Publisher Health

Oregon State University scientists have taken a key step toward better understanding neurodegenerative diseases by using a suite of biophysical techniques to learn more about a motor protein whose malfunction is associated with many disorders.
The study, published in the journal eLife, represents important progress toward improved care for the millions of people around the world affected by conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease and multiple sclerosis.
Neurodegenerative diseases occur when nerve cells in the brain and spinal cord, known as neurons, break down, function abnormally and eventually die. As neurons deteriorate, patients typically experience a range of gradually worsening neurological symptoms that can progress to debilitation and, in many cases, death.
According to the Harvard NeuroDiscovery Center, 5 million people in the United States have Alzheimer’s disease and 1 million have Parkinson’s. There are also 400,000 MS patients and 30,000 have ALS, a disease that reached the public’s consciousness when baseball star Lou Gehrig was diagnosed with it in 1939.
Neurodegenerative conditions onset primarily in mid- to late-life, meaning the incidence is expected to rise as the U.S. population ages. Demographic data suggest that without new interventions more than 12 million Americans will be affected by neurodegenerative diseases by 2050.
Elisar Barbar, head of the Department of Biochemistry and Biophysics in the OSU College of Science, and Kayla Jara, program coordinator for Oregon State’s genetic code expansion center, GCE4All, led a deep dive into dynein, one of the two types of motor proteins within cells; the other type is kinesin.

In a study using a first-of-its kind mouse model of aging that mimics breast cancer development in estrogen receptor-positive post-menopausal women, investigators at Georgetown Lombardi Comprehensive Cancer Center and colleagues have determined that over-expression, or switching on of the Esr1 gene, could lead to elevated risk of developing estrogen receptor-positive breast cancer in older women.
In a second study from the same research lab, investigators found that in the specially bred mice given anti-hormonal drugs (e.g., tamoxifen and letrozole) similar to those currently used by women to lower their breast cancer risk, the elevated risk of developing breast cancer due to over-expression of Esr1 could be lowered or reversed.
The findings appeared simultaneously December 1, 2022, in the American Journal of Pathology.
“In the clinic, we currently use tests for over-expression of particular patterns of genes to predict the probability of whether a woman’s breast cancer could become metastatic,” says Priscilla Furth, M.D., professor of oncology and medicine at Georgetown Lombardi and corresponding author of both studies. “If validated in human studies, detection of over-expression of Esr1-related genes could be a new signature to add to current prognostic tools that would help post-menopausal women at risk for estrogen receptor-positive breast cancer decide what their best risk reduction strategy might be.”
Most women start menopause in their late 40s or early 50s, with a risk of increased new cases of breast cancer peaking around 70 years of age. A substantial proportion of these breast cancers are fed by over-expression of the Esr1gene, resulting in higher expression of related estrogen pathway genes that help spur breast cancer development.
During human menopause, when overall estrogen levels typically decline, the breast tissue of some women can show an increase in expression levels of the estrogen receptor or even increased levels of local estrogen production. To model this in mice, the investigators followed the mice as they aged through their natural reproductive cycle and decreased circulating estrogen levels. They then looked to see what factors were involved in resulting cancers by comparing outcomes in mice that were designed to overexpress one of two different genes: Esr1, which would model the increase in estrogen receptor levels, or CYP19A1, a gene that models the increase in local estrogen production. They found that Esr1 over-expression resulted in more breast cancers than CYP19A1 overexpression and was accompanied by high activation of estrogen pathway genes.
In the second study, they gave the mice estrogen-suppressive drugs, such as tamoxifen and letrozole, as a preventive measure to see if the drugs could resolve abnormal activation of estrogen pathway genes, which indeed turned out to be the case.
The investigators were guided in their study by the use of the PAM50 (Prediction Analysis of Microarray 50) prognostic tool. The tool reads a sample of the tumor and determines expression levels for a group of 50 genes. The scientists found that many genes related to proliferation of breast cancer cells in the PAM50 tool were significantly expressed only in Esr1 mice and this correlated with development of the same type of estrogen receptor-positive breast cancers that develop in humans, thereby giving them new evidence of which other genes might be implicated in inducing breast cancer in post-menopausal women. In current clinical practice, the results of the PAM50 test have helped predict the chance of metastasis for some ER-positive, HER2-negative breast cancers.
“One of the more important challenges in translating our findings from mice to people is the collection of breast cancer cells for testing with PAM50 or other prognostic tools,” says Furth. “Removing breast tissue, even with a fine needle, is still invasive and perhaps unavoidable. However, we have developed a method in my lab that requires collecting just a few tumor cells from a small tissue sample, as our process expands and grows the cells many-fold so that we can have adequate cancer cell numbers to run through prognostic tools like PAM50.”
The scientists are hoping other researchers, including commercial prognostic tool developers, take note of this research advance and incorporate risk factors associated with some of the genes linked to Esr1 in their tools, potentially enabling women to better avoid over-treatment or make more precise treatment choices.

Cambridge researchers have developed a method for measuring overall fitness accurately on wearable devices — and more robustly than current consumer smartwatches and fitness monitors — without the wearer needing to exercise.
Normally, tests to accurately measure VO2max — a key measurement of overall fitness and an important predictor of heart disease and mortality risk — require expensive laboratory equipment and are mostly limited to elite athletes. The new method uses machine learning to predict VO2max — the capacity of the body to carry out aerobic work — during everyday activity, without the need for contextual information such as GPS measurements.
In what is by far the largest study of its kind, the researchers gathered activity data from more than 11,000 participants in the Fenland Study using wearable sensors, with a subset of participants tested again seven years later. The researchers used the data to develop a model to predict VO2max, which was then validated against a third group who carried out a standard lab-based exercise test. The model showed a high degree of accuracy compared to lab-based tests, and outperforms other approaches.
Some smartwatches and fitness monitors currently on the market claim to provide an estimate of VO2max, but since the algorithms powering these predictions aren’t published and are subject to change at any time, it’s unclear whether the predictions are accurate, or whether an exercise regime is having any effect on an individual’s VO2max over time.
The Cambridge-developed model is robust, transparent and provides accurate predictions based on heart rate and accelerometer data only. Since the model can also detect fitness changes over time, it could also be useful in estimating fitness levels for entire populations and identifying the effects of lifestyle trends. The results are reported in the journal npj Digital Medicine.
A measurement of VO2max is considered the ‘gold standard’ of fitness tests. Professional athletes, for example, test their VO2max by measuring their oxygen consumption while they exercise to the point of exhaustion. There are other ways of measuring fitness in the laboratory, like heart rate response to exercise tests, but these require equipment like a treadmill or exercise bike. Additionally, strenuous exercise can be a risk to some individuals.

Malaria is found in more than 90 countries around the world, causing 241 million cases and an estimated 627,000 deaths every year. Vaccines are one intervention that could help eliminate this deadly disease, yet a highly effective vaccine remains elusive. Recent technological advances in vaccine development-such as the mRNA vaccines for SARS-CoV2-could lead to a new generation of malaria vaccines.
Now, a research team led by George Washington University has developed two mRNA vaccine candidates that are highly effective in reducing both malaria infection and transmission. The team also found that the two experimental vaccines induced a powerful immune response regardless of whether they were given individually or in combination. The study was published today in npj Vaccines, an open-access scientific journal that is part of the Nature Portfolio.
“Malaria elimination will not happen overnight but such vaccines could potentially banish malaria from many parts of the world,” Nirbhay Kumar, a professor of global health at the George Washington University Milken Institute School of Public Health, said. “The mRNA vaccine technology can really be a game changer. We saw how successful this technology was in terms of fighting COVID and for this study we adapted it and used it to develop tools to combat malaria.”
Kumar and the research team focused on the parasite Plasmodium falciparum, one of four parasite species that cause malaria and the deadliest to humans. Transmitted through the bite of the Anopheles mosquito, P. falciparum together with P. vivax are responsible for more than 90% of all malaria cases globally, and 95% of all malaria deaths. Most cases and deaths occur in sub-Saharan Africa but half the world’s population is at risk of contracting this deadly disease. Kumar’s team developed two mRNA vaccines to disrupt different parts of the parasite’s life cycle.
The researchers immunized one group of mice with a mRNA vaccine targeting a protein that helps the parasites move through the body and invade the liver. They immunized another group of mice with a vaccine targeting a protein that helps parasites reproduce in a mosquitoe’s midgut. The immunized mice were then challenged with the parasite causing infection and vaccine induced antibodies were tested to interrupt malaria transmission.
The study found both vaccines induced a potent immune response in the mice and were highly effective in reducing infection in the host and in the mosquito vector. The presence of protective antibodies during transmission of parasites to healthy mosquitoes dramatically reduced the parasite load in the mosquitoes, an important step in disrupting malaria transmission, according to the researchers.
“These vaccines were highly effective at preventing infection and they wiped out transmission potential almost entirely,” Kumar said.
The team also immunized mice with both vaccines together and found that co-immunization effectively reduced infection and transmission without compromising the immune response.
To see how the mRNA vaccines stacked up against other nucleic acid -based vaccine platforms, Kumar and the team repeated the experiment using DNA plasmids. The mRNA vaccines were far superior in inducing an immune response compared to the DNA-based vaccines, they found.
The team hopes to usher the vaccines through additional research, including studies in nonhuman primate models, with the goal of producing vaccines that can be used safely in humans.
“To have a vaccine cocktail that can effectively disrupt multiple parts of the malaria parasite’s life cycle is one of the holy grails of malaria vaccine development,” Kumar said. “This study brings us one step closer to producing vaccines that can be used safely in humans to prevent illness, save lives-with the ultimate goal of defeating this disease.”
The study, which was supported by the National Institutes of Health, was published in the Dec. 1 issue of npj Vaccines. The team, which has filed for a patent, developed the vaccines in partnership with scientists from the University of Pennsylvania and other collaborators.
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Materials provided by George Washington University. Note: Content may be edited for style and length.

Many successful drugs have their origins in natural sources such as plants, fungi, and bacteria, but screening natural products to identify potential drugs remains a difficult undertaking.
A new approach using molecular biology, analytical chemistry, and bioinformatics to integrate information from different screening platforms addresses some of the biggest challenges in natural products drug discovery, according to a study published November 30 in Proceedings of the National Academy of Sciences.
A major challenge has been determining the mechanism of action and biological target of a novel bioactive compound. Another central challenge is identifying the molecule or molecules driving biological activity in a complex mixture from nature.
“These two big concepts have been at the heart of our collaborative program, and this paper brings those two questions together in a fully integrated approach,” said corresponding author John MacMillan, professor of chemistry and biochemistry at UC Santa Cruz.
In addition to MacMillan, the collaboration involves Scott Lokey, professor of chemistry and biochemistry and director of the Chemical Screening Center at UC Santa Cruz, Roger Linington at Simon Fraser University in British Columbia, and Michael White at the University of Texas Southwestern Medical Center.
By integrating the results of two completely different screening platforms and combining this with next-generation metabolomics analysis of their natural products libraries, the researchers created a unique and powerful framework for natural product biological characterization. Using this approach to screen a small collection of randomly selected microbial natural product fractions, they were able to identify a known compound (trichostatin A) and confirm its mechanism of action; link a known compound (surugamide) with novel biological activity (cyclin-dependent kinase inhibition); and discover new compounds (parkamycins A and B) with complex biological activity.

In Coral Bracho’s poem, translated by Forrest Gander from the Spanish, we are witnesses to the thoughts of the poet’s mother, who died from complications of Alzheimer’s. The mother vividly depicts the terror of losing yourself within a formerly capable and operating mind and body. Initially, she answers her own questions rapidly with both confusion and confidence. Soon the questions vanish, as she begins to describe the environment around her in a state of imaginative, surreal speculation. Selected by Victoria ChangIllustration by R. O. Blechman(Intuitions. She)By Coral Bracho, translated by Forrest GanderMy suitcase isn’t here,but neither is the room.What room? I haven’t been in anyroom here, but there must have been one.Did I sleep in it?There were some people, but I don’t know if I was there.Where’d they leave their bags?Two of them just passed me bybefore they turned into the corridor.But into which one? All the hallways are white,and they seem to be padded.It must be those two who brought me to this place.Probably they went to shower,and no doubt they assume I know how to get there,or to the room,or to some more central hallwaythat must be around here somewhere,which is where the suitcases go,one next to the other on some contraption of red tubes.But who knows if mine is there too.I hear the noise of the showers.They’re open full blast and the water gushes out and swirls away, but there’s something dirtythat doesn’t drain off.First I have to find my suitcase,although there’s no place in the showers to put it.Those people who came in aren’t here anymore.I’m going to wait here, see if someone comes bywho can tell me how to get back. Or see if theywant to guide me.Victoria Chang is a poet whose new book of poems is “The Trees Witness Everything” (Copper Canyon Press, 2022). Her fifth book of poems, “Obit” (2020), was named a New York Times Notable Book and a Time Must-Read. She lives in Los Angeles and teaches in Antioch University’s M.F.A. program. Coral Bracho is the author of many books of poetry, including “Firefly Under the Tongue” (New Directions, 2008) and “It Must Be a Misunderstanding” (New Directions, 2022), in which this poem appears. She is the recipient of the Aguascalientes National Poetry Prize, a Guggenheim fellowship and the Xavier Villaurrutia Award, among other accolades. Bracho was born in Mexico City and still resides there.

The tech multibillionaire said his company, Neuralink, was seeking government approval to test his device in people, and predicted it could happen in six months. Others have been conducting similar tests for years, but no device has been marketed commercially.In a presentation showcasing the Neuralink implant that Elon Musk hopes will someday connect the human brain to a computer, two monkeys were reportedly moving computer cursors with their brains.The feat was first documented by others in a human in 2006 in the pre-YouTube era and with technology that is far more cumbersome, mooring patients to a computer with a cord.Mr. Musk’s presentation on Wednesday night offered little that was significantly new from previous demonstrations of the device. He continued to claim that the implant could make computer control possible for people with paralysis outside of a lab setting. But experts in the field questioned whether the demonstration showed major progress with the device, especially given the breadth of work underway nationwide.“These are incremental advances,” Daniel Yoshor, a neurosurgeon and neuroscientist at the Perelman School of Medicine at the University of Pennsylvania who has worked with similar devices, said after watching the presentation. “The hardware is impressive but does not represent a dramatic advance in restoring or enhancing brain function.”Neuralink does not have approval from the Food and Drug Administration to sell the device. Mr. Musk said on Wednesday that the company had submitted most of its paperwork to the agency to seek permission to implant its device in a human. He predicted a test in humans in six months, but any step toward trials in people would be up to the F.D.A. after a full evaluation of the risks of surgical implantation and safety of the device.Neuralink originally scheduled the event for the end of October, before Mr. Musk, a multibillionaire, postponed the presentation amid one of the more chaotic months of his career. He recently completed his off-again, on-again purchase of Twitter, which has commanded much of his attention — and generated considerable controversy — over management of the social media company.While Mr. Musk juggles that and other duties — he also oversees the electric carmaker Tesla and the rocket company SpaceX — Neuralink is emerging from a period of change. Last year, Max Hodak, the company’s president and one of its co-founders, left to launch his own venture in the field. Neuralink’s chief executive is officially Jared Birchall, a wealth manager who runs Mr. Musk’s family office.Wednesday night’s presentation focused on the “Link” device, which resembles an inch-wide stack of several coins with hundreds of hair-thin threads. A surgical robot would cut a hole in the skull and slip the electrode threads into the gray matter of the brain, according to Mr. Musk’s 2020 company presentation. The coin-like piece would sit flush with the skull.Leaders in the field of brain-computer interface technology have been closely watching Neuralink’s investment in a device that operated without protruding wires or hardware. Yet Mr. Musk’s presentations thus far have concerned and underwhelmed many of them.A 2021 Neuralink presentation of a monkey playing the video game Pong with his mind was similar to a primate demonstration at Brown University in 2001, though it had a far clunkier system.A diagram showing different steps of the Neuralink implantation process.NeuralinkIn a 2020 presentation showcasing a pig with the implant, Mr. Musk suggested the device could “solve” conditions including paralysis and insomnia and could even give a user “superhuman vision.” Such applications sound like science fiction to scientists who are singularly focused on restoring basic functions, like typing, speaking or lifting a fork, to those who have lost them after a spinal cord injury or a dire diagnosis. For such patients, the benefits weigh favorably against the small, but serious, risk of brain surgery.“No one is talking about implanting able-bodied people,” said Cindy Chestek, an associate professor of biomedical engineering at the University of Michigan whose lab is working on restoring function to amputees.On Wednesday night, Mr. Musk said plans for his device included making the blind see and giving someone with a severed spinal cord “full-body functionality.” The claims drew applause from the audience, but do not reflect the state of the field.“I would not say that with confidence,” Dr. Yoshor said after Mr. Musk had claimed the Neuralink device would give sight to people who have never seen before. “I would be highly unsure of this kind of device in a patient with congenital blindness.”Safety will be the F.D.A.’s primary concern in considering whether the device could be tested in humans, said Cristin Welle, an associate professor of neuroscience at the University of Colorado, who helped draft F.D.A. guidance on brain-computer implants before leaving the agency in 2016.Dr. Welle said regulators will focus on whether the device would damage the brain or present unreasonable risks to patients. She said device durability would also be considered, given the potential for brain fluids to eat through insulation coating the hundreds of hairlike electrodes on the Link device.So far, Neuralink has tested the device on sheep, pigs and primates, according to records filed with the Agriculture Department.Several other companies and scientists have already obtained approval from the F.D.A. to study similar devices in humans. In 2004, researchers conducted human trials with the Utah array, a device the size of a baby aspirin and fitted with spikes that is surgically placed on the brain. It connects through a wire to a small computer installed on the head that transmits to a computer. This neural interface system is called BrainGate.Gertrude the pig and her brain activity charted by a Neuralink implant in the 2020 presentation.NeuralinkWith the pieces in place, scientists seek patterns in the electrical current of neurons that signal the brain’s intention to type letters or lift a hand. The code, in turn, commands a computer or robot to perform the task.Nearly three dozen patients have undergone testing with the Utah array device. Using the technology, people with paralysis or other disabilities have lifted a cinnamon latte with a robotic arm in 2011, typed letters quoting Shakespeare in 2012 and lifted forkfuls of mashed potatoes in 2016.But the Utah array is not suited to long-term use. It rises up out of the skull, tethers users to a cord linked to a computer and exposes them to the risk of a brain infection. For these and other reasons, companies like Neuralink are working to build devices that are fully implanted.

A new serological test in which an NAU professor played an important role in developing can not only help humanity prepare for and respond to the next pandemic, it also can be pivotal in the search for viral triggers of diseases like diabetes and celiac disease.
Jason Ladner, an assistant professor in the Department of Biological Sciences and the Pathogen & Microbiome Institute (PMI), was a leading innovator on PepSeq, a technology that allows scientists to test antibody binding against hundreds of thousands of protein targets at one time, instead of testing one at a time. When we’re trying to track a contagious virus like coronavirus and figure out how to respond to it, getting answers quickly can be the answer between life and death.
This protocol is laid out in detail in an article published earlier in November in Nature Protocols.
“PepSeq: a fully in vitro platform for highly multiplexed serology using customizable DNA-barcoded peptide libraries” describes the novel approach for conducting highly multiplexed serology assays and details the team’s approach for designing and synthesizing custom PepSeq libraries, as well as how to use these libraries to conduct assays and interpret the data. The hope, Ladner said, is to provide a roadmap for scientists everywhere to use the protocol in their own research, moving us closer to answers on some major infectious diseases.
It’s an important step forward as concerns about bioterrorism, zoonotic diseases and the next pandemic are never far away and understanding these pathogens will help enable scientists to develop vaccines as well as tracking their movement and evolution.
“Serology assays are important for diagnosing many human and animal infections,” he said. However, traditional assays often lack sensitivity and/or specificity. Our approach can help to identify which proteins most commonly stimulate an antibody response during infection and which epitopes are specific for the pathogen of interest, rather than being cross-reactive across related pathogens.”
What is PepSeq?

Alzheimer’s disease has always had its puzzles and contradictions. For Pacific Northwest National Laboratory (PNNL) researcher Vladislav Petyuk, whose research on the progressive, age-related disease spans over a decade, some of the struggles have come from studies where “we can only connect the dots a pair at a time.”
Petyuk’s research touches multiple areas in biological and computational science at PNNL. He has produced dozens of publications on Alzheimer’s disease. But now he sees the needle moving in the right direction.
“Over the last 10 years,” Petyuk said, “research has been moving away from a single drug target towards focusing more on the proteins that have a role in cognitive resilience.”
Cognitive resilience is a measure of the brain’s ability to continue to work even with a high Alzheimer’s disease neuropathology that would normally produce the hallmark dementia. This means that, in some people, the brain shows the symptoms of the disease, but it does not impact the person’s ability to function. What makes some brains sensitive, and some resilient, is an open question.
Petyuk recently collaborated with a multi-institutional team in a study that examined a large Alzheimer’s disease cohort of over 1800 people. The researchers drew on previously collected blood samples and brain tissue, along with large-scale data analysis to search for central themes in early identification, prevention, and treatment of the disease.
The research findings published in Science Advances (November 2022), help explain the progression of Alzheimer-related dementia in each patient. Further, the findings outline a multilevel biological classification system that predicts disease severity and future neurological symptoms. “Assessment of a patient’s brain and blood proteins, and other biological molecules, reveal patterns that can then be targeted for tailored intervention,” said Petyuk.

As cancers grow and potentially spread to new parts of the body, they often shed cells and DNA into the blood stream. DNA can be analyzed for both the amount of DNA present and whether any potential mutations exist that may aid providers in deciding on treatments.
These tests, known as liquid biopsies, have become standard practice for certain types of cancer, especially those for which there are drugs that target distinct DNA mutations. Whether liquid biopsies could help providers understand which patients may do better than others, though, is unknown.
DNA found in the blood may also be from normal cells. Measuring the amount of DNA that’s been shed by a tumor compared to the body’s typical amount of DNA, defined as the tumor fraction, may be a new tool to predict survival and guide treatment discussions for patients whose cancer has spread from the breast, prostate, lung or colon, a new study finds.
When tumor DNA made up at least 10% of the DNA in the bloodstream of patients with metastatic cancer, researchers discovered, those patients were much less likely to survive than those with less tumor DNA in the bloodstream, across all cancer types studied.
The measurement was just as accurate when it looked at patients with metastatic breast or lung cancer who had less than 1% of tumor DNA in their bloodstreams; these patients had a better chance of living longer than patients with more tumor DNA in the bloodstream.
“There are two reasons to look at anything analytically like this in a patient’s tumor,” said first author Zachery Reichert, M.D., Ph.D., a clinical associate professor and medical oncologist who specializes in urologic oncology at the University of Michigan Health Rogel Cancer Center. “One is it tells you what to do next. The other is it can help you counsel a patient on what to expect.”
“In several cancers, we have multiple options for treatment without knowing which one is better for whom,” he continued. “A better understanding of the disease risk will help the patient and provider better balance the treatment risks.”