Culture

In a world first, Monash University researchers have identified a key biomolecule that enhances the repair of your gut lining by prompting stem cells to regenerate damaged tissue.

A strong cellular lining is essential for a healthy gut as it provides a barrier to the billions of microbes and harmful toxins present in our intestinal tract. This barrier is often damaged by infection and inflammation, which causes many painful symptoms.

The study, published in Cell Stem Cell and led by Professor Helen Abud and Dr Thierry Jardé from Monash Biomedicine Discovery Institute, investigated the environment that surrounds gut stem cells and used "mini gut" organoid methodology where tiny replicas of gut tissue were grown in a dish. The study defined key cells that reside in close proximity to stem cells in the gut that produce the biomolecule Neuregulin-1 that acts directly on stem cells to kick-start the repair process.

"Our really important discovery is that supplementation with additional Neuregulin-1 accelerates repair of the gut lining by activation of key growth pathways," Professor Abud said.

"Our findings open new avenues for the development of Neuregulin 1-based therapies for enhancing intestinal repair and supporting rapid restoration of the critical gut function."

Gastrointestinal disease, such as Crohn's disease and ulcerative colitis, is a major health issue worldwide and results in severe damage to the epithelial cell layer lining the gut. Under these conditions, the intestine has a limited capacity to repair efficiently to restore its main absorptive function and is associated with symptoms including diarrhoea, dehydration, loss of weight and malnutrition. Developing ways to support intestinal tissue repair will dramatically improve patient recovery.

"It was very exciting to observe that Neuregulin 1 can not only drive cells to divide but enhances stem cell properties which supercharges these cells into a repair program," Dr Jardé said.

"This shortens the period of damage. The gut lining is injured during common chemotherapy treatment for cancer and we were also able to show recovery is significantly improved with application of Neuregulin-1 following chemotherapy.

Researchers at McGill University have discovered bacterial organelles involved in gene expression, suggesting that bacteria may not be as simple as once thought. This finding could offer new targets for the development of new antibiotics.

The study, published in Proceedings of the National Academy of Sciences, is the first to show that E. coli uses similar strategies to regulate gene transcription as other more complex cell types.

Just like the human body is made up of organs that perform specialized functions, individual cells contain specialized compartments - such as energy-producing mitochondria - called organelles. Complex cells contain many different organelles, most of which are enclosed by a membrane that holds them together. Because bacteria do not have membrane-bound organelles, they were assumed to lack them altogether.

Stephanie Weber, an assistant professor in McGill's Department of Biology, and her team are the first to show that bacteria do in fact have such specialized compartments.

"Our paper provides evidence for a bacterial organelle that is held together by "sticky" proteins rather than a membrane," says Weber, who is the study's senior author.

The bacterial organelles described in the study are formed in a similar fashion to membraneless cellular compartments found in more complex eukaryotic cells (cells with a nucleus) through a process called phase separation, the same phenomenon that causes oil and vinegar to separate in salad dressing.

"This is the first direct evidence of phase separation in bacteria, so it may be a universal process in all cell types, and could even have been involved in the origin of life," explains Weber.

Because of the small size of the bacterial cells they were studying, Weber's team used an imaging technique - photo activated localization microscopy - to track the organelle-forming proteins.

Weber is now trying to understand exactly how the proteins assemble into organelles. Because they're involved in the first steps of gene expression - transcription - she believes they might also be an interesting target for the development of a new generation of antibiotic drugs, which are urgently needed to combat drug resistance.

BUFFALO, N.Y. -- Millions of children fail to reach their developmental potential worldwide, in part due to higher rates of exposure to current and legacy pollutants.

Researchers studying chemical exposures among children in Uruguay turned to an unlikely data collection device as part of a recent study: silicone wristbands.

These wristbands -- the kind many people around the world wear to show their support for a cause or organization -- are extremely effective in capturing certain types of harmful chemicals, and they're easy for children to wear.

Researchers from the University at Buffalo and the Catholic University of Uruguay used the wristbands to examine the extent of chemical exposure among a small group of children in Montevideo, Uruguay. The 6- to 8-year-olds wore the bands for seven days. After analyzing the wristbands, researchers found an average of 13 pollutants in each one collected. Some of the wristbands showed exposure to DDT, a harmful pesticide that has been banned for use in many countries, including the U.S., since the 1970s.

The study, published recently in the journal Science of the Total Environment, is the first to apply silicone wristbands to measure children's exposure to chemicals in a country outside of the U.S. The study was conducted as part of an ongoing research project in Montevideo led by Katarzyna "Kasia" Kordas, PhD, the paper's senior author. Kordas is an associate professor of epidemiology and environmental health in UB's School of Public Health and Health Professions and co-director of UB's Community for Global Health Equity.

The UB RENEW (Research and Education in eNergy, Environment and Water) Institute provided funding for the study.

"One of the key findings from this research is that we still observe industrial and agricultural chemicals that have been banned from production for years and even decades," said Steven C. Travis, the study's first author, who is a PhD student in the Department of Chemistry in UB's College of Arts and Sciences.

"We were also able to find specific differences between chemical exposures of the children in our study compared to children in the U.S., and identify potential reasons for differences in exposure," added Travis, whose major PhD adviser, Diana Aga, Henry Woodburn Professor of Chemistry in UB's College of Arts and Sciences, is a paper co-author.

Silicone wristbands have become a popular method in recent years to measure personal exposures to organic chemicals because they are easy to wear and are a non-invasive sampling method. They also have a greater capacity to hold semi-volatile chemicals, and can capture chemicals for a longer period of time. More than 1,500 chemicals have been sampled using silicone wristbands, Travis said.

Researchers analyzed wristbands in this study for 45 chemicals from among five groups: polychlorinated biphenyls (PCBs), pesticides, polybrominated diphenyl ethers (PBDEs), organophosphorus flame retardants (OPFRs) and novel halogenated flame-retardant chemicals (NHFRs). NHFRs were the only chemical group not detected. Anywhere from eight to 19 chemicals were detected in each of 23 wristbands collected.

"The use of wristbands as a personal sampling device is an excellent alternative for assessing what harmful chemicals are accumulating in children's bodies, rather than the old-fashioned way of collecting blood and measuring the chemical concentrations in the blood," said Aga.

PCBs were found in 19 of the 23 wristbands. The researchers noted that the entry and trade of PCBs wasn't regulated in Uruguay until 2007, and that there were an estimated 40,000 transformers -- a major source of PCBs -- operating in the country in 2006.

The presence of PBDEs was confirmed in 22 out of 23 wristbands. Concentrations of this chemical group, however, were much lower than those found in U.S. studies. That was surprising, according to the researchers.

"With this study, we've been able to link different exposures to certain lifestyle characteristics," Travis said. "For example, we are able to suggest that not having carpets in the home may lead to lower exposure to brominated flame retardants, which were used widely in the production of carpet padding. Also, with the use of other studies, we can uncover differences in exposure based on various modes of transportation."

Eleven wristbands contained all six OPFRs analyzed. Pesticides were also present, including DDT, which was found in 20 wristbands.

"It is very concerning that young children are exposed to multiple chemicals, including those that have been banned in the U.S. because of demonstrated harms to health," said Kordas. "We know that when chemicals occur together in so-called mixtures, they could be more detrimental to children's development than each chemical alone."

Travis added, "This emphasizes that we need to be more careful with the chemicals that we use for industrial and agricultural purposes, since they have the potential to remain in the environment and can affect people over decades."

The formation of four-stranded DNA has been tracked in living human cells, allowing scientists to see how it works, and its possible role in cancer.

DNA usually forms the classic double helix shape discovered in 1953 - two strands wound around each other. Several other structures have been formed in test tubes, but this does not necessarily mean they form within living cells.

Quadruple helix structures, called DNA G-quadruplexes (G4s), have previously been detected in cells. However, the technique used required either killing the cells or using high concentrations of chemical probes to visualise G4 formation, so their actual presence within living cells under normal conditions has not been tracked, until now.

A research team from the University of Cambridge, Imperial College London and Leeds University have invented a fluorescent marker that is able to attach to G4s in living human cells, allowing them to see for the first time how the structure forms and what role it plays in cells.

The study is published today in Nature Chemistry.

Rethinking the biology of DNA

One of the lead researchers Dr Marco Di Antonio, who began the work at the University of Cambridge in the laboratory of Professor Sir Shankar Balasubramanian and now leads a research team in the Department of Chemistry at Imperial, said: "For the first time, we have been able to prove the quadruple helix DNA exists in our cells as a stable structure created by normal cellular processes. This forces us to rethink the biology of DNA. It is a new area of fundamental biology, and could open up new avenues in diagnosis and therapy of diseases like cancer.

"Now we can track G4s in real time in cells we can ask directly what their biological role is. We know it appears to be more prevalent in cancer cells and now we can probe what role it is playing and potentially how to block it, potentially devising new therapies."

The team thinks G4s form in DNA in order to temporarily hold it open and facilitate processes like transcription, where the DNA instructions are read and proteins are made. This is a form of 'gene expression', where part of the genetic code in the DNA is activated.

G4s appear to be associated more often with genes involved in cancer, and are detected in larger numbers within cancer cells. With the ability to now image a single G4 at a time, the team say they could track their role within specific genes and how these express in cancer. This fundamental knowledge could reveal new targets for drugs that interrupt the process.

Natural formation

The team's breakthrough in being able to image single G4s came with a rethink of mechanisms usually used to probe the working of cells. Previously, the team had used antibodies and molecules that could find and attach to the G4s, but these needed very high concentrations of the 'probe' molecule. This meant the probe molecules might be disrupting the DNA and actually causing them to form G4s, instead of detecting them naturally forming.

Dr Aleks Ponjavic, now an academic in the Schools of Physics & Astronomy and Food Science and Nutrition at the University of Leeds, jointly lead the research in the laboratory of Professor Sir David Klenerman and developed the method of visualising the new fluorescent marker with microscopy.

He said: "Scientists need special probes to see molecules within living cells, however these probes can sometimes interact with the object we are trying to see. By using single-molecule microscopy, we can observe probes at 1000-fold lower concentrations than previously used. In this case our probe binds to the G4 for just milliseconds without affecting its stability, which allows us to study G4 behaviour in their natural environment without external influence."

For the new probe, the team used a very 'bright' fluorescent molecule in small amounts that was designed to stick to the G4s very easily. The small amounts meant they couldn't hope to image every G4 in a cell, but could instead identify and track single G4s, allowing them to understand their fundamental biological role without perturbing their overall prevalence and stability in the cell.

The team were able to show that G4s appear to form and dissipate very quickly, suggesting they only form to perform a certain function, and that potentially if they lasted too long they could be toxic to normal cell processes.

Unraveling a key motif: The T lymphocytes of the immune system work to destroy infected cells or cancer cells. To do so, they have to identify the threat: Molecules perceived as foreign - so-called antigens - bind to the T-cell receptor on the T cell surface. Now research groups led by Dr. Susana Minguet und Prof. Dr. Wolfgang Schamel from the University of Freiburg's signaling research Clusters of Excellence BIOSS and CIBSS have succeeded in demonstrating how this identification mechanism activates T cells to switch to attack mode. In a study published in the journal Nature Immunology, they describe a previously undiscovered domain of the T-cell receptor and demonstrate that this so-called RK motif improves immune therapies against cancer in pre-clinical studies.

The T-cell receptor is a tiny machine made up of many individual proteins. When it recognizes an infected or a tumor cell in the body, a so-called lymphocyte specific kinase binds to the T-cell receptor at the newly discovered RK motif. This binding switch on the T-cell receptor activating the T cell to become a killer cell and thus, eliminate the threat.. "We were astounded that this RK motive has never been described before," say Minguet and Schamel of the discovery: "Immunologists have been studying the T-cell receptor for more than 30 years now."

The findings serve to build a bridge between the perception of a threat and the activation of the immune response at the molecular level, shedding light on an essential operating principle of the immune system. T cells fulfill various functions: Cytotoxic T cells, so-called killer cells, are particularly responsible for destroying the body's own cells when they pose a threat to it - because they have been infected by bacteria or viruses or because they have changed into cancer cells. The T cells identify antigens exclusively on cells and then release toxic substances to destroy these target cells.

In immunotherapy against cancer, doctors try to strengthen this ability of the immune system. CAR T-cell therapy, which is already being used successfully for the treatment of patients at the Medical Center - University of Freiburg, uses artificial receptors synthetized in the lab on patient-derived T cells to specifically kill the cancer cells of the very same patient . In studies conducted at the Center for Chronic Immunodeficiency and in cooperation with Prof. Dr. Robert Zeiser, University Medical Center and also a member of CIBSS - Centre for Integrative Biological Signalling Studies, the researchers demonstrated in preclinical studies that CAR T cells equipped with the RK motif destroy more cancer cells than T cells that do not possess this motif.

The scientists discovered the RK motif with a combination of biochemistry, synthetic biology, and immunology. They demonstrated that the RK motif is normally hidden to prevent un-desired T cell activation and it is exposed only after binding to the antigen, this may explain why it has remained undetected until now. This unique combination of disciplines is a product of the integrative approach at the Cluster of Excellence CIBSS. The biochemical analyses enable a detailed understanding of the molecular signals, while their immunological understanding and medical application explain their function in the body.

"This discovery allows us to control T cells more precisely. And now we can do this very specifically, because this is the only cell type to use this novel activation mechanism," explains Minguet. "In the future, this may not only help in the treatment of cancer but possibly also improve therapies for autoimmune diseases or even immunodeficiencies."

Other scientists who contributed to the study included Prof. Dr. Maja Köhn from BIOSS and CIBSS, Prof. Dr. Stefan Günther from the Pharmaceutical Bioinformatics Lab at the University of Freiburg, and Dr. Kristian Schweimer and Prof. Dr. Birgitta Wöhrl from the University of Bayreuth. The study was also supported by the University of Freiburg's Collaborative Research Centres 850 "Control of Cell Motility in Morphogenesis, Cancer Invasion, and Metastasis" and 1160 "Immune-Mediated Pathology as a Consequence of Impaired Immune Reactions." Dr. Frederike Hartl, Faculty of Biology of the University of Freiburg, carried out a large part of the work.

In a new laboratory study, experts from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) investigated how many microplastic particles would be absorbed in the muscle tissue of young European sea bass after being given feed with extremely high microplastic particle content for a period of four months. At least with regard to this particular food fish, their findings are good news: only an extremely small percentage of the plastic particles ingested found their way into the fish fillets; the majority were excreted. The experts take this finding as a first indication that fish fillets can still be safe for human consumption, even if the fish eaten are subjected to extreme microplastic pollution. Their study has now been published in the July issue of the journal Marine Pollution Bulletin.

By now, fish are subjected to microplastic particles in all of their habitats - in rivers, lakes and seas, as well as aquaculture. Further, it has been confirmed that the animals ingest these tiny particles together with their food. In a new study conducted at the Centre for Aquaculture Research, part of the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) in Bremerhaven, scientists have for the first time investigated how many of the ingested particles make their way from the sea bass' digestive tract to the bloodstream, and subsequently to the muscle tissue. "This question is relevant for us human beings, especially because, as a rule, we don't eat the whole fish, including its innards, but only the fillets," explains Dr Sinem Zeytin, an AWI biologist and first author of the study.

For the laboratory experiment, adolescent European sea bass (Dicentrarchus labrax) were fed pellets consisting of fish meal, wheat bran, vitamins and fish oil, which the scientists had laced with a powder of yellow-orange fluorescing microplastic particles, for 16 weeks. The particles had a diameter of one to five micrometres (thousandths of a millimetre), so as to be representative of the smallest size category for microplastic. In the course of the experiment, every sea bass ingested roughly 163 million of these microscopically small plastic particles. Once the experiment was over, the experts filleted the fish to measure the particle content, while also gathering samples from their blood, gills, intestinal tract and internal organs like the liver for subsequent analysis. They heated part of the fillets in caustic potash, which completely dissolved the muscle tissue. The resultant fluid was then pressed through a filter that captured all of the plastic. They counted the number of particles present using a fluorescence microscope - first manually, and then using an automated technique.

One to two microplastic particles per five grams of fish fillet

The results came as a pleasant surprise to the researchers. "Even though we subjected the sea bass to extremely high microplastic pollution in comparison to their natural setting, in the end there were only 1 or 2 particles in every five grams of their fillets," Sinem Zeytin reports. "This, along with the fact that the fish grew very well and were in perfect health, tells us that the fish can apparently isolate and excrete these particles before they have a chance to penetrate their tissues. For everyone who enjoys eating sea bass, that's very good news," adds Dr Matthew Slater, Head of the Aquaculture Research Group at the AWI.

As Slater explains, due to the nature of the study, it's also possible that those microplastic particles detected weren't actually in the muscle cells, but instead in the tiny amounts of residual blood in the fillets. "In fact, during our study we found virtually no indications that the particles pass from the blood into the muscle cells," the AWI expert explains. That being said, initial analyses of other tissues confirmed that the particles do pass from the digestive tract to the bloodstream.

But how do the microplastic particles get from the digestive tract to the bloodstream? According to Sinem Zeytin, "So far, we have identified two ways: either the microscopically small plastic fragments manage to squeeze between two cells in the intestinal wall, or special transporter cells actively separate the particles from the remainder of the feed and pass them on, just like they do with minerals and nutrients."

Which of these two processes is predominant, whether there are other processes, and just how particle transport works in each one are questions the experts will seek to answer in future experiments.

Researchers at Tel Aviv University, led by Prof. Yaniv Assaf of the School of Neurobiology, Biochemistry and Biophysics and the Sagol School of Neuroscience and Prof. Yossi Yovel of the School of Zoology, the Sagol School of Neuroscience, and the Steinhardt Museum of Natural History, conducted a first-of-its-kind study designed to investigate brain connectivity in 130 mammalian species. The intriguing results, contradicting widespread conjectures, revealed that brain connectivity levels are equal in all mammals, including humans.

"We discovered that brain connectivity -- namely the efficiency of information transfer through the neural network -- does not depend on either the size or structure of any specific brain," says Prof. Assaf. "In other words, the brains of all mammals, from tiny mice through humans to large bulls and dolphins, exhibit equal connectivity, and information travels with the same efficiency within them. We also found that the brain preserves this balance via a special compensation mechanism: when connectivity between the hemispheres is high, connectivity within each hemisphere is relatively low, and vice versa."

Participants included researchers from the Kimron Veterinary Institute in Beit Dagan, the School of Computer Science at TAU and the Technion's Faculty of Medicine. The paper was published in Nature Neuroscience on June 8.

"Brain connectivity is a central feature, critical to the functioning of the brain," Prof. Assaf explains. "Many scientists have assumed that connectivity in the human brain is significantly higher compared to other animals, as a possible explanation for the superior functioning of the 'human animal.'" On the other hand, according to Prof. Yovel, "We know that key features are conserved throughout the evolutionary process. Thus, for example, all mammals have four limbs. In this project we wished to explore the possibility that brain connectivity may be a key feature of this kind -- maintained in all mammals regardless of their size or brain structure. To this end we used advanced research tools."

The project began with advanced diffusion MRI scans of the brains of about 130 mammals, each representing a different species. (All of the brains were removed from dead animals, and no animals were euthanized for the purposes of this study.) The brains, obtained from the Kimron Veterinary Institute, represented a very wide range of mammals -- from tiny bats weighing 10 grams to dolphins whose weight can reach hundreds of kilograms. Since the brains of about 100 of these mammals had never been MRI-scanned before, the project generated a novel and globally unique database. The brains of 32 living humans were also scanned in the same way. The unique technology, which detects the white matter in the brain, enabled the researchers to reconstruct the neural network: the neurons and their axons (nerve fibers) through which information is transferred, and the synapses (junctions) where they meet.

The next challenge was comparing the scans of different types of animals, whose brains vary greatly in size and/or structure. For this purpose the researchers employed tools from Network Theory, a branch of mathematics that enabled them to create and apply a uniform gauge of brain conductivity: the number of synopses a message must cross to get from one location to another in the neural network.

"A mammal's brain consists of two hemispheres connected to each other by a set of neural fibers (axons) that transfer information," Prof. Assaf explains. "For every brain we scanned, we measured four connectivity gages: connectivity in each hemisphere (intrahemispheric connections), connectivity between the two hemispheres (interhemispheric), and overall connectivity. We discovered that overall brain connectivity remains the same for all mammals, large or small, including humans. In other words, information travels from one location to another through the same number of synapses. It must be said, however, that different brains use different strategies to preserve this equal measure of overall connectivity: some exhibit strong interhemispheric connectivity and weaker connectivity within the hemispheres, while others display the opposite."

Prof. Yovel describes another interesting discovery. "We found that variations in connectivity compensation characterize not only different species but also different individuals within the same species," he says. "In other words, the brains of some rats, bats, or humans exhibit higher interhemispheric connectivity at the expense of connectivity within the hemispheres, and the other way around -- compared to others of the same species. It would be fascinating to hypothesize how different types of brain connectivity may affect various cognitive functions or human capabilities such as sports, music or math. Such questions will be addressed in our future research."

"Our study revealed a universal law: Conservation of Brain Connectivity," Prof. Assaf concludes. "This law denotes that the efficiency of information transfer in the brain's neural network is equal in all mammals, including humans. We also discovered a compensation mechanism which balances the connectivity in every mammalian brain. This mechanism ensures that high connectivity in a specific area of the brain, possibly manifested through some special talent (e.g. sports or music) is always countered by relatively low connectivity in another part of the brain. In future projects we will investigate how the brain compensates for the enhanced connectivity associated with specific capabilities and learning processes."

A phase 1/2 trial involving 1,077 healthy adults found that the vaccine induced strong antibody and T cell immune responses up to day 56 of the ongoing trial. These responses may be even greater after a second dose, according to a sub-group study of 10 participants

Compared to the control group (given a meningitis vaccine), the SARS-CoV-2 vaccine caused minor side effects more frequently, but some of these could be reduced by taking paracetamol. There were no serious adverse events from the vaccine

Based on their results, the authors say that further clinical studies, including in older adults, should be done with this vaccine. The current results focus on the immune response measured in the laboratory, and further testing is needed to confirm whether the vaccine effectively protects against infection

Promising early stage results from a phase 1/2 clinical trial of the UK's vaccine candidate against SARS-CoV-2 (the virus that causes COVID-19) are published today in The Lancet.

The early stage trial finds that the vaccine is safe, causes few side effects, and induces strong immune responses in both parts of the immune system - provoking a T cell response within 14 days of vaccination (ie, a cellular immune response, it could find and attack cells infected with the virus), and an antibody response with 28 days (ie, humoral immune response, it could find and attack the virus when it was circulating in the blood or lymphatic system).

An ideal vaccine against SARS-CoV-2 should be effective after one or two vaccinations, work in target populations including older adults and those with other health conditions, confer protection for a minimum of six months, and reduce onward transmission of the virus to contacts. The current trial is too preliminary to confirm whether the new vaccine meets these requirements, but phase 2 (in the UK only) and phase 3 trials to confirm whether it effectively protects against SARS-CoV-2 infection are happening in the UK, Brazil and South Africa.

Explaining how the vaccine works, study lead author Professor Andrew Pollard, University of Oxford, UK, says: "The new vaccine is a chimpanzee adenovirus viral vector (ChAdOx1) vaccine that expresses the SARS-CoV-2 spike protein. It uses a common cold virus (adenovirus) that infects chimpanzees, which has been weakened so that it can't cause any disease in humans, and is genetically modified to code for the spike protein of the human SARS-CoV-2 virus. This means that when the adenovirus enters vaccinated people's cells it also delivers the spike protein genetic code. This causes these people's cells to produce the spike protein, and helps teach the immune system to recognise the SARS-CoV-2 virus." [1]

He continues: "The immune system has two ways of finding and attacking pathogens - antibody and T cell responses. This vaccine is intended to induce both, so it can attack the virus when it's circulating in the body, as well as attacking infected cells. We hope this means the immune system will remember the virus, so that our vaccine will protect people for an extended period. However, we need more research before we can confirm the vaccine effectively protects against SARS-CoV-2 infection, and for how long any protection lasts." [1]

The new trial included 1,077 healthy adults aged 18-55 years with no history of COVID-19, and took place in five UK hospitals between 23 April and 21 May 2020 [2]. The data included in the paper covered the first 56 days of the trial and is ongoing.

The participants either received the new COVID-19 vaccine (543 people) or the meningococcal conjugate vaccine (534 people). 113 participants (56 given the COVID vaccine, and 57 in the control group) were also asked to take paracetamol before and for 24 hours after their vaccination to help reduce vaccine-associated reactions (as the COVID-19 vaccine was given in a high dose to help induce a strong immune response).

All participants gave additional blood samples and underwent clinical assessments to determine if the vaccine was safe and whether it provoked an immune response. Participants were also asked to record any adverse events throughout the trial.

The participants were split into four groups. Group 1 (88 people) had additional safety monitoring to form the phase 1 part of the trial, and had antibody and T cell responses assessed. Group 2 (412 people) had extra blood taken to assess for antibody and T cell responses, and group 4 (567 people) had serum taken to assess for antibody response only. In groups 1, 2 and 4 half the participants received the COVID-19 vaccine and half received the control vaccine. Group 3 (10 people) received only the COVID-19 vaccine, and were given an extra dose of vaccine 28 days after the first dose to determine safety and whether this boosted antibody and T cell responses.

The vaccine was found to have an acceptable safety profile and there were no serious adverse events. Fatigue and headache were the most commonly reported reactions (around 70% [340/487] of all participants given the COVID-19 vaccine only reported fatigue, and 68% [331/487] reported headache, compared with around 48% [227/477] and 41% [195/477], respectively, of participants in the control group without paracetamol). Other common side effects included pain at the injection site, muscle ache, malaise, chills, feeling feverish, and high temperature.

Participants taking paracetamol around their vaccination had reduced pain, chills, feeling feverish, muscle ache, headache, and malaise in the two days following vaccination. In addition, in the 10 people who received the extra dose of the COVID-19 vaccine, side effects were less common after the second dose.

The authors found that there were strong antibody and T cell responses from the vaccine. T cell responses targeting the SARS-CoV-2 spike protein were markedly increased (in the 43 participants studied), peaking 14 days after vaccination (median 856 spot-forming cells per million peripheral blood mononuclear cells), with this level declining slightly by day 56 of the trial (to median 424 spot-forming cells per million peripheral blood mononuclear cells) . The T cell response did not increase with a second dose of the vaccine, which is consistent with other vaccines of this kind.

Antibody responses peaked by day 28 (median 157 ELISA units - studied in 127 participants) and remained high until the measurement at day 56 in the trial (median 119 ELISA units - studied in 43 participants) for those given a single vaccine. This response was boosted by a second dose (median 639 ELISA units at day 56 in these 10 participants).

28 days after vaccination, neutralising antibody responses against SARS-CoV-2 were detected in 32 of 35 participants (91%) (when measured in MNA80 neutralisation assay), and in 35 of 35 participants (100% - when measured in PRNT50 neutralisation assay) who received a single dose of the COVID-19 vaccine. These responses were present in all participants who had a booster dose of the vaccine (nine of nine participants in MNA80 assay at day 42, and ten of ten in Marburg VN assay on day 56).

The authors found that taking paracetamol did not affect immunogenicity of the COVID-19 vaccine.

Co-author, Professor Sarah Gilbert, University of Oxford, UK, says: "There is still much work to be done before we can confirm if our vaccine will help manage the COVID-19 pandemic, but these early results hold promise. As well as continuing to test our vaccine in phase 3 trials, we need to learn more about the virus - for example, we still do not know how strong an immune response we need to provoke to effectively protect against SARS-CoV-2 infection. If our vaccine is effective, it is a promising option as these types of vaccine can be manufactured at large scale. A successful vaccine against SARS-CoV-2 could be used to prevent infection, disease and death in the whole population, with high risk populations such as hospital workers and older adults prioritised to receive vaccination." [1]

The authors note some limitations, including that more research is needed to confirm their findings in different groups of people - including older age groups, those with other health conditions, and in ethnically and geographically diverse populations. The authors note that these groups are being recruited in their ongoing phase 2 and 3 trials of the vaccine in the UK, Brazil and South Africa. In the current trial, 91% (979/1,077) of participants were white and the average age of participants was 35 years.

They also note that a small number of participants had detectable neutralizing antibodies and T cell responses against SARS-CoV-2 spike protein before vaccination, likely to be due to past asymptomatic infection as potential participants with recent COVID-19-like symptoms or with a history of positive PCR test for SARS-CoV-2 were excluded from the study.

The authors say the participants recruited in this study will be followed-up for at least one year to continue to study the vaccine's safety and the immune response it provokes.

Writing in a linked Comment discussing both Articles, lead author Assistant Professor Naor Bar-Zeev (who was not involved in the two studies), International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, USA, says: "These trial reports are hugely anticipated. The results of both studies augur well for phase 3 trials, where the vaccines must be tested on much larger populations of participants to assess their efficacy and safety... Both trials used adenovirus vectors to deliver and study the COVID-19 vaccine, an innovative and efficient means of vaccine development in the midst of a pandemic. Capable of generating humoral, cellular, and innate responses, adenovirus vectored vaccines have much potential."

However, he warns of the preliminary nature of the two vaccine candidates. He continues: "The platform [adenovirus vectored vaccines] only achieved European Commission regulatory licensure on July 1, 2020, with the Ebola vaccine. Much remains unknown about these and other COVID-19 vaccines in development, including longevity of response and immunogenicity in older adults or other specific groups, such as those with comorbidities who are often excluded from clinical trials, or ethnic or racial groups more severely affected by COVID-19."

Researchers at EPFL are able to get paralyzed rodents walking again by stimulating the animals' damaged spinal cords. This promising treatment has already helped paraplegics regain mobility during clinical trials at Lausanne University Hospital (CHUV). Now, using artificial intelligence, the researchers can pinpoint which neurons are involved in the gait reacquisition process. The results, which have been published in Nature Biotechnology, could lead to the development of new approaches, making treatments even more effective, as well as paving the way for advances in other areas of biomedical research.

Rodent spinal cords - like those of human beings - contain some 50 different types of nerve cells, or neurons. Not all of these cells, however, respond in the same way to the gait recovery treatment developed at EPFL, which is based on a combination of exercises and electrical and chemical spinal cord stimulation. By precisely identifying the types of neurons involved, however, researchers can better understand what happens at a cellular level when these stimuli result in immediate gait recovery. They can then specifically target those neurons that are activated by stimulation, thereby boosting the treatment's effectiveness.

As part of these efforts, Grégoire Courtine's laboratory has developed a machine learning method that can be applied to any kind of single-cell technology, and identify which cells are most important for the task at hand. The application of this method to single-cell biology is particularly exciting as techniques such as single-cell RNA sequencing provide precise cell-by-cell measurements of all the genes a cell could express, allowing researchers to pinpoint the key cellular mechanisms.

The scientists compared their results using two groups of mice: ones that had relearned how to walk after a spinal cord injury and those that remained paralyzed in their lower limbs due to a lack of treatment. However, when such a treatment could change the expression of thousands of genes, identifying within these massive datasets the specific neurons that aid in the mice's recovery is a challenging problem. To tackle this, Courtine's team developed a machine-learning method. Dubbed Augur, it is capable of learning to pinpoint the cell types that best account for differences between two conditions by automatically considering the expression levels of thousands of genes.

Augur provides a priority score, predicting which cells display the greatest differences between paralyzed mice and those that have regained mobility. When Augur prioritizes a certain type of neuron, it means that that neuron is critical to gait recovery induced by electrochemical stimulation. Conversely, neurons that are not prioritized by Augur behave in a similar manner in mobile and non-mobile mice and therefore probably do not play a major role in the response to treatment.

"It is a robust statistical method that can be applied to any perturbation," say the paper's two first authors Michael Skinnider and Jordan Squair. "The more accurately Augur can assign a particular type of neuron to the two groups of mice, the more relevant those particular nerve cells are. They are therefore more likely to be involved in gait recovery."

Using this method, the researchers were able to identify a type of neuron that plays an important role in gait recovery in mice. They can now observe the mechanisms at work in greater detail, and also target them with pharmacological treatment to increase the overall effectiveness.

This method will be of interest to many biomedical studies, according to Courtine: "Whether you are working on cancer, Crohn's disease, COVID, or multiple sclerosis, the central question remains the same, what type of cell is at the source of the problem? Our method speeds up the investigative process, and for this reason we have made Augur freely available."

If you've ever wondered why we get goosebumps, you're in good company -- so did Charles Darwin, who mused about them in his writings on evolution. Goosebumps might protect animals with thick fur from the cold, but we humans don't seem to benefit from the reaction much -- so why has it been preserved during evolution all this time?

In a new study, Harvard University scientists have discovered the reason: the cell types that cause goosebumps are also important for regulating the stem cells that regenerate the hair follicle and hair. Underneath the skin, the muscle that contracts to create goosebumps is necessary to bridge the sympathetic nerve's connection to hair follicle stem cells. The sympathetic nerve reacts to cold by contracting the muscle and causing goosebumps in the short term, and by driving hair follicle stem cell activation and new hair growth over the long term.

Published in the journal Cell, these findings in mice give researchers a better understanding of how different cell types interact to link stem cell activity with changes in the outside environment.

"We have always been interested in understanding how stem cell behaviors are regulated by external stimuli. The skin is a fascinating system: it has multiple stem cells surrounded by diverse cell types, and is located at the interface between our body and the outside world. Therefore, its stem cells could potentially respond to a diverse array of stimuli -- from the niche, the whole body, or even the outside environment," said Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology, who led the study in collaboration with Professor Sung-Jan Lin of National Taiwan University. "In this study, we identify an interesting dual-component niche that not only regulates the stem cells under steady state, but also modulates stem cell behaviors according to temperature changes outside."

A system for regulating hair growth

Many organs are made of three types of tissue: epithelium, mesenchyme, and nerve. In the skin, these three lineages are organized in a special arrangement. The sympathetic nerve, part of our nervous system that controls body homeostasis and our responses to external stimuli, connects with a tiny smooth muscle in the mesenchyme. This smooth muscle in turn connects to hair follicle stem cells, a type of epithelial stem cell critical for regenerating the hair follicle as well as repairing wounds.

The connection between the sympathetic nerve and the muscle has been well known, since they are the cellular basis behind goosebumps: the cold triggers sympathetic neurons to send a nerve signal, and the muscle reacts by contracting and causing the hair to stand on end. However, when examining the skin under extremely high resolution using electron microscopy, the researchers found that the sympathetic nerve not only associated with the muscle, but also formed a direct connection to the hair follicle stem cells. In fact, the nerve fibers wrapped around the hair follicle stem cells like a ribbon.

"We could really see at an ultrastructure level how the nerve and the stem cell interact. Neurons tend to regulate excitable cells, like other neurons or muscle with synapses. But we were surprised to find that they form similar synapse-like structures with an epithelial stem cell, which is not a very typical target for neurons," Hsu said.

Next, the researchers confirmed that the nerve indeed targeted the stem cells. The sympathetic nervous system is normally activated at a constant low level to maintain body homeostasis, and the researchers found that this low level of nerve activity maintained the stem cells in a poised state ready for regeneration. Under prolonged cold, the nerve was activated at a much higher level and more neurotransmitters were released, causing the stem cells to activate quickly, regenerate the hair follicle, and grow new hair.

The researchers also investigated what maintained the nerve connections to the hair follicle stem cells. When they removed the muscle connected to the hair follicle, the sympathetic nerve retracted and the nerve connection to the hair follicle stem cells was lost, showing that the muscle was a necessary structural support to bridge the sympathetic nerve to the hair follicle.

How the system develops

In addition to studying the hair follicle in its fully formed state, the researchers investigated how the system initially develops -- how the muscle and nerve reach the hair follicle in the first place.

"We discovered that the signal comes from the developing hair follicle itself. It secretes a protein that regulates the formation of the smooth muscle, which then attracts the sympathetic nerve. Then in the adult, the interaction turns around, with the nerve and muscle together regulating the hair follicle stem cells to regenerate the new hair follicle. It's closing the whole circle -- the developing hair follicle is establishing its own niche," said Yulia Shwartz, a postdoctoral fellow in the Hsu lab. She was a co-first author of the study, along with Meryem Gonzalez-Celeiro, a graduate student in the Hsu Lab, and Chih-Lung Chen, a postdoctoral fellow in the Lin lab.

Responding to the environment

With these experiments, the researchers identified a two-component system that regulates hair follicle stem cells. The nerve is the signaling component that activates the stem cells through neurotransmitters, while the muscle is the structural component that allows the nerve fibers to directly connect with hair follicle stem cells.

"You can regulate hair follicle stem cells in so many different ways, and they are wonderful models to study tissue regeneration," Shwartz said. "This particular reaction is helpful for coupling tissue regeneration with changes in the outside world, such as temperature. It's a two-layer response: goosebumps are a quick way to provide some sort of relief in the short term. But when the cold lasts, this becomes a nice mechanism for the stem cells to know it's maybe time to regenerate new hair coat."

In the future, the researchers will further explore how the external environment might influence the stem cells in the skin, both under homeostasis and in repair situations such as wound healing.

"We live in a constantly changing environment. Since the skin is always in contact with the outside world, it gives us a chance to study what mechanisms stem cells in our body use to integrate tissue production with changing demands, which is essential for organisms to thrive in this dynamic world," Hsu said.

PROVIDENCE, R.I. [Brown University] -- Which sleep stage is most important for learning: REM or non-REM? Does sleep improve learning by enhancing skills while people snooze, or by cementing those skills in the brain so that they're less likely to forget them? Do these processes occur every time someone sleeps, or only after they have learned something new?

The answer to these questions, according to a new study on visual learning, is "all of the above."

"Sleep is good for many processes in the body and mind, but the controversy was how sleep is good," said corresponding author Yuka Sasaki, a professor of cognitive, linguistic and psychological sciences (research) at Brown University. "Do non-REM sleep and REM sleep make different contributions, or does the sleep stage not matter? We think we have one answer, because we clearly show the difference in the roles of non-REM sleep and REM sleep in visual perceptual learning."

In the study, published in Nature Neuroscience on Monday, July 20, young adults were trained to identify a letter and the orientation of a set of lines on a textured background in two different tasks: one before sleep and one after sleep. Between the two tasks, the researchers analyzed the participants' brain waves while they were sleeping and simultaneously measured the concentrations of two different chemicals in their brains: an excitatory neurotransmitter called glutamate and an inhibitory neurotransmitter called gamma-aminobutyric acid. Separately, the researchers performed the same analyses on people who did not participate in the visual learning tasks.

By measuring the ratio of these two chemicals in the brain -- called the excitation/inhibition (E/I) balance -- scientists can gather clues about the state of a particular brain area. Sometimes, such as when a brain area has a high E/I balance, neurons are actively forming new connections, which means that the brain area has a high degree of plasticity.

Conversely, when a brain area has low E/I balance, it is said to be in a state of stabilization. During stabilization, less important neural connections are pruned away, thereby increasing the efficiency and resiliency of the connections that remain. Both plasticity and stabilization are integral to the learning process: Plasticity typically translates to performance gains, and stabilization prevents new learning from being overwritten or interfered with by future learning.

This new study found that plasticity and stabilization occur during different stages of sleep.

During non-REM (NREM) sleep, the visual areas of participants' brains exhibited an E/I balance suggestive of increased plasticity. The pattern was found even among participants who did not partake in the visual learning tasks, which means that it occurs even in the absence of learning.

However, the REM stage appears to be necessary for people to reap the benefits of the increased plasticity they exhibit during NREM sleep. During REM sleep, the chemical concentrations in participants' brains indicated that their visual areas underwent stabilization. (This process occurred only in the participants who partook in the visual learning tasks, which suggests that, in contrast to plasticity, stabilization during sleep occurs only in the presence of learning.)

Participants who only underwent NREM sleep did not exhibit any performance gains, likely because the new, post-sleep task interfered with their learning of the pre-sleep task. Conversely, those who underwent both NREM and REM sleep exhibited significant performance gains for both the pre-sleep and post-sleep task.

"I hope this helps people realize that both non-REM sleep and REM sleep are important for learning," Sasaki said. "When people sleep at night, there are many sleep cycles. REM sleep appears at least three, four, five times, and especially in the later part of the night. We want to have lots of REM sleep to help us remember more robustly, so we shouldn't shorten our sleep."

Going forward, Sasaki and her colleagues would like to see if their findings can be generalized to other types of learning. They would also like to combine this research with their past research on visual perceptual learning and reward.

"Previously, we showed that reward enhances visual learning through sleep, so we'd like to understand how that works," she said. "It's ambitious, but maybe we could expand this research to other types of learning so we could remember better and develop better motor learning, better visual skills and better creativity."

Boston, Mass. - In the early days of the COVID-19 pandemic, the disease was characterized by many as a flu-like respiratory infection mainly affecting the lungs. Now, physicians recognize that the coronavirus can impact organs throughout the body. In a collaboration among physicians at Beth Israel Deaconess Medical Center (BIDMC) and Columbia University Irving Medical Center, researcher-clinicians have conducted an extensive review of the latest findings on COVID-19's effect on organ systems outside the lungs. Their review, published in Nature Medicine, also summarized proposed mechanisms behind these wide-ranging systemic effects and provided clinical guidance for physicians.

"Scientists all over the world are working at an unprecedented rate towards understanding how this virus specifically hijacks biological mechanisms of the human body that are normally protective," said co-lead author Kartik Sehgal, MD, a hematology/oncology fellow in the Cancer Center at BIDMC. "We hope that our review will be a comprehensive resource for physicians, nurses and other health care workers caring for patients with COVID-19, and provide impetus to consideration of all organ systems involved while developing research priorities and therapeutic strategies."

Based on their own experiences caring for patients with COVID-19 as well as recent reports in the scientific literature, the team of clinicians -- co-led by Columbia cardiology fellows Aakriti Gupta, MD and Mahesh V. Madhavan, MD, and senior author Donald Landry, MD, PhD, chair of medicine at the Columbia University Irving Medical Center -- delineate the myriad fronts on which the coronavirus may attack the body.

Beyond the severe respiratory distress now associated with severe COVID-19, the virus also may increase patients' risk of heart attack, kidney failure and clotting disorders, the physicians report. Neurological symptoms, including headache, dizziness, fatigue, and loss of smell, may occur in about a third of patients. Patients with severe cases of COVID-19 are also at risk for strokes caused by blood clots and delirium. "Physicians need to think of COVID-19 as a multisystem disease," said Gupta. "There's a lot of news about clotting but it's also important to understand that a substantial proportion of these patients suffer kidney, heart, and brain damage."

Scientists suspect these various complications may all stem from the systemic inflammation that can occur as the immune system attempts to fight off the virus's attack on the body, especially cells that line the blood vessels. When the virus attacks blood vessel cells, inflammation increases, and blood begins to form clots, big and small. These blood clots can travel all over the body and wreak havoc on organs, perpetuating a vicious cycle. In addition, the downstream messenger signals of the immune system may spiral out of control in severe cases, contributing to these widespread effects.

"Future studies following patients who experienced complications during hospitalizations for COVID-19 will be crucial," said Madhavan. "It really was quite astounding to see the significant ramifications this virus had on these other systems."

Breaking this cycle may be a promising way to treat patients with severe cases of COVID-19. A recent clinical trial has found that at a drug called dexamethasone -- a steroid the globally suppresses the immune system -- reduced deaths in ventilated patients by one-third.

"It's a relatively new virus and we're still learning about its long-term effects," said Sehgal. "The recognition of multi-system involvement by COVID-19 is important for optimal care of these patients while hospitalized, and to develop a comprehensive post-hospital discharge follow up plan."

BOSTON (July 20, 2020, 8:00 a.m. EDT)--The nation needs to strengthen and increase funding for federal nutrition research and improve cross-governmental coordination in order to accelerate discoveries, grow the economy, and - most importantly - improve public health, food/nutrition security, and population resilience, according to a high-level group of research, policy, and government experts.

Their new white paper, supported by The Rockefeller Foundation and entitled "Strengthening national nutrition research: Rationale and options for a new coordinated federal research effort and authority," is published today in the American Journal of Clinical Nutrition from the American Society for Nutrition (ASN).

The group's recommendations were announced during a live streaming event on July 15 hosted by the Bipartisan Policy Center. A coalition of major organizations is standing in support of the paper and the need for greater investment and coordination in federal nutrition research.

Currently, nutrition research is separately conducted and supported by more than 10 federal departments and agencies. The authors lay out two complementary strategies for harmonizing these efforts and expanding federal investment in nutrition science. The strategies are:

improving cross-government coordination of nutrition research, through policies such as a new Office of the National Director of Food and Nutrition or new U.S. Task Force on Federal Nutrition Research; and,

strengthening and accelerating nutrition research within the National Institutes of Health (NIH), including creating a new National Institute of Nutrition, among other options.

"Every day, our country suffers massive health, social, and economic costs of poor diets. The COVID-19 pandemic has further highlighted the burdens of diet-related diseases on population resilience," said Dariush Mozaffarian, M.D., Dr.P.H., principal investigator and dean and Jean Mayer Professor at the Friedman School of Nutrition Science and Policy at Tufts University. "The nation has come together to achieve major science challenges in the past, such as putting a man on the moon. We need a similar major national effort to address current nutrition challenges, generating the critical science to rapidly treat and prevent diet-related diseases, improve health equity, increase population resilience to COVID-19 and future pandemics, and drive fundamental and translational discoveries for better lives."

Over the last 20 years, the number of adults with diabetes has more than doubled and today, half of all American adults suffer from diabetes or pre-diabetes. Cardiovascular disease afflicts about 122 million Americans and causes roughly 840,000 deaths each year. These preventable diet-related illnesses are resulting in skyrocketing healthcare costs, widening diet-related health disparities, and weakened national security and military readiness. Our food systems are also creating unparalleled challenges to our natural resources.

"The American Society for Nutrition has long advocated to strengthen nutrition research, and this new white paper comprehensively assesses federal nutrition research efforts, bringing to light challenges and opportunities for better health for Americans," said ASN Past President Richard D. Mattes, Ph.D., M.P.H., R.D.. "Strengthening and investing in federal nutrition research will generate new discoveries to improve the health of Americans; reduce chronic diseases, disparities, and healthcare costs; strengthen military readiness and American businesses, and reinvigorate farming and rural communities."

DALLAS, July 20, 2020 -- People who regularly exercise tend to have a lower risk of high blood pressure, even if they live in areas where air pollution is relatively high, according to new research published today in the American Heart Association's flagship journal Circulation.

The risk-benefit relationship between air pollution and physical activity is an important public concern because more than 91% of people worldwide live in areas where air quality does not meet World Health Organization (WHO) guidelines.

"Extended outdoor activity in urban areas increases the intake of air pollutants, which can worsen the harmful health effects of air pollution," said study author Xiang Qian Lao, Ph.D., an associate professor at the Jockey Club School of Public Health and Primary Care at The Chinese University of Hong Kong in Shatin, Hong Kong. "While we found that high physical activity combined with lower air pollution exposure was linked to lower risk of high blood pressure, physical activity continued to have a protective effect even when people were exposed to high pollution levels. The message is that physical activity, even in polluted air, is an important high blood pressure prevention strategy."

Researchers studied more than 140,000 non-hypertensive adults in Taiwan and followed them for an average of 5 years. Researchers classified the weekly physical activity levels of each adult as inactive, moderately active or highly active.

Researchers also classified level of exposure to fine particulate matter (PM2.5) as low, moderate and high. PM2.5 is the most commonly used indicator of air pollution. High blood pressure was defined as 140/90 mm Hg. The American Heart Association/American College of Cardiology 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults defines high blood pressure as 130/80 mm Hg.

The researchers found:

Overall, people who are highly active and exposed to low levels of pollution had a lower risk of developing high blood pressure. People who were inactive and exposed to highly polluted air had a higher high blood pressure risk.

Each increase in PM2.5 level was associated with a 38% increase in risk of incident hypertension, whereas each increase in physical activity level lead to a 6% lower risk of hypertension. This suggests that reducing air pollution is more effective in preventing high blood pressure.

The benefits of regular physical activity held up regardless of pollution level. People who exercised moderately had a 4% lower risk of high blood pressure than those who didn't exercise. People who exercised at a high level had a 13% lower risk of high blood pressure than the non-exercisers.

"This is the largest study to analyze the combined effects of air pollution and regular physical activity on high blood pressure. Our findings indicate that regular physical activity is a safe approach for people living in relatively polluted regions to prevent high blood pressure. Exercise should be promoted even in polluted areas. The findings also put a spotlight on how strongly pollution can impact blood pressure, and how important it is to control pollution levels to prevent high blood pressure," Lao said.

In 2004, the American Heart Association issued a scientific statement concluding exposure to air pollution contributes to cardiovascular illness and death. A 2010 update elaborated on those risks, which include heart attack, stroke, arrhythmia and heart failure. Writing group author Russell V. Luepker, M.D., M.S., a volunteer expert for the American Heart Association said, "This study confirms our understanding of the role of physical activity in the prevention of cardiovascular diseases including hypertension. It also reminds us of the importance of air pollution in the development of cardiovascular diseases. The link between pollution and cardiovascular disease may include the development of hypertension along with other factors associated with particulate matter in air pollution."

The findings of this study are limited and cannot be generalized to other populations with higher exposure to air pollution because it only included people living in Taiwan, where ambient air was moderately polluted (the annual PM2.5 concentration was 2.6 times of the limit recommended by the World Health Organization). Researchers did not distinguish between outdoor and indoor physical activity, meaning they could not exclusively examine the association of PM2.5 and hypertension relative to physical activity outdoors or indoors. Researchers also included indoor cigarette smoking as a variable.

Engineers have taken their inspiration from shells and grapefruits to create what they say is the first manufactured non-cuttable material.

This new material, which could be used in the security and health and safety industries, can turn back the force of a cutting tool upon itself.

The lightweight material - named Proteus after the shape-changing mythical god - is made of ceramic spheres encased in a cellular aluminium structure that in tests could not be cut by angle grinders, drills or high-pressure water jets.

An international research team, led by Durham University, UK, and Fraunhofer Institute for Machine Tools and Forming Technology IWU in Chemnitz in Germany, got the idea for the new material from the tough cellular skin of the grapefruit and the fracture resistant shells of molluscs.

Abalone sea creatures are built from tiles interlinked with a biopolymer material that make them resistant to fractures.
To resist the most violent forcible entry tools, organic materials such as aragonite tiles - found in mollusc shells - were replaced in the new material with industrial, alumina ceramics and an aluminium, metallic foam matrix.

The new material is strong, light and non-cuttable. The researchers say, it could be used to make bike locks, lightweight armour and in protective equipment for people who work with cutting tools.

The findings are published in the journal Scientific Reports.
The new material system is dynamic with an evolving internal structure that creates high-speed motion where it interacts with the cutting tools. The dynamic response is more akin to living structures.

The material is made from a cellular aluminium structure wrapped around ceramic spheres and this has a doubly destructive effect on cutting tools.
When cut with an angle grinder or drill, the vibrations created by the ceramic spheres inside the casing blunt the cutting disc or drill bit.

The interaction between the disc and ceramic sphere creates an interlocking, vibrational connection that resists the cutting tool indefinitely.

The blade is gradually eroded, and eventually rendered ineffective as the force and energy of the disc or the drill is turned back on itself, and it is weakened and destroyed by its own attack.

In addition, the ceramics fragment into fine particles, which fill the cellular structure of the material and harden as the speed of the cutting tool is increased due to interatomic forces between the ceramic grains. In this way the adaptive nature of the material further repulses any attack.

Water jets were also found to be ineffective because the curved surfaces of the ceramic spheres widen the jet, which substantially reduces its speed and weakens its cutting capacity.

Lead author Dr Stefan Szyniszewski, Assistant Professor of Applied Mechanics, in the Department of Engineering, Durham University, said: "We were intrigued by how the cellular structure of the grapefruit and the tiled structure of mollusc shells can prevent damage to the fruit or the creatures inside, despite being made of relatively weak organic building blocks.

"These natural structures informed the working principle of our metallic-ceramic material, which is based on dynamic interaction with the applied load, in contrast to passive resistance.

"Essentially cutting our material is like cutting through a jelly filled with nuggets. If you get through the jelly you hit the nuggets and the material will vibrate in such a way that it destroys the cutting disc or drill bit.

"The ceramics embedded in this flexible material are also made of very fine particles which stiffen and resist the angle grinder or drill when you're cutting at speed in the same way that a sandbag would resist and stop a bullet at high speed.

"This material could have lots of useful and exciting applications in the security and safety industries. In fact, we are not aware of any other manufactured non-cuttable material in existence as of now."

Study co-author Dr Miranda Anderson, Department of Philosophy, University of Stirling said: "Because the successful resistance of our material system requires it to undergo internal transformations, we chose the name Proteus.

"In 1605, Francis Bacon compared natural materials to Proteus who 'ever changed shapes' and he argued that through experimentation we can reveal the metamorphic qualities of materials."

Dr Szyniszewski added: "This is what we've achieved with this new material and we're excited by its potential."

The researchers have a patent pending for their material technology and they hope to work with industry partners so it can be developed into products for the marketplace.