Scientists at the University of Cambridge have discovered that a type of white blood cell — called a regulatory T cell — exists as a single large population of cells that constantly move throughout the body looking for, and repairing, damaged tissue.
This overturns the traditional thinking that regulatory T cells exist as multiple specialist populations that are restricted to specific parts of the body. The finding has implications for the treatment of many different diseases — because almost all diseases and injuries trigger the body’s immune system.
Current anti-inflammatory drugs treat the whole body, rather than just the part needing treatment. The researchers say their findings mean it could be possible to shut down the body’s immune response and repair damage in any specific part of the body, without affecting the rest of it. This means that higher, more targeted doses of drugs could be used to treat disease — potentially with rapid results.
“We’ve uncovered new rules of the immune system. This ‘unified healer army’ can do everything — repair injured muscle, make your fat cells respond better to insulin, regrow hair follicles. To think that we could use it in such an enormous range of diseases is fantastic: it’s got the potential to be used for almost everything,” said Professor Adrian Liston in the University of Cambridge’s Department of Pathology, senior author of the paper.
To reach this discovery, the researchers analysed the regulatory T cells present in 48 different tissues in the bodies of mice. This revealed that the cells are not specialised or static, but move through the body to where they’re needed. The results are published today in the journal Immunity.
“It’s difficult to think of a disease, injury or infection that doesn’t involve some kind of immune response, and our finding really changes the way we could control this response,” said Liston.
He added: “Now that we know these regulatory T cells are present everywhere in the body, in principle we can start to make immune suppression and tissue regeneration treatments that are targeted against a single organ — a vast improvement on current treatments that are like hitting the body with a sledgehammer.”
Using a drug they have already designed, the researchers have shown — in mice — that it’s possible to attract regulatory T cells to a specific part of the body, increase their number, and activate them to turn off the immune response and promote healing in just one organ or tissue.

“By boosting the number of regulatory T cells in targeted areas of the body, we can help the body do a better job of repairing itself, or managing immune responses,” said Liston.
He added: “There are so many different diseases where we’d like to shut down an immune response and start a repair response, for example autoimmune diseases like multiple sclerosis, and even many infectious diseases.”
Most symptoms of infections such as COVID are not from the virus itself, but from the body’s immune system attacking the virus. Once the virus is past its peak, regulatory T cells should switch off the body’s immune response, but in some people the process isn’t very efficient and can result in ongoing problems. The new finding means it could be possible to use a drug to shut down the immune response in the patient’s lungs, while letting the immune system in the rest of the body continue to function normally.
In another example, people who receive organ transplants must take immuno-suppressant drugs for the rest of their lives to prevent organ rejection, because the body mounts a severe immune response against the transplanted organ. But this makes them highly vulnerable to infections. The new finding helps the design of new drugs to shut down the body’s immune response against only the transplanted organ but keep the rest of the body working normally, enabling the patient to lead a normal life.
Most white blood cells attack infections in the body by triggering an immune response. In contrast, regulatory T cells act like a ‘unified healer army’ whose purpose is to shut down this immune response once it has done its job — and repair the tissue damage caused by it.
The researchers are now fundraising to set up a spin-out company, with the aim of running clinical trials to test their findings in humans within the next few years.

Researchers from the University of Tokyo performed the first study to quantify highly processed food consumption and to investigate its association with diet quality among Japanese children and adolescents. Highly processed foods (HPFs) accounted for over one-fourth of the total energy intake amongst youths. Consumption was negatively associated with the intake of healthy foods, such as fruits, vegetables and pulses, and positively associated with the consumption of confectioneries.
It’s common knowledge that poor-quality diets are considered major risk factors for many health issues and even noncommunicable diseases such as Type 2 diabetes. Therefore, researchers seek to understand factors related to diet quality as a way to improve people’s health. Research on HPFs has been rapidly increasing, highlighting their potential impact on public health. However, few studies have been conducted in Japan, with none focusing on children and adolescents, due to challenges in assessing them.
“Our previous research on HPF consumption in adults in Japan found that higher consumption was negatively associated with diet quality. This significant finding prompted us to investigate whether similar associations exist in younger generations,” said Assistant Professor Nana Shinozaki from the School of Public Health. “My team and I ran a cross-sectional study, one where many people are assessed in a short space of time rather than fewer people over a long period of time, to understand the association between HPF consumption and overall diet quality among Japanese children and adolescents. We found that higher HPF consumption is associated with poorer diet quality in 1,318 participants aged 3-17 years.”
This probably doesn’t come as a surprise to many, but it’s important to note that this is the first time hard data has been put to this specific demographic, and that fact might aid in improving public health. One of the difficulties in research on diets is that so many of the issues lack precise definitions. For this reason, Shinozaki and her team picked an existing dietary classification framework developed by researchers at the University of North Carolina at Chapel Hill (UNCCH) in the U.S. to classify the food that participants consumed, and the Healthy Eating Index-2020 and the Nutrient-Rich Food Index 9.3 to evaluate the quality of their diets. Under the UNCCH classification, HPFs are defined as “multi-ingredient, industrially formulated mixtures processed to the extent that they are no longer recognizable as their original plant/animal source.”
“The biggest challenge was collecting detailed dietary data, which are essential to identify which foods are HPFs, on eight days over the course of a year from a large sample of about 1,300 individuals,” said Shinozaki. “This process of assessment by researchers, and assessments by participants or parents, was highly burdensome for both participants and investigators due to the need for accurate and consistent recording of dietary intake. Our research could not have been accomplished without the support of research dietitians throughout Japan, who played a crucial role in supporting participants and collecting data.”
What might surprise some readers is that the cliché of Japan’s national diet being the model of healthy eating is a little inaccurate and out of date.
“Professor Kentaro Murakami (of the University of Tokyo) recently found that in a nationally representative sample of Japanese adults, the mean total score of the Healthy Eating Index-2015, a widely accepted diet quality index, was similar to that of average Americans. This finding suggests that the Japanese diet would not be as healthy as expected,” said Shinozaki. “Wherever you may be, at the individual level, increasing the consumption of unprocessed or minimally processed foods, especially fresh fruits and vegetables, would be helpful. At the societal level, public awareness campaigns, policy and regulation, or food availability and market changes to promote the reduction of HPFs could be beneficial. Our findings support ongoing efforts to develop nutritional guidelines and public health strategies aimed at reducing the prevalence of diet-related diseases.”

An international research team has discovered a new way to effectively treat cancer, by using nutrients to reactivate suppressed metabolic pathways in cancer cells.
The researchers used a common amino acid, tyrosine, packaged as a nanomedicine, to change the metabolism of melanoma, a deadly skin cancer, and prevent cancer growth.
Australia has the highest rate of skin cancer in the world. This new approach could be combined with current therapies to better treat melanoma. The technique also has the potential to treat other types of cancer.
The study, Nutrient-delivery and metabolism reactivation therapy for melanoma, was led by Professor Wenbo Bu from Fudan University and Professor Dayong Jin from the University of Technology Sydney, and recently published in the journal Nature Nanotechnology.
Tyrosine has limited bioavailability in living organisms. However, the researchers used a new nanotechnology technique to package it into tiny particles called nanomicelles, which are attracted to cancer cell membranes, and break down easily, boosting absorption.
The research team then tested the innovative treatment in mice and in human-derived melanoma cells in the lab and found that the tyrosine nanomicelles reactivated dormant metabolic pathways, triggered melanin synthesis, and inhibited tumour growth.
“Uncontrolled rapid growth is a key feature that distinguishes cancer cells from normal cells. In cancer cells some metabolic pathways are over-activated, and others are suppressed, to create the environment necessary for rapid spread,” said Professor Jin.

“While a few metabolism-based drugs for cancer have been developed previously, such as aromatase inhibitors impeding estrogen synthesis in breast cancer and HK2 inhibitors targeting glycolysis in various cancers, these work by suppressing over-activate metabolic pathways,” he said.
“Our research shows for the first time that cancer can be stopped by reactivating metabolic pathways that are dormant. And this can be done using simple nutrients, such as amino acids, sugars, and vitamins, which are safe, readily available and well tolerated,” said Professor Bu.
Different types of cancer will respond to different nutrients. Melanoma cells develop from melanocytes — skin cells that produce melanin. Tyrosine is needed to produce melanin and it can stimulate melanin production, hence its effectiveness with melanoma.
The reactivation of melanin synthesis forces the melanoma cell to reduce glycolysis, the process of converting sugar to energy, which is believed to be the mechanism for its anti-cancer effect.
Melanoma cells are also susceptible to heat stress. The researchers found that by combining tyrosine nanomicelle treatment with near-infrared laser treatment, they were able to eradicate melanoma in mice after six days and it did not reoccur during the study period.
The findings suggest a promising a new frontier in the use of nanomedicine for cancer therapy.

Researchers from the University of Helsinki and HUS investigated the effects of recurring mutations in the KLHL6 gene in diffuse large B-cell lymphoma, the most common cancer of the lymphatic system.
The KLHL6 protein is part of a cellular system tasked with disposing of excess and unnecessary proteins. In many cancers, this system is disrupted, which advances malignant growth.
The researchers found that the KLHL6 protein breaks down the B-cell receptor and demonstrated that certain mutations lead to an increase in the number of these receptors.
“The B-cell receptor is an antibody on the surface of B-lymphocytes and a tool with which normal cells identify pathogens and fight against them. In corrupted cells, the B-cell receptor is activated in an anomalous manner, resulting in tissue growth and the development of lymphoma,” says Doctoral Researcher Leo Meriranta, MD, from the University of Helsinki.
Absence of KLHL6 protein predicts poor treatment outcomes
In some of the cancer patients enrolled in the study, the KLHL6 protein was entirely absent from cells. Laboratory modelling revealed that the loss of KLHL6 in lymphoma cells increased the number of B-cell receptors manifold.
Professor of Oncology Sirpa Leppä, who heads the research group, emphasises the clinical significance of KLHL6.

“The lymphoma cases where the KLHL6 protein was absent were associated with a poor prognosis. The identification of pathogenic mechanisms relevant to these patients is particularly important for improving their prognoses through drug development,” Leppä says.
Importance of therapy tailoring increasing
A British-American research group also reported similar findings simultaneously with the researchers from the University of Helsinki and HUS.
“The similar results obtained with different study designs are a solid indication that KLHL6 protein disruption plays a key role in some B-cell diseases,” Meriranta says.
He emphasises that, in the future, treatment outcomes can be improved by targeting therapies on the basis of cancer biomarkers.
“The new findings open avenues to tailoring therapies, as the abnormal amount and activity of the B-cell receptor can be targeted pharmacologically. However, more research is still needed,” Meriranta notes.
Diffuse large B-cell lymphoma Every year, roughly 700 people in Finland develop diffuse large B-cell lymphoma. The most common symptom is enlarged lymph nodes. The disease is treated with immunochemotherapy, a combination of antibodies and cytostatic drugs. In roughly one-third of the patients, the cancer is not cured and can be fatal.

Swedish researchers have surveyed all people under the age of 25 who have had cancer since 1958. The study, led by researchers at Linköping University and Region Östergötland, shows that cancer survivors are at greater risk for cardiovascular diseases, other cancers and other diagnoses later in life. In addition, the researchers saw that socioeconomic factors played a role in survival.
Since 1958, Sweden has registered all cancer patients in the National Cancer Register. Swedish researchers have now used this register to study all cancer survivors who had cancer as a child, adolescent or adult to examine outcomes in later life. The results have been published in the scientific journal The Lancet Regional Health — Europe.
“If you’ve had cancer as a child or adolescent, you have an increased risk of almost all diagnoses in the future. This study lays the foundation for understanding why this is so and what decision-makers need to take into account when it comes to cancer care,” says Laila Hübbert, researcher at Linköping University and consultant at the Cardiology Clinic at Vrinnevi Hospital in Norrköping.
The study’s data spans 63 years. From this data, approximately 65,000 cancer patients under the age of 25 were compared with a control group of 313,000 individuals (a ratio of 1:5), where age, sex and housing situation were matched with the patient group. From other registers, the researchers retrieved information on morbidity, mortality and demography.
The researchers found that the cancer survivors were about three times more likely to develop cancer later in life, 1.23 times more likely to have cardiovascular disease and had a 1.41 times higher risk of accidents, poisoning and suicide.
At present, the healthcare system usually follows up cancer survivors five years after the end of treatment. In other words, you are usually considered healthy if the cancer has not returned after five years, and no further follow-up is planned. But the current study, and also previous ones, show that this is probably not enough.
“Cancer survivors carry with them a fragility for the rest of their lives that puts them at higher risk of new diseases. It’s mainly the chemotherapy and radiation treatment that increases the risk of cardiovascular disease. This means that patients shouldn’t be released prematurely without planned and ongoing follow-up. It’s important to identify these risk factors and diseases early,” says Laila Hübbert.

The researchers have also seen that socioeconomic factors play a major role in the risk of disease and death after cancer in young years. Thanks to a cross-check of registers, the researchers were able to see that the risk increases for those with a lower level of education, a foreign background, or who remain unmarried. At the same time, this study shows that the risk of disease and death after cancer in children and adolescents is the same regardless of where you live in Sweden.
Martin Singull is a professor of mathematical statistics and has worked closely with the clinics in order to analyse and combine the large amounts of data that come from many different sources.
“We have used proven statistical models. But it’s the complexity of the data that makes it challenging. It comes from different sources, and we also want to be able to pick out the information we want. That’s why we’ve also collaborated with computer scientist Robin Keskisärkkä, who has built the database,” says Martin Singull.
The next step for the researchers is to break down the results and probe into specific questions and understand why things look the way they do. This will include looking more at socioeconomic factors, cardiovascular disease linked to cancer, so-called cardio-oncology, and other forms of cancer.
“There aren’t really many countries that can carry out such a comprehensive survey. In Sweden, we have such fine comprehensive and high-quality national registers so it’s unique to be able to do this,” says Laila Hübbert.

In a study with 991 adults, scientists at DZNE show that the most common forms of frontotemporal dementia (FTD) as well as the neurological diseases amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP) can be recognised by blood testing. Their procedure is not yet ready for routine medical use, but in the long term it could facilitate disease diagnosis and advance the development of new therapies already now. The findings published in the journal “Nature Medicine” are based on the measurement of certain proteinsin the blood, which serve as biomarkers. The study also involved the University Hospital Bonn (UKB) and other research institutions in Germany and Spain.
FTD, ALS and PSP form a spectrum of neurodegenerative diseases with overlapping symptoms characterised by dementia, behavioral symptoms, paralysis and muscle wasting, movement impairment and other serious impairments. In Germany, it is estimated that up to 60,000 people are affected by one of these diseases. Although they are relatively rare, their consequences for health are nevertheless severe. “As yet, there is no cure for any of these diseases. And, with current methods, it is not possible to reach a conclusive diagnosis of the molecular pathology of these diseases during a patient’s lifetime, since brain tissue must be examined,” explains Prof. Anja Schneider, a research group leader at DZNE and Director of the Department of Old Age Psychiatry and Cognitive Disorders at UKB.
Diagnostic markers
“However, a diagnosis of the underlying pathology is required for the development of therapies and for stratifying patients according to their disease. Only such stratification allows targeted and therefore potentially effective disease-modifying treatments to be tested,” continues Schneider, who is also affiliated with the University of Bonn. “We now show that PSP, behavioral variant of FTD and the vast majority of ALS cases with the exception of a particular mutation can be recognised by blood testing and this also applies to their underlying pathology. Our study is the first to find pathology specific biomarkers. Initially, application is likely to be in research and therapy development. But in the long term, I consider it realistic that these biomarkers will also be used for diagnosis in medical routine. However, further studies are required for this. In fact, it would be particularly important to determine how these biomarkers develop longitudinally, that is, over the course of a disease, and how early they rise in the disease course.”
Detection of proteins
The new blood test, which is based on the measurement of so-called tau and TDP-43 proteins, could provide decisive evidence for diagnosis. There is a particularly strong need for the “behavioural variant of FTD” which was investigated here. This is because the symptoms of this most common type of FTD can be due to two different pathologies — i.e. abnormal processes — in the brain, which can generally only be differentiated by analysing tissue after death. Only in those few cases where the disease is genetic can DNA analysis provide certainty during a patient’s lifetime. The blood test now enables a precise diagnosis to be made during a patient’s lifetime, even if there is no mutation. This, in turn, is a prerequisite for testing new therapies against these various FTD pathologies in clinical trials.
Abnormal aggregates
“It is well known that tau and TDP-43 proteins play key roles in FTD, ALS and PSP, as they form abnormal aggregates in the brain in these diseases. The events differ between the diseases, however. Our investigations suggest that blood levels of the proteins reflect these disease processes,” says Schneider. “We have found that the combination of both markers is required for the diagnosis of behavioural FTD, respectively its subtypes, whereas TDP-43 is sufficient for ALS and the tau protein for PSP. However, for the tau marker, we are actually looking at two specific variants, so called isoforms, of the tau protein.”

Tiny bubbles of lipids
The method employs a special twist: This is because the proteins are not measured directly in the blood plasma. Such measurements turned out to be inconclusive, especially because tau proteins free-floating in blood are usually fragmented. Instead, Schneider and colleagues determined the levels of two forms of tau proteins and those of TDP-43 proteins found inside so-called vesicles. These are tiny bubbles of lipids that are secreted by cells of the body and that can ultimately enter the bloodstream. Through multi-stage preparation, which included centrifugation of the blood samples, the researchers were able to capture the proteins contained in vesicles.
Collaborative research
The results are based on data and blood samples from study collectives in Germany and Spain with a total of 991 adults. They were affected by FTD, ALS, PSP or belonged to a control group with healthy individuals. This situation with independent groups of volunteers allowed the findings to be extensively validated. On the one hand, this involved the so-called DESCRIBE cohorts: As part of these research initiatives, DZNE, along with several German university hospitals, is compiling data and biosamples from people with neurodegenerative diseases. This ensemble comprised more than 700 patients. From the Spanish side, the “Sant Pau” cohort, which is run by the “Hospital de la Santa Creu i Sant Pau” in Barcelona, joined the project with over 200 participants. “With these relatively rare diseases, you have to work across sites and institutes in order to be able to include as many study participants as possible and thus reach statistically robust results,” explains Schneider. “Such undertakings are an integral part of the strategy of DZNE, for which we have established structures and procedures over the years. This is complex to do, but it pays off. Our study is a good example of collaboration in medical research — within Germany and beyond.”

Within each of our cells, long strands of DNA are folded into chromosomes and capped with protective structures called telomeres. But telomeres shorten as we age, eventually getting so whittled down that our chromosomes become exposed, and our cells die. However, the specifics of when and how this shortening occurs and whether certain chromosomes are more affected than others have been unclear — until now.
Scientists at the Salk Institute have developed a groundbreaking tool called Telo-seq, designed to revolutionize the study of telomeres in aging and disease. Compared to existing methods, which struggle to sequence whole telomeres and can only measure their average length across all chromosomes, the new technique allows researchers to determine the entire sequence and precise length of telomeres on each individual chromosome.
The researchers are already using Telo-seq to reveal novel telomere dynamics in human health and disease with unprecedented resolution. The findings, published in Nature Communications on June 18, 2024, will inspire a flurry of new studies and telomere-targeting therapeutics to treat age-related diseases.
“Previous methods for measuring telomere length were low resolution and rather inaccurate,” says the study’s senior author Jan Karlseder, professore, chief science officer, and Donald and Darlene Shiley Chair for Research on Aging at Salk. “We could hypothesize about how individual telomeres might play a role in aging and cancer, but it was simply impossible to test those hypotheses. Now we can.”
Karlseder and colleagues collaborated closely with experts at Oxford Nanopore Technologies to combine aspects of their long-read sequencing technique with novel biochemistry and bioinformatics approaches. The resulting method starts at the end of each telomere and sequences well into the subtelomere region. This allows the scientists to identify which chromosome they are looking at and examine its telomere structure and composition in detail.
Using this technique, the researchers have described numerous features of telomere biology that had not been accessible to scientists before. So far, they’ve observed that within individual human samples, each chromosome arm can have different telomere lengths, and these telomeres can vary significantly in their shortening rates. These dynamics vary in different tissues and cell types within the same person, likely for many reasons including the amount of stress and inflammation affecting different parts of the body. Altogether, this suggests that there are potential chromosome arm-specific factors influencing telomere dynamics in aging and disease.
“Aging is an incredibly heterogeneous process that affects everyone differently,” says Karlseder. “We are very interested in whether differences in aging are related to different telomere shortening rates between people or chromosomes, and how we might be able to slow this down to promote healthy aging.”
Telo-seq can also improve our understanding of telomere-driven diseases. Many telomeropathies involve stem cells that run out of telomere length and lose their ability to divide into new, functional cells. This can lead to hair loss, immune disorders, or certain cancers. Telo-seq will allow scientists to investigate whether these diseases are inherited within families or associated with individual chromosomes, in order to develop more targeted interventions.

While telomere shortening can have devastating effects on a cell’s lifespan, the opposite scenario can be equally damaging. When telomere repair mechanisms are overactivated, cells can enter an “immortal” state and divide indefinitely, leading to cancer.
To repair a damaged telomere, cells can either use the telomerase enzyme or another mechanism known as the alternative lengthening of telomeres (ALT). The length and composition of the telomeres will differ depending on which maintenance mechanism was used but, until now, there was no efficient way for scientists or clinicians to measure this.
“With Telo-seq, we can quickly determine whether a cancer is telomerase-positive or ALT-positive,” says first author Tobias Schmidt, a postdoctoral researcher in Karlseder’s lab. “This is critical because ALT-positive cancers are often more aggressive and require different treatment approaches than telomerase-positive cancers. In this sense, Telo-seq could be used as a quick and reliable diagnostic tool to identify cancer types and guide more personalized treatment plans.”
Beyond its many immediate clinical applications, Karlseder and Schmidt say Telo-seq’s greatest impact will be in igniting a new era of telomere research.
“Telo-seq will allow us to answer questions about development, aging, stem cells, and cancer that we simply couldn’t address with previous tools,” says Karsleder. “We don’t even know what we’ve been missing, and I think the things we’re starting to learn now are really just the tip of the iceberg. It’s a very exciting time for telomere science.”
Other authors include Candy Haggblom, Jeffrey R. Jones, and Fred H. Gage of Salk, Kelly A. Frazer of UC San Diego, and Carly Tyer, Preeyesh Rughan, Xiaoguang Dai, Sissel Juul, and Scott Hickey of Oxford Nanopore Technologies, Inc.
This work was supported by the National Institute of Aging (P30AG068635, AG0773424), the National Cancer Institute (CA227934, CA234047, P30CA014195), the National Institute for General Medicine (GM142173), the Helmsley Charitable Trust, the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego (AG062429), the European Molecular Biology Organization (ALTF 668-2019), the JBP Foundation (#2021-2961), the Paul F. Glenn Center for Biology of Aging Research at Salk Institute, and an AHA-Allen Initiative in Brain Health and Cognitive Impairment award made jointly through the American Heart Association and The Paul G. Allen Frontiers Group (19PABH134610000).

Sepsis patients could be treated based on their immune system’s response to infection, not their symptoms.
New research uncovers how different people respond to sepsis based on their genetic makeup, which could help identify who would benefit from certain treatments and lead to the development of targeted therapies.
The team, from the Wellcome Sanger Institute, the University of Oxford, and collaborators, built on their previous work that identified different subgroups of patients with sepsis. They aimed to understand more about why sepsis response varies between patients and the different underlying immune response pathways.
The new study, published today (18 June) in Cell Genomics, details the genetic basis of variability in sepsis response, and the different regulators and cell types involved in the different immune responses in each subgroup of patients.
Having a more detailed understanding of sepsis at a molecular level could identify those who would benefit from different therapies, helping to design rapid tests, organise clinical trials, and develop targeted treatments based on the individual immune response.
The ultimate aim is for patients to receive the most effective treatment for their sepsis more quickly, based on their immune response rather than their symptoms. In the future, this approach to personalised medicine could also be applied to other less severe infections, not just sepsis.
Sepsis causes an estimated 11 million deaths worldwide per year, with one death every three seconds. In the UK alone, at least 245,000 people are affected by sepsis, and 48,000 people die each year.1
Sepsis arises when the body has an extreme response to an infection and injures its own tissues and organs. Sepsis can cause different downstream immune responses in different people. Depending on this immune response, the treatment varies. However, it is difficult to identify which response is happening based on symptoms alone. Sepsis can progress quickly, and if the wrong treatment is given, valuable time could be lost.

Previously, researchers from the Wellcome Sanger Institute, the University of Oxford and collaborators, identified how expression of a small set of genes allowed them to categorise who was most at risk from poorer outcomes from sepsis and COVID-192.
Building on their previous work, in this new study the team investigated the impact of genetic variants that regulate gene expression, known as expression quantitative trait locus, or eQTLs. This provides insight into how an individual’s genetic makeup could influence the way they respond to sepsis. This information can help classify who would benefit from targeted therapies, which act on the immune system in different ways.
The team analysed data from the UK Genomic Advances in Sepsis (GAinS) study that contained 1,400 patients with sepsis due to community-acquired pneumonia and faecal peritonitis3 from intensive care units across the UK.
They found that genetic variation in groups of patients is associated with differences in immune response during sepsis. They then used this to identify key genetic regulators in each group, helping to describe what biological networks, cells, and mechanisms are involved in each response.
Understanding the regulatory networks underlying the different patient responses provides additional information for developing treatments that work with the immune system and are a step towards a personalised medicine approach to treating sepsis.
In related research, rapid tests that identify different subtypes of sepsis are also being developed by Dr Julian Knight at the University of Oxford4. These aim to quickly show those who would benefit from targeted treatments.

The next steps would be to further investigate the immune response to find targeted treatments for each immune response or different stages of the immune response.
Dr Katie Burnham, first author from the Wellcome Sanger Institute, said: “Our study is the next step towards being able to treat sepsis based on someone’s genetics and their particular immune response, instead of their symptoms, which can vary greatly from person to person. Our research found two groups of people, with opposite immune responses, and identified the genetic regulators involved. Being able to molecularly categorise patients with sepsis allows clinicians to correctly identify who could benefit from the available treatments and gives new direction to those developing targeted therapies.”
Dr Julian Knight, co-senior author from the University of Oxford, said: “Understanding who is at greater risk from sepsis and how they respond to the disease is a huge task. Research such as this, that dives deeper into the molecular basis of the disease, aids in the ongoing development of tests that could identify different subtypes of sepsis and allow medical professionals to treat this straight away. Our research can be directly translated into the clinic and we hope that it allows us to start to develop an efficient, targeted approach to treating this life-threatening disease.”
Dr Emma Davenport, co-senior author from the Wellcome Sanger Institute, said: “Sepsis is a complicated and devastating disease that impacts millions of people around the world each year. Understanding the molecular processes that happen during sepsis, and how genetics plays a role in this, can help give answers to long-standing questions, improve patient outcomes, and allow for the development of effective clinical trials that lead to new targeted treatments as quickly as possible.”

Osteoporosis is a skeletal condition that leads to the weakening of bones, making them porous, fragile, and prone to breakage. A whopping 8.9 million fractures are caused by osteoporosis annually, with one fracture occurring every three seconds! The aging population is the most vulnerable to primary osteoporosis, given, their frailty, and often, requires long-term therapy and support. Advances in healthcare and the corresponding rise in the aging population have put a strain on available resources, underscoring the need for effective therapies against osteoporosis.
Induction of parathyroid hormone (PTH) signaling using the PTH-derived peptide — teriparatide, has demonstrated strong bone-promoting effects in patients with osteoporosis. These effects are mediated by osteogenesis, the process of bone formation involving the differentiation and maturation of bone-forming cells called osteoblasts. However, PTH induction is also associated with the differentiation of macrophages into osteoclasts, which are specialized cells responsible for bone resorption. Although, bone remodeling by osteoblasts and osteoclasts is crucial for maintaining skeletal health, PTH-induced osteoclast differentiation can decrease treatment efficacy in patients with osteoporosis. However, precise molecular mechanisms underlying the dual action of PTH signaling in bone remodeling are not well understood.
To bridge this gap, Professor Tadayoshi Hayata and Ms. Chisato Sampei, from Tokyo University of Science, along with their colleagues, conducted a series of experiments to identify druggable target genes downstream of PTH signaling in osteoblasts. Explaining the rationale behind their study published on 20 May, 2024, in the Journal of Cellular Physiology, corresponding author, Prof. Hayata says, “In Japan, it is estimated that 12.8 million people, or one in ten people, suffer from osteoporosis, which can significantly deteriorate their quality of life. Teriparatide is classified as a drug that promotes bone formation, but it also promotes bone resorption, which may limit bone formation. However, the full scope of its pharmacological action remains unknown.”
The researchers treated cultured mouse osteoblast cells and mice with teriparatide. They then assessed gene expression changes induced by PTH in both the cultured cells and bone cells isolated from the femurs of the treated animals, using advanced RNA-sequencing analysis. Among several upregulated genes, they identified a novel PTH-induced gene — ‘Gprc5a’, encoding an orphan G protein-coupled receptor, which has been previously explored as a therapeutic target. However, its precise role in osteoblast differentiation had not been fully understood.
PTH induction has been known to activate the cyclic adenosine monophosphate (cAMP) and protein kinase C (PKC) signaling pathways. Interestingly, the team found that in addition to PTH induction, activation of cAMP and PKC also resulted in overexpression of Gprc5a, albeit to a lesser extent, underscoring the potential involvement of other molecular pathways. Notably, upregulation of Gprc5a was suppressed upon inhibition of transcription, but, remained unaffected upon suppressing protein synthesis, suggesting that Gprc5a could be transcribed early on in response to PTH signaling and serves as a direct target gene.
Furthermore, the researchers examined the effect of Gprc5a downregulation on osteoblast proliferation and differentiation. Notably, while PTH induction alone did not affect cell proliferation, Gprc5a knockdown resulted in an increase in the expression of cell-cycle-related genes and osteoblast differentiation markers. These findings suggest that Gprc5a suppresses osteoblast proliferation and differentiation.
Diving deeper into the molecular mechanisms underlying the effects of Gprc5a, in PTH-induced osteogenesis, the researchers identified Activin receptor-like kinase 3 (ALK3) — a bone morphogenetic protein (BMP) signaling pathway receptor, as an interacting partner of Gprc5a. In line with their speculation, overexpression of Gprc5a indeed, led to suppression of BMP signaling via receptors including ALK3.
Overall, these findings reveal that Gprc5a — a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation, by partially suppressing BMP signaling. Gprc5a can thus, be pursued as a novel therapeutic target while devising treatments against osteoporosis. The study sheds light on the complex process of bone remodeling and explains the bone-promoting and bone-resorbing effects of PTH signaling.
“Our study shows Gprc5a may function as a negative feedback factor for the bone formation promoting effect of teriparatide. Suppressing Gprc5a function may, therefore, increase the effectiveness of teriparatide in non-responding patients. In the future, we hope that our research will lead to improved quality of life and healthy longevity for people suffering from osteoporosis,” concludes Prof. Hayata.
We too hope that these findings pave the way for the development of effective therapies that can improve the lives of people living with osteoporosis.

The over-the-counter supplement nicotinamide riboside, a form of vitamin B3, increased the walking endurance of patients with peripheral artery disease, a chronic leg condition for which there are few effective treatments.
In a preliminary, randomized, double-blind clinical trial led by Northwestern University and University of Florida scientists, patients who took nicotinamide riboside daily for six months increased their timed walking distance by more than 57 feet, compared to participants who took a placebo. As expected, walking speed declined in those who took a placebo, because peripheral artery disease causes progressive declines in walking performance.
“This is a signal that nicotinamide riboside could help these patients,” said Christiaan Leeuwenburgh, Ph.D., a UF professor of physiology and aging and senior author of the clinical trial report. “We are hoping to conduct a larger follow-up trial to verify our findings.”
Leeuwenburgh, whose research specializes in anti-aging treatments, collaborated with Mary M. McDermott, M.D., a physician and professor of medicine at Northwestern University and an expert in peripheral artery disease. With a large team of collaborators, Leeuwenburgh and McDermott published their findings June 13 in the journal Nature Communications.
The scientists recruited 90 people with an average age of 71 who had peripheral artery disease, or PAD, to test the effects of nicotinamide riboside. The supplement is increasingly popular as an anti-aging treatment — sales exceeded $60 million in 2022 in the U.S. alone — but there has been scant evidence of any benefit in healthy people. Nicotinamide riboside is a precursor for the essential compound NAD, which plays roles in the body related to energy generation, improved blood flow and DNA repair.
Because PAD is associated with problems generating energy within muscle cells, McDermott and Leeuwenburgh thought that nicotinamide riboside, by improving energy generation, could help improve walking in people with the disease.
And indeed that’s what they found. Participants taking the supplement walked an average of 23 feet more in a six-minute walking test after six months, while those taking a placebo walked 34 feet less. Those who took at least 75% of the pills they were supposed to take performed even better, adding more than 100 feet to their walking distance, compared to people who took a placebo.

(The researchers also tested if resveratrol, a compound best known for being in red wine, could boost the effects of nicotinamide riboside; they found no additional benefits.)
PAD affects more than 8.5 million Americans over the age of 40. Caused by the buildup of fatty deposits in arteries, and associated with diabetes and smoking, the disease reduces blood flow to the limbs, especially the legs. Walking often becomes painful, and the disease typically causes declines in walking ability over time. Supervised walking exercise is first line therapy for PAD, but most people with the condition do not have access to supervised exercise.
In addition to a larger trial focused on patients suffering from PAD, Leeuwenburgh hopes to test the effects of nicotinamide riboside on walking performance in healthy older adults.
“We need to test it on a healthy older population before we recommend healthy people take it,” he said.