Tag Archives: #bloodvessels

New Biomaterial Regrows Blood Vessels and Bone, RCSI Research (Medicine)

Scientists have developed a new biomaterial that regrows blood vessels and bone, potentially providing a single-stage approach when repairing large bone defects.

The study, led by researchers from RCSI University of Medicine and Health Sciences and SFI AMBER Centre, is published in the Journal of Controlled Release.

Previous RCSI-led research had found that activating a mechanosensitive gene, called placental growth factor (PGF), at different doses promoted bone regeneration and grew new blood vessels. Using this knowledge, the researchers developed a biomaterial that delivers PGF at different concentrations.

Inspired by the natural way in which bone defects regenerate, the biomaterial first releases a high dose of PGF, promoting blood vessel growth, and follows it with a more sustained lower dose, which promotes bone regeneration. When tested in a pre-clinical model, the biomaterial successfully repaired large bone defects while also regrowing blood vessels.

Current biomaterials that promote both blood vessel and bone growth typically require using more than one therapeutic drug, which means designing a more complex system that faces more challenges. Furthermore, drugs that have been approved for use in the clinic have been controversially associated with dangerous side-effects, highlighting the need for new strategies.

“More testing is needed before we can begin clinical trials, but if proven successful, this biomaterial could benefit patients when repairing bone defects by providing an alternative to current systems,” said Professor Fergal O’Brien, the study’s principal investigator and RCSI’s Director of Research and Innovation.

“In addition to repairing bone defects, our approach to regenerative medicine executed in the study provides a new framework for evaluating regenerative biomaterials for other tissue engineering applications. We are now applying this concept of ‘mechanobiology informed regenerative medicine’ to identify new therapeutics in other areas, including cartilage and spinal cord repair.”

The biomaterial was developed by researchers from the Tissue Engineering Research Group (TERG) based at RCSI and the SFI AMBER Centre. Their work was supported by the Irish Research Council, the EU BlueHuman Interreg Atlantic Area Project, the European Community’s Horizon 2020 research and innovation programme under European Research Council Advanced Grant agreement n° 788753 (ReCaP) and the Health Research Board of Ireland under the Health Research Awards – Patient-Oriented Research Scheme.

“By using a mechanobiology-informed approach, we were able to identify a promising new therapeutic candidate for bone repair and also determine the optimal concentrations required to promote both angiogenesis and osteogenesis within a single biomaterial,” said Dr Eamon Sheehy, the study’s first author and researcher in TERG.

“The regeneration of large bone defects remains a significant clinical challenge, but hopefully our new biomaterial will continue to prove beneficial in further trials.”


Reference: Eamon J. Sheehy, Gregory J. Miller, Isabel Amado, Rosanne M. Raftery, Gang Chen, Kai Cortright, Arlyng Gonzalez Vazquez, Fergal J. O’Brien, Mechanobiology-informed regenerative medicine: Dose-controlled release of placental growth factor from a functionalized collagen-based scaffold promotes angiogenesis and accelerates bone defect healing, Journal of Controlled Release, 2021, , ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2021.03.031. (https://www.sciencedirect.com/science/article/pii/S0168365921001425)


Provided by RCSI University


About RCSI University of Medicine and Health Sciences

Ranked number one globally for Good Health and Well-being in the Times Higher Education (THE) University Impact Rankings 2020, RCSI University of Medicine and Health Sciences is an international not-for-profit university, with its headquarters in Dublin.

RCSI is exclusively focused on education and research to drive improvements in human health worldwide. It is among the top 250 universities worldwide in the THE World University Rankings (2020) and its research is ranked first in Ireland for citations. RCSI has been awarded Athena Swan Bronze accreditation for positive gender practice in higher education.

Visit the RCSI MyHealth Expert Directory to find the details of our experts across a range of healthcare issues and concerns. Recognising their responsibility to share their knowledge and discoveries to empower people with information that leads them to better health, these clinicians and researchers are willing to engage with the media in their area of expertise.

Keep calm! How Blood Vessels Are Kept in Check (Medicine)

The inner surface of blood vessels is lined by a wafer-thin layer of cells known as the endothelium, which forms a crucial barrier between blood and the surrounding tissue. The single-layered cell structure promotes the exchange of oxygen and nutrients, while simultaneously preventing the uncontrolled leakage of blood components. Only when the metabolic needs of the surrounding tissue increase, e.g., during growth, wound healing or tumor development, do endothelial cells abandon this stable cell association in order to divide and form new blood vessels. The signals that trigger this activation have been throroughly studied. Previously, however, little was known about how endothelial cells maintain their stable resting state. This is what scientists at Berlin Institute of Health (BIH) at Charité have now investigated together with an international team of researchers. They have published their findings in the journal Nature Cell Biology.

Michael Potente is a cardiologist and blood vessel researcher. He arrived at the BIH from the Max Planck Institute for Heart and Lung Research just a few months ago, and is now moving into his new laboratory in the recently opened Käthe Beutler Building on Campus Berlin Buch. There he will conduct research at the BIH & MDC Center for Vascular Biomedicine. “Even in these turbulent times, we have been working vigorously on our major project to better understand blood vessels,” explains the Professor of Vascular Biomedicine. “Blood vessels are everywhere in the body, and they also play a key role in many illnesses.”

Normally, blood vessels in the adult body are in a stable resting state. New vascular capillaries sprout only rarely, for example, during the female menstrual cycle, wound healing or during pathological processes such as tumor growth. The signals that stimulate the endothelial cells to divide are largely known. “We wanted to understand instead what keeps endothelial cells in a dormant state – also known as quiescence,” says Michael Potente.

The scientists from his team already had a good idea where to look: “There are factors that prevent cells from proliferating. One such factor is FOXO1, which controls the transcribing of genetic information in cells; if we switch off FOXO1 in endothelial cells, this leads to excessive vessel growth. Conversely, we can stop blood vessel formation by specifically switching on this factor. We wanted to find out how exactly FOXO1 does this,” explains Jorge Andrade, one of the three lead authors of the paper.

S-2-hydroxyglutarate as “endothelial calming factor”?

To do this, the scientists transferred a continuously active form of FOXO1 into endothelial cells. This caused the endothelial cells to stop dividing and remain in a state of inactivity. To find out how FOXO1 does this, the researchers investigated the metabolism of the cells. For this purpose, they isolated all metabolic products from the cells, which are also known as metabolites. “In this process, we saw that the concentration of 2-hydoxyglutarate, in particular, increased due to FOXO1. This metabolite has already become very well known in cancer medicine,” reports Ana Costa, another lead author of the paper. However, the researchers found that this is a special form of 2-hydroxyglutarate called S-2-hydroxyglutarate. “This variant differs in structure and function from the metabolite produced in some cancer cells,” Costa says.

To confirm the role of S-2-hydroxyglutarate as a possible “endothelial calming factor,” the scientists conducted further experiments on endothelial cells. They added the substance to normal endothelial cells in various concentrations and for different lengths of time. “We observed that S-2-hydroxyglutarate alone is able to keep endothelial cells in a state of quiescence,” explains Chenyue Shi, the third lead author of the paper. Further research showed that S-2-hydroxyglutarate exerts its effect by controlling the transcription of growth-controlling genes. In mouse models, the metabolite also prevented the growth of new vessels, but had no negative effects on existing blood vessels. When the scientists removed S-2-hydroxyglutarate, endothelial cells regained their ability to form new blood vessels.

Targeted influence on blood vessels

“Especially given the fact that ‘too many’ or ‘too few’ new blood vessels play a role in many diseases, it is enormously important for us to better understand the basic mechanisms underlying these processes,” is how Potente summarizes the results. “Our long-term goal is to be able to therapeutically influence the development and function of blood vessels in a targeted manner, and if possible, without any side effects. We have come one step closer to this goal with our work.”

Featured image: Restricted blood vessel growth due to S-2-hydroxyglutarate. Retinal vessels of a mouse in which S-2-hydroxyglutarate levels are selectively increased in the endothelium. Blood vessels (blue), nuclei of dividing endothelial cells (yellow), resting endothelial cells (green), other cells dividing (red). | Photo: BIH/Michael Potente


Reference: Jorge Andrade, Chenyue Shi, Ana S. H. Costa,……,Michael Potente: “Control of endothelial quiescence byFOXO-regulated metabolites” Nature Cell Biology 2021 DOI 10.1038/s41556-021-00637-6


Provided by Berlin Institute of Health

UofG To Investigate the Effects of COVID-19 On Blood Vessels and Blood Pressure (Medicine)

A project at the University of Glasgow that is aiming to better understand the effects that COVID-19 infection has on blood vessels and blood pressure has received a grant of £250,000 from national charity Heart Research UK

Research has shown that people who are older, obese, male or those who have other medical problems including high blood pressure, heart disease, diabetes, cancer, or chronic lung conditions, have a higher risk of developing severe COVID-19. High blood pressure is a major risk factor for cardiovascular disease and is very common with more than one quarter of adults in the UK affected.

The virus causing COVID-19 enters the body’s cells through a receptor called ACE2 which is found in the lungs, heart, blood vessels, kidneys, liver, and bowel. ACE2 is very important for maintaining many of the body’s important processes including blood pressure, inflammation, and wound healing.

COVID-19 can also cause damage to the walls of the blood vessels which makes the risk of blood clots higher and this has been seen more often in people with high blood pressure. The reasons for this are not yet known which is why we need to understand more about the links between COVID-19 and high blood pressure.

This study, which will be led by Professor Sandosh Padmanabhan, Professor of Cardiovascular Genomics and Therapeutics, aims to answer whether:
• High blood pressure makes COVID-19 infection worse and if so, why.
• COVID-19 infection makes high blood pressure worse and if so, why.
• Monitoring and management of high blood pressure needs to be a greater priority during the pandemic.

The study will look at routinely collected health records for people in the West of Scotland who attended hospital or had a positive test for COVID-19 between April 2020 and April 2021. This will be compared to the records of patients who attended hospital during 2019, for another reason. They will also look in detail at a group of people with high blood pressure.

Prof Padmanabhan’s team will also study a group of people that have recovered from COVID-19 infection. They will undergo blood pressure monitoring, and tests of heart and blood vessel health. These tests will be repeated after 12 and 18 months to see if there have been any changes. They will be compared to a group of people who have not had COVID-19.

Finally, the study will look at markers in the blood (biomarkers) with the aim of identifying any which are linked with high blood pressure, cardiovascular disease, or death in COVID-19.

This study will give us a better understanding of the links between COVID-19 infection and high blood pressure, and help to improve the long-term outcomes for survivors of COVID-19. Also, the findings may lead to recommendations on the monitoring and management of blood pressure during the pandemic.

Prof Padmanabhan said: “The current COVID-19 pandemic, caused by the SARS-CoV-2 virus, has exposed unexpected cardiovascular vulnerabilities at all stages of the disease. The mechanism by which the SARS-CoV-2 virus causes infection is believed to directly and indirectly affect the cardiovascular system potentially resulting in new-onset hypertension, heart failure and stroke and represents an insidious feature of long-COVID.

“The burden of hypertension as a consequence of the COVID-19 pandemic is unknown, but given the scale of the infection especially among the young this will be a major concern for the future. In this project, we plan to generate valuable evidence that will inform hypertension management strategies and reduce cardiovascular risk for survivors of COVID-19.”

Kate Bratt-Farrar, Chief Executive of Heart Research UK, said: “We are delighted to be supporting the work of Professor Padmanabhan and his team, who are conducting vital research into one of the biggest medical challenges the world has ever faced.

“We have known for some time that those with pre-existing cardiovascular conditions are more susceptible to developing severe complications from COVID-19. We hope that this research will help to explain why this is the case, reduce the risk for this vulnerable group and, ultimately, help to save more lives.

“Our grants are all about helping patients. They aim to bring the latest developments to those who need them as soon as possible.

“The dedication we see from UK researchers is both encouraging and inspiring, and we at Heart Research UK are proud to be part of it.”


Provided by University of Glasgow

The Blood May Hold Clues to Some of COVID-19’s Most Mysterious Symptoms (Medicine)

The most severe cases of COVID-19 begin with leaky blood vessels. Breaches in the vascular system cause inflammation and coagulation, as fluid floods the lungs. Meanwhile, a host of seemingly unrelated symptoms set in. Blood pressure drops, arrhythmias test the heart, and the central nervous system takes a beating.

Erin Norris and Pradeep Singh discuss their research in the laboratory of Sidney Strickland. © Rockefeller University

Some studies suggest that such disparate symptoms may have a single culprit—a tiny molecule known as bradykinin—and scientists now suspect that SARS-CoV-2 is capable of toppling the delicate system that keeps this signaling substance in check. The result is a runaway bradykinin storm, the hallmarks of which just happen to be inflammation, blood coagulation, and heart, lung, and brain complications.

Rockefeller’s Sidney Strickland knows a thing or two about bradykinin, having studied it at length in the context of neurodegenerative diseases, inflammation, and blood coagulation. His lab was the first to demonstrate that the β-amyloid peptide, thought to cause Alzheimer’s disease by forming sticky plaques in the brain, also sets in motion a cascade of molecular events leading to the release of bradykinin, a likely cause of inflammation and coagulation in Alzheimer’s. Strickland’s pursuit of this relatively uncelebrated cascade may explain why vascular problems often crop up in neurodegenerative conditions.

So when COVID-19 began presenting not as a straightforward infection but a complex systemic disease—complete with the telltale signs of a bradykinin storm—the Strickland lab was ready.

“When we began looking into COVID-19, our first thought was that the inflammation characteristic of severe cases might be coming from the plasma contact system,” says Erin Norris, a research assistant professor in Strickland’s lab. The plasma contact system works by activating a plasma protein known as Factor XII, which triggers coagulation and, along the way, releases bradykinin to induce inflammation. “By investigating the plasma contact system, we can study inflammation and coagulation all at once,” she says.

A promising hypothesis

The first step for the Strickland lab is demonstrating that the novel coronavirus does indeed set off a bradykinin storm—a theory that matches the sundry symptoms but remains unproven.

Because research on a dangerous pathogen like SARS-CoV-2 requires extreme safety precautions, the lab is testing the idea using a faux coronavirus, developed in the lab of Paul Biensiasz, that is less cumbersome to work with than the real pathogen. By observing how the faux coronavirus interacts with plasma samples in the lab, scientists can determine whether the artificial virus does indeed set off a bradykinin storm by way of the contact system. If confirmed, the implications for clinicians managing severe COVID-19 cases could be imminent.

“There are existing medications that block the contact system and inhibit the production of bradykinin without interfering with the body’s main clotting pathways,” Norris says.

In a separate set of experiments, Strickland’s lab is also analyzing plasma samples from COVID-19 patients in various stages of the disease. They’re hoping to find a correlation between the severity of symptoms and the level of contact system activation since there is currently no way for doctors to predict which newly infected patients are at risk of developing life-threatening disease. If, for example, it turns out that the plasma contact system goes into overdrive before a patient takes a turn for the worse, clinicians could use this information to identify severe cases early on.

“We could create a test to determine the extent of contact system activation and use it to identify which patients are most likely to experience coagulopathy or inflammation,” Strickland says. “If certain patients are more likely to develop serious problems, it would be great to know this early on so approved medications could be employed.”

Although the research is still in its early stages, the plasma contact system is an increasingly appealing target in the fight against COVID-19. “Something is leading to coagulation and inflammation,” Strickland says. “The contact system is promising because it can do both.”

Provided by Rockefeller University

Enzyme Discovery is Missing Piece in Understanding How to Rein in Blood Vessels That Fuel Cancer (Medicine)

By unleashing the power of an enzyme that limits blood vessel growth, it may be possible to develop new or better treatments for multiple health conditions.

Most living things need oxygen to grow and thrive. Even cancerous tumors. That’s why tumors will readily sprout new blood vessels if their oxygen is starved, creating new lifelines for survival.

© Scripps Research

A study published today from Scripps Research pinpoints the precise molecular machinery that makes this happen, providing scientific insights that can potentially be translated into medicines that help kill tumors and stop cancer from spreading in the body.

The findings also may enable new interventions that promote healthy blood-vessel development for people with heart disease and other conditions, says the study’s leader Xiang-Lei Yang, PhD, a professor In the Department of Molecular Medicine at Scripps Research.

The research appears in the journal PLOS Biology.

“We’ve uncovered a key regulation step that drives blood-vessel development for tissues deprived of adequate oxygen—finally creating a more complete picture of the complex process that enables cancer tumors to adapt and survive,” says Yang. “By blocking this process on a molecular level, we found it’s possible to inhibit tumor growth.”

The study culminates a years-long project initiated by first author Yi Shi, PhD, who began the work as a staff scientist in Yang’s lab but recently finished his contributions from Nankai University in Tianjin, China, where he is now a faculty member.

Over the past decade, Yang and her team have published several key discoveries relating to how cells create blood vessels, delving into previously unknown roles of genes that regulate this function. Prior studies dealt with genes known as c-Myc and HIF-1, which promote blood vessel development and have strong links to cancer.

In the new study, Yang’s team looked at negative regulators of blood vessel growth—or proteins that turn the function off—to find out what causes them to become inactivated when tissues are deprived of oxygen, which is what happens within a solid tumor.

Their central focus was an enzyme known as SerRS (seryl-tRNA synthetase), most commonly known to exist in the gel-like substance within cells. There, the enzyme kicks off the first step of making new proteins. However, the enzyme is also found within the nucleus, performing an entirely different but vital job: Limiting unhealthy blood vessel growth by tamping down the function of c-Myc and HIF-1.

In the study, the researchers found that SerRS can be “silenced” by proteins known as ATM/ATR, which manage DNA damage responses. These proteins activate when tissues are deprived of oxygen. When this happens, new blood vessel growth can go unchecked and tumors can flourish.

Through separate experiments involving mice and human breast cancer cells, the team confirmed that by blocking the effect of ATM/ATR on SerRS, they were able to successfully reduce tumor growth.

Notably, Yang says, SerRS is part of an evolutionarily ancient family of enzymes called tRNA synthetases, which begin the process of making proteins that go on to form blood, skin, bones and other essential elements of human life. The findings of this study show that SerRS has evolved extra functions beyond making proteins.

“It’s possible that SerRS regulates more than blood vessel development,” Yang says. “This is a compelling finding that opens the door to further investigation into how broad its influence may reach in the human body.”

The study, “Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis,” is authored by Yi Shi, Ze Liu, Qian Zhang, Ingrid Vallee, Zhongying Mo, Shuji Kishi and Xiang-Lei Yang.

This work was supported by grants from the National Institutes of Health, the National Natural Science Foundation of China, aTyr Pharma through an agreement with Scripps Research, and a fellowship from the National Foundation for Cancer Research.

Reference: Shi Y, Liu Z, Zhang Q, Vallee I, Mo Z, Kishi S, et al. (2020) Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis. PLoS Biol 18(12): e3000991. doi:10.1371/journal.pbio.3000991

Provided by Scripps Research

Hair-like Structures in Cells of the Vessel Wall May be Relevant for Diabetes Treatment (Medicine)

A new study from Karolinska Institutet and the Helmholtz Diabetes Research Center shows that primary cilia, hair-like protrusions on endothelial cells inside vessels, play an important role in the blood supply and delivery of glucose to the insulin-producing beta cells in the pancreatic islets. The findings are published in eLife and may be relevant for transplantation therapies in diabetes, as formation of functional blood vessels is important for the treatment to be successful.

©Kyoto

When blood glucose levels rise, beta cells in pancreatic islets release insulin into the blood stream. Insulin triggers glucose uptake in a variety of tissues including fat and muscle. Glucose and other nutrients must cross the vascular barrier to reach beta cells inside pancreatic islets. Similarly, newly released insulin must cross the blood vessels into the blood stream to reach its target tissues.

Endothelial cells can be found on the inside of blood vessels. Vessels in the pancreatic islets form a dense network with many small pores in the endothelial cell membrane, facilitating the exchange of molecules across the vessel wall.

Small hair-like structures

Now, researchers have investigated how pancreatic islet vessel formation and function are affected by primary cilia, small hair-like structures found on beta cells and endothelial cells. Professor Per-Olof Berggren’s research group at The Rolf Luft Research Center for Diabetes and Endocrinology, the Department of Molecular Medicine and Surgery, Karolinska Institutet in Sweden and Dr. Jantje Gerdes’ research group at the Helmholtz Diabetes Research Center in Munich, Germany, have previously shown that insulin secretion is modulated by cilia on beta cells.

In the new study, the researchers examined a mouse model of Bardet-Biedl Syndrome, a disease caused by cilia dysfunction. They were able to show that when endothelial cilia are dysfunctional, the blood supply to the pancreatic islets is less efficient. Newly formed vessels have larger diameters and fewer pores that allow nutrients to pass through the vessel wall.

Less efficient at delivering glucose

“Consequently, the smallest blood vessels, the capillaries, become less efficient at delivering glucose to the beta cells,” says Yan Xiong, assistant professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and first author of the study.

Signaling via the growth factor VEGF-A was identified as a key player in this process. Endothelial cells that lack functional cilia are less sensitive to VEGF-A compared to normal endothelial cells, resulting in impaired signaling via the VEGFR2 receptor.

“In summary, we have demonstrated that primary cilia, specifically those on endothelial cells, regulate pancreatic islet vascularisation and vascular barrier function via the VEGF-A/VEGFR2 signaling pathway,” says Dr. Gerdes, one of the senior authors of the study.

Novel therapeutic avenues

The formation of functional blood vessels is an important factor in transplantation therapies. Beta cell replacement therapy could potentially treat and cure type 1 diabetes, and the formation of a functional interface between beta cells and blood vessels is an important step towards longer graft survival and diabetes remission.

“This study improves the understanding of how primary cilia facilitate efficient blood vessel formation, and potentially offers novel therapeutic avenues to enable effective pancreatic islet transplantation in diabetes and possibly transplantation of other organs as well,” says Dr. Berggren, the other senior author of the study.

Reference: Yan Xiong et al. Islet vascularization is regulated by primary endothelial cilia via VEGF-A-dependent signaling, eLife (2020). DOI: 10.7554/eLife.56914

Provided by Karolinska Institutet

Differences In Immunity and Blood Vessels Likely Protect Children From Severe COVID-19 (Medicine)

Differences in the immune systems and better blood vessel health were among the factors protecting children from severe COVID-19, according to a new review.

Differences in the immune systems and better blood vessel health were among the factors protecting children from severe COVID-19, according to a new review. ©Thiago Cerqueira

A huge body of global COVID-19 literature was reviewed by experts at the Murdoch Children’s Research Institute (MCRI), the University of Melbourne and the University of Fribourg and published in the Archives of Disease in Childhood to unravel the reasons for age-related differences in COVID-19 severity and symptoms.

MCRI and University of Melbourne Professor Nigel Curtis said that while a number of hypotheses provided potential explanations as to why adults were at higher risk and children protected from severe disease and death from COVID-19, most do not explain why COVID-19 severity rises steeply after the age of 60-70 years.

Professor Curtis said in stark contrast to other respiratory viruses, severe disease and death due to COVID-19 was relatively rare in children.

“Most children with COVID-19 have no or only mild symptoms, most commonly fever, cough, sore throat and changes in sense of smell or taste,” he said. “Even children with the usual risk factors for severe infections, such as immunosuppression, were not at high risk of severe COVID-19 disease.”

Professor Curtis said damage to the thin layer of endothelial cells lining various organs, especially the blood vessels, heart, and lymphatic vessels, increased with age and there was an association between conditions that affect these cells and severe COVID-19.

“We know pre-existing blood vessel damage plays an important role in COVID-19 severity and can lead to blood clots, causing strokes and heart attacks. COVID-19 can infect these endothelial cells and cause blood vessel inflammation,” he said.

“The endothelium in children has experienced far less damage compared with adults and their clotting system is also different, which makes children less prone to abnormal blood clotting.”

Professor Curtis said diseases associated with chronic inflammation that develop with advanced age including diabetes and obesity were also linked with severe COVID-19.

He said more recent immunisation with live vaccines, such as the MMR vaccine against measles, mumps, and rubella, that could boost the immune system might play a role in protecting children.

Dr Petra Zimmermann from the University of Fribourg said there were also other important differences in the immune system between children and adults.

“Children have a stronger innate immune response, which is the first-line defence against COVID-19,” she said.

“Another important factor is ‘trained immunity’ which primes innate immune cells after mild infections and vaccinations, leading to a type of ‘innate immune memory’.

“Children infected with COVID-19 often have co-infections with other viruses. Recurrent viral infections could lead to improved trained immunity, making kids more effective at clearing COVID-19.”

Dr Zimmermann said different levels of microbiota (bacteria and other germs) in the throat, noise, lung and stomach, also influenced susceptibility to COVID-19.

“The microbiota plays an important role in the regulation of immunity, inflammation and in the defence against illnesses,” she said. “Children are more likely to have viruses and bacteria, especially in the nose, where these bugs might limit the growth of COVID-19.”

Dr Zimmermann said the vitamin D level, with its anti-inflammatory properties, was also generally higher in children.

“The overlap between risk factors for severe COVID-19 and vitamin D deficiency, including obesity, chronic kidney disease and being of black or Asian origin, suggests that vitamin D supplementation may play a role in helping prevent or treat COVID-19,” she said.

“In many countries, vitamin D is routinely supplemented in infants younger than one year of age and in some countries even up to the age of three years.”

Professor Curtis said understanding the underlying age-related differences in the severity of COVID-19 would provide important insights and opportunities for prevention and treatment of SARS-CoV-2 infections.

References: Petra Zimmermann, Nigel Curtis, “Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections”, BMJ, 2020. https://adc.bmj.com/content/early/2020/11/30/archdischild-2020-320338 http://dx.doi.org/10.1136/archdischild-2020-320338

Provided by Mudroch Children’s Research Institute

About MCRI

MCRI specialises in discoveries that transform child health.

Murdoch Children’s Research Institute (MCRI) is the largest child health research institute in Australia and one of the top three worldwide for research quality and impact*. Their team of more than 1200 talented researchers is dedicated to making discoveries to prevent and treat childhood conditions. Many of their researchers are also clinicians at the Royal Children’s Hospital in Melbourne, where the Institute is based. Their research is informed by the problems facing their patients but it also means when a discovery is made, this is quickly transformed into practical treatments for children in the hospital.

The Institute marked its 30th anniversary in 2016. Their story began in 1986 when paediatrician Professor David Danks established the original Murdoch Institute with the unparalleled generosity and support of Dame Elisabeth Murdoch.

MCRI research improves the lives of millions of kids each year. They research health conditions including diabetes, allergies, asthma, premature birth and mental health problems, which are on the rise in their children, and conditions including cancer and genetic disorders that remain unsolved.

How SARS-CoV-2 Reaches the Brain? (Neuroscience)

Using post-mortem tissue samples, a team of researchers from Charité – Universitätsmedizin Berlin have studied the mechanisms by which the novel coronavirus can reach the brains of patients with COVID-19, and how the immune system responds to the virus once it does. The results, which show that SARS-CoV-2 enters the brain via nerve cells in the olfactory mucosa, have been published in Nature Neuroscience*. For the first time, researchers have been able to produce electron microscope images of intact coronavirus particles inside the olfactory mucosa.

An electron microscope image (ultrathin section, artificially colored) shows a section of a ciliated cell in the olfactory mucosa. Large numbers of intact SARS-CoV-2 particles (red) are found both inside the cell and on cellular processes. Yellow: kinocilia. © Photo: Michael Laue/RKI & Carsten Dittmayer/Charité

It is now recognized that COVID-19 is not a purely respiratory disease. In addition to affecting the lungs, SARS-CoV-2 can impact the cardiovascular system, the gastrointestinal tract and the central nervous system. More than one in three people with COVID-19 report neurological symptoms such as loss of, or change in, their sense of smell or taste, headaches, fatigue, dizziness, and nausea. In some patients, the disease can even result in stroke or other serious conditions. Until now, researchers had suspected that these manifestations must be caused by the virus entering and infecting specific cells in the brain. But how does SARS-CoV-2 get there? Under the joint leadership of Dr. Helena Radbruch of Charité’s Department of Neuropathology and the Department’s Director, Prof. Dr. Frank Heppner, a multidisciplinary team of researchers has now traced how the virus enters the central nervous system and subsequently invades the brain.

As part of this research, experts from the fields of neuropathology, pathology, forensic medicine, virology and clinical care studied tissue samples from 33 patients (average age 72) who had died at either Charité or the University Medical Center Göttingen after contracting COVID-19. Using the latest technology, the researchers analyzed samples taken from the deceased patients’ olfactory mucosa and from four different brain regions. Both the tissue samples and distinct cells were tested for SARS-CoV-2 genetic material and a ‘spike protein’ which is found on the surface of the virus. The team provided evidence of the virus in different neuroanatomical structures which connect the eyes, mouth and nose with the brain stem. The olfactory mucosa revealed the highest viral load. Using special tissue stains, the researchers were able to produce the first-ever electron microscopy images of intact coronavirus particles within the olfactory mucosa. These were found both inside nerve cells and in the processes extending from nearby supporting (epithelial) cells. All samples used in this type of image-based analysis must be of the highest possible quality. To guarantee this was the case, the researchers ensured that all clinical and pathological processes were closely aligned and supported by a sophisticated infrastructure.

“These data support the notion that SARS-CoV-2 is able to use the olfactory mucosa as a port of entry into the brain,” says Prof. Heppner. This is also supported by the close anatomical proximity of mucosal cells, blood vessels and nerve cells in the area. “Once inside the olfactory mucosa, the virus appears to use neuroanatomical connections, such as the olfactory nerve, in order to reach the brain,” adds the neuropathologist. “It is important to emphasize, however, that the COVID-19 patients involved in this study had what would be defined as severe disease, belonging to that small group of patients in whom the disease proves fatal. It is not necessarily possible, therefore, to transfer the results of our study to cases with mild or moderate disease.”

Immunofluorescence staining shows a nerve cell (pink) inside the olfactory mucosa which has been infected with SARS-CoV-2 (yellow). Supporting (epithelial) cells appear blue. © Photo: Jonas Franz/Universitätsmedizin Göttingen

The manner in which the virus moves on from the nerve cells remains to be fully elucidated. “Our data suggest that the virus moves from nerve cell to nerve cell in order to reach the brain,” explains Dr. Radbruch. She adds: “It is likely, however, that the virus is also transported via the blood vessels, as evidence of the virus was also found in the walls of blood vessels in the brain.” SARS-CoV-2 is far from the only virus capable of reaching the brain via certain routes. “Other examples include the herpes simplex virus and the rabies virus,” explains Dr. Radbruch.

The researchers also studied the manner in which the immune system responds to infection with SARS-CoV-2. In addition to finding evidence of activated immune cells in the brain and in the olfactory mucosa, they detected the immune signatures of these cells in the cerebral fluid. In some of the cases studied, the researchers also found tissue damage caused by stroke as a result of thromboembolism (i.e. the obstruction of a blood vessel by a blood clot). “In our eyes, the presence of SARS-CoV-2 in nerve cells of the olfactory mucosa provides good explanation for the neurologic symptoms found in COVID-19 patients, such as a loss of the sense of smell or taste,” explains Prof. Heppner. “We also found SARS-CoV-2 in areas of the brain which control vital functions, such as breathing. It cannot be ruled out that, in patients with severe COVID-19, presence of the virus in these areas of the brain will have an exacerbating impact on respiratory function, adding to breathing problems due to SARS-CoV-2 infection of the lungs. Similar problems might arise in relation to cardiovascular function.”

References: Meinhardt J et al., Olfactory transmucosal SARS-CoV-2 invasion as port of central nervous system entry in individuals with COVID-19. Nat Neurosci 2020. doi: 10.1038/s41593-020-00758-5 https://www.nature.com/articles/s41593-020-00758-5

Provided by Charité

Biofriendly Protocells Pump Up Blood Vessels (Biology / Chemistry)

An international team comprising researchers from the University of Bristol, and Hunan and Central South Universities in China, have prepared biocompatible protocells that generate nitric oxide gas – a known reagent for blood vessel dilation – that when placed inside blood vessels expand the biological tissue.

Enzyme-mediated Nitric Oxide Production in Vasoactive Erythrocyte Membrane-enclosed Coacervate Protocells. ©Nature Chemistry (2020).

In a new study published today in Nature Chemistry, Professor Stephen Mann and Dr Mei Li from Bristol’s School of Chemistry, together with Associate Professor Jianbo Liu and colleagues at Hunan University and Central South University in China, prepared synthetic protocells coated in red blood cell fragments for use as nitric oxide generating bio-bots within blood vessels.

Coating the protocells led to increased levels of biocompatibility and longer blood circulation times. Critically, the team trapped an enzyme inside the protocells which, in the presence of glucose, produced hydrogen peroxide. This was then used by haemoglobin in the protocell membrane to degrade the drug molecule hydroxyurea into nitric oxide gas.

When placed inside small pieces of blood vessels, or injected into a carotid artery, the protocells produced sufficient amounts of nitric oxide to initiate the biochemical pathways responsible for blood vessel vasodilation.

Although at a very early stage of development, the new approach could have significant benefits in biomedicine, cellular diagnostics and bioengineering.

Professor Stephen Mann, Co-Director of the Max Planck Bristol Centre for Minimal Biology at Bristol, said: “This work could open up a new horizon in protocell research because it highlights the opportunities for creating therapeutic, cell-like objects that can directly interface with living biological tissues.”

Associate Professor Jianbo Liu at Hunan University added: “We are all really excited about our proof-of-concept studies but there is a lot of work still to be done before protocells can be used effectively as bio-bots in therapeutic applications. But the potential looks enormous.”

References: Liu, S., Zhang, Y., Li, M. et al. Enzyme-mediated nitric oxide production in vasoactive erythrocyte membrane-enclosed coacervate protocells. Nat. Chem. (2020). https://www.nature.com/articles/s41557-020-00585-y https://doi.org/10.1038/s41557-020-00585-y

Provided by University of Bristol