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Providence began reaching out to more than 700 patients after The Times contacted the hospital system about its billing and debt-collection practices.One of the country’s largest nonprofit hospital chains, Providence, will refund payments made by more than 700 low-income patients who were wrongly charged for medical care that should have been free.The patients qualified for Medicaid, the government health insurance for people with low incomes, but were nonetheless billed for health care and then referred to debt-collection firms. The practice was the result of a program, known as Rev-Up, that was designed to maximize revenues by wringing as much money as possible from patients — even those whose incomes were so low they should never have been billed at all.Rev-Up, which Providence created with the help of the consulting firm McKinsey & Company, was the subject of a New York Times investigation last month.Providence began reaching out to the patients in late September, weeks after The Times asked the hospital system to comment on its billing and debt-collection practices, according to Melissa Tizon, a spokeswoman for Providence. She said the hospital system, which is not disclosing the total amount of money it is refunding, had been planning to issue the refunds for months.In February, Bob Ferguson, the attorney general of Washington State, sued Providence, accusing it of violating state law in part by deploying debt collectors to go after more than 55,000 patient accounts. Providence is fighting the lawsuit.Under state law in Washington, where Providence is based, hospitals must provide free care to patients whose income falls below 300 percent of the federal poverty level, or about $83,250 in annual income for a family of four. The group typically includes anyone who qualifies for Medicaid, and, until 2019, Providence waived all medical costs for people covered by the program.That year, Providence — which operates 51 hospitals and more than 900 clinics across the country — changed its practices and began sending Medicaid patients to debt collectors, The Times reported last month.Ms. Tizon blamed an “unintended error” that occurred when Providence was updating how it identified those eligible for charity care, “causing some Medicaid patients to receive collection notices.”Ms. Tizon said Providence was reaching out to about 760 patients who qualified for Medicaid but were wrongly billed. She said the hospital system would repay their costs and interest, and work with credit-reporting agencies to “reverse any negative impact on credit.”Last week, Gregory Hoffman, Providence’s chief financial officer, sent a message about the Times investigation to employees.“As I read the story, I did not recognize the organization that was being described because it is not the organization we serve. I am sorry you had to read it,” he wrote. He added that Providence would reach out to “each of the patients featured in the article to talk with them about their experience and ensure they have the financial assistance they need.”Providence also purchased full-page ads in The Oregonian and The Seattle Times newspapers that promoted its charity-care practices. The ads ran on the same day that The Times published its investigation.The article prompted calls for action from state and federal lawmakers. Dr. Lisa Reynolds, an Oregon state representative, said her state’s attorney general should look into Providence’s collection practices there.Senator Patty Murray, the Washington Democrat who chairs the Senate’s health committee, sent a letter to Providence’s chief executive, Dr. Rod Hochman, expressing concern about The Times’s findings and inquiring about Providence’s collection practices.Ms. Tizon said on Tuesday that Providence was preparing a response to Ms. Murray’s letter. She added that the hospital system offered to meet with the senator in February, after the state’s lawsuit was made public, but that Ms. Murray did not respond. “She has, however, reached out several times to Providence leaders asking for campaign contributions,” Ms. Tizon said.

New research from the University of Cincinnati bolsters a hypothesis that Alzheimer’s disease is caused by a decline in levels of a specific protein, contrary to a prevailing theory that has been recently called into question.
UC researchers led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the research on Oct. 4 in the Journal of Alzheimer’s Disease.
Questioning the dominant hypothesis
The research is focused on a protein called amyloid-beta. The protein normally carries out its functions in the brain in a form that is soluble, meaning dissolvable in water, but it sometimes hardens into clumps, known as amyloid plaques.
The conventional wisdom in the field of Alzheimer’s research for more than 100 years stated that Alzheimer’s was caused by the buildup of amyloid plaques in the brain. But Espay and his colleagues hypothesized that plaques are simply a consequence of the levels of soluble amyloid-beta in the brain decreasing. These levels decrease because the normal protein, under situations of biological, metabolic or infectious stress, transform into the abnormal amyloid plaques.
“The paradox is that so many of us accrue plaques in our brains as we age, and yet so few of us with plaques go on to develop dementia,” said Espay, professor of neurology in the UC College of Medicine, director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute and a UC Health physician. “Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies.”
Sturchio noted that many research studies and clinical trials over the years have aimed at reducing amyloid plaques in the brain, and some have lessened plaques, but until the September 27 announcement of a positive trial by Biogen and Eisai (lecanemab), none slowed the progression of Alzheimer’s disease. More importantly, in support of their hypothesis, in some clinical trials that reduced the levels of soluble amyloid-beta, patients showed worsening in clinical outcomes.

A large part of our DNA is made up of selfish repetitive DNA elements, some of which can jump from one site in the genome to another, potentially damaging the genome. Researchers from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) describe how different types of repetitive DNA elements are controlled by the same silencing mechanism in fruit fly ovaries. Central to their findings is an uncharacterized protein that the researchers named “Kipferl,” which ensures the effective control of jumping genes. The findings suggest that different selfish elements compete for the host genome defense system and that Kipferl might be the first of a series of similarly acting molecules yet to be uncovered. The findings are published in eLife.
About half of the human genome, and a fifth of the fruit fly genome, is composed of genetic parasites resembling genes that can make copies of themselves, and insert themselves into random areas of our genome, potentially disrupting normal gene expression. Multiple defense mechanisms have evolved to keep these so-called transposons in check. One such mechanism is an RNA interference system called the piRNA pathway. The piRNA pathway is a small RNA silencing pathway conserved throughout the animal kingdom, from sponges to mammals. This silencing mechanism uses piRNAs generated from transposon-rich sequences in the DNA called “piRNA clusters.” piRNAs are small RNAs that couple with so-called Argonaute proteins of the silencing machinery to target the transposons complementary to their sequence. Hence, these piRNAs serve as blueprints to identify and silence transposons with complementary sequences in the genome, no matter how far they were able to jump.
The fruit fly Drosophila melanogaster, in which the piRNA pathway was first identified, uses a protein called “Rhino” to find piRNA clusters in the genome. However, how Rhino recognizes the piRNA clusters in the DNA remained unknown. “Previous in vitro data had shown an affinity of Rhino for a specific epigenetic mark, the chromatin modification H3K9me3,” says IMBA group leader Julius Brennecke, the corresponding author of the study. This modification is a marker of “heterochromatin,” a form of tightly packed DNA in which genes are silenced. However, H3K9me3 is not specific to piRNA clusters but is also frequently found in other densely packed regions of the genome. There, H3K9me3 is bound by the main heterochromatin protein 1 (HP1), a close relative of Rhino. Why HP1 and Rhino bind to different subsets of heterochromatin, even though they both have a comparable affinity for the same chromatin modification, was long unclear. “Without a question, H3K9me3 was required, but not sufficient to explain Rhino’s binding to chromatin. Hence, we knew that there must be additional molecular cues that help target Rhino to piRNA clusters,” Brennecke adds.
In the search for this molecular cue, the team cataloged direct interactors of Rhino, looking for a partner protein that might be able to guide Rhino to piRNA clusters. Using a combination of genetic, genomic, and imaging approaches, the researchers identified Rhino’s “companion” in Drosophila ovaries: a protein containing several Zinc-finger folds that they called “Kipferl.” Kipferl does not only bind to Rhino but also uses its Zinc-fingers for the sequence-specific binding to guanosine-rich DNA motifs. The team found that most piRNA clusters are defined through the combination of Kipferl’s specific DNA binding sites with local heterochromatin. At these sites, Rhino’s interaction with H3K9me3 epigenetic marks is stabilized by Kipferl, which explains why Rhino only binds to a small part of all the heterochromatin found across the genome.
To add a level of complexity, the team knew that Rhino not only localizes to piRNA clusters. Recently Rhino had been shown to bind to so-called “Satellite arrays.” These are repetitive sequences of non-coding and non-transposing DNA located close to the chromosomes’ centromeres. “We saw a striking effect on Rhino when we generated flies with mutant or absent Kipferl and looked at them under the microscope,” says first author Lisa Baumgartner, a doctoral candidate in the Brennecke lab at IMBA. When Kipferl was mutated, Rhino no longer localized to the piRNA clusters across the genome. Instead, it strongly accumulated at genomic Satellite arrays. “Instead of smaller dots distributed around the nucleus, we saw Rhino forming distinct crescent-like shapes. Based on this very first observation, we named the new protein ‘Kipferl’, after a popular croissant-shaped Austrian pastry. We only found out much later that these structures corresponded to Mega-base stretches of Satellite arrays.” Hence, the scientists showed that Kipferl helped to properly distribute Rhino to piRNA clusters and avoid its sequestration to Satellite arrays.
Rhino is one of the fastest-evolving proteins in the fly genome. Brennecke and his team hypothesize that this fast evolution might well be due to positive evolutionary pressure coming from the Satellite arrays. “The Satellite arrays do not transpose but can recombine. However, if they do so in an uncontrolled manner, whole chromosome arms could be lost. Hence, the Satellite arrays might need a control mechanism involving Rhino and other piRNA pathway components to help package them into tight heterochromatin. This might be the reason why the Satellite arrays appear to want to sequester all the Rhino they could find,” explains Baumgartner.
Baumgartner thinks that Rhino and the piRNA pathway might have very different roles in their interactions with the Satellite arrays or the piRNA clusters and transposons. “The jumping and multiplication of transposons pose a danger to the functionality of the genome, thus making it necessary that the piRNA pathway silences them,” she says. “Therefore, in the eyes of transposons, the piRNA pathway is the ‘enemy’ that prevents them from spreading through the genome. Satellite arrays, on the other hand, simply need an additional layer of control to ensure that they can maintain their high copy number without damaging the genome through unwanted recombination. Therefore, in the eyes of the Satellite arrays, I would imagine Rhino to be a factor that ensures their survival,” she elaborates.
Based on these observations and analyses, the scientists suggest that the Satellite arrays might be using another partner protein like Kipferl to help localize Rhino to their DNA. “To counter the sequestration of Rhino by the Satellite arrays, we speculate that Kipferl might have evolved out of a necessity to help retarget Rhino to the piRNA clusters. Hence, our findings suggest that Rhino might be caught in a crossfire of genetic conflicts,” says Brennecke. Furthermore, Rhino is expressed both in testes and ovaries in the fruit fly, while Kipferl is only expressed in ovaries. “Kipferl might be the first of several Rhino guidance factors yet to be uncovered,” concludes Brennecke.

Enrollment has begun in an early-stage clinical trial evaluating bacteriophage therapy in adults with cystic fibrosis (CF) who carry Pseudomonas aeruginosa (P. aeruginosa) in their lungs. The trial is evaluating whether the bacteriophage, or “phage,” therapy is safe and able to reduce the amount of bacteria in the lungs of volunteers. The trial is being conducted by the Antibacterial Resistance Leadership Group (ARLG), funded by the National Institute of Allergy and Infectious Diseases. Investigators aim to enroll up to 72 adults at 16 CF centers across the United States.
Phages are viruses that can kill or neutralize specific bacteria while leaving non-target bacteria and human cells unharmed. For more than a century, researchers have considered the potential use of phages as therapeutics, theorizing that mixtures of bacteriophages might be used on their own, or in conjunction with antibiotics, to treat bacterial infections — especially those resistant to antibiotics.
P. aeruginosa, a serious and sometimes deadly bacterium frequently acquired in healthcare settings, is the most common bacterial cause of CF exacerbations. P. aeruginosa can take advantage of the tissue damage caused by CF changes in mucus to infect and colonize the lungs. Multidrug-resistant P. aeruginosa infections are becoming increasingly common, and in recent years, only a handful of new antibiotics have been approved to treat them.
“The prevalence of antibiotic resistance is concerning, and the need for more effective therapeutics for vulnerable populations, such as people with cystic fibrosis, is especially urgent,” said NIAID Director Anthony S. Fauci, M.D. “Although research on bacteriophage therapy may still be in its infancy in the United States, we hope that this study, and others like it, could open the doors to a new type of therapy for difficult-to-treat bacterial infections.”
The experimental phage therapeutic, WRAIR-PAM-CF1, is manufactured by Adaptive Phage Therapeutics, Gaithersburg, Maryland. It contains a cocktail of four bacteriophage species that naturally infect P. aeruginosa and take over its cellular processes, killing the bacterium in the process. The phages in the cocktail are highly specific and do not attack human cells. They have been cultivated, purified, and extensively studied in a lab setting. Genetic analyses of these phages have determined that they do not carry harmful genes that could accidentally be transferred to the bacteria they infect, such as genes that could confer antibiotic resistance.
The trial will enroll CF patients who chronically harbor P. aeruginosa in their respiratory tracts. Participants will receive the phage cocktail as a single IV infusion at one of three dosage levels. Researchers will gather data on safety and microbiological activity; how the phages function in the body; how the cocktail affects the participants’ lung function; whether the therapy works differently on P. aeruginosa from different geographical regions; and whether the therapy changes participants’ overall quality of life.
The trial will begin as a Phase 1b trial and will expand to a Phase 2 trial. First, two participants per dosage level will receive an unblinded infusion of the therapeutic and will be closely monitored for four days thereafter. If no serious safety issues are identified, researchers will begin enrolling additional participants, who will be randomly assigned to receive a single infusion of the therapeutic at one of the three dosage levels, or a placebo infusion. This part of the trial will be double-blinded, so neither the participants nor the investigators will know who is receiving placebo. An assessment of the therapeutic’s safety and microbiological impact will be conducted after eight participants have completed each dosage. The results of this assessment will determine which dosage will be given in the next stage of the trial. The Phase 2 trial will enroll up to 50 participants who will be randomly assigned to receive the selected dose of the phage cocktail or a placebo. Each volunteer will make multiple follow-up visits to monitor their health and reaction to the experimental therapeutic.
The ARLG is a clinical research consortium supported by NIAID which works to combat the antibacterial resistance crisis and improve patient care. ARLG’s mission is to prioritize, design, and execute clinical research that will impact the prevention, diagnosis, and treatment of infections caused by antibiotic-resistant bacteria.
NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

Acetaminophen use during pregnancy is associated with sleep and behavior problems consistent with attention deficit hyperactivity disorder (ADHD), according to a study by Penn State College of Medicine researchers.
Acetaminophen is a common drug used to treat a variety of issues, including fever, infection, muscle pain, headache, migraine, colds and allergies. Traditionally, the medication has been considered by medical professionals to be safe for use during pregnancy. However, according to Kristin Sznajder, assistant professor of public health sciences and lead author, emerging studies support the idea that this drug may affect child development and may be associated with attention problems.
Sznajder said their new study confirms these trends and was also the first to observe an association between acetaminophen use during pregnancy and child sleep challenges.
“Pregnant people experience pain, fever and other ailments that could be alleviated through the use of acetaminophen,” said Sznajder, a Huck Institutes of the Life Sciences researcher. “While the medication may provide relief in the moment, research increasingly indicates there may be downstream effects that could be detrimental to child development. More research is needed so appropriate recommendations can be made to pregnant people.”
The researchers used data from a study of more than 2,400 women who had never given birth before and followed them and their children from the third trimester of pregnancy to 3 years postpartum. Women were surveyed once during their pregnancies about their medication use and frequency and stress levels. Of these, 41.7% of women reported using acetaminophen during pregnancy.
The participants were then interviewed at 1, 6, 12, 18, 24, 30 and 36 months after their child was born. At the 36-month interview, participants were asked to rate their child using a three-point scale to describe how often they exhibit a wide variety of neurodevelopmental and behavioral outcomes (very often true, somewhat or sometimes true, and not true) like “can’t sit still or restless,” “avoids looking others in the eyes” and “doesn’t want to sleep alone.” Scores for each behavior were then compiled to determine whether children scored highly in the domains of emotionally reactive, anxious or depressed, withdrawn, sleep problems and aggressive behavior.

A milestone report from the University of Kansas appearing this week in the Proceedings of the National Academy of Sciences proposes a new technique for modeling molecular life with computers.
According to lead author Ilya Vakser, director of the Computational Biology Program and Center for Computational Biology and professor of molecular biosciences at KU, the investigation into computer modeling of life processes is a major step toward creating a working simulation of a living cell at atomic resolution. The advance promises new insights into the fundamental biology of a cell, as well as faster and more precise treatment of human disease.
“It is about tens or hundreds of thousands of times faster than the existing atomic resolution techniques,” Vakser said. “This provides unprecedented opportunities to characterize physiological mechanisms that now are far beyond the reach of computational modeling, to get insights into cellular mechanisms and to use this knowledge to improve our ability to treat diseases.”
Until now, a major hurdle to modeling cells via computer has been how to approach proteins and their interactions that lie at the heart of cellular processes. To date, established techniques for modeling protein interactions have depended on either “protein docking” or “molecular simulation.”
According to the investigators, both approaches have advantages and drawbacks. While protein docking algorithms are great for sampling spatial coordinates, they do not account for the “time coordinate,” or dynamics of protein interactions. By contrast, molecular simulations model dynamics well, but these simulations are too slow or low-resolution.
“Our proof-of-concept study bridges the two modeling methodologies, developing an approach that can reach unprecedented simulation timescales at all-atom resolution,” the authors wrote.

Firefighters are the heroes of our society, protecting us around the clock. But those 24-hour shifts are hard on the body and increase the risk of cardiometabolic diseases, such as heart disease and diabetes, as well as cancer. In collaboration with the San Diego Fire-Rescue Department, scientists from the Salk Institute and UC San Diego Health conducted a clinical trial and found that time-restricted eating improved measures of health and wellbeing in firefighters. The lifestyle intervention only required the firefighters to eat during a 10-hour window and did not involve skipping meals.
The new findings, published in Cell Metabolism on October 4, 2022, may also have implications for shift workers, such as military personnel; health care, food service, and transportation professionals; telecommunications staff; and new parents, whose schedules often mimic shift work when caring for a new baby.
“Doctors and researchers are always thinking about the magic pill that can cure or reduce disease. Our study showed that shift workers with high blood pressure, blood sugar, or cholesterol can benefit from a simple lifestyle intervention called time-restricted eating,” says Salk Professor Satchidananda Panda, co-corresponding author of the study and holder of the Rita and Richard Atkinson Chair. “It’s not a pill, but a healthy habit that can significantly reduce these three risks of disease without any adverse side effects.”
Almost every cell in the body has a 24-hour biological clock that produces circadian (daily) rhythms. These rhythms regulate behavior (e.g., when to be active and when to rest) and physiology (e.g., blood pressure, blood sugar, muscle function). Circadian rhythms coordinate with the environment in part by regular, timed cycles of light and dark and eating and fasting. Disruptions to these cycles, which can occur with shift work, can impact health, leading to obesity, heart disease, diabetes, and cancer.
Nearly 30 percent of Americans are considered shift workers, in which the individual must stay awake for two to three hours between 10:00 p.m. and 5:00 a.m. for at least 50 days a year. Increasing sleep and reducing calorie intake are often difficult, but previous studies have suggested that time-restricted eating (eating within a certain window of time) may offer a simple behavioral change to improve health.
“We were excited to participate in this clinical trial because our department is always looking for innovative ways to improve the health of our firefighters,” says San Diego Fire-Rescue Health and Safety Battalion Chief David Picone.

Both time-restricted eating (TRE) and high-intensity interval training (HIIT) have been shown to improve cardiometabolic health in people who are overweight and at risk of serious disease. Now a randomized, controlled trial has tested whether combining these two approaches is more effective than either of them on their own. The results, publishing in the journal Cell Metabolism on October 4, show that the combination improved the average long-term glycemic control compared to a no-intervention control group and induced 2-fold greater reductions in fat mass and visceral fat area compared with each intervention in isolation.
“Isolated TRE and HIIT have received increasing attention for being effective and feasible strategies for at-risk populations,” says senior author Trine Moholdt, head of the Exercise, Cardiometabolic Health, and Reproduction Research Group at Norwegian University of Science and Technology (NTNU). “We wanted to compare the effects of the combination of TRE and HIIT with their isolated effects and to determine whether TRE and HIIT would act synergistically in improving health in individuals with risk for cardiometabolic disease. This finding highlights the importance of changing both dietary and physical activity habits for individuals who wish to rapidly improve their health and lower their disease risk.”
The trial had four arms: HIT alone, TRE alone, the TRE-HIIT combination, and a control group. A total of 131 women were enrolled, with 32 or 33 in each arm. All of them had overweight or obesity and had risk factors for cardiometabolic diseases like type 2 diabetes and cardiovascular disease. TRE was defined as consuming all daily calories within a 10-hour time window. HIIT was defined as exercise done at 90% of maximum heart rate for 35 minutes, three times per week. The exercise sessions were supervised by the investigators, and the participants were asked to log their first and last calories every day.
The interventions lasted for 7 weeks. Several measures were taken both before and after the study, including the participants’ blood pressure, body mass index, fat and cholesterol levels in the blood, and several measures of blood glucose and insulin levels.
The researchers found that the participants who combined TRE and HIIT were able to improve their average long-term glycemic control measured as HbA1c. They were also able to effectively reduce fat mass and visceral fat and increase their cardiorespiratory fitness measured as peak oxygen uptake. However, there were no statistically significant differences in blood lipids, appetite hormones, or vital signs after any of the interventions compared with the control group.
Another important finding from the study was that adherence to the study was high. “High adherence rates are important,” says first author Kamilla La Haganes, a PhD student at NTNU. “Adherence rates to general lifestyle recommendations are low, and our diet-exercise strategies may serve as an alternative.” After the study was completed, 18 participants from the control group also chose to try one of the study interventions.
“We recommend this kind of program for people who wish to have a relatively simple way of changing diet and exercise habits and improving their health,” Moholdt says. “TRE is a less tedious and time-efficient method to lose weight compared with daily calorie counting, and HIIT is tolerable and safe for previously sedentary individuals and can be completed within 30-40 minutes.”
A limitation of the study was that the intervention period was only 7 weeks; longer-term investigations are needed to determine effects and feasibility for longer periods of time. The study also took place during COVID-19 lockdowns, which affected the participants’ lifestyles and could have influenced the results.
The researchers are currently inviting the participants back for follow-up testing 2 years after they completed the study to find out if they have continued with the interventions. They also plan to determine whether the combination of TRE and HIT will induce the same health benefits and have equally good adherence rates in a completely home-based setting. That study will include both men and women. “Together, these two new studies will tell us more about the long-term feasibility and also the possibility for implementation in a real-world setting,” Haganes says. “Additionally, we can investigate if there are any sex differences in response to these interventions.”
This research is supported by the Liaison Committee for Education, Research and Innovation in Central Norway, the EFSD/Novo Nordisk Foundation Future Leaders Awards Programme, the Norwegian University of Science and Technology (NTNU), and by a Novo Nordisk Foundation Challenge Grant.
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Evidence in mice and human brain tissue reveals a mechanism that may explain the sex-based differences in Alzheimer’s disease, including why females are more vulnerable. Researchers report October 4 in the journal Cell that female brains show higher expression of an X-linked enzyme called ubiquitin-specific peptidase 11 (USP11) compared to males, resulting in greater accumulation of a protein called tau.
“This study sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women,” says co-senior study author David Kang of Case Western Reserve University.
Women are afflicted by Alzheimer’s disease roughly twice as frequently as men. The mechanistic basis for this increased vulnerability has not been clear. One potential explanation is that women exhibit significantly higher tau deposition in the brain.
The process of eliminating excess tau begins with the addition of a chemical tag called ubiquitin to the tau protein. Because dysfunction of this process can lead to abnormal accumulation of tau, Kang and co-senior study author Jung-A Woo of Case Western Reserve University looked for increased activity of the enzymatic systems that either add or remove the ubiquitin tag.
They found that both female mice and humans naturally express higher levels of USP11 in the brain than males, and also that USP11 levels correlate strongly with brain tau pathology in females but not in males. Moreover, when they genetically eliminated USP11 in a mouse model of brain tau pathology, females were preferentially protected from tau pathology and cognitive impairment. Males were also protected against tau pathology in the brain, but not nearly to the extent as in females.
The results suggest that excessive activity of the USP11 enzyme in females drives their increased susceptibility to tau pathology in Alzheimer’s disease. But the authors caution that mouse models of tauopathy may not fully capture the sexual dimorphism in tau pathology seen in humans.
“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,” Kang says. “Our hope is to develop a medicine that works in this way, in order to protect women from the higher risk of developing Alzheimer’s disease.”
This work received support from the National Institutes of Health and the Department of Veterans Affairs. A
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Exercise is well-known to help people lose weight and avoid gaining it. However, identifying the cellular mechanisms that underlie this process has proven difficult because so many cells and tissues are involved.
In a new study in mice that expands researchers’ understanding of how exercise and diet affect the body, MIT and Harvard Medical School researchers have mapped out many of the cells, genes, and cellular pathways that are modified by exercise or high-fat diet. The findings could offer potential targets for drugs that could help to enhance or mimic the benefits of exercise, the researchers say.
“It is extremely important to understand the molecular mechanisms that are drivers of the beneficial effects of exercise and the detrimental effects of a high-fat diet, so that we can understand how we can intervene, and develop drugs that mimic the impact of exercise across multiple tissues,” says Manolis Kellis, a professor of computer science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard.
The researchers studied mice with high-fat or normal diets, who were either sedentary or given the opportunity to exercise whenever they wanted. Using single-cell RNA sequencing, the researchers cataloged the responses of 53 types of cells found in skeletal muscle and two types of fatty tissue.
“One of the general points that we found in our study, which is overwhelmingly clear, is how high-fat diets push all of these cells and systems in one way, and exercise seems to be pushing them nearly all in the opposite way,” Kellis says. “It says that exercise can really have a major effect throughout the body.”
Kellis and Laurie Goodyear, a professor of medicine at Harvard Medical School and senior investigator at the Joslin Diabetes Center, are the senior authors of the study, which appears today in the journal Cell Metabolism. Jiekun Yang, a research scientist in MIT CSAIL; Maria Vamvini, an instructor of medicine at the Joslin Diabetes Center; and Pasquale Nigro, an instructor of medicine at the Joslin Diabetes Center, are the lead authors of the paper.