Insights & Outcomes: Transplant access, atmospheric rivers, and mind states
This month, Insights & Outcomes searches for evidence of atmospheric rivers thousands of years ago, explores the inner workings of a pair of important proteins, takes a hard look at access to liver transplants, and tracks neural patterns relating to spontaneous behavior in real time.
Following the mutations of a Parkinson’s protein
Mutations in the gene LRRK2 are the most common cause of familial Parkinson’s disease, which generally afflicts people later in life with shaking, stiffness, and uncontrollable muscle movements. LRRK2, a signaling enzyme within brain cells, is thought to affect the functions of lysosomes, organelles that digest and recycle degraded materials no longer needed by cells (a function that has earned them a reputation as the cell’s garbage collection processing system), and provide nutrients to brain cells.
But how mutations to these genes lead to disease pathology is not well understood. New research from the lab of Yale’s Pietro De Camilli, the John Klingenstein Professor of Neuroscience and Professor of Cell Biology, suggests that mutations may affect the protein’s ability to regulate the remodeling of cellular membranes, thereby disrupting its ability to regulate traffic to and from the lysosome.
This disruption may lead directly or indirectly to the death of dopamine-secreting neurons, which is a hallmark of Parkinson’s, said De Camilli, who is also a Howard Hughes Medical Institute investigator. The hypothesis, however, needs to be tested in living cells, he added.
The research was published in the journal Proceedings of the National Academy of Sciences. The first author of the study is Xinbo Wang, a postdoctoral associate at Yale School of Medicine.
Take me to the (atmospheric) river
So-called “atmospheric” rivers have brought record-breaking levels of rainfall and flooding in parts of the western United States in recent years. Researchers studying whether these trends will continue think they’ve found answers in the North Atlantic climate of 16,000 years ago.
Scientists say atmospheric rivers — concentrated pathways of atmospheric moisture transport from the tropics to the poles— are key drivers of increased flooding in parts of the U.S. and elsewhere. However, the ephemeral nature of atmospheric rivers makes them difficult to document in climate models and archival data that cover long timescales.
In a new study in Science Advances, researchers focused on a specific time period 16,000 years ago when the region that is now the western U.S. was known to have a wetter climate. For the study, the researchers developed new simulations that reveal an increased frequency of atmospheric rivers.
“Investigating the behavior of atmospheric rivers in previous, altered climates — which we can probe with geological data — helps us understand their sensitivity to the state of the climate system and, therefore, better predict how they might behave in a future warmer world,” said Juan Lora, an assistant professor of Earth & planetary sciences in Yale’s Faculty of Arts and Sciences and co-author of the study.
Lora said the appearance of those long-ago atmospheric rivers coincided with a weakened Atlantic Meridional Overturning Circulation (AMOC) — the Atlantic Ocean’s main water circulation system. Recent observations suggesting a potential weakening of AMOC make the new findings particularly relevant for the future of western U.S. hydroclimate, Lora added.
The first author of the new study is Jessica Oster of Vanderbilt University.
Every time a cell divides, the nuclear “envelope” — the membrane that encloses DNA in the nucleus of eukaryotic cells — breaks down to allow genetic information to be allocated to the new daughter cells. In the new cell, the nuclear envelope then assembles and seals again to protect the genome. Failure to reform the nuclear envelope after cell division can damage DNA and has been linked to the progression of several cancers.
Using live-cell imaging of nuclear envelope formation in the early embryo of the worm C. elegans, a team led by Shirin Bahmanyar, associate professor in molecular, cellular and developmental biology in Yale’s Faculty of Arts and Sciences, discovered how a master regulator, the small DNA-binding protein BAF, binds to specific proteins within the nuclear envelope membrane for proper assembly and sealing.
Through genetic analysis, the researchers determined which of the many nuclear envelope membrane proteins play essential roles in this process — and which proteins function redundantly. One such protein, the ESCRT-II/III protein CHMP-7, becomes critical for rebuilding the nuclear envelope when sealing is faulty.
By combining quantitative image analysis with the C. elegans model, the researchers were able to track the consequences of impaired nuclear envelope sealing and nuclear assembly to failed embryonic development.
Accessing liver transplants
Chronic liver disease and liver cirrhosis are leading causes of death in the United States. While liver transplantation can be a life-saving option for patients with these diseases, there are too few donated livers to meet need; over 11,000 people were on the liver transplant waiting list at the end of 2021.
Equitable access to available livers is essential, researchers say.
“We know that gender, racial, and socioeconomic disparities in liver transplantation access exist, and we know that geographic distance to transplant centers contributes to inequitable access,” said Peter Kahn, a pulmonary and critical care fellow at Yale School of Medicine. “So we looked at the whole of the U.S. population to assess travel time to liver transplant centers and how that might vary by region.”
In a study published in the journal Liver Transplantation, Kahn and his colleagues found that around a third of the U.S. population lives within 30 minutes of the nearest center and about two-thirds live within 90 minutes. However, almost a quarter of the population — or 76.5 million people — lives more than two hours from the closest center.
Access also varies considerably at the state level, the researchers found. In eight states, more than 90% of the population lives within two hours of the nearest center, while there are nine states in which more than 75% of the population live more than two hours away. Eleven states in the continental U.S. don’t have a liver transplant center at all. There’s also travel time variability among the different transplant regions defined by the United Network for Organ Sharing, the study showed.
The researchers proposed several approaches for addressing these geographic disparities, including expanding telemedicine to reduce wait times for transplant evaluations and embracing new liver preservation techniques that could increase the number of livers available for transplant.
“We can also learn from others,” said Walter Mathis, an assistant professor of psychiatry at Yale School of Medicine and a co-author of the study. “Countries like the U.K. have reduced geographic disparities by strengthening partnerships between transplant centers and regional hospitals, which we could do as well.”
Measuring ‘states of mind’ — in real time
Scientists have been able to differentiate broad patterns of brain activity in animals, including humans, when they transition between behavioral states like sleep and waking or resting and arousal. However, it has been difficult to track those varying neural signatures in real time, such as brain activity that occurs in the milliseconds when a student’s wandering attention snaps into focus at the sound of a professor’s voice.
Now, a multidisciplinary Yale team bridging neuroscience and mathematics, using advanced imaging technology, have captured the neuronal events in the brains of mice when they engage in spontaneous behavior such as running on a wheel in a cage.
“We intuitively understand our sense of fidgeting, anxious pacing, or resting comfortably, yet we are only beginning to understand how those different states correspond to brain activity,” said Yale’s Michael Higley, an associate professor of neuroscience and biomedical engineering and a member of the Kavli Institute for Neuroscience and the Wu Tsai Institute, both of which are at Yale.
Not surprisingly, the cross disciplinary team found elevated overall activity in the mouse brain when the animals shifted from a restful state to arousal, as exemplified by running on a wheel in a cage. But the researchers also discovered that these state transitions happen spontaneously and correspond to patterns of neural activity whose changes are coordinated across widespread areas of the neocortex.
“As much as the amount of activity, it’s the coordination of signals over space and time that matter,” Higley said.
The work was led by Hadas Benisty and Daniel Barson of the Department of Neuroscience and also included other members of Yale’s neuroscience (Jess Cardin) and applied math (Ronald Raphael Coifman) departments.
The study is published in the journal Nature Neuroscience.
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