Cortisone and other related glucocorticoids are extremely effective at curbing excessive immune reactions. But previously, astonishingly little was known about how they exactly do that. A team of researchers from Charité — Universitätsmedizin Berlin, Uniklinikum Erlangen and Ulm University have now explored the molecular mechanism of action in greater detail. As the researchers report in the journal Nature, glucocorticoids reprogram the metabolism of immune cells, activating the body’s natural “brakes” on inflammation. These findings lay the groundwork for development of anti-inflammatory agents with fewer and less severe side effects.
The glucocorticoid cortisone is actually naturally present in the body as cortisol, a stress hormone. The organism releases cortisol to improve the body’s responses to stress. Cortisol intervenes in sugar and fat metabolism and affects other parameters, including blood pressure and respiratory and heart rate. At higher doses, it also inhibits the activity of the immune system, which makes it useful for medical purposes: Due to their excellent efficacy, synthetic glucocorticoid derivates that inhibit inflammation, even more than the natural substance present in the body, are used to treat a wide range of immune-mediated inflammatory diseases. They are among the most widely used medications of all.
Glucocorticoids affect not only genes, but also cellular energy sources
However, glucocorticoid-based medications also have side effects, especially at higher doses and when administered for longer periods. These side effects are related to the other effects of the body’s own cortisol. They include high blood pressure, osteoporosis, diabetes, and weight gain. With the aim of developing anti-inflammatory agents with fewer and less severe side effects, a team of researchers led by Prof. Gerhard Krönke, director of the Department of Rheumatology and Clinical Immunology at Charité, has now conducted a closer study of how the immunosuppressive effects of glucocorticoids exactly works.
“It was previously known that glucocorticoids activate a number of genes in different cells of the body,” Krönke explains. “But through this mechanism, they mainly activate the resources present in the body. This does not adequately explains its strong immunosuppressive effect. In our study, we have now been able to show that glucocorticoids affect more than just the gene expression in immune cells. It also affects the cell´s powerhouses, the mitochondria. And that this effect on cell metabolism is in turn crucial to the anti-inflammatory effects exerted by glucocorticoids.”
Swords to plowshares
For the study, the research team focused on macrophages, a type of immune cell responsible for eliminating intruders such as viruses and bacteria. These cells can also play a role in the emergence of immune-mediated inflammatory diseases. The researchers studied how these immune cells — derived in this case from mice — responded to inflammatory stimuli in a laboratory setting and what effects additional administration of a glucocorticoid had. The researchers observed that in addition to its effect on gene expression, glucocorticoids had a major effect in reversing changes in the cell metabolism that had been initiated by the inflammatory stimuli.

“When macrophages are put into ‘fight’ mode, they redirect their cellular energy into arming for a fight. Instead of supplying energy, their mitochondria produce the components needed to fight intruders,” Krönke says, describing the processes involved. “Glucocorticoids reverse the process, switching the ‘fight’ mode back off and turning swords into plowshares, so to speak. A tiny molecule called itaconate plays an especially important role in this.”
Itaconate mediates anti-inflammatory effect of glucocorticoids
Itaconate is an anti-inflammatory substance that the body naturally produces inside its mitochondria. Macrophages produce it early on when they are activated so that the inflammatory reaction will subside after a certain period. Generation of this natural immune “brake,” however, requires sufficient fuel. When the cell´s powerhouses are arming up for a fight, that is no longer the case, so itaconate production dwindles to a halt after a while. With normal, short-term inflammation, this timing is effective because the immune response has also subsided in the meantime.
“With a persistent inflammatory stimulus, the drop-off in itaconate production is an issue because there is then no immune ‘brake’ even though the immune system is still running on all cylinders, eventually contributing to chronic inflammation,” explains Dr. Jean-Philippe Auger, a scientist at the Department of Medicine 3 — Rheumatology and Immunology at Uniklinikum Erlangen and the first author of the study. “This is where glucocorticoids intervenes. By reprogramming the mitochondrial function, they ramp up the formation of itaconate in the macrophages, restoring its anti-inflammatory effect.”
The search for new active substances
Using animal models for asthma and rheumatoid arthritis, the researchers were able to demonstrate how much the anti-inflammatory effect of glucocorticoids depends on itaconate. Glucocorticoids had no effect in animals that were unable to produce itaconate. So, if itaconate mediates the immunosuppressant effect of cortisone, wouldn’t it be possible to administer itaconate directly, instead of glucocorticoids?
“Unfortunately, itaconate isn’t a particularly good candidate as an anti-inflammatory drug, because it’s unstable, and due to its high reactivity, it could cause side effects if administered systemically,” Krönke explains. “Aside from that, we assume the processes in humans to be a bit more complex than those in mice. So our plan is to look for new synthetic compounds that are just as effective as glucocorticoids at reprogramming the mitochondrial metabolism inside immune cells, but have fewer and less severe side effects.”

Infection with the influenza virus leads to lung injury through inflammation over-activation that causes collateral damage to cells required for breathing. Such damage can be life-threatening, but scientists have a new preventative treatment. A team from St. Jude Children’s Research Hospital, University of Houston, Tufts University School of Medicine and Fox Chase Cancer Center created a drug that can prevent flu-induced lung injury. In a mouse model, the drug achieves a novel balance between shutting down runaway inflammation and allowing the immune system to stop the virus. The findings were published today in Nature.
“Our drug significantly increased survival and lowered symptoms of influenza virus infection,” said co-corresponding author Paul Thomas, PhD, St. Jude Department of Host-Microbe Interactions. “It dampened dangerous inflammation and even seemed to improve the adaptive response against the virus.”
In a series of experiments, the drug UH15-38 protected against lethal influenza. Results showed that the drug protected mouse models from similar amounts of influenza that humans experience, even at low doses. Additionally, the team found that a high drug dose could fully protect against an infection with a substantial amount of virus, which would usually be deadly. The models were protected even if they received the dose days after infection, a difficult achievement for an influenza therapeutic.
“This drug can also do something we’ve never seen before,” Thomas said. “We’re able to start five days after the initial infection and show that we’re still providing some benefit.”
Providers must administer modern antiviral drugs within the first few days of infection to be effective. This study suggests that UH15-38 may fill a currently unmet need, as patients with severe disease have often been infected for several days by the time they get to a doctor. The breakthrough results from understanding how influenza and the immune system interact to cause lung injury.
Sending influenza-infected cells down the right path
“Infected lung cells create inflammation that alerts the immune system that there’s a problem, but too much of it generates runaway inflammation that can cause major problems,” Thomas said. “We need to strike a delicate balance between maintaining enough of these processes to get rid of the virus, but not so much that you’re getting this runaway inflammation.”
The collaborating scientists achieved a Goldilocks amount of inflammation using clever chemistry. Their new drug inhibited one part of a major inflammation protein in immune cells: Receptor-Interacting Protein Kinase 3 (RIPK3). RIPK3 controls two cell death pathways in response to infection: apoptosis and necroptosis. Necroptosis is highly inflammatory, but apoptosis is not. Both pathways are used in the antiviral response. UH15-38 was designed to prevent RIPK3 from starting necroptosis while maintaining its pro-apoptotic properties.

“Knocking out RIPK3 entirely is not great because then the immune system can’t clear the virus,” Thomas said. “When we knocked out just necroptosis, the animals did better because they still had apoptosis and could still get rid of infected cells, but it wasn’t as inflammatory.”
Stopping lung inflammation and injury
“We also showed that the improved survival was the direct result of the reduction in local inflammation and improved lung cell survival,” Thomas said.
In a series of prior studies, the Thomas lab found that a specific set of cells in the lung are collateral damage in the runaway inflammatory response. These cells, Type 1 alveolar epithelial cells, handle gas exchange, letting oxygen in and carbon dioxide out. Loss of these cells leads to an inability to breathe. The current study demonstrated that this group of literal breath-taking cells was spared in the presence of the drug. Additionally, inflammation-related immune cells, such as neutrophils, were far less prevalent in the lungs of treated animals.
“Often the worst part of influenza illness happens after the virus is controlled when runaway inflammation destroys lung cells,” Thomas said. “UH15-38 can dampen that influenza-caused inflammation while leaving viral clearance and the other functions of the immune and tissue responses intact. That makes it a promising candidate to move forward toward the clinic.”

CAR T cell therapy has revolutionized the way certain types of cancer are treated, and the longer those CAR T cells live in a patient’s body, the more effectively they respond to cancer. Now, in a new study, researchers at Children’s Hospital of Philadelphia (CHOP) and Stanford Medicine have found that a protein called FOXO1 improves the survival and function of CAR T cells, which may lead to more effective CAR T cell therapies and could potentially expand its use in difficult-to-treat cancers. The findings were published online today by the journal Nature.
T cells are a type of immune cell that recognize and kill pathogens in order to protect the host. Cancer is often able to evade the body’s immune system, but as a result of CAR T cell therapy, a patient’s own T cells can be reprogrammed to recognize and kill these cancer cells, which has led to FDA-approved treatments for certain types of lymphomas and leukemias.
However, fewer than 50% of patients who receive CAR T cell therapy remain cured after a year. One of the reasons for this is that CAR T cells often don’t survive long enough in patients to completely eradicate their cancer. Prior research has demonstrated that patients who are cured through CAR T cell therapy often have CAR T cells that live longer and can more successfully fight cancerous cells.
To determine what helps CAR T cells live longer, researchers wanted to understand the underlying biology behind memory T cells, which are a type of natural T cell whose purpose is to persist and retain function. One protein of interest, FOXO1, which activates genes associated with T cell memory, has previously been studied in mice but remains under-researched in human T cells or CAR T cells.
“By studying factors that drive memory in T cells, like FOXO1, we can enhance our understanding of why CAR T cells persist and work more effectively in some patients compared to others,” said senior study author Evan Weber, PhD, an Assistant Professor of Pediatrics at the University of Pennsylvania Perelman School of Medicine and cell and gene therapy researcher within the CHOP Center for Childhood Cancer Research (CCCR) and the Center for Cellular and Molecular Therapeutics (CCMT).
To learn more about the role of FOXO1 in human CAR T cells, the researchers in this study used CRISPR to delete FOXO1. They found that in the absence of FOXO1, human CAR T cells lose their ability to form a healthy memory cell or protect against cancer in an animal model, supporting the notion that FOXO1 controls memory and antitumor activity.
Researchers then applied methods to force CAR T cells to overexpress FOXO1, which turned on memory genes and enhanced their ability to persist and fight cancer in animal models. In contrast, when the researchers overexpressed a different memory-promoting factor, there was no improvement in CAR T cell activity, suggesting that FOXO1 plays a more unique role in promoting T cell longevity.
Importantly, researchers also found evidence that FOXO1 activity in patient samples correlates with persistence and long-term disease control, thereby implicating FOXO1 in clinical CAR T cell responses.
“These findings may help improve the design of CAR T cell therapies and potentially benefit a wider range of patients,” Weber said. “We are now collaborating with labs at CHOP to analyze CAR T cells from patients with exceptional persistence to identify other proteins like FOXO1 that could be leveraged to improve durability and therapeutic efficacy.”
This study was supported by the National Cancer Institute Immunotherapy Discover and Development grants 1U01CA232361-A1, K08CA23188-01, U01CA260852, and U54CA232568-01; the National Human Genome Research Institute grant K99 HGHG012579 (C.A.L.); the Parker Institute for Cancer Immunotherapy; V Foundation for Cancer Research; Society for Immunotherapy of Cancer Rosenberg Scholar Award; Stand Up 2 Cancer — St. Baldrick’s — NCI grant SU2CAACR-DT1113; and the Virginia and D.K. Ludwig Fund for Cancer Research and NCI grant U2C CA233285.

Cells contain various specialised structures — such as the nucleus, mitochondria or peroxisomes — known as “organelles”. Tracing their genesis and determining their structure is fundamental to understanding cell function and the pathologies linked to their dysfunction. Scientists at the University of Geneva (UNIGE) have combined high resolution microscopy and kinematic reconstruction techniques to visualise, in motion, the genesis of the human centriole. This organelle, essential to the organisation of the cell skeleton, is associated — in case of dysfunction — with certain cancers, brain disorders or retinal diseases. This work, published in the journal Cell, elucidates the complexities of centriole assembly. It also opens up many new avenues for the study of other cell organelles.
Organelle genesis proceeds according to a precise sequence of successive protein recruitment events. Visualising this assembly in real time provides a better understanding of the role of these proteins in organelle structure or function. However, obtaining a video sequence with sufficient resolution to distinguish such complex microscopic components faces a number of technical limitations.
Inflating cells for better observation
This is particularly true of the centriole. This organelle, measuring less than 500 nanometers (half a thousandth of a millimeter), is constituted of around 100 different proteins organised into six substructural domains. Until a few years ago, it was impossible to visualise the structure of the centriole in detail. The laboratory of Paul Guichard and Virginie Hamel, co-directors of research in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Science, has changed this situation by using the technique of expansion microscopy. This cutting-edge technique enables cells and their constituents to be progressively inflated without being deformed, so that they can then be observed — using conventional microscopes — with very high resolution.
Obtaining images of the centriole with such high resolution enables the exact location of proteins at a given time but gives no information on the order of appearance of substructural domains or of individual proteins. Marine Laporte, a former research and teaching fellow in the UNIGE group and first author of the study, used expansion microscopy to analyse the location of 24 proteins in the six domains in over a thousand centrioles at different stages of growth.
Reorganising images to set them in motion
”This very tedious work was followed by a pseudo-temporal kinematic reconstruction. In other words, we were able to put these thousands of images taken at random during centriole biogenesis back into chronological order, to reconstruct the various stages in the formation of centriole substructures, using a computer analysis we developed,” explains Virginie Hamel, co-leader of the study.
This unique approach, which combines the very high resolution of expansion microscopy and kinematic reconstruction, has enabled us to model the first 4D assembly of the human centriole. ”Our work will not only deepen our understanding of centriole formation, but also open up incredible prospects in cellular and molecular biology, since this method can be applied to other macromolecules and cellular structures to study their assembly in space and time,” concludes Paul Guichard.

Humans can sense five different tastes: sour, sweet, umami, bitter, and salty, using specialized sensors on our tongues called taste receptors. Other than allowing us to enjoy delicious foods, the sensation of taste allows us to determine the chemical makeup of food and prevents us from consuming toxic substances.
Researchers at the UNC School of Medicine, including Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology, and Yoojoong Kim, PhD, a postdoctoral researcher in the Roth Lab, recently set out to address one very basic question: “How exactly do we perceive bitter taste?”
A new study, published in Nature, reveals the detailed protein structure of the TAS2R14 bitter taste receptor. In addition to solving the structure of this taste receptor, the researchers were also able to determine where bitter-tasting substances bind to TAS2R14 and how they activate them, allowing us to taste bitter substances.
“Scientists know very little about the structural make up of sweet, bitter, and umami taste receptors,” said Kim. “Using a combination of biochemical and computational methods, we now know the structure of the bitter taste receptor TAS2R14 and the mechanisms that initializes the sensation of bitter taste in our tongues.”
This detailed information is important for discovering and designing drug candidates that can directly regulate taste receptors, with the potential to treat metabolic diseases such as obesity and diabetes.
From Chemicals to Electricity to Sensation
TAS2R14s are members of the G protein-coupled receptor (GPCR) family of bitter taste receptors. The receptors are attached to a protein known as a G protein. TAS2R14 stands out from the others in its family because it can identify more than 100 distinct substances known as bitter tastants.

Researchers found that when bitter tastants come into contact with TAS2R14 receptors, the chemicals wedge themselves into to a specific spot on the receptor called an allosteric site, this causes the protein to change its shape, activating the attached G protein.
This triggers a series of biochemical reactions within the taste receptor cell, leading to activation of the receptor, which can then send signals to tiny nerve fibers — through the cranial nerves in the face — to an area of the brain called the gustatory cortex. It is here where the brain processes and perceives the signals as bitterness. And of course, this complex signaling system occurs almost instantaneously.
Cholesterol’s Role in Bitter Taste Reception
While working to define its structure, researchers found another unique feature of TAS2R14 — that cholesterol is giving it a helping hand in its activation.
“Cholesterol was residing in another binding site called the orthosteric pocket in TAS2R14, while the bitter tastant binds to the allosteric site,” said Kim. “Through molecular dynamics simulations, we also found that the cholesterol puts the receptor in a semi-active state, so it can be easily activated by the bitter tastant.”
Bile acids, which are created in the liver, have similar chemical structures with cholesterol. Previous studies have suggested that bile acids can bind and activate TAS2R14, but little is known about how and where they bind in the receptor.

Using their newfound structure, researchers found that bile acids might be binding to the same orthosteric pocket as cholesterol. While the exact role of bile acid or cholesterol in TAS2R14 remains unknown, it may play a role in the metabolism of these substances or in relation to metabolic disorders such as obesity or diabetes.
How This Can Help Drug Development
The discovery of this novel allosteric binding site for bitter tasting substances is unique.
The allosteric binding region is located between TAS2R14 and its coupled G protein is called G-protein alpha. This region is critical to form a signaling complex, which helps to transfer the signal from the taste receptor to the G-protein to the taste receptor cells.
“In the future, this structure will be key to discovering and designing drug candidates that can directly regulate G proteins through the allosteric sites,” said Kim. “We also have the ability to affect specific G-protein subtypes, like G-protein alpha or G-protein beta, rather than other G-protein pathways that we don’t want to cause any other side effects.”
Roth and Kim have made a number of new discoveries, but some leave more questions than answers. While running a genomics study, they found that the TAS2R14 protein in complex with the GI is expressed outside the tongue, especially in the cerebellum in the brain, the thyroid, and the pancreas. Researchers are planning future studies to elucidate the function these proteins may have outside of the mouth.
This work was supported by the NIH Illuminating the Druggable Genome Initiative.

Undertaking the majority of daily physical activity in the evening is linked to the greatest health benefits for people living with obesity, according to researchers from the University of Sydney, Australia who followed the trajectory of 30,000 people over almost 8 years.
Using wearable device data to categorise participant’s physical activity by morning, afternoon or evening, the researchers uncovered that those who did the majority of their aerobic moderate to vigorous physical activity- the kind that raises our heartrate and gets us out of breath- between 6pm and midnight had the lowest risk of premature death and death from cardiovascular disease.
The frequency with which people undertook moderate to vigorous physical activity (MVPA) in the evening, measured in short bouts up to or exceeding three minutes, also appeared to be more important than their total amount of physical activity daily.
The study, led by researchers from the University’s Charles Perkins Centre is published in the journal Diabetes Care today.
“Due to a number of complex societal factors, around two in three Australians have excess weight or obesity which puts them at a much greater risk of major cardiovascular conditions such as heart attacks and stroke, and premature death,” said Dr Angelo Sabag, Lecturer in Exercise Physiology at the University of Sydney.
“Exercise is by no means the only solution to the obesity crisis, but this research does suggest that people who can plan their activity into certain times of the day may best offset some of these health risks.”
Smaller clinical trials have shown similar results, however the large scale of participant data in this study, the use of objective measures of physical activity and hard outcomes, such as premature death, makes these findings significant.

Joint first author Dr Matthew Ahmadi also stressed that the study did not just track structured exercise. Rather researchers focused on tracking continuous aerobic MVPA in bouts of 3 minutes or more as previous research shows a strong association between this type of activity, glucose control and lowered cardiovascular disease risk compared with shorter (non-aerobic) bouts.
“We didn’t discriminate on the kind of activity we tracked, it could be anything from power walking to climbing the stairs, but could also include structured exercise such as running, occupational labour or even vigorously cleaning the house,” said Dr Ahmadi, National Heart Foundation postdoctoral research fellow at the Charles Perkins Centre, University of Sydney.
While observational, the findings of the study support the authors original hypothesis, which is the idea — based on previous research — that people living with diabetes or obesity, who are already glucose intolerant in the late evening, may be able to offset some of that intolerance and associated complications, by doing physical activity in the evening.
The researchers used data from UK Biobank and included 29,836 adults aged over 40 years of age living with obesity, of whom 2,995 participants were also diagnosed with Type 2 diabetes.
Participants were categorised into morning, afternoon of evening MVPA based on when they undertook the majority of their aerobic MVPA as measured by a wrist accelerometer worn continuously for 24 hours a day over 7 days at study onset.
The team then linked health data (from the National Health Services and National Records of Scotland) to follow participants health trajectory for 7.9 years. Over this period they recorded 1,425 deaths, 3,980 cardiovascular events and 2,162 microvascular disfunction events.

To limit bias, the researchers accounted for differences such as age, sex, smoking, alcohol intake, fruit and vegetable consumption, sedentary time, total MVPA, education, medication use and sleep duration. They also excluded participants with pre-existing cardiovascular disease and cancer.
The researchers say the length of the study follow-up and additional sensitivity analysis bolster the strength of their findings however, due to the observational design, they cannot completely rule out potential reverse causation. This is the possibility that some participants had lower aerobic MVPA levels due to underlying or undiagnosed disease.
Professor Emmanuel Stamatakis, Director of the Mackenzie Wearables Research Hub at the Charles Perkins Centre and senior author on the paper, said the sophistication of studies in the wearables field is providing huge insights into the patterns of activity that are most beneficial for health.
“It is a really exciting time for researchers in this field and practitioners alike, as wearable device-captured data allow us to examine physical activity patterns at a very high resolution and accurately translate findings into advice that could play an important role in health care,” said Professor Stamatakis.
“While we need to do further research to establish causal links, this study suggests that the timing of physical activity could be an important part of the recommendations for future obesity and Type 2 diabetes management, and preventive healthcare in general.”

Over 12 million people worldwide suffer from a chronic infection with the hepatitis D virus. This most severe viral liver disease is associated with a high risk of dying from liver cirrhosis and liver cancer. It is caused by the hepatitis D virus (HDV), which uses the surface proteins of the hepatitis B virus (HBV) as a vehicle to specifically enter liver cells via a protein in the cell membrane — the bile salt transporter protein NTCP. This cell entry can be prevented by the active agent bulevirtide, which is approved as a drug under the name Hepcludex. An international research team has now succeeded in deciphering the molecular structure of bulevirtide in complex with the HBV/HDV receptor NTCP at the molecular level. The research results published in the journal Nature Communications pave the way for more targeted and effective treatments for millions of people chronically infected with HBV/HDV.
The entry inhibitor bulevirtide is the first and currently only approved drug (under the drug name Hepcludex) for the treatment of chronic infections with the hepatitis D virus. The active agent effectively inhibits the replication of hepatitis D viruses and leads to a significant improvement in liver function. However, the exact mechanism by which bulevirtide interacts with the virus entry receptor on the surface of the liver cells — the bile salt transporter protein NTCP (short for: sodium taurocholate cotransporting polypeptide) — and thereby inhibits the entry of the viruses into the cells was previously unknown.
In order to understand the molecular interaction of bulevirtide and NTCP at the molecular level, the researchers first generated an antibody fragment that specifically recognises the NTCP-bulevirtide complex and makes it accessible for analysis when bound to nanoparticles. This complex was then analysed using cryo-electron microscopy, which allowed to visualise structural details with atomic resolution. The research results represent a milestone in understanding both the interaction of HBV and HDV with their cellular entry receptor NTCP and the mechanism of cell receptor blockade by bulevirtide.
How bulevirtide blocks the cell entry receptor NTCP
The analysis showed that bulevirtide forms three functional domains in the interaction with the HBV/HDV receptor NTCP: a myristoyl group that interacts with the cell membrane on the outside of the cell; an essential core sequence (‘plug’) that fits precisely into the bile salt transport tunnel of the NTCP like the bit of a key into a lock; and an amino acid chain that stretches across the extracellular surface of the receptor, enclosing it like a brace.
“The formation of a ‘plug’ in the transport tunnel and the associated inactivation of the bile salt transporter is so far unique among all known virus-receptor complexes. This structure explains why the physiological function of the NTCP is inhibited when patients are treated with bulevirtide,” says Prof Stephan Urban, DZIF Professor of Translational Virology and Deputy Coordinator of the DZIF research area Hepatitis, in whose laboratory at Heidelberg University the active agent bulevirtide was developed.
“Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents — so-called peptidomimetics — with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration,” adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen.

Evolutionary adaptation of hepatitis B viruses to host species
The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV.
“Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs,” adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen.
“Our research results are an important step in the fight against hepatitis D and B. By understanding the structure of bulevirtide and its binding to NTCP, we can potentially develop more targeted and effective treatments for millions of people chronically infected with HBV/HDV,” says Prof. Kaspar Locher, last author of the publication and head of the structural biology team at ETH Zurich, summarising the study results.

New research from the University of Eastern Finland sheds light on the significance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting the activity of coregulator proteins.
Glucocorticoids regulate vital biological processes by affecting gene encoding through a DNA-binding transcription factor, namely the glucocorticoid receptor. The activity of the glucocorticoid receptor is made extensive use of in medicine because glucocorticoids have a strong anti-inflammatory effect. For this reason, synthetic glucocorticoids are one of the most prescribed drugs in the world. They are used to treat inflammatory diseases, such as rheumatoid arthritis, and as adjuvant therapy for cancer patients to alleviate the side effects of cancer therapy. In blood cancer, glucocorticoids are important drugs that limit the growth of cancer cells.
However, recent studies have shown that the glucocorticoid receptor also has an oncogenic, or cancer-promoting, effect in cancers like breast and prostate cancer. In prostate cancer, the glucocorticoid receptor can replace the activity of the androgen receptor, which is main oncogenic factor in this cancer, when its activity is inhibited by drug therapy. Thus, glucocorticoids help prostate cancer develop resistance to drug therapy.
“Due to these drug resistance and cancer-promoting effects, it is important to study how the glucocorticoid receptor functions on the cellular and molecular level in cancer,” Academy Research Fellow, Docent Ville Paakinaho of the University of Eastern Finland notes.
The Paakinaho Lab has published two recent genome-wide deep sequencing studies on the subject. The first, published in Nucleic Acids Research, explored how the glucocorticoid receptor replaces the androgen receptor on the molecular level.
“This study showed that the glucocorticoid receptor can only use regulatory regions that are already active in prostate cancer cells,” says Doctoral Researcher Laura Helminen of the University of Eastern Finland.
In other words, glucocorticoid receptor-mediated drug resistance emerges through these regulatory regions, and by affecting the activity of these areas, the harmful effects of glucocorticoids in prostate cancer could be prevented. Bioinformatics analyses indicated the pioneer transcription factor FOXA1 as one possible target. FOXA1 is known to have cancer-promoting properties, which is why the researchers assumed that inhibiting its activity would limit the development of glucocorticoid receptor-mediated drug-resistant prostate cancer. Surprisingly however, the effect was exactly the opposite: inhibiting the activity of FOXA1 further increased the activity of the glucocorticoid receptor — and the development of drug resistance.

This is because FOXA1 was found to be involved in the silencing of the glucocorticoid receptor gene, and this is what increased its activity when FOXA1 was inhibited.
“Research often reveals the unexpected, and that’s part of its charm,” Paakinaho says.
The activity of the glucocorticoid receptor in regulatory regions can, however, be influenced in drug-resistant prostate cancer through an alternative pathway. Coregulator proteins were identified as an alternative target through which the glucocorticoid receptor affects the regulation of gene expression. These proteins include EP300 and CREBBP. Several pharmaceutical companies are developing small-molecule inhibitors targeting these proteins, and some are already being studied in patients.
In another study by the Paakinaho Lab, the researchers explored ways to inhibit glucocorticoid receptor-mediated effects by inhibiting coregulator proteins. These findings were reported in Cellular and Molecular Life Sciences.
“Silencing the EP300 and CREBBP proteins with a small-molecule inhibitor clearly prevented the activity of the glucocorticoid receptor in prostate cancer cells,” Project Researcher Jasmin Huttunen of the University of Eastern Finland says.
This allowed the growth of drug-resistant prostate cancer cells to be inhibited. Furthermore, the researchers found that silencing EP300 and CREBBP also effectively inhibited the activity of the androgen receptor especially in prostate cancer cells that have an amplification of the androgen receptor gene. This amplification is found in up to half of patients with advanced prostate cancer.
Surprisingly, the EP300 and CREBBP inhibitor also inhibited the activity of FOXA1, while still preserving its ability to silence the expression of the glucocorticoid receptor gene. By using the EP300 and CREBBP inhibitor, it was possible to block the activity of FOXA1 without the development of glucocorticoid receptor-mediated drug resistance. Ultimately, inhibiting the activity of both the androgen and the glucocorticoid receptor was found to be primarily due to the limitation of FOXA1 activity. The study suggests that treatment targeting coregulator proteins could also be effective in untreated prostate cancer.
The studies were funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland.

Only recently, a new era in medicine began with the first RNA vaccines. These active substances are modified RNAs that trigger immune responses of the human immune system. Another approach in RNA medicine targets the body’s own RNA and its protein modulators by specifically tailored active substances. Peng Wu, research group leader at the Chemical Genomics Centre at the Max Planck Institute of Molecular Physiology in Dortmund, and colleagues, have now developed the first small-molecule inhibitors against the RNA-modifying enzyme METTL16. The methyltransferase is responsible for the regulation of different RNAs and is a promising anti-cancer target. The new findings lay the foundation for a comprehensive investigation of the role of METTL16 in health and disease and are a step closer towards the development of therapeutic agents targeting such RNA modifiers.
RNA has long been considered only as a passive messenger in the cell, produced by DNA transcription to transfer genetic information to the protein factories, the ribosomes. However, it has turned out, that RNA does much more than that. In addition to the coding DNA just described, there is also non-coding DNA controlling many cellular processes by regulating the activity of genes at many levels. No less than a dozen RNA classes have been identified nowadays. RNAi for example, is used by the cell to degrade particular RNA targets to silence genes, when it comes to fighting foreign viral DNA.
Readers, writers, and erasers
RNA interacts with a plethora of biomolecules, not only other RNAs or DNA but also proteins and metabolites. The resulting regulatory complexes control diverse vital cellular processes and errors can cause diseases. RNA’s fate is determined by chemical modifications that affect its stability, structure and interactions and thereby its fate. More than 170 distinct RNA modifications have been described so far. The most abundant is the methylation on the N6-position of the RNA-nucleotide adenosine (m6A). It allows the cell to quickly respond to environmental changes by initiating appropriate cellular responses, such as division, differentiation or migration. This is why RNA-methylation needs to be tightly controlled, taken care of by a set of proteins: “writers” deposit, “readers” recognize and “erasers” remove the methyl group.
New substance prevents writing to RNA
Aberrant RNA methylation has been associated with cancers and other human diseases, making “writers” an attractive therapeutic target. Only a handful of RNA m6A writers have been identified so far. And only for one of them, METTL3, potent inhibitors have been reported. These molecules prevent the writer from absorbing the ink, the biomolecule S-adenosyl methionine (SAM). The group of Peng Wu has now identified the first inhibitor of the writer METTL16. However, in contrast to the before-mentioned inhibitors, it showed a different mode of action: it prevents the interaction of METTL16 with RNA. The scientists were able to identify this new type of inhibitor by developing an assay evaluating the disruption between METTL16 and a fluorophore-labeled mRNA substrate.
“Certain cancer cells have elevated writer levels and are also more vulnerable to reduction of SAM levels, which makes them promising anticancer targets. However, the exact biological consequences of METTL16’s binding to RNA substrates are not yet clearly determined. With our work, we lay the foundation for a better investigation of the role of METTL16 in disease and health, but also for the development of novel RNA-targeting therapeutics,” says Peng Wu.

Children and young people who are overweight or obese are at significantly higher risk of iron deficiency, according to a study by nutritional scientists at the University of Leeds.
Researchers from the School of Food Science and Nutrition examined thousands of medical studies from 44 countries involving people under the age of 25 where levels of iron and other vitamins and minerals had been recorded alongside weight.
They found that iron deficiency was associated with both underweight and overweight children and adolescents.
By contrast, zinc and vitamin A deficiencies were only observed in children who were undernourished, leading researchers to conclude that iron deficiency in overweight children is probably due to inflammation disrupting the mechanisms that regulate iron absorption.
The results of the research which was funded by the UK Biotechnology and Biological Sciences Research Council are published today (10 May 2024) in the journal BMJ Global Health.
Iron deficiency in children has a negative effect on brain function, including attention, concentration and memory, and can increase the risk of conditions, such as autism and ADHD.
It is already recognised as a problem in adults living with obesity, but this research is the first to look at the association in children.

Lead author Xiaomian Tan, a Doctoral Researcher in the University of Leeds’ School of Food Science and Nutrition said: “The relationship between undernutrition and critical micronutrients for childhood growth and development is well established, but less is known about the risk of deficiencies in iron, vitamin A and zinc in children and adolescents who are overweight or obese, making this a hidden form of malnutrition.
“Our research is hugely important given the high prevalence of obesity in children. We hope it will lead to increased recognition of the problem by healthcare practitioners and improvements in clinical practice and care.”
Hidden hunger
Historically the problem has been linked to malnutrition and is a particular concern for lower- and middle-income countries where hunger may be the leading cause of mortality for young children.
Increasingly though it is being recognised that vitamin and mineral deficiencies can also occur in people who are overweight and obese and who have a nutrient-poor but energy-dense diet, something which has been described as ‘hidden hunger’.
In high-income countries it is associated with ultra-processed foods that are high in fat, sugar, salt, and energy but in lower- and middle-income countries obesity is often associated with poverty and monotonous diets with limited choices of staples such as corn, wheat, rice, and potatoes.

Many developing countries are now facing a double burden of malnutrition alongside overnutrition due to the rapid increase in the global prevalence of obesity in recent decades, especially in children aged between five and 19.
Undernutrition versus overnutrition
The research also highlights differences in focus between higher income countries and developing nations, with most studies in Africa and Asia focusing on undernutrition and those from North America and Europe focusing entirely on overnutrition.
The researchers say this is particularly concerning as both Africa and Asia are experiencing the highest double burden of malnutrition due to economic growth and the transition to a western-style high-sugar, high-fat diet.
Between the years 2000 and 2017, the number of overweight children under the age of five in Africa increased from 6.6 to 9.7 million, and in Asia that figure rose from 13.9 to 17.5 million. At the same time, there was an increase in the number of stunted children under 5, from 50.6 to 58.7 million in Africa.
Research supervisor Bernadette Moore, Professor of Nutritional Sciences in Leeds’ School of Food Science and Nutrition, said: “These stark figures underscore the fact that the investigation of micronutrient deficiencies in relation to the double burden of malnutrition remains critically important for child health.
“By the age of 11 here in the UK, one in three children are living with overweight or obesity, and our data suggests that even in overweight children inflammation leading to iron deficiency can be an issue.
“Iron status may be the canary in the coalmine, but the real issue is that prolonged inflammation leads to heart disease, diabetes and fatty liver.”
Increasing physical activity and improving diet have been shown to reduce inflammation and improve iron status in children and the researchers are now calling for further studies into the effectiveness of these interventions.
They also believe that more research is needed into micronutrient deficiencies and the double burden of malnutrition and overnutrition in countries where there are currently gaps in data.