Insights & Outcomes: nuclear pores, phase mazes, and pharmacy deserts
This month, Insights & Outcomes kicks off the fall semester with some hot-off-the-presses research on pharmacy “deserts,” nuclear pores, the way skin cells find their true purpose — and news of an early career award for some innovative planetary research.
Sizing up nuclear pores
The nucleus in a cell is a fortress that protects precious genetic information stored inside and its size is usually proportionate to the size of the cell that shelters it. However, in cancerous cells, the nucleus becomes so distorted that clinicians can diagnose the disease from its size alone.
But how does the cell regulate the size of the nucleus in the first place? The answer lies in the many membranes that envelope the nucleus and help ferry genetic information to its proper destinations within the cell, Yale University researchers discovered.
In a new study, a team led by Dr. Shirin Bahmanyar, associate professor of molecular, cellular & developmental biology, and former Yale graduate student Michael Mauro, now at Columbia University, used high-resolution quantitative fluorescence microscopy to study the process in living C. elegans worms. They found that a protein called Ndc1 controls the attachment of membranes that encapsulate the nucleus and the density of openings called nuclear pores and also helps drive the rate of expansion of the nucleus.
“It’s like inflating a balloon, with air coming through pores of the nucleus and membranes expanding like the latex allowing the nucleus to grow,” Mauro said.
To the researchers’ surprise, they also found increased membrane production alone could make nuclei bigger even when Ndc1 isn’t there to insert new pores. In cases when nuclei grow abnormally large, the jobs of increasing nuclear pores and increasing membranes become uncoupled, leaving no checks on limiting size of nuclei.
The research is not only important to our understanding of how cancer can hijack the nucleus but also helps answer fundamental biology questions such as how the size of the nucleus governs the transition, in embryos, from maternal to individual control of genome activation and influences the timing of the cell cycle. The work was published in the journal eLife.
Defining pharmacy deserts
Pharmacy deserts, areas where people lack access to pharmacies, are a major driver of health care disparities in the United States. While the location of these deserts is often determined by distance to the nearest pharmacy, this doesn’t fully capture access issues, Yale researchers argue.
“Particularly in urban settings, distance may not be the right measure,” said Peter Kahn, a pulmonary and critical care fellow in Yale School of Medicine’s Department of Internal Medicine. “In these areas, short distances can sometimes take a long time to travel.”
In a new study, Kahn, Walter Mathis, assistant professor of psychiatry, and a group of colleagues calculated the number of pharmacy deserts based on travel time in the four largest U.S. cities — New York, Los Angeles, Chicago, and Houston — and considered walking, car travel, and public transportation. They reported their findings in the Journal of the American Pharmacists Association.
Defining pharmacy deserts as areas where a pharmacy couldn’t be reached by 15 minutes of travel, they found that the number of pharmacy deserts differed in each city depending on the mode of transportation. For instance, New York City and Chicago, which have more robust public transportation systems, had fewer pharmacy deserts when traveling by public transportation than by car or walking. But Los Angeles and Houston, both of which lack comparable public transportation options, had more pharmacy deserts when traveling by public transit. And whether determined by distance or travel time, pharmacy deserts were more often found in predominantly Black and Latinx neighborhoods, they said.
Ultimately, this more nuanced understanding will help address the problem, the researchers say. “Knowing more about the barriers to pharmacy access and where they persist will help us reduce the number of pharmacy deserts,” said Mathis.
Eyes on the planetary research prize
The American Astronomical Society’s Division for Planetary Sciences has awarded its 2022 Harold C. Urey Prize for outstanding achievement in planetary research by an early career scientist to Juan Lora, an assistant professor in Yale’s Department of Earth and Planetary Sciences.
Lora earned the prize for his development of a novel global circulation model (GCM) of the Saturn moon Titan, which Lora has used to successfully explain Titan’s precipitation patterns and surface liquid distribution. The model incorporates the effects of atmospheric hazes as well as the impact of Titan’s subsurface hydrology.
Lora’s model is important for the success of NASA’s Dragonfly drone mission to the surface of Titan. Lora is one of the principal investigators of the mission.
Lora has applied similar techniques to Earth’s hydroclimate in order to understand changes in atmospheric rivers, which are a key component of the water cycle affected by climate change.
The prize organizers also lauded Lora for his mentorship of students and early career scientists.
Managing an enzyme misfire
The human immune system is primed to fight off microbial invaders but sometimes it can misfire, causing inflammatory disease. For instance, an enzyme that plays a key regulatory role in the function of immune system cells called macrophages has been linked to inflammatory bowel disease, arthritis, and an inability to clear infections.
A team of Yale chemists and immunobiologists set out to explore the biochemistry of the enzyme, laccase domain-containing 1 (LACC1), and discovered that one of its products — a common supplement used by body builders — may be a potential nutraceutical to combat those inflammatory diseases. Yale’s Zheng Wei, who has joint appointments in the labs of Jason Crawford and Richard Flavell, set out to describe the biochemical steps involved in how LACC1 contributes to pro-inflammatory macrophage function in mice and humans.
For their research, the team infected mice lacking LACC1 with a strain of the Salmonella bacteria and then treated them with the product of LACC1 — the amino acid L-ornithine, which is commonly used as an athletic supplement and sleep aid. The treated mice showed a renewed ability to combat infection, leading researchers to speculate that L-ornithine may also aid in the treatment of other inflammatory diseases.
Co-corresponding authors of the paper, which is published in the journal Nature, are Crawford, an associate professor of chemistry and of microbial pathogenesis and director of the Institute of Biomolecular Design and Discovery on Yale West Campus, and Flavell, Sterling Professor of Immunobiology and investigator of the Howard Hughes Medical Institute.
Navigating phase mazes
Some of the most important systems in medicine, energy, and industry hinge on the interplay between phases of matter — such as vapors, liquids, and solids — when they come into contact.
There are mixtures, such as oil and water, that are relatively easy to understand, in part because they have a minimal number of components. But what if, as is the case with cell membranes, there are thousands of components? How can scientists understand phase behavior in an environment such as that?
In a new study published in the journal Physical Review Research, lead author Isabella Graf, a postdoctoral associate in the Yale Department of Physics, and Benjamin Machta, assistant professor of physics and member of the Quantitative Biology Institute, offer a path out of the phase maze.
Graf and Machta have developed a theoretical framework to systematically reduce the complexity of mixtures with as many as a million components. Rather than examining components in the high dimensional space of possible mixtures, the new framework focuses on ranking the primary physical features of the components themselves — and how those physical features determine phase behavior.
“We believe that our work is particularly useful for systems with a huge number of components and will allow us to find principles underlying phase separation in such systems,” Graf said.