Life in the Yukon can be tough for young red squirrels.
Frigid winters, food scarcity, intense competition for territories and the threat of becoming prey to large predators like the Canada lynx are just some of the trials they face.
Early-life struggles and trauma can literally get under their skin, affecting long-term survival, said Lauren Petrullo, a University of Arizona assistant professor in the Department of Ecology and Evolutionary Biology. Scientists want to know what factors, if any, can buffer young squirrels against these threats.
Petrullo is part of the Kluane Red Squirrel Project, a multi-university long-term field project involving the University of Alberta, University of Michigan, University of Colorado Boulder and University of Saskatchewan. The project has tracked and studied thousands of wild North American red squirrels in the southwestern part of Canada’s Yukon territory for over 30 years.
A new study — which Petrullo led with David Delaney, a postdoctoral fellow at the University of Colorado Boulder — finds that the more challenges young squirrels face in the year they are born, the shorter their adult lifespan.
Red squirrels who make it past their first year of life live about 3 1/2 years, on average, but early life adversity can cut life expectancy by at least 14%.
But there’s a big caveat.

“The ecosystem red squirrels inhabit in this region is unique,” Petrullo said. “Every three to seven years, their favorite food — seed from cones of white spruce trees — is produced in superabundance during what we call a food boom. We found that these booms, even though rare, can interrupt the biological embedding of early-life adversity. If a squirrel had a harsh first year of life, if they were lucky enough to experience a food boom in their second year of life, they lived just as long — if not longer — in spite of early-life adversity.”
The team replicated a food boom by offering wild squirrels in the Yukon peanut butter as a supplemental food source. The peanut butter didn’t have the same effect as the naturally occurring food boom did.
“This suggests that the buffering effect we see is not really just about an increase in available calories,” Petrullo said. “It’s probably about shifts in larger population-level dynamics, like competition.”
What squirrels can teach us about humans
Petrullo and her colleagues are eager to tease out the mechanisms that link squirrels’ early developmental conditions with later-life survival. What they learn could inform scientific understanding of human resilience, too.
“Our findings in red squirrels echo what we know about how early-life adversity can shorten adult lifespan in humans and other primates,” Petrullo said. “Humans vary widely in how vulnerable or resilient they are to challenges faced during early development. Our study demonstrates that future environmental quality might be an important factor that can explain why some individuals appear to be more, or less, susceptible to the consequences of early-life adversity.”
While it might be surprising that scientists can glean insights about human resilience from wild red squirrels, Petrullo pointed out that squirrels are rodents, and rodents are commonly used as models for humans in laboratory settings.

“Many lab experiments have limited relevance for broader dynamics between ecology and evolution, because it can be hard to really replicate the ecological challenges that animals have evolved to cope with in a lab setting,” she said.
Wild red squirrels, on the other hand, allow for such investigations and are an especially useful study group for questions regarding the early-life environment, Petrullo said. Although growing up as a young squirrel in the Yukon can be difficult, with lots of things making early development challenging, there are also things that can go right.
“Some red squirrels have the luck of being born into gentler early environments, akin to being born with a silver spoon,” Petrullo said. “Because of this, we’ve got this really nice individual variation in early-life environmental quality across a natural ecological environment.”
This environment, however, is expected to experience a great deal of change as global temperatures continue to rise.
“As food boom patterns begin to change,” Petrullo said, “the pathways that connect early-life experiences and lifespan may change as well, potentially offering important insight into how animals may adapt to increasingly challenging environments.”

A team of researchers at Johannes Gutenberg University Mainz (JGU) has identified a mechanism that causes mitochondrial dysfunction in Alzheimer’s patients resulting in a reduction of the supply of energy to the brain. “This effect is attributable to an RNA modification which has not previously been reported,” said Professor Kristina Friedland of the Institute of Pharmaceutical and Biomedical Sciences at JGU. She supervised the related study in collaboration with her colleague Professor Mark Helm. Their results contribute to the better understanding of the pathophysiology of Alzheimer’s disease. Also involved in the research were groups at the Mainz University Medical Center, the Institute of Molecular Biology (IMB), Université de Lorraine, and the Medical University of Vienna. The corresponding paper has been published in Molecular Psychiatry.
The ‘powerhouse of the cell’ affected by functional disorder
Mitochondria, often referred to as the powerhouse of the cell, are organelles inside cells that are in charge of the provision of energy throughout the body and particularly in the brain. For 95 percent of its energy, the brain is reliant on the metabolism of glucose in the mitochondria. It has long been known that impairment of glucose metabolism occurs in the early stages of Alzheimer’s disease. This impairment is due to dysfunctioning of the mitochondria induced by the aging process and the build-up of amyloid-beta.
A source of energy in the form of adenosine triphosphate (ATP) is formed in the inner mitochondrial membrane by means of a sequence of reactions known as the respiratory chain. Involved in this process are more than one thousand proteins that are transported from the cellular nuclei to the mitochondria. “But there are also proteins that are synthesized by the mitochondria themselves. One of these is ND5, a subunit of complex I of the respiratory chain,” explained Professor Kristina Friedland. A substance called NADH gives electrons to complex I, which transfers these to ubiquinone, resulting in ubiquinol. During this process, four proteins are pumped from the matrix into the intermembrane space. ND5 plays an important role in this connection and any mutations of the mitochondrial encoded gene of this subunit can result in serious mitochondrial disorders, such as Leigh syndrome.
It has already been demonstrated that the mRNA that provides the instructions for the synthesis of this protein can undergo methylation. In body cells, mRNA carries the genetic information and — together with tRNA — is responsible for its translation into proteins. Methylation of mRNA leads to a change to its chemical structure so that it can no longer correctly interact with tRNA. “The synthesis process is undermined and fewer proteins of the subunit ND5, which is of central relevance to complex I, are formed because the whole process commences with the respiratory chain,” added Friedland.
TRMT10C enzyme causes methylation and thus inhibition of the synthesis of ND5
The teams of Friedland and Helm at the Institute of Pharmaceutical and Biomedical Sciences at Mainz University were able to show that it is an enzyme called TRMT10C that induces this methylation and thus the subsequent repression of ND5. The researchers observed suppression of the biosynthesis of proteins of the ND5 subunit in a suitable cell model as well as in the brains of Alzheimer’s patients.
As the authors stated in their article in Molecular Psychiatry: “As a consequence, here demonstrated for the first time, TRMT10C induced m1A methylation of ND5 mRNA leads to mitochondrial dysfunction. Our findings suggest that this newly identified mechanism might be involved in Aβ-induced mitochondrial dysfunction.” The research was funded as part of the Collaborative Research Center / Transregio 319 “RMaP: RNA Modification and Processing.”

A common practice of shoulder surgeons may be impairing the success of rotator cuff surgery, a new study from orthopedic scientists and biomedical engineers at Columbia University suggests.
During the surgery, surgeons often remove a tissue called the bursa while repairing torn tendons in the shoulder joint, but the study suggests that the small tissue plays a role in helping the shoulder heal.
“It is common to remove the bursa during shoulder surgery, even for the simple purpose of visualizing the rotator cuff,” says Stavros Thomopoulos, PhD, the study’s senior author and the Robert E. Carroll and Jane Chace Carroll Laboratories Professor of Orthopaedic Surgery at Columbia University Vagelos College of Physicians and Surgeons.
“But we really don’t know the role of the bursa in rotator cuff disease, so we don’t know the full implications of removing it,” Thomopoulos says. “Our findings in an animal model indicate that surgeons should not remove the bursa without carefully considering the consequences.”
The challenge of rotator cuff surgery
If you haven’t yet injured your shoulder, it may just be a matter of time.
Most damage to tendons in the rotator cuff comes from wear and tear that accumulates over years of repetitive motions. Among people over 65, about half have experienced a rotator cuff tear, which can make simple daily tasks like combing one’s hair difficult and painful.

More than 500,000 rotator cuff surgeries are performed each year in the United States to repair these injuries, restore range of motion, and alleviate pain, but they frequently fail — ranging from one in five surgeries in young patients to as high as 94% in elderly patients with large tears.
Rotator cuff repairs usually fail because of poor healing between tendon and bone where the tendon is reattached to the bone.
Bursa: friend or foe?
The bursa is a thin, fluid-filled sac originally thought to protect the tendons by providing a cushion between the tendons and adjacent bones.
The bursa often becomes inflamed, sometimes concurrently, when underlying tendons are injured, and surgeons often remove the tissue because they suspect it is a source of shoulder inflammation and pain. But recent studies suggest the tissue may be playing other biological roles besides mechanical cushioning, including promoting healing of injuries to the tendons in the shoulder.
To explore the role of the bursa in rotator cuff disease, Thomopoulos and graduate student Brittany Marshall examined rats with repaired rotator cuff injuries, with and without bursa removal.

Bursa removal impairs uninjured tendons
After the rats underwent repair of a rotator cuff injury, the researchers measured the mechanical properties of the repaired tendon and an adjacent undamaged tendon, the quality of the underlying bone, and changes to protein and gene expression.
The researchers found that the presence of the bursa protected the undamaged tendon by maintaining its mechanical properties and protected the bone by maintaining its morphometry. When the bursa was removed, strength of the undamaged tendon deteriorated and the bone quality deteriorated.
“The loss of mechanical integrity in the uninjured tendon in the absence of the bursa was striking,” Thomopoulos says. Uninjured tendons in the shoulder frequently degenerate over time after the initial injury, and “the animal data imply that retaining the bursa may prevent or delay progression of this pathology.”
In the damaged tendon, the researchers found that the bursa promoted an inflammatory response and activated wound healing genes, but no changes were seen in the mechanical properties of the repaired tendon two months after the repair. It’s possible that differences in mechanical properties would be detected after a longer healing period, Thomopoulos says, something that the research team is currently investigating.
“Overall, what we’re seeing is a beneficial role of the bursa for rotator cuff health, in contrast with the historical view that the inflamed bursa is detrimental,” says Thomopoulos.
The researchers documented similar changes to cells and proteins in bursa samples from patients who underwent surgery to repair rotator cuff injuries, suggesting comparable processes may occur in people.
The bursa as a drug delivery depot
If the bursa is not removed, the tissue could be used to deliver drugs to the repaired tendon to improve healing.
Thomopoulos and Marshall explored this possibility by injecting corticosteroid microspheres into the bursa of their rat model after tendon injury. Steroids are often used to treat musculoskeletal injuries and reduce inflammation.
“The treatment results are somewhat preliminary and require additional timepoints and mechanical characterization before we can draw strong conclusions,” Thomopoulos says, “but our initial data supports the idea that the bursa can be therapeutically targeted to improve rotator cuff healing.”

Researchers at the Francis Crick Institute, the National Cancer Institute (NCI) of the U.S. National Institutes of Health (NIH) and Aalborg University in Denmark, have found that vitamin D encourages the growth of a type of gut bacteria in mice which improves immunity to cancer.
Reported today in Science, the researchers found that mice given a diet rich in vitamin D had better immune resistance to experimentally transplanted cancers and improved responses to immunotherapy treatment. This effect was also seen when gene editing was used to remove a protein that binds to vitamin D in the blood and keeps it away from tissues.
Surprisingly, the team found that vitamin D acts on epithelial cells in the intestine, which in turn increase the amount of a bacteria called Bacteroides fragilis. This microbe gave mice better immunity to cancer as the transplanted tumours didn’t grow as much, but the researchers are not yet sure how.
To test if the bacteria alone could give better cancer immunity, mice on a normal diet were given Bacteroides fragilis. These mice were also better able to resist tumour growth but not when the mice were placed on a vitamin D-deficient diet.
Previous studies have proposed a link between vitamin D deficiency and cancer risk in humans, although the evidence hasn’t been conclusive.
To investigate this, the researchers analysed a dataset from 1.5 million people in Denmark1, which highlighted a link between lower vitamin D levels and a higher risk of cancer. A separate analysis of a cancer patient population also suggested that people with higher vitamin D levels2 were more likely to respond well to immune-based cancer treatments.
Although Bacteroides fragilis is also found in the microbiome in humans, more research is needed to understand whether vitamin D helps provide some immune resistance to cancer through the same mechanism.

Caetano Reis e Sousa, head of the Immunobiology Laboratory at the Crick, and senior author, said: “What we’ve shown here came as a surprise — vitamin D can regulate the gut microbiome to favour a type of bacteria which gives mice better immunity to cancer.
“This could one day be important for cancer treatment in humans, but we don’t know how and why vitamin D has this effect via the microbiome. More work is needed before we can conclusively say that correcting a vitamin D deficiency has benefits for cancer prevention or treatment.”
Evangelos Giampazolias, former postdoctoral researcher at the Crick, and now Group Leader of the Cancer Immunosurveillance Group at the Cancer Research UK Manchester Institute, said: “Pinpointing the factors that distinguish a ‘good’ from a ‘bad’ microbiome is a major challenge. We found that vitamin D helps gut bacteria to elicit cancer immunity improving the response to immunotherapy in mice.
“A key question we are currently trying to answer is how exactly vitamin D supports a ‘good’ microbiome. If we can answer this, we might uncover new ways in which the microbiome influences the immune system, potentially offering exciting possibilities in preventing or treating cancer.”
Romina Goldszmid, Stadtman Investigator in NCI’s Center For Cancer Research, said: “These findings contribute to the growing body of knowledge on the role of microbiota in cancer immunity and the potential of dietary interventions to fine-tune this relationship for improved patient outcomes. However, further research is warranted to fully understand the underlying mechanisms and how they can be harnessed to develop personalized treatment strategies.”
This research was funded by Cancer Research UK, the UK Medical Research Council, the Wellcome Trust, an ERC Advanced Investigator grant, a Wellcome Investigator Award, a prize from the Louis-Jeantet Foundation, the Intramural Research Program of the NCI, part of the National Institutes of Health, CCR-NCI and the Danish National Research Foundation.
Research Information Manager at Cancer Research UK, Dr Nisharnthi Duggan said: “We know that vitamin D deficiency can cause health problems, however, there isn’t enough evidence to link vitamin D levels to cancer risk. This early-stage research in mice, coupled with an analysis of Danish population data, seeks to address the evidence gap. While the findings suggest a possible link between vitamin D and immune responses to cancer, further research is needed to confirm this.
“A bit of sunlight can help our bodies make vitamin D but you don’t need to sunbathe to boost this process. Most people in the UK can make enough vitamin D by spending short periods of time in the summer sun. We can also get vitamin D from our diet and supplements. We know that staying safe in the sun can reduce the risk of cancer, so make sure to seek shade, cover up and apply sunscreen when the sun is strong.”

For most human proteins, there are no small molecules known to bind them chemically (so called “ligands”). Ligands frequently represent important starting points for drug development but this knowledge gap critically hampers the development of novel medicines. Researchers at CeMM, in a collaboration with Pfizer, have now leveraged and scaled a method to measure the binding activity of hundreds of small molecules against thousands of human proteins. This large-scale study revealed tens of thousands of ligand-protein interactions that can now be explored for the development of chemical tools and therapeutics. Moreover, powered by machine learning and artificial intelligence, it allows unbiased predictions of how small molecules interact with all proteins present in living human cells. These groundbreaking results have been published in the journal Science, and all generated data and models are freely available for the scientific community.
The majority of all drugs are small molecules that influence the activity of proteins. These small molecules — if well understood — are also invaluable tools to characterize the behavior of proteins and to do basic biological research. Given these essential roles, it is surprising that for more than 80 percent of all proteins, no small-molecule binders have been identified so far. This hinders the development of novel drugs and therapeutic strategies, but likewise prevents novel biological insights into health and disease.
To close this gap, researchers at CeMM in collaboration with Pfizer have expanded and scaled an experimental platform that enables them to measure how hundreds of small molecules with various chemical structures interact with all expressed proteins in living cells. This yielded a rich catalog of tens of thousands of ligand-protein interactions than can now be further optimized to represent starting points for further therapeutic development. In their study, the team led by CeMM PI Georg Winter has exemplified this by developing small-molecule binders of cellular transporters, components of the cellular degradation machinery and to understudied proteins involved in cellular signal transduction. Moreover, taking advantage of the large dataset, machine learning and artificial intelligence models were developed that can predict how additional small molecules interact with proteins expressed in living human cells.
“We were amazed to see how artificial intelligence and machine learning can elevate our understanding of small-molecule behavior in human cells. We hope that our catalog of small molecule-protein interactions and the associated artificial intelligence models can now provide a shortcut in drug discovery approaches,” says Georg Winter. To maximize the potential impact and usefulness for the scientific community, all data and models are made freely available through a web application. “This was an outstanding partnership between industry and academia. We are delighted to present the results which were obtained through three years of close collaboration and teamwork between the groups. It’s been a great project,” says Dr Patrick Verhoest, Vice President and Head of Medicine Design at Pfizer.

What happens in the body when we are hungry and see and smell food? A team of researchers at the Max Planck Institute for Metabolism Research has now been able to show in mice that adaptations in the liver mitochondria take place after only a few minutes. Stimulated by the activation of a group of nerve cells in the brain, the mitochondria of the liver cells change and prepare the liver for the adaptation of the sugar metabolism. The findings, published in the journal Science, could open up new avenues for the treatment of type 2 diabetes.
The researchers fed hungry mice that could only see and smell the food without eating it. After just a few minutes, the researchers analysed the mitochondria in the liver and found that processes normally stimulated by food intake were activated.
Mitochondria in the liver get ready
The studies show that it is sufficient for the mice to see and smell food for a few minutes to influence the mitochondria in the liver cells. This is mediated by a previously uncharacterised phosphorylation in a mitochondrial protein. Phosphorylation is an important modification for the regulation of protein activity. The researchers also show that this phosphorylation affects the sensitivity of the liver to insulin. The researchers have thus discovered a new signalling pathway that regulates insulin sensitivity in the body.
Nerve cells in the hypothalamus
The effect on the liver is mediated by a group of nerve cells called POMC neurons. These neurons are activated within seconds by the sight and smell of food, signalling the liver to prepare for the incoming nutrients. The researchers also showed that the activation of POMC neurons alone is sufficient to adapt the mitochondria in the liver, even in the absence of food.
“When our senses detect food, our body prepares for food intake by producing saliva and digestive acid. We knew from previous studies that the liver also prepares for food intake. Now we have taken a closer look at the mitochondria in liver cells, because they are essential cell organelles for metabolism and energy production, and realised how surprisingly fast this adaptation takes place,” explains Sinika Henschke, first author of the study. Jens Brüning, head of the study and director at the Max Planck Institute for Metabolism Research: “Our study shows how closely the sensory perception of food, adaptive processes in the mitochondria and insulin sensitivity are linked. Understanding these mechanisms is also important because insulin sensitivity is impaired in type 2 diabetes mellitus.”
Jens Brüning is also a research group leader at the CECAD Cluster of Excellence in Ageing Research at the University of Cologne and Director of the Department of Endocrinology, Diabetology and Preventive Medicine at Cologne University Hospital.

A new tool to identify infants most at risk for severe respiratory syncytial virus (RSV) illness could aid pediatricians in prioritizing children under 1 to receive a preventive medication before RSV season (October-April), according to Vanderbilt University Medical Center (VUMC) research published in Open Forum Infectious Diseases and to be presented at the American Thoracic Society 2024 International Conference.
Study authors considered factors including birth month, birth weight and whether an infant has siblings to determine who is most at risk of severe RSV illness and could benefit from the medication nirsevimab, commonly used as a preventive in newborns.
“We developed a tool to identify babies at highest risk for a severe infection due to RSV,” said the study’s presenter Ferdinand Cacho, MD,pediatric pulmonology fellow in the Center for Asthma Research at VUMC.
“RSV is a common respiratory infection that can cause fever, cough, runny nose, and difficulty breathing. In some babies, the infection can be so severe they need to be admitted to the hospital and be in the intensive care unit,” he said.
The Centers for Disease Control & Prevention recommends early immunization with nirsevimab for all infants, but a shortage in October 2023 made it necessary to prioritize for high-risk infants who weren’t eligible for immunization with a different agent known as palivizumab.
Nirsevimab is long-acting drug and only requires one dose while palivizumab is short-acting, requires monthly injections during RSV season, and is restricted to use in a subset of high-risk infants. Both medications are monoclonal antibodies used to prevent RSV lower respiratory tract infection in newborns and young children.
“Timely identification of infants at highest risk of RSV-related morbidity is key to prevention,” said lead author Brittney Snyder, PhD, research assistant professor in the Division of Allergy, Pulmonary and Critical Care Medicine at VUMC.

“Our personalized risk prediction tool may have applications in allocating expensive and/or limited immunoprophylaxis (immunization with nirsevimab or palivizumab) to achieve the greatest benefit and in promoting RSV prevention among families with high-risk infants,” she said.
Snyder and colleagues researched de-identified patient records of nearly 430,000 children insured by the Tennessee Medicaid Program, including infants who did not receive RSV immunoprophylaxis in the first year of life.
Among 429,365 infants in the study, 713 had severe RSV LRTI requiring ICU admission. The tool (equation) had good predictive accuracy and internal validation that indicated a good fit, the authors reported.
“Our tool was validated in a population of approximately 430,000 babies insured by the Tennessee Medicaid program, so our next step is to validate this tool in other populations, such as a U.S.-wide study and in international populations,” Cacho said. “This tool can help providers, health care institutions, and policymakers prioritize a limited resource so that the most vulnerable babies receive it.”

The antibiotic vancomycin, recommended as first-line treatment for infection caused by the deadly superbug C. difficile (C. diff), may not be living up to its promise, according to new research from the University of Houston College of Pharmacy.
C. diff infection is the leading cause of death due to gastroenteritis in the U.S. It causes gastrointestinal symptoms ranging from diarrhea and abdominal pain to toxic megacolon, sepsis and death.
Based on 2018 clinical practice guidelines, the use of oral vancomycin has increased by 54% in the past six years, but the clinical cure rates have decreased from nearly 100% in the early 2000’s to around 70% in contemporary clinical trials.
“Despite the increasing prevalence of data showing reduced effectiveness of vancomycin, there is a significant lack of understanding regarding whether antimicrobial resistance to these strains may affect the clinical response to vancomycin therapy,” reports Anne J. Gonzales-Luna, research assistant professor in the Department of Pharmacy Practice and Translational Research, UH College of Pharmacy, in the journal Clinical Infectious Diseases. “In fact, the prevailing view has been that antibiotic resistance to these strains are unlikely to impact clinical outcomes, given the high concentrations of vancomycin in stools.”
But the team arrived at a different conclusion after sifting through research included in a multicenter study, which included adults treated with oral vancomycin between 2016-2021 for C. diff infection.
“We found reduced vancomycin susceptibility in C. difficile was associated with lower 30-day sustained clinical response and lower 14-day initial cure rates in the studied patient cohort,” said Gonzales-Luna.
The finding is cause for concern.
“It’s an alarming development in the field of C. diff as there are only two recommended antibiotics,” said Kevin Garey, professor of pharmacy practice and translational research. “If antimicrobial resistance increases in both antibiotics, it will complicate the management of C. diff infection leading us back to a pre-antibiotic era.”
Others on the research team include Taryn A. Eubank from UH and Chetna Dureja and Julian G Hurdle from Texas A&M Health Science Center in Houston.

A newly developed nanomaterial that mimics the behavior of proteins could be an effective tool for treating Alzheimer’s and other neurodegenerative diseases. The nanomaterial alters the interaction between two key proteins in brain cells — with a potentially powerful therapeutic effect.
The innovative findings, recently published in the journal Advanced Materials, were made possible thanks to a collaboration between University of Wisconsin-Madison scientists and nanomaterial engineers at Northwestern University.
The work centers around altering the interaction between two proteins that are believed to be involved in setting the stage for diseases like Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis, or ALS.
The first protein is called Nrf2, a specific type of protein called a transcription factor that turns genes on and off within cells.
One of Nrf2’s important functions is its antioxidant effect. While different neurodegenerative diseases result from separate disease processes, a commonality among them is the toxic effect of oxidative stress on neurons and other nerve cells. Nrf2 combats this toxic stress in brain cells, helping to stave off disease.
Jeffrey Johnson, a professor in the UW-Madison School of Pharmacy, has been studying Nrf2 as a promising target for treating neurodegenerative diseases for decades alongside his wife Delinda Johnson, a senior scientist at the pharmacy school. In 2022, the Johnsons and another group of collaborators found that increasing Nrf2 activity in a specific cell type in the brain, the astrocyte, helped protect neurons in mouse models of Alzheimer’s disease, leading to significantly less memory loss.
While this previous research suggested that increasing Nrf2’s activity could form the basis of an Alzheimer’s treatment, scientists have found it challenging to effectively target the protein within the brain.

“It’s hard to get drugs into the brain, but it’s also been very hard to find drugs that activate Nrf2 without a lot of off-target effects,” says Jeffrey Johnson.
Enter the new nanomaterial. Known as a protein-like polymer, or PLP, the synthetic material is designed to bind to proteins as if it were itself a protein. This nano-scale imitator is a product of a team led by Nathan Gianneschi, a professor of chemistry at Northwestern and faculty member at the university’s International Institute for Nanotechnology.
Gianneschi has designed multiple PLPs to target various proteins. This particular PLP is structured to alter the interaction between Nrf2 and another protein called Keap1. The proteins’ interaction, or pathway, is a well-known target for treating many conditions because Keap1 essentially controls when Nrf2 responds to — and combats — oxidative stress. Bound together under unstressed conditions, Keap1 releases Nrf2 to do its antioxidant work when needed.
Gianneschi and the Johnsons were connected via Robert Pacifici, chief science officer at the CHDI Foundation, which funds research aimed at treating Huntington’s disease, another neurodegenerative condition. The foundation has funded both the Johnsons’ and Gianneschi’s work in the past.
“Just in passing, Nathan and his colleagues at Grove Biopharma, a preclinical biotech startup focused on therapeutic targeting of protein-protein interactions, said to Robert that they were thinking about moving to target Nrf2,” says Johnson. “And Robert said, ‘If you’re going to do that, you should call Jeff Johnson.'”
Soon, the Johnsons and Gianneschi were discussing the possibility of the UW-Madison lab providing mouse model brain cells needed to test Gianneschi’s protein-like nanomaterial.

Jeffrey Johnson says he was initially somewhat skeptical about the PLP approach, given his unfamiliarity with it and the general difficulty of precisely targeting proteins in brain cells.
“But then one of Nathan’s students came up here with it and put it on our cells, and I’ll be damned if it didn’t work really well,” he says. “We really dove into it then.”
The resulting research showed that Gianneschi’s PLP was very effective at binding to Keap1, which freed up Nrf2 to accumulate in cells’ nuclei, amping up its antioxidant function. Importantly, it did so without causing the unwanted off-target effects that have hampered other strategies aimed at better activating Nrf2.
While that work was performed in cells in culture, the Johnsons and Gianneschi are now taking it a step further in mouse models of neurodegenerative diseases. It’s a line of research that they hadn’t expected to be involved in but are now excited to be pursuing.
“We don’t have the expertise in biomaterials,” says Delinda Johnson. “So getting that from Northwestern and then moving forward on the biological side here at UW shows that these types of collaborations are really important.”

Osaka University researchers discovered liver resident macrophages’ pivotal role in defending against gut bacteria and related substances entering via the portal vein, particularly under compromised intestinal barrier conditions. Identified as “sentinel macrophages,” they are activated by isoallo-lithocholic acid. This finding holds promise for developing preventive and therapeutic strategies for liver chronic inflammatory diseases, such as metabolic dysfunction-associated steatohepatitis (MASH), by enhancing the function of these macrophages to mitigate inflammation and improve treatment efficacy.
The liver and intestines are directly connected via the portal vein, a blood vessel that transports nutrients absorbed in the intestines directly to the liver. The intestines harbor numerous gut bacteria, and sometimes these bacteria and their related substances can enter the liver through the portal vein. This is especially problematic when the intestinal barrier is compromised, as seen in conditions like ulcerative colitis or leaky gut syndrome, allowing many gut bacteria and related substances to reach the liver. Under normal circumstances, the liver’s immune system is able to defend against the invading gut bacteria and related substances and prevent inflammation, but the exact mechanism behind this was unclear.
Using innovative technologies like in vivo imaging of the liver and analysis of single-cell gene expression while preserving tissue locational information, a research group led by Yu Miyamoto and Masaru Ishii at the Graduate School of Medicine of Osaka University has revealed that certain resident macrophages near the entrance of the liver protect it against intestinal bacteria and related substances. Their findings are illustrated in Figure 1. Dr. Miyamoto, a lead author of the study, explained, “Our technology showed that these ‘sentinel macrophages’ play a crucial role in protecting the liver from inflammation caused by intestinal bacteria and related substances.” Additionally, the study found that isoallo-lithocholic acid (isoallo-LCA), a secondary bile acid produced by some gut bacteria, trigger the activation of these sentinel macrophages.
With the rise in conditions like leaky gut due to modern lifestyles (stress, high-fat diets, and lack of exercise), there is increasing concern about inflammation affecting various organs, including the liver. Metabolic dysfunction-associated steatohepatitis (MASH), often accompanied by the leaky gut, has been particularly concerning due to its ever increasing incidence and challenging treatment. This research shed light on how liver sentinel macrophages defend against gut commensal invaders, offering hope that enhancing their functions could lead to the development of new preventive and therapeutic strategies for liver chronic inflammatory diseases, including MASH.