“Previous research has shown that disruption of the blood-brain barrier is increased in people with cerebral small vessel disease,” said study author Danielle Kerkhofs, M.D., of Maastricht University Medical Center in Maastricht, Netherlands. “People with cerebral small vessel disease also may have brain lesions called white matter hyperintensities. Such lesions are visible by MRI and believed to be signs of brain damage and a marker of the severity of disease. For our study, we wanted to see if a leaky blood-brain barrier was linked to degeneration of brain tissue even before these brain lesions appear. We looked at normal brain tissue, surrounding and close to the brain lesions, because we consider this ’tissue at risk.'”

The study involved 43 people with cerebral small vessel disease with an average age of 68. Researchers used MRI at the start of the study to measure the leakiness of the blood-brain barrier for each participant. They then used another brain imaging technique to measure the integrity of the tissue’s microstructure surrounding brain lesions. This imaging technique was repeated two years later to see whether the brain tissue integrity has decreased.

Researchers measured the relationship between blood-brain barrier leakage and changes in brain tissue. They found the higher the tissue volume with blood-brain barrier leakage at the start of the study, the greater the loss of brain tissue integrity was around brain lesions two years later. For every 10% increase in leakage volume at the start of the study, after two years the diffusivity of the brain tissue increased by 1.4 %, representing a decrease in brain tissue integrity. They also found a similar relationship involving the leakage rate of the blood-brain barrier — a higher leakage rate at the start of the study resulted in more loss of tissue microstructure around the brain lesions.

“Our results support the theory that a compromised blood-brain barrier may play an early role in loss of brain tissue integrity as part of the cerebral small vessel disease process, even before brain lesions are visible on MRI,” said Kerkhofs. “The change in integrity of brain tissue at risk, close to the brain lesions, could be a promising biomarker in future cerebral small vessel disease studies examining possible prevention strategies and treatment options.”

A limitation of the study was that the short follow-up period may have underestimated the associations. Kerkhofs said future studies should measure such changes in larger groups of people over longer periods of time.

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Following the team’s previous research, which identified that the concentration of specific molecules in saliva changes rapidly after a traumatic brain injury, the researchers embarked on a three-year study in elite rugby to establish if these ‘biomarkers’ could be used as a diagnostic test for sport-related concussion.

Using DNA sequencing technology in the laboratory at the University of Birmingham, the research team tested these biomarkers in saliva samples from 1,028 professional men’s rugby players competing in English rugby’s top two leagues — the Premiership and Championship.

The results of SCRUM (Study of Concussion in Rugby Union through MicroRNAs), published today (March 23) in the British Journal of Sports Medicine, has for the first time shown that specific salivary biomarkers can be used to indicate if a player has been concussed. Additionally, the research has found these biomarkers provide further insights into the body’s response to injury as it evolves from immediately after trauma, to several hours and even days later.

The scientific breakthrough provides a new laboratory-based non-invasive salivary biological concussion test, which could have wide-reaching use and potential to reduce the risk of missing concussions not only in sport — from grassroots to professional levels — but also in wider settings such as military and healthcare.

In community sport, these biomarkers may provide a diagnostic test that is comparable in accuracy to the level of assessment available in a professional sport setting. While, at an elite level of rugby, the concussion test may be used in addition to the existing World Rugby Head Injury Assessment (HIA) protocol.

Marker Diagnostics, a subsidiary of Swiss biotechnology company Marker AG, is in the process of commercialising the patented salivary concussion test as an over-the-counter test for elite male athletes. It has also obtained a CE Mark for test, which has been named MDx.100.

The team now aims to collect further samples from players in two elite men’s rugby competitions in order to provide additional data to expand the test and develop its use to guide the prognosis and safe return to play after concussion and to further establish how it will work alongside the HIA process.

The team will present their findings and planned next research steps at the World Rugby Laws and Welfare Symposium to be held later this month.

Meanwhile, Marker Diagnostics and the University of Birmingham are also currently carrying out several additional studies to further validate and expand the test for use in different groups that were not included in the SCRUM study, including women, young athletes and community sports players.

The research is part of the REpetitive COncussion in Sport (ReCoS) research programme being led by the University of Birmingham through the National Institute for Health Research’s Surgical Reconstruction and Microbiology Research Centre (NIHR SRMRC) based at University Hospitals Birmingham NHS Foundation Trust (UHB).

First author Dr Valentina Di Pietro, of the University of Birmingham and NIHR SRMRC, said: “Concussion can be difficult to diagnose, particularly in settings such as grass roots sports where evaluation by a specialist clinician is not possible. Consequently, some concussions may go undiagnosed.

“There are also concerns regarding the long-term brain health of those exposed to repeated concussions.

“A non-invasive and accurate diagnostic test using saliva is a real game changer and may provide an invaluable tool to help clinicians diagnose concussions more consistently and accurately.

“In professional sports, this diagnostic tool may be used in addition to current head injury assessment protocols and return to play evaluation to ensure the safety of individuals.”

Senior author Antonio Belli, Professor of Trauma Neurosurgery at the University of Birmingham, Consultant Neurosurgeon at UHB, and Director of NIHR SRMRC, added: “Conducting a study in a professional contact sports setting has meant we have been able to collect invaluable data enabling us to make significant advances in our biological knowledge and understanding of concussion and its diagnosis.

“Crucially, the differences in the salivary concentration of these biomarkers are measurable within minutes of injury, which means we can make rapid diagnoses.

“The ability to rapidly diagnose concussion using biomarkers in addition to existing tools solves a major unmet need in the sporting world as well as in military and healthcare settings, particularly in injuries without significant visible symptoms.”

Author Dr Simon Kemp, RFU’s Medical Services Director, said: “This study is an important part of the portfolio of collaborative research initiatives the RFU undertakes into concussion.

“While still a way from having something that can be used in community rugby, it is extremely encouraging to now be able to start to develop a rapid and non-invasive test which could add real value particularly at a grassroots level of the game.

“We would like to thank all the players and clubs who participated in the study and to World Rugby for granting permission for us to extend the duration of the HIA from 10 to 13 minutes in order for the saliva samples to be captured. We wouldn’t have been able to do it without this support.

“We will now be working with World Rugby to secure further research options in two elite men’s competitions.”

Author Dr Matt Cross, Head of Science and Medical Operations at Premiership Rugby, said: “We would like to thank our clubs and all of the players for volunteering to be part of this very important research project.

“The findings from the study are clearly promising and highlight the potential for salivary biomarkers to further support clinical decision making and the accurate identification and diagnosis of concussion in a range of different sporting and non-sporting settings.

“Premiership Rugby and the Premiership clubs support a number of player welfare focused research projects, and we are looking forward to continuing to collaborate and support further research in the next phase of this specific project from 2021-22 onwards.”

Dr Éanna Falvey, World Rugby Chief Medical Officer, added: “Elite Rugby’s Head Injury Assessment process has proven an invaluable tool in the identification of concussion with an accuracy of over 90 per cent, but we are continually evaluating the latest developments in science and technology to identify potential enhancements.

“This study, its rigour and outcomes demonstrates the value in a targeted, scientific approach and reflects rugby’s progressive commitment to player welfare.”

Tinus Maree, CEO of Marker AG, said: “This ground-breaking validation of the biomarker panel shows that we can use the simple swab collection of saliva to accurately and specifically diagnose concussion.

“It is a biological measure of mild traumatic brain injury and will contribute to a new global standard of care for the injury and a meaningful reduction of the cost and health burden associated with concussion.

“We are grateful to our collaborators, especially to Dr Simon Kemp and the RFU, for their efforts and visionary support of this important work.”

The study, fully supported by The Rugby Players’ Association, saw the team obtaining saliva samples from male professional players in the top two tiers of England’s elite rugby union competition during the 2017-18 and 2018-19 rugby seasons.

Saliva samples were collected pre-season from 1,028 players. They were also collected from 156 of these players during standardised World Rugby head injury assessments (HIAs) at three time points — in-game, post-game, and 36-48 hours post-game. The HIA protocol, used by rugby medical staff, includes a neurological examination, a series of cognitive tests and evaluation of gait and balance to determine if a player has been concussed.

‘Control’ samples were also collected from 102 uninjured players and 66 players who were removed from the game due to musculoskeletal injuries.

Using samples collected during the 2017-18 season, the team identified a panel of a combination of 14 salivary biomarkers — known as small non-coding RNAs or sncRNAs — that was highly accurate (96%) at identifying concussed players from all other groups.

This included players with suspicion of mild traumatic brain injury who had a concussion ruled out after a structured HIA; uninjured controls from the same game; and players who had suffered musculoskeletal injuries.

The panel was prospectively tested during the 2018-19 season, and the research showed it could successfully predict whether players would be positive or negative for concussion via the HIA protocol in 94% of cases.

The study was funded by the Midland Neurosciences Teaching and Research Fund, NIHR SRMC, Medical Research Council, Rugby Football Union and Marker AG.

“The current drug treatments block healthy cells from becoming infected by the virus,” said Yiyang Lu, a PhD student in the Dar lab at the University of Illinois Urbana-Champaign. “The latent reservoir poses a bigger problem because it can start producing the virus at any time. Consequently, patients have to remain on antiretroviral therapy all their lives to prevent a viral rebound.”

So far, there are two types of drug treatment strategies: shock-and-kill, where reactivated cells are killed due to HIV, and a second drug cocktail prevents other cells from being infected, or block-and-lock, which forces the virus into a deep latent state so that it does not reactivate again. The problem with the first approach is that there are always some leftover reservoirs that do not get activated. The problem with the second approach, which the researchers are trying to solve, is that there aren’t many drugs that have been discovered.

Since the transition from latency occurs randomly, measuring the fluctuations in gene expression can provide more coverage than the average gene expression. “Commercial drug screens usually look at mean gene expression. Instead, we used a drug screen that looks at fluctuations in gene expression. Our screen allowed us to therefore find more compounds that could have been overlooked,” Lu said.

“We implemented a time-series drug screening approach that are less commonly used in other labs,” said Roy Dar, an assistant professor of bioengineering at Illinois and faculty member of the Carl R. Woese Institute for Genomic Biology. The researchers used a T- cell population, which is a reservoir for HIV, that had been infected by the virus. They imaged the cells in 15-minute intervals for 48 hours and tested over 1800 compounds. They looked at noise maps to identify which drugs can modulate the gene expression.

Using the screen, they were able to find five new latency-promoting chemicals, raising the possibility that similar screens can be successfully adapted to study other systems that exhibit variability in gene expression, such as cancer. They are currently working on understanding how the five novel drugs suppress viral reactivation. “We want to test if these drugs have off-target effects in terms of how many other genes they affect in the host cells,” Dar said. “We also want to test these drugs in patient samples to see whether these drugs suppress HIV in them.”

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Materials provided by Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign. Original written by Ananya Sen. Note: Content may be edited for style and length.

Topological materials burst onto the scene in the physical sciences about fifteen years ago, decades after their existence had been theorized. Called ‘topological’ because their bulk electronic bands are “knotted” together, the surfaces of topological insulators “untie the knot” and become metallic. Researchers at the Ames Laboratory’s Center for the Advancement of Topological Semimetals (CATS) are seeking to discover, understand, and control the exceptional conduction properties of these materials.

Much of modern technology relies on crystalline materials, which are solids composed of a repeating (periodic) arrangement of atoms that forms a lattice. Due to the periodicity, the lattice looks the same after certain symmetry operations such as translation, specific rotations, mirror, and/or inversion. The existence or absence of these symmetries affect electronic band topology and surface electronic conduction. Magnetic ordering can modify the symmetries exhibited by the material, providing an additional means to control the topological state.

In collaboration with scientists at Oak Ridge National Laboratory’s Spallation Neutron Source, McGill University, and the University of Missouri Research Reactor Center, the CATS team discovered the existence of low-symmetry helical magnetic ordering in EuIn2As2 which supports a highly sought-after topological state called an axion insulator. This state shares similarities with the axion particle in quantum chromodynamics which is a candidate component of dark matter. In solid-state materials, it provides remarkable parallel coupling between magnetic and electrical properties.

In the presence of EuIn2As2’s complex helical magnetic ordering, the axion state leads to topological features in the surface electronic spectrum called Dirac cones. When a Dirac cone occurs on a surface of the material penetrated by a fundamental axis of the magnetic ordering, the cone has no energy gap and the surface exhibits resistanceless conduction tied to the orientation of the electronic spin. The other surfaces have gapped Dirac cones and support half-integer quantized electrical conduction. The researchers predict that application of a relatively moderate magnetic field switches which surfaces support which type of Dirac cone, allowing the surface conduction to be tuned.

The ability to switch between surface states by a magnetic field provides an experimental avenue to examine the unique properties of its topological states. This tunability is also promising for technologies such as high-precision sensors, resistanceless nanowires, magnetic storage media, and quantum computers. Future studies will look at bulk crystals while applying a magnetic field and will synthesize and study nanoscale-thin films in order to pave the way for technological applications.

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The international study, led by the University of Sheffield’s Neuroscience Institute, may have a significant impact on the future treatment of Parkinson’s patients who develop the illness due to PINK1 defect or similar gene defects.

The development of novel treatments and therapies to slow down disease progression, halt or reverse Parkinson’s may now focus on enhancing the generation of new dopamine-producing neurons, rather than just trying to protect these neurons from dying later.

The findings, published today (23 March 2021) in Scientific Reports, used two model systems to measure how inactivation of the PINK1 gene affects dopamine-producing neurons in the adult brain.

Dopamine-producing neurons are the most severely affected brain cells in Parkinson’s disease. It is typically thought that Parkinson’s genes, such as PINK1, cause early death of these neurons, with symptoms developing when neuron numbers fall. However, here, researchers found that a deficiency in PINK1 resulted in fewer dopamine-producing neurons being made throughout life.

Professor Oliver Bandmann, Professor of Movement Disorders Neurology at the Sheffield Institute for Translational Neuroscience (SITraN), said: “Neurogenesis is the process by which new neurons are formed in the brain. Recent evidence suggests that this process is ongoing throughout life but the relevance of this is poorly understood in neurodegenerative disorders such as Parkinson’s disease.”

“We know that mutations in the PINK1 gene cause an early onset, inherited form of Parkinson’s disease. If we can further our understanding about the impact of this genetic mutation on the dopamine-producing neurons we can develop new therapeutic approaches that aim to mitigate those effects.”

In collaboration with the University of Luxembourg, researchers used two complementary model systems to examine how neurons are reproduced throughout our lifetime.

Professor Marysia Placzek, Professor of Developmental Neurobiology in the Department of Biomedical Science, said: “This study attests to the power of using simple model organisms for pre-clinical translational research. We used the zebrafish to demonstrate that dopamine-producing neurons are generated into adulthood at a rate that decreases with age and that PINK1-deficiency impairs neurogenesis of these neurons, significantly in early adult life. Our international collaborators then confirmed these results in a human organoid cell model.”

The observation of impaired adult dopaminergic neurogenesis in PINK1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in Parkinson’s disease. Future research will aim to identify the precise mechanisms that link Parkinson’s genes to neurogenesis. This will allow us to explore the development of gene therapy or small molecule approaches to enhance neurogenesis in the brain of patients with Parkinson’s. The development of new therapies for brain diseases like Parkinson’s is the main focus of the Sheffield Institute for Translational Neuroscience (SITraN).

The research was funded by the Medical Research Council (MRC), Parkinson’s UK and the Wellcome Trust.

Parkinson’s disease is the second most common neurodegenerative disease, with approximately 10 million people affected worldwide. Currently, only symptomatic treatment options are available to patients.

The University of Sheffield launched a sustained fundraising effort for Parkinson’s disease research at the end of 2019. Since then, Sheffield staff, students, alumni and the general public have come together to raise more than £350,000 so far. The ongoing efforts of this campaign are set to continue as Sheffield dedicates itself to backing the next breakthrough.

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In the study published in Nature Ecology and Evolution, the researchers examined the genomes of more than 400 modern humans to investigate the interbreeding events between ancient humans and modern human populations who arrived at Island Southeast Asia 50,000-60,000 years ago.

In particular, they focused on detecting signatures that suggest interbreeding from deeply divergent species known from the fossil record of the area.

The region contains one of the richest fossil records (from at least 1.6 million years) documenting human evolution in the world. Currently there are three distinct ancient humans recognised from the fossil record in the area: Homo erectus, Homo floresiensis (known as Flores Island hobbits) and Homo luzonensis.

These species are known to have survived until approximately 50,000-60,000 years ago in the cases of Homo floresiensis and Homo luzonensis, and approximately 108,000 years for Homo erectus, which means they may have overlapped with the arrival of modern human populations.

The results of the study showed no evidence of interbreeding. Nevertheless, the team were able to confirm previous results showing high levels of Denisovan ancestry in the region.

Lead author and ARC Research Associate from the University of Adelaide Dr João Teixeira, said: “In contrast to our other cousins the Neanderthals, which have an extensive fossil record in Europe, the Denisovans are known almost solely from the DNA record. The only physical evidence of Denisovan existence has been a finger bone and some other fragments found in a cave in Siberia and, more recently, a piece of jaw found in the Tibetan Plateau.”

“We know from our own genetic records that the Denisovans mixed with modern humans who came out of Africa 50,000-60,000 years ago both in Asia, and as the modern humans moved through Island Southeast Asia on their way to Australia.

“The levels of Denisovan DNA in contemporary populations indicates that significant interbreeding happened in Island Southeast Asia.

“The mystery then remains, why haven’t we found their fossils alongside the other ancient humans in the region? Do we need to re-examine the existing fossil record to consider other possibilities?”

Co-author Chris Stringer of the Natural History Museum in London added:

“While the known fossils of Homo erectus, Homo floresiensis and Homo luzonensis might seem to be in the right place and time to represent the mysterious ‘southern Denisovans’, their ancestors were likely to have been in Island Southeast Asia at least 700,000 years ago. Meaning their lineages are too ancient to represent the Denisovans who, from their DNA, were more closely related to the Neanderthals and modern humans.”

Co-author Prof Kris Helgen, Chief Scientist and Director of the Australian Museum Research Institute, said: “These analyses provide an important window into human evolution in a fascinating region, and demonstrate the need for more archaeological research in the region between mainland Asia and Australia.”

Helgen added: “This research also illuminates a pattern of ‘megafaunal’ survival which coincides with known areas of pre-modern human occupation in this part of the world. Large animals that survive today in the region include the Komodo Dragon, the Babirusa (a pig with remarkable upturned tusks), and the Tamaraw and Anoas (small wild buffalos).

“This hints that long-term exposure to hunting pressure by ancient humans might have facilitated the survival of the megafaunal species in subsequent contacts with modern humans. Areas without documented pre-modern human occurrence, like Australia and New Guinea, saw complete extinction of land animals larger than humans over the past 50,000 years.”

Dr Teixeira said: “The research corroborates previous studies that the Denisovans were in Island Southeast Asia, and that modern humans did not interbreed with more divergent human groups in the region. This opens two equally exciting possibilities: either a major discovery is on the way, or we need to re-evaluate the current fossil record of Island Southeast Asia.”

“Whichever way you choose to look at it, exciting times lie ahead in palaeoanthropology.”