Despite smoking’s well-known role in causing lung cancer, a significant number of patients who develop lung tumors have never smoked. While scientists are still working to understand what spurs cancer in so-called “never-smokers,” a study led by scientists at Washington University School of Medicine in St. Louis demonstrates new possibilities for treating these baffling tumors.
The new analysis suggests that 78% to 92% of lung cancers in patients who have never smoked can be treated with precision drugs already approved by the Food and Drug Administration to target specific mutations in a patient’s tumor. The researchers found that most never-smokers’ lung tumors had so-called driver mutations, specific mistakes in the DNA that fuel tumor growth and that can be blocked with a variety of drugs. In contrast, only about half of tumors in people who smoke have driver mutations.
The study appears Sept. 30 in the Journal of Clinical Oncology.
“Most genomic studies of lung cancer have focused on patients with a history of tobacco smoking,” said senior author Ramaswamy Govindan, MD, a professor of medicine. “And even studies investigating the disease in patients who have never smoked have not looked for specific, actionable mutations in these tumors in a systematic way. We found that the vast majority of these patients have genetic alterations that physicians can treat today with drugs already approved for use. The patient must have a high-quality biopsy to make sure there is enough genetic material to identify key mutations. But testing these patients is critical. There is a high chance such patients will have an actionable mutation that we can go after with specific therapies.”
In the U.S, about 10% to 15% of lung cancers are diagnosed in people who have never smoked, and that proportion can be has high as 40% in parts of Asia.
The researchers analyzed lung tumors from 160 patients with lung adenocarcinoma but no history of tobacco smoking. They also compared data from these patients to data in smokers and never-smokers from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium, projects led by the National Institutes of Health (NIH) to characterize different types of cancer. The scientists verified never-smoker status by examining the mutation patterns in these patients and comparing them to mutation patterns in lung cancers of patients who had smoked. Past work led by Govindan and his colleagues found that smokers’ lung tumors have about 10 times the number of mutations as the lung tumors of never-smokers.
“Tobacco smoking leads to characteristic changes in the tumor cells, so we can look for telltale signs of smoking or signs of heavy exposure to secondhand smoke, for example,” said Govindan, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But very few of these patients’ tumors showed those signs, so we could verify that this was truly a sample of lung cancer tumors in patients who had never smoked or had major exposure to tobacco smoke.”
The researchers also found that only about 7% of these patients showed evidence of having mutations present at birth that raised the risk of cancer — either inherited or arising randomly — furthering the mystery of what causes lung cancer in never-smokers.
“There appears to be something unique about lung cancer in people who have never smoked,” Govindan said. “We didn’t find a major role for inherited mutations, and we don’t see evidence of large numbers of mutations, which would suggest exposure to secondhand smoke. About 60% of these tumors are found in females and 40% in males. Cancer in general is more common among men, but lung cancer in never-smokers, for some unexplained reasons, is more common among women. It is possible additional genes are involved with predispositions to cancers of this kind, and we just don’t know what those are yet.”
The study also shed light on the immune profiles of these tumors, which could help explain why most of them do not respond well to a type of immunotherapy called checkpoint inhibitors. Unlike the smokers’ lung tumors studied, very few of the never-smokers’ tumors included immune cells or immune checkpoint molecules that these drugs trigger to fight the cancer.
“The most important finding is that we identified actionable mutations in the vast majority of these patients — between 80% and 90%,” Govindan said. “Our study highlights the need to obtain high-quality tumor biopsies for clinical genomic testing in these patients, so we can identify the best targeted therapies for their individual tumors.”
This work was supported by the National Institutes of Health (NIH), grant numbers 2U54HG00307910 and U01CA214195; and the Mesothelioma Biomarker Discovery Laboratory.
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Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.

Unvaccinated pregnant women are increasingly being hospitalized with COVID-19 during a nationwide surge of the Delta variant, according to research from UT Southwestern Medical Center.
The study — which covers more than 1,500 cases in the Dallas area since May 2020 — offers a snapshot of what doctors believe is happening in communities across the country. The research shows the proportion of pregnant COVID-19 patients requiring hospitalization increased to 10 to 15% in late August and early September, more than double the percentage of last year before the emergence of the Delta variant.
“This is a concerning trend, and we’re primarily seeing these cases in unvaccinated women,” said Emily Adhikari, M.D., Assistant Professor of Obstetrics and Gynecology, and a lead author of the study published in the American Journal of Obstetrics and Gynecology.
Dr. Adhikari said the findings offer the first objective evidence that the case number and severity of illness in pregnant women rose with a spike in the Delta variant. The study included 1,515 pregnant women diagnosed with COVID-19 who received care from Parkland Health & Hospital System — Dallas County’s public hospital — from May 2020 through Sept. 4, 2021.
Overall, 82 patients had severe or critical illness, including 10 requiring ventilators, and two deaths. The proportion of severe or critical cases was around 5% until after the new year, and were then largely nonexistent in February and most of March.
However, the rise of the Delta variant coincided with a new wave of hospitalizations that peaked this August and early September, including more than a third of COVID-19 cases the week of Aug. 29. By this time, genetic sequencing conducted at UT Southwestern showed nearly all the local variants sequenced were the Delta B.1.617.2 strain.
Of the 82 patients hospitalized since May 2020, all but one were unvaccinated.
Dr. Adhikari acknowledged that some women fear the vaccine may not be safe to take during pregnancy, but said research has debunked those concerns. She co-authored a JAMA article earlier this year that elaborated on the issue of vaccines and pregnancy.
Dr. Adhikari said pregnant women are at greater risk for complications with any type of severe respiratory infection, so these findings further emphasize the need for pregnant and lactating women in all communities to get vaccinated for COVID-19.
“If they are exposed and infected, they run a higher risk of severe illness from this most recent Delta variant,” said Dr. Adhikari, Medical Director of Perinatal Infectious Diseases at Parkland. “Pregnant women should get immunized as soon as possible.”
The genomic sequencing that revealed nearly all the local SARS-CoV-2 variants were Delta was performed in the McDermott Center Next Generation Sequencing (NGS) Core with analysis performed by the McDermott Bioinformatics Lab, both under the supervision of Helen H. Hobbs, M.D., a Howard Hughes Medical Institute investigator and Professor of Internal Medicine and Molecular Genetics, who directs the Eugene McDermott Center for Human Growth and Development at UT Southwestern. Jeffrey SoRelle, M.D., Assistant Professor of Pathology and a co-author on the study, is collaborating with Dr. Hobbs by providing all positive COVID-19 samples tested at UT Southwestern and interpreting sequencing results with support from a rapid, focused PCR-based test. The collaboration with the McDermott Center Next Generation Sequencing (NGS) Core at UT Southwestern allows whole genome whole sequencing of SARS-CoV-2 virus in a state-of-the-art facility that performs NGS coupled with bioinformatic analysis.
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Opioids are a class of substances that control sensations such as pain and emotions in animals. While plant-derived opioid narcotics such as morphine are the most well-recognized, other opioid molecules like endorphins can also be synthesized by the body or artificially developed in laboratories. Opioids exert their actions by binding to opioid receptors present on the surface of cells. While opioid receptors were earlier thought to be limited to the central nervous system (CNS), their recent discovery in other parts of the body has prompted questions about their effects in other parts of the body, including the immune system.
In a recent study published in Frontiers in Immunology, Prof. Chiharu Nishiyama, Kazuki Nagata, and Ayumi Okuzumi from the Tokyo University of Science and Prof. Hiroshi Nagase from the University of Tsukuba attempted to understand the effects of opioids on the immune system. They tested the effects of KNT-127 — an artificially synthesized opioid that activates delta opioid receptors — on immune responses in live animal and cell culture experiments.
When mice with inflammatory bowel disease (IBD) were treated with KNT-127, they showed a reduction in the severity of colitis — a form of colon inflammation — indicated by lower weight loss and colon atrophy and improved disease activity scores. Similar results were also obtained in a recovery model, confirming the beneficial effects of KNT-127 against colonic inflammation.
Although these results were promising, an important caveat still loomed. “Before proceeding with additional experiments, we had to rule out the role of CNS opioid receptors in the anti-inflammatory effects of KNT-127,” says Prof. Nishiyama, the lead researcher on the study. To address this, the researchers performed similar experiments with YNT-2715, a peripheral KNT-127 that cannot cross over from the blood to the brain. The results were similar to those observed with KNT-127, confirming that its anti-inflammatory effects were indeed CNS-independent.
Encouraged by this, the group examined other immune-related effects of KNT-127 treatment in the colitis model. They found that during disease progression, the opioid reduced the serum levels of IL-6, a pro-inflammatory factor, while also decreasing the number of macrophages in the mesenteric lymph nodes (MLNs). Interestingly, they also observed an increase in the number of regulatory T cells (Tregs) in MLNs. Together, their results showed that KNT-127 suppresses the inflammation caused by macrophages during disease progression and enhances the anti-inflammatory response due to Tregs during recovery.
Finally, to understand the direct effects of KNT-127 on immune cells, the researchers performed in vitro experiments in which they treated macrophages derived from bone marrow or T cells from spleen with the drug. The results were consistent with those from animal experiments, revealing increased secretion of the pro-inflammatory signals as well as enhanced development of Tregs in response to KNT-127 treatment.
Altogether, the findings demonstrated that KNT-127 can directly act on immune cells and reduce the severity of inflammation, making it a good candidate for the treatment of IBD. “Several people around the world suffer from diseases related to colon inflammation, and so far, optimal treatment strategies are lacking. Our findings show that KNT-127 and other activators of opioid receptors could be promising therapeutic options for such diseases,” comments Prof. Nagase, the chief drug developer behind the synthetic opioid, while also cautioning of the road ahead. “Of course, before these drugs are used clinically, additional experiments will be required to elucidate how they exert their immunomodulatory functions and what their effects on other immune diseases are,” he adds.
Nevertheless, Prof. Nishiyama and her team are confident that their study represents an important milestone, not only towards the treatment of IBD but also towards our understanding of the “brain-gut axis” — the interrelationship between brain and gut function — which has received increasing attention in recent years. “Today, we know that poor mental health has physical manifestations. For example, stress worsens inflammation in the gut, which in turn affects the health of the brain. Our results on the immune-related effects of opioids, which commonly act on the brain, is a step toward unraveling the biological mechanisms that govern the reciprocative relationship of gut health and the immune system with the CNS,” mentions Prof. Nishiyama, excited about what the future holds.
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Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.

A British clinical trial found no sign of danger in getting a flu shot and a second dose of a Covid-19 vaccine at the same time. The results are welcome news for strained health care workers as flu season hits. The study supports the advice of U.S. health authorities.In the study, doctors recruited 679 people between April and June across Britain. At the time, all of the volunteers had received their first dose of a Covid-19 vaccine, either from AstraZeneca or Pfizer-BioNTech, the two vaccines that were first authorized there.When the volunteers returned for the second dose of their Covid-19 vaccine, the researchers gave half of them a flu shot at the same time, and the other half a placebo.The researchers then monitored the volunteers for side effects, such as aches and fevers.“There are no safety concerns raised in this trial,” the authors wrote in their preliminary report, which was posted online on Thursday but has not yet been published in a scientific journal.In addition to looking at the safety of the vaccines, the researchers also collected blood to measure antibodies to the coronavirus. Some combinations of different vaccine brands led to a slightly lower level of antibodies, and a slightly higher level in other cases. But the researchers did not suspect that any combination of a flu and Covid vaccine would result in a lower effectiveness than each given individually.The researchers did not speculate about what immune responses people will experience if they get a flu shot at the same time as a third Covid-19 shot, which many people may be doing now that the Biden administration has authorized boosters for large swaths of at-risk Americans.

A new Oregon State University study on foot-and-mouth disease among buffalo in South Africa could help explain how certain extremely contagious pathogens are able to persist and reach endemic stage in a population, long after they’ve burned through their initial pool of susceptible hosts.
The findings, publishing in Science Magazine, are particularly relevant as the world’s human population is closing in on the two-year anniversary of the COVID-19 pandemic, and researchers and policymakers are facing the reality that the virus is not going away anytime soon.
The study raises the same question that many are asking now about COVID-19, said lead author Anna Jolles, an epidemiology professor in OSU’s Carlson College of Veterinary Medicine with a dual appointment in the College of Science. After responding to the disaster situation, what happens next?
“Is there any way of really limiting the infection after it becomes endemic?” she said. “A study in a lab can’t answer that, because this is a question at the population scale, and in the lab you don’t have whole animal populations and all the variation among hosts, pathogens or the environment. Looking in wild hosts is one way to get insights into how this can play out.”
Co-authors on the paper include OSU assistant professor Brianna Beechler and associate professor Jan Medlock.
Foot-and-mouth disease does not cause serious illness in buffalo, though when it spreads to cattle and other cloven-hoofed species, it can cause painful sores in the mouth and on the feet. It does not infect humans.

Deciding when to start or grow a family is deeply personal and complex. When someone begins using a contraceptive, it may seem obvious they are not planning to get pregnant anytime soon. But a study recently published in PLOS ONE found that pregnancy intentions often change over as short as a 12-month time period, and that they specifically vary with partner status, household income, and employment status.
“When we think about whether or when people would like become pregnant, people often assume that there is one big life plan,” said Claudia Geist, associate professor and associate Dean for Research in the University of Utah’s School for Cultural and Social Transformation and lead author of the study. “However, we know that things shift across the lifespan.”
While some studies have identified potential factors that influence pregnancy decisions, few studies have assessed how these decisions may change or shift over time and which personal circumstances are associated with the change. This study aimed to support providers in being more flexible and responsive to contraceptive clients’ needs. Understanding how much pregnancy intentions can change in just one year adds to ongoing efforts to de-stigmatize and support the common practices of switching and ending various contraceptive methods.
The researchers followed a cohort of people who participated in the HER Salt Lake Contraceptive Initiative, a prospective study that recruited participants from four family planning clinics in Salt Lake County, Utah between September 2015, and March 2017. Eligible participants were between ages 18 and 45 and either initiating a new contraceptive or switching to a different contraceptive method. In addition, they needed to be intending to prevent pregnancy for at least one year.
The analysis includes 2,825 participants who provided pregnancy intention data at both the time of enrollment and the 12-month follow-up. Participants were asked to respond to the question, “What are your future pregnancy plans?” Response options included: “I am currently trying to get pregnant” (only available at 12-month follow-up) “I would like to get pregnant in the next year” “I would like to get pregnant in the next 2-5 years, but not in the next year” “I would like to get pregnant in the next 5-10 years, but not before then” “I am uncertain if or when I would like to become pregnant” (only available at enrollment) I do not plan on getting pregnant at any time in the future “Other”At the 12-month follow up, the majority (79%) of participants maintained their pregnancy timing intention, while just under 20% reported a change. Among those who initially said they never wanted a pregnancy, 22% changed their mind over the course of a year. About 10% of participants shifted their pregnancy timing to desire a pregnancy earlier than at the time of enrollment.
“I expected change, but I didn’t expect as much change as we found,” said Geist. “We found that economic stability, including more household income and/or full-time employment, seems to put people in a frame of mind where they consider a pregnancy after previously stating to never want a pregnancy.”
In addition to economic stability, researchers considered relationship status, sexual identity and educational status and aspiration. Exploring the associations between changes in personal circumstances and shifts in pregnancy intentions, researchers hope to offer insight to clinicians who provide contraception.
“The rapid changes we found over 12 months are a stark reminder that health care providers need to check in frequently about the pregnancy desires of their patients,” said Geist.
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Materials provided by University of Utah. Original written by Morgan Aguilar. Note: Content may be edited for style and length.

As the days get shorter and the nights start earlier, take these steps to help prevent seasonal affective disorder.For about 1 in 20 people in the northern half of the United States, cooling temperatures and shorter, darker days may signal the onset of seasonal affective disorder, or SAD, a type of depression that typically arrives in the fall or winter, then goes away in the spring.Unlike mild cases of the “winter blues,” SAD symptoms make it difficult to function. It tends to start with so-called “vegetative symptoms”: an increased appetite and a craving for carbohydrates like french fries or ice cream, the urge to sleep longer hours, difficulty getting up in the morning and feeling wiped out at work.Then, in three to four weeks, “the mood plummets,” said Michael Terman, a professor of clinical psychology at Columbia University and an expert in seasonal affective disorder. Patients with SAD develop major depression, which includes persistent feelings of sadness, withdrawal from friends and family and a loss of interest in activities that were once enjoyable.Researchers don’t yet know why some people develop SAD and others do not, but the disorder is believed to run in families and is more common among women. SAD develops in the fall and winter because shorter daylight hours and less sunlight shift the body’s internal clock, and certain mood-regulating hormones, like serotonin, oscillate with the seasons.The good news is that because SAD is tied to the changing seasons, “you can predict its onset and ward it off,” Dr. Terman said.If you have already started experiencing vegetative symptoms — for example you are sleeping longer and having more difficulty waking up — or if you already know you are susceptible to seasonal affective disorder, experts said it’s best to start implementing preventive measures before major depression sets in.Bright light therapy, which typically involves sitting near a light box for about half an hour each morning, is considered the most effective treatment for SAD, several specialists in the field said.Two meta-analyses of randomized, controlled trials demonstrated that bright light therapy was superior to a control when treating SAD. And one study found that over the course of four weeks, 61 percent of the 33 patients who received bright light therapy saw their symptoms disappear compared to 32 percent of the those who received a placebo.Bright light therapy usually works more quickly than medication, said Dr. Terman, president of the Center for Environmental Therapeutics, a nonprofit that researches nonpharmaceutical interventions and teaches people how to use them. “It does, however, require consistent use upon waking.”The Center for Environmental Therapeutics has a handy tool that can help you figure out the optimal time of day to do light box therapy based on your circadian rhythms. But for many, and especially those who are currently experiencing depression, it will be best to also seek the guidance of a health care professional. Light boxes are not regulated by the Food and Drug Administration, so consumers need to do some research to make sure they are purchasing one that clinicians would consider effective.“Most of what you find on the web is garbage,” said Dr. Paul H. Desan, an associate professor of psychiatry at the Yale School of Medicine who has studied seasonal affective disorder for decades.An ideal box will have a large screen that shines light downward, akin to how the sun shines from the sky. The light should have an intensity of 10,000 lux, which is a measure of how much light is received by the eye. Lux declines the farther that you are from the light source, the experts said.A 2019 study by Dr. Desan and his colleagues examined 24 light boxes and found that only seven of them met the investigators’ clinical criteria. Some advertised 10,000 lux, for example, but only produced this intensity “at unreasonably close distances, over a restricted field or with unacceptable glare or unevenness of illumination.”Dr. Desan and his collaborators named six reputable models on their website, currently ranging in price from $129 to $369. (But keep in mind that this is not an exhaustive list and there may be other models that are just as effective that were not included in the study.) Other models can be found in this guide from Wirecutter, which is owned by The New York Times.Bright light therapy is typically done during late fall and winter, but it can also be used at other times of the year. Dr. Desan recommended that anyone beginning treatment for SAD spend 30 minutes in front of their light box every day before 8 a.m. for at least three weeks.“If it hasn’t helped at that point, it’s probably not going to help,” he said.Some people may also benefit from medication, such as an antidepressant.If you have eye-related concerns or a physical condition, like diabetes, that predisposes you to eye disease, then it’s best to check with your doctor before using bright light therapy.Dawn simulation devices, which help you wake up by gradually increasing the amount of light in your bedroom, were shown to be even more effective than a light box in a 2001 study, however Dr. Desan cautioned that he knows of no device currently on the market that has been solidly supported by research and accepted by experts. Dr. Terman agreed.Another type of device called a negative ion generator has shown some promise — high doses of negative ions have been associated with lower depression scores in some studies. But additional research is needed to further evaluate the efficacy of these devices in treating seasonal affective disorder.Some people assume that taking vitamin D supplements can help cure seasonal affective disorder. But studies indicate that is not the case, so there is no need to take additional vitamin D unless a blood test shows you have a deficiency.Finally, while bright light therapy is the first recommended treatment for SAD, getting outside regularly can offer other opportunities to soak in some light.“You might want to retreat like the hibernating bear, but don’t,” said Dr. Norman E. Rosenthal, the psychiatrist whose research team identified and named the disorder in the 1980s. His book “Winter Blues” outlines strategies to beat seasonal affective disorder.“Walking outside even 20 or 30 minutes each day could make a huge difference,” he added.For ideas, look to Scandinavia, where various cultural practices offer cheerful ways to get through the winter.Norwegians have a custom called koselig, which is about creating a cozy, happy environment with the people you love — and it includes spending a lot of time in nature. Participating in outdoor activities like skiing, snowshoeing or hiking will get you out of your house, into the sunlight and socializing with others. You might also borrow some inspiration from the Danish custom of hygge and aim to make your home a more comfortable space to spend the chilly days ahead. The Swedish version is called mys. Think crackling fires, soft throw blankets, fuzzy socks, warm foods and good times with friends.Candles are especially vital in Scandinavian culture. “Where Americans see a fire hazard, the Danes see an antidepressant,” wrote Penelope Green, a reporter with The New York Times, in a 2016 article about hygge. In fact, she noted, the Danish word for spoilsport is lyseslukker, “which literally means, ‘one who puts out the candles.’”In essence, winter can become a time “for cultivating internal joys,” Dr. Rosenthal said. “Once you have your SAD under control, it becomes possible.”

“This is an entirely new way to do cancer research,” said Nevan Krogan, PhD, director of UCSF’s Quantitative Biosciences Institute who is co-senior author, along with Trey Ideker, PhD, professor at UC San Diego School of Medicine, on a set of three related papers that appear Sept. 30, 2021, in Science. “We realized we need another way to look at cancer that takes it a step beyond DNA.”
Krogan and Ideker look to proteins, which carry out the vast majority of functions in the body — and which take on a collection of forms that far outnumber our genes, providing a much more expansive view of the activity underlying cancer.
“We’re elevating the conversation about cancer from individual genes to proteins, allowing us to look at how the varying mutations we see in patients can have the same effects on protein function,” said Ideker, noting that this work represents new technological capacity to explain the effects mutations in a more precise way. “We’ve produced the first map looking at cancer through the lens of interactions between proteins.”
The effort to map these effects, dubbed Cancer Cell Map Initiative (CCMI), is revealing, on a monumental scale, genetic patterns and organizing principles that underlie the disease and potential new ways to tackle it.
The team’s new studies describe the approach in detail, and highlight findings when it was applied to breast cancer and cancers of the head and neck.
Looking Beyond Gene Mutations to the Protein Disruptions They Cause
Our genes contain instructions for building proteins. which then interact with other proteins, almost always in large groups called complexes. These protein complexes often regulate an activity or turn a function on or off. If the underlying gene has a mutation, the resulting protein complexes will as well.

Nerve cells (neurons) send signals throughout the brain and the body along long processes called axons; these communication and information processes consume high levels of energy. A recent study conducted at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, shows that the support cells around axons provide a way to boost local energy production. The new findings, published in the journal Neuron, help explain how long axons maintain sufficient energy levels and could have implications for the treatment of several neurological disorders, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), linked to disruptions in axonal energy supply.
“Many major neurological disorders involve the degeneration of axons, mitochondrial dysfunction, decreased energy levels, or problems with oligodendrocytes,” said Zu-Hang Sheng, Ph.D., senior investigator at NINDS. “Our findings uncover a way for axons to maintain energy and could help us better understand the causes of neurological disorders and how we might treat them.”
All cells including neurons use adenosine triphosphate (ATP) for fuel, which is created by structures within cells called mitochondria. The NINDS research team led by Dr. Sheng discovered that oligodendrocytes — cells that typically support axons by wrapping them in an insulating material called myelin — release an enzyme, SIRT2, that ramps up mitochondrial activity. This enzyme, when picked up by axons, provides a local power boost by increasing energy production.
“Neurons require considerable amounts of ATP for energy, but ATP has a hard time traveling down long axons,” said Dr. Sheng. “We wanted to understand how neurons can keep energy levels high inches, or even sometimes feet, all the way along the axon.”
Like regional power plants built to provide electricity to remote locations, mitochondria are located along long axons to generate ATP in areas where it is needed. Previous studies showed that axons that have had myelin removed contain more mitochondria, while genetic changes that affect oligodendrocytes also impact energy production in axons.
Using a state-of-the-art energy sensor that changes color based on local ATP availability, Dr. Sheng’s team compared energy levels in neurons and their axons grown in cell dishes with or without oligodendrocytes. What they saw was that the axons grown with oligodendrocytes had significantly more ATP than those without, suggesting there was some connection between the support cells and the levels of energy in axons.
Next, Dr. Sheng and his colleagues created “conditioned media” by growing oligodendrocytes in lab dishes for several days and then collecting media but not the cells. The conditioned media was then added to dishes containing neurons, and this treatment also increased ATP levels, which meant that oligodendrocytes were releasing cellular components into their environment that ramped up energy production in axons.
The question remained: what was being released by the oligodendrocytes? To answer this, Drs. Chamberlain and Huang, two leading authors of the study, and their collaborators isolated exosomes — packages released from cells that contain signaling molecules — from oligodendrocytes and showed that they too can increase energy production in axons. Taking advantage of a previous study that identified many components within exosomes, the researchers focused on a protein called SIRT2 and confirmed that it is present at high levels in oligodendrocytes, but not neurons.
SIRT2 also made an intriguing target because it is an enzyme that modifies proteins, including those in mitochondria and specifically those linked to ATP production. When the researchers genetically turned on SIRT2 in neurons, they saw significantly higher ATP levels. In contrast, when neurons were grown with oligodendrocytes missing the gene for SIRT2, no increase in energy was seen. Finally, when SIRT2-containing exosomes were added to the spinal cords of mice lacking the gene for SIRT2, there was a strong increase in mitochondrial function. Together, these findings suggest oligodendrocytes help axons maintain high levels of energy when needed.
Several neurodegenerative diseases, including ALS, have been linked to a failure of mitochondria to produce sufficient energy in neurons and their axons. The discovery of SIRT2 as a transcellular signal that can boost energy production locally within axons means that this pathway could be a potential target for future therapies for certain neurodegenerative disorders.
This study was supported by the Intramural Research Program at NINDS.

Researchers at Uppsala University have designed new antibodies that might provide more effective treatment methods for Alzheimer’s disease. By designing antibodies that bind even to the smaller aggregates, or clumps, of the amyloid-beta protein, it may be possible to check the progress of the disease.
Developing effective treatment methods for Alzheimer’s disease has proved difficult. The most effective, which have just been approved, only provide marginal effects. There are several major reasons why they are not effective, one of which is that the antibodies used do not bind to all the types of toxic clumps that cause Alzheimer’s disease.
In Alzheimer’s disease, the amyloid-beta protein begins to form clumps. This process is called aggregation, and the clumps created are called aggregates. The research group has previously shown that treatment with the peptide somatostatin causes the body to begin breaking down building blocks of the aggregate. In the new study, the researchers use an antibody that can bind to the toxic aggregates to stop them from harming cells.
The problem with the treatment methods currently tested in patient studies is that the antibodies bind much more strongly to large clumps and hardly at all to small clumps. The small clumps are just as toxic as the large ones and many think that they are actually even more dangerous since they can move more.
The purpose of the current study was to develop an antibody format that can bind to both large and small clumps of amyloid-beta. Antibodies use the avidity effect to bind strongly to their targets. This requires the binding of both arms of the antibody to the same target at the same time.
The distance between the arms of the antibody is crucial for how small an aggregate the antibody can bind to strongly. If the aggregate is smaller than the distance between the arms, they do not bind to the aggregate strongly. If it is larger, they bind to the aggregate very strongly. In the new article, the researchers have developed a new antibody format with shorter distances between the arms so that they bind to smaller aggregates. The new format also has more binding sites to make the binding extra strong.
“Thanks to the avidity effect, the new antibody format is at least 40 times stronger in binding to the clumps. The new type of antibody can also bind to small aggregates with avidity, which we have not previously seen any other antibody do. That is fantastic,” says Greta Hultqvist, Senior lecturer and Associate Professor in Protein drug design at Uppsala University who led the study.
The effects of the antibodies were also tested in a cell culture experiment, which showed that the new antibody format could save cells from death caused by amyloid-beta aggregates. Although no pre-clinical experiments were included, the team thinks their results suggest that the new antibody design could be more effective than those trialled so far.
“The focus of the study was targeting the amyloid-beta protein in Alzheimer’s disease, but the new antibody design can be general and applicable to other disease-causing clumps. From a long-term perspective, we hope that the new format can open up new avenues for the generation of future treatments, not only in Alzheimer’s disease, but also other diseases where proteins start to form aggregates, like Parkinson’s disease,” says Fadi Rofo, doctoral student and first author of the study.
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Materials provided by Uppsala University. Original written by Elin Bäckström. Note: Content may be edited for style and length.