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Led by researchers from the University of California at Irvine, a new study reveals that a long-lived Chilean rodent, called Octodon degus (degu), is a useful and practical model of natural sporadic Alzheimer’s Disease. The findings were published today in Acta Neuropathologica Communications.
“We found robust neurodegenerative features in cognitively impaired aged degus, including hippocampal neuronal loss, altered parvalbumin and perineuronal net staining in the cortex, and increased c-Fos neuronal activation in the cortex that is consistent with the neural circuit hyperactivity that are commonly reported in human Alzheimer’s Disease patients,” explained corresponding author Xiangmin Xu, PhD, professor and Chancellor’s Fellow of anatomy and neurobiology in the UCI School of Medicine, and director of the Center for Neural Circuit Mapping. “By focusing on a subset of aged degus that show AD-like behavioral deficits and correlative neuropathology, we establish outbred degus as a natural model of sporadic AD and demonstrate the potential importance of wild-type outbred genetic backgrounds for AD pathogenesis.”
This study was motivated by the need to settle earlier debates of whether degus can be a useful natural model of AD. There is a critical need for non-murine, natural animal models for Alzheimer’s research as particularly highlighted by the NIH RFA “New/Unconventional Animal Models of Alzheimer’s Disease.” The handful of published papers on degus of differing genetic backgrounds yield inconsistent findings about sporadic AD-like pathological features, with notably differing results between lab in-bred degus versus outbred degus.
“We suspect that inconsistent findings between different studies may have been due to comparing neuropathology results from laboratory in-bred colonies versus more genetically diverse outbred degus, relatively low statistical power for sample size, and the absence of behavioral screening,” said Xu.
This study revealed that outbred, aged degus possessing both behavioral and neuropathological characteristics that resemble human AD pathologies, have clear advantages over common rodent models (mice and rats) for studying AD. Further, a portion of the outbred degu population naturally develops additional conditions similar to type-2 diabetes, macular degeneration, and atherosclerosis with age, which provides an avenue to investigate AD comorbidities in the degu.
“Our findings, taken together, show spontaneous AD-like correlative phenotypes in cognitive performance and neuropathology in aged, outbred degus. This supports that aged degus are a useful and practical model of natural sporadic AD,” said Xu.
Zhiqun Tan, PhD, an associate researcher with UCI’s CNCM and UCIMIND, and B. Maximiliano Garduño, a graduate student in the UCI Department of Anatomy & Neurobiology, are co-first authors of the paper. Other members of the research team include Todd Holmes, PhD, from the UCI School of Medicine Department of Physiology & Biophysics; Lujia Chen, a graduate student in biomedical engineering at UCI; and their international collaborators Patricia Cogram, PhD, associate professor, and Pedro Fernández Aburto, PhD, from the Institute of Ecology and Biodiversity at the University of Chile. This study was supported by the National Institutes of Health.
Alzheimer disease (AD) is an age-related progressive neurodegenerative disorder characterized by irreversible cognitive decline and specific pathologic lesions in the brain that greatly impair the lives of individuals suffering from the condition. There are approximately 44 million people suffering from AD worldwide, of which over 90 percent of those cases are late-onset and occur sporadically.
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When the Golden State Warriors’ Steph Curry makes a free throw, his brain draws on motor memory. Now researchers at UC San Francisco (UCSF) have shown how this type of memory is consolidated during sleep, when the brain processes the day’s learning to make the physical act of doing something subconscious.
The study, published Dec. 14, 2022, in Nature, shows the brain does this by reviewing the trials and errors of a given action. In the analogy, that means sorting through all the free throws Curry has ever thrown, weeding out the memory of all the actions except those that hit the mark, or that the brain decided were “good enough.” The result is the ability to make the free throw with a high degree of accuracy without having to think about the physical movements involved.
“Even elite athletes makes errors, and that’s what makes the game interesting,” said Karunesh Ganguly, MD, PhD, a professor of neurology and member of the UCSF Weill Institute for Neurosciences. “Motor memory isn’t about perfect performance. It’s about predictable errors and predictable successes. As long as the errors are stable from day to day, the brain says, ‘Let’s just lock this memory in.'”
Ganguly and his team found that the “locking in” process involves some surprisingly complex communication between different parts of the brain and takes place during the deep restorative slumber known as non-REM sleep.
Sleep is important because our conscious brains tend to focus on the failures, said Ganguly, who previously identified the sleep-associated brain waves that influence skill retention.
“During sleep, the brain is able to sift through all the instances it’s taken in and bring forward the patterns that were successful,” he said.

The great hope of cancer immunotherapy is to bolster our own immune cells in specific ways to keep cancer cells from evading our immune system. Although much progress has been made, immunotherapy does not always work well. Jessica Thaxton, PhD, MsCR, in the immunotherapy group at the UNC Lineberger Comprehensive Cancer Center, wants to know why. She thinks one reason is the stress response experienced by T cells once they infiltrate solid cancers.
The Thaxton lab’s latest work, published in the journal Cancer Research, shows in detail how the stress response in T cells can lead to their inability to curtail tumor growth. Thaxton’s group found that T cells exposed to the environment of solid cancers undergo a natural response to stress that shuts off their function, limiting T cell ability to kill tumors. By manipulating multiple proteins in the stress response pathway inside T cells, Thaxton’s team showed that it was possible to overcome the intrinsic T cell stress response to allow the immune system to thwart cancer growth.
At the center of this research is a protein called PKR ER-like kinase (PERK), which is a major stress sensor for all cell types, including T cells, but has not been deeply studied in the context of immunity. That is, when a T cell is under duress — like when faced with the hostile environment created by cancer cells — it is PERK that responds to the stress in a way that causes cells to stop secreting proteins in an effort to help the cell survive.
“Halting protein translation is protective in most cells and is part of the acute arm of the T cell’s stress response,” said Thaxton, senior author of the paper and associate professor of cell biology and physiology at the UNC School of Medicine. “Everything in the scientific literature indicates that the acute arm of the PERK-mediated stress response aims to protect cells in hostile environments.”
But Thaxton’s group hypothesized that — in the context of tumor suppression — this natural T cell stress response would be detrimental to effective tumor immunotherapy.
“T cells are among the body’s most highly secretory cells, producing approximately 800,000 proteins per minute in states of activation against foreign invaders,” she said. “In order for immunotherapy to be effective, T cells have to secrete things such as cytotoxic cytokines in order to kill tumor cells.”
She postulated that the PERK response could be halting protein secretion in a way that made T cells less effective at combating tumors.

A collaborative study involving Baylor College of Medicine, the University of Cambridge and the University of Exeter Medical School reveals a new gene associated with obesity and maladaptive behavior. The evidence shows that rare mutations in the gene for the serotonin 2C receptor play a role in the development of obesity and dysfunctional behaviors in humans and animal models. The findings, published in the journal Nature Medicine, have both diagnostic and therapeutic implications.
“Serotonin is a chemical produced in the brain that acts as a neurotransmitter, that is, it relays messages from one part of the brain to another. Serotonin communicates the message by binding to brain cells carrying serotonin receptors. These brain cells are involved in a variety of functions, including mood, appetite and some social behaviors, among others,” said co-corresponding author Dr. Yong Xu, professor of pediatrics- nutrition and molecular and cellular biology at Baylor.
In the current study, the Xu lab and the lab of Dr. I. Sadaf Farooqi at the University of Cambridge, collaborated to investigate the role of one of the serotonin receptors, namely serotonin 2C receptor, in weight regulation and behavior. By combining the individual expertise of each lab — basic and genetic animal studies in the Xu lab and human genetics in the Farooqi lab — the team was able to make the case that serotonin 2C receptor is an important regulator of body weight and certain behaviors.
The project started with the finding that some children diagnosed with severe obesity carried rare mutations or variants of the serotonin 2C receptor gene. The researchers identified 13 different variants associated with obesity in 19 unrelated people. Further characterization of the variants revealed that 11 of them cause loss-of-function of the receptor.
“People who carried loss-of-function variants had hyperphagia, or an extreme appetite, some degree of maladaptive behavior and emotional lability, which refers to rapid, often exaggerated changes in mood including strong emotions such as uncontrollable laughing or crying or heightened irritability or temper,” Xu said.
The researchers found that animal models carrying one of the human loss-of-function mutations also became obese, which confirmed the team’s suspicion that loss-of-function mutations of the serotonin 2C receptor gene were involved in obesity.

Comparing the genetics and relocation patterns of habitat “haves” and “have-nots” among two populations of threatened rattlesnakes has produced a new way to use scientific landscape data to guide conservation planning that would give the “have-nots” a better chance of surviving.
The study suggests that a collection of six relatively closely situated but isolated populations of Eastern massasauga rattlesnakes in northeast Ohio could grow their numbers if strategic alterations were made to stretches of land between their home ranges. The findings contributed to the successful application for federal funding of property purchases to make some of these proposed landscape changes happen.
Reconnecting these populations could not only help restore Eastern massasaugas to unthreatened status, but establish a thriving habitat for other prey and predator species facing threats to their survival — satisfying two big-picture conservation concerns, researchers say.
“We aren’t just protecting massasaugas — we’re protecting everything else that’s there,” said H. Lisle Gibbs, professor of evolution, ecology and organismal biology at The Ohio State University and senior author of the study. “Even though we are focused on this species, protection of the habitat has all these collateral benefits.”
The research was published recently in the journal Ecological Applications.
Eastern massasauga rattlesnakes live in isolated spaces in midwestern and eastern North America and were listed as threatened under the Endangered Species Act in 2016 because of loss and fragmentation of their wetland habitat.

Testing the contents of a simple sample of wastewater can reveal a lot about what it carries, but fails to tell the whole story, according to Rice University engineers.
Their new study shows that composite samples taken over 24 hours at an urban wastewater plant give a much more accurate representation of the level of antibiotic-resistant genes (ARGs) in the water. According to the Centers for Disease Control and Prevention (CDC), antibiotic resistance is a global health threat responsible for millions of deaths worldwide.
In the process, the researchers discovered that while secondary wastewater treatment significantly reduces the amount of target ARG, chlorine disinfectants often used in later stages of treatment can, in some situations, have a negative impact on water released back into the environment.
The lab of Lauren Stadler at Rice’s George R. Brown School of Engineering reported seeing levels of antibiotic-resistant RNA concentrations 10 times higher in composite samples than what they see in “grabs,” snapshots collected when flow through a wastewater plant is at a minimum.
Stadler and lead authors Esther Lou and Priyanka Ali, both graduate students in her lab, reported their results in the American Chemical Society journal Environmental Science & Technology: Water.
The results could lead to better protocols for treating wastewater to lower the prevalence of antibiotic-resistant genes in bacteria that propagate at plants and can transfer those genes to other organisms in the environment.

Killings of children and teenagers under 18 increased sharply in 2020, federal researchers reported. Black communities were disproportionately affected.As the pandemic spread across the United States in 2020, the number of children who were killed rose precipitously, as did the number injured by firearms, scientists reported in two studies on Monday.A majority of the homicides were among Black children, and almost half were among children in the southern United States. Each of those groups also accounted for most of the children brought to pediatric hospitals with gun injuries.The rate of child homicide in the United States rose by about 28 percent in 2020, from 2.2 per 100,000 in 2019 to 2.8 per 100,000 in 2020, researchers at the Centers for Disease Control and Prevention found.Homicide is the leading cause of death among American children, making the United States an outlier among similarly developed nations, where car accidents, cancer and other illnesses and injuries are the top causes of death.About half of those are caused by firearms. But younger children are more likely to be killed by physical assaults than by firearms, including beatings or attacks with sharp objects or blunt instruments.Gun homicides have also risen greatly among children in recent years. In a review of recent data on firearms, The New York Times reported last week that gun homicides involving children had increased by more than 73 percent since 2018 and that the disparity in risk between Black children and others was rapidly widening.The authors of the new study, published in JAMA Pediatrics, said the data highlighted a public health concern “warranting immediate attention.” Child homicides are “fundamentally preventable,” yet they are becoming “more common, not less,” an accompanying editorial said.Overall, older children and boys of all ages were more likely to be victims of gun violence than younger children and girls. The C.D.C. found a decline in homicide rates overall among girls, infants and children under 6 as well as among white children, Asian or Pacific Islander children and children in the Northeast.Homicides of younger children often occur in or near the home and are most commonly perpetrated by parents and caregivers. The homicides often are linked to child abuse and neglect and reflect the stresses experienced by families, said Dr. Elinore J. Kaufman, a trauma surgeon at University of Pennsylvania Perelman School of Medicine and a co-author of the editorial accompanying the homicide study.“I don’t think we’re doing a good job of taking care of families, and it shows,” Dr. Kaufman said in an interview.Older children and teenagers, on the other hand, were more likely to be killed in altercations with acquaintances or strangers in public places, she noted. Guns are more likely to be involved in these killings, and the violence reflects the deprivation that disproportionately affects Black people and other communities of color.The study noted that racial segregation exposed children of color to “concentrated poverty, segregated and underfunded educational systems, environmental hazards, lack of safe play spaces and limited opportunity.”The researchers suggested that such inequitable living conditions might play a large role in the persistent disparities in child homicide rates.As a trauma surgeon, Dr. Kaufman said, she has seen the fallout of record gun violence in Philadelphia, which went up during the pandemic and has continued with little evidence of abating.“We’re sitting at that high plateau and not seeing much in terms of improvement, except maybe a tiny bit,” Dr. Kaufman said.The increase in child homicides is part of a decade-long trend. Rates have been rising slowly but steadily since 2013 after declining from 2007 to 2013. In 2020, the first year of the pandemic, the number spiked, and 2,058 children aged 17 and younger were homicide victims, up from 1,611 in 2019.A research letter by pediatric surgeons at University of Utah School of Medicine was also published in JAMA Pediatrics on Monday. That study compared the number of children coming into the nation’s pediatric hospitals for care during two 21-month periods, one of them leading up to the pandemic and the other starting in April 2020, as the pandemic was gaining traction.The number of children seeking care for gun injuries increased to 2,759 during the second 21-month period, up from 1,815 during the first period, an increase of just over 50 percent.

One of the first real-world data studies comparing the new bivalent mRNA COVID-19 booster vaccines with the original monovalent vaccines reports the bivalent conveyed greater short-term protection against symptomatic COVID-19 infection in adults.
The multi-state study from the Centers for Disease Control and Prevention’s VISION Network found that the bivalent booster dose provides greater short-term protection against symptomatic COVID-19 infections which generate emergency department and urgent care visits or hospitalization, compared to prior receipt of two, three or even four doses of first-generation vaccines without a bivalent booster vaccine.
How well the bivalent shots protect against COVID-19-associated medical visits had previously been largely unknown.
“This study clearly shows the benefit conveyed by a bivalent booster vaccine — lowering the risk that you will have to go to the E.D. or be hospitalized due to COVID,” said study co-author Shaun Grannis, M.D., M.S., vice president for data and analytics at Regenstrief Institute and Regenstrief Professor of Medical Informatics at Indiana University School of Medicine.
The study found that from mid-September to mid-November 2022, adults who had received bivalent COVID-19 booster vaccines made 57 percent fewer COVID-19 related emergency department or urgent care visits compared to adults without prior vaccination and 51 percent fewer visits compared to adults who first had received monovalent vaccines. Bivalent booster vaccine effectiveness against hospitalization was also significant — 61 percent compared to adults without prior vaccination and 44 percent compared to adults who were vaccinated with first generation vaccines.
Among adults who had completed a primary vaccine series or one or more monovalent boosters, greater time since the most recent dose was associated with greater relative protection following the bivalent booster vaccine.
Data from immunocompromised individuals were not included in this study of the effectiveness of bivalent mRNA vaccines.
The authors conclude, “These findings support efforts to improve coverage with bivalent vaccines, although optimal timing for receipt of bivalent vaccine booster doses needs to be established. All eligible persons should stay up to date with recommended COVID-19 vaccination, including receiving a bivalent booster dose. In addition, persons should consider taking other precautions to avoid respiratory illness this winter season, including masking in public indoor spaces, especially in areas where COVID-19 community levels are high, to protect themselves and others and reduce strain on the health care system during an ongoing surge in multiple respiratory viruses.”
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Neuromuscular disorders affect millions of people worldwide. Now a discovery made at the Montreal Clinical Research Institute of Montreal (IRCM) opens the door to the development of targeted therapies.
Published in the journal Nature Communications, the development caps several years of research by doctoral student Viviane Tran under the direction of Université de Montréal medical professor Dr. Jean-François Côté, the IRCM’s president and scientific director, with international partners.
The formation of muscles, a complex process, requires the action of specialized cells, the myoblasts. In order for skeletal muscle to develop and regenerate, myoblasts must align with each other, move towards each other, and touch each other until their membranes are joined. This is called the myoblast fusion stage and is the basis for the formation of muscle fibers.
During embryogenesis, myoblast fusion is crucial, with mutations in certain genes resulting in the extremely rare clinical myopathy called Carey-Fineman-Ziter syndrome.
In adults, an army of satellite cells is responsible for muscle growth and regeneration. In response to activation signals, satellite cells proliferate, differentiate and fuse to repair damaged myofibers. The proteins and signaling pathways that control this fusion are still being identified.
‘We didn’t think it possible’
“Until recently, myoblast fusion was the subject of only basic research,” said Dr. Côté.

A recent study by York University researchers suggests an innovative artificial intelligence (AI) technique they developed is considerably more effective than the human eye when it comes to predicting therapy outcomes in patients with brain metastases. The team hopes the new research and technology could eventually lead to more tailored treatment plans and better health outcomes for cancer patients.
“This is a sophisticated and comprehensive analysis of MRIs to find features and patterns that are not usually captured by the human eye,” says York Research Chair Ali Sadeghi-Naini, associate professor of biomedical engineering and computer science in the Lassonde School of Engineering, and lead on the study.
“We hope our technique, which is a novel AI-based predictive method of detecting radiotherapy failure in brain metastasis, will be able to help oncologists and patients make better informed decisions and adjust treatment in a situation where time is of the essence.”
Previous studies have shown that using standard practices, such as MRI imaging — assessing the size, location — and number of brain metastases — as well as the primary cancer type and overall condition of the patient, oncologists are able to predict treatment failure (defined as continued growth of the tumour) about 65 per cent of the time. The researchers created and tested several AI models and their best one had an 83 per cent accuracy.
Brain metastases are a type of cancerous tumour that develops when primary cancers in the lungs, breasts, colon or other parts of the body are spread to the brain via the bloodstream or lymphatic system. While there are various treatment options, stereotactic radiotherapy is one of the more common, with treatment consisting of concentrated doses of radiation targeted at the area with the tumour.
“Not all of the tumours respond to radiation — up to 30 per cent of these patients have continued growth of their tumour, even after treatment,” Sadeghi-Naini says. “This is often not discovered until months after treatment via follow-up MRI.”
This delay is time patients with brain metastases cannot afford, as it is a particularly debilitating condition with most people succumbing to the disease between three months to five years after diagnosis. “It’s very important to predict therapy response even before that therapy begins,” Sadeghi-Naini continues.