Culture

DALLAS, Nov. 16, 2020 -- Patients with plaque build-up in their arteries, who suffered a transient ischemic attack (TIA) or a minor ischemic stroke, also called a warning stroke, and were treated with the newer blood thinner ticagrelor plus aspirin were 27% less likely to have another stroke within 30 days, according to late-breaking research presented today at the American Heart Association's Scientific Sessions 2020. The virtual meeting is Friday, November 13-Tuesday, November 17, 2020, and is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care worldwide. The manuscript of this study is simultaneously published today in Stroke, a journal of the American Heart Association.

In this sub-analysis of the THALES trial, The Acute Stroke or Transient IscHemic Attack Treated with Ticagrelor and Aspirin for PrEvention of Stroke and Death trial, ticagrelor benefitted patients with plaque build-up in their arteries (atherosclerosis) more than patients whose stroke had another cause. These findings, coupled with previous research, show a combination of both ticagrelor and aspirin is more effective than either medication alone.

"In our opinion, health care professionals should now consider both ticagrelor and aspirin to prevent another stroke in patients who experience a warning stroke. Our research shows treating patients within 24 hours of their first symptoms using this newer regimen is effective, especially when the cause of the stroke is due to plaque build-up in the arteries," said the study's lead author Pierre Amarenco, M.D., professor of neurology at Paris University and chair of the department of Neurology and Stroke Center and the SOS-TIA clinic at Bichat hospital in Paris, France.

Of the more than 11,000 participants originally enrolled in the multinational THALES trial (conducted in 2018 and 2019), about one in five (2,351) had plaque build-up in their arteries. Researchers randomized those patients into two groups - aspirin plus ticagrelor or aspirin alone - to identify whether the combination of medications was a more effective treatment than either medication on its own.

After an initial dose of 180 mg, researchers added 90 mg twice a day of ticagrelor to 75-100 mg of daily aspirin for one month, and the risk of another stroke or death was reduced by 27% among these patients.

The THALES trial is a randomized, placebo-controlled, double-blind, international, multi-site study. It is currently in Phase III and began in January of 2018.

Researchers at Karolinska Institutet in Sweden report promising results from an in vitro combination therapy against COVID-19. In a study published in EMBO Molecular Medicine, the researchers show that a combination of remdesivir, an approved drug against COVID-19, and hrsACE2, a medicine currently in phase II trials for COVID-19 treatment, reduced the viral load of SARS-CoV-2 and inhibited viral replication in cell cultures and organoids.

Remdesivir, the only approved drug against COVID-19 disease, works by inhibiting an enzyme that prevents the virus from multiplying. In high doses, however, it can cause damage to the liver and the lungs.

Human recombinant soluble ACE2 (hrsACE2) is a genetically modified variant of the cell membrane protein angiotensin converting enzyme 2 (ACE2) that the coronavirus uses to enter our cells. Previous laboratory studies have shown that hrsACE2 lures the coronavirus to attach itself to the enzyme copy, hrsACE2, instead of to the actual cells, thereby reducing the viral load in cells.

In this study, the researchers tested combining remdesivir and hrsACE2 in cell cultures from monkeys, liver spheroids and 3D kidney replicas, so-called organoids grown from human stem cells.

By combining these two substances, the researchers were able to achieve a dual effect: reduced viral load and reduced viral proliferation to nearby cells. In addition, they achieved this effect with comparably low doses of each substance, which lowered their toxicity and made them safer to use.

"By targeting different aspects of the viral cycle simultaneously, we may be able to increase the effectiveness of the treatment while reducing the risk for potential side-effects," says Ali Mirazimi, corresponding author and adjunct professor in the Department of Laboratory Medicine, Karolinska Institutet. "Combination therapy is a model that has been used successfully in HIV therapeutics. So far, we have only tested our combination therapy in cell cultures and engineered tissues, but we hope that it can pave the way for clinical trials."

HrsACE2 is currently being evaluated in a double-blinded, placebo-controlled phase II trial involving 200 people with severe COVID-19.

Weak students in high-performing math classes, especially boys, feel more shame compared to students in low-performing math classes. Stronger students, in turn, feel more bored and enjoy mathematics less in high-performing math classes, according to a new study.

Researchers at Åbo Akademi University, the University of Helsinki and the University of Turku have investigated whether the so-called big-fish-little-pond effect (BFLPE) can explain the relationship between feelings and mathematics and students' gender. BFLPE is based on students comparing themselves against the average ability of a group. Thus, if students have better-than-average ability, their academic self-image improves, and likewise, it deteriorates if students perceive themselves to be at a level of knowledge below the group average.

This is the first study to show that BFLPE affects feelings of pride and shame to a greater extent among students with weaker knowledge of mathematics than among students with strong math skills. The study is also the first to show that BFLPE affects feelings of pleasure and boredom more among students with a strong knowledge of mathematics. The study involved 1,322 Finnish students who were 14-15 years old, a total of 77 groups.

- We found that in groups where many students are strong in mathematics, the effect on pride related to one's own knowledge is often negative. This effect was particularly prominent among students with weak knowledge of mathematics. An interesting result was that boys experienced more shame in high-performance mathematics classes while girls did not, says Johan Korhonen, assistant professor of educational psychology at Åbo Akademi University.

This may have to do with mathematics being traditionally perceived as a male subject. According to the researchers, the social comparison between students does not necessarily explain why especially high-performing students experience boredom in the classroom--rather, this may have to do with pedagogical methods and expectations on students.

- As a way to reduce BFLPE, strategies could be developed for how to handle performance-related feelings in the classroom. For example, teachers could actively work with individualized and meaningful feedback, and refrain from stereotyping mathematics as a male subject. More encouragement for low-performing students in groups where there are high-performing students, combined with setting individual goals for everyone, could also help reduce the impact, says Korhonen.

Clean drinking water is considered to be one of the earth's most precious and threatened resources. Recent studies show that increasing concentrations of pharmaceuticals can be found in surface waters, which can end up in drinking water. TalTech environmental scientists are looking for ways to treat drinking water from hazardous pharmaceutical residues.

TalTech research group of the Laboratory of Environmental Technology led by Senior Researcher Niina Dulova published an article in the journal Environmental Research titled "Individual and simultaneous degradation of sulfamethoxazole and trimethoprim by ozone, ozone/hydrogen peroxide and ozone/persulfate processes: A comparative study".

Niina Dulova says, "Removal of hazardous micropollutants of different origins from water is still one of the unresolved problems in today's environmental technology. Our study investigated application of new efficient water treatment methods for elimination of two micropollutants: sulfamethoxazole and trimethoprim. These antibiotics are widely used to treat lung and kidney diseases both in veterinary and human medicine."

The application of advanced oxidation processes that take advantage of the high oxidizing capacity of radicals is considered to be the most effective tool for removal of micropollutants from water. These technologies are applied to remove poorly biodegradable substances from water almost completely through mineralization. Advanced oxidation processes can be classified in different ways, but they are mostly divided into categories according to the source of free radicals. Conventionally the oxidants used to form free radicals include hydrogen peroxide (H2O2) and ozone (O3), but in recent years other alternative oxidants, such as persulfate (PS), have been used increasingly.

"In our study we focused on the O3, combined O3/H2O2 and O3/PS processes. The latter, O3/PS technology, is an evolving promising solution in the field of radical-based oxidation processes. The efficiency of the O3/PS process in the decomposition of antibiotic residues (sulfamethoxazole, trimethoprim and a combination of sulfamethoxazole and trimethoprim) in water has not been studied previously and our findings are promising," Niina Dulova says.

The current EU Water Framework Directive does not address the issues of these antibiotic residues in water. Therefore, our wastewater treatment plants do not consider it necessary to tackle the problem. However, the situation will change over the next five years as the European Union is on the way towards establishing stricter water framework directives. This would also change the requirements for our water treatment plants. The best solution in this case would be the introduction of a new water treatment technology, i.e. a free radical based process," Dulova says.

Currently ozone is mainly used in water treatment plants for water disinfection, which, however, is not sufficient to remove hazardous pharmaceutical residues. Only using ozone also for oxidation would remove antibiotic residues from water.

Niina Dulova says, "If you ask why water containing antibiotic residues is hazardous to people, the answer is be very concrete: when exposed to water contaminated with such antibiotic residues, bacteria develop resistance to these antibiotics. This, in turn, makes it increasingly difficult to treat people exposed to these bacteria with antibiotics in the future."

Alzheimer's disease develops over decades. It begins with a fatal chain reaction in which masses of misfolded beta-amyloid proteins are produced that in the end literally flood the brain. Researchers including Mathias Jucker from the Hertie Institute for Clinical Brain Research (HIH) in Tübingen and the German Center for Neurodegenerative Diseases (DZNE) show in the journal Nature Neuroscience that this chain reaction starts much earlier in mice than commonly assumed. This means that in addition to the well-known early phase of the disease with protein deposits but without symptoms of dementia, there is an even earlier phase in which the chain reaction is triggered by invisible tiny seeds of aggregation. If this is confirmed to occur also in humans, a treatment addressing the causes of disease would have to prevent this process. The scientists have already identified an antibody that might accomplish this.

To this end, they searched among the already known antibodies directed against misfolded beta-amyloid proteins for antibodies that can recognize and possibly also eliminate these early seeds of aggregation that currently escape biochemical detection. Of the six antibodies investigated, only aducanumab had an effect: Transgenic mice that were treated for only 5 days before the first protein deposits manifested, later on in life showed only half of the usual amount of deposits in their brains. "This acute antibody treatment obviously removes seeds of aggregation, and the generation of new seeds takes quite some time, so that much less deposits are formed in the weeks and months after the treatment." Mathias Jucker commented on the findings. "Indeed, the mice had only half the brain damage six months after this acute treatment."

Although research on Alzheimer's has been dealing with seeds of aggregation for quite some time, nobody really knows what they look like. They are currently only defined by their role as triggers for this fatal chain reaction. In this respect, they are similar to so-called prions that cause BSE in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans. Pathogenic prions force their correctly folded peers into their abnormal shape. Jucker and coworkers therefore used the antibody aducanumab to learn more about the structure of the seeds of aggregation. They were able to show that aducanumab recognizes protein aggregates, but not individual beta-amyloid chains. The scientists now hope to use the antibody as a fishhook to isolate and better describe these seeds of aggregation.

"Our results suggest that we need to focus more on this very early phase of Alzheimer's and look for biomarkers for it. We also need more antibodies that recognize different types of the seeds of aggregation and help us to understand how they trigger the chain reaction and how they can be used for therapy," Jucker said.

There is currently consensus that treatment of Alzheimer's disease must begin earlier, not when memory decline has already begun. However, the results of the Tübingen scientists are now redefining the term "earliness" in mice. Until now, the phase with protein deposits but without symptoms of dementia has been considered to be "early". The new studies suggest that a treatment of Alzheimer's that addresses the causes should start much earlier.

In a paper published in TECHNOLOGY, a team of researchers from Massachusetts General Hospital (MGH) have demonstrated 24-hour rat liver viability in a normothermic machine perfusion (NMP) system. Rat liver perfusion is an efficient and cost-effective method to study how various pharmacologic agents impact liver parenchyma.

Normothermic machine perfusion (NMP) has the challenge of mirroring in-vivo settings as closely as possible for the liver allograft. This allows drugs, enzymatic reactions, repair processes, and metabolic pathways to affect liver function to their full capacity. However, under normothermic conditions (35-38°C), the perfusions become exponentially more complex when the perfusion duration is extended, severely limiting our ability to observe liver physiology and pharmacologic effects after 6 hours.

This work builds on existing NMP systems with critical modifications in technique and design to
extend the perfusion time of a rat liver allograft without complications or ischemic events. Addressing these issues in NMP greatly expands the armamentarium of experiments that can be conducted to assess how livers responds to physiologic insults and pharmacologic agents over time ex-vivo.

Another major achievement of this research is the identification of perfusion metrics that are predictive of long-term (24-hour) perfusion success. Liver oxygen consumption and rises in intra-hepatic resistance (see image) are shown to be early predictive markers of perfusion system contamination. These markers can be utilized in future experiments to assess the stability of long NMP experiments which can save valuable time and resources in pharmacologic studies.

The team from MGH is working now to utilize long-term rat liver normothermic perfusions to trial different pharmacologic delivery mechanisms, such as lipid nanoparticles, as a novel method of targeted drug delivery.

An acebuchin-oil-enriched diet helps to reduce arterial blood pressure, as shown by a study carried out by the Cardiovascular Physiopathology research group at the Physiology Department of the University of Seville. Furthermore, their work shows that acebuche oil has a greater impact in reducing hypertension than extra virgin olive oil.

This research group from the US Faculty of Pharmacy, led by Professor Carmen María Vázquez Cueto together with Professor Alfonso Mate Barrero, has been investigating the physiopathological mechanisms involved in the development of arterial hypertension (AHT) for over 20 years, with special interest in finding natural products that help to alleviate the organ damage caused by this disorder. The acebuche, also know as the wild olive tree, is a variety of tree widely found throughout Spain and covering almost nine million hectares in Andalusia. However, little data is available on the composition and therapeutic potential of acebuchin oil. The studies mainly focus on the composition and pharmacological effects of olive tree leaves and extra virgin olive oil.

Following their research, in which they gave mice a diet enriched with acebuchin oil or extra virgin olive oil, the researchers detected that the acebuchin-oil-enriched diet significantly reduced blood pressure in hypertensive animals. However, a lesser antihypertensive effect was found in animals fed a diet enriched with extra virgin olive oil.

At the same time, the study showed that the diet enriched in acebuchin oil reduces ocular oxidative stress produced by AHT to a greater degree than the diet enriched in extra virgin olive oil. Furthermore, the former also has a greater impact in regulating the systems related with this oxidative stress.

In particular, the researchers studied variations in the morphology of the hypertensive retina, which are prevented by the acebuched-oil-enriched diet. AHT causes a change in the retina's morphology (showing "thinned" layers in the retina). This outcome can be counteracted with an acebuchin-oil-enriched diet, obtaining better results than with a diet enriched in extra virgin olive oil.

AHT is a high-prevalence disease on a global scale (30-45% of the general population) where systolic blood pressure values rise above 139 mmHg and/or diastolic blood pressure is above 89 mmHg. AHT damage manifests itself in different organs and is a major risk factor in cardiovascular, kidney, brain and eye diseases. In particular, AHT constitutes an important risk factor for the development of retinal vascular diseases, such as hypertensive retinopathy and retinal arterial and venous obstructions, which are associated with high-prevalence ocular pathologies such as cataracts, glaucoma, age-related macular degeneration and choroidopathies.

The Cardiovascular Physiopathology research group has applied to the Spanish Patent and Trademark Office (OEPM), through the University of Seville, for a patent on the "Use of acebuchin oil in retinal damage associated with arterial hypertension and associated retinal pathologies".

According to a new study from Copenhagen Business School, on the role of privacy and decentralization in the cryptocurrency community, developers are creating cryptocurrencies in such a way that regulatory oversight will not be possible, neither will any wait and see attempt to override them in the future. The research is published in the Journal of Information Technology.

"If decentralized privacy-preserving cryptocurrencies become popular in the future, to the point they can be routinely exchanged without users having to convert to other currencies and systems, there is no obvious way for regulators to impose post-hoc regulation," says Associate Professor Rob Gleasure from the Department of Digitalization, Copenhagen Business School.

"What the regulators do not realize is those who control the code will control the rules and so far, they have not accepted this and are in denial," he adds.

Monero cryptocurrency

"People tend to focus on less controversial systems like Bitcoin, Ethereum, Hyperledger, etc. We shine a light on those developing the most potentially disruptive currencies," says co-author Dr. Robin Renwick, a research analyst from the Applied Research and Innovation team at Trilateral Research.

The case study concentrated on Monero, seen as the posterchild for this privacy-focused cryptocurrency community. They have been described as anti-establishment and cypherpunk and, according to the U.S. Department of Justice using them is indicative of possible criminal conduct.

The research focused on the privacy attitudes of users, developers, cryptographic researchers, business architects and regulators and adopted a boundary object perspective to make sense of disagreements between these collaborating social worlds.

"What makes this research different is we were able to get good access to users and developers in a community that is not normally researched," adds Dr. Robin Renwick.

Privacy is personal

"Monero strongly believe the privacy trade-off that allows for our digital transactions to leave an explicit data trail behind it has not been worth it. They argue we went into this digital finance system and have given away all of our data, but we did not actually consent to this."

"Basically this whole system of crime detection has been built on tracking our transactions but Monero argue it won't work anymore as it wasn't fair to start with, so regulators will need to find another way to track crime," says Associate Professor Rob Gleasure.

The research points out that even if regulators tried to ban these privacy-preserving cryptocurrencies, it would be extremely hard to enforce across all jurisdictions - given the decentralised nature of these projects.

They recommend regulators and criminal investigators need to begin planning for the future possibility of exchanges which could ultimately mean identity linkable transaction records may not exist.

The Monero protocol, for example allows users and businesses to remain compliant, but keeps the control of this with the entity that owns the information, ultimately being able to be shared when required by investigative agencies or supervisory bodies, instead of transaction surveillance and monitoring.

"If these cryptocurrency communities have their own financial system which exists separately, and they become impossible to regulate, then it's important to understand and understand this early. Once regulators accept it, they can then begin developing new methods to compensate," concludes Associate Professor Rob Gleasure.

A recent study has shown that a UV light technology already used to prevent the spread of other airborne diseases in buildings has the potential to be effective against Covid-19.

The research, published in the journal PeerJ, found that upper room UV germicidal irradiation (UVGI) can kill SARS-CoV-2 virus particles, which can be transmitted by aerosolised droplets that float in the air.

UVC is known to be very effective at 'killing', or inactivating, microorganisms however this type of UV light is harmful to humans. Upper room UVGI cleverly uses UVC light to create an irradiation field above the heads of room occupants so it can disinfect the air whilst keeping people within the room safe.

The study, led by researchers from Queen Mary University of London and Leeds Beckett University, tested the feasibility of upper room UVGI to reduce Covid-19 transmission by analysing historical published data examining the effect of UV irradiation on coronaviruses. Evaluating all the data, the research team showed that SARS-CoV-2 virus particles found in the air are likely to be susceptible to UVC, and also that the levels of UVC light required to inactivate the virus would be practical and safe for upper room applications.

It is now becoming widely accepted that transmission of SARS-CoV-2 virus particles through tiny respiratory droplets, is one of the main ways Covid-19 spreads between people. The risk of airborne transmission is especially high in poorly ventilated buildings and there is an urgent need for technologies to reduce the spread of Covid-19 within these spaces.

Professor Clive Beggs, Emeritus Professor of Applied Physiology at Leeds Beckett University, said: "Now we know that Covid-19 infection can occur from airborne exposure to the virus, finding ways to minimise the risk of transmission, particularly in buildings is becoming increasingly important. Whilst we know wearing masks and opening windows are effective ways to minimise the spread of Covid-19 indoors, these measures aren't always practical, especially in winter."

"Upper room UVGI is already a well-established technology and has proven effective to prevent the spread of other diseases such as measles and tuberculosis within buildings. This study shows that we have good reason to believe this technology could also protect indoor spaces such as offices, or restaurants and bars, and help to allow us to start to return to 'normal' life in a safe way."

Dr Eldad Avital, Reader in Computational (& Experimental) Fluids and Acoustics at Queen Mary, said: "Now it becomes more of an engineering problem of how we can use this technique to prevent the spread in buildings. This is where computational fluid dynamics becomes important as it can start to address questions around how many UVGI lights are needed and where they should be used. One thing we know is particularly important for these systems is air movement, so for them to work effectively in poorly ventilated spaces, you might need to use ceiling fans or other devices to ensure that larger aerosol particles are adequately irradiated."

The research team are now focusing their efforts on understanding how UV air disinfection technologies could be put into practice. One project they're currently working on will investigate the use of a low-cost air purifier system to 'disinfect' air based on the UVC technology. "The idea is that air could be taken out of the room using an air purifier and disinfected with UVC light, before the 'clean' air is then put back into the room," said Dr Avital.

"Another interesting area we're looking into is using ionisers to disinfect the air. These systems release negative ions into the air which latch on to positive ions, such as viruses, making them heavier. This causes them to fall to the ground or onto surfaces, where they can then be removed using normal cleaning approaches."

A new study reports that, for several species of oceanic sport fish, individual fish that are caught, released and recaught are more likely to be caught again than scientists anticipated. The findings raise some interesting questions for policy makers tasked with preserving sustainable fisheries.

The study makes use of data from tagging programs, in which researchers tag fish and release them into the wild. When those fish are caught, and the tag information is returned to the researchers, it can give scientists information that informs fishery policies.

"Fisheries researchers who work in tagging programs have long noticed that certain fish seem to get caught repeatedly, and we set out to determine the implications of this phenomenon," says Jeff Buckel, co-author of the study and a professor of applied ecology at North Carolina State University.

To that end, researchers examined decades' worth of Atlantic coast tagging datasets on four fish species: black sea bass (Centropristis striata), gray triggerfish (Balistes capriscus), red grouper (Epinephelus morio), and Warsaw grouper (Hyporthodus nigritus). Using a computational model, the researchers determined that - for the black sea bass and both types of grouper - survival was significantly higher after the second, third, and fourth release as compared to the first release.

"Think of it this way," says Brendan Runde, first author of the study and a Ph.D. student at NC State. "Let's say you tagged 1,000 fish and recaptured 100 of them for a first time. After re-releasing those 100 fish, you would only expect to recapture 10 of them a second time. But that's not what we're seeing. We're seeing much higher numbers of fish getting recaptured after the second time.

"Our hypothesis is that this increase in catch rate stems from selection for robust individuals," Runde says.

In other words, because some fish don't survive the first release, and you can't catch a dead fish, the fish that were robust enough to survive their first encounter were more likely to survive following catch-and-release events.

The finding could have a significant impact on stock assessments, which inform fishery policies.

"One might assume that every catch and release in a recreational fishery is a unique fish," Buckel says. "So that if 5 million black sea bass were caught and released in a given year, that would mean there were at least 5 million black sea bass in a fishery. For these three species of fish and likely many others, that's just not true. At least some of those 5 million catches were the same fish getting caught over and over again."

"Reliable estimates of how many unique fish are released are critical to accurately assessing the health of the population," says Kyle Shertzer, a co-author of the study and stock assessment scientist at NOAA Fisheries.

"On the positive side, the study also suggests that for many species fish mortality from being released appears lower than we thought," Buckel says. "For those species, if a fish survives its first release, it has an even better chance of surviving subsequent releases."

"We think that the issues raised by our findings are likely relevant for many marine fish stock assessments that rely on catch-and-release data - though this will vary based on the species and the details of how each stock assessment is performed," Runde says.

For the first time ever, craniofacial growth in children can be studied comprehensively using data from six historic adolescent growth studies. Researchers from the University of Missouri School of Medicine analyzed more than 15,000 cranial radiographs from nearly 2,000 participants to create the Craniofacial Growth Consortium Study (CGCS). The mission of the CGCS is to provide translational evidence-based outcomes to help shape critical research and clinical care of patients with craniofacial conditions.

"This study presents an unparalleled opportunity to examine craniofacial growth from childhood into adulthood," said principal investigator Richard Sherwood, PhD, professor and Vice Chair of Research of pathology and anatomical sciences and professor of orthopaedic surgery. "While the six existing studies have been used for decades to quantify and describe growth, there has never been a detailed comparison of the growth trajectories among the studies."

Sherwood said the combined dataset provides a unique opportunity for detailed investigation of craniofacial growth. The ultimate goals of the research is to develop individualized predictions of future growth for use by clinicians to optimize treatment timing.

Researchers collected data from multiple radiographs for each child, taking care to ensure reliable accuracy. After analyzing all of the images in each of the studies, researchers used a powerful Bayesian longitudinal statistical approach to model growth curves for craniofacial measures and estimate growth milestones. Those milestones include the age of peak growth velocity and the age of cessation of growth within each of the six studies

"We were pleasantly surprised by the considerable consistency among the six studies," Sherwood said. "There was great similarity regarding growth milestone estimates and the overall shape of the growth curve. These similarities suggest there is only minor variation among studies resulting from differences in protocol, sample or geographic origin."

Because there is no systematic difference between growth of the six original studies, Sherwood is confident that the data can be combined and analyzed as a single collection.

"The CGCS gives us a better representation of normal variation in craniofacial growth than we have ever had," Sherwood said. "Our next step is to develop prediction models that will be useful to clinicians in developing treatment regimens."

The replacement of lost neurons is a holy grail for neuroscience. A new promising approach is the conversion of glial cells into new neurons. Improving the efficiency of this conversion or reprogramming after brain injury is an important step towards developing reliable regenerative medicine therapies. Researchers at Helmholtz Zentrum München and Ludwig Maximilians University Munich (LMU) have identified a hurdle towards an efficient conversion: the cell metabolism. By expressing neuron-enriched mitochondrial proteins at an early stage of the direct reprogramming process, the researchers achieved a four times higher conversion rate and simultaneously increased the speed of reprogramming.

Neurons (nerve cells) have very important functions in the brain such as information processing. Many brain diseases, injuries and neurodegenerative processes, are characterized by the loss of neurons that are not replaced. Approaches in regenerative medicine therefore aim to reconstitute the neurons by transplantation, stem cell differentiation or direct conversion of endogenous non-neuronal cell types into functional neurons.

Researchers at Helmholtz Zentrum München and LMU are pioneering the field of direct conversion of glial cells into neurons which they have originally discovered. Glia are the most abundant cell type in the brain and can proliferate upon injury. Currently, researchers are able to convert glia cells into neurons - but during the process many cells die. This means that only few glial cells convert into functional nerve cells, making the process inefficient.

Exploring new approaches

Magdalena Götz and her team investigated potential hurdles in the conversion process and took a new route: While most studies have focused on the genetic aspects of direct neuronal reprogramming, they decided to study the role of mitochondria and cell metabolism in this process. This was inspired by their previous work in collaboration with Marcus Conrad's group at Helmholtz Zentrum München showing that cells die due to excessive reactive oxygen species in the conversion process.

"We hypothesized that if we were able to help reprogramming the metabolism of glia cells towards the metabolism of a neuron, this could improve the conversion efficiency", explains Gianluca Russo, first-author of the study. Given their previous data, the researchers focused on mitochondria, the cell's powerhouse. The group extracted mitochondria from neurons and astrocytes (a specific type of glia cell) of mice and compared them by studying their proteins in collaboration with Stefanie Hauck's group of proteomic experts at Helmholtz Zentrum München. Surprisingly, they found that mitochondria of neurons and astrocytes differ in 20 percent of their proteome. This means that between astrocytes and neurons every fifth mitochondrial protein is different.

Reprogrammed neurons activate neuron-enriched mitochondrial proteins at a late stage

"Knowing how different the mitochondrial proteome of neurons is from astrocytes, we needed to see if and when neurons converting from astrocytes actually acquire the mitochondrial proteome of a neuron or not", says Giacomo Masserdotti, co-last author of the study. In a standard reprogramming process, glia cells like astrocytes convert to neurons within a few days and develop into functional neurons within two weeks. "It was striking that cells showed mitochondrial proteins, which are typical for neurons, relatively late in the reprogramming process, only after one week. Since most cells die before this time, this could be a hurdle. In addition, cells that failed to be reprogrammed, still expressed astrocyte-enriched mitochondrial proteins." With this new insight, the researchers hypothesized that the failure of turning on neuronal mitochondrial proteins may be blocking the conversion process.

Improving and accelerating the conversion through metabolism

To overcome this hurdle, the group employed CRISPR/Cas9 technology in close cooperation with Stefan Stricker's and Wolfgang Wurst's groups at Helmholtz Zentrum München. With new gene activation tools developed by this group, neuron-enriched mitochondrial proteins could be activated at an early stage of the reprogramming process of astrocytes to neurons. By manipulating one to two mitochondrial proteins only, the researchers gained four times more reprogrammed neurons. On top of that, the neurons appeared and matured faster, as revealed by continuous live imaging.

"I was amazed that changing the expression of few mitochondrial proteins actually drives the speed of reprogramming", says Magdalena Götz, the lead author of the study. "This shows how important the cell-type-specific differences of mitochondrial proteins are. And indeed, together with our proteome experts at Helmholtz Munich, we are discovering further organellar differences between cell types that reach up to 70 percent. This will pave the way to further improve the reprogrammed neurons to resemble as much as possible endogenous neurons also after brain injury in vivo."

Until now, it was unclear whether a survived SARS-CoV-2 infection or COVID-19 leads to a persistent immunological memory and thus can protect against a new infection. Several studies had shown that SARS-CoV-2 specific antibodies are only detectable for a few months in many people who have survived COVID-19 and may therefore only provide temporary protection against re-infection. A research team at the Medical Center - University of Freiburg led by Dr. Maike Hofmann, Dr. Christoph Neumann-Haefelin and Prof. Dr. Robert Thimme has now been able to show: after recovery from SARS-CoV-2 infection, immune cells are formed which remain in the body and could mediate a rapid immune response in case of re-infection. The Freiburg study was published in the online edition of the renowned scientific journal Nature Medicine on November 12, 2020.

"These so-called memory T-cells after SARS-CoV-2 infection look similar to those after a real flu. We are therefore confident that the majority of people who have survived SARS-CoV-2 infection have some protection against re-infection with SARS-CoV-2," explains Dr. Hofmann, a scientist at the Department of Medicine II at the Medical Center - University of Freiburg.

Professor Thimme, Medical Director of the Department of Medicine II, emphasizes how important a good translational research environment such as that at the Medical Center - University of Freiburg is in the current situation: "In order to obtain robust research results within a few months, close networking between clinic and science at the highest level is a basic requirement: On the one hand, patients with COVID-19 are treated on our wards and continue to be cared for in a special outpatient clinic even after the infection has healed. On the other hand, our clinic has great expertise in the analysis of immune cells in viral infections such as hepatitis B and C."

The Medical Center - University of Freiburg is not involved in the development of vaccines against SARS-CoV-2. However, Dr. Neumann-Haefelin, Head of the Gerok Liver Center at the University Hospital Freiburg, is optimistic: "Our results suggest that immunity against SARS-CoV-2 can be achieved after an infection. Similarly, vaccines currently being tested in trials could provide significant protection against SARS-CoV-2".

"The deciphering of complex immune responses has long been part of the research focus of the University and the Medical Center - University of Freiburg. Thanks to the high scientific quality onsite, we can now make an important contribution to the corona pandemic," says Prof. Dr. Norbert Südkamp, Dean of the Medical Faculty at the Albert-Ludwigs-University of Freiburg.

A team of scientists from the University of Leeds have developed a new hydrogel that has significant potential for oral care products that can help with dry mouth relief.

The team developed this bio-inspired lubricant to act as an alternative to saliva without additional lipid content. For instance, dry mouth syndrome or xerostomia pose a limitation to the lubrication of oral surfaces in absence of natural saliva, while extra lipid intake is undesirable for these patients especially for the elderly population, where this syndrome is prevalent.

Additionally the developed formulation can be potentially used to replicate the lubricating properties of fat content in food products, providing the possibility of decreasing caloric content, without sacrificing sensory related attributes.

The synergistic superlubricity of the novel microgel-reinforced hydrogel offers a unique prospective towards the fabrication of biocompatible aqueous lubricants for dry mouth therapy or design of non-obesogenic nutritional technologies.

Principal Investigator Anwesha Sarkar, Professor of Colloids and Surfaces at Leeds, said, "The excelling lubrication performance of this patented microgel-reinforced hydrogel is attributed to the synergistic interactions between the proteinaceous microgels and the biopolymeric hydrogel with benefits of both viscous and boundary lubrication."

"The development of this bio-inspired aqueous lubricant technology as alternative to saliva is a high priority. To date, such superlubricity is not achieved by any other commercial dry mouth therapies as they lack boundary lubrication properties.

"With the help of ERC Proof of Concept Funding, we are now collaborating with Nexus at the University of Leeds and expect to license this technology soon to industries to ultimately provide sustained relief to dry mouth patients."

DALLAS - Nov. 17, 2020 - Research presented today by UT Southwestern cardiologists at the annual American Heart Association (AHA) Scientific Sessions 2020 showed that Black and Hispanic people were more likely to be hospitalized with COVID-19 than white patients, and that nonwhite men with cardiovascular disease or risk factors were more likely to die.

In one of the conference's late-breaking research sessions, James de Lemos, M.D., a professor of internal medicine who holds a distinguished chair in cardiology at UTSW, discussed COVID-19 Cardiovascular Disease Registry: Design, Implementation, and Initial Results.

The American Heart Association COVID-19 Cardiovascular Disease Registry was created by volunteers and AHA staff and launched in the spring at the outset of the pandemic. To date, the registry has gathered records on more than 22,500 patients from 109 U.S. health care centers in 34 states, including data points on patient demographics, cardiovascular risk factors, comorbidities, medications prior to admission, treatments during hospitalization, disease severity measures, and laboratory results.

In a related study, Racial and Ethnic Differences in Treatment and Outcomes for Patients Hospitalized with COVID-19: Findings from the American Heart Association COVID-19 Cardiovascular Disease Registry, deLemos and his team studied 8,000 COVID-19 patients who were hospitalized from Jan. 17 to July 22. This group was treated at 88 hospitals. One-third were Hispanic, 25.5 percent were non-Hispanic Black, 6.3 percent were Asian, and 35.2 percent were non-Hispanic white. Black patients were younger with higher rates of obesity, high blood pressure, and diabetes, and were also more likely to require a ventilator or kidney dialysis than white patients.

"The results highlight the disproportionate burden of COVID-19 among Black and Hispanic patients, and imply there are factors in the U.S. that existed prior to hospitalization that are driving these disparities in COVID hospitalization and death," says de Lemos, who served as co-chair of the steering committee for the registry.

In another late-breaking session, Ann Marie Navar, M.D., Ph.D., reported that a review of nearly 20,000 patients revealed that cardiovascular disease or CVD risk factors in COVID-19 patients dramatically increased the risk of in-hospital mortality. The risk of death was particularly high for older, nonwhite men.

Navar's research team studied electronic health records from 54 health systems that use a COVID-19 database provided by Cerner, a health information technology firm. The results, measured from January to May and shared in "Impact of Cardiovascular Disease on Outcomes Among Hospitalized COVID-19 Patients: Results From >14,000 Patients Across the U.S.," showed that in-hospital mortality ranged from 28.5 percent for patients with hypertension to 28.6 percent for those with diabetes, 25.5 percent for those with coronary artery disease, and 38.4 percent for those with heart failure.

Just 1.5 percent of the patients had a stroke while hospitalized for COVID-19, but the mortality rate was 56 percent among this group. Similarly, 5 percent of patients had a heart attack, and 55.5 percent of these individuals died during their hospital stay.

"These data reflect what doctors and nurses on the front lines in hospitals across the U.S. are actually seeing, where more than 1 in 15 patients hospitalized with COVID-19 does not make it home," says Navar. She conducted the research at the Duke Clinical Research Institute before joining UT Southwestern as an associate professor of internal medicine and population and data sciences.