Publisher Health

Cutting-edge imaging sheds new light on cells that break down bone Imaging technology developed at Garvan shows that bone-resorbing osteoclasts gather in distinct pockets, leading to new insights for osteoporosis and cancer treatment.
Bone may seem as if it’s a hard, lifeless structure, but now the cells living within have been imaged in unprecedented detail, thanks to an innovative imaging method developed at the Garvan Institute of Medical Research.
The new method lets researchers study cells inside the bones of mice, to visualise not just isolated sections, but the entire length of a bone. With a new level of visual detail, the researchers discovered that osteoclasts, cells that break down bone tissue, are more active in some parts of the bone compared to others. This knowledge could be used to develop new treatments for osteoporosis, and for dormant cancer cells, which can stay hidden in bone for years until they are reactivated by osteoclasts.
“Our method has given us an unprecedented window into how cells go about breaking down bone, giving us a new way to investigate osteoporosis and cancer relapse in bone,” says Professor Tri Phan, Head of the Intravital Microscopy Lab and Gene Expression (IMAGE) Lab, immunologist at St Vincent’s Hospital Sydney, Co-Director of the Precision Immunology Program at Garvan and senior author of the paper, published in Nature Protocols.
“We can finally image processes inside bone that we thought were happening, but which were until now beyond the limits of conventional microscopy techniques. We are only beginning to understand the implications of this exciting technology.”
Giving disease-causing cells no place to hide
Osteoclasts are crucial to the normal maintenance and repair processes of bone, but when they are overly active, they can cause excessive breakdown, known as osteoporosis.

A new study helps to identify children who are at the highest risk of a severe respiratory syncytial virus (RSV) infection and who would thus benefit most from new RSV prevention measures.
A registry study covering all Finnish and Swedish children and their family members identified 16 major risk factors for a severe RSV infection. The researchers created a clinical prediction model to predict the risk of hospitalisation from an RSV infection and showed that the model performed well in both countries.
This very large study on risk factors for a severe RSV infection, led by researchers from the University of Helsinki and Helsinki University Hospital, was recently published in the journal Lancet Digital Health.
The study confirmed that the risk for a severe RSV infection is highest at less than six months of age, and that the risk increases if the infant is born premature, has certain congenital conditions and young siblings. The new prognostic factors identified include esophageal malformations and a less severe congenital heart disease.
In recent years, both a long-acting antibody that protects against an RSV infection and a vaccine given to mothers during pregnancy have been developed to prevent RSV infections. When targeted properly, such drugs can prevent a large number of complications in young children and decrease the number of hospital and intensive care stays, but it is not yet clear how widely these approaches should be used.
“It may not be possible to offer these new preventive measures to all children. Our research helps to identify the children who need them most, both at the individual level and in the population,” says the lead author of the study, Pekka Vartiainen, a Postdoctoral Researcher from the Institute for Molecular Medicine Finland FIMM, University of Helsinki, and a MD specialising in paediatrics at HUS.
The disease burden of RSV infections is high
RSV is a common virus that causes respiratory infections, but it can be dangerous, especially for the infants. The disease burden of RSV epidemics is high all over the world. Globally, over 100,000 children die each year because of RSV infections.

According to a Finnish study, surface treatment and moisture affect the antibacterial properties of wood. Based on the findings, treated wood should be increasingly used as surface material.
Research indicates that several pathogenic bacteria can remain contagious on a range of surfaces from hours to days and weeks. While wood as a surface material is known for its antibacterial properties, dry contamination via hands has so far been poorly understood, as most prior research has involved adding bacteria in liquid droplets to materials.
Researchers from the University of Helsinki, Natural Resources Institute Finland (Luke) and the University of Eastern Finland investigated the effects of surface treatment on the antibacterial activity of wood. In addition, they examined the antibacterial properties of 18 different surface materials commonly used indoors. These surfaces were exposed to bacteria that in real life are transmitted by dry hands, after which bacteria quantities were investigated in the laboratory.
“The least bacterial growth was observed on the surfaces of smooth materials, such as tile, laminate, vinyl cork and lacquer-coated wood. On untreated and, consequently, porous wooden surfaces, there was slightly more growth. However, variation was seen between different tree species: the lowest number of bacterial colonies was recorded on white oak and black walnut. The study encompassed commercial tree species from Finland, the United States and Japan,” says Associate Professor Tuula Jyske from the University of Helsinki.
In addition, the study focused on the viability of the bacteria Staphylococcus epidermidis and Bacillus aerius/licheniformis, found commonly on the skin, on a range of materials. Staphylococcus epidermidis causes staphylococcus infections. In the study, B. aerius/licheniformis represented a bacterial strain producing dormant spores, which was expected to retain viability on surfaces better than sporeless bacteria. The tests were carried out in a controlled manner in an exposure chamber following the application of bacterial aerosols.
The experiments demonstrated that the viability of S. epidermidis, which occurs on the skin, was reduced on almost all of the surfaces studied. Untreated oak had the most negative effect on the viability of the bacteria; in contrast, the number of B. aerius/licheniformis colonies remained the same in most materials.
The study shows that the manifestation of the antibacterial properties of wood depends in many ways on the quality and conditions of the contamination.
“In moist conditions, the structure of porous wooden has the capacity to dry out bacteria, while in dry conditions bacteria are able to spread via hands more effectively to porous surfaces than to non-porous surfaces. In both cases, the chemical constituents of wood significantly limit bacterial growth,” Jyske says.
Based on the findings that bacterial contamination via dry hands prevailed less than expected, treated wood should increasingly be used as surface material. The desired hygienic properties of wooden surfaces can be influenced by surface treatment and by favouring certain tree species.
“We will certainly see more pandemics down the line, which makes preventing contamination via surfaces important. And lacquer-coated wood still looks like wood, which is why its restorative effects related to wellbeing remain unchanged,” Jyske notes.

Inflammatory bowel diseases (IBDs), such as Crohn’s disease or ulcerative colitis, arise when there is a dysregulation of the cell signalling pathways controlling the maintenance of homeostasis in the gut, leading to a chronic inflammatory response.
Researchers from the Cusack group have provided insights into the interactions of two molecules — XIAP and RIPK2 — involved in these signalling pathways.
Signalling pathways in the gut: a delicate balance
Inflammation is a useful immune response to the constant exposure of cells to stressors such as pathogens. However, too much signalling leads to an undesirable amount of inflammation, which, in consequence, affects the organism’s normal functioning.
The gut inflammatory response involves a complex machinery that gives rise to a chain reaction involving several molecules. NOD1 and NOD2 are receptors in charge of identifying the bacterial fragments that we are exposed to. When they recognise these fragments, they start the ‘fight back’ response by activating the RIPK2 kinase.
This kinase then ‘recruits’ another molecule, called XIAP, which reacts by attaching a specific chain of amino acids (the ubiquitin chain) to RIPK2. This reaction is necessary for the recruitment of more proteins to trigger the inflammatory response.
“This signaling pathway keeps under control the bacteria in your gut. It’s very finely balanced because you don’t want to kill all the bacteria but you don’t want them to grow too much either,” said Stephen Cusack, co-corresponding author of the publication. “Inflammatory bowel diseases tend to arise when there is a dysregulation of this NOD2 signalling and of the whole downstream chain reaction.”
One way to treat these diseases is, therefore, to target proteins in the signalling pathway to keep things under control. Erika Pellegrini, former EMBL staff researcher in the Cusack group and co-corresponding author, has worked on such targets since 2013. “When I started my project on RIPK2, it was clear that this kinase was a good target for IBDs because it is only involved in the NOD1/NOD2 signalling pathways,” explained Pellegrini. “A drug targeting this kinase would block this signalling pathway without affecting other cellular processes.”

An international study led by the University of Granada has identified for the first time the optimal number of steps at which most people obtain the greatest benefits, and also shows that the pace at which you walk provides additional benefits.
The idea that you should take 10,000 steps a day originated in Japan in the 1960s, but had no scientific basis. Researchers have now shown that, if we focus on the risk of dying from cardiovascular disease, most of the benefits are seen at around 7,000 steps.
An international study led by the University of Granada (UGR) has provided the first scientific proof for how many steps you need to take per day to significantly reduce the risk of premature death: 8,000. Given the average length of a human stride (76 centimetres for men and 67 centimetres for women), taking 8,000 steps is equivalent to walking approximately 6.4 kilometres a day.
Researchers have also shown that the pace at which we walk has additional benefits, and that it is better to walk fast than slow. With regard to the risk of dying from cardiovascular disease, most of the benefits are seen at around 7,000 steps.
The study, published this week in one of the world’s leading cardiology journals (Journal of the American College of Cardiology), identifies for the first time the optimal number of steps at which most people obtain the greatest benefits, and also shows that the pace at which you walk provides additional benefits.
The research was carried out in collaboration between researchers from the Netherlands (Radboud University Medical Center), Spain (Universities of Granada and Castilla-La Mancha) and the United States (Iowa State University).
“Traditionally, many people thought that you had to reach about 10,000 steps a day to obtain health benefits — an idea that came out of Japan in the 1960s but had no basis in science,” explains the lead author of the study, Francisco B. Ortega, a professor at the UGR’s Department of Physical Education and Sports.

Special proteins — known as membrane transporters — are of key importance for the mobility of sperm cells. A research team from the Heidelberg University Biochemistry Center (BZH) headed by Prof. Dr Cristina Paulino has, with the aid of cryo-electron microscopy, for the first time succeeded in decoding the structure of such a transporter and its mechanism. According to the researchers, these findings will enable a better understanding of the molecular foundations of reproductive capacity and could, in the long term, contribute to developing new approaches to treating fertility disorders and new methods of specific contraception.
Sperm cells differ fundamentally in structure and function from other cell types. After all, their only task is to track down and fuse with the egg. Sperm cells only achieve their full activity in what is called capacitation, which means the maturing of the cells in the semen. One of the final steps of this biochemical process involves increasing the sperm’s mobility. If the cells are not able to move autonomously, or only to a limited extent, the result is generally reduced fertility or a complete lack of reproductive capacity. The sperm cells cannot reach and fertilise the egg cell.
Within this final maturation process, special proteins found in the sperm membrane have a particular role. Known as membrane transporters, they are responsible for transporting nutrients, for instance, into or out of the cell. “Transporting certain ions into the cell leads to a rise in sperm mobility. For that reason, the proteins responsible for the transport are directly linked to the fertility of a sperm and thereby with the male capacity for reproduction,” Prof. Paulino underlines. Her research group at the BZH is working on the membrane transporters of sea urchins, a model system for investigating sperm.
With the assistance of cryo-electron microscopy, the scientists have now been able to decode the structure of an important sperm membrane transporter at the molecular level. Amongst other things, they discovered what its functional units look like, and how they interconnect and interact. “We have observed that the key protein is, like a lego toy, constructed from different building units. These building blocks are basically known from other proteins, but have never been observed in such a combination. With the aid of this information, we were able to decode the mechanism of this transporter for the first time,” explains Dr Valeria Kalienkova from the University of Bergen (Norway), a former member in Prof. Paulino’s research group.
According to Dr Martin Peter, a member of Prof. Paulino’s research team, these new findings will be helpful in the next step, developing potential substances that influence this mechanism. They may make it possible to activate or deactivate the functions of the proteins. The extent to which these findings can be transferred to the mechanisms of human sperm will call for further investigation. In the long term, they contain potential for finding new ways of treating infertility, or vice versa, of preventing the sperm from fertilising the egg cell.
The results of the research studies have appeared in the journal Nature. Due to the research group moving from the Netherlands to Germany, the studies were carried out both at the University of Groningen (Netherlands) and at the Heidelberg University Biochemistry Center. They were funded by the Dutch Research Council, and the Swiss National Science Foundation.

A new tool to rapidly grow cancer-killing white blood cells could advance the availability of immunotherapy, a promising therapy which harnesses the power of the body’s immune response to target cancer cells.
Washington State University researchers have developed a minifridge-sized bioreactor that is able to manufacture the cells, called T cells, at 95% of the maximum growth rate — about 30% faster than current technologies. The researchers report on their work in the journal Biotechnology Progress. They developed it using T cells from cattle, developed by co-author Bill Davis of WSU’s Veterinary College, and anticipate it will perform similarly on human cells.
In 2022, there were over 1,400 different types of therapies using T cells in development, with seven approved by the FDA for a variety of cancer treatments. Use of the therapy, called chimeric antigen receptor T cell (CAR-T), is limited, however, because of the cost and time needed to grow T cells. Each infusion treatment for a cancer patient requires up to 250 million cells.
“The manufacturing demand for this growing number of therapies is not being met, so there is a gap that needs to be filled in terms of biomanufacturing solutions,” said first author Kitana Kaiphanliam, a postdoctoral researcher in WSU’s Gene and Linda Voiland School of Chemical Engineering and Bioengineering. “At the end of the day, they need to be upscaled, so they can be used by more people.”
The bioreactor uses centrifugal force to act on the growing cells while they are suspended as a dense, cloud and continuously bathed by the inward flow of medium containing nutrients. The prototype comes out of four decades of research on designing a centrifugal bioreactor to rapidly densify and expand cells, led by Chemical Engineering Professor Bernie Van Wie, Kaiphanliam’s advisor and a co-author on the paper.
The most recent prototype is also self-contained within a sterile cabinet.
“It acts like a biosafety cabinet. It can be used in circumstances where clean manufacturing facilities are not available or easily accessible, so it can democratize these cell-based therapies,” said Kaiphanliam.
The researchers are working to improve the bioreactor. They hope to add multiple chambers and expect that they’ll eventually be able to produce enough cells in three days for three doses of a therapy. They also plan to start testing with human T cells and have begun communicating with cancer researchers on beta testing at Fred Hutchinson Cancer Center. Kaiphanliam and co-author Brenden Fraser-Hevlin have also started a company, Ananta Technologies Inc., with the idea of eventually producing and marketing the technology.
“I recognized the potential that this bioreactor could have on cell-based therapies and manufacturing for these therapies, and I didn’t want to see it stuck in an academic laboratory,” said Kaiphanliam. “I really hope having novel technologies to help with manufacturing reduces that financial barrier for these life-saving therapies.”
The work was predominately funded by a National Science Foundation Early-Concept Grant for Exploratory Research (EAGER) award. Additional support came from the WSU Office of Commercialization’s Gap Fund, the Palouse Club Cougar Cage pitch competition and the Washington Research Foundation. To protect the associated intellectual property and further enhance the commercial value of this technology, the Office of Commercialization has filed a U.S. patent application that is pending.

The discovery of a physical interaction between two proteins in brain cells that can be traced in mice to control of movement, anxiety and memory could one day open the door to development of new schizophrenia treatment strategies, researchers say.
The research group is the first to determine that the two proteins, both among the dozens of proteins related to risk for the development of schizophrenia, bind to each other under normal conditions in multiple regions of the brain, and that their connection was found in mice to be key to maintaining normal movement, memory function and anxiety regulation.
When that connection doesn’t happen as it should, they found, behavior can be negatively affected — in mice, disruption to the proteins’ ability to interact increased hyperactivity, reduced risk avoidance and impaired memory. Though delusions and hallucinations are hallmark symptoms of schizophrenia, the condition also encompasses additional symptoms, including movement and memory problems.
“These two proteins are seemingly unrelated, and our study has provided a link between them that wasn’t recognized before,” said lead author Chen Gu, associate professor of biological chemistry and pharmacology in The Ohio State University College of Medicine.
“There are more than 100 genes that have been identified as risk genes for schizophrenia, but we still don’t know the real mechanisms behind those risks,” Gu said. “We’re hopeful that getting a better understanding of this mechanism could help in the long run to find a new treatment that could benefit patients with schizophrenia.”
The study was published recently in the journal Molecular Psychiatry.
Previous post-mortem studies have identified risk genes for schizophrenia based on signs of protein dysfunction detected in brain tissue. Among them are the proteins in this study: MAP6, which has a role in supporting a neuron’s cytoskeleton or, more specifically, microtubules, and Kv3.1, which helps control the maximal frequency of electrical signaling by neurons.

The risks of serious injury from most sports and exercise are astonishingly small, according to the results of a five-year study led by researchers at the University of Bath in the UK.
The study, funded by the British Medical Association, shows that even forms of sport sometimes considered risky by the public, such as road cycling, are generally safe, suggesting the benefits of taking part in fitness activities far outweigh the dangers.
This is the first time in England and Wales that researchers have attempted to describe and quantify the relative risks of trauma resulting from sport or some other physical activity. It’s hoped that the study’s results will make it easier for both participants and organisers of activities to make their pursuits safer still.
Data for the new study — which is published today in the journal Injury Prevention, published by BMJ — came from hospitals nationwide, where participants of sports and exercise presented with major trauma.
The researchers found that between 2012 and 2017, a total of 11,702 trauma injuries resulted from sports and exercise.
Dr Sean Williams, a researcher at the Department for Health and the Centre for health and Injury and Illness Prevention at the University of Bath, and principal investigator of the study, said: “This work demonstrates that engaging in fitness activities is overwhelmingly a safe and beneficial pursuit.
“While no physical activity is entirely without risk, the chance of serious injury is exceedingly low when compared to the myriad health and wellness advantages gained from staying active.”
The study examined 61 sports and other physical activities undertaken nationally, irrespective of their popularity, and provided a comparable estimate of the risks to participants.

Cannabidiol (CBD) and cannabigerol (CBG) might someday help bone fracture patients manage their pain, according to a Penn State study. In a study in mice, the researchers unexpectedly found that the cannabinoids also promoted fracture healing.
The results were published in the Journal of Bone and Mineral Research.
Scientists estimate that more than 178 million people suffer from bone fracture injuries annually around the globe. According to corresponding author Reyad Elbarbary, associate professor of orthopaedics and rehabilitation at Penn State College of Medicine, current methods for managing pain, often nonsteroidal anti-inflammatory drugs (NSAIDS) like aspirin, are not optimal.
“NSAIDS may help patients manage pain, but they also reduce inflammation, which is a crucial first step in fracture healing,” Elbarbary said. “An alternative for pain management is needed that does not prevent inflammation from occurring.”
Elbarbary and his team’s primary goal was to measure CBD and CBG’s separate abilities to alleviate pain in mice. The team, in what they called the first study to analyze cannabinoids in the context of fracture healing and pain management, found that the cannabinoids were comparable to the NSAIDS in their ability to manage pain. But they said they were also surprised to find that CBD and CBG helped with the fracture healing process. With immunofluorescence microscopy, microcomputer tomography imaging and biomechanical testing, the researchers studied the fracture healing process — everything from bone density and bone strength to the expression of genes that are necessary for the progression of fracture healing.
In the early phase of treatment, the cannabinoids were associated with an increase in the abundance of periosteal bone progenitors, which later develop into specialized bone cells that help bone tissue form. During the later phase of healing, CBD and CBG accelerated the process by which the body absorbs minerals to strengthen newly formed bone.
“Both treatments led to higher bone volume fraction and mineral density than with NSAID treatments, which leads to a functional and healthy newly formed bone,” Elbarbary said. “We still have a lot to learn about the biological mechanisms behind what we observed.”
According to Elbarbary, future research will focus on defining the cellular and molecular processes behind the cannabinoids’ role in early and late stages of fracture healing, as well as developing a clinical formulation for use in adult fracture patients. While CBD is already approved by the Federal Drug Administration to treat seizures in children, finding a formulation, or dose, that is suitable for adults in the context of bone fractures will be a critical next step, Elbarbary said.