Insights & Outcomes: From secret shoppers to hungry ribosomes

This month, Insights & Outcomes turns its attention to a variety of subtle factors and influences that play a role in protein development, Tourette Syndrome, multiple sclerosis, and health care inequity.

As always, you can find more science and medicine research news on Yale News’ Science & Technology and Health & Medicine pages.

When genes and their environment break bad

One of the most vexing problems facing scientists in the search for the root causes of autoimmune and other diseases is accounting for the interaction of genes and environment.

For instance, in multiple sclerosis (MS), a disorder in which the immune system attacks healthy cells in the central nervous system, scientists have found many gene variants linked to the disease but none with a notably large effect. The International MS Genetics Consortium, founded by David Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology and professor of Immunobiology at Yale, has discovered over 200 non-coding gene variants and eight coding variants that are associated with a risk of developing the disease. However, each variant has only a small effect on disease risk.

Hafler has explored the biological mechanisms that underly the genetics of MS cases and other autoimmune diseases. In the last decade, he and his colleagues have shown that dietary salt can worsen MS symptoms by disrupting the activity of regulatory T cells, which help moderate immune response in people. “It’s not bad genes, it’s not a bad environment,” Hafler said, “but it’s a bad interaction between the two.”

In his latest study, a team led by Hafler discovered an example of how those interactions work. They found that a rare, genetic coding variant called histone deacetylase 7 (HDAC7), which can decrease the likelihood of developing MS, is crucial to the function of regulatory T cells. The absence of the variant caused severe inflammation in mouse models of MS. “It is emerging that genetic variants that have small effects on disease risk can have major biological effects,” Hafler said. The research was published in the journal Science Translational Medicine. Lead authors of the paper are Yale’s Pierre-Paul Axisa and Tomokazu Sumida.

Secret shoppers’ and health care inequity

In two new studies, Yale researchers examined the use of race in risk assessment tools for certain surgeries and the best methodologies for designing “secret shopper” studies to understand health care inequities.

Dr. Daniel Wiznia, assistant professor of orthopaedic surgery at Yale School of Medicine and assistant professor of mechanical engineering & materials science at the School of Engineering & Applied Sciences, is senior author of both studies.

For one study, the researchers looked at the use of “secret shoppers,” or “simulated patients,” to evaluate health care delivery systems. In this method, trained “shoppers” contact health care facilities and pose as patients seeking care, a process that can illuminate and evaluate everything from appointment scheduling to access to specialty care for different demographic groups.

Writing in Archives of Public Health, Wiznia, first author Kelsey Ranking, and co-authors Alison Mosier-Mills and Walter Hsiang, all of Yale, detail best practices for designing “secret shopper” studies. The tips include how to develop a call script, how to effectively record and report data, and when to place calls.

A separate study, published in the Journal of Racial and Ethnic Health Disparities, asserts that race should not be used in calculating the risk of complications following total joint arthroplasty (TJA) surgery.

TJA surgery can vastly improve quality of life for patients with osteoarthritis, helping them regain functional independence. Calculators that assess the risk of complications following TJA surgery can help surgeons and patients make informed decisions about the risks involved in having surgery.

However, Wiznia and his colleagues say risk assessment tools can harm patients by assigning penalties for factors that are not related to the risk of a postoperative complication — such as race and insurance status. For example, patients who are Black can be assigned an additional three risk points regardless of their overall health, reducing their likelihood for receiving adequate care.

Patients from racial and ethnic minority groups, patients with Medicaid insurance, and patients with lower incomes already face numerous healthcare disparities related to TJA care,” the authors write, “and biased risk scores that include race or insurance coverage as factors only compound these disparities.”

Chloe Dlott of Yale is first author of the study. Mary O’Connor of Vori Health is co-author.

Tracking the neuronal beginnings of Tourette

The verbal and motor ticks that mark Tourette Syndrome typically develop in children from the ages of 6 to 10, but it has been unclear when deficits in the area of the brain governing motor control develop. A new study by Yale researchers suggests that neuronal deficits in Tourette patients can be detected in very early fetal development.

A team headed by Melanie Brady — a member in the lab of Flora Vaccarino, the Harris Professor in the Child Study Center and professor of neuroscience — used stem cells generated from five patients with Tourette Syndrome to create brain organoids in laboratory dishes that mimic the development of neurons in the basal ganglia.

Normally, progenitor cells within the basal ganglia generate inhibitory GABAergic and cholinergic interneurons that migrate to the mature portion of the basal ganglia and to many other areas of the brain. In Tourette Syndrome, the researchers found, these neurons fail to generate normally and are present in reduced numbers. This explains a deficiency of these GABAergic and cholinergic interneurons found post-mortem in the adult basal ganglia in brains of Tourette patients.

Intriguingly, the authors noted a connection between the level of neuronal deficits in organoids and the severity of Tourette symptoms in patients from whom stem cells were harvested. For instance, the organoids generated from a patient with the mildest symptoms exhibited the lowest loss of interneuron gene expression than patients with more severe symptoms. The findings may eventually help clinicians predict the severity of Tourette Syndrome and identify new drug targets that might mitigate symptoms of the disorder.

Identifying potential underpinnings of the etiology of Tourette Syndrome may lead to earlier diagnoses and broaden our approaches to disorder management and we are hopeful that these findings point us in the right direction,” Brady said. The paper was published in the journal Nature Molecular Psychiatry.

When the protein machine gets hungry

Protein synthesis is the most energy-consuming task cells undertake and makes most of life’s functions possible. But what happens when the cell’s protein-making machine, known as the ribosome, doesn’t get fed?

More than half the energy expended by a cell supports the ribosome in stringing together amino acids into specific sequences that shape the form and function of proteins. In times of plenty, a molecule called bacterial elongation factor G (EF-G) triggers the release of energy-rich guanosine triphosphate (GTP) that fuels construction of proteins. But in a nutrient-poor environment, levels of EF-G decline and protein production slows or stops.

However, a Yale team headed by Weiwei Han in the lab of Eduardo Groisman, the Waldemar Von Zedtwitz Professor of Microbial Pathogenesis, found that one type of gut bacteria crucial to human health possesses a second form of EF-G — known as EF-G2. EF-G2 can continue protein synthesis without breaking down energy-rich GTP and is necessary for colonization of the gut. When the bacterium is deprived of carbon, levels of EF-G2 increase 10-fold, the team found.

When the organism is starving, it can shift to a slow mode of protein synthesis by an alternate form of EFG,” Groisman said. The study was published in the EMBO Journal.

Research Redux:

Reconsidering oxygen’s role in growth of tumors

Potential new treatment for ‘brain fog’ in long-COVID patients

Driver of cystic fibrosis lung inflammation yields target for treatment

Yale device delivers data from ‘Hell Planet’

Eyes offer a window into the mystery of human consciousness

Source link


Leave a Reply

Your email address will not be published. Required fields are marked *