Why Don’t T Cells Destroy Solid Tumors during Immunotherapy?

3-D image of a T cell experiencing cell stress: endoplasmic reticulum (green), mitochondria (purple).
 Illustration Credit: Elizabeth Hunt, Thaxton lab

Led by Jessica Thaxton, PhD, MsCR, UNC School of Medicine scientists and colleagues found that targeting key proteins that control the T cell response to stress could help researchers develop more potent cancer immunotherapies.

The great hope of cancer immunotherapy is to bolster our own immune cells in specific ways to keep cancer cells from evading our immune system. Although much progress has been made, immunotherapy does not always work well. Jessica Thaxton, PhD, MsCR, in the immunotherapy group at the UNC Lineberger Comprehensive Cancer Center, wants to know why. She thinks one reason is the stress response experienced by T cells once they infiltrate solid cancers.

The Thaxton lab’s latest work, published in the journal Cancer Research, shows in detail how the stress response in T cells can lead to their inability to curtail tumor growth. Thaxton’s group found that T cells exposed to the environment of solid cancers undergo a natural response to stress that shuts off their function, limiting T cell ability to kill tumors. By manipulating multiple proteins in the stress response pathway inside T cells, Thaxton’s team showed that it was possible to overcome the intrinsic T cell stress response to allow the immune system to thwart cancer growth.

The clever glue keeping the cell’s moving parts connected

This liquid droplet is actually made from protein molecules. It acts as a glue that keeps the microtubule attached, via moving motor proteins, to an actin cable – a process essential for cell division to proceed.
 Illustration Credit: Ella Maru Studios, Courtesy of Paul Scherrer Institute

Researchers from Paul Scherrer Institute PSI and ETH Zurich have discovered how proteins in the cell can form tiny liquid droplets that act as a smart molecular glue. Clinging to the ends of filaments called microtubules, the glue they discovered ensures the nucleus is correctly positioned for cell division. The findings, published in Nature Cell Biology, explain the long-standing mystery of how moving protein structures of the cell’s machinery are coupled together.

Couplings are critical to machines with moving parts. Rigid or flexible, whether the connection between the shafts in a motor or the joints in our body, the material properties ensure that mechanical forces are transduced as desired. Nowhere is this better optimized than in the cell, where the interactions between moving subcellular structures underpin many biological processes. Yet how nature makes this coupling has long baffled scientists.

Now researchers, investigating a coupling crucial for yeast cell division, have revealed that to do this, proteins collaborate such that they condense into a liquid droplet. The study was a collaboration between the teams of Michel Steinmetz at Paul Scherrer Institute PSI and Yves Barral at ETH Zurich, with the help of the groups of Eric Dufresne and Jörg Stelling, both at ETH Zurich.

Scientists use machine learning to gain unprecedented view of small molecules

Metabolites are extremely small – the diameter of a human hair is 100,000 nanometers, while that of a glucose molecule is approximately one nanometer.
Illustration Credit: Matti Ahlgren/Aalto University.

A new tool to identify small molecules offers benefits for diagnostics, drug discovery and fundamental research.

A new machine learning model will help scientists identify small molecules, with applications in medicine, drug discovery and environmental chemistry. Developed by researchers at Aalto University and the University of Luxembourg, the model was trained with data from dozens of laboratories to become one of the most accurate tools for identifying small molecules.

Thousands of different small molecules, known as metabolites, transport energy and transmit cellular information throughout the human body. Because they are so small, metabolites are difficult to distinguish from each other in a blood sample analysis – but identifying these molecules is important to understand how exercise, nutrition, alcohol use and metabolic disorders affect wellbeing.

Learning from habitat ‘haves’ to help save a threatened rattlesnake

The study suggests that a collection of six relatively closely situated but isolated populations of Eastern massasauga rattlesnakes in northeast Ohio could grow their numbers if strategic alterations were made to stretches of land between their home ranges.
Photo Credit: Scott Martin

Comparing the genetics and relocation patterns of habitat “haves” and “have-nots” among two populations of threatened rattlesnakes has produced a new way to use scientific landscape data to guide conservation planning that would give the “have-nots” a better chance of surviving.

The study suggests that a collection of six relatively closely situated but isolated populations of Eastern massasauga rattlesnakes in northeast Ohio could grow their numbers if strategic alterations were made to stretches of land between their home ranges. The findings contributed to the successful application for federal funding of property purchases to make some of these proposed landscape changes happen.

Reconnecting these populations could not only help restore Eastern massasaugas to unthreatened status, but establish a thriving habitat for other prey and predator species facing threats to their survival – satisfying two big-picture conservation concerns, researchers say.

“We aren’t just protecting massasaugas – we’re protecting everything else that’s there,” said H. Lisle Gibbs, professor of evolution, ecology and organismal biology at The Ohio State University and senior author of the study. “Even though we are focused on this species, protection of the habitat has all these collateral benefits.”

Daylong wastewater samples yield surprises

Rice University engineers compared wastewater “grabs” to daylong composite samples and found the grab samples were more likely to result in bias in testing for the presence of antibiotic-resistant genes.
 Illustration Credit: Stadler Research Group/Rice University

Testing the contents of a simple sample of wastewater can reveal a lot about what it carries, but fails to tell the whole story, according to Rice University engineers.

Their new study shows that composite samples taken over 24 hours at an urban wastewater plant give a much more accurate representation of the level of antibiotic-resistant genes (ARGs) in the water. According to the Centers for Disease Control and Prevention (CDC), antibiotic resistance is a global health threat responsible for millions of deaths worldwide.

In the process, the researchers discovered that while secondary wastewater treatment significantly reduces the amount of target ARG, chlorine disinfectants often used in later stages of treatment can, in some situations, have a negative impact on water released back into the environment.

The lab of Lauren Stadler at Rice’s George R. Brown School of Engineering reported seeing levels of antibiotic-resistant RNA concentrations 10 times higher in composite samples than what they see in “grabs,” snapshots collected when flow through a wastewater plant is at a minimum.

Fossil CSI: Mysterious site was ancient birthing grounds

Adult and young of the ichthyosaur species Shonisaurus popularis chase ammonoid prey 230 million years ago, in what is now Berlin-Ichthyosaur State Park, Nevada, U.S.A.
Illustration Credit: Gabriel Ugueto 

Today’s marine giants—such as blue and humpback whales—routinely make massive migrations across the ocean to breed and give birth in waters where predators are scarce, with many congregating year after year along the same stretches of coastline. Now, new research from a team of scientists—including researchers with the University of Utah (Natural History Museum of Utah and Department of Geology & Geophysics), Smithsonian Institution, Vanderbilt University, University of Nevada, Reno, University of Edinburgh, University of Texas at Austin, Vrije Universiteit Brussels, and University of Oxford—suggests that nearly 200 million years before giant whales evolved, school bus-sized marine reptiles called ichthyosaurs may have been making similar migrations to breed and give birth together in relative safety.

The findings, published today in the journal Current Biology, examine a rich fossil bed in the renowned Berlin-Ichthyosaur State Park (BISP) in Nevada’s Humboldt-Toiyabe National Forest, where many 50-foot-long ichthyosaurs (Shonisaurus popularis) lay petrified in stone. Co-authored by Randall Irmis, NHMU chief curator and curator of paleontology, and associate professor, the study offers a plausible explanation as to how at least 37 of these marine reptiles came to meet their ends in the same locality—a question that has vexed paleontologists for more than half a century.

The Donnan Potential, Revealed at Last

Staff scientist Ethan Crumlin at Berkeley Lab's Advanced Light Source.
Photo Credit: Marilyn Sargent/Berkeley Lab

The Donnan electric potential arises from an imbalance of charges at the interface of a charged membrane and a liquid, and for more than a century it has stubbornly eluded direct measurement. Many researchers have even written off such a measurement as impossible.

But that era, at last, has ended. With a tool that’s conventionally used to probe the chemical composition of materials, scientists at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) recently led the first direct measurement of the Donnan potential.

“We were naïve enough to believe we could do the impossible.”

Ethan Crumlin, Berkeley Lab staff scientist, Advanced Light Source (ALS)

Crumlin and his collaborators recently reported the measurement in Nature Communications.

Such a measurement could yield new insights in many areas that focus on membranes. The Donnan potential plays a critical role in transporting ions through a cellular membrane, for example, which ties it to biological functions ranging from muscle contractions to neural signaling. Ion exchange membranes are also important in energy storage strategies and water purification technologies.

Alien Planet Found Spiraling to its Doom around an Aging Star

An artist's concept of the Kepler-1658 system. Kepler-1658b, orbiting with a period of just 3.8 days, was the first exoplanet candidate discovered by Kepler. 
Illustration Credit: Gabriel Perez Diaz/Instituto de Astrofísica de Canarias

For the first time, astronomers have spotted an exoplanet whose orbit is decaying around an evolved, or older, host star. The stricken world appears destined to spiral closer and closer to its maturing star until collision and ultimate obliteration.

The discovery offers new insights into the long-winded process of planetary orbital decay by providing the first look at a system at this late stage of evolution. Death-by-star is a fate thought to await many worlds and could be the Earth's ultimate adios billions of years from now as our Sun grows older.

"We've previously detected evidence for exoplanets inspiraling toward their stars, but we have never before seen such a planet around an evolved star," says Shreyas Vissapragada, a 51 Pegasi b Fellow at the Center for Astrophysics | Harvard & Smithsonian and lead author of a new study describing the results. "Theory predicts that evolved stars are very effective at sapping energy from their planets' orbits, and now we can test those theories with observations."

Mouse pups cry for help most urgently while active

Mouse pups produce ultrasonic vocalizations, called isolation USVs, when they are separated from the nest. It’s a survival mechanism – baby mice need their parents to regulate their temperature and feed them – that diminishes with age.

But before the USV reflex peters out around 20 days after birth, the rate at which mouse pups cry varies a lot, even within the same individual at the same age, according to Katherine Tschida, the Mary Armstrong Meduski ’80 Assistant Professor of psychology in the College of Arts and Sciences. Exploring this variation, researchers in the Tschida Lab found a link between mouse pup USV rates and their activity levels; the greater amount of body movement, the higher the rate of vocalizations. The connection is important for understanding mouse neural circuitry and development and provides a richer understanding of behavioral differences in mouse models of communication disorders, including autism spectrum disorder (ASD.)

“Rates of Ultrasonic Vocalizations are More Strongly Related Than Acoustic Features to Non-vocal Behaviors in Mouse Pups” was published Dec. 19 in Frontiers in Behavioral Neuroscience. Tschida and doctoral student Nicole Pranic are first authors. Contributions were made by Thomas Cleland, professor of psychology; Chen Yang, programmer and analyst in the Cleland Lab; and by Caroline Kornbrek ’23.

Scientists from NUS and NUHS identify predictive blood biomarker for cognitive impairment and dementia

Prof Barry Halliwell (left) and Dr Irwin Cheah (right), together with their collaborators from the National University Health System, have discovered that low levels of ergothioneine in blood plasma may predict an increased risk of cognitive impairment and dementia.
Photo Credit: National University of Singapore

Identification of elderly persons at risk of developing cognitive impairment and dementia could be made possible by examining ergothioneine levels in the blood

A recent study by a team comprising researchers from the National University of Singapore (NUS) and the National University Health System (NUHS) revealed that low levels of ergothioneine (ET) in blood plasma may predict an increased risk of cognitive impairment and dementia, suggesting possible therapeutic or early screening measures for cognitive impairment and dementia in the elderly.

The research teams were led by Professor Barry Halliwell from the Department of Biochemistry under the NUS Yong Loo Lin School of Medicine and Associate Professor Christopher Chen and Dr Mitchell Lai from the Memory, Ageing and Cognition Centre under NUHS. The results of their most recent study were published in the scientific journal Antioxidants.