides a level of tolerance that researchers refer to as “bite-proof protection,” or the idea that a child could accidentally eat a peanut-contaminated product and still be within a safe threshold that either limits a serious reaction or prevents one altogether.¹ As mentioned earlier, Dr. Kim is a parent to children with allergies, and applies his firsthand experience when discussing the implications of these treatments. He says that the greatest problem that comes with allergies, outside of the inherent danger of exposure, is the fear that exposure may occur. In pediatric cases, this fear may contribute to social isolation, like missing birthday parties or homeschooling instead of the opportunity to have normal fun with friends. He also addressed the financial burden of buying allergen-free foods, something he hopes that one day his research can help alleviate. Among his plans for future research is a desire to fix the issues with all three treatment methods and find their optimal dosages.

He hopes to see all three forms of treatment as viable, approved treatment options in the near future.

Figure 2. Visual representation of a liquid dropper used in SLIT treatment.

Image courtesy of Pexels Stock Image.

References

1. Interview with Edwin H. Kim, MD, MS. 09/19/23 2. Kim, E.H; Keet, C.A; Virkud, Y.V; Chin, S; Ye, P; Penumarti, A; Smeekens, J; Guo, R; Yue, X; Li, Q;

medicine and public health

A Super-Suit for the Heart Cardiac Patches can protect the Heart

By Sai Satvik Kolla

Figure 2. Design of cardiac patch. Photo courtesy of Lin Zhang and Ziheng Guo

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magine a super-suit straight from a comic book. This suit detects damage, collects data, and helps heal faster. It is made from state-of-the-art materials and cannot be easily worn or broken down. Best of all, it is flexible and comfortable, fitting perfectly to the body.

Now imagine the same suit, only it is designed to be worn by the heart, not the body. That is Dr. Wubin Bai’s and his team’s latest project: an approach to a fully bioresorbable and electrically conductive cardiac patch.1 Dr. Bai’s journey to the University of North Carolina at Chapel Hill is filled with discovery and exploration. As an undergraduate,

Dr. Wubin Bai

Dr. Bai studied physics, giving him an understanding of natural laws. While attending graduate school in Materials Science and Engineering at MIT, he began to apply engineering to tackle realworld problems. Going to Northwestern for postdoc training opened his mind to opportunities for materials engineering research. Upon coming to UNC-Chapel Hill, Dr. Bai wanted to start a lab with an integrated approach to problem-solving. He says, “My first goal was to try and establish a research program that can cherish a broad cohort of experts within their vibrant, dynamic areas.”2 The Bai Lab’s goal with this project was to address one of the most prevalent global health conditions. Dr. Bai stated, “Cardiac disease is one of the top critical diseases in the world, from the number of patients and deaths per year. The heart is a special organ that undergoes constant movement and geometric deformation. Our goal was to make an electronic device that can conform to the heart without restricting its movement and maintaining its function. It is a perfect organ to showcase our development of stretchable electronics.”2 Dr. Bai’s cardiac patch possesses many benefits, primarily benefiting those at risk for or who have experienced a heart attack. This is because the patch’s electrical therapy allows the damage done to cardiovascular tissue to heal. Heart function is also improved, decreasing the risk of future heart attacks.1

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medicine and public health The patch design also possesses far superior elasticity to traditional patches on the market. This is due to bioresorbable metals and polymers combined with a uniquely thin geometry.

The exceptional elasticity allows the Bai Lab’s patch to better conform to the heart than existing patches.1 Cardiac patches are an alternative treatment for cardiac disease in the current Figure 1. Schematic of cardiac patch. market. The patches Photo courtesy of Lin Zhang. utilize conductive materials to deliver electrical signals straight to the heart, improving heart contraction and correcting irregular heartbeats.

However, these patches are not biodegradable, possess only moderate elasticity, and have high electrical resistance. Dr. Bai’s and the Bai Lab’s research improves upon existing cardiac patches by using bioresorbable, superior materials, meaning the body can absorb them once the patch’s use has been served or it no longer operates. The patch’s bioresorbable properties also ease a massive burden on cardiothoracic surgeons and their patients. Traditional patches require removal surgery once their time is up; however, this patch dissolves into the body.1 Dr. Bai remarked on this function of the technology, saying, “One aspect I learned is that nowadays, most cardiac-related surgeries take hours on the surgical table, making surgeons incredibly exhausted. These surgeries also have a high risk of surgical failure. We hope these devices can be as convenient as the more established treatment categories.”2 Not only does Dr.

Bai’s patch alleviate the requirement for removal surgery, but its improved electrical conductivity and elasticity over the current patches in the market will provide physicians and cardiothoracic surgeons with a robust alternative to treating cardiac disease.1 Where can the patch go from here? Dr. Bai and his group have numerous fascinating ideas.

“There are several levels from our perspective. There is more material integration that we want to do. Innovation is needed to make the device more capable for long-term usage.

We know that electronics are functional, our cell phones.

Nevertheless, they are also submissive to damage; we cannot afford that inside the body.”2 Along with these improvements, Dr. Bai is also interested in integrating the technology with machine learning and AI capabilities so that the patch can be used to collect patient physiological data. This addition will help physicians better understand cardiac disease progression and generate personalized treatment plans for each patient. Dr. Bai says, “Diseases are different for individuals. Different body weights, physiological parameters, different metabolic characteristics.

That determines those diseases that need to be treated in a more tailored, personalized way. The reference base for such personalized treatment comes from the information collected by the cardiac patch.”2

“Our goal was to make an electronic device that can conform to the heart without restricting its movement and maintaining its function.”

Finally, Dr. Bai had a small message to send to the undergraduate community.

“We are fascinated by the impressive, motivated, and talented undergrads at UNC. We hope to take in more undergrads and expand our lab platforms to allow for multidisciplinary approaches to tackling problems and experiencing the journey of finding solutions to concurrent impactful questions.”2 Working with cutting-edge technology and designing life-saving devices, the Bai Lab does remarkable work in material science. The sky is the limit for this cardiac patch technology, and the innovations that will continue to spring out of the Bai lab in the coming years will be exciting.

References

Figure 3. The Bai lab group. Photo courtesy of Xiaochen Li.

1. Ryu, H.; Wang, X.; Xie, Z.; Kim, J.; Liu, Y.; Bai, W.; Song, Z.; Song, J. W.; Zhao, Z.; Kim, J.; Yang, Q.; Xie, J. J.; Keate, R.; Wang, H.; Huang, Y.; Efimov, I. R.; Ameer, G. A.; Rogers, J. A. Materials and Design Approaches for a Fully Bioresorbable, Electrically Conductive and Mechanically Compliant Cardiac Patch Technology. Adv. Sci. 2023, vol 10, 2303429.

2. Interview with Dr. Wubin Bai, 09/14/2023

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medicine and public health

Addressing the Inevitable Diagnosis with a Censored Covariate

A

By Shreya Kusumanchi

genetic time bomb haunts unsuspecting individuals at Chapel Hill, recognizes the as time ticks until a clinical diagnosis of Huntington’s importance of tracking the disease. Often abbreviated to HD, this devastating and progression of HD and the role of rare neurodegenerative disorder affects individuals’ cognitive, SDMT as a measure of outcome. Dr. emotional, and motor abilities. HD is caused by a genetic Garcia and her research team are mutation in the HTT gene that encodes the protein huntingtin. analyzing data from observational This mutation causes an abnormal number of CAG repeats studies that provided SDMT scores in the nucleotide sequence coding for huntingtin, resulting to create statistical programs in an abnormally massive protein product and formations of that predict the diagnosis and clumps within the neurons which disrupts its function.1 Since trajectory of HD. Dr. Tanya P. Garcia this mutation is dominantly inherited, onset of HD is virtually In Figure 1, SDMT scores are inevitable for those individuals with a parent with Huntington’s. plotted to demonstrate the change in cognitive impairment The number of CAG repeats one has (with the normal range over time for individuals with HD. The first graph uses “time being from 10-35 repeats) plays a significant role in determining since study entry” whilst the second graph uses “time to clinical when symptoms will manifest.1 Understanding Huntington’s diagnosis,” —a significant distinction emphasized by Dr. Garcia disease progression can be essential for treating patients at the and her team. She describes that “by investigating HD as a earliest onset of symptoms. function of time till diagnosis, researchers can understand how Huntington’s disease is rare but chronic. This means symptoms vary before and after diagnosis.”4 Furthermore, the that the onset of symptoms can take years or decades, making second graph reveals that SDMT scores worsen both before and research data on individuals with HD limited. Consequently, after diagnosis since it adjusts for individuals being in different scientists studying the disease may opt for conducting long- stages of the disease. In contrast, the first graph’s data is less term, longitudinal studies that closely monitor individuals strong and, hence, more difficult to conclude how symptoms with HD and collect data without intervention. These studies evolved over time. are monumental in tracking symptoms or signs of HD before Additionally, studies can end before all individuals reach an official, clinical diagnosis. Due to the scarcity of individuals the criteria for diagnosis. So, scientists can only assume that with HD, researchers must work with a limited number of diagnosis will occur after the study, which is the “phenomenon study participants. As a result, scientists may also notice that known as right censoring.”4 Those individuals who have not individuals in these studies might be more advanced in disease yet been diagnosed represent “right-censored” data points progression than others. Some show serious motor and cognitive because their time of clinical diagnosis is beyond the last time impairment, a common symptom of HD, while others are they were observed. In this analysis, time until diagnosis serves asymptomatic.2 To measure the degree of cognitive impairment, as a covariate, or independent variable, that predicts changes individuals with HD can be given in dependent variables, such as neuropsychological assessment SDMT scores. For those individuals tools like Symbol Digit Modalities that are yet to have a clinical Test (SDMT) to evaluate cognitive diagnosis for HD, their covariate function. Low SDMT scores can values are censored. indicate cognitive impairment, Dr. Garcia found that it is especially in one’s processing important to keep the individuals speed, attention, and memory.3 with right-censored data to These scores are standardized achieve more accurate estimates against common SDMT scores of the disease progression. To within an individual’s age group. continue with statistical analysis, Dr. Tanya Garcia, an associate researchers must decide whether professor in the Department the right-censored data at time of of Biostatistics at the Gillings Figure 1. Two graphs showing symbol digit modalities diagnosis should be replaced by School of Global Public Health at test or SDMT scores of Huntington disease patients the data from the last observed the University of North Carolina either time of study entry or time till diagnosis point of the study or, perhaps,

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medicine and public health the mean, median or mode of the The ACE imputation method study. These are some options to differs from other imputation fill in the gaps of the right-censored techniques, such as multiple data, known as imputation, to have a conditional mean imputation (MCMI) complete dataset for analysis. where censored data values are Existing imputation methods replaced with the conditional mean of require that the model used to the data. The ACE imputation method make the imputations are correct, accounts for when the chosen model but finding that correct imputation does not accurately represent the model is difficult. Dr. Garcia and data by doing robust adjustments. To her team developed the Active evaluate these imputation methods, a Correction for Error in Imputation simulation study was done, as shown (ACE) imputation method to in Figure 3. The simulation indicates attribute right-censored data that the error in the parameters of the attempts to predict the age of clinical disease trajectory, revealing that MCMI diagnosis and adjust for error. This is Figure 3. Results of simulation studies for had a larger empirical standard error achieved by utilizing semiparametric ACE imputation, MCMI (multiple conditional (ESE), mean squared errors (MSE), and theory.4 The semiparametric theory mean imputation), and the Oracle estimator to standard error estimate (SEE) than is a framework that incorporates estimate parameters with average standard error the ACE imputation method. These parametric and non-parametric estimate (SEE), the empirical standard error findings demonstrate the superiority of models. The parametric aspects of (ESE), the average mean squared errors (MSE), ACE over other methods. this theory assume the data follows a and the observed coverage probability (CPr) of From a scientific standpoint, Dr. particular distribution or relationship. the Wald-type confidence intervals with nominal Garcia explains that modeling disease Based on this assumed distribution, 95% coverage. progression for HD “can open doors for one can approximate parameters other neurodegenerative diseases that that best fit the data and create statistical inferences like linear do not have the genetic mutation.”6 Her larger research goal is regression.5 On the other hand, non-parametric aspects assume to expand these statistical models showing disease progression no distribution in the data, instead, they strictly depend on to chronic diseases outside of HD. the data to estimate relationships. Oftentimes, statisticians use Dr. Garcia and her team are making significant strides in more complex methods like local regression and kernel density modeling HD progression. The ACE imputation model shows estimation to understand patterns in the data.5 Dr. Garcia and evidence that it is more accurate than existing methods like her team employed semi-parametric theory to allow for more the MCMI when estimating the disease trajectory as a function flexibility when interpreting results since it does not make any of time to diagnosis. Using the power of statistical modeling strict assumptions about the data. Furthermore, Dr. Garcia and and imputation methods, Dr. Garcia hopes to find broader her team strived to adjust for errors between the imputed right- implications of these methods for more chronic diseases. These censored data values and true covariate values and correct for efforts are crucial for improving early detection in individuals the difference. with chronic conditions allowing them to start treatment sooner.

References

Figure 2. Ranking of outcomes of Huntington’s disease for fastest disease progression with cHUDRS or composite unified Huntington’s disease rating scale, TMS or total motor score, SDMT or symbol digits modality test, and TFC or total functional capacity.

1. NIH. Huntington’s Disease | National Institute of Neurological Disorders and Stroke. www.ninds. nih.gov/health-information/disorders/huntingtonsdisease#:~:text=HD%20is%20caused%20by%20a. (accessed October 10, 2023).

2. Mayo Clinic Staff. Huntington’s Disease - Symptoms and Causes. https://www.mayoclinic.org/diseases-conditions/ huntingtons-disease/symptoms-causes/syc-20356117. (accessed October 17, 2023).

3. Strobera, L.B.; Brucec, J.M.; Arnettd, P.A.; etc. “A new look at an old test: Normative data of the symbol digit modalities test –Oral version” Elsevier Multiple Sclerosis and Related Disorders. 2020.

4. Grosser, K.F.; Lotspeich, S.C.; Garcia, T.P.; “Mission Imputable: Correcting for Berkson Error When Imputing a Censored Covariate.”2023. (Under review) 5. Davidian M. Methods Based on Semiparametric Theory for Analysis in the Presence of Missing Data. Annual Review of Statistics and Its Application. 2022;9(1):167-196. doi:https:// doi.org/10.1146/annurev-statistics-040120-025906 6. Interview with Tanya P. Garica, PhD. 09/26/2023.

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medicine and public health

Breaking Barriers, Building Health: Innovative Paths to Chronic Disease Prevention in Minority Communities

By Simran Malik

Image courtesy of Flickr

I

n the fight against chronic disease, innovation is reshaping the future of minority communities. These communities face unique challenges through their racial, ethnic, and socioeconomic background, which causes them to have twice the risk of developing chronic disease – a fact that is especially true for Black, Hispanic, and Native American communities.1 Combatting these disparities requires a multifaceted approach that involves tailored healthcare strategies and a personalized treatment plan for individuals with a unique background. Dr. Deshira Wallace, an assistant professor at the Department of Health Behavior at the UNC Gillings Schools of Global Public Health, examines the onset of chronic disease in minority communities, and works on understanding how we can utilize interdisciplinary approaches for disease prevention.

Dr. Wallace has always been interested in creating a bridge between researchers and policymakers.

She believes that there needs to be greater conversation between the two in order to effectively translate research into policy.

Although she was Dr. Wallace initially interested in

environmental science, Dr. Wallace became interested in public health after she witnessed stereotyping of Latin Americans in terms of chronic disease. She explained that there was always a specific jargon associated with the Latin American community that grouped an incredibly diverse population into an umbrella by clinicians, which led to generalizations in disease management by physicians. For example, she noticed that after Latinos shared their racial status to their care provider, they tend to make assumptions about their diet based off a previously stereotyped perception of Latin American cuisine. However, the diverse Latin American population comes with dietary practices that vary from region to region. Therefore, these generalizations about diet demonstrate how little clinicians know about minority patient backgrounds, which can be particularly harmful for these communities who are already at greater risk for disease from other factors. In general, Americans don’t take into account regionality which leads to racialization of people into categories and, eventually, into stereotypes.4 In order to diverge from stereotyping, Dr. Wallace believes that doctors should have more conversation with patients about their needs. She reflects these conversations in her research, where she examines their personal background and how certain factors lead to the onset of disease. One of the long-term goals that she envisions for medicine is to be more critical on who we are talking about. Rather than labelling everyone as Black Americans, Latinos, Asians, etc., society should be more specific on who they are talking about.

Clinicians typically examine diet, exercise, and lifestyle

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medicine and public health

“A third of all adults in the United States are pre-diabetic, yet there is not proper screening to diagnose all [of the] people”

Figure 1. Medical costs are a burden for many Americans.

Image courtesy of The Blue Diamond Gallery. choices when considering the onset of disease. However, the particular circumstances that create barriers to a healthy lifestyle are rarely considered Therefore, rather than looking at the typical factors that lead to disease, Dr. Wallace examines these barriers. For example, she doesn’t tell people what to eat; rather, she focuses on food security. Instead of asking “What do you eat?”, she asks “Do you have food to eat?”. She assesses if people are able to exercise in the first place. She determines if people have access to medications. She looks at depression and anxiety, short-term and long-term stress. She looks at minority discrimination as a stressor in people’s lives. Overall, Dr. Wallace looks at the structure of minority communities’ lifestyle that lead to disease. The assessment of such factors is vital in a healthcare setting, so that clinicians can properly treat her patients.

Currently, Dr. Wallace is conducting many studies, but one noteworthy study that she highlights is concentrated on is on Pre-Type II Diabetes in the Latin American community. She found that when people are initially diagnosed as pre-diabetic, their response is the same as if they were told they had Type II diabetes. Type II diabetes is a condition where patients can not properly metabolize glucose as it doesn’t enter their cells.

Glucose is a vital for our survival because we use it to create ATP, a molecule that provides us energy. Type II diabetes can be a deadly condition if not managed correctly. Diabetic patients are typically treated with doses of Insulin, but Insulin is very expensive and not easily accessible to everyone.

People are defined as pre-diabetic when their blood sugar levels aren’t considered a diabetic level (over 126 mg/dL) but are approaching a high level (100-125 mg/dL).2 A third of all adults in the United States are pre-diabetic, yet there is not proper screening to diagnose all people as diabetic.3 Doctors typically find pre-Type II diabetes when screening for another condition. When doctors tell patients they are pre-diabetic, they simply tell them very general recommendations are given, such as exercising more and eating healthier. However, due to certain barriers, it’s not that simple. Minority patients have other barriers that prevents them from leading a healthier lifestyle, and because of this, when patients are initially told they are prediabetic, they become quite distressed. Dr. Wallace is trying to delve deep into the thought process for these Latin American patients when told they are pre-diabetic, and she is trying to research ways to intervene in the diagnosis phase to help people change their behaviors in a tailored way, rather than a generalized way.

Dr. Wallace doesn’t fault clinicians for not counseling

patients-- rather, she believes in an entire reform of the healthcare model where we provide certain patients a team of professionals working to understand the circumstances of patients. For example, the team can include clinical social workers and pharmacists. By having this interdisciplinary team, the clinical side of medicine and the public health side of medicine are able to work together. This will allow for a better understanding of patients, specifically minority communities, and their needs to better diagnose and treat their chronic diseases.

References

1. Bhargava, H. Minorities and Chronic Disease: Obstacles to Care. WebMD. https://www.webmd.com/diabetes/features/ minority-chronic-condition-burden (accessed October 5th, 2023) 2. Diabetes Tests. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/basics/gettingtested.html#:~:text=A%20fasting%20blood%20sugar%20 level,higher%20indicates%20you%20have%20diabetes. (accessed October 5th, 2023) 3. Prediabetes. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/basics/prediabetes. html#:~:text=Approximately%2096%20million%20 American%20adults,%2C%20heart%20disease%2C%20 and%20stroke.(acessed October 5th, 2023) 4. Interview with Dr. Wallace, PhD. 09/22/23 5. Bonora, M. ATP Synthesis and Storage. National Library of Medicine. https://www.ncbi.nlm.nih. gov/pmc/articles/PMC3360099/#:~:text=In%20 general%2C%20the%20main%20energy,oxidative%20 phosphorylation%E2%80%94to%20produce%20ATP.

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medicine and public health

Treating the Untreatable:

The Fight Against Recurrent Ovarian Cancer

by Baylee Materia

Illustrated by Spoorthi Marada

D

r. Linda Van Le spends her time thinking about the future. Eager to start her career in medicine, she entered Stanford University at the age of 16 and was accepted to UC San Francisco School of Medicine at the age of 19. As the Leonard D. Palumbo Distinguished Professor of Gynecologic Oncology at UNC, the co-editor of the widely used 13th edition of Te Linde’s Operative Gynecology textbook, and a mentor for the International Gynecologic Cancer Society’s Global Oncology Fellowship program based in Danang, Vietnam, she is passionate about educating the next generation of doctors with the skills necessary to advance patient care. This desire is also what drives her research. She serves as the principal investigator for UNC’s Ovarian CAR T Trials, which test new ways to treat recurrent epithelial ovarian cancer.2 Ovarian cancer is the fifth leading cause of cancer deaths among women in the United States, but it is one of the most lethal. The first symptoms are nonspecific, and early tumors are difficult to feel during pelvic exams. Thus, the cancer often grows undetected until patients note their symptoms and present with advanced disease.1 Once detected, ovarian cancer is typically treated with platinum-based chemotherapy. Platinum agents work by binding to the cancer DNA to prevent growth. This method has been proven to be effective for the majority of ovarian cancer patients. However, others will develop “platinum resistance” – their cells do not respond to the standard platinumbased treatment. Medical options for these individuals are limited, and prognosis is bleak.2 Dr. Van Le and her team are currently conducting clinical trials into various chimeric antigen receptor (CAR) T-cell immunotherapies for platinum resistant ovarian cancer patients.

According to Dr. Van Le, advancements in immunotherapy are ushering in a “new and exciting time” for ovarian cancer research. Chemotherapy is cytotoxic and nonspecific -- killing both cancerous and noncancerous cells -- and manifests as hair loss, anemia, and white blood cell suppression. Alternatively, immunotherapy aids the patient’s natural immune system in killing the cancer cells without cytotoxic side effects.2 T-cells are a type of lymphocyte of the adaptive immune system which target and attack the body’s infected cells. CAR T therapy takes advantage of these killer T-cells. CARs are synthetic receptors that are designed to bind to surface antigens on cancer cells.3 Investigators at UNC have discovered that ovarian cancer cells possess an antigen called B7-H3. To treat these cancer cells using immunotherapy, a blood sample is collected from the patient, and their T-cells are isolated and modified with CARs that specifically target B7-H3. When injected back into the patient, the CAR T-cells specifically target and destroy the cancerous

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Dr. Linda Van Le

medicine and public health an experimental procedure is variable. Thus, reducing the cost of treatment is imperative before it can be made more widely available.2 Dr. Van Le’s project is currently a phase I clinical trial. This means that a small group of patients is administered the therapy to test for drug safety and potential side effects, and cancer eradication is not guaranteed. Dr. Van Le is incredibly grateful for the patients that choose to undergo this difficult process: “God bless our patients. They are contributing to the welfare of others. This is phase I, and there is no promise of efficacy, but they are working so hard to live, and I respect that so much.”2 Because the trial is still in its early stages, there are currently few conclusive results. However, no patients have had adverse outcomes to the treatment thus far. The full clinical trial is not expected to be completed for some time. While the road ahead is long, the dedication of Dr. Van Le and her colleagues means that a brighter future for those battling recurrent ovarian cancer is within arm’s reach.

Figure 1. Ovarian cancer cells captured by scanning electron microscopy. Image courtesy of Cedars Sinai. cells that express B7-H3.4,5 While immunotherapy in ovarian cancer treatment is promising, the process presents physical and financial difficulties for patients. First, patients must undergo lymphodepletion, which is a type of chemotherapy that suppresses their natural immune system to increase the efficacy of the CAR T treatment.

CAR T-cells are then administered to the patient through a catheter in the abdomen. Dr. Van Le’s research group is unique in their use of intraperitoneal delivery of CAR T cells.2 Following this therapy, patients are monitored in close proximity for any side effects. One potential side effect is cytokine release syndrome (CRS), which causes high fevers, rigors, headaches, and muscle pain that can progress to fatal tachycardia, hypotension and hypoxia.6 Another unique and significant side effect of CAR T cell therapy is ICANS, immune effector cell-associated neurotoxicity syndrome, which is associated with severe confusion, seizurelike activity, and impaired speech. Fortunately, with close monitoring and medication, the T cell treatment can be shut down if necessary. Today, each CAR T therapy cycle costs between $500,000 and $700,000. Insurance coverage for such

Figure 2. Collection and Administration of CAR cs. Image by Santomasso et al. courtesy of Dr. Van Le.

References

1. Ovarian Cancer. https://www.cancer.org/cancer/types/ ovarian-cancer.html (accessed 2023-10-03).

2. Interview with Linda Van Le, M.D. 09/27/23.

3. National Cancer Institute. https://www.cancer.gov/aboutcancer/treatment/research/car-t-cells#top (accessed 2023-1015).

4. Phase I Study of Autologous CAR T-Cells Targeting the B7-H3 Antigen in Recurrent Epithelial Ovarian. https:// clinicaltrials.gov/study/NCT04670068 (accessed 2023-10-03).

5. Ma, S.; Li, X.; Wang, X.; Cheng, L.; Li, Z.; Zhang, C.; Ye, Z.; Qian, Q. Current Progress in CAR-T Cell Therapy for Solid Tumors. International Journal of Biological Sciences 2019, 15 (12). DOI:10.7150/ijbs.34213.

6. Santomasso, B.; Bachier, C.; Westin, J.; Rezvani, K.; Shpall, E. J. The Other Side of Car T-Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden.

American Society of Clinical Oncology Educational Book 2019, No. 39, 433–444. DOI:10.1200/edbk_238691.

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medicine and public health

A Misguided Intestinal Immune Response Inflammatory immune cells attacking intestinal microbiota leads to IBD

By Isha Mistry Image courtesy of Professor Sarkis K. Mazmanian

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icrobiotas, or foreign microorganisms consisting of bacteria, viruses, and fungi – wreak havoc on the human body. Fortunately for humans, the immune system is normally able to clear out these invading microbiotas.

But sometimes, this immune response can be misguided, because we rely on microbiotas to function properly in some places. The intestine is filled with microbiota necessary to digest food, and when these microbiotas get mistakenly attacked by inflammatory immune cells, it leads to a disease known as Inflammatory Bowel Disease, or IBD. IBD cannot be cured, and the disease has an early onset, about late teens and early 20s.

Researchers like Dr. Terry Furey aim to “better understand at a molecular level the contributors to the onset and progression of the disease, as well as response to different treatments…to help us come up with better treatment options to improve the quality of life of people who have the disease.”1 Inflammatory Bowel Disease consists of two primary subtypes: Crohn’s Disease and Ulcerative Colitis. The main goal Dr. Furey and his collaborators had in the article which studied Crohn’s disease in adult patients, was to increase their understanding of the differences that occur at the cellular and molecular levels between IBD patients and non-IBD patients.

His team compared gene expression in diverse cell types in the colon epithelium, a layer that lines the colon, in both people with and without Crohn’s Disease.

To research these diverse cell types, Dr. Furey and his colleagues relied on functional genomics experiments. These methods allow for ways to assay, or investigate, specific cellular processes such as gene expression and gene regulation.

Overall, it helps researchers “get a more comprehensive picture of the molecular state of Dr. Terry Furey

a particular tissue sample”1 according to Dr. Furey. Specifically, the main method they used allowed them to investigate cellular and molecular differences occurring at the single-cell level between patients with and without Crohn’s Disease. This single-cell analysis technology allows the researchers to get a more detailed and precise picture of a tissue that is composed of many different cell types.

From their analysis using single-cell technology, the researchers saw that many diverse types of cells line the epithelium. The graph in Figure 1 shows the different epithelial cell types, designated by distinct colors, which the researchers uncovered in their analysis. The experiments led to a significant discovery in which they found that the main difference between patients with and without Crohn’s Disease, is that “the portions of different [specific] cell types were changed in disease that are important for normal epithelial cell barrier function.”1 There were different proportions of each specific cell in patients with the disease compared to those without the disease. The histogram in Figure 2 compares cell type proportions in control patients, ones without the disease, to patients with Crohn’s disease.

T h e s e differences are a key finding that contributes to helping the researchers better understand why a misguided immune response may be occurring in patients with Crohn’s Disease. Figure 1. Various cell types uncovered in Essentially, Dr. samples. Figure courtesy of Kanke et al.

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Figure 2. Differing levels of cell types Crohn’s disease patients vs. control. Figure courtesy of Kanke et al.

Furey and his collaborators believe that this difference “reflects a decrease in barrier function that is contributing to the disease.”1 The barrier function Dr. Furey refers to is the intestinal barrier function. In our intestine, there is a barrier, known as the “intestinal mucosa”,2 which separates the lumen, that stores digested food, from a layer called the “lamina propria.”2 This layer is lined with immune system cells which help ensure none of the microbiota escape into other parts of our body. If this barrier becomes more porous, due to the decreased barrier function, then the bacteria and microbes may reach the immune system layer and prompt the inflammatory immune response seen in Crohn’s Disease.

The road to making this significant discovery was not easy, and Dr. Furey and his colleagues did encounter a few hurdles when conducting their analysis. Their main challenge was associated with their use of single-celled technology, which is a fairly new technology. Dr. Furey has been collaborating with Dr. Shehzad Sheikh for over ten years, who is a clinical scientist who actively sees patients with IBD. Dr. Sheikh’s lab coordinates with physicians taking samples from consented patients during clinical procedures, and he had to preserve and transfer the cell samples back to the lab to be used in the experiments.

Overall, there was a great deal of thorough communication and coordination necessary between physicians, Dr. Sheikh, Dr. Furey, and other researchers to pull off these assays and experiments in a timely manner using this new single-cell technology.

To continue his research and expand on these differences in the molecular level, Dr. Furey and his colleagues are “currently focused on trying to understand how genetics are influencing these changes in molecular profiles in IBD patients and putting them at higher risk of the inappropriate immune response and the development of inflammation.”1 The team is looking to see how and why an individual may be genetically susceptible to this inflammatory immune response. Dr. Furey believes that an important theme in human health and genomic research is that these research projects are never single lab endeavors, and instead the research is about “Team Science”1 in which small advances made together help push the field forward.

So, he will continue collaborating with Dr. Sheikh and others to continue making these small, but crucial advancements to better understand IBD and to improve the quality of life of those that have it.

References

Figure 3. Intestinal Barrier. Figure courtesy of Vancamelbeke and Vermiere.

1. Interview with Terry Furey, Ph.D. 9/26/23.

2. Maaike Vancamelbeke; Séverine Vermeire. The intestinal barrier: a fundamental role in health and disease 2017 3. Matt Kanke; Meaghan M Kennedy Ng; Sean Connelly; Manvendra Singh; Matthew Schaner; Michael T Shanahan; Elizabeth A Wolber; Carolina Beasley; Grace Lian; Animesh Jain; et al. Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease Patients 2022.

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Fighting Malnutrition Before Conception Focus on Implementing Effective Nutrition Programs

By Ria Patel Image courtesy of Wikimedia Commons.

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olic acid, choline, protein, iron, calcium, vitamin D, potassium, and fiber: these are just a few of the key nutrients emphasized in a diet for people who are pregnant. For the most part, experts have reached a consensus on why these nutrients are recommended during pregnancy, and early childhood — they provide the essential benefits and support needed to meet the extra demands of a pregnancy.1 Additionally, when appropriately integrated into a diet, these nutrients can help prevent risks associated with pregnancy, birth, and child development. These risks can range anywhere from gestational diabetes — which is when diabetes onset occurs during pregnancy — to preeclampsia, a serious high blood pressure condition during pregnancy.2 But despite a universal acknowledgement of the benefits of preventative nutrition, malnutrition is still estimated to be the global underlying cause of 45% of child mortality,3 and anemia (the lack of sufficient healthy red blood cells) still contributes to 20% of the maternal mortality rate.3 According to Dr. Stephanie Martin, the answer as to why this problem persists lies not in what experts know to prevent these outcomes, but in how the interventions to these global health injustices are delivered and implemented.1 Dr. Stephanie Martin is an assistant professor at the University of North Carolina at Chapel Hill where she teaches nutrition-related courses such as NUTR 723: Community Nutrition. In addition to teaching, she facilitates bi-weekly meetings with students in order to discuss their academic and professional interests surrounding nutrition.

Additionally, Dr. Martin conducts implementation research to improve the quality and impact of nutrition programs with a focus on maternal, family, and young child nutrition. Dr. Martin’s Dr. Stephanie Martin interests in these specific areas of

Figure 1. Dr. Martin and her team in Kenya. Figure courtesy of Dr. Stephanie Martin. research stem from her passion for public health topics. More specifically, her interests in public health relate to working to address consequences that arise as a result of because of inequities.1 Her experience of working in global health for two non-governmental organizations over the span of 13 years drove her interests in preventative nutrition and health in infants and during pregnancy into a passion as well. During this time, she focused on implementing programs related to child and maternal nutrition. But after working to implement those programs on both governmental and community levels, Dr. Martin wondered if her efforts were truly making an impact, especially considering the consistent, poor statistics related to malnutrition.1 To address her concerns, Dr. Martin decided to pursue a higher education at Cornell University and earn her PhD in nutrition. Her research interests then began to revolve around finding ways for communities to both maximize the efficacy of programs related to maternal, family, and child nutrition, and to support families in practicing recommended nutrition behavior.

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Figure 2. Atlas.ti Research Software. Figure courtesy of Wikimedia Commons.

Currently, Dr. Stephanie Martin is attempting address these issues by researching the underlying factors that contribute to malnutrition and obesity in underserved adolescent populations in Kenya. She works collaboratively with CFK Africa (a nongovernmental organization co-founded by a Carolina alum) and focuses on finding key factors to help her best address adolescent malnutrition in Kenyan informal settlements.1 The CFK Africa research project is especially unique since Dr. Martin and her team integrate a combination of both qualitative and quantitative data to design a nutrition-based program that can be implemented in the schools of the Kenyan informal settlements. It will address all forms of malnutrition focused on adolescents in Kenya. Dr. Martin and her team use quantitative data from a survey of 320 adolescent girls in Kenya, which asks about their nutritional experiences. For qualitative data, they use translated interview transcripts from students, teachers, and parents who discuss the nutritional and physical activity of the adolescents in Kenya.1 Dr. Martin’s choice in including qualitative data gives the team a better understanding of the adolescents’ and their accompanying caretakers’ personal experiences, so that programs can best meet their needs when implementing a nutritional intervention.

To derive and create qualitative data from the interview transcripts, Dr. Martin uses a software called Atlas.ti. Atlas. ti allows Dr. Martin and her partners to work collaboratively, efficiently, and cost-effectively in their analysis of the qualitative data by “de-coding” the transcripts. On Atlas.ti, Dr. Martin and her team organize documents from interviewed adolescent girl and boy students, ranging from 13 to 19 years old, as well as from their parents and teachers. They break down large transcripts into smaller excerpts that are denoted by certain codes which summarize factors that influence the adolescent’s nutrition, physical activity, education, and their personal suggestions for

Figure 4. Factors that influence diet and physical activity according to adolescents in Kenya. Figure courtesy of Dr. Stephanie Martin. change. These codes are usually short phrases that summarize key components relevant to the study, including “Factors that influence food eaten: money/economics” and “Eating at school: suggested/desired changes”. Dr. Martin plans on using the findings from this research to help CFK Africa devise interventions to promote a healthier lifestyle for these adolescents. In fact, a graphical protype of the findings Dr. Martin and her team have gathered so far are included in Figure 4. Dr. Martin and CFK Africa hope to implement these programs into the schools the adolescents attend so that they can establish healthy habits to benefit their long-term health and be prepared to carry out a healthy conception and pregnancy in the future.

Clearly, Dr. Martin’s current efforts serve to bridge the gap between the theoretical research and the actual programs implemented. She acknowledges that public health interventions are of minimal use if research, public policy, and interventions do not address the inequities in global health. Additionally, she encourages the importance of working collaboratively with her partners to understand that the challenges with nutrition lie less with a lack of knowledge, but more with challenges with resources and implementation.

Thanks to Dr. Martin, communities are now one step closer to understanding effective ways to better their nutrition and to implement these programs efficiently across the board.

References

Figure 3. The CFK Africa Team. Figure courtesy of Dr. Stephanie Martin.

1. Interview with Stephanie L. Martin, Ph.D. 09/29/2023 2. The Importance of Nutrition in Pregnancy and Lactation: Eat Better, Not More https://www.ohsu.edu/school-ofmedicine/moore-institute/importance-nutrition-pregnancyand-lactation-eat-better-not-more#:~:text=There%20is%20 an%20association%20between,preeclampsia%20and%20 high%20blood%20pressure (accessed October 1st, 2023) 3.Role of Nutrition in Preventing Child and Maternal Deaths: Technical Guidance Brief, https://www.usaid.gov/rolenutrition-preventing-child-and-maternal-deaths-technicalguidance-brief (accessed October 1st, 2023).

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medicine and public health Figure 3. U.S. Department of Agriculture Food Assistance Program. Photo by Preston Keres/US Department of Agriculture, PDM 1.0.

SNAP Decisions: How Federal Assistance Impacts Population

By Arora Rohrbach

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ood insecurity affects, on average, 1 in 10 American households each year.1 Federal initiatives like the Supplemental Nutrition Assistance Program (SNAP) serve to alleviate financial strain related to the cost of food and enable low-income households to purchase sufficient food. However, the program is only made available to households that meet certain criteria. Beyond federal guidelines, each state can opt into different policies that affect the size of their programs.

One such optional policy is broad-based categorical eligibility (BBCE). Under this policy, states can increase the income limit for eligibility, meaning households making up to two times the federal poverty level are able to receive SNAP benefits, and/or eliminate the asset test, which places a cap on the resources that a household can possess to be eligible (including funds in bank accounts, cash, and vehicles owned).2 This enables more households to take advantage of SNAP and makes it easier to afford nutritious food.

Variation among the states that adopt these kinds of policies and their resultant population health is of particular interest to Dr. Anna Austin, an assistant professor in the Department of Health Behavior at the University of North Carolina Dr. Anna Austin

at Chapel Hill. She has investigated the associations between the expansion of SNAP access and various measures of health, such as mental health and child safety. Dr. Austin found that increased access to SNAP is associated with lower levels of suicidality among adults,2 fewer Child Protective Services (CPS) investigated reports of child neglect,3 and decreased foster care entries.4 Dr. Austin relies on existing literature to find the avenues she wants to explore in her data-driven research.5 She uses data from federal sources of national data such as the U.S. Census Bureau, meaning that a vast amount of information is available to her. Additionally, Dr. Austin looks at several years’ worth of data, because the patterns in which she is interested tend to require a longer timescale to become clear. To find associations, Dr. Austin looks at previously established trends—such as how increased financial help decreases negative mental health outcomes— and sees whether she can connect a financial support program like SNAP to a similar result.5 According to Dr. Austin, many of her findings pass the “sniff test,” meaning that the associations appear straightforward to most casual readers. However, for the findings to be useful in applications in medicine and patient care or in developing public policy, the association must be supported by data over time.5 Across the country, the COVID-19 pandemic caused many uncharacteristically quick policy changes.6 Many states, North Carolina included, passed emergency measures to expand SNAP and other programs to alleviate the financial strain of mandated isolation. However, these policies expired in early 2023.6 Considering Dr. Austin’s findings of improved adult mental health outcomes and increased child safety when SNAP is more easily accessible,2,3 she hypothesizes that the removal of SNAP access will yield decreased population health.5 Currently, local

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medicine and public health food kitchens are experiencing increased strain due to a large population no longer eligible for SNAP still needing assistance obtaining food.5 The U.S. Census Bureau’s weekly small-scale Household Pulse Survey has shown increased reports of households experiencing food insecurity and financial stress since government assistance programs returned to their prepandemic policies.5,7 It will take years before data exists that encompasses the full extent of pandemic-era policies and their impacts on population health.5 The change in size of federal assistance programs (both expansion and shrinking) is still actively affecting low-income households. The trends showing that SNAP expansion is associated with positive health outcomes found by Dr. Austin and her team took place over the course of several years (Figure 1, 2).2,3,4 This explains why population health findings do not translate easily to health policy, despite seeming directly relevant.5 Expanding SNAP costs money, and when the data shows that the population may not significantly benefit until two or three years have passed, legislators can be hesitant to fund it.5 The pandemic introduced a number of confounding variables that could affect the data. Confounding variables separately affect the state’s likelihood to choose to expand SNAP and affect the given health outcome (mental health, child safety, etc.).5 Some examples of confounding variables include political beliefs and socioeconomic status, but these are nebulous traits that are hard to quantify. So, Dr. Austin must choose specific, measurable factors which could represent these traits, such as marijuana legalization, state minimum wage, and percent of population unemployed.2,3 Adjusting for these factors allows Dr. Austin to directly compare data across states and isolate trends of interest. The expansion of SNAP during the pandemic was accompanied by the expansion of several other programs, such as Medicaid, which could reduce population risk factors.5 On the other hand, the constant news of sickness and death could negatively impact population health, increasing those risk factors.5 Both of these examples are confounding variables that could affect population health independently of SNAP’s specific impact during pandemic years. This creates a uniquely complex framework for health behavior researchers like Dr. Austin moving forward.

In 2022, SNAP and similar programs were responsible for lifting 7.1 million Americans out of poverty.8 Dr. Austin’s research goes beyond finances, emphasizing the role SNAP plays in the physical and mental well-being of adults and children.2,3,4

Figure 1. Change in CPS-investigated reports of neglect before and after increasing the income limit eligible for SNAP. Image courtesy of Dr. Anna Austin.

Figure 2. Change in new foster care entries before and after adopting BBCE. Image courtesy of Dr. Anna Austin.

Regardless of the size of the program, it is clear that SNAP helps to alleviate the stress of purchasing food and promotes the safety of vulnerable populations. COVID-19 enabled the expansion of these programs, but such a life-altering situation need not be a prerequisite for the existence of a program such as SNAP. The program is a vital safety net in day-to-day life, easing the path to financial self-sufficiency for many Americans. The enduring significance of SNAP is evident not only in times of crisis, but also in the everyday pursuit of an equitable and compassionate society, where no one is left to overcome food insecurity on their own.

References

1. U.S. Department of Agriculture Economic Research Service. Food Security in the U.S. https://www.ers.usda.gov/ topics/food-nutrition-assistance/food-security-in-the-u-s/ key-statistics-graphics/#foodsecure (accessed Oct. 1, 2023).

2. Austin, A.E.; Frank, M.; Shanahan, M.E.; Reyes, H.L.M.; Corbie, G.; Naumann, R.B. JAMA Netw Open. 2023, 6. doi: 10.1001/jamanetworkopen.2023.8415.

3. Austin, A.E.; Shanahan, M.E.; Frank, M.; Naumann, R.B.; Reyes, H.L.M.; Corbie, G.; Ammerman, A.S. JAMA Pediatr.

2023, 177, 294-302.

4. Austin, A.E.; Naumann, R.B.; Shanahan, M.E.; Frank, M. Child Abuse & Neglect, 2023, 145, doi:10.1016/j. chiabu.2023.106399.

5. Interview with Anna E. Austin, Ph.D. 9/20/2023.

6. U.S. Department of Agriculture Food and Nutrition Service. North Carolina: COVID-19 Waivers & Flexibilities. https://www.fns.usda.gov/disaster/pandemic/covid-19/ north-carolina (accessed Oct. 1, 2023).

7. U.S. Census Bureau. Household Pulse Survey: Measuring Social and Economic Impacts during the Coronavirus Pandemic. https://www.census.gov/programs-surveys/ household-pulse-survey.html (accessed Oct. 1, 2023).

8. Burns, K. and Creamer, J. U.S. Census Bureau: Supplemental Poverty Measure in 2022 Higher Than Pre-Pandemic Level. https://www.census.gov/library/ stories/2023/09/supplemental-poverty-measure. html#:~:text=The%20Supplemental%20Poverty%20 Measure%20(SPM,Census%20Bureau%20data%20 released%20today (accessed Oct 10, 2023).

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Deciphering Human Choices: The Power of Discounting Theory Exploring the Science of Everyday Decision-Making.

By Simran Bhatia Image courtesy of Wikimedia Commons uman behavior, despite the diversity of our backgrounds, cultures, and experiences, often follows patterns that can be surprisingly universal. At the core of understanding these patterns lies the Discounting Theory- a powerful framework that sheds light on the choices we make when faced with immediate and delayed outcomes. Individuals typically prefer immediate rewards over delayed rewards, even if the latter holds a higher objective value. This preference arises from our inclination to “discount the value of delayed rewards relative to more immediate ones,” a phenomenon at the heart of the Discounting Theory.1 This phenomenon, the discounting of a delayed outcome, is accurately modeled by a mathematical function that creates a hyperboloid plot—a visual representation illustrating the decrease in the subjective value of an outcome as delay increases (Figure 1). One key distinction in applying

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Figure 1. Subjective value of $100 delayed gain vs. time of delay in months. Figure courtesy of Dr. Sara Estle.

the hyperboloid function to model gains versus losses lies in amount effects. Amount effects occur when the objective value of a delayed outcome influences the rate of discounting. In existing literature, this effect has only been observed in delayed gains.2 The greater the objective value of a delayed reward, the less steeply it is discounted. With losses, however, the amount of loss has no impact on the discounting of the loss.2 While the Discounting Theory has far-reaching applications, prior research primarily focuses on relatively simple choices such as those “between smaller, immediate rewards and larger, delayed rewards.”3 Dr. Sara Estle, an assistant teaching professor of Psychology and Neuroscience at UNC-Chapel Hill, recognized the need to explore more complex decisionmaking. In our everyday lives, decisions often unfold in a complex interplay of positive and negative consequences, where an immediate loss can lead to a delayed gain or vice-versa. The ability of the Discounting Theory and the hyperboloid function to account for choices in these nuanced scenarios had yet to be empirically tested.

To test the ability of Discounting Theory to account for real-world Dr. Sara Estle choices, Dr. Estle focused her research efforts on combination outcomes. In a study involving 41 undergraduate students from Washington University in St. Louis, Dr. Estle and her colleagues conducted two experiments to determine whether the hyperboloid function model of Discounting Theory continues to hold true in more complex

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psychology and neuroscience decision-making situations.3 The experimental design was comprised of two phases. Phase 1 was a loss-only scenario where subjects made a series of choices between an immediate or delayed loss until the subjective value of the delayed loss was determined. For instance, if the participant chose to pay $40 now rather than $80 in the future, the subsequent scenario Figure 2. Example of the iterative process used in phases 2 and 3 to determine subjective would require a choice between value of a combination outcome. Each row is a pair of options and, the highlighted paying $60 now or $80 in the future. option is the “choice” made by the participant. The final row shows the subjective value The iterative process continued until of the combination-outcome scenario determined through the process. Figure courtesy the procedure converged “upon an of Dr. Sara Estle. amount of an immediate loss that is close to the subjective value of the delayed loss.”3 In other functions that describe behavior, that is really meaningful.”2 The words, the subjective value of the immediate loss would be results provide a framework for understanding concepts such equal to the subjective value of the delayed loss at the end of as “impulsivity and self-control and, the variables that impact the series of choices. In phase 2, participants completed a similar decisions that people are making.”2 This insight holds significant iterative procedure that incorporated combination-outcomes: value because, in the future, it can allow researchers to have a an immediate gain followed by a subsequent delayed loss. deeper understanding of how certain outcomes can be framed The choices within this iterative procedure “converged on a to promote favorable choices over less ideal ones (i.e., emphasize subjective value of the combination outcome”3 (Figure 2). In self-control rather than potentially destructive impulsivity).2 Experiment 1, the amount of the initial gain was greater than In the past, Discounting Theory has demonstrated its broad that of the delayed loss, resulting in a net gain whereas in applicability to human behavior in diverse circumstances.

Experiment 2, the combination outcome resulted in a net loss.

Expanding its reach opens up prospects for its utilization in Dr. Estle and her team found that the hyperboloid model behavioral therapy, treatment for substance use disorders, of Discounting Theory was still accurate in “describing behavior” enhancing parenting strategies, and optimizing healthcare within combination-outcome scenarios involving an immediate practices, to name a few. Currently however, additional research gain followed by a delayed loss.2 As demonstrated in Figure 3, is necessary to discern how these discoveries can be applied the hyperboloid function perfectly illustrates the decline in the effectively to enhance the attractiveness of a delayed reward for subjective value of a combination outcome for both net-loss individuals in the present. and net-gain, as delay increases. Furthermore, the research team observed an amount effect for outcomes involving delayed losses that were preceded by an immediate gain. The amount effect remained absent in loss-only scenarios (i.e., Phase 1), in alignment with the findings of previous studies.

Looking at the big picture, Dr. Estle envisions the possibility of extending these findings beyond the scope of monetary decision-making models. She further explains that “when we’re able to identify these mathematical models and

Figure 3. Hyperboloid fit for net gain and net loss combination-outcome scenarios. “Large,” “Medium,” and “Small” refer to the objective amount of the gain or loss.

Amount effects are clear in both scenarios—objectively larger gains/losses hold higher subjective value. Figure courtesy of Dr. Sara Estle.

References

1. Story, G.; Vlaev, I.; Seymour, B.; Darzi, A.; Dolan, R. Front. Behav. Neurosci. 2014, 8.

2. Estle, S. Interview with Dr. Estle, 2023.

3. Estle, S.; Green, L.; Myerson, J.; Yeh, Y.-H. 119 (1), 36–48. https://doi.org/10.1002/jeab.813.

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The Power of Sleep: Synaptic Magic and Memory

By Samantha Breen

Image courtesy of Wikimedia Commons

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he age-old question of why we sleep has puzzled scientists for generations. Rest is not only for sleep – it’s essentially the key to unlocking memory potential. Dr. Graham Diering has investigated the importance of sleep as a “reset” for memory consolidation and brain health. His recent research has shed light on the relationship between sleep, synaptic plasticity, and their impact on overall well-being and memory.

Dr. Graham Diering is the principal investigator of the Diering Lab, a neuroscience research lab in the University of North Carolina at Chapel Hill Department of Cell Biology and Physiology. The Diering Lab approaches neuroscience through a multidisciplinary approach to understand the connection between sleep, cognitive function, neurodevelopmental disorders, and neurodegenerative disorders.

Sleep allows the brain to reset and restore itself to a healthy state, counterbalancing the effects of wakefulness and simultaneously preserving our memories. Dr. Diering explains the dual function of sleep,

stating that “during our waking hours, we accumulate a vast amount of information.

Sleep helps maintain a balance between memory preservation and synaptic homeostasis.”1 Sleep also affects retrieval, which is the reason why older, more impactful events are remembered with greater clarity than recent events. Diering elaborates on synaptic plasticity and how our synapses perform a kind of “sorting process” while sleeping. This process involves functional proteins including Arc and Homer.1 These functional proteins actively contribute to the brain’s synaptic plasticity during sleep, helping to consolidate and optimize memory storage. The brain subconsciously “sorts” through its connections, prioritizing the “relevant” ones and disregarding those that are deemed“less important.”. Synapses tied to emotion and neuromodulators like dopamine and noradrenaline are preferentially consolidated during sleep, with trivial synapses being discarded. If the brain becomes cluttered with routine experiences – like where one parked their car or what one wore yesterday – the

brain’s capacity for learning or memory will quickly become depleted. This selective weakening frees up space for new learning.

Dr. Diering’s explanation of sleep underscores that it is not only integral to preserving memory, but is also uniquely tailored to different brain regions. He points out that sleep isn’t a “one-sizefits-all” for the brain; instead, it varies across different regions based on levels of

“Sleep isn't a "onesize-fits-all" for the brain”

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Dr. Graham Diering

psychology and neuroscience medications that enhance functions of sleep. Understanding the underpinnings of sleep’s benefits could pave the way for the development of more targeted medicines.

Dr. Diering and his team have made significant strides in the understanding of sleep and synaptic plasticity, the mechanisms behind the sleeping brain and have paved the way for more effective treatments that preserve cognitive health and well-being.

Figure 1. Synaptic plasticity during sleep. Figure courtesy of istock by K_E_N. activity. For example, while studying for an exam, that particular part of the brain will become more exhausted than, say, the region involved in a football game.

“So, there’s that idea that your entire brain is benefiting from sleep, but individual brain regions benefit proportionally more from sleep based on their usage during a wake,”1 says Dr. Diering. He adds that localized sleep most likely has a cellular basis, with individual neurons accumulating their own sleep need based on experience.

It is clear that sleep is a highly complex and individualized process.

Dr. Diering’s insights also take into account the broader implications, particularly in neurodegenerative diseases. The most recent article from Dr. Diering and his team of researchers is about sleep disruption in Alzheimer’s Disease. Sleep disruption and deprivation are common in Alzheimer’s patients but they have been identified as risk factors for developing Alzheimer’s or dementia. They used a mouse model of Alzheimer’s Disease with an overexpression of a human diseaselinked tau protein, a major pathology in Alzheimer’s Disease. The study uncovered that sleep disruption is an early and significant factor in the disease’s progression, occurring before other signs of pathology. Experimentally induced sleep disruption accelerated cognitive decline, with sex-specific differences: female mice exhibited earlier sleep disruption but greater resilience, while males were highly sensitive to it. Sleep

disruption in Alzheimer’s is not only a risk factor, but drives the disease and affects key mechanisms of neurodegeneration.

It accelerates amyloid plaque formation, or the aggregation of abnormal protein fragments in the brain, spreads pathogenic tau protein, and triggers neuroinflammation. The observed sleep disruption phenotype in Alzheimer’s patients is a robust predictor of cognitive decline, emphasizing the need to slow the disease’s progression by enhancing sleep quality. This research underscores the critical role of sleep in the context of Alzheimer’s, and opens avenues for novel treatments and further investigations into the broader implications of sleep disturbances on neurodegenerative diseases.2 There are many different ways to improve quality of sleep. Sleep medications such as Melatonin, and sedatives like Ambien are used by many people. “While these drugs can induce sleep, there is limited evidence of their ability to provide the functional benefits of natural, healthy sleep,”1 Diering says.

“We have medicines right now that target sleep behavior but not sleep function.”

Dr. Diering adds that melatonin, the most common sleep-inducing drug, is essentially a placebo. It has been proven ineffective in every trial, and is sold as a supplement without FDA approval or regulation. Ambien is a strong sedative, but there is little evidence suggesting it leads to better quality sleep. Data proves that prolonged use can increase the risk of dementia, highlighting a need for

“Understanding the underpinnings of sleep's benefits could pave the way for the development of more targeted medicines.”

“It is clear that sleep is a highly complex and individualized process.” """

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References

1. Interview with Graham Diering, Ph.D. 9/19/23 2. Graham H. Diering. (2023).

Remembering and forgetting in sleep: Selective synaptic plasticity during sleep driven by scaling factors Homer1a and Arc. Neurobiology of Stress.

psychology and neuroscience

WIRED FOR STRESS:

A NEUROLOGICAL PERSPECTIVE

By Zehra Gundogdu

Image courtesy of Wikimedia Commons

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reparing for exams, waiting for application decisions, and performing poorly in classes are all stressful experiences that most university students can relate to. Stress is an unavoidable aspect of human life, and although some may find it motivating, it is detested by many. Common stressful experiences that may seem like simple aspects of daily life may lead to detrimental effects on one’s well-being. The brain is one of the most complex organs in the human body; humans only understand approximately 10 percent of the functions of the human brain.1 The way that your brain reacts to stressful situations can be correlated to neurological disorders.

Neurological disorders occur when there are irregularities in the brain functions; they can be as simple as a headache or as complex as schizophrenia. Depending on the way an individual’s brain reacts, stress can be a risk factor of trait anxiety.2 Trait anxiety describes the tendency to constantly experience negative emotions.3 Scientists have been striving to reveal connections between specific neurological stressors and disorders. One of the many brilliant scientists who pursue this research is Dr. Aysenil Belger, professor of Psychiatry at the University of North Carolina at Chapel Hill. She studies neural mechanisms of stress and anxiety disorders and aims to delve deep into neurological disorders.

About the Researcher

Dr. Belger has been a professor at the University of North Carolina at Chapel Hill since December of 1999 and has published many pieces of remarkable work on different neurological disorders including schizophrenia and autism.

Dr. Belger received a PhD in physiological psychology and psychobiology at the University of Illinois Urbana-Champaign.

After receiving a PhD in physiological psychology, she worked as a post-doctorate student and an associate professor at Yale

University before starting her professional career. Dr. Belger traveled to the United States from Turkey because she believed that there were more opportunities for the type of psychological research that she wanted to pursue here in the states. Dr. Belger states she is interested in the “why” behind concepts in psychology rather than just the theoretical aspect Dr. Asyenil Belger of it.3 Her past and current research topics correlate with her passion for understanding the reasoning behind and connections between neurological disorders perfectly.

Stress Studies

Dr. Belger works alongside many other successful scientists to conduct her research. In one of her more recent stress related studies, she partnered with Dr. Alana Campbell, associate professor of Psychiatry at the University of North Carolina at Chapel Hill. In this study, they gathered salivary cortisol data from 147 adolescents in North Carolina to assess stress as a risk factor in anxiety development. Cortisol is commonly known as the stress hormone due to its abundance in the bloodstream during stressful experiences. Additionally, background information about the participants such as their ethnicity and other diagnoses recorded to control the experiment. Controlling the experiment is important to isolate stress as the variable leading to anxiety.

The participants cortisol levels were recorded during a resting state and a stressful experience, a total of 5 times during the

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Figure 1. FAA activation and recovery/reactivity slopes after stress. Figure courtesy of Glier et al. study. During the resting state, participants were instructed to rest with their eyes closed for three minutes and then with their eyes open for another three minutes. An electroencephalogram (EEG), a tool that measures brain activity, recording was taken at both resting states. To induce stress on the participants, the common Trier Social Stress Test for Children (TSST) method was used4. The participants were required to read a passage in front of behavioral specialists. This form of public speaking is intended to intentionally produce stress in the individuals. Additionally, the researchers collected data using frontal alpha asymmetry (FAA)—a method used to understand emotional processing in the brain—due to its reliability in adolescent brains.

The cortisol levels in participants pre-stress were found to be lower than post-stress, which was an expected outcome.

The results were mainly focused on the significant role of FAA activation. Those with high state anxiety after the TSST tests had a longer cortisol recovery slope. Those with higher trait anxiety had a less sharp cortisol reactivity slope. These results show that there is a significant correlation between state anxiety and cortisol recovery and trait anxiety and cortisol reactivity. In simpler terms, the way the brain reacts to stress can provide an understanding of its vulnerability to anxiety disorders.4

that are not engaged or are engaged in different profiles to find an association with poor outcomes in terms of substance use. Her current stress study revealed an interesting correlation between stress levels and development of state and trait anxiety, disclosing the real detrimental effects of a stressful lifestyle. The twist to her future research will be that she plans to focus on substance use in adolescence and its correlation with stress response.

What the Future Holds

Dr. Belger continues to study stress and anxiety disorders in adolescents with her current research project where she focuses on decision making brain circuits through neuroimaging.3 To obtain these neuroimaging’s she will work alongside Dr. Jessica Cohen, an active researcher in the Psychology department at the University of North Carolina at Chapel Hill. Neuroimaging allows researchers to gain a more intricate understanding of how different regions of the brain synchronize to support behavioral and cognitive functions. will examine neural circuits

Figure 2. Research conduction method for the study discussed. Figure courtesy of Glier et al.

References

1. Gidron, Y. Trait Anxiety. https://link.springer. com/referenceworkentry/10.1007/978-1-4419-10059_1539#:~:text=Definition,of%20neuroticism%20versus%20 emotional%20stability 2. Glier, S.; Campbell, A.; Corr, R.; Pelletier-Baldelli, A.; Belger, A. Individual Differences in Frontal Alpha Asymmetry Moderate the Relationship between Acute Stress Responsivity and State and Trait Anxiety in Adolescents.

Biological Psychology 2022, 172, 108357. DOI:10.1016/j. biopsycho.2022.108357.

3. Interview with Aysenil Belger, Ph.D. 9/29/2023 4. Boyd, R. Do People Only Use 10 Percent of Their Brains? https://www.scientificamerican.com/article/do-people-onlyuse-10-percent-of-their-brains/#:~:text=Ultimately%2C%20 it’s%20not%20that%20we,for%20Scientific%20 American’s%20free%20newsletters (accessed 2023-10-24).

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Restoring Cognitive Ability From The Insult of Intermittent Adolescent Binge Drinking

By Aldrin Mosqueda Illustrated by Emily Ormond

W

ithin the social circles of university students, it is not uncommon to find individuals who partake in regular partying and alcohol consumption. Friends of these individuals tend to watch over these intense partiers to make sure they are being responsible. However, while they may protect them from falling on the ground or dancing with random strangers, they are not equipped to save them from the lasting neurological damage that adolescent alcohol use exposes them to. Dr. Ryan Vetreno, along with pioneering alcohol use research scientist Dr. Fulton Crews, who leads the 10-component consortium Neurobiology of Adolescent Drinking in Adulthood (NADIA), has taken significant steps towards providing the scientific community with innovative approaches to tackle these neurological challenges caused by adolescent alcohol abuse.

Dr. Vetreno is an assistant professor at the Bowles Center of Alcohol Studies in the University of North Carolina at Chapel Hill’s School of Medicine, specifically in the Department of Psychiatry and Department of Pharmacology. Dr. Vetreno received his Ph.D. in Neuroscience at Binghamton University and spent his post-doctoral training with Dr. Crews at the UNC Chapel Hill School of Medicine where he utilizes rat models for his alcohol studies.

Dr. Vetreno models college-like binge drinking behavior by using an adolescent intermittent ethanol exposure (AIE) model in rats. The model allows him to observe neuroinflammation and how cholinergic cells are being affected by it. Cholinergic cells are neurons in the brain that use the acetylcholine neurotransmitter (carries excitatory messages) to communicate with and modulate other neurons and neurocircuitry. The cholinergic cells of the basal forebrain, which are integral to cognitive functioning,2 project to the hippocampus and frontal cortex, which are involved in various memory functions including long-

term memory and spatial memory.4 In the AIE model, rats are given a binge dose of alcohol,7 for 2-days-on then 2-days-off cycle from postnatal day 25 to postnatal day 54, encompassing the rats’ adolescent stage of development.8 This model mimics a binge drinking model of 4-5 drinks in a single sitting in human adolescents.

Neuroinflammation is exactly how it sounds: inflammation in the brain. In relation to neuroinflammation, a Dr. Ryan Vetreno reduction of cholinergic cells (along with other neuronal cell populations) in the basal forebrain could result in long-term changes in arousal, sleep patterns, cognition, and other brain functions observed in an alcohol use disorder.1 In Dr. Vetreno’s studies, rats were subjected to exercise following the conclusion of AIE due to its beneficial effects in all aspects of overall health and wellness. Exercise has been shown to have anti-inflammatory effects in the brain. Dr. Vetreno tested this on a reversal study (a study to reverse the inflammatory effects to the brain) following the same AIE paradigm. To elaborate, after AIE exposure, he subjects the rat subjects to voluntary exercise by installing a running wheel in the rats home cage. He hypothesized that exercise would reverse the reduction of cholinergic cells in the basal forebrain and the restoration of the cholinergic phenotype. This can result

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Figure 1. Diagram of cholinergic loss due to Adolescent Intermittent Ethanol and restoration of it through exercise. Figure courtesy of Vetreno et al. in the restoration of the cognitive deficits caused by the insult of alcohol. As he hypothesized, Dr. Vetreno found that there were now more cholinergic cells in the basal forebrain. However, he was unsure where these cells came from. The popular belief was that when there were no signs of activity, the cells were gone for good. Looking at the possibility that these were new cells being generated by neurogenesis, he stained the brain to show where newborn cholinergic cells were happening. However, he found that neurogenesis was not the cause of the cholinergic cell recovery he observed. Dr. Vetreno continued to investigate from the origin of these cells until he realized that they may have always been there. This proved to be case when he considered epigenetic factors.

Unlike the genome, the epigenome is more directly influenced by what is happening to the environment, which then influences which genes are going to be expressed. Think of the genome as the blueprint and the epigenome as engineers on what certain things will be made out of that blueprint. Working with Dr. Subhash Pandey, Director of the Center for Alcohol Research in Epigenetics at the University of Illinois at Chicago and pioneer of epigenetic work, Dr. Vetreno used chromatin immunoprecipitation (CHIP) analysis and found that TrkA and ChAT, both of which are cholinergic gene markers (or the blueprint), were both methylated or transcription suppressed.

CHIP analyses is a method of marking proteins in the epigenome.

In this case, they showed where the suppressing markers were methylating or silencing the initial steps on the blueprint, that is active transcription of cholinergic genes. This discovery meant that cholinergic cells do not die from the insult of adolescent binge drinking, but instead become silenced. This causes the cells to be in a stem-cell like state where they are waiting to be told to reactivate the silenced genes that make up a cholinergic neuron. This goes against the dogma that if markers of neurons are not there, then the neuron is gone. Dr. Vetreno now tested if these cells could get “reactivated.”

During the study, Dr. Vetreno observed that particular anti-inflammatory influences on the brain like exercise essentially remove the blocking compounds from the promoters and reactivate them as cholinergic neurons. Not only

that, he observed this behavior in other neuron populations as well. This study was replicated with anti-inflammatory drugs like indomethacin and galantamine and found that they provide the same removal of blocking compounds in the same promoters.

These preclinical studies show promising results that impaired cognitive function caused

by AIE could possibly be treated with novel drugs and consistent exercise. Furthermore, it shows great promise in treating cognitive deficits in patients with chronic alcohol use disorder (AUD). Dr. Vetreno and his team have made great progress and contributions to the scientific community, and he plans to continue studies on anti-inflammatory treatments.

Furthermore, he will investigate whether the restoration of cholinergic deficits will continue to occur if delayed treatment was given instead of immediately after AIE.

References

1. Vetreno, R. P.; Broadwater, M.; Liu, W.; Spear, L. P.; Crews, F. T. Adolescent, but Not Adult, Binge Ethanol Exposure Leads to Persistent Global Reductions of Choline Acetyltransferase Expressing Neurons in Brain. PLoS One 2014, 9 (11), e113421. https://doi.org/10.1371/journal. pone.0113421.

2. Psychology, P. Basal Forebrain (Location + Function).

Practical Psychology. https://practicalpie.com/basalforebrain/ (accessed 2023-10-23).

3. Crews, F. T.; Vetreno, R. P. Cholinergic REST-G9a Gene Repression through HMGB1-TLR4 Neuroimmune Signaling Regulates Basal Forebrain Cholinergic Neuron Phenotype.

Frontiers in Molecular Neuroscience 2022, 15.

4. Hippocampus: What Is It, Location, Function, and More | Osmosis. https://www.osmosis.org/answers/hippocampus (accessed 2023-10-23).

5. Interview with Ryan P. Vetreno, Ph.D. 10/05/23 6. Crews, F. T.; Fisher, R. P.; Qin, L.; Vetreno, R. P. HMGB1 Neuroimmune Signaling and REST-G9a Gene Repression Contribute to Ethanol-Induced Reversible Suppression of the Cholinergic Neuron Phenotype. Mol Psychiatry 2023, 1–14. https://doi.org/10.1038/s41380-023-02160-6.

7. Patrick, M. E.; Terry-McElrath, Y. M. Prevalence of High-Intensity Drinking from Adolescence through Young Adulthood: National Data from 2016-2017.

Subst Abuse 2019, 13, 1178221818822976. https://doi. org/10.1177/1178221818822976.

8. Vetreno, R. P.; Bohnsack, J. P.; Kusumo, H.; Liu, W.; Pandey, S. C.; Crews, F. T. Neuroimmune and Epigenetic Involvement in Adolescent Binge Ethanol-Induced Loss of Basal Forebrain Cholinergic Neurons: Restoration with Voluntary Exercise. Addiction Biology 2020, 25 (2), e12731. https://doi.org/10.1111/adb.12731.

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From Psychedelics to Antidotes: Developments In Treatments for Depression

By Nik Li

Image courtesy of FLY:D via Unsplash

The 1970s and Beyond:

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fter hearing the term“psychedelics,” nearly everyone’s mind leaps to the 1970s, an era characterized by psychedelic drugs, hippies, and a variety of emerging movements. Psychedelics have since then been reduced to drug use and the disruption of neurochemistry, cultivating a rather negative connotation in the eyes of the public. However, what the 70s lacked was extensive research that currently suggests that psychedelics could be applied to broader things– particularly treating mental illnesses.

As the medical community advances in the 21st century, exploration into the molecular structure of psychedelic drugs may potentially lead to new methods of treatment for depression and various mood disorders.

Why Psychedelics?

We must start with the most evident question: why apply psychedelics

Dr. Jeff DiBerto

as a treatment? A quick view at census data reveals that overall health and mental well-being in the U.S. is declining.1As rates of depression climb throughout the nation, many existing medications are no longer effective due to an increase in resistance to the drug in the population, leaving many individuals ill and optionless. It wasn’t until recently that scientists, along with the FDA, redesigned psilocybin2 as “Breakthrough Therapy” for severe depression, forging a path for psychedelics to be studied as an alternative treatment.

In a collective effort to study psychedelics as treatment, a team of researchers at UNC reviewed psychedelic drugs in detail, studying their molecular structure and how they function in the brain. One of these researchers is Dr. DiBerto, a coauthor of “Molecular Insights Into Psychedelic Drug Action” and recent Ph.D. graduate at UNC’s School of Pharmacology, he is passionate about hallucinogens and how they work in neurochemistry. Through a personal interview with DiBerto,3 it was revealed that his long-standing interest in psychedelics originates from his middle school obsession with 70s music; rock bands and musicians in the decade would oftentimes indulge in psychedelic drugs to enhance their craft. Furthermore, his intrigue about the drug’s neurological aspects comes from his observations of “how similar hallucinations and schizophrenia are,” propelling him to dive deeper into how psychedelics react to certain receptors in the brain.

DiBerto states that although

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Figure 1. A picture of the chemical structure of serotonin: a compound responsible for regulating mood. Figure courtesy of Wikimedia Commons. psychedelics being used as a medical treatment has not yet been well funded or studied, he and his supervisors have been an integral part in “bringing psychedelic drug research up to speed in the modern health community.”3 Specifically, DiBerto and his team review concepts of molecular localization, signaling and coupling, as well as its relation to receptors in neurochemistry.

What Is Known

Although there remains a lack of funds and research surrounding the topic, there are a few concepts that scientists are certain of, including 5-HT2ARS receptors, regulation, and multiple pathways. 5-HT2ARS receptors, or serotonin receptors, mediate excitatory transmissions, making them relevant in the study of psychedelics, as psychedelics and antidepressants typically target these receptors to generate their effects.

Through an analytical sequence, Dr. Bryan

psychology and neuroscience be a fascinating new alternative to their existing treatments. Additionally, UNC is always on the cutting edge of medical technology and breakthroughs, making DiBerto’s research very relevant. The team of researchers have been immensely successful in summarizing and bringing structural insights to psychedelic drugs up to speed, but there is still a significant amount to explore. Which psychedelics are most effective in treating depression and how to construct the perfect molecule for disorder treatments are two examples of what remains untouched.

Hopefully one day Dr. DiBerto’s research will lead to a more thoroughly developed and deep understanding of the role that psychedelic drugs play in our brain.

Figure 2. A diagram of neurons, containing membranes and the 5-HT2AR receptors.

Figure courtesy of Vargas et al.

Roth and colleagues have discovered that a single amino acid difference in 5-HT2AR antagonists4/agonists5 has notable impacts on the efficacy of psychedelic agonists.

Localization

The specificity of pathways goes hand in hand with the concept of localization—the idea of getting receptors to where they need to be to react with certain proteins. 5-HT receptors are rich in synaptic membranes (Laduron 1983)— think tiny microcellular compartments. If the receptors aren’t in the right location, then connections don’t traffic. In DiBerto’s own words, the “position is critical” for the effects of a drug to function properly.

Conflicting Perspectives

Although there have been promising advancements in the medicinal community, there exist countering sides and arguments of ethicality. Some individuals are against this unconventional approach to healthcare—the utilization of drugs to

treat conditions. However, people must keep in mind that scientists are branching out because existing antidepressants have already built immunity and resistance to treating depression.

Researchers already have insight to the structure and antidepressant properties of psychedelics; thus, new studies must be conducted. However, the influence of psychedelics does vary among different individuals as diverse genes and DNA may react differently. Therefore, scientists are still moving forward the research slowly, taking on one study at a time.

Importance to UNC Community

Needless to say, research into psychedelics and their neurochemistry is significant in the development of mental disorder treatments, but also particularly important to the UNC community. In a high-stress environment such as a university, the mental wellbeing of students and staff should be prioritized.

For those currently battling mental health conditions with ineffective medications, psychedelic research could

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References

1. The state of Mental Health in America. Mental Health America. (n.d.). https://mhanational.org/issues/ state-mental-health-america 2. Jeffery DiBerto | Department of Pharmacology 3. https://www.med.unc.edu/pharm/ congratulations-to-our-new-phdjeffrey-diberto/ 4. Interview with Jeffery DiBerto, Ph.D. 9/18/23 5.Zhang, Stackman, “The Role of Serotonin 5-HT2A Receptors in Memory and Cognition.” Frontiers, 22 Sept. 2015, 6. www.frontiersin.org/articles/10.3389/ fphar.2015.00225/full. Accessed 2 Oct. 2023.

7. Slocum, DiBerto, Roth, “Molecular Insights Into Psychedelic Drug Action.” JNC Wiley, 11 Nov. 2021, https://onlinelibrary.wiley.com/doi/ epdf/10.1111/jnc.15540?src=getftr

psychology and neuroscience

Rats, Lobsters, and MRIs: A Non-Invasive Way to Study the Brain in Animals

By Tara Penman

Image courtesy of Flickr

T

he magnetic resonance imaging technique (MRI), is a magnetic field, some protons change how their spin are aligned, medical test common in hospitals. MRIs can see up-close, to fit the direction of the strong magnetic field. Afterwards, the detailed parts of the body in order to take pictures. Whereas MRI coil stops releasing radio waves. Subsequently, the spin MRIs are commonplace in human imaging, Dr. Yen-Yu Ian Shih, gradually moves back to the main direction of the magnetic field, Director, Center for Animal MRI (CAMRI), uses the technique for while releasing energy. MRI technology is able to register the a different purpose – neuroimaging research. He released energy and visualize it. Different parts doesn’t conduct his brain scans on live humans, of the brain carry different spin properties and but he has explored many other species. When release energy at different rates. By designing asked about the weirder things he’s scanned, Dr. specialized strategies to acquire better images, Shih replied, “We have scanned lobsters, turtle these areas can “light up” differently on the MRI.2 1 eggs, a few birds, shark brains, and some plants.”

While many labs focus on studying one All life, including human bodies, are made very specific disease or mechanism for years on of matter. An understanding of how matter in end, CAMRI is more of a consultant firm, facilitates the body behaves is essential to understanding other labs in their research by providing their technology. Matter is constructed by building MRI services. In 2023 alone, CAMRI was involved blocks, called atoms. The building blocks, atoms, in nine different publications. CAMRI has served are made of smaller parts, called subatomic over 100 labs in the research triangle area. Most particles. When an atom has different amounts of these services were performed on a 9.4 Tesla of subatomic particles, the atom can be made MRI scanner originally installed in 2005, funded more positively-charged, negatively-charged, by the National Institute of Health (NIH). The or neutral. A proton is a positively-charged scanner is equipped to look at small to mediumDr. Yen-Yu Ian Shih subatomic particle, and is most commonly used sized animals, but that has also included subjects in the MRI technique. Some subatomic particles can move such as human reproductive cells and much more. One of Dr. around, or “spin.” Protons can spin in one of two directions. Shih’s previous collaborations dealt with understanding the Protons spin in all animals and humans at any given time. When effect of alternate circulation in strokes caused by lack of blood a proton spins, a magnetic field is generated, which can attract supply to the brain, by studying rats with an altered brain flow.1,6 and repel different charges. MRIs use powerful coils to release, or Another collaboration this year delved into understanding emit radio waves. When the protons are introduced to a strong how alcohol abuse occurs by comparing the differences in

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Figure 1. Proton Alignment in an MRI scanner. Image courtesy of Kathryn Broadhouse. abuse between adult and adolescent rats.1,4 CAMRI has also incorporated various types of brain stimulation and recording techniques into MRI studies, with a goal to better understanding brain circuit and network functions. Understanding what areas “light up” in the brain between the different groups of experimental animal subjects can help provide insight into brain function and diseases.

Dr. Shih hopes to highlight how animal models can guide future treatments for human diseases, conditions, and how the brain works; therefore, ideas established in the lab can translate to actual patients in hospitals. As Dr. Shih said regarding what CAMRI chooses to research: “At this point, we are not confining ourselves to study specific conditions or disorders.”1 His primary focus is in using animal models to understand how the brain works, and improving non-invasive brain research methods. While other approaches for studying the brain involve implanting a device called an electrode to read brain waves,3 an MRI can study almost any living subjects or plant without harm from surgery, by reading the energy released from protons or other subatomic particles seen on the MRI.1,2 Many invasive techniques require sacrificing the animal subjects following the measurement, which lead to a substantial number of subjects needed to produce significant findings. Dr. Shih hopes that partnering with CAMRI will allow more labs to utilize preclinical MRI platforms. This would allow for a smaller amount of subjects

Figure 2. CAMRI teammates pose with their MRI – a BioSpec 94/30US semiconductor MRI. Image courtesy of CAMRI.

to be used and tracked over time, minimizing both challenges logistically and potential harm to experimental animals.1 Although there are many benefits to this neuroimaging technology, Dr. Shih is currently working to address some of its limitations as well. MRIs are very loud; they can be up to 125 decibels (as loud as a rock concert)! When trying to understand the specific effects of a disease or disorder in rodents, it may be difficult to differentiate what signals are the target of the study, and what is the effect of the loud noise or stress. Dr. Shih is working on technology that will minimize the loud acoustic noise made by turning on and off the imaging hardware, thereby reducing the amount of noise that an animal is exposed to in the MRI.1 This past spring, the building where CAMRI is housed, Marsico Hall, flooded unexpectedly in the middle of the night.1 Water from an upper floor seeped down into the basement, damaging the MRI machine and several lab spaces. Dr. Shih didn’t dwell on what happened or why the flooding occurred.

Rather, he focused on how researchers can move forward from setbacks. This past summer, CAMRI installed another 9.4 Tesla scanner to enhance their service quality and capacity. Both of their MRI scanners are up and running, now credited in more publications and improving their scanning technique. All in the name of discovery: one animal brain at a time.

References

1. Interview with Yen-Yu Ian Shih, Ph.D. 9/29/23 2. Broadhouse, K.M. The Physics of MRI and How We Use It to Reveal the Mysteries of the Mind. Front. Young Minds.

2019, 7.

3. Pilitsis, J.G.; Khazen, O.; Patel, S. Deep Brain Simulation – Advantages, Risks, and Conditions Treated. [accessed September 24 2023]. https://www.aans.org/en/Patients/ Neurosurgical-Conditions-and-Treatments/Deep-BrainStimulation#:~:text=Deep%20brain%20stimulation%20 (DBS)%20is.

4. Lee, S.; Shnitko, T.A.; Hsu, L.; Broadwater, M.A.; Sardinas, M.; Tzu-Wen, W.W.; Robinson, D.L.; Vetreno, R.P.; Crews, F.T.; Yen-Yu, I.S. Acute Alcohol Induces Greater DoseDependent Increase in the Lateral Cortical Network Functional Connectivity in Adult than Adolescent Rats.

Addiction Neuroscience. 2023, 7.

5. National Institute of Biomedical imaging and bioengineering. “Magnetic Resonance Imaging (MRI).” National Institute of Biomedical Imaging and Bioengineering, National Institute of Biomedical Imaging and Bioengineering, 17 July 2018, www.nibib.nih.gov/scienceeducation/science-topics/magnetic-resonance-imaging-mri.

6. Kao, Y.C.J.; Oyarzabal, E.A.; Zhang, H.; Faber, J.E.; Shih, Y.Y.I. Role of Genetic Variation in Collateral Circulation in the Evolution of Acute Stroke: A Multimodal Magnetic Resonance Imaging Study. Stroke. 2017, 48, 754-761.

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The Obesity Epidemic: Is the Brain to Blame?

By Julia Sallean

Figure 1. Confocal image of Sagittal brain slice in the midline region of the thalamus. Neurons are expressing the eYEP gene (in green), which allows for visualization of the targeted neurons that were investigated for their role in feeding. Image courtesy of Dr. Daniel Christoffel.

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merica has a crisis on its hands.

According to the American Obesity Association, 50% of Americans are expected to be obese by 2025.1 That number is projected to climb another ten percent by 2030.2 Classified as a global epidemic for over twenty-five years, obesity claims millions of lives and billions of dollars annually. Overeating is a direct cause of obesity, but the underlying cause of overeating still remains somewhat of a mystery within the body. However, promising new research suggests that at least part of the blame might lie in an unexpected place: our brains.

According to Dr. Daniel Christoffel of the University of North Carolina at Chapel Hill’s Behavioral and Integrative Neuroscience Program, one root cause of overeating pertains to reward processing in the brain, or the brain’s response to rewarding stimuli. Inspired by his research surrounding addiction reward processing from his post-doctoral training at Stanford, Dr. Christoffel explores obesity under the same principles.3 In his research, he aims to see if the brain responds to food in the same way it responds to drugs, and if there is potential for adaptations over time.

“We live in a country where more and more people are overeating,” says Dr. Christoffel. “We are surrounded by these

very palatable foods.”3 According to his research, highly palatable, calorically dense foods like chips or cake cause a unique response in the brain. We learn to crave these types of foods and the more we eat them, the harder it is to say no the next time. It makes sense, after all—when we daydream about food, it’s rarely about salads. But neurologically, what part of the brain is wrestling control away?

Dr. Daniel Christoffel Dr. Christoffel and his team have narrowed the answer to this question down to a specific pathway between the

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thalamus and the nucleus accumbens, a region of the brain associated with reward processing. By using mouse models to monitor neurological activity in their experiments, they found that weakening this synaptic connection caused mice to eat less palatable food. The reverse, they discovered, was also true. “Then the question became what’s going on specifically in major cell types,” remarked Dr. Christoffel.3 The focus shifted towards how the signal is processed in major cell types in the brain area, which are defined by the type of dopamine receptor they express. New research on this topic is focused on how dopamine and other neuromodulators affect the signal sent into the nucleus accumbens, and what specifically happens in the neuron receiving the signal.

“We live in a country where more and more people are overeating” Scientists can control neural activity through receptors called DREADDS, which allow for easier, more convenient

psychology and neuroscience

Figure 2. Confocal image of nucleus accumbens region using in situ hybridization. Image is taken in order to probe for genes of interest in relation to hunger. Image courtesy of Dr. Daniel Christoffel. study of neural pathways when a mouse eats highly palatable foods. By modifying neuron activity, this research could not only establish a definitive process behind the reward processing mechanism in the brain, but could also provide information for potentially inhibiting it.4 Future research surrounding this topic could become invaluable in suppressing overconsumption not just in mice, but in humans. If we can modify neural activity to discover more about this thalamus and nucleus accumbens pathway, we can potentially use this information to create novel surgeries or medications that inhibit reward processing and the desire to overeat.

Dr. Christoffel’s research could provide valuable information to combat obesity in other ways as well. His research found that chronic exposure to highly palatable foods makes it harder to refuse each time an individual is exposed to them.3 So while one caloric meal alone is not enough to get the brain hooked on candy bars and cheeseburgers, a few dozen meals might do the trick. Think of the brain like an elastic band: stretchable and easy to adapt. One experience of a highly palatable food is treated as an acute challenge that the brain disregards—a deviation from normal. However, just like when you stretch out a rubber band too many times, the brain loses its ability to bounce back once highly palatable

food becomes the new normal. It loses its elasticity, and now responds with lasting change. As Dr. Christoffel states, “For someone that has a loss of control over eating, their capacity to not choose the preferable, calorically dense food is diminished.”3 Ultimately, the blame lies somewhere between our decisions and how our brains react to them. In a world bombarded with calorically dense foods, it can feel impossible to choose a meal that isn’t flawed. Research like Dr. Christoffel’s shouldn’t scare people into choosing the salad every time, but instead inform them on what exactly is happening inside the brain when they do choose a cheeseburger instead. It could expand the current understanding of obesity and the reward processing behind overeating, while potentially inspiring medicine that could fight against it. So, in the end, the brain isn’t the enemy. In fact, it could be the key to unlocking some of the mysteries behind obesity, bringing people one step closer to a world that is healthier for us all.

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References

1. Michael Bergen; Cision: New Study Predicts 50% of Americans with Obesity. https://www.prnewswire.com/ news-releases/new-study-predicts-50of-americans-with-obesity-301206163. html 2. World Health Organization: Obesity. https://www.who.int/news-room/factsin-pictures/detail/6-facts-on-obesity (accessed Oct 1st, 2023) 3. Interview with Daniel J Christoffel Ph.D. 9/10/23 4. Christoffel DJ, Walsh JJ, Heifets BD, Hoerbelt P, Neuner S, Sun G, Ravikumar V K, Wu H, Halpern CH & Malenka RC. Nat Cummun 2021 Apr; 12 2135. https:// www.nature.com/articles/s41467-02122430-7

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“Equipped with his five senses, man explores the universe around him and calls the adventure Science.”

- Edwin Powell Hubble

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scıentific

Fall 2023 | Volume 18 | Issue 1

This publication was funded at least in part by Student Fees which were appropriated and dispersed by the Student Government at UNC-Chapel Hill as well as the Carolina Parents Council.