With a goal of understanding and addressing immunotherapy’s limitations, researchers at Washington University School of Medicine in St Louis have found that the immune system can be its own worst enemy in the fight against cancer. In a new study in mice, a subset of immune cells — type 1 regulatory T cells, or Tr1 cells — did its normal job of preventing the immune system from overreacting but did so while inadvertently restraining immunotherapy’s cancer-fighting power.

“Tr1 cells were found to be a heretofore unrecognized obstacle to immunotherapy’s effectiveness against cancer,” said senior author Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology & Immunology, and director of the Bursky Center for Human Immunology & Immunotherapy at Washington University School of Medicine. “By removing or circumventing that barrier in mice, we successfully reenergized the immune system’s cancer-fighting cells and uncovered an opportunity to expand the benefits of immunotherapy for more cancer patients.”

The study is available in Nature.

Cancer vaccines represent a new approach to personalize cancer immunotherapy. Aimed at the mutant proteins specific to a patient’s tumor, such vaccines induce killer T cells to attack tumor cells while leaving healthy cells unharmed. Schreiber’s group previously showed that more effective vaccines also activate helper T cells, another immune cell type, that recruit and expand additional killer T cells to destroy the tumors. But when they tried to add increased amounts of the helper T cell target to supercharge the vaccine they found they generated a different type of T cell that inhibited rather than promoted tumor rejection.

“We tested the hypothesis that by increasing helper T cell activation we would induce enhanced elimination of the sarcoma tumors in mice,” said first author Hussein Sultan, PhD, an instructor in pathology & immunology. So he injected groups of tumor bearing mice with vaccines that activated killer T cells equally while triggering a different degree of helper T cell activation.

Much to the researchers’ surprise in this latest study, the vaccine meant to hyperactivate helper T cells produced the opposite effect and inhibited tumor rejection.

“We thought that more helper T cell activation would optimize elimination of the sarcoma tumors in mice,” Sultan said. “Instead, we found that vaccines containing high doses of helper T cell targets induced inhibitory Tr1 cells that completely blocked tumor elimination. We know that Tr1 cells normally control an overactive immune system, but this is the first time they have been shown to dampen its fight against cancer.”

Tr1 cells normally put the brakes on the immune system to prevent it from attacking the body’s healthy cells. But their role in cancer has not been seriously explored. Looking through previously published data, the researchers found that tumors from patients who had responded poorly to immunotherapy had more Tr1 cells compared with tumors of patients who had responded well. The number of Tr1 cells also increased in mice as tumors grew bigger, rendering the mice insensitive to immunotherapy.

To bypass the inhibiting cells, the researchers treated the vaccinated mice with a drug that enhances killer T cells’ fighting power. The drug, developed by biotechnology startup Asher Biotherapeutics, carries modifications in the immune-boosting protein called interleukin 2 (IL-2) that specifically revs up killer T cells and reduces the toxicity of unmodified IL-2 treatments. The additional boost from the drug overcame Tr1 cells’ inhibition and rendered the immunotherapy more effective.

“We are committed to personalizing immunotherapy and broadening its effectiveness,” said Schreiber. “Decades of researching basic tumor immunology have expanded our understanding of how to trigger the immune system to achieve the most robust antitumor response. This new study adds to our understanding of how to improve immunotherapy to benefit more people.”

As co-founder of Asher Biotherapeutics — which provided the mouse version of the modified IL-2 drugs — Schreiber is indirectly involved in the company’s clinical trials testing the human version of the drug as a monotherapy in cancer patients. If successful, the drug has the potential to be tested in combination with cancer treatment vaccines.

To help protect drivers and machine operators from the dangers of drifting off, engineers at the University of California, Berkeley, have created prototype earbuds that can detect the signs of drowsiness in the brain.

The earbuds detect brain waves in the same way as an electroencephalogram (EEG), a test that doctors use to measure electrical activity in the brain. While most EEGs detect brain waves using a series of electrodes attached to the head, the earbuds do so using built-in electrodes that are designed to make contact with the ear canal.

The electrical signals detected by the ear buds are smaller than those picked up by a traditional EEG. However, in a new study, the researchers show that their Ear EEG platform is sensitive enough to detect alpha waves, a pattern of brain activity that increases when you close your eyes or start to fall asleep.

“I was inspired when I bought my first pair of Apple’s AirPods in 2017. I immediately thought, ‘What an amazing platform for neural recording,'” said study senior author Rikky Muller, an associate professor of electrical engineering and computer sciences at UC Berkeley. “We believe that this technology has many potential uses, and that classifying drowsiness is a good indicator that the technology can be used to classify sleep and even diagnose sleep disorders.”

Using an earbud as an EEG electrode poses a variety of practical challenges. In order to obtain an accurate EEG, electrodes need to make good contact with the skin. This is relatively easy to achieve in traditional EEGs, which use flat metal electrodes stuck to the scalp. However, it is much trickier to design an earbud that will fit snugly — and comfortably — in a wide variety of ear sizes and shapes.

When Muller’s team started working on the project, other groups developing Ear EEG platforms were either using wet electrode gels to ensure a good seal between the earbud and the ear canal, or creating custom-molded earpieces for each individual user. She and her team wanted to design a model that was dry and user generic, so that anyone could stick them in their ears and get reliable readings.

“My personal goal was to try to make a device that could be used every day by someone who would really benefit from it,” said Ryan Kaveh, a UC Berkeley postdoctoral scholar and co-first author of the study. “In order to do that, I knew that it would have to be reusable, fit a variety of people, and [be] easy to manufacture.”

Kaveh co-led the study with graduate student Carolyn Schwendeman and collaborated with Ana Arias’s lab at UC Berkeley to design the final earpiece in three sizes: small, medium and large. The earpiece incorporates multiple electrodes in a cantilevered design that applies gentle outward pressure to the ear canal and uses flexible electronics to ensure a comfortable fit. The signals are read out through a custom, low-power, wireless electronic interface.

In a 2020 paper, the researchers showed that these earpieces can detect a number of physiological signals, including eye blinks, alpha brain waves and the auditory steady-state response, which is the brain’s response to hearing a steady pitch. In the new study, they improved the earpiece design and incorporated machine learning to demonstrate how the earpieces could be used in a real-world application.

As part of the experiment, they asked nine volunteers to wear the earpieces while doing a series of boring tasks in a darkened room. Every so often, the volunteers were asked to rate their level of drowsiness, and their response times were measured.

“We found that even when the signal quality from the earpieces seemed worse, we could still classify the onset of drowsiness with the same level of accuracy as much more complicated, bulky systems,” Kaveh said. The earpieces also retain their accuracy when categorizing drowsiness in brand-new users, a characteristic of devices that could work ‘out of the box’.

Muller, who developed the Ear EEG with the support of the Bakar Fellowship and the Bakar Prize, is continuing to refine the design and explore other potential applications of the device, which can also record signals beyond EEG, such as heart beats, eye movements and jaw clenches.

“Wireless earbuds are something we already wear all the time,” Muller said. “That’s what makes Ear EEG such a compelling approach to wearables. It doesn’t require anything extra.”

This study was supported in part by the Ford University Research Program and a Bakar Spark Award.

A recent study from the University of Illinois Urbana-Champaign and the University of Pretoria in South Africa demonstrates how African conservation managers could create and optimize elephant movement corridors across a seven-country region. The study offers a map showing landscape connections that would support elephants’ habitat needs and allow for more gene flow among populations.

“Other research groups have integrated genetic and spatial data before, but usually it’s done on a more local scale. Ours was the first to combine both types of data for southern African elephants across such a large geographic area,” said lead author Alida de Flamingh, who completed the study as part of her doctoral program in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at Illinois. She is now a postdoctoral researcher at the Carl R. Woese Institute for Genomic Biology.

Scale is meaningful because African elephants have very large home ranges — roaming up to 11,000 square kilometers, or more than 2.7 million acres — and they often travel long distances out of their way to avoid unsuitable habitat. Capturing that scale in a single analysis was no easy feat.

“This was a massive effort. We went out with our partners in the Conservation Ecology Research Unit at the University of Pretoria to collect non-invasive DNA samples from elephant dung across the whole range,” de Flamingh said. “CERU also contributed data from GPS trackers on 80 collared elephants across nearly 54,000 locations.”

GPS collar data shows how elephants move across the landscape but can’t indicate whether that movement leads to gene flow. Conversely, DNA data documents gene flow, but can’t show how elephants moved to make that happen. Integrating the two data sets required a landscape genetics approach.

“Landscape genetics adapts some ideas from electrical circuit theory to discuss how animals might move and achieve gene flow. Our approach looks at resistances or costs elephants encounter as they move along multiple pathways through the region, accounting for the possibility of losing or gaining individual paths,” said co-author Nathan Alexander, a postdoctoral researcher at the Illinois Natural History Survey. Alexander worked on the project during his doctoral program in the Department of Natural Resources and Environmental Sciences in ACES.

Costs in this case included steep slopes, barren areas with little to no vegetation, densely populated human settlements, and areas far from water. The researchers combined these environmental challenges with DNA data to explain how elephants might navigate their habitat, identifying key routes to maintain gene flow across protected areas.

“We did not find a simple linear relationship where more suitable habitats are less costly. Instead, we found a pronounced nonlinear pattern where the least suitable habitats have the biggest impact on elephant movement or distribution across the landscape,” de Flamingh said. “Intermediate habitats aren’t necessarily dictating their movements as much as these really, really unsuitable habitats. That’s positive, if you think about it. They’re tolerant of intermediate habitats and can still move through them.”

What qualifies as a “really, really unsuitable” habitat? The researchers identified areas like the vegetation-free Makgadikgadi salt pans in Botswana, as well as densely populated human settlements. Providing connections for elephants that avoid these areas will also reduce human-elephant conflict, a distinct threat to elephants.

De Flamingh said the insights gained from this study can help governmental authorities and NGOs in southern Africa to develop robust conservation initiatives on the ground.

“Southern Africa has the largest number of elephants in all of Africa. So any conservation efforts there, especially those that avoid human-elephant conflict, would protect pretty large populations of elephants,” said senior author Al Roca, an animal sciences professor in ACES. “Our partners at CERU, as well as our funders — the International Fund for Animal Welfare and the African Elephant Conservation Fund of the U.S. Fish and Wildlife Service — are really critical in those efforts.”

The study, “Integrating habitat suitability modeling with gene flow improves delineation of landscape connections among African savanna elephants,” is published in Biodiversity and Conservation. The paper is dedicated to the memory of co-author Rudi van Aarde, who was instrumental in launching the study as head of CERU, and who passed away while the research was ongoing.

Roca is also affiliated with the Carl R. Woese Institute for Genomic Biology, the Illinois Natural History Survey, and the School of Information Sciences at Illinois.

“Over that embryonic period [up to eight weeks from conception], triploidy had rarely been reported in mammals outside of women,” said Mandi de Mestre, professor of equine medicine at Cornell University. “The study tells us that over the first six weeks of gestation, this will likely be the primary cause of pregnancy loss following natural conception.”

de Mestre is the corresponding author of “Naturally Occurring Horse Model of Miscarriage Reveals Temporal Relationship Between Chromosomal Aberration Type and Point of Lethality,” published in the Proceedings of the National Academy of Sciences.

Human miscarriages occur in 10-20% of pregnancies and are commonly associated with chromosomal errors, but there have been no suitable animal models that truly duplicate the features of the condition. The new research findings will help veterinarians better understand the causes of pregnancy loss in horses and identifies horses as an excellent model for studying human miscarriage.

“We were able to study the impact of chromosome errors across the entire pregnancy in the horse,” de Mestre said. “We found that triploidy is only associated with losses in early pregnancy.”

In the study, de Mestre’s laboratory at Cornell, and earlier at The Royal Veterinary College, London, received 256 fetus and placenta samples from veterinarians who treated horses with failed pregnancies over a period of 10 years. Using the samples, the researchers were able to investigate the prevalence of different types of chromosomal copy number errors associated with pregnancy loss. They found that chromosomal errors occurred in 57.9% of pregnancy losses up to day 55 of gestation, in 57.2% of losses between days 56 and 110 and in only 1.4% of losses between days 111 and the end of pregnancy. Aneuploidy (loss or gain of a single whole chromosome) was mainly associated with miscarriages in the first 10 weeks of pregnancy, while deletions or duplications of only part of a chromosome were found in miscarriages after 110 days. These findings turned out to be remarkably similar to those observed in a number of large studies in women, according to the paper.

Horses are a good model for studying human pregnancies because they have a similar gestation period — 11 months compared to nine months in women — and the embryo develops at a similar rate in the early stages. In addition, horse chromosomes have a very similar genetic content to human chromosomes, which makes them particularly relevant for the study of chromosome errors.

Reasons for miscarriage in women in very early pregnancy have been difficult to determine because most fetuses during this period are lost at home, leaving scientists without material — and data — to study. The study’s findings provide insight into the frequency of chromosome errors over the equivalent period of the first six weeks of human gestation.

Because of the value of horses and the emotional attachment their owners have to them, horses receive a high level of care, with routine tracking of pregnancies, which then provide extensive data for research.

Other animal models, such as mice, are not comparable to human pregnancies. Mice have a gestation period of about three weeks, and natural pregnancy losses in mice are low.

In terms of equine health, the study provides new details about common chromosomal abnormalities that will likely change the clinical management of pregnancies. For example, if a clinician determines that a horse has a major chromosomal error, they may no longer choose to extend that pregnancy by administering hormones, a common practice in pregnant mares. The study will also point researchers toward the development of new diagnostic tests for chromosome abnormalities in horse fetuses and investigating molecular mechanisms that lead to these abnormalities.

“This research has provided a foundation for understanding the genetic causes of pregnancy loss in horses, often referred to as pregnancy loss of unknown cause,” said Shebl Salem, a postdoctoral researcher in de Mestre’s Equine Pregnancy Lab and a co-first author of the study.

Other co-first authors include Jessica Lawson of the Royal Veterinary College in London, United Kingdom; and Donald Miller, de Mestre lab manager.

The study was partly funded by the Horserace Betting Levy Board and Thoroughbred Breeders Association.

There has been mounting interest in the value of psychedelic-inspired compounds as treatments for brain disorders including depression, post-traumatic stress disorder and substance use disorder. Psychedelic compounds like LSD, DMT and psilocybin promote the growth and strengthening of neurons and their connections in the brain’s prefrontal cortex. The new tool could help scientists unlock the benefits of psychedelic treatments for patients with brain disorders.

“It’s important to think about the cellular mechanisms that these psychedelics act upon,” said Christina Kim, an assistant professor of neurology at the UC Davis Center for Neuroscience and School of Medicine, and an affiliate of the UC Davis Institute for Psychedelics and Neurotherapeutics. “What are they? Once we know that, we can design different variants that target the same mechanism but with fewer side effects.”

This research provides scientists with a new technique that could be used to track step by step the molecular signaling processes that are responsible for these compounds’ beneficial neuroplastic effects. What’s more, CaST accomplishes the task of cellular tagging in rapid time, taking 10 to 30 minutes rather than the hours typical of other tagging methods.

“We designed these proteins in the lab that can be packaged into DNA and then put into harmless adeno-associated viruses,” Kim said. “Once we deliver the CaST tool and these proteins into neurons, then they incubate inside the cells and start expressing.”

The research was conducted in collaboration with David Olson, founding director of the Institute for Psychedelics and Neurotherapeutics and a professor in the departments of Chemistry and Biochemistry and Molecular Medicine.

A snapshot of the brain

The CaST tool takes advantage of changes in intracellular calcium concentrations, a nearly universal marker to track activity in a neuron. When neurons exhibit high activity, they exhibit high calcium levels. CaST uses this cue to tag the cell with a small biomolecule called biotin.

In the study, Kim and her colleagues dosed mice with the psychedelic psilocybin. They then used CaST in tandem with biotin to identify neurons with increased calcium in the prefrontal cortex. The prefrontal cortex is an area affected by many brain disorders and also an area where psychedelics promote neuronal growth and strengthening.

The researchers also monitoring the head-twitch responses in the mice. Head-twitch responses are the primary behavioral correlate for hallucinations caused by psychedelics.

“What’s nice about CaST is that it can be used in a freely behaving animal,” said Kim, noting that other cellular tagging technologies require stabilizing a mouse’s head to accomplish imaging. “Biotin is also a great tagging substrate because there are many pre-existing commercial tools that can report whether biotin is present or not just by a simple staining and imaging method.”

The proof-of-concept experiment gave what Kim called “a camera snapshot” of the areas in the prefrontal cortex activated by psilocybin.

Next steps

Kim and her colleagues are now working on methods to enable brain-wide cellular labeling with the CaST tool. Additionally, they’re exploring ways to enrich the signature of individual proteins produced by neurons affected by psychedelics.

“We can send those samples to the UC Davis Proteomics Core Facility and they can give us an unbiased picture of all the proteins we identified,” Kim said. “We want to examine their entire contents in terms of what proteins they express, what genes they express, and try to see what’s different in psilocybin-treated animals versus control animals or animal models of diseases.”

The goal is to identify how psychedelics benefit the cellular profiles of those with brain disorders, elucidating the step-by-step cellular process of their therapeutic effects.

Kim expressed interest in conducting future experiments in collaboration with Olson’s lab that use the CaST tool to compare the neuronal activity induced by psychedelics to the activity induced by non-hallucinogenic neurotherapeutics.

“CaST will be an important tool for studying the mechanisms of action of these neurotherapeutic drugs,” Kim said.

Additional UC Davis authors on the study include lead authors Run Zhang and Maribel Anguiano, and Isak K. Aarrestad, Sophia Lin, Joshua Chandra and Sruti S. Vadde.

The work was supported by grants from the Brain and Behavior Research Foundation, Kinship Foundation, Arnold and Mabel Beckman Foundation, NIH, NSF and the Boone Family Foundation.

“Few stars have been thought to generate enough UV radiation through flares to impact planet habitability. Our findings show that many more stars may have this capability,” said astronomer Vera Berger, who undertook the study while in the Research Experiences for Undergraduates program at IfA, an initiative supported by the National Science Foundation.

Berger and her team used archival data from the GALEX space telescope to search for flares among 300,000 nearby stars. GALEX is a now-decommissioned NASA mission that simultaneously observed most of the sky at near-and far-UV wavelengths from 2003 to 2013. Using new computational techniques, the team mined novel insights from the data.

“Combining modern computer power with gigabytes of decades-old observations allowed us to search for flares on thousands and thousands of nearby stars,” said Michael Tucker, a PhD graduate of IfA and now a postdoctoral fellow at Ohio State University.

UV’s double edge

According to researchers, UV radiation from stellar flares can either erode planetary atmospheres, threatening their potential to support life, or contribute to the formation of RNA building blocks, which are essential for the creation of life.

This study challenges existing models of stellar flares and exoplanet habitability, showing that far-UV emission from flares is on average three times more energetic than typically assumed, and can reach up to twelve times the expected energy levels.

“A change of three is the same as the difference in UV in the summer from Anchorage, Alaska to Honolulu, where unprotected skin can get a sunburn in less than 10 minutes,” said Benjamin J. Shappee, an Associate Astronomer at IfA who mentored Berger.

Hidden causes

The exact cause of this stronger far-UV emission remains unclear. The team believes it might be that flare radiation is concentrated at specific wavelengths, indicating the presence of atoms like carbon and nitrogen.

“This study has changed the picture of the environments around stars less massive than our Sun, which emit very little UV light outside of flares,” said Jason Hinkle, a PhD candidate at IfA who co-authored the study.

According to Berger, now a Churchill Scholar at the University of Cambridge, more data from space telescopes is needed to study the UV light from stars, which is crucial for understanding the source of this emission.