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In 2020,bulevirtide (BLV) was conditionally approved for treating chronic hepatitis delta (CHD), an inflammation of the liver caused by hepatitis D virus (HDV). Now real-world studies of patients treated outside of clinical trials confirm that long-term suppressive therapy with BLV monotherapy has the potential to reduce viral replication and improve liver tests of these difficult-to-treat patients for the first time in 45 years, report investigators in the Journal of Hepatology and its companion journal JHEP Reports.
Two of the studies, led by Pietro Lampertico, MD, PhD, Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, were designed to assess the effectiveness and safety of patients with advanced HDV-related compensated cirrhosis being treated with BLV 2mg monotherapy and the consequences of discontinuing this treatment.
“HDV is the most severe form of chronic viral hepatitis,” explained Dr. Lampertico. “For many years, the only therapeutic option was the off-label administration of pegylated-interferon-alpha (PegIFNa), an approach characterized by suboptimal efficacy, an unfavorable safety profile and several contraindications.”
In a study of 18 patients with HDV-related advanced cirrhosis treated with BLV 2 mg/day for 48 weeks, Dr. Lampertico and colleagues demonstrated significant virological, biochemical and combined response rates associated with improvement of liver function.
“The efficacy and safety of BLV monotherapy in patients with advanced compensated cirrhosis were unknown before this study. Virological and biochemical responses to BLV monotherapy that we observed in our difficult-to-treat patients with HDV-related compensated cirrhosis were similar to those shown in the phase III registration study,” Dr. Lampertico noted.
In a case report, Dr. Lampertico and co-investigators demonstrated that HDV could be successfully eradicated from both serum and liver following a three-year course of BLV monotherapy, despite the persistence of HBsAg, in a patient with HDV-related compensated cirrhosis and esophageal varices. During the 72-week off-BLV follow-up, liver biopsy, intrahepatic HDV RNA and hepatitis D antigen were undetectable, less than 1% of hepatocytes were HBsAg positive and all were negative for hepatitis B core antigen.
“We were surprised to demonstrate that HDV can be eradicated following a finite course of an entry inhibitor administered as monotherapy such as BLV 2mg/day, despite the persistence of HBsAg positivity,” commented Dr. Lampertico.
In a study in JHEP Reports led by PD Dr. med. Katja Deterding, MD, Department. of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, Hannover, Germany, investigators report the first data from the largest multicenter cohort of patients to date who were treated with BLV under real-world conditions, including 50 patients with signs of significant portal hypertension, elevated pressure in the major vein that leads to the liver.
The retrospective analysis of 114 cases covered 4,289 patient weeks of BLV treatment. Viral response was observed in 87 cases while hepatic inflammation improved, and treatment was well tolerated. More than 50% of patients showed a virologic response with less than 10% of patients not achieving an HDV RNA drop of at least 90% after 24 weeks. An improvement of biochemical hepatitis activity as measured by the liver enzyme alanine transaminase (ALT) values was observed regardless of virologic response. Investigators concluded that treatment was safe and well tolerated and associated with improvements in liver cirrhosis and portal hypertension with prolonged treatment.
“In line with other real-world cohorts and clinical trials our real-world study confirms the antiviral activity of BLV,” noted Dr. Deterding. “We were surprised to see an improvement in biochemical hepatitis activity even in cases without viral response. Potential explanations for this phenomenon include anti-inflammatory properties of BLV.”
“This is the first time that patients with HDV-related chronic advanced liver disease can be treated with an antiviral therapy since 1977 when HDV was discovered. Long-term suppressive therapy with BLV 2 mg/day has the potential to improve survival, of these difficult-to-treat patients for the first time in 45 years,” concluded Dr. Lampertico. “We also found that BLV treatment can be successfully discontinued in some HDV patients who achieved long-term viral suppression while on therapy.”
HDV infection occurs when people become infected with both hepatitis B and D virus either simultaneously (co-infection) or acquire the hepatitis D virus after first being infected with hepatitis B (super-infection). According to the World Health Organization, HDV affects nearly 5% of individuals with a chronic infection resulting from hepatitis B virus (HBV). Populations that are more likely to have HBV and HDV co-infection include indigenous populations, recipients of hemodialysis and individuals who inject drugs.

While a popular hobby for many, fishing is also a pastime full of uncertainty. Each time you have something on the line, you can never be completely sure what type of fish you’ve hooked until you pull it out of the water. In a similar way, scientists “fishing” for biomarkers — molecules whose health care applications include signaling for the presence of cancer — in biofluids such as blood can also encounter unpredictability. Finding a specific protein biomarker in a pool of thousands is like trying to catch a particular fish species in the vast ocean.
Luckily, a team of researchers from Syracuse University’s College of Arts and Sciences (A&S), SUNY Upstate Medical University, Ichor Therapeutics, and Clarkson University have devised a tiny, nano-sized sensor capable of detecting protein biomarkers in a sample at single-molecule precision. Fittingly coined as “hook and bait,” a tiny protein binder fuses to a small hole created in the membrane of a cell — known as a nanopore – which allows ionic solution to flow through it. When the sensor recognizes a targeted molecule, the ionic flow changes. This change in flow serves as the signal from the sensor that the biomarker has been found.
“These nanopores are equipped with hooks that pull certain protein biomarkers from a solution,” says Liviu Movileanu, professor of physics in A&S, who co-authored the study along with postdoctoral researcher Mohammad Ahmad. “By fishing them from the solution quickly and accurately, we can better identify and quantify protein biomarkers that are associated with various hematological malignancies and solid tumors.”
The team’s latest research, published in Nature Communications, addresses previous challenges that existed in making this technology generalizable. Their new findings formulate a sensor design architecture that can be applied to a broad range of protein targets.
Combining Innovative Technologies
For the first time, the team coupled nanopore technology with antibody mimetic technology — artificially designed protein scaffolds that bind and interact with a specific biomarker and behave like antibodies. Cells inside the body design their own antibodies which bind to and eliminate unwanted substances. When it comes to therapeutics, scientists engineer small proteins to penetrate cells and stimulate the production of antibodies which target specific pathogens like viruses or bacteria.

“Researchers design the scaffolds using established scaffolds from mother nature and adapt them using evolutionary mutagenesis — where they scan billions of DNA mutations until they find some that interact strongly with a specific protein,” says Movileanu, whose work on the project was supported by a $1.2 million grant from the National Institutes of Health. “Creating highly specific protein detection technologies will address these demands and also accelerate discoveries of new biomarkers with potential consequences for the progression of pathological conditions.”
According to Movileanu, in addition to working in a clean solution, the sensor is also highly effective in complex biofluids, like blood serum, that contain numerous antibodies.
“Essentially you have a very specific hook that targets a very specific protein,” he explains. “Since the signal encodes the exact protein that you are targeting, this technique does not have false positives, making it practical for biomedical diagnostics.”
To validate their findings, the team tested their hypothesis using a blood serum sample. With their technology, they were able to identify and quantify epidermal growth factor receptor (EGFR), a protein biomarker in various cancers. In addition, numerous calibrations of the sensors were conducted using other biophysical techniques.
At the Forefront of Diagnosis
While their paper provides a concept prototype, Movileanu says the project paves the way for broad applications. For example, by integrating the sensors into nanofluidic devices, this technology would allow scientists to test for many different biomarkers at once in a specimen, providing a fundamental basis for biomarker detection in complex biofluids.
“The future of medicine won’t rely as much on imaging and biopsies when diagnosing cancers,” says Movileanu. “Instead, researchers will use nano-sensor technology, like what we are developing in our lab, to test blood samples for the presence of various biomarkers associated with different cancers. This research is critical to the future of prognostics, diagnostics and therapeutics.”

New research from Carnegie Mellon University’s Robotics Institute (RI) aims to increase autonomy for individuals with such motor impairments by introducing a head-worn device that will help them control a mobile manipulator. Teleoperated mobile manipulators can aid individuals in completing daily activities, but many existing technologies like hand-operated joysticks or web interfaces require a user to have substantial fine motor skills to effectively control them. Research led by robotics Ph.D. student Akhil Padmanabha offers a new device equipped with a hands-free microphone and head-worn sensor that allows users to control a mobile robot via head motion and speech recognition.
More than five million people in the United States live with some form of paralysis and may encounter difficulties completing everyday tasks, like grabbing a glass of water or putting on clothes. New research from Carnegie Mellon University’s Robotics Institute (RI) aims to increase autonomy for individuals with such motor impairments by introducing a head-worn device that will help them control a mobile manipulator.
Teleoperated mobile manipulators can aid individuals in completing daily activities, but many existing technologies like hand-operated joysticks or web interfaces require a user to have substantial fine motor skills to effectively control them. Research led by robotics Ph.D. student Akhil Padmanabha offers a new device equipped with a hands-free microphone and head-worn sensor that allows users to control a mobile robot via head motion and speech recognition. Head-Worn Assistive Teleoperation (HAT) requires fewer fine motor skills than other interfaces, offering an alternative for users who face constraints with technology currently on the market.
In addition to Padmanabha, the research team includes Qin Wang, Daphne Han, Jashkumar Diyora, Kriti Kacker, Hamza Khalid, Liang-Jung Chen, Carmel Majidi and Zackory Erickson. In a human study, participants both with and without motor impairments performed multiple household and self-care tasks with low error rates, minimal effort and a high perceived ease of use. The research team will present their paper, “HAT: Head-Worn Assistive Teleoperation of Mobile Manipulators,” at the IEEE’s International Conference on Robotics and Automation in London this spring.

People whose mothers are overweight during pregnancy and nursing may become obese as adults because early overnutrition rewires developing brains to crave unhealthy food, according to a Rutgers study in Molecular Metabolism.
Rutgers researchers traced this link from mother to child in mice with an experiment that began by letting some mice get obese on unlimited high-fat food during pregnancy and breastfeeding while keeping others slim on limitless healthy food. They found that mice born to obese mothers stay slim in adulthood on unlimited healthy food but overeat more than mice born to lean mothers when given access to unhealthy food.
The findings indicate that while people whose mothers were overweight during pregnancy and nursing may struggle to moderate their consumption of treats, they could safely eat their fill of healthy foods.
The study may also help inform the development of brain-altering drugs that reduce cravings for unhealthy food.
“People born to overweight or obese mothers tend to be heavier in adulthood than people born to leaner mothers, and experiments like this suggest that the explanation goes beyond environmental factors such as learning unhealthy eating habits in childhood,” said Mark Rossi, a professor of psychiatry at Rutgers Robert Wood Johnson Medical School and senior author of the study. “Overnutrition during pregnancy and nursing appears to rewire the brains of developing children and, possibly, future generations.”
In the experiment, researchers gave the high-fat food to three sister mice and the healthy chow to another three of their sisters. Once breastfeeding was complete, the researchers turned their attention to the nearly 50 pups — who predictably started at heavier or lighter weights, depending on their mom’s diet.
Their weights converged (at healthy levels) after all the pups received several weeks of unlimited healthy chow, but they diverged again when the researchers offered them constant access to the high-fat diet. All the mice overate, but the offspring of overweight mothers overate significantly more than the others.
Further analysis indicated that the differing behaviors probably stemmed from differing connections between two parts of the brain — the hypothalamus and the amygdala — that arose because of differing maternal nutrition during pregnancy and breastfeeding.
The study has mixed implications for people born to overweight mothers who struggle with their own weight. On the one hand, it suggests the possibility of staying lean while eating healthy food to satiety and avoiding junk entirely. On the other hand, it suggests that efforts to eat moderate quantities of unhealthy treats may spur overconsumption and obesity.
Looking forward, the study’s finding about disrupted brain circuits in the two groups of mice may help inform the creation of drugs that would block the excess desire to consume unhealthy foods.
“There’s still more work to do because we don’t yet fully understand how these changes are happening, even in mice,” Rossi said. “But each experiment tells us a little more, and each little bit we learn about the processes that drive overeating may uncover a strategy for potential therapies.”

Genes long known to control the formation of bones before birth also control bone healing later in life, a new study found.
Led by researchers at NYU Langone Health, a new study pinpointed key Hox genes, specific to each location in the body, as the controllers of stem cells involved in both forming and repairing bone. HOX proteins act like the body’s “zip code,” specifying the position of limbs in the fetus by encoding instructions for transcription factors, which attach to DNA and influence the action of genes.
Such adjustments guide immature stem cells as they multiply and mature in the womb, say the study authors, to become heart muscle, nerves, bones, etc., and in the right places. Bone is among the tissues that keep pools of stem cells on hand into adulthood, ready to mature into needed replacement cells that maintain healthy tissue and heal broken bones.
Published online recently in the journal Development, the new work found that Hox genetic programs in adulthood control a bone stem cell type called periosteal stem and progenitors cells or PSCPs. These cells play a central role in healing bones according to the womb-determined positions in which they first formed. Already known to encode the spatial code that sets the body’s formation plan, HOX genes were shown in the study to give adult stem cells from different locations the properties needed to regenerate the particular bone in which they reside.
During aging, such stem cells become depleted, the researchers say, resulting in weaker bones that are more likely to fracture and slower to heal. In an effort to counter this loss in healing, the research team demonstrated that increasing the activity of the gene that directs the building of the Hoxa10 transcription factor in the tibia, the larger of the two “shin bones,” in aging mice caused a 32.5% restoration of fracture repair capacity.
“Our data revealed a previously unknown function for Homeobox or Hox genes as essential location-specific regulators of stem cell maturity in adulthood, with short-term local increases in their expression able to drive healing,” said corresponding study author Philipp Leucht, MD, PhD, the Raj-Sobti-Menon Associate Professor in the Department of Orthopedic Surgery at NYU Langone Health. “The therapeutic promise of adult stem cells as a source of bone-making cells in healing-compromised people is massive.”
Bone Requires Attention

A fundamental question in the field has been whether bone healing is driven more by stem cells in the marrow in a bone’s center, or by those known to pool in the nearby periosteum, the outer bone layer made of up tough connective tissue and cell-filled areas. Both stem cell types have the capacity to mature into osteoblasts, the cells that lay down new bone in response to a fracture, but the current study argues that stem cells in the periosteum, the PSPCs, are the important contributors to bone repair.
The study result builds on the understanding that, to keep stem cells pools on hand, they must get signals to continually divide and multiply without maturing, maintaining their “stemness” until needed. The body regulates bone repair by controlling the degree to which stem cells stay immature, with the most primitive cells playing the largest role in healing due to their flexibility and ability to quickly multiply.
In the current study, the researchers found that Hox deficiency leads to an increase in the stem cells’ propensity to differentiate into mature bone cell types. Conversely, when the team increased Hoxa10 expression in tibia stem and progenitor cells, it reprogrammed them into a more stem-cell-like state, a needed step if they are to become new bone-making cells as part of healing.
Specifically, say the authors, PSPCs exist as a mixed stem cell population that includes those with the most stemness, naïve periosteal stem cells (PSCs), alongside more mature periosteal progenitor 1 (PP1s) and periosteal progenitor 2 (PP2s) cells. The current study authors found that Hoxa10 expression was most abundant in PSCs and was significantly reduced as cells progressed along the lineage hierarchy to PP1 and PP2. Experiments that increased the activity of the Hox genes in these more mature progenitors brought about a 3-fold increase of PSCs as cells were reprogrammed into a more primitive stem cell identity.
“PSPCs have distinguishing characteristics that form the basis for future cell-based therapies, including their greater tendency to naturally regenerate bone than many related stem cell groups,” said co-corresponding lead author Kevin Leclerc, a post-doctoral scholar in Leucht’s lab. “By modifying Hox activity in these cells, we can help them regenerate bone more effectively in individuals with deficient bone-healing capacity.”
Along with Leucht and Leclerc, study authors from the Department of Orthopedic Surgery are Lindsey Remark, Malissa Ramsukh, Anne Marie Josephson, Laura Palma, Paulo EL Parente, Margaux Sambon, Sooyeon Lee, Emma Muiños Lopez, and co-senior author Sophie Morgani. The study was funded by National Institutes of Health grants R01AG056169, K08AR069099, S10OD010751, 5P30CA016087 642, and P41 EB017183, as well as by Perlmutter Cancer Center support grant P30CA016087, the Patricia and Frank Zarb Family, and the CTSI TL1 post-doctoral scholarship of the New York Stem Cell Foundation.

The sense of taste is among the first to come into contact with food before we ingest it, but whether animals can taste basic or alkaline food and how they do it remained unclear until now. A research group led by Yali Zhang, PhD, Principal Investigator at the Monell Chemical Senses Center, recently addressed this significant question, as they similarly did for sour taste in 2021 on the lower end of the pH scale. Their work, published today in Nature Metabolism and highlighted in Nature, identified a previously unknown chloride ion channel, which they named alkaliphile (Alka), as a taste receptor for alkaline pH.
pH, the scale of how acidic or basic a substance is, plays an essential role for living organisms because many biological processes, such as breaking down food and enzymatic reactions, need the level of pH to be just right. While we are familiar with sour taste, which is associated with acids and allows us to sense the acidic end of the pH scale, little is known about how animals perceive bases on the opposite end of the pH spectrum. Detecting both acids and bases, which are commonly present in food sources, is important because they can significantly impact the nutritional properties of what animals consume.
Zhang’s group found that Alka is expressed in the fly’s gustatory receptor neurons (GRNs), the counterpart of taste receptor cells of mammals. When facing neutral food versus alkaline food, wild-type flies normally choose neutral foods because of the toxicity of high pH. In contrast, flies lacking Alka lose the ability to discriminate against alkaline food when presented with it. If the pH of a food is too high, in humans it can be harmful and cause health concerns such as muscle spasms, nausea, and numbness. Likewise, after fruit flies eat food with high pH, their lifespan can be shortened.
The team’s work demonstrates that Alka is critical for flies to stay away from harmful alkaline environments. “Detecting the alkaline pH of food is an advantageous adaptation that helps animals avoid consuming toxic substances,” said Zhang.
To understand how Alka senses high pH, Zhang’s group performed electrophysiological analyses and found that Alka forms a chloride ion (Cl-) channel that is directly activated by hydroxide ions(OH-). Like olfactory sensory neurons in mammals, the concentration of Cl- inside the fly’s GRN is typically higher than outside this nerve cell. Zhang proposes that when exposed to high-pH stimuli, the Alka channel opens, leading to negatively charged Cl- flowing from inside to outside the fly’s GRN. This efflux of Cl- activates the GRN, ultimately signaling to the fly brain that the food is alkaline and should be avoided. “Our work shows that Cl- and Cl- channels, which have been overlooked for a long time, have crucial functions in taste signaling to the brain,” said Zhang.
In addition, Zhang’s group studied how flies detect the taste of alkaline substances using light-based optogenetic tools. They found that when they turned off alkaline GRNs, the flies were no longer bothered by the taste of alkaline food. Conversely, they activated these alkaline GRNs by shining red light on them. Interestingly, when these flies were given sweet food and exposed to red light at the same time, the flies did not want to eat the sweet food anymore. “Alkaline taste can make a big impact on what flies choose to eat,”said Zhang.
Overall, Zhang’s group has established that Alka is a new taste receptor dedicated to sensing the alkaline pH of food. In the future, his team aims to explore whether there are analogous high-pH detectors in mammals. “Our work has settled the argument about whether there is a taste for alkaline things,” said Zhang. “There definitely is.”
Research on new taste qualities of animals, including humans, has important implications for understanding dietary habits and developing strategies for improving nutrition.
This research was funded by the National Institute on Deafness and Other Communication Disorders and the Ambrose Monell Foundation.

Muscle degeneration, the most prevalent cause of frailty in hereditary diseases and aging, could be caused by a deficiency in one key enzyme in a lipid biosynthesis pathway. Researchers at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences characterize how the enzyme PCYT2 affects muscle health in disease and aging in laboratory mouse models. The findings are published on March 20 in Nature Metabolism.
Muscle degeneration in inherited diseases and aging affects hundreds of millions of people worldwide. Degeneration of skeletal muscles, the body’s protein reservoir, leads to general physiological decline, a condition called frailty. Now, a research team led by Domagoj Cikes at IMBA and Josef Penninger at IMBA and the University of British Columbia (UBC) uncover the central role of an enzyme called PCYT2 in muscle health. PCYT2 is known as the bottleneck enzyme in a major synthesis pathway of ethanolamine-derived phospholipids, the phosphatidylethanolamines (PEs). Based on patient data and using laboratory mouse and zebrafish models, they show that mutations affecting PCYT2, or its reduced activity, are conserved hallmarks of muscle degeneration across vertebrates. Specifically, they demonstrate that PCYT2 deficiency in muscles affects mitochondrial function and the physicochemical properties of the myofiber membrane.
Membrane rigidity, aging, and conservation in vertebrates
Lipids are ubiquitously present in biological membranes and are present at particularly high concentrations in the membranes of nerve cells and neural tissues. Following reports that PE-based molecules enhance the membrane rigidity of liposomes, Domagoj Cikes, the study’s co-corresponding author and a former postdoctoral researcher in the Penninger lab at IMBA, hypothesized that this lipid species may play an important role in tissues subjected to constant shear stress, such as muscle tissue. “This assumption prompted me to selectively deplete PCYT2 in muscle tissues of animal models and study the outcome. In parallel, clinicians reported patient cases of mutations affecting PCYT2. The patients presented a condition called complex hereditary spastic paraplegia, a severe, multi-symptomatic disease characterized by leg muscle weakness, stiffness, and muscle wasting that worsened with time. However, given that the disease was just recently discovered, the underlying pathophysiological biology is vastly unknown,” says Cikes.
The researchers demonstrated that the levels of functional PCYT2 are linked to human muscle health and affect the muscle tissues of mice and zebrafish. The mouse models in particular showed striking and severe phenotypes of muscle growth retardation and quick deterioration upon PCYT2 depletion. They noted that this phenotype of fast deterioration in the mouse models resembled accelerated aging. Thus, Cikes and colleagues showed that PCYT2 plays a conserved role in vertebrates.
PEs are also abundant in mitochondrial membranes. Therefore, the researchers examined how PCYT2 depletion in muscle tissues affects mitochondrial membrane homeostasis and found that PCYT2 depletion indeed altered mitochondrial function and muscle energetics. However, a mitochondrial therapeutic approach was not sufficient to rescue the phenotype in mice. “This prompted us to think that there must be an additional mechanism driving the pathology,” says Cikes. Indeed, the team showed that the organization of the cell membrane lipid bilayer played an additional role. “This represents a novel pathophysiological mechanism that might also be present in other lipid-related disorders,” says Cikes.
In addition, the team demonstrated that PCYT2 activity decreased during aging in humans and mice. Using a targeted delivery technique of active PCYT2, the scientists were able to rescue muscle weakness in PCYT2-depleted mouse models and improve muscle strength in old mice.
Technical advances to explain the biology and pathophysiology
Having linked muscle health in vertebrates with PEs and muscle membrane composition, the researchers studied the role of lipid species in biological membranes. As biological work with lipids is particularly challenging, they also needed to think of ways to advance the available research applications. By adapting a technique developed by Kareem Elsayad at the Vienna BioCenter Core Facilities (VBCF) to measure tissue stiffness using Brillouin Light Scattering (BLS), the researchers were able to examine the physical properties of biological membranes. With this technique, the team demonstrated a considerable decrease in membrane surface stiffness when PCYT2 was depleted in mouse muscles. “In addition, our current work makes another leap forward in the field of lipid biology, as we were able to peek into the lipid bilayer of cell membranes and examine the local properties of structural lipids,” says Cikes. The technique is based on isolating Giant Plasma Membrane Vesicles (GPMVs) from biological tissues and studying the physicochemical properties and geometry of the membrane bilayer by means of an intercalating dye. This approach allows the scientists to examine how well the lipids in the bilayer are matched and whether they observe gaps, hydrophilic components, and leakages through the membrane.
The biology of lipids — crucial, yet understudied
“Current knowledge on the biology of lipids is largely over-simplified. The whole lipid field is summarized into a handful of molecular families, such as cholesterols, triglycerides, phospholipids, and fatty acids. It is a vast and unexplored molecular universe where the function of most species in health and disease is unknown.” says Cikes. By shedding light on the central effect of a lipid biosynthesis pathway in muscle health, Cikes and the team wish to highlight the importance and discovery potential of lipid research. “Our current work demonstrates a fundamental, specific, and conserved role of PCYT2-mediated lipid synthesis in vertebrate muscle health and allows us to explore novel therapeutic avenues to improve muscle health in rare diseases and aging,” concludes Penninger.
Josef Penninger was the founding director of IMBA and is currently the director of the Life Sciences Institute at the University of British Columbia (UBC), Vancouver, Canada.

In experiments with mice and humans, a team led by Johns Hopkins Medicine researchers says it has identified a particular intestinal immune cell that impacts the gut microbiome, which in turn may affect brain functions linked to stress-induced disorders such as depression. Targeting changes mediated by these immune cells in the gut, with drugs or other therapies, could potentially bring about new ways to treat depression.
The findings of the study were published March 20, 2023 in the journal Nature Immunology.
“The results of our study highlight the previously unrecognized role of intestinal gamma delta T cells (γδ T cells) in modifying psychological stress responses, and the importance of a protein receptor known as dectin-1, found on the surface of immune cells, as a potential therapeutic target for the treatment of stress-induced behaviors,” says Atsushi Kamiya, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study’s senior author.
Dectin-1 binds to certain antigens, or proteins, to signal immune cells to activate in specific ways. This receptor, the researchers say, may be involved in the microbiome alteration and immune-inflammatory responses in the colon of mice, which suggests that it may be involved in stress responses via γδ T cells in the intestinal immune system.
On the basis of previous studies suggesting that immune inflammatory responses in the gut are related to depression, Kamiya and his team designed experiments to focus on understanding stress-induced behaviors produced by an imbalance in the gut microbiota — types of microorganisms found in a specific environment, such as bacteria, fungi and viruses.
To this end, the team examined the effects of chronic social defeat stress (CSDS) on the gut microbiota in mice. CSDS is a standard rodent test to study stress-induced disorders such as depression. In a series of experiments, the researchers simulated potential stress inducing environments that could mimic similar responses in human environments. After each exposure, the mice were assessed and classified as stress-resilient (stress did not diminish social interactions) or stress-susceptible (stress increased social avoidance).

Fecal samples were then collected and put through genetic analysis to identify the diversity of bacteria in the gut microbiota of the mice. The analysis showed that the intestinal organisms were less diverse in stress-susceptible mice than in stress-resilient mice. It specifically revealed that there were less Lactobacillus johnsonii (L. johnsonii) — a type of probiotic, or “good” bacteria — in stress-susceptible mice compared to stress-resilient mice.
“We found that stress increased the γδ T cells, which in turn increased social avoidance,” says Xiaolei Zhu, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study’s lead author. “However, when the stressed mice were given L. johnsonii, social avoidance decreased and the γδ T cells went to normal levels, suggesting that CSDS-induced social avoidance behavior may be the result of lower levels of the bacteria and γδ T cell changes.”
Looking for potential natural approaches for prevention of depression rooted somehow in the gut, the researchers explored how changes in dectin-1 on CSDS-induced elevation of γδ T cells responded to pachyman. A compound extracted from wild mushrooms, pachyman is used as a natural anti-inflammatory agent and for treating depression in Eastern medicine. For this experiment, mice were fed a dose of pachyman, which was shown in previous research to affect immune function. Data from flow cytometry analysis — a technology used to measure the physical and chemical characteristics of a population of cells — provided evidence that dectin-1 binds to pachyman, inhibiting CSDS-induced γδ17 T cell activity and easing social avoidance behavior.
To gain insight into how the alterations in the gut microbiota could impact the human brain, the researchers investigated the makeup of gut organisms in people with major depressive disorder (MDD) compared to people without MDD. From June 2017 to September 2020, 66 participants, ages 20 or older, were recruited at Showa University Karasuyama Hospital, Keio University Hospital and Komagino Hospital in Tokyo, Japan. Of the study participants, 32 had MDD (17 women and 15 men). The other 34 participants (18 women and 16 men) who did not have MDD formed the control group.
Stool samples were collected from all study participants, who had comprehensive evaluations including psychiatric history and standard screening assessments for depression and anxiety. In these assessments, higher scores indicate greater depressive symptoms. Genetic analysis of the stool samples showed no difference in the diversity of intestinal bacteria between the subjects with MDD and the control group. However, the relative abundance of Lactobacillus was inversely related to higher depression and anxiety scores in the MDD group, meaning that the more Lactobacillusfound in the gut, the lower the potential for depression and anxiety, the researchers say.
“Despite the differences of intestinal microbiota between mice and humans, the results of our study indicate that the amount of Lactobacillus in the gut may potentially influence stress responses and the onset of depression and anxiety,” says Kamiya.
The investigators say more research is needed to further understand how γδ T cells in the intestinal immune system may impact the neurological functions in the brain and the role of dectin-1 in other cell types along the gut-brain connection under stress conditions.
“These early-stage findings show that, in addition to probiotic supplements, targeting drugs to such types of receptors in the gut immune system may potentially yield novel approaches to prevent and treat stress-induced psychiatric symptoms such as depression,” says Kamiya.
In addition to Kamiya and Zhu, other researchers who contributed to the study are Shinji Sakamoto, Koki Ito, Mizuho Obayashi, Lisa Unger, Yuto Hasegawa, Matthew Smith, Peter Calabresi, Hui Li and Tza-Huei Wang from The Johns Hopkins University; Chiharu Ishii, Shinji Fukuda, Shunya Kurokawa and Taishiro Kishimoto from Keio University in Japan; Shinya Hatano and Yasunobu Yoshikai from Kyushu University in Japan; Shin-ichi Kano from the University of Alabama at Birmingham; and Kenji Sanada from Showa University in Japan.

Custom-made to attack cancer cells, CAR T-cell therapies have opened a new era in the treatment of human cancers, particularly, in hematologic malignancies. All too often, however, they display a frustrating trait inherited from the body’s own immune system cells: a drastic loss of cancer-fighting fervor known as “exhaustion.” Exhaustion is not only seen in cancer-fighting T cells but is also frequent in the setting of viral infections, such as human immunodeficiency virus (HIV), hepatitis B/C viruses (HBV, HCV) and COVID-19 (SARS-CoV-2).
The lapse into listlessness has diminished the effectiveness of CAR T-cell therapies in some patients and prompted scientists to try to find its source. In a new study, scientists at Dana-Farber Cancer Institute and NYU Grossman School of Medicine show the commanding role of a specialized group of proteins in the nuclei of our cells, called mSWI/SNF (or BAF) complexes, both in activating T cells to attack cancer and triggering exhaustion.
The discovery, reported online today in the journal Molecular Cell, suggests that targeting certain of these complexes, either by gene-cutting technologies such as CRISPR or with targeted drugs, could reduce exhaustion and give CAR T cells (and in general, all tumor-fighting T cells) the staying power to take on cancer.
“CAR T cells and other therapies made from living cells have enormous potential in treating cancer and a range of other diseases,” says the study’s senior author, Cigall Kadoch, PhD, of Dana-Farber and the Broad Institute of MIT and Harvard. “To reach that potential, however, the field had wrestled with the problem of exhaustion. Our findings in this study indicate new, clinically-actionable ways of addressing this.”
CAR (chimeric antigen receptor) T cells are made by collecting thousands of a patient’s immune system T cells and equipping them with genes that help them latch onto and destroy cancer cells. After the modified cells reproduce into the millions, they’re injected back into the patient, where they strike at cancer cells.
“The problem is that most engineered T cells, like CAR T cells, tucker out,” Kadoch says. “They get activated, just as normal T cells in our body do when they encounter an infected or diseased cell, but they quickly stop proliferating and fail to go on the attack. We and other groups have wanted to understand why: what are the determinants of T cell exhaustion?”
Research over the years has suggested that exhaustion (as well as activation and the acquisition of memory-like features) are not controlled by a single gene or a few genes but by the coordination of many genes that together generate an exhaustion “program” for the cell.

Kadoch and her colleagues began focusing on mSWI/SNF complexes years ago as potential regulators of these programs. These complexes, the focus of the Kadoch Laboratory, are large molecular machines that glide along the genome like cursors on a line of text. Where they stop, they can open up DNA strands, switching on genes in that area, and where they disappear from results in the closing of DNA and the shutting off of those genes.
Such complexes qualify as the kind of master switch that could potentially control the exhaustion program. Kadoch and her team decided to track their patterns over the entire course of T cell activation and exhaustion: to determine where they’re situated on the genome of battle-ready T cells and how those positions change as exhaustion sets in.
“We did the most comprehensive profiling ever of the occupancy of these complexes in T cells across time, in both mouse and human contexts,” Kadoch remarks. “We found that they move around in a state-specific manner, which raises the question of why they move; how do they know where to go in each state?”
The biggest influences on their location, it turned out, were certain transcription factors, proteins critical to activating highly specific sets of genes. The factors guide mSWI/SNF complexes and steer them to precise sites on the genome.
“At each stage of T cell activation and exhaustion, a different constellation of transcription factors appears to guide these complexes to specific locations on the DNA,” Kadoch states.

As this profiling work was under way, co-senior author Iannis Aifantis, PhD, and his colleagues at NYU Grossman School of Medicine were systematically shutting down genes in T cells to see which ones, when silenced, slowed or stopped the process of exhaustion. “We found that all the top hits in our screen — the genes whose inhibition had the greatest impact on exhaustion — encoded the very mSWI/SNF complexes central to Cigall’s lab,” Aifantis relates. “Our labs then together performed a detailed series of joint experiments that showed that if you stifle the genes encoding various components of these complexes, the T cells not only don’t get exhausted, but they proliferate even more than before.”
The two labs followed up these findings by employing a group of newly-developed small molecule inhibitors and degraders targeting mSWI/SNF complexes. They found that in response to these inhibitors, genes that promote cell exhaustion became less active while those that spur activation became more active. “We essentially reversed the exhaustion program with these inhibitors,” she says, “and resulting cells resembled more memory-like and activated T cell features.”
The findings are especially timely given that the first compounds that specifically inhibit the catalytic activity of mSWI/SNF complexes are now being tested in phase 1 clinical trials for cancer. Experiments in animal models of melanoma, acute myelogenous leukemia and other settings hint at the promise of such compounds. In addition to favorable changes in T cells, when the groups treated the animals with CAR T cells that had been exposed to mSWI/SNF inhibitors, tumor growth was reduced.
“Our labs are excited by these findings on numerous fronts- from identifying another important example of the wide repertoire of mSWI/SNF functions in human biology, to the opportunity to target these functions to improve immunotherapeutic approaches for the treatment of cancer and other conditions.” Says Kadoch. “We have a lot more to do in this space, but this work provides an important new foundations.”
The co-first authors of the study are Elena Battistello, PhD, of the Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, and Kimberlee Hixon, and Dawn E. Comstock, of Dana-Farber and the Broad Institute. The co-authors are W. Nicholas Haining, BM, BCh, and Jun Qi, PhD, of Dana-Farber; Clayton K. Collings, PhD, Kasey S. Cervantes, and Madeline M. Hinkley, of Dana-Farber and the Broad Institute; Xufeng Chen, PhD, Javier Rodriguez Hernaez, MSc, Soobeom Lee, MSc, Konstantinos Ntatsoulis, MSc, and Aristotelis Tsirigos, PhD, of the Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine; Kathryn Hockemeyer, MD, PhD, of NYU and Dana-Farber; Annamaria Cesarano, MSc, and Fabiana Perna, MD, PhD, of Indiana University School of Medicine; and Matthew T. Witkowski, PhD, of the University of Colorado.
This work was supported in part by the National Institutes of Health (grants 1F31CA271427-0, 5F30CA239317, T32GM007753, T32GM144273, and 1DP2CA195762), the Switzerland National Science Foundation; the Lymphoma Research Foundation; the National Cancer Institute (grants 5R01CA173636, 5R01CA228135, 5P01CA229086, 5R01CA242020, 1R01CA243001, and 1R01CA252239); the Mark Foundation for Cancer Research Emerging Leader Award, the Vogelstein Foundation. NYU Langone’s Genome Technology Center is partially supported by the Cancer Center Support grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.

The human body is made up of thousands of tiny lymphatic vessels that ferry white blood cells and proteins around the body, like a superhighway of the immune system. It’s remarkably efficient, but if damaged from injury or cancer treatment, the whole system starts to fail. The resulting fluid retention and swelling, called lymphedema, isn’t just uncomfortable — it’s also irreversible.
When lymphatic vessels fail, typically their ability to pump out the fluid is compromised. Georgia Institute of Technology researchers have developed a new treatment using nanoparticles that can repair lymphatic vessel pumping. Traditionally, researchers in the field have tried to regrow lymphatic vessels, but repairing the pumping action is a unique approach.
“With many patients, the challenge is that the lymphatic vessels that still exist in the patient aren’t working. So it’s not that you need to grow new vessels that you can think of as tubes, it’s that you need to get the tubes to work, which for lymphatic vessels means to pump,” said Brandon Dixon, a professor in the George W. Woodruff School of Mechanical Engineering. “That’s where our approach is really different. It delivers a drug to help lymphatic vessels pump using a nanoparticle that can drain into the diseased vessels themselves.”
The researchers published their findings in “Lymphatic-Draining Nanoparticles Deliver Bay K8644 Payload to Lymphatic Vessels and Enhance Their Pumping Function” in Science Advances in February.
The Benefit of Nanotechnology for Drug Delivery
The drug the researchers used, S-(-)-Bay K8644 or BayK, normally targets L-type calcium channels that enable the skeletal, cardiac, and endocrine muscles to contract. In effect, the application of BayK throughout the body would lead to convulsions and spasms.

Using nanoparticles designed to drain into lymphatic vessels after injection focuses the drug solely into the lymphatic vessels, draining the injection site. As a result, the drug is available within lymphatic vessels at a locally high dose. When lymph is eventually returned into the circulation, it’s diluted in the blood so much that it doesn’t affect other systems in the body, making the drug for lymphedema applications both targeted and safe.
“Lymphatic tissues work like river basins — regionally you have vessels that drain the fluid out of your tissues,” said Susan Thomas, Woodruff Associate Professor of Mechanical Engineering in the Parker H. Petit Institute for Bioengineering and Bioscience. “This method is like putting nanoparticles in the river to help the river flow better.”
The research is the perfect blend of Dixon’s and Thomas’ respective expertise. Dixon’s lab has been studying how lymphatics function in animal models for years. Thomas engineers nanoparticle drug delivery technologies that deploy in the lymphatic system.
“He develops analysis tools and disease models related to the lymphatic system, and I develop lymphatic-targeting drug delivery technologies,” Thomas said. “Tackling lymphedema as a widely prevalent condition for which there are no efficacious therapies was the perfect opportunity to leverage our strengths to hopefully move the needle on developing new strategies to serve this underserved patient population.”
Testing the Therapy
The Dixon and Thomas lab teams tested the formulation using rodent models. They first mapped the model’s lymph node system by injecting a fluorescent substance to see how it traveled. Then they applied a pressure cuff to measure how the lymphatic system fails to function when compromised. From there, they evaluated how formulating BayK in a lymph-draining nanoparticle influenced the drug’s effects. The delivery system allowed the drug to act within the lymphatic vessel, as demonstrated by increased vessel pumping and restored pumping pressure, and drastically reduced the concentration of BayK in the blood, which is typically associated with unwanted side effects.
The researchers are expanding the formulation to more advanced disease models to move it closer to human application. They will also explore how it can be used to prevent or treat lymphedema in combination with other existing or new therapies now being developed.