Publisher Health

A new study from Lawson Health Research Institute and Western University published in the journal Microbiome has found changes in the microbiome in multiple locations in the body are linked to the formation of kidney stones.
The human microbiome comprises trillions of microorganisms, including healthy bacteria. In recent years, research has begun to uncover its role in health and numerous diseases.
The research team examined the gut, urinary and salivary microbiomes in 83 patients who had kidney stones and compared them to 30 healthy controls. They found changes in all three microbiomes were linked to kidney stone formation.
“Kidney stone disease has been rising in recent years, affecting roughly 10 per cent of people,” says Dr. Jeremy Burton, Lawson Scientist and Research Chair of Human Microbiome and Probiotics at St. Joseph’s Health Care London (St. Joseph’s). “While previous research has shown a connection between the gut microbiome and kidney stones in those who have taken antibiotics, we also wanted to explore the connection to other microbiomes in the hopes we can advance understanding and potential treatments.”
Study participants included people who had formed kidney stones, had not had antibiotic exposure in the last 90 days and were having the stones removed surgically at St. Joseph’s.
“Our testing — called shotgun metagenomic sequencing — allowed us to discover which bacteria were present in the gut and the genetic capabilities of those bacteria, or how it functions. We also did a simpler sequencing of the oral and urinary samples,” explains Dr. Kait Al, lead author on the study and Postdoctoral Research Fellow at Western’s Schulich School of Medicine & Dentistry.
Kidney stones are most commonly formed from calcium oxalate, which is a waste product produced by the body. Historically, it was thought people with specific gut microbes, like one bacterium called Oxalobacter formigenes that breaks down oxalate, were less likely to form kidney stones. This study suggests there are other factors.

“It’s a more complex story. The microbes form a kind of network that’s stable and beneficial in healthy people, but in those with kidney stones, that network is broken down. They’re not producing the same vitamins and useful metabolites, not just in the gut but also in the urinary tract and oral cavity,” Dr. Al explains.
There was also evidence that those with kidney stones had been exposed to more antimicrobials, as they had more antibiotic-resistant genes.
“We found not only that those who got kidney stones had an unhealthy microbiome, including a gut microbiome that was more likely to excrete toxins to the kidneys, but also that they were antibiotic resistant,” explains Dr. Burton, also an Associate Professor in the Department of Microbiology and Immunology at Schulich Medicine & Dentistry.
The research team says that although more research is needed, these initial findings shed light on the overall importance of a person’s microbiome and keeping it as healthy as possible, with a microbiome-friendly diet and minimal antibiotic use potentially part of the solution.
The study was funded in part through the Weston Foundation and supported by the American Urological Association.

University of Virginia Alzheimer’s researchers have discovered how harmful tau proteins damage the essential operating instructions for our brain cells, a finding which could lead to new treatments.
The toxic protein, the researchers found, warps the shape of the nuclei of nerve cells, or neurons. This alters the function of genes contained inside and reprograms the cells to make more tau.
While the protein has long been a prime suspect in Alzheimer’s and other neurodegenerative “tauopathies,” the new research from UVA’s George Bloom, Ph.D.; his recently graduated student Xuehan Sun, Ph.D.; and collaborators is among the first to identify concrete physical harms that tau causes to neurons. As such, it offers researchers exciting leads as they work to develop new treatments for Alzheimer’s disease and tauopathies, which are now untreatable.
“A lot of fantastic research has been done by other labs to learn how toxic tau spreads from neuron to neuron in the brain, but very little is known about exactly how this toxic tau damages neurons, and that question is the motivation for our new paper,” said Bloom, of UVA’s Departments of Biology, Cell Biology and Neuroscience, as well as the UVA Brain Institute, the Virginia Alzheimer’s Disease Center and UVA’s Program in Fundamental Neuroscience. “The toxic tau described here is actually released from neurons, so if we can figure out how to intercept it when it’s floating around in the brain outside of neurons, using antibodies or other drugs, it might be possible to slow or halt progression of Alzheimer’s disease and other tauopathies.”
Alzheimer’s and Tauopathies
Tauopathies are characterized by the buildup of tau inside the brain. Alzheimer’s disease is well known, but there are many other tauopathies, including frontotemporal lobar degeneration, progressive supranuclear palsy and chronic traumatic encephalopathy. These diseases typically present as dementia, personality changes and/or movement problems. There are no treatments available for non-Alzheimer’s tauopathies, so the UVA researchers were eager to better understand what is happening, so that scientists can find ways to prevent or treat it.
Bloom and his team discovered that tau “oligomers” — assemblages of multiple tau proteins — can have dramatic effects on the normally smooth shape of neuronal nuclei. The oligomers cause the nuclei to fold in on themselves, or “invaginate,” disrupting the genetic material contained within. The physical location and arrangement of genes affects how they work, so this unnatural rearrangement can have dire effects.

“Our discovery that tau oligomers alter the shape of the nucleus drove us to the next step — testing the idea that changes in gene expression are caused by the nuclear shape change,” Bloom said. “That’s exactly what we saw for many genes, and the biggest change is that the gene for tau itself increases its expression almost three-fold. So bad tau might cause more bad tau to be made by neurons — that would be like a snowball rolling downhill.”
The researchers found that patients with Alzheimer’s disease had twice as many invaginated nuclei as people without the condition. Increases were also seen in lab mice used as models of Alzheimer’s and another tauopathy.
The researchers say that additional research into how this process happens could open the door to new ways to prevent and treat Alzheimer’s and other tauopathies.
Findings Published
The researchers have published their findings in the scientific journal Alzheimer’s & Dementia. The article is open access, meaning it is free to read. The research team consisted of Xuehan Sun, Guillermo Eastman, Yu Shi, Subhi Saibaba, Ana K. Oliveira, John R. Lukens, Andrés Norambuena, Joseph A. Thompson, Michael D. Purdy, Kelly Dryden, Evelyn Pardo, James W. Mandell and Bloom. The researchers have no financial interest in the work.
The research was supported by the National Institutes of Health, grant RF1 AG051085; the Owens Family Foundation; the Cure Alzheimer’s Fund; Rick Sharp Alzheimer’s Foundation; Webb and Tate Wilson; and the NanoString nCounter Grant Program.
To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

A pilot clinical trial led by University of Cincinnati researchers at the Lindner Center of HOPE found electrical stimulation of the spinal cord is feasible, well-tolerated and shows therapeutic potential to treat depression.
The results of the trial were published in the journal Molecular Psychiatry on Dec. 20.
Research Background
Principal investigator Francisco Romo-Nava, MD, PhD, said his research focuses on how brain-body communication is involved in psychiatric disorders.
“We think that the connection between the brain and the body is essential for psychiatric disorders,” said Romo-Nava, associate professor in the Department of Psychiatry and Behavioral Neurosciences at UC, associate chief research officer for the Research Institute at the Lindner Center of HOPE and a UC Health physician scientist. “Many of the symptoms of mood disorders or eating disorders or anxiety disorders have to do with what one could interpret as dysregulation in this brain-body interaction.”
Romo-Nava said pathways of neurons located in the spinal cord convey information from the body to regions of the brain that are involved in the emotional experience we know as mood. When functioning properly, the brain uses this information to constantly make adjustments to help regulate a person’s mood.
While major depressive disorder can have many different causes, one contributor could be this pathway being overloaded with information.

“For example, chronic stress could lead to a hyperactive brain-body circuit that eventually burns the system out and prevents it from adjusting itself in an effective and optimal way,” Romo-Nava said.
The research team looked at different ways to modulate this interaction between the brain and body and developed a novel approach through noninvasive spinal cord stimulation. Romo-Nava obtained a patent in 2020 for the stimulation method used after working with UC’s Office of Innovation.
The spinal cord stimulation is designed to decrease the flow of information in the brain-body circuit so that the brain is better able to readjust and regulate itself.
“Spinal cord stimulation is thought to help the brain modulate itself as it should by decreasing the noise or decreasing the hyperactive signaling that may be in place during a depressive syndrome,” Romo-Nava said.
The investigational device that was used is no larger than a shoe box, with the active electrode placed on the patient’s back and the return electrode placed on their right shoulder.
Trial Details
With funding through a Brain & Behavior Research Foundation NARSAD Young Investigator Award, Romo-Nava designed the pilot study to test the feasibility and tolerability of spinal cord stimulation for patients with major depressive disorder.

A total of 20 patients were enrolled in the trial, with half randomized to receive the active version of the spinal cord stimulation and half receiving a different version of current that was not expected to have much of an effect.
Patients went to the Lindner Center of HOPE for three 20-minute sessions a week for eight weeks, for a total of 24 spinal stimulation sessions.
Trial Results
Romo-Nava said like with most pilot studies, the primary focus of the study was the feasibility and safety of the intervention and how well patients tolerated the stimulation. The study was designed so that the dose of stimulation could be decreased if needed, but Romo-Nava said all patients tolerated the initially prescribed dose well.
“We used a current that is so small that it’s about 10 times smaller than the one known to induce tissue damage, so that’s also pretty encouraging because there’s a lot to explore in terms of what is the optimal dose and session frequency,” he said.
Side effects of the treatment were mild, including skin redness at the site of stimulation and brief non-painful itching or burning sensations that only lasted during the treatment sessions. The skin redness typically did not last more than 20 minutes after a session, Romo-Nava said.
A virtual reconstruction of how the current from the device moves through the body showed the current reaches spinal gray matter in the spinal cord, but does not reach the brain itself.
“That supports our hypothesis that it is the modulation of these pathways of information that then may induce an effect on the mood-relevant areas in the brain,” he said. “So it is not the current that reaches the brain, it is the change in the signal that then has an effect. This study is not sufficient to prove all of these components of the hypothesis, but we think it’s a great start.”
Patients that received the active stimulation had a greater decrease in the severity of their depressive symptoms compared to the control group, but Romo-Nava cautioned the study was limited by its small sample size. These results will need to be replicated in much larger studies to be confirmed.
“We need to be cautious when we interpret these results because of the pilot nature and the small sample size of the study,” he said. “While the primary outcome was positive and it shows therapeutic potential, we should acknowledge all the limitations of the study.”
Data showed participants’ resting blood pressure did not change over the course of the eight weeks, but their diastolic blood pressure (the bottom number of a blood pressure reading) decreased for a short time after each session in a cumulative way during the study.
“That may mean that we may be actually inducing a form of plastic effect on the brain-body interaction circuit that is also involved in autonomic functions like blood pressure and heart rate,” Romo-Nava said. “This is very preliminary, but it is also another signal that is in the right direction.”
Moving forward, Romo-Nava said the research team is seeking additional funding to put together an expanded trial and develop a portable version of the spinal cord stimulation device. If further studies confirm the stimulation is safe and effective to treat psychiatric disorders, future work will also be needed to find the optimal dose, frequency and conditions it can be used for.

CAMBRIDGE, MA — Using a type of artificial intelligence known as deep learning, MIT researchers have discovered a class of compounds that can kill a drug-resistant bacterium that causes more than 10,000 deaths in the United States every year.
In a study appearing today in Nature, the researchers showed that these compounds could kill methicillin-resistant Staphylococcus aureus (MRSA) grown in a lab dish and in two mouse models of MRSA infection. The compounds also show very low toxicity against human cells, making them particularly good drug candidates.
A key innovation of the new study is that the researchers were also able to figure out what kinds of information the deep-learning model was using to make its antibiotic potency predictions. This knowledge could help researchers to design additional drugs that might work even better than the ones identified by the model.
“The insight here was that we could see what was being learned by the models to make their predictions that certain molecules would make for good antibiotics. Our work provides a framework that is time-efficient, resource-efficient, and mechanistically insightful, from a chemical-structure standpoint, in ways that we haven’t had to date,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering.
Felix Wong, a postdoc at IMES and the Broad Institute of MIT and Harvard, and Erica Zheng, a former Harvard Medical School graduate student who was advised by Collins, are the lead authors of the study, which is part of the Antibiotics-AI Project at MIT. The mission of this project, led by Collins, is to discover new classes of antibiotics against seven types of deadly bacteria, over seven years.
Explainable predictions
MRSA, which infects more than 80,000 people in the United States every year, often causes skin infections or pneumonia. Severe cases can lead to sepsis, a potentially fatal bloodstream infection.

Over the past several years, Collins and his colleagues in MIT’s Abdul Latif Jameel Clinic for Machine Learning in Health (Jameel Clinic) have begun using deep learning to try to find new antibiotics. Their work has yielded potential drugs against Acinetobacter baumannii, a bacterium that is often found in hospitals, and many other drug-resistant bacteria.
These compounds were identified using deep learning models that can learn to identify chemical structures that are associated with antimicrobial activity. These models then sift through millions of other compounds, generating predictions of which ones may have strong antimicrobial activity.
These types of searches have proven fruitful, but one limitation to this approach is that the models are “black boxes,” meaning that there is no way of knowing what features the model based its predictions on. If scientists knew how the models were making their predictions, it could be easier for them to identify or design additional antibiotics.
“What we set out to do in this study was to open the black box,” Wong says. “These models consist of very large numbers of calculations that mimic neural connections, and no one really knows what’s going on underneath the hood.”
First, the researchers trained a deep learning model using substantially expanded datasets. They generated this training data by testing about 39,000 compounds for antibiotic activity against MRSA, and then fed this data, plus information on the chemical structures of the compounds, into the model.
“You can represent basically any molecule as a chemical structure, and also you tell the model if that chemical structure is antibacterial or not,” Wong says. “The model is trained on many examples like this. If you then give it any new molecule, a new arrangement of atoms and bonds, it can tell you a probability that that compound is predicted to be antibacterial.”
To figure out how the model was making its predictions, the researchers adapted an algorithm known as Monte Carlo tree search, which has been used to help make other deep learning models, such as AlphaGo, more explainable. This search algorithm allows the model to generate not only an estimate of each molecule’s antimicrobial activity, but also a prediction for which substructures of the molecule likely account for that activity.

Potent activity
To further narrow down the pool of candidate drugs, the researchers trained three additional deep learning models to predict whether the compounds were toxic to three different types of human cells. By combining this information with the predictions of antimicrobial activity, the researchers discovered compounds that could kill microbes while having minimal adverse effects on the human body.
Using this collection of models, the researchers screened about 12 million compounds, all of which are commercially available. From this collection, the models identified compounds from five different classes, based on chemical substructures within the molecules, that were predicted to be active against MRSA.
The researchers purchased about 280 compounds and tested them against MRSA grown in a lab dish, allowing them to identify two, from the same class, that appeared to be very promising antibiotic candidates. In tests in two mouse models, one of MRSA skin infection and one of MRSA systemic infection, each of those compounds reduced the MRSA population by a factor of 10.
Experiments revealed that the compounds appear to kill bacteria by disrupting their ability to maintain an electrochemical gradient across their cell membranes. This gradient is needed for many critical cell functions, including the ability to produce ATP (molecules that cells use to store energy). An antibiotic candidate that Collins’ lab discovered in 2020, halicin, appears to work by a similar mechanism but is specific to Gram-negative bacteria (bacteria with thin cell walls). MRSA is a Gram-positive bacterium, with thicker cell walls.
“We have pretty strong evidence that this new structural class is active against Gram-positive pathogens by selectively dissipating the proton motive force in bacteria,” Wong says. “The molecules are attacking bacterial cell membranes selectively, in a way that does not incur substantial damage in human cell membranes. Our substantially augmented deep learning approach allowed us to predict this new structural class of antibiotics and enabled the finding that it is not toxic against human cells.”
The researchers have shared their findings with Phare Bio, a nonprofit started by Collins and others as part of the Antibiotics-AI Project. The nonprofit now plans to do more detailed analysis of the chemical properties and potential clinical use of these compounds. Meanwhile, Collins’ lab is working on designing additional drug candidates based on the findings of the new study, as well as using the models to seek compounds that can kill other types of bacteria.
“We are already leveraging similar approaches based on chemical substructures to design compounds de novo, and of course, we can readily adopt this approach out of the box to discover new classes of antibiotics against different pathogens,” Wong says.
In addition to MIT, Harvard, and the Broad Institute, the paper’s contributing institutions are Integrated Biosciences, Inc., the Wyss Institute for Biologically Inspired Engineering, and the Leibniz Institute of Polymer Research in Dresden, Germany.

Vaccine development aims at protecting as many people as possible from infections. Short protein fragments of pathogens, so-called epitopes, are seen as a promising new approach for vaccine development. In the scientific journal Cell Systems, bioinformaticians from Heinrich Heine University Düsseldorf (HHU) now present a method for identifying those epitopes that promise safe immunisation across the broadest possible population group. They have also computed vaccine candidates against the coronavirus SARS-CoV-2 using their HOGVAX tool.
During the coronavirus pandemic, so-called mRNA vaccines proved particularly successful and flexible. These vaccines target the so-called spike proteins — characteristic structures on the surface of the virus. The mRNA contains the sequence of the spike protein, which is produced in the body after vaccination and then trains the human immune system.
“Epitopes” — short fragments of pathogen proteins that are capable of triggering an immune response — are seen as an alternative method to mRNA and a promising approach for obtaining targeted immune responses quickly, cost-effectively and safely.
Everyone has a unique immune system: Depending on their infection history, the immune system is trained to handle and react to different proteins. “This is a fundamental problem of vaccines based on epitopes,” explains Professor Dr Gunnar Klau, holder of the Chair of Algorithmic Bioinformatics at HHU. Together with his PhD student Sara Schulte and Professor Dr Alexander Dilthey from the Institute of Medical Microbiology and Hospital Hygiene, he considered a new approach to developing such vaccines.
Professor Klau compares the problem with a chef who needs to create a new dish for a large event: “Some guests have allergies, while others do not like certain ingredients, so the chef needs to select ingredients that as many of the guests as possible can eat and will enjoy.”
Translated to vaccine development, this means that they are seeking epitopes that trigger a good immune response in as many people as possible. This is necessary because it is not possible to pack an unlimited number of protein fragments into a vaccine so that the various immune systems can seek out the sequences suitable for them — the carrier medium simply does not have sufficient capacity.
The team of three researchers took a special approach with their bioinformatic tool “HOGVAX.” Sara Schulte: “Instead of stringing the epitopes for the vaccine together end-to-end, we use identical sequences at the beginning and end of the epitopes so we can overlay them. The identical section, known as the ‘overlap’, is thus only represented once in the vaccine, which enables us to save a huge amount of space.” This in turn enables many more epitopes to be included in a vaccine.
In order to manage the epitopes and their longest overlaps efficiently, the researchers use a data structure known as a “hierarchical overlap graph” (for short: HOG). Klau: “To stay with the cooking analogy: HOG corresponds to a compressed or shrunk cookbook, from which the chef can now select the recipes that are suitable for all guests.”
Professor Dilthey: “As a test, we applied HOGVAX to data for the SARS-CoV-2 virus and we were able to integrate significantly more epitopes than other tools. According to our calculations, we would be able to reach — and immunise — more than 98% of the world population.”
Sara Schulte comments on the further perspectives for their results: “In the future, we will work on adapting HOGVAX for use in cancer therapy. The aim here is to develop agents specifically designed for individual patients that attack tumour cells in a targeted manner.”

The human brain continues to be built after we are born for far longer than previously recognized, suggests research by Shawn Sorrells, assistant professor of neuroscience in the Kenneth P. Dietrich School of Arts and Sciences. Sorrells’s research on postnatal brain development, published today inthe journal Nature, shines light on fundamental processes that contribute to the development of important brain functions, such as learning, memory and spatial navigation.
The new research suggests that a subset of inhibitory neurons within the entorhinal cortex, or EC — an area of the brain essential for forming memories — continue to migrate into this region where they build new neuronal connections from birth through toddlerhood. The study suggests that extensive postnatal neuronal migration across the EC might underlie critical neuroplasticity periods during which the brain is especially receptive to changes and adaptations. The discovery also points to a possible reason why EC neurons are more susceptible to neurodegeneration, since other recent studies have found that this same type of neuron is impacted early in Alzheimer’s disease.
By analyzing brain samples that were provided, in part, by the epilepsy tissue bank at UPMC Children’s Hospital and the Neuropathology Department at UPMC Presbyterian Hospital, Sorrells’ research team was first to show that, unlike what was previously thought, neuronal migration of such scale and duration is extensive within regions that control thoughts and emotions. The discovery offers an explanation for how the human brain makes billions of new neurons over a very short time span through a mechanism that allows neurons to continue arriving after birth.
“It is generally thought that the brain is done recruiting neurons by the time an individual is born,” said Sorrells. “We were incredibly excited to learn that not only does large-scale neuronal migration continue into specific brain regions, but that this process also continues into ages when children are crawling and beginning to walk.”

The intricate process of duplicating genetic information, referred to as DNA replication, lies at the heart of the transmission of life from one cell to another and from one organism to the next. This happens by not just simply copying the genetic information; a well-orchestrated sequence of molecular events has to happen at the right time. Scientists around Prof. Maria-Elena Torres-Padilla from Helmholtz Munich have recently uncovered a fascinating aspect of this process known as “replication timing” (RT) and how special this is when life commences. The new results are now published in Nature.
The process of DNA replication timing (RT) refers to the specific moments when different regions of our genetic code are duplicated. Researchers from the Institute for Epigenetics and Stem Cells at Helmholtz Munich have implemented a technique called “Repli-seq” to delve into the intimate relationship between RT and the adaptability of cells, the cellular plasticity. Intriguingly, they also uncovered a new relationship between RT and how the genes fold into three-dimensional structures inside the cell nucleus.
Starting with the earliest stage of an embryo, the zygote — the very beginning of an organism’s life — researchers have created a map of RT from this single-cell stage to the stage at which the embryo implants in the mother’s womb, called a blastocyst. The unexpected discovery is that the RT in the single-celled embryo is not very ordered, leading to the suggestion that genome duplications are very flexible in these early cells. However, after the 4-cell stage, the RT becomes more defined. There is a gradual process happening, mirroring the gradual acquisition of modifications to the DNA and associated proteins, the so-called chromatin marks, that indicate the genes’ activity and importance in the cell’s functions.
Maria-Elena Torres-Padilla, corresponding author of the study, explains further: “This is remarkable, as this tells us that these early embryo cells have a very ‘plastic’ genome duplication program. Because these early cells are totipotent, that means, they can create every single cell in our bodies. We think that what we discovered in this study is one of the reasons why these cells are so remarkably capable of generating all the body.” The new findings about DNA replication can serve as a tool to reprogram cells. Dr. Tsunetoshi Nakatani, the first author of the study, adds: “We can envision changing the cell identity by changing its RT program into a more flexible one.”
The results further show, that RNA polymerase, commonly known as the enzyme responsible for reading the genetic code and transcribing it into RNA, contributes to determining the exact RT program, providing some cues as to how to be able to manipulate such program in the future. The research team has discovered that the three-dimensional structure of the genome takes shape first, and the RT program is established consequently. This is an exciting finding, as it posits that how our genome accommodates into the three-dimensional space of the cell nucleus influences the flexibility of the RT program.
In conclusion, DNA replication timing is a fascinating piece of the puzzle in the grand narrative of life. It demonstrates how the precision of genetic replication is intimately tied to the capacity of the cells from the early embryo to generate other cell types in our body. As researchers continue to explore these connections, we gain a deeper understanding of the very essence of life’s transmission, cell to cell, organism to organism, and of what makes a cell capable of generating a new body.

The maintenance of a balanced lipid homeostasis is critical for our health. While consumption of excessive amounts of fatty foods contributes to metabolic diseases such as obesity and atherosclerosis, fat is an indispensable component of our diet. Digested lipids supply the body with essential building blocks and facilitate the absorption of important vitamins. In a new study published in the journal Nature, a team of researchers led by Professor Manolis Pasparakis and their collaborators Professor Aleksandra Trifunovic and Professor Christian Frezza at the Excellence Cluster CECAD of the University of Cologne, and Professor Jörg Heeren at the University of Hamburg, report on a new mechanism that regulates the processing and transport of dietary lipids by the intestine.
The researchers studied the function of mitochondria — organelles acting as powerhouses of the cell — in enterocytes, cells that line the intestine and specialize in the absorption and transport of nutrients from digested food. They found that disruption of mitochondrial function in the intestines of mice caused abnormal accumulation of dietary fat in enterocytes and impaired delivery of lipids to the peripheral organs.
A key finding of the study was that, when mitochondria did not function properly, enterocytes showed impaired packaging and transport of lipids in the form of chylomicrons. Chylomicrons are crucial carriers of dietary fats, and their proper formation and transport are essential for the absorption of nutrients.
“This discovery marks a significant leap forward in understanding the crucial role of mitochondria in dietary lipid transport and metabolism,” said Dr Chrysanthi Moschandrea, the lead author of the study. The implications of this discovery go beyond the realm of basic research. “These findings provide new perspectives for the better understanding of the gastrointestinal symptoms in patients suffering from mitochondrial disease, and may also lead to new therapeutic approaches,” added Professor Aleksandra Trifunovic.
The maintenance of a balanced lipid homeostasis is critical for our health. While consumption of excessive amounts of fatty foods contributes to metabolic diseases such as obesity and atherosclerosis, fat is an indispensable component of our diet. Digested lipids supply the body with essential building blocks and facilitate the absorption of important vitamins. In a new study published in the journal Nature, a team of researchers led by Professor Manolis Pasparakis and their collaborators Professor Aleksandra Trifunovic and Professor Christian Frezza at the Excellence Cluster CECAD of the University of Cologne, and Professor Jörg Heeren at the University of Hamburg, report on a new mechanism that regulates the processing and transport of dietary lipids by the intestine.
The researchers studied the function of mitochondria — organelles acting as powerhouses of the cell — in enterocytes, cells that line the intestine and specialize in the absorption and transport of nutrients from digested food. They found that disruption of mitochondrial function in the intestines of mice caused abnormal accumulation of dietary fat in enterocytes and impaired delivery of lipids to the peripheral organs.
A key finding of the study was that, when mitochondria did not function properly, enterocytes showed impaired packaging and transport of lipids in the form of chylomicrons. Chylomicrons are crucial carriers of dietary fats, and their proper formation and transport are essential for the absorption of nutrients.
“This discovery marks a significant leap forward in understanding the crucial role of mitochondria in dietary lipid transport and metabolism,” said Dr Chrysanthi Moschandrea, the lead author of the study. The implications of this discovery go beyond the realm of basic research. “These findings provide new perspectives for the better understanding of the gastrointestinal symptoms in patients suffering from mitochondrial disease, and may also lead to new therapeutic approaches,” added Professor Aleksandra Trifunovic.

A surprising MIT study published in Nature at the end of 2016 helped to spur interest in the possibility that light flickering at the frequency of a particular gamma-band brain rhythm could produce meaningful therapeutic effects for people with Alzheimer’s disease. In a new review paper in the Journal of Internal Medicine, the lab that led those studies takes stock of what a growing number of scientists worldwide have been finding out since then in dozens of clinical and lab benchtop studies.
Brain rhythms (also called brain “waves” or “oscillations”) arise from the synchronized, network activity of brain cells and circuits as they coordinate to enable brain functions such as perception or cognition. Lower-range gamma frequency rhythms, those around 40 cycles a second, or Hz, are particularly important for memory processes, and MIT’s research has shown that they are also associated with specific changes at the cellular and molecular level. The 2016 study and many others since then have produced evidence initially in animals and more recently in humans that various non-invasive means of enhancing the power and synchrony of 40Hz gamma rhythms helps to reduce Alzheimer’s pathology and its consequences.
“What started in 2016 with optogenetic and visual stimulation in mice has expanded to a multitude of stimulation paradigms, a wide range of human clinical studies with promising results and is narrowing in on the mechanisms underlying this phenomenon,” wrote the authors including Li-Huei Tsai, Picower Professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT.
Though the number of studies and methods has increased and the data has typically suggested beneficial clinical effects, the article’s authors also clearly caution that the clinical evidence remains preliminary and that animal studies intended to discern how the approach works have been instructive but not definitive.
“Research into the clinical potential of these interventions is still in its nascent stages,” the researchers, led by MIT postdoc Cristina Blanco-Duque, wrote in introducing the review. “The precise mechanisms underpinning the beneficial effects of gamma stimulation in Alzheimer’s disease are not yet fully elucidated, but preclinical studies have provided relevant insights.”
Preliminarily promising
The authors list and summarize results from 16 clinical studies published over the last several years. These employ gamma frequency sensory stimulation (e.g. exposure to light, sound, tactile vibration, or a combination), trans cranial alternating current stimulation (tACS), in which a brain region is stimulated via scalp electrodes, or transcranial magnetic stimulation (TMS), in which electric currents are induced in a brain region using magnetic fields. The studies also vary in their sample size, design, duration and in what effects they assessed. Some of the sensory studies using light have tested different colors and different exact frequencies. And while some studies show that sensory stimulation appears to affect multiple regions in the brain, tACS and TMS are more regionally focused (though those brain regions still connect and interact with others).

Given the variances, the clinical studies taken together offer a blend of uneven but encouraging evidence, the authors write. Across clinical studies involving patients with Alzheimer’s disease, sensory stimulation has proven safe and well tolerated. Multiple sensory studies have measured increases in gamma power and brain network connectivity. Sensory studies have also reported improvements in memory and/or cognition as well as sleep. Some have yielded apparent physiological benefits such as reduction of brain atrophy, in one case, and changes in immune system activity in another. So far, sensory studies have not shown reductions in Alzheimer’s hallmark proteins, amyloid or tau.
Clinical studies stimulating 40Hz rhythms using tACS, ranging in sample size from only one to as many as 60, are the most numerous so far and many have shown similar benefits. Most report benefits to cognition, executive function and/or memory (depending sometimes on the brain region stimulated) and some have assessed that benefits endure even after treatment concludes. Some have shown effects on measures of tau and amyloid, blood flow, neuromodulatory chemical activity, or immune activity. Finally a 40Hz stimulation clinical study using TMS in 37 patients found improvements in cognition, prevention of brain atrophy and increased brain connectivity.
“The most important test for gamma stimulation is without a doubt whether it is safe and beneficial for patients,” the authors wrote. “So far, results from several small trials on sensory gamma stimulation suggest that it is safe, evokes rhythmic EEG brain responses, and there are promising signs for AD symptoms and pathology. Similarly, studies on transcranial stimulation report the potential to benefit memory and global cognitive function even beyond the end of treatment.”
Studying underlying mechanisms
In parallel, dozens more studies have shown significant benefits in mice including reductions in amyloid and tau, preservation of brain tissue and improvements in memory. But animal studies also have offered researchers a window into the cellular and molecular mechanisms by which gamma stimulation might have these effects.
Before MIT’s original studies in 2016 and 2019 researchers had not attributed molecular changes in brain cells to changes in brain rhythms, but those and other studies have now shown that they affect not only the molecular state of neurons, but also the brain’s microglia immune cells, astrocyte cells that play key roles in regulating circulation and indeed the brain’s vasculature system. A hypothesis of Tsai’s lab right now is that sensory gamma stimulation might promote the clearance of amyloid and tau via increased circulatory activity of brain fluids.

A hotly debated aspect of gamma stimulation is how it affects the electrical activity of neurons and how pervasively. Studies indicate that inhibitory “interneurons” are especially affected, though, offering a clue about how increased gamma activity, and its physiological effects, might propagate.
“The field has generated tantalizing leads on how gamma stimulation may translate into beneficial effects on the cellular and molecular level,” the authors wrote.
Gamma going forward
As the authors make clear that more definitive clinical studies are needed, they note that at the moment, there are now 15 new clinical studies of gamma stimulation underway. Among these is a phase 3 clinical trial by the company Cognito Therapeutics, which has licensed MIT’s technology. That study plans to enroll hundreds of participants.
Meanwhile, some recent or new clinical and preclinical studies have begun looking at whether gamma stimulation may be applicable to neurological disorders other than Alzheimer’s, including stroke or Down syndrome. In experiments with mouse models, for example, an MIT team has been testing gamma stimulation’s potential to help with cognitive effects of chemotherapy, or “chemobrain.”
“Larger clinical studies are required to ascertain the long-term benefits of gamma stimulation,” the authors conclude. “In animal models the focus should be on delineating the mechanism of gamma stimulation and providing further proof of principle studies on what other applications gamma stimulation may have.”
In addition to Tsai and Blanco-Duque, the paper’s other authors are Diane Chan, Martin Kahn, and Mitch Murdock.

Acute spinal cord injury (SCI) patients lose body weight and muscle mass, despite being on a high-calorie diet while in the intensive care unit. Their muscle wasting is substantial and extends beyond what can explained by inactivity or denervation (loss of nerve supply) alone.
Research led by The Ohio State University Wexner Medical Center and College of Medicine published in the journal Science Translational Medicine sheds new light and decodes early muscle loss after SCI to provide an unprecedent first understanding that muscle wasting is: rapid and severe a systemic phenomenon glucocorticoid dependentResearchers found that the severity of this SCI-induced systemic muscle wasting depends on location of the spinal cord injury (lesion level). More precisely, it depends on whether the adrenal gland becomes denervated after high thoracic injury (above T5), or not (after low thoracic injury).
These findings have direct clinical ramifications.
“Patients with a low body mass index (BMI) have a much higher risk to die shortly after suffering a spinal cord injury. With a better understanding of this muscle wasting and aggravated weight loss, we hope to explore new ways to reduce deaths in this fragile patient population,” said Jan Schwab, MD, PHD, the William E. Hunt & Charlotte M. Curtis Chair and a professor of neurology and neurosciences at the Ohio State College of Medicine.
Researchers found that systemic muscle loss is worsened when the adrenal glands become deprived of central nervous system control resulting in a skewed hormonal (endocrine) tone. When this happens, hypercortisolism (excess cortisol release) often develops after the spinal cord injury.
“This hypercortisolism then acts on specific receptors in the muscle of the entire body to cause muscle loss. Interfering with this pathway could rescue muscle tissue and improve the response to rehabilitation,” said first author Markus Harrigan, a member of Schwab’s research lab and Ohio State’s dual-degree MD-PhD Medical Scientist Training Program as well as a Ruth L. Kirschstein Individual NIH-Research Fellow.

This research also provides new insights on how to maintain muscle integrity while reducing the risk to develop higher degree pressure ulcers that often plague these patients, Harrigan said. The study builds on previous Ohio State research into the effects of SCI on the immune system that undermine immune system function, enhance infection susceptibility and contribute to infectious complications.
“We now start to understand how an injury of the spinal cord leads to spinal cord disease affecting the entire body,” said Schwab, who is also medical director of the Belford Center for Spinal Cord Injury and a Scholar of the Chronic Brain Injury Initiative at Ohio State. “Our future research will search for ways to block these complications and protect the adrenal gland from receiving ‘false’ autonomic nervous system information originating from the spinal cord below the lesion site.”
Ohio State scientists collaborated with researchers in Berlin, Germany, along with Nationwide Children’s Hospital in Columbus, Ohio, and the University of Missouri.
This research is supported by funding from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke grant F31NS117124; The Ohio State University Center for Muscle Health and Neuromuscular Disorders grant; NIH/National Institute of Neurological Disorders and Stroke grant 5R35NS111582; NIH/ National Institute of Disability, Independent Living and 855 Rehabilitation Research grant 90SI5020; NIH/National Institute of Neurological Disorders and Stroke grant R01NS118200; Craig H. Neilsen Foundation grant 596764; European Union Era Net — Neuron Program, SILENCE grant 01EW170A; Wings for Life Spinal Cord Research Foundation grant, and the William E. Hunt and Charlotte M. Curtis Endowment.