New research has uncovered a surprising role for so-called “jumping” genes that are a source of genetic mutations responsible for a number of human diseases. In the new study from Children’s Medical Center Research Institute at UT Southwestern (CRI), scientists made the unexpected discovery that these DNA sequences, also known as transposons, can protect against certain blood cancers.
These findings, published in Nature Genetics, led scientists to identify a new biomarker that could help predict how patients will respond to cancer therapies and find new therapeutic targets for acute myeloid leukemia (AML), the deadliest type of blood cancer in adults and children.
Transposons are DNA sequences that can move, or jump, from one location in the genome to another when activated. Though many different classes of transposons exist, scientists in the Xu laboratory focused on a type known as long interspersed element-1 (L1) retrotransposons. L1 sequences work by copying and then pasting themselves into different locations in the genome, which often leads to mutations that can cause diseases such as cancer. Nearly half of all cancers contain mutations caused by L1 insertion into other genes, particularly lung, colorectal, and head-and-neck cancers. The incidence of L1 mutations in blood cancers such as AML is extremely low, but the reasons why are poorly understood.
When researchers screened human AML cells to identify genes essential for cancer cell survival, they found MPP8, a known regulator of L1, to be selectively required by AML cells. Curious to understand the underlying basis of this connection, scientists in the Xu lab studied how L1 sequences were regulated in human and mouse leukemia cells. They made two key discoveries. The first was that MPP8 blocked the copying of L1 sequences in the cells that initiate AML. The second was that when the activity of L1 was turned on, it could impair the growth or survival of AML cells.
“Our initial finding was a surprise because it’s been long thought that activated transposons promote cancer development by generating genetic mutations. We found it was the opposite for blood cancers, and that decreased L1 activity was associated with worse clinical outcomes and therapy resistance in patients,” says Jian Xu, Ph.D., associate professor in CRI and senior author of the study.
MPP8 thus suppressed L1 in order to safeguard the cancer cell genome and allow AML-initiating cells to survive and proliferate. Cancer cells, just like healthy cells, need to maintain a stable genome to replicate. Too many mutations, like those created by L1 activity, can impair the replication of cancer cells. Researchers found L1 activation led to genome instability, which in turn activated a DNA damage response that triggered cell death or eliminated the cell’s ability to replicate itself. Xu believes this discovery may provide a mechanistic explanation for the unusual sensitivity of myeloid leukemia cells to DNA damage-inducing therapies that are currently used to treat patients.
“Our discovery that L1 activation can suppress the survival of certain blood cancers opens up the possibility of using it as a prognostic biomarker, and possibly leveraging its activity to target cancer cells without affecting normal cells,” says Xu.
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Researchers at the Francis Crick Institute have found that blocking a specific protein could increase tumour sensitivity to treatment with PARP inhibitors. Their work published in Science , suggests combining treatments could lead to improved therapy for patients with inheritable breast cancers.
Some cancers, including certain breast, ovarian and prostate tumours, are caused by a fault in the BRCA1 or BRCA2 genes, which are important for DNA repair. Treatment for these cancers has greatly improved thanks to the discovery of PARP inhibitors, drugs which capitalise on this weakness in the cancer as they block a back-up repair mechanism. This means the cancer cells cannot repair breaks in their DNA, which stops the tumour from growing.
However, in many cases, the cancer eventually develops resistance to this treatment and the tumour starts to regrow aggressively. Finding new ways to effectively kill cancer cells before this resistance develops, or re-sensitise them to treatment, is crucial to offer patients an improved chance of survival.
In their study, the research team used human cells to screen for proteins that affect their sensitivity to PARP inhibitor drugs. They found that blocking a protein, DNPH1, sensitised BRCA-defective cancer cells to treatment with the PARP inhibitor, leading to cell death in the laboratory.
Importantly, cells that had acquired resistance to the PARP inhibitor were killed when this protein was also blocked. And, as the combination did not affect healthy cells, this discovery suggests that DNPH1 is a promising target for future drug development.
Stephen West, lead author and group leader of the DNA Recombination and Repair Laboratory at the Crick says: “PARP inhibitors were a great breakthrough in the treatment of certain cancers, extending the lives of many people. However, patients have to take these drugs for the rest of their lives which sadly gives most tumours time to mutate and eventually develop resistance.
“We want to improve treatments for these patients by finding a way to strengthen PARP inhibitors so they completely kill the cancer. While more work needs to be done, in the lab and then in clinical trials, we’ve found a really promising potential treatment combination.”
In further experiments, the researchers characterised the role of the DNPH1 protein. It acts as a ‘scavenger’, removing faulty nucleotides from the pool of nucleotides which are used to build DNA. Without this process, this nucleotide ‘junk’ is incorporated into strands of DNA. The incorporation of faulty nucleotides is the key determinant that makes the cells more susceptible to the effects of PARP inhibitors.
Kasper Fugger, lead author and postdoc in the DNA Recombination and Repair Laboratory at the Crick says: “By investigating the function of DNPH1 and finding the molecules it interacts with, we have a good understanding of how the protein works in cells. This knowledge should help us to more effectively kill cancer cells by developing an inhibitor drug, which is specific enough to be used safely in people.”
The researchers are now collaborating with pharmaceutical companies to develop an inhibitor of the DNPH1 protein which, if shown to be safe and effective in clinical trials, could be used alongside PARP inhibitors as a cancer treatment.
The topic of DNA repair in cancer was the focus of a virtual conference, Medicine at the Crick, held in February. The event was part of a series which showcases major advances in biomedical science and brings together lab-based scientists together and clinicians to consider the potential impact on patient treatment.
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Two studies published in the open-access journal PLOS Pathogens provide new evidence supporting an important role for the immune system in shaping the evolution of SARS-CoV-2, the virus that causes COVID-19. These findings — and the novel technology behind them — improve understanding of how new SARS-CoV-2 strains arise, which could help guide treatment and vaccination efforts.
For the first study, Rachel Eguia of Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues sought to better understand SARS-CoV-2 by investigating a closely related virus that has circulated widely for a far longer period of time: the common-cold virus 229E.
229E and SARS-CoV-2 are both in the coronavirus family, which features a “spike protein” that enables infection of human cells. A person who is infected with 229E develops an immune response against the spike protein that protects them from reinfection, but only for a few years. Whether reinfection then occurs because the immune response wears off or because 229E evolves to escape it has been unclear.
Eguia and colleagues addressed this question by testing the activity of serum samples collected from patients in the 1980s-90s against spike proteins from both old 229E strains and strains that evolved later on. They found that the old spike proteins were vulnerable to the older sera. However, modern spike proteins were able to evade older sera while remaining vulnerable to sera from modern patients.
This analysis suggests that modern strains of 229E have accumulated spike protein mutations that enable them to evade older sera. These findings raise the possibility that SARS-CoV-2 and other coronaviruses could undergo similar evolution, and that COVID-19 vaccines may require periodic updates to remain effective against new strains.
The authors add, “The human common-cold coronavirus evolves over the span of years to decades to erode neutralization by human polyclonal serum antibodies. This work suggests that human coronaviruses undergo significant antigenic evolution that may contribute to eventual re-infections.”
For the second study, Sung Hee Ko of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and colleagues developed new technology for genetic sequencing of the SARS-CoV-2 spike protein, enabling detection of multiple SARS-CoV-2 strains that may be present at the same time within a single infected patient.
Previous studies have used standard sequencing methods to produce a single genetic sequence from an individual patient, obscuring the potential presence of multiple SARS-CoV-2 strains. By contrast, the new technology highlights virus diversity within each patient and enables tracking of the evolution of new SARS-CoV-2 strains during acute infection.
Indeed, when the researchers applied the new method to human respiratory samples, they found new SARS-CoV-2 variants arising within the same patient over the course of acute infection. The precise mutations in these variants suggest that they arose in response to selective pressure from the immune system.
Future application of the new technology could improve understanding of how the evolution of new SARS-CoV-2 variants within a single patient impacts their outcomes. The findings also suggest that patients might see greater benefits from early treatment with antiviral drugs capable of targeting multiple strains, than from delayed treatment with a single antiviral drug.
The authors add, “We used new technology to show that coronavirus variants with mutated spike proteins can arise early in the course of infection. Our results suggest more virus evolution in each person than previously thought, with potential implications for clinical outcomes and for the emergence of transmissible variant strains.”
Together, these two studies deepen understanding of how new SARS-CoV-2 strains arise in response to immune system activity, potentially paving the way for additional research and improved treatment.
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A rare and controversial mutation in the phospholipase D3 (PLD3) protein — previously linked to Alzheimer’s disease — interferes with PLD3’s vital recycling function inside neurons. Matthew Schrag of Vanderbilt University Medical Center and colleagues report these new findings in a paper published April 8th in PLOS Genetics.
About 1 percent of people with Alzheimer’s disease carry a specific mutation in their PLD3 gene. The question of whether or not this mutation leads to Alzheimer’s disease has remained controversial, however, due to its rarity and because the protein’s function was previously unknown. In the new study, Schrag’s team delved deeper into the function of this gene and its link to the disease. The researchers found that PLD3 is located in lysosomes inside neurons. Lysosomes are highly acidic sacs of enzymes that act as the recycling system of the cell. PLD3 produces an important component of the membrane of these acidic organelles, and this function is lost in the mutant form. In the brains of people with Alzheimer’s disease, PLD3 occurred near buildups of toxic proteins called β-amyloid plaques. Furthermore, people with high levels of PLD3 had fewer β-amyloid plaques and less cognitive decline, suggesting that normal PLD3 helps protect against the disease.
Together, these discoveries establish the PLD3 mutation places a person at higher risk of developing Alzheimer’s disease, most likely by disrupting its role in the lysosome. The researchers propose that future studies should focus on investigating whether boosting PLD3 can have a protective effect that reduces the effects of the disease. Ultimately, these findings may yield new drug targets for Alzheimer’s disease therapies and improve our understanding of the role of the lysosome in this common and burdensome disease.
“The discovery of Phospholipase D3 as a genetic risk factor for Alzheimer’s disease points to the critically important role of the lysosome in dementia,” the authors add. “Targeting experimental therapies to these lysosomes could lead us to new approaches to treat this disease.”
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Six years ago, Michael Niederweis, Ph.D., described the first toxin ever found for the deadly pathogen Mycobacterium tuberculosis. This toxin, tuberculosis necrotizing toxin, or TNT, became the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. The toxin is released as M. tuberculosis bacteria survive and grow inside their human macrophage host, killing the macrophage and allowing the escape and spread of the bacteria.
For 132 years, the lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death. M. tuberculosis infects 9 million people a year and kills more than 1 million.
Now, in another groundbreaking work, the University of Alabama at Birmingham researcher and colleagues describe how two small ESX proteins made by the M. tuberculosis bacteria mediate secretion of TNT by pore formation in the membranes that envelop the bacteria. This finding may have broad application because a distinctive three-amino acid motif found on EsxE and EsxF — tryptophan/any-amino-acid/glycine, known in shorthand as WXG — is also found on many other small mycobacterium proteins and on the large WXG100 superfamily of bacterial proteins that resemble EsxE and EsxF.
“Here, we show for the first time that small Esx proteins of the WXG100 family have an important molecular function inside the Mtb cell by mediating toxin secretion,” said Niederweis, a professor in the UAB Department of Microbiology. “Our results suggest a dynamic mechanism of pore formation by small Esx proteins that might be applicable to other members of the large WXG100 protein family. Thus, our study not only represents a major advancement in our understanding of secretion of TNT and likely of other proteins in M. tuberculosis, but also describes a biological function for Esx-paralogs in M. tuberculosis and their homologs in the large WXG100 protein family in Gram-positive bacteria.”
TNT is one of two domains in the M. tuberculosis outer membrane protein CpnT; activity of the TNT domain of CpnT in the cytosol of the macrophage induces macrophage death by hydrolyzing NAD+. M. tuberculosis has an inner membrane and an outer membrane, and a protein needs to get through each layer to be secreted outside of the bacterium. How CpnT gets to the outer membrane was unknown.
EsxE and EsxF are part of the same gene segment as CpnT, and the UAB researchers hypothesized that the two small proteins might be involved in secretion of the toxin.

Alzheimer’s disease is known for its slow attack on neurons crucial to memory and cognition. But why are these particular neurons in aging brains so susceptible to the disease’s ravages, while others remain resilient?
A new study led by researchers at the Yale School of Medicine has found that susceptible neurons in the prefrontal cortex develop a “leak” in calcium storage with advancing age, they report April 8 in the journal Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association. This disruption of calcium storage in turns leads to accumulation of phosphorylated, or modified, tau proteins which cause the neurofibrillary tangles in the brain that are a hallmark of Alzheimer’s.
These changes occur slowly, building over many years, and can be seen within neurons in the brains of very old monkeys, the researchers report.
“Altered calcium signaling with advancing age is linked to early-stage tau pathology in the neurons that subserve higher cognition,” said corresponding author Amy Arnsten, the Albert E. Kent Professor of Neuroscience and professor of psychology and member of the Kavli Institute of Neuroscience at Yale University.
These vulnerable neurons face another problem. As they age, they tend to lose a key regulator of calcium signaling, a protein called calbindin, which protects neurons from calcium overload, and is abundant in the neurons of younger individuals.
“With age, these neurons face a double whammy, with an excessive calcium leak that initiates toxic actions, as well as diminished levels of the protectant, calbindin,” said Arnsten.
Neurons in the prefrontal cortex require relatively high levels of calcium to perform their cognitive operations, but the calcium must be tightly regulated. However, as regulation is lost with increasing age, neurons become susceptible to tau pathology and degeneration. Essentially, neurons “eat” themselves from within.
“Understanding these early pathological changes may provide strategies to slow or prevent disease progression,” Arnsten said.
The study is a collaboration between the labs of Arnsten and Angus Nairn at Yale; Dibyadeep Datta and Shannon N. Leslie are co-first authors of the research.
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Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

When you think of ways to treat opioid use disorder, you might think methadone clinics and Narcotics Anonymous meetings. You probably don’t imagine stretches and strengthening exercises.
But Anne Swisher — professor at the West Virginia University School of Medicine — is working to address opioid misuse in an unconventional way: through physical therapy. She and her colleagues have enhanced physical therapy instruction at WVU to emphasize the profession’s role in preventing and treating opioid use disorder.
“Students have different interests and passions within the profession, and they find their niche,” said Swisher, a researcher and director of scholarship in the Division of Physical Therapy. “No matter what their passion is, there is a way they can make a difference, whether it’s by preventing people from starting down the road of opioids — by minimizing pain medication and doing movement interventions — or whether it’s by helping people in the recovery process become healthier overall.”
Swisher and her team devised a model to show doctor of physical therapy students how key topics in their curriculum — such as women’s health, pediatric care and sports therapy — could all address opioid use disorder in various ways.
Their model — which was published in rehabilitation journal Physical Therapy — is innovative because it goes beyond musculoskeletal issues and addresses how physical therapists can assist people across the lifespan, from neonatal to hospice settings. It also illustrates how physical therapists can help improve human movement across what Swisher calls the “whole addiction spectrum.”
“In our curriculum, our students learn about all of these different aspects — what to do with somebody who’s critically ill, the appropriate developmental milestones for children, how to help older people stay active — but it was really just a matter of connecting it all together,” she said.

Scientists could be a step closer to finding a way to reduce the impact of traumatic memories, according to a Texas A&M University study published recently in the journal Nature Neuroscience.
The report details a study by researchers from the Department of Psychological and Brain Sciences and the Institute for Neuroscience. Stephen Maren, professor of psychological and brain sciences, said the group’s findings suggest that procedures used by clinicians to indirectly reactivate traumatic memories render a window whereby those memories can be altered, or even erased completely.
In therapy, imaginal reminders are often used to safely retrieve traumatic memories of experiences. For example, Maren said a military veteran wounded by an improvised explosive device may be asked to re-experience trauma cues — like the lights and sounds of the explosion — without the negative consequences. The idea is that the fear responses can be dampened through this exposure therapy.
“The one major challenge is when you do the extinction procedures, it doesn’t erase the original trauma memory,” Maren said. “It’s always there and can bubble back up, which is what causes relapse for people who re-experience fear.”
With this in mind, the researchers hoped to answer whether they could isolate a memory and drive fear responses by reactivating it artificially — and potentially disrupt the original memory itself. Maren said their findings suggest that procedures currently used by clinicians to indirectly reactivate traumatic memories create an opportunity to change or eliminate them.
To do this, the researchers used a conditioning procedure in which a cue becomes indirectly associated with a fearful event. When the cue is presented later, it indirectly reactivates a memory of the event and increases activity in the hippocampus, a brain area important for memory.
The study showed that indirectly reactivating a contextual fear memory through re-exposure to the cue can make the memory vulnerable to disruption. Maren said further research is needed to answer if scientists can produce a permanent loss of the traumatic information.
Authors on the study are Maren, Reed L. Ressler, Travis D. Goode, Sohmee Kim and Karthik R. Ramanathan. This research was funded by the National Institutes of Health.
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Materials provided by Texas A&M University. Original written by Caitlin Clark. Note: Content may be edited for style and length.

Damage to the autism-associated gene Dyrk1a, sets off a cascade of problems in developing mouse brains, resulting in abnormal growth-factor signaling, undergrowth of neurons, smaller-than-average brain size, and, eventually, autism-like behaviors, a new study from Scripps Research, Florida, finds.
The study from neuroscientist Damon Page, PhD, describes a new mechanism underlying the brain undergrowth seen in individuals with Dyrk1a mutations. Page’s team used those insights to target the affected pathway with an existing medicine, a growth hormone. It restored normal brain growth in the Dyrk1a mutant mice, Page says.
“As of now, there’s simply no targeted treatments available for individuals with autism spectrum disorders caused by DYRK1A mutations,” Page says. “This represents a first step in evaluating a potential treatment that could be used in the clinic.”
Their study appears Thursday in the journal Biological Psychiatry.
To track the effects of missing Dyrk1a genes, Jenna Levy, the paper’s first author and a graduate student in Page’s lab, engineered mice to have one or two broken copies of Dyrk1a in their developing brain tissue. The brains of both sets of mice developed abnormally, she found, displaying decreased brain size and number of neurons, as well as reduced number of other brain cells.
Downstream effects
The scientists also conducted “unbiased” proteomic studies, to see if the mutant mice had abnormally high or low levels of other unknown proteins that might impact brain development. Using a technique called “high-resolution tandem mass spectrometry coupled to liquid chromatography,” they found that the Dyrk1a mutant mice had reduced levels of 56 cellular proteins, and increased levels of 33. Many of those were known autism risk genes, some implicated in sending growth signals, Levy says.

It’s one thing to decide among two or three snacks available at a friend’s house. But what do people do when they’re faced with a vending machine offering 36 different options?
A new study using eye-tracking technology suggests that the amount of time people spend looking at individual items may actually help them decide. Findings showed that people tended to choose snacks they spent more time looking at, sometimes even over snacks that they rated more highly.
“We could do pretty well predicting what people would choose based just on their ratings of the snacks available to them. But we could do an even better job by accounting for how much they looked at each item,” said Ian Krajbich, co-author of the study and associate professor of psychology and economics at The Ohio State University.
But the amount of time people spend looking at individual items isn’t the whole story of how people decide when they have many alternatives, Krajbich said.
“It’s a little more complicated than that,” he said.
Krajbich conducted the study with lead author Armin Thomas of Technische Universität Berlin and Felix Molter of Freie Universität Berlin. The research was published this week in the journal eLife.