“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.