Dara Shifrer, the study’s author and assistant professor of sociology at PSU, said these findings are especially salient now as the public education system is dismantled by a pandemic, fundamentally altering the lives of children and their parents.

The study looked at the value-added scores of 4,500 teachers in a large urban district as they moved between schools between 2007 and 2013. The idea of value-added models is to measure the impact a teacher has on student learning by comparing new test scores to previous ones, and comparing test score gains across teachers. Supporters of the approach say looking at how much a student has progressed in a year, regardless of where they started from, captures the effectiveness of a teacher.

Shifrer said that if that’s true, then a teacher’s score should remain constant regardless of the school they work in or the type of students they teach.

Instead, when she tracked individual teachers, she found that their scores increased when they switched into high-performing (often low-poverty) schools and decreased when they switched into low-performing (often high-poverty) schools.

“If the teacher moved to a school where there were more poor students, more English language learners, or generally more challenging teaching environments, then their scores dropped,” Shifrer said. “The changes in individuals’ teachers’ scores over time were consistent with shifts in the economic status and race of students in their classrooms and schools.”

The study focused on scores from the Education Value-Added Assessment System (EVAAS), which is used in a dozen states, including Arkansas, California, Delaware, Georgia, Indiana, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, Texas and Virginia.

Shifrer said the study is more evidence that factors beyond a teacher’s control — socioeconomic background, the impact of social inequality, racial segregation — affect students’ learning and whether we view teachers and schools as ‘effective.’

For example, the COVID-19 pandemic forced schools nationwide to pivot to online learning, which left behind many students who didn’t have computers or home internet access or whose families had to deal with health issues, layoffs and other concerns.

“These value-added scores haven’t solved the problem of how to evaluate teacher quality and they limit our ability to understand how students learn and what affects it,” she said. “Policymakers need to recognize how powerfully social inequality outside of schools affects what’s happening inside of schools.”

Shifrer said that educational disparities will be most effectively addressed by targeting inequality in society. The study recommends that teachers who work in high-poverty schools be paid a higher salary and schools should be sufficiently funded to provide the social services that are necessary to support their students. She said the pandemic has only made it more clear how society relies on schools not just for educating children but also for facilitating parents’ ability to work, and by providing children with food and other social supports.

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Materials provided by Portland State University. Original written by Cristina Rojas. Note: Content may be edited for style and length.

That part of the peptide drawn from a SARS-CoV virus turned out to have an unexpected but significant influence on how it stably binds with a receptor central to the immune system’s ability to attack diseased cells.

In a study published by the Proceedings of the National Academy of Sciences, researchers at Rice University’s Brown School of Engineering and the University of Texas MD Anderson Cancer Center revealed models at atomic resolution that detail not only the binding but also, for the first time, the unbinding mechanisms that underlie a key component of the immune system.

They say better understanding of the entire mechanism could lead to advancements in immunotherapy that boosts the body’s ability to fight disease.

Rice computer scientist Lydia Kavraki, alumnus Jayvee Abella and postdoctoral researcher Dinler Antunes, led the study.

“Finding good targets to trigger a protective immune response is very challenging, especially in cancer research,” Antunes said. “The fact that this particular peptide was predicted not to bind to HLAs (human leukocyte antigens) by sequence-based methods highlights a blind spot in our current prediction capacity.

“By incorporating structural analysis, we can detect the contribution of these secondary interactions to peptide binding and stability, hopefully enabling us to find better targets for antiviral vaccine development and T-cell-based cancer immunotherapy,” he said.

The researchers used their simulations to illuminate details of how the intracellular SARS peptide, QFKDNVILL, binds to an MHC receptor protein known as HLA-A?24:02, primarily at dominant anchors on both ends of the peptide (at positions 2 and 9) and presents them for inspection to the immune system’s T cells.

Stable binding of a peptide and MHC is a prerequisite to the activation of T cells, which look for peptides not normally found in healthy cells. If the peptide and protein don’t bind, the T cell is not prompted to attack.

“That much was known from previous studies of the bound and unbound states of many such complexes,” Kavraki said. “What they didn’t capture was the intermediate states and the transitions that lead from one state to another, especially the unbinding.

“I think this is the only analysis that shows the unbinding of peptides from the MHC with atomic resolution,” Kavraki said. “Other peptides have similar characteristics and we think they would have similar behaviors.”

All of these interactions were revealed in great detail through Markov state models that analyze how systems change over time. In this case, the models revealed the importance of secondary sites that support the peptide’s primary anchors. That’s where position 4 stood out.

“There are the main, canonical anchors that people know, but there are these secondary interactions that contribute to the binding and the stability,” Antunes said. “These are harder to capture, but in this study, it seems that position 4 plays a very important role. When you mutate it, it affects the behavior of the peptide as it unbinds from the molecule.”

The researchers modeled mutations of the MHC to see how they would influence binding and found they supported the importance of position 4 to the stability of the complex.

“Our computational approach was able to make predictions on the effect of mutations that are then experimentally verified,” said co-author Cecilia Clementi, a former Rice professor who recently became Einstein Professor of Physics at the Free University of Berlin.

The researchers developed a two-stage process to simplify the computational complexity of atom-scale analysis of large molecules. The first stage used a technique called umbrella sampling to accelerate the initial exploration of the molecules. The second, exploratory stage used adaptive sampling, in which simulations are driven to accelerate the construction of the Markov model.

“The challenge is that these MHCs are pretty large systems for computational chemists to simulate,” said Abella, whose research on the topic formed much of his doctoral thesis. “We had to make some approximations and leverage advances in these classes of methods to move forward.

“We’re not the first one to study unbinding, but what characterizes our work over others is that we keep full atomic resolution in our simulations,” he said. “Other works use a technique known as a Markov chain Monte Carlo, whereas we use molecular dynamics, which lets us incorporate time into our computation to capture the kinetics.”

Their methods can be applied to other peptide-MHC complexes with existing 3D models. “This was, in some sense, a feasibility study to show we can use molecular dynamics and build a Markov state model of a system this size,” Abella said.

The researchers also noted the study’s relevance to the current fight against COVID-19, as the SARS peptide they viewed, QFKDNVILL, is highly similar to the NFKDQVILL peptide in SARS-CoV-2, with the same binding pockets in positions 2, 4 and 9.

“These results suggest that both peptides can bind to HLA-A*2402 and provide targets for anti-viral T-cell responses, which are of great interest in light of the current pandemic,” said co-author Gregory Lizée, a professor in the Department of Melanoma Medical Oncology at MD Anderson. “But these results also shed light on many other potential immune targets, including those of other viruses and even human cancers.”

Kavraki noted that experimental work by longterm collaborator Lizée and Kyle Jackson, a graduate research assistant at Lizée’s lab who produced the mutant proteins, were critical to validate their simulations. Kavraki’s own lab won a National Science Foundation (NSF) Rapid Response Research grant to help identify fragments of SARS-CoV-2 viral proteins as possible targets for vaccine development.

Kavraki is the Noah Harding Professor of Computer Science and a professor of bioengineering, mechanical engineering and electrical and computer engineering.

The Cancer Prevention and Research Institute of Texas, the Gulf Coast Consortia, the NSF, the Einstein Foundation Berlin and the Welch Foundation supported the research.

Several years ago, biologist Denise Montell, a distinguished professor at UC Santa Barbara, found that sometimes cells survive after what was considered the critical step in cellular suicide. Now, she and her lab have identified two key factors involved in this remarkable recovery.

The findings, published in Nature Communications, indicate that this survival mechanism may be critical to normal tissue recovery from extreme stress rather than a fluke occurrence. Understanding its nuances could also provide new strategies for treating cancers.

Apoptosis is the most common way cells commit suicide, and this process is critical in maintaining an organism’s wellbeing. Living things need a way to terminate cells when they are badly injured or their DNA is damaged. Apoptosis is also part of natural turnover, especially in blood cells, skin cells and the lining of the gut.

“Before our work, people really thought that apoptosis was an all-or-nothing decision,” said Montell, Duggan Professor in the Department of Molecular, Cellular, and Developmental Biology. “You either committed to suicide and went through with it, or you didn’t.”

Scientists considered the activation of an enzyme appropriately called “executioner caspase” to be the point of no return. This enzyme essentially slices and dices many of the cell’s proteins. But it turns out apoptosis is more nuanced than previously known, and sometimes cells survive the executioner caspase via another process — anastasis.

Back from the brink

This phenomenon first came to Montell’s attention around 2010. Generally, scientists studying apoptosis use extreme conditions that cause all the cells in their sample to die. A doctoral student in her lab at the time was curious whether cells could survive the activation of caspase if he removed the substance that induced apoptosis. To everyone’s surprise, many of them did.

Since then scientists have observed anastasis in cells from many different organisms, including humans, mice and fruit flies. Montell and her team decided to search for genes that would either enhance or inhibit the ability of cells to undergo this process.

To this end, the researchers applied a technique they developed in 2016. By breeding transgenic fruit flies that express a specific protein that is cut by the executioner caspase, they initiated a series of events that ultimately makes the cells fluoresce green. That permanently identifies any cell that has survived through this phase of apoptosis.

With this tool on hand, the team, led by former postdoctoral fellow Gongping Sun, set out to identify the genes involved in anastasis. Given they couldn’t investigate all 13,000 genes in the fruit fly genome, the researchers combed their own data as well as the literature to identify candidate genes, eventually settling on about 200 to investigate further.

Sun and her lab mates took hundreds of fruit flies and knocked out the expression of a different gene in half of the cells of each animal. This enabled them to control for other factors that might influence the results.

In the paper published in 2016, the team found that some cells undergo anastasis during normal development of the fruit fly. In the new paper, they therefore looked for changes in the percentage of cells that went through this process during development. They also tested the genes for their ability to affect anastasis in response to stresses like radiation and heat.

Distinguishing between genes involved in anastasis and those that are simply necessary for basic survival was a challenge. “Because if it’s necessary for survival, period, then it’s also going to be necessary for recovery from the brink of death,” Montell said.

So, the team looked not only at how many cells in a sample fluoresced green after the experiment, but the ratio of green cells to non-green cells. If the gene in question was necessary for basic survival, but not involved in anastasis, it affects all cells equally. This would impact the overall number of fluorescent cells, but leave the ratio unchanged.

The researchers found two proteins, and the genes that coded for them, were instrumental in anastasis. The first, AKT1, is a well-studied and renowned survival protein that is activated in response to growth factors, essentially telling the cell to grow and divide. Scientists were aware that it can block the activation of executioner caspase, but the team discovered it can also make the difference between survival and death after caspase has been triggered.

The other protein, CIZ1, is not as well-studied, and shows up in a number of unrelated papers across the literature. In nearly all these instances it appears that CIZ1 also promotes survival from stress. For instance, a decreased amount of CIZ1 is associated with increased age-dependent neurodegeneration in mice.

The involvement of these two proteins in anastasis indicates that it is probably a very ancient process. “Not just the phenomenon of cells recovering from the brink of death, but even the mechanism — the molecules involved — are so deeply conserved in evolution that flies and mice are using the same molecules,” Montell said.

Apoptosis and fighting cancer

These findings are a huge step forward in understanding apoptosis on a fundamental level. They also suggest possible applications — especially in efforts to combat cancer.

Apoptosis serves an important function in maintaining stable equilibrium within complex organisms. Under normal circumstances — say UV damage to a skin cell — the body wants the injured cell to die so that it doesn’t develop into a condition like melanoma.

“However, if you were subjected to extreme stress you might not want every cell to commit apoptosis,” Montell said. “That might result in permanent tissue damage from which it would be very hard to recover.”

In response to severe but temporary trauma, it could be beneficial for some of the cells to be able to bounce back. Montell suspects this is the primary reason that organisms evolved a way to circumvent apoptosis.

The temporary nature of the stress seems to be the critical factor both in the role anastasis plays in promoting healing and in the mechanism itself. When a cell is under extreme stress, like radiation or chemical exposure, two things happen simultaneously: The cell activates the apoptosis response — including executioner caspase — while also activating pro-survival responses.

“It’s like putting on the accelerator and the brake at the same time,” Montell said.

The apoptotic factors reinforce themselves, so if the stressful conditions persist, the process crosses a threshold and the cell dies. But if the stress is only transient, the pro-survival pathway is already poised to kick in and help the cell recover. Researchers don’t fully understand how the cell turns off the apoptotic pathway, but proteins like AKT1 and CIZ1 are likely involved.

There is, however, a dark side to this survival mechanism. “Anastasis could be a good thing if you’re trying to repair a damaged tissue, but it could be a bad thing in that it might promote the growth of tumors,” Montell pointed out, “especially in response to chemotherapy and radiation treatments, which are extreme temporary stresses.”

This matches the experience of many physicians, Montell explained. A lot of cancer patients initially respond well to treatments; their tumors shrink and their condition improves. But unfortunately, the tumors often grow back. And scientists aren’t certain why this is.

Some think the resurgence could be the result of drug-resistant cells that exist in the tumor, which then seed the relapse. This paper provides another hypothesis — “the idea that the treatment itself could induce the cancer cells to undergo this stress-dependent survival process,” Montell said.

This notion could fundamentally change the way doctors think about preventing relapse. There isn’t much you can do against drug-resistant cells, Montell said, but if the relapse is due to this survival mechanism, these findings could inform new therapies.

Drugs that inhibit AKT1 are currently in clinical trials. These could be combined with other therapies to increase their effectiveness, potentially enabling doctors and researchers to inhibit anastasis in cancer cells while promoting it normal cells.

What’s more, successful cancer cells can actually induce apoptosis in the T cells that the immune system sends to attack them, according to Montell. This presents another target for anastasis therapies.

“There’s this ongoing war between the immune system and cancer,” Montell said, “and if you can tip the balance even a little bit, you can start to win.”