Culture

The bacterium Staphylococcus epidermidisis primarily a harmless microbe found on the skin and in the noses of humans. Yet some strains of this species can cause infections - in catheters, artificial joints, heart valves, and in the bloodstream - which are difficult to treat. These bacteria are often resistant to a particularly effective antibiotic, methicillin, and are among the most feared germs in hospitals. How these usually harmless skin microbes become deadly pathogens has been unclear up to now.

An international research team has now discovered what distinguishes peaceful S. epidermidis microorganisms from the many dangerous invaders. The scientists have identified a new gene cluster that enables the more aggressive bacteria to produce additional structures in their cell walls. This morphological alteration allows the staphylococci to attach more easily to human cells forming the blood vessels, a process via which they can persist in the bloodstream to become pathogens. These new cell wall structures may also allow the spread of methicillin resistance, by transferring it, for example, from Staphylococcus epidermidis to its more dangerous relative Staphylococcus aureus.

The study was carried out under the direction of researchers of the Cluster of Excellence "Controlling Microbes to Fight Infections" (CMFI) of the University of Tübingen and the German Center for Infection Research (DZIF) in cooperation with universities in Copenhagen, Hamburg, Shanghai and Hanover as well as the German Center for Lung Research (DZL) in Borstel. The results are being published in the journal Nature Microbiology.

Set apart by structure

A considerable portion of the cell walls of Staphylococci - like other gram-positive bacteria - is made up of teichoic acids. Chain-like, these polymers cover the bacterial surface. Their chemical structures vary according to species. "During our examination we determined that many pathogenic strains of S. epidermidis have an additional gene cluster that contains information for the synthesis of wall teichoic acids that are actually typical of S. aureus," says researcher Dr. Xin Du of the Cluster of Excellence of the CMFI and DZIF. She adds that experiments have shown S. epidermidis bacteria with only species-specific teichoic acids in their walls are not very invasive, colonizing the surfaces of the skin and mucous membranes. If the wall teichoic acids for S. aureus are also present, Xin Du explains, they are unable to attach effectively to those surfaces. Instead, they are more successful in penetrating the tissues of their human host. "At some point, a few S. epidermidis clones took on the corresponding genes from S. aureus and became threatening pathogens as a result," says Professor Andreas Peschel of the Cluster of Excellence CMFI and of the DZIF.

It's long been known that bacteria can share genetic material through gene transfer. Bacteriophages - viruses that infect bacteria - carry out the transfer. Mostly, this takes place within one species and requires similar surface structures to which the bacteriophages bind. "Differing cell wall structures normally prevent gene transfer between S. epidermidis and S. aureus. But in S. epidermidis strains that can also produce the wall teichoic acids of S. aureus, that type of gene transfer suddenly becomes possible between different species," explains Peschel. That would explain, he continues, how S. epidermidis could transfer methicillin resistance to even more threatening - and then methicillin-resistant - S. aureus, adding that more investigation is still needed. The new findings are an important step, says Peschel, towards developing better treatments or vaccinations against dangerous pathogens such as S. epidermidis ST 23, which has been known for fifteen years and belongs to the group of HA-MRSE (healthcare-associated methicillin-resistant S. epidermidis).

On 17 May 2021, the UK moved to step three of the Government's Roadmap out of Lockdown - which allowed for the lifting of a ban on foreign travel. Yet, travelling to amber and red list countries still carries strict regulations. UK residents can use proof of vaccination or Covid status (via the NHS app) to comply with travel restrictions in different countries - a scheme known as vaccine passports. However, issues remain to be resolved on how they will be implemented and used, and public opinion appear polarised.

Researchers from the University of Surrey's School of Hospitality and Tourism Management, Professor Iis Tussyadiah, Dr Athina Ioannou, and Professor Graham Miller, conducted two studies to explore public opinion about vaccine passports. First, they mined opinions from Twitter from December 2020, the start of vaccination rollout, to April 2021 and, using topic modelling, extracted major themes from relevant tweets. 14 major themes were identified. Those supporting vaccine passports argued that they will allow people access to services and to go on holiday, ease international travel, help the economy to recover and society to return to normality. Those rejecting the scheme cited issues of civil liberties, discrimination, privacy and surveillance.

The social media analysis was supplemented by an online survey, distributed to 1,000 UK residents between 14 and 20 May 2021, further exploring the prevalence of different shades of opinion on this matter. When considering vaccine passports, people surveyed generally agreed on their benefits. Only about a third agreed that vaccine passports will restrict individual freedom, increase discrimination, and threaten privacy. Half of those surveyed stated they intend to use vaccine passports in general, for travel, and to go to pubs, restaurants, and shops in the near future. Only 20% reported being unwilling to use them, with 30% undecided.

To gauge the extent that people plan to travel according to the planned Roadmap, respondents were asked if they intend to travel immediately after step three of the Roadmap and in summer 2021, after step four of the Roadmap. About a third reported intention to travel domestically after step three and more than half after step four. Although the numbers are smaller for international travel, nevertheless, 15% plan to embark on international travel after step three and 25% after step four. There is a weak but significant correlation between those intending to travel and positive sentiment towards vaccine passports.

Professor lis Tussyadiah, Professor of Intelligent Systems in Service and Acting Head of School of Hospitality and Tourism Management at the University of Surrey, said;

"The global tourism sector has been particularly hard hit by the Covid-19 pandemic - the largest challenge the sector has ever faced. I am delighted that half of the UK residents surveyed would be willing to adopt vaccine passport in order to travel. These findings will help inform the government and the travel and tourism industry in finding ways to move forward with confidence post pandemic."

Researchers will ensure this study is used to capitalise on existing consumer awareness of vaccine passports, while addressing ongoing concerns identified by the work. Uptake is likely to be increased if perceived drawbacks are addressed. For institutions providing and requesting proof of vaccination or Covid status for travel, it is clear that issues pertaining to privacy and exclusion will need to be addressed, including by providing alternative mechanisms for those who have not been vaccinated to access services safely.

DURHAM, N.C. -- Biomedical engineers at Duke University have developed an automatic process that uses streamlined artificial intelligence (AI) to identify active neurons in videos faster and more accurately than current techniques.

The technology should allow researchers to watch an animal's brain activity in real time, as they are behaving.

The work appears May 20 in Nature Machine Intelligence.

One of the ways researchers study the activity of neurons in living animals is through a process known as two-photon calcium imaging, which makes active neurons appear as flashes of light. Analyzing these videos, however, typically requires a human circling every burst of intensity they see in a process called segmentation. While this may seem straightforward, these bursts often overlap in spaces where thousands of neurons are imaged simultaneously. Analyzing just a five-minute video this way could take weeks or even months.

"People try to figure out how the brain works by recording the activity of neurons as an animal does a behavior to study the relationship between the two," said Yiyang Gong, the primary author on the paper. "But manual segmentation creates a big bottleneck and doesn't allow researchers to see the activation of the neurons in real-time."

Gong, an assistant professor of biomedical engineering, and Sina Farsiu, a professor of biomedical engineering, previously addressed this bottleneck in a 2019 paper, where they shared the development of a deep-learning platform that maps active neurons as accurately as humans in a fraction of the time. But because videos can be tens of gigabytes, researchers still have to wait hours or days for them to process.

Now, the team is making their platform work in real-time.

"Our goal was to improve our approach to be more intelligent so it can target and learn from the important data in the videos rather than parse through all of the extra noise," said Gong.

To make their approach more intelligent, the team developed signal processing algorithms that pre-process the data before being analyzed by the neural network. These algorithms help improve the signal-to-noise ratio and remove the background fluctuations in the video, highlighting active neurons while obscuring inactive neurons and other unneeded data.

The team also adapted their neural network to scan fewer layers, because it doesn't need as much data to learn how to accurately identify and segment the activated neurons.

The result is a system that features an unusual upgrade. Not only is it an order of magnitude faster than their previous work, it's also slightly more accurate.

Because their platform can highlight active neurons so quickly, researchers can use the tool to detect neurons in real-time and examine how certain activation patterns match animal behavior. Due to the tool's usefulness in neuroscience experiments, the team has made a version of the network available online.

"Rather than wait until the end of an experiment, the speed of our network allows us to learn things during the experiment," said Gong. "We now have a new potential to explore how different kinds of stimulation can affect neuronal activation and animal behavior."

The team is already exploring new ways to continue to improve their tool for wider use.

"The algorithm can always use further optimization," said Gong. "We've shown that this works really well for the two-photon calcium imaging, but there are a lot of different optical microscopes in neuroscience, and ultimately we'd like to make a neural network that works for all of these imaging modalities."

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as apathy and lack of emotion, and cognitive impairment. We have reported that VB6 (pyridoxal) levels in peripheral blood of a subpopulation of patients with schizophrenia is significantly lower than that of healthy controls. More than 35% of patients with schizophrenia have low levels of VB6 (clinically defined as male:

VB6 is not synthesized de novo in humans, but is primarily obtained from foods. In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(-)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency. After feeding for 4 weeks, plasma VB6 level in VB6(-) mice decreased to 3% of that in control mice. The VB6(-) mice showed social deficits and cognitive impairment. Furthermore, the VB6(-) mice showed a marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brain, suggesting enhanced NA metabolism in VB6(-) mice. We confirmed the increased NA release in the prefrontal cortex and the striatum of VB6(-) mice through in vivo microdialysis. These findings suggest that the activities of NAergic neuronal systems are enhanced in VB6(-) mice.

Furthermore, VB6 supplementation directly into the brain using an osmotic pump ameliorated the hyperactivation of the NAergic system and behavioral abnormalities. indicating that the enhanced NA turnover and the behavioral deficits shown in the VB6(-) mice are attributed to VB6 deficiency in the central nervous system. In addition, the ?2A adrenergic receptor agonist guanfacine also improved the hyperactivated NAergic system in the frontal cortex and behavioral disorders. These results show that the behavioral deficits in VB6(-) mice may be caused by an enhancement of NAergic signaling.

Schizophrenic patients with VB6 deficiency, who account for more than 35% of all patients, present with relatively severe clinical symptoms and treatment resistance. Our findings suggest that a new therapeutic strategy targeting the NAergic system might be effective for these patients. They will also provide evidence based on pathophysiology for a new therapeutic strategy called "VB6 treatment for schizophrenia," which we are currently conducting clinical research on.

Tsukuba, Japan - Carbonic anhydrases are essential enzymes that are present in virtually all living things; all eight classes of carbonic anhydrases that have been identified to date need a metal ion to function. But now, researchers from Japan have discovered that metal is not crucial for all carbonic anhydrases.

In a study published this month in BMC Biology, researchers from the Faculty of Life and Environmental Sciences at the University of Tsukuba have described two members of the COG4337 protein family that are the first known examples of carbonic anhydrase enzymes that do not require a metal ion to function.

Carbonic anhydrases catalyze the conversion of carbon dioxide (CO2) into bicarbonate (HCO3-), and vice versa. They are central to a wide range of physiological processes, including regulation of acid-base balance, respiration, and photosynthesis, and are crucial for all carbon-based life, from bacteria to humans. All previously identified classes of carbonic anhydrase contain a metal cofactor -- zinc, cadmium, cobalt, or manganese -- that is essential for the activity of these enzymes, so when the researchers at the University of Tsukuba identified that the COG4337 proteins were similar to known carbonic anhydrases, they expected metal ions to be important for these new proteins too.

"Because the active site of most carbonic anhydrases contains a metal ion that facilitates interconversion between CO2 and HCO3-, we were surprised to find that the COG4337 proteins did not require any of the eight different metals we tested, and actually were less functional in the presence of zinc," lead author Professor Yoshihisa Hirakawa says.

When the researchers made a model of COG4337 protein structure, they found that there was an active site, or pocket, that may hold on to CO2 while the enzyme converts it to HCO3-. Interestingly, unlike other carbonic anhydrases, these novel enzymes don't seem to carry out the reverse reaction of converting HCO3- to CO2. In addition, the investigators saw that these COG4337 proteins tend to congregate in the plastids and mitochondria of the microalga Bigelowiella natans, which is where CO2 metabolism takes place.

"These proteins are expressed by many cyanobacteria and eukaryotic microalgae that live in environments with fairly diverse metal contents. It is possible that this enzyme evolved in an ancestral microbe to adapt to metal-poor environments, such as the open ocean," Professor Hirakawa explains.

Given the widespread expression of carbonic anhydrases in ecologically important species of microalgae, this novel type of metal-independent carbonic anhydrases may play an important role in the global carbon cycle. Understanding more about how these enzymes work could also be useful for artificial photosynthesis, an important source of renewable energy.

Tokyo, Japan - Most people don't think much about the food scraps they throw away; however, investigators from the Institute of Industrial Science at The University of Tokyo have developed a new method to reduce food waste by recycling discarded fruit and vegetable scraps into robust construction materials.

Worldwide industrial and household food waste amounts to hundreds of billions of pounds per year, a large proportion of which comprises edible scraps, like fruit and vegetable peels. This unsustainable practice is both costly and environmentally unfriendly, so researchers have been searching for new ways to recycle these organic materials into useful products.

"Our goal was to use seaweed and common food scraps to construct materials that were at least as strong as concrete," explains Yuya Sakai, the senior author of the study. "But since we were using edible food waste, we were also interested in determining whether the recycling process impacted the flavor of the original materials."

The researchers borrowed a "heat pressing" concept that is typically used to make construction materials from wood powder, except they used vacuum-dried, pulverized food scraps, such as seaweed, cabbage leaves, and orange, onion, pumpkin, and banana peels as the constituent powders. The processing technique involved mixing the food powder with water and seasonings, and then pressing the mixture into a mold at high temperature. The researchers tested the bending strength of the resulting materials and monitored their taste, smell, and appearance.

"With the exception of the specimen derived from pumpkin, all of the materials exceeded our bending strength target," says Kota Machida, a senior collaborator. "We also found that Chinese cabbage leaves, which produced a material over three times stronger than concrete, could be mixed with the weaker pumpkin-based material to provide effective reinforcement."

The new, robust materials retained their edible nature, and the addition of salt or sugar improved their taste without reducing their strength. Furthermore, the durable products resisted rot, fungi, and insects, and experienced no appreciable changes in appearance or taste after exposure to air for four months.

Given that food waste is a global financial burden and environmental concern, it is crucial to develop methods for recycling food scraps. Using these substances to prepare materials that are strong enough for construction projects, but also maintain their edible nature and taste, opens the door to a wide range of creative applications from the one technology.

Researchers have flipped traditional 3D printing to create some of the most intricate biomedical structures yet, advancing the development of new technologies for regrowing bones and tissue.

The emerging field of tissue engineering aims to harness the human body's natural ability to heal itself, to rebuild bone and muscle lost to tumours or injuries.

A key focus for biomedical engineers has been the design and development of 3D printed scaffolds that can be implanted in the body to support cell regrowth.

But making these structures small and complex enough for cells to thrive remains a significant challenge.

Enter a RMIT University-led research team, collaborating with clinicians at St Vincent's Hospital Melbourne, Australia, who have overturned the conventional 3D printing approach.

Watch and embed the timelapse video

Instead of making the bioscaffolds directly, the team 3D printed moulds with intricately-patterned cavities then filled them with biocompatible materials, before dissolving the moulds away.

Using the indirect approach, the team created fingernail-sized bioscaffolds full of elaborate structures that, until now, were considered impossible with standard 3D printers.

Lead researcher Dr Cathal O'Connell said the new biofabrication method was cost-effective and easily scalable because it relied on widely available technology.

"The shapes you can make with a standard 3D printer are constrained by the size of the printing nozzle - the opening needs to be big enough to let material through and ultimately that influences how small you can print," O'Connell, a Vice-Chancellor's Postdoctoral Fellow at RMIT, said.

"But the gaps in between the printed material can be way smaller, and far more intricate.

"By flipping our thinking, we essentially draw the structure we want in the empty space inside our 3D printed mould. This allows us to create the tiny, complex microstructures where cells will flourish."

Versatile technique

O'Connell said other approaches were able to create impressive structures, but only with precisely-tailored materials, tuned with particular additives or modified with special chemistry.

"Importantly, our technique is versatile enough to use medical grade materials off-the-shelf," he said.

"It's extraordinary to create such complex shapes using a basic 'high school' grade 3D printer.

"That really lowers the bar for entry into the field, and brings us a significant step closer to making tissue engineering a medical reality."

The research, published in Advanced Materials Technologies, was conducted at BioFab3D@ACMD, a state-of-the-art bioengineering research, education and training hub located at St Vincent's Hospital Melbourne.

Co-author Associate Professor Claudia Di Bella, an orthopedic surgeon at St Vincent's Hospital Melbourne, said the study showcases the possibilities that open up when clinicians, engineers and biomedical scientists come together to address a clinical problem.

"A common problem faced by clinicians is the inability to access technological experimental solutions for the problems they face daily," Di Bella said.

"While a clinician is the best professional to recognise a problem and think about potential solutions, biomedical engineers can turn that idea into reality.

"Learning how to speak a common language across engineering and medicine is often an initial barrier, but once this is overcome, the possibilities are endless."

Future treatment toolkit

Currently there are few treatment options for people who lose a significant amount of bone or tissue due to illness or injury, making amputation or metal implants to fill a gap common outcomes.

While a few clinical trials of tissue engineering have been conducted around the world, key bioengineering challenges still need to be addressed for 3D bioprinting technology to become a standard part of a surgeon's toolkit.

In orthopedics, a major sticking point is the development of a bioscaffold that works across both bone and cartilage.

"Our new method is so precise we're creating specialised bone and cartilage-growing microstructures in a single bioscaffold," O'Connell said.

"It's the surgical ideal - one integrated scaffold that can support both types of cells, to better replicate the way the body works."

Tests with human cells have shown bioscaffolds built using the new method are safe and non-toxic.

The next steps for the researchers will be testing designs to optimise cell regeneration and investigating the impact on cell regrowth of different combinations of biocompatible materials.

Step-by-step: How to reverse print a bioscaffold

The new method - which researchers have dubbed Negative Embodied Sacrificial Template 3D (NEST3D) printing - uses simple PVA glue as the basis for the 3D printed mould.

Once the biocompatible material injected into the mould has set, the entire structure is placed in water to dissolve the glue, leaving just the cell-nurturing bioscaffold.

Study first author, PhD researcher Stephanie Doyle, said the method enabled researchers to rapidly test combinations of materials to identify those most effective for cell growth.

"The advantage of our advanced injection moulding technique is its versatility," Doyle said.

"We can produce dozens of trial bioscaffolds in a range of materials - from biodegradable polymers to hydrogels, silicones and ceramics - without the need for rigorous optimisation or specialist equipment.

"We're able to produce 3D structures that can be just 200 microns across, the width of 4 human hairs, and with complexity that rivals that achievable by light-based fabrication techniques.

"It could be a massive accelerator for biofabrication and tissue engineering research."

Digital medicine is opening up entirely new possibilities. For example, it can detect tumors at an early stage. But the effectiveness of new AI algorithms depends on the quantity and quality of the data used to train them.

To maximize the data pool, it is customary to share patient data between clinics by sending copies of databases to the clinics where the algorithm is being trained. For data protection purposes, the material usually undergoes anonymization and pseudonymization processes - a procedure that has also come in for criticism. "These processes have often proven inadequate in terms of protecting patients' health data," says Daniel Rueckert, Alexander von Humboldt Professor of Artificial Intelligence in Healthcare and Medicine at TUM.

Smart algorithms support doctors

To address this problem, an interdisciplinary team at TUM has worked with researchers at Imperial College London and the non-profit OpenMined to develop a unique combination of AI-based diagnostic processes for radiological image data that safeguard data privacy. In a paper published in Nature Machine Intelligence, the team has now presented a successful application: a deep learning algorithm that helps to classify pneumonia conditions in x-rays of children.

"We have tested our models against specialized radiologists. In some cases the models showed comparable or better accuracy in diagnosing various types of pneumonia in children," says Prof. Marcus R. Makowski, the Director of the Department of Diagnostic and Interventional Radiology at the Klinikum rechts der Isar of TUM.

Data remain onsite

"To keep patient data safe, it should never leave the clinic where it is collected," says project leader and first author Georgios Kaissis of the TUM Institute of Medical Informatics, Statistics and Epidemiology. "For our algorithm we used federated learning, in which the deep learning algorithm is shared - and not the data. Our models were trained in the various hospitals using the local data and then returned to us. Thus, the data owners did not have to share their data and retained complete control," says first author Alexander Ziller, a researcher at the Institute of Radiology.

Data cannot be traced back to individuals

To prevent identification of institutions where the algorithm was trained, the team applied another technique: secure aggregation. "We combined the algorithms in encrypted form and only decrypted them after they were trained with the data of all participating institutions," says Kaissis. And to ensure 'differential privacy' - i.e. to prevent individual patient data from being filtered out of the data records - the researchers used a third technique when training the algorithm. "Ultimately, statistical correlations can be extracted from the data records, but not the contributions of individual persons," says Kaissis.

First-ever combination of privacy-protecting methods

"Our methods have been applied in other studies," says Daniel Rueckert. "But we have not yet seen large-scale studies using real clinical data. Through the targeted development of technologies and the cooperation between specialists in informatics and radiology, we have succeeded in training models that deliver precise results while meeting high standards of data protection and privacy."

Rickmer Braren, the deputy director of the Department of Diagnostic and Interventional Radiology notes: "It is often claimed that data protection and the utilization of data must always be in conflict. But we are now proving that this does not have to be true." The scientists add that their method can be applied to other medical data, and not just x-rays. For example speech and text.

Data protection opens up enormous potential for digital medicine

The combination of the latest data protection processes will also facilitate cooperation between institutions, as the team showed in a paper published in Nature Machine Intelligence in 2020. Their privacy-preserving AI method can overcome ethical, legal and political obstacles - thus paving the way for widespread use of AI, says Braren. And this is enormously important for research into rare diseases.

The scientists are convinced that their technology, by safeguarding the private sphere of patients, can make an important contribution to the advancement of digital medicine. "To train good AI algorithms, we need good data," says Kaissis. "And we can only obtain these data by properly protecting patient privacy," adds Rueckert. "This shows that, with data protection, we can do much more for the advancement knowledge than many people think."

Further information:

With the appointment in 2020 of the Alexander von Humboldt Professor Daniel Rueckert and the new Director of the Department of Diagnostic and Interventional Radiology Prof. Marcus R. Makowski, TUM decisively strengthened its activities in AI research and its applications in radiology.

A rare mutation that causes Parkinson's disease-like symptoms interrupts the flow of dopamine in the brain, suggests a study in fruit flies published today in eLife.

The findings provide more detailed insights about why young children with this mutation develop these symptoms. This new information, as well as previous evidence that therapies helping to improve dopamine balance in the brain can alleviate some symptoms in the flies, suggests that this could be a beneficial new treatment strategy.

Parkinson's disease causes progressive degeneration of the brain that leads to impaired movement and coordination. Current treatments focus on replacing or increasing the levels of dopamine to help reduce movement-related symptoms. But these drugs can have side effects, do not resolve all symptoms, and often stop working over time.

"Although the exact cause of Parkinson's disease remains unclear, studies of rare mutations that lead to the early onset of similar symptoms in some families have helped us learn more about possible causes, and suggested approaches for alleviating symptoms," says first author Jenny Aguilar, a former graduate student at the Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, US.

To learn more, Aguilar and colleagues studied genetically modified fruit flies with a mutation that causes a Parkinson's disease-like condition in young children, called dopamine transporter deficiency syndrome (DTDS).

They showed that the mutation impairs the function of a so-called 'gate protein' that ushers dopamine from the outside of the cell inside. The mutation causes the gate protein to become stuck facing the inside of the cell more frequently, meaning that dopamine builds up outside. This slows the ability of the flies to motor coordinate their take off. "Over time, this dopamine build-up may lead to the production of less dopamine, causing worsening movement problems and other symptoms," Aguilar says.

The team next treated the flies with a malaria drug called chloroquine, which has been shown in animals to increase the number of other proteins by preventing them from being recycled. They found that the drug helped to alleviate some of the flies' movement problems.

While chloroquine is a widely available drug, it has side effects that make it unlikely to serve as a treatment for Parkinson's disease-like symptoms, except in rare circumstances. This work suggests that developing treatments to improve the function of the dopamine-transporting protein may relieve movement symptoms and also stop the progressive loss of dopamine production.

"Our study provides a blueprint for using fruit flies to learn more about how problems with dopamine-transporting proteins contribute to Parkinson's-like symptoms," concludes senior author Aurelio Galli, Professor at the Department of Surgery, University of Alabama at Birmingham, US. "This could pave the way for further research into new treatment approaches that focus on improving dopamine transport."

BUFFALO, N.Y. - To improve the development of new saliva-based diagnostic tests and personalized medicine, the National Institute of Dental and Craniofacial Research (NIDCR) has supported the development of the Human Salivary Proteome Wiki, the first public platform that catalogs and curates data on each of the thousands of proteins within our saliva.

Detailed in an article published on Tuesday, May 25 in the Journal of Dental Research, the wiki provides researchers and clinicians with rich, unbiased evidence from multiple independent studies to help explore the dynamic and complex nature of saliva, as well as analytical tools to search for data by tissue type, disease and more.

"This community-based data and knowledge base will pave the way to harness the full potential of the salivary proteome for diagnosis, risk prediction, and therapy for oral and systemic diseases, and increase preparedness for future emerging diseases and pandemics," says Stefan Ruhl, DDS, PhD, lead investigator of the study, curator of the Human Salivary Proteome Wiki, and professor of oral biology in the University at Buffalo School of Dental Medicine.

Saliva facilitates digestion, taste, swallowing and speech, and serves as the first line of defense against pathogens in the mouth, shielding the body from harmful microbes. Saliva's role in immune responses, as well as the ease with which it may be collected as a fluid sample, make it a desirable tool in precision medicine and noninvasive diagnostics. During the COVID-19 pandemic, it was widely used to detect the virus and track the body's immune response.

A challenge in saliva's study, however, is the high level of variability in the thousands of salivary proteins. Therefore, normal ranges for the composition of saliva need to be established to define the status of health, says Ruhl, who in 2020, co-authored research on how saliva is made, pinpointing the origins of proteins in human saliva back to its sources.

"Saliva has become an attractive body fluid for on-site, remote and real-time monitoring of oral and systemic health. The scientific community needs a saliva-centered information platform that keeps pace with the rapid accumulation of new data and knowledge," says William Lau, PhD, of the National Institutes of Health (NIH) and first author of the study.

"The Human Salivary Proteome Wiki will improve salivary sciences, saliva-based diagnostics, precision medicine and dentistry, and ultimately facilitate personalized treatment for both oral and systemic diseases," says Preethi Chander, PhD, program director of the NIDCR Salivary Biology and Immunology Program.

Modernized to 'harness the full potential of the salivary proteome'

Funded by NIDCR and developed in collaboration with the NIH Center for Information Technology, the Human Salivary Proteome Wiki was released in 2019 as a user-friendly public database to provide rich analytical, curation, and annotation tools for the biomedical research community.

The database compiles information and research on the salivary proteome, genome, transcriptome (types and levels of mRNA expressed in salivary gland tissue), and glycome (array of sugars attached to salivary glycoproteins).

Users may submit proposals to add, and remove or modify data to an interdisciplinary team of curators who ensure information is accurate and supported by sound scientific evidence. Annotations are also credited to the researchers and clinicians who submit them to the wiki, helping drive references to critical research.

The researchers will also host a series of activities that bring contributors together to inspire novel ideas and foster cross-discipline collaborations.

Scientists from the UK's University of Bath explore racemases - an important type of enzyme that is linked to certain cancers and other life-threatening diseases while also being critical to cell function - in a paper published in the prestigious journal Chemical Society Reviews. The scientists also propose new strategies for finding drugs that neutralise these enzymes.

Many racemases and epimerases perform vital roles in human and animal cells, and in disease-causing organisms. They facilitate proper nerve function, the degradation of toxic substances, the formation of bacterial cell walls and the conversion of certain drugs into their active form (the best known conversion is seen with ibuprofen, which is taken as a mixture of isomers and converted in the liver to the active S-isomer). But while normal levels of racemase and epimerase function are generally beneficial, increased levels can be harmful. Because of this, there is considerable interest in developing drugs that impact these enzymes.

There have been promising outcomes in lab experiments where racemases (and related epimerases) have been targeted with experimental drug molecules. These molecules reduce the functional activity of racemases and have the potential to be developed into new treatments for a wide range of diseases, including prostate, breast and brain cancers; Alzheimer's disease and other dementias; bacterial and viral infections; Chagas disease, and the complications of diabetes.

Notable successes in developing racemase-fighting molecules include the identification of D-cycloserine (a natural product discovered in 1954), which is used in the treatment of tuberculosis - a major global health threat.

Until now, there has been no general review of how drugs can be used to stop these potent enzymes from working. The new Bath paper explores all known strategies used to design or discover such drugs, including methods adopted to measure racemase function and by extension drug effectiveness. The paper also surveys recent advances in the development of drugs targeting specific enzymes, including alpha-methylacyl-CoA racemase - an enzyme that is linked to prostate cancer, and which is the focus of the team's own research.

In addition, the Bath researchers set out to develop a coherent model of how racemases and epimerases perform their functions. Their hope is to use this model to design and develop more effective drugs.

What makes racemases and epimerases special is their ability to change the chirality of molecules - that is, the way in which groups in the molecules twist. Many biological molecules exhibit chirality, and the direction of a given molecule's twists determines how it functions: mirror-image molecules with the exact same structure can behave very differently in biological systems. This mirror-image phenomenon is known as stereochemical isomerism, and the mirror-image molecules are the isomers.

In biological systems, one of the two stereochemical isomers predominates, but there are many examples where the less abundant isomer plays a specific, critical role in the cell. For example, the amino-acid L-serine is abundant in the proteins and the membranes of all cells, while its isomer D-serine has a specialised role in neurotransmission in humans and other higher animals. Racemases and epimerases catalyse the formation of the less abundant of the two isomers from the more abundant, and hence change the way in which the molecule twists. They perform their reactions using several different chemical strategies, but by far the most common is the removal of a proton from an activated carbon atom followed by delivery of a proton from the opposite side to quench the resulting intermediate.

As well as the role they play in human health, racemases and epimerases have important biotechnology applications in green and sustainable routes to chemicals with high economic value. These enzymes can be used to produce difficult-to-access stereochemical isomers of amino acids and other molecules that are important in the food, cosmetics, pharmaceutical and fine chemicals industries.

For many years, the Bath team has worked on the α-methylacyl-CoA racemase (AMACR) - an enzyme that is overactivated in prostate and other cancers. Research on this enzyme, and on finding compounds to stop it from working, has been funded by several organisations, including Prostate Cancer UK.

Dr Matthew Lloyd, lead author of the paper, said: "Racemases and epimerases have traditionally been seen as niche enzymes, however their pivotal position within biological processes means they make excellent drug targets and can be exploited in the manufacture of important chemicals that have great economic value because they are used in the food, cosmetic, pharmaceutical and other industries.

"Our systematic analysis of racemase enzymes, the reactions they catalyse and the ways in which they can be stopped from working reveal several common themes and suggest several new avenues of research. Thanks to our detailed review, we now have a much better theoretical understanding of how these enzymes work, and this knowledge is essential if these enzymes are to be effectively targeted by the new drugs being developed."

He added: "It's also clear that there are several potential strategies to develop new drugs, such as fragment-based drug design and virtual screening, which are ripe for exploitation. We hope this paper will stimulate new research on these under-appreciated enzymes."

Simon Grieveson, head of research at Prostate Cancer UK, said: "Prostate cancer is the most common cancer in men, and we desperately need better treatments. That's why we're committed to funding research like this which explores promising new ways of tackling the disease.

"Through their detailed lab work, Dr Lloyd and his team have successfully found ways to target and suppress a key protein involved in prostate cancer growth. We look forward to seeing how this research progresses over the coming years and its role in the development of new treatments for men."

An international and multidisciplinary team led by researchers at the University of Oxford, University of Glasgow, and University of Heidelberg, has uncovered the interactions that SARS-CoV-2 RNA establishes with the host cell, many of which are fundamental for infection. These discoveries pave the way for the development of new therapeutic strategies for COVID-19 with broad-range antiviral potential.

The genetic information of SARS-CoV-2 is encoded in an RNA molecule instead DNA. This RNA must be multiplied, translated, and packaged into new viral particles to produce the viral progeny. Despite the complexity of these processes, SARS-CoV-2 only encodes a handful of proteins able to engage with viral RNA. To circumvent this

limitation SARS-CoV-2 hijacks cellular proteins and repurposes it for its own benefit. However, the identity of these proteins has remained unknown until now.

Researchers from the University of Oxford in collaboration with other labs across UK and Europe have developed a new approach to discover in a comprehensive manner the proteins that 'stick' to SARS-CoV-2 RNA in infected cells. With this method, authors uncovered that SARS-CoV-2 RNA hijacks more than a hundred cellular proteins, which appear to play critical roles in the viral life cycle.

This work, published in Molecular Cell, identifies many potential therapeutic targets with hundreds of available drugs targeting them. In a proof-of-principle experiment, authors selected four drugs targeting four different cellular proteins. These drugs caused from moderate to strong effects in viral replication.

'These exciting results are only the beginning,' said Alfredo Castello, one of the researchers that has led the work. 'With hundreds of compounds that target these critical cellular proteins, it will be possible to identify novel antivirals. Our efforts, together with those of the scientific community, should focus now on testing these drugs in infected cells and animal models to uncover which ones are the best antivirals.'

An unexpected observation of this study is that viruses from different origin such as SARS-CoV-2 and Sindbis, hijack a similar repertoire of cellular proteins. This discovery is very important, as cellular proteins with important and wide-spread roles in virus infection have potential as target for broad-spectrum antiviral treatments.

'In this stage of the pandemic in which vaccines have proved their value,' added Alfredo Castello. 'It becomes fundamental to develop new therapeutic approach to counteract emergent vaccine-resistant variants or novel pathogenic viruses with pandemic potential.'

Professor Shabaz Mohammed adds: 'These new methods to discover the interactors of viral RNA builds on nearly 6 years of joined effort between the Castello and Mohammed labs using Sindbis virus as discovery model. This pre-existent work allowed us to react rapidly at the beginning of the COVID-19 pandemic and study the interactions between SARS-CoV-2 and the host cell in a reduced timeframe. Our methodology will now be ready to respond rapidly to future viral threads.'

Alzheimer's disease is the main cause of dementia and current therapeutic strategies cannot prevent, slow down or cure the pathology. The disease is characterized by memory loss, caused by the degeneration and death of neuronal cells in several regions of the brain, including the hippocampus, which is where memories are initially formed. Researchers from the Netherlands Institute for Neuroscience (NIN) have identified a small molecule that can be used to rejuvenate the brain and counteract the memory loss.

New cells in old brains

The presence of adult-born cells in the hippocampus of old people was recently demonstrated in scientific studies. It suggests that, generally speaking, the so-called process of adult neurogenesis is sustained throughout adulthood. Adult neurogenesis is linked to several aspects of cognition and memory in both animal models and humans, and it was reported to sharply decrease in the brains of patients with Alzheimer's disease. Researchers also found that higher levels of adult neurogenesis in these patients seem to correlate with better cognitive performance before death. "This could suggest that the adult-born neurons in our brain may contribute to a sort of cognitive reserve that could later on provide higher resilience to memory loss", says Evgenia Salta, group leader at the NIN. Therefore, researchers from the NIN investigated if giving a boost to adult neurogenesis could help prevent or improve dementia in Alzheimer's disease.

A small molecule with big potential

Salta: "Seven years ago, while studying a small RNA molecule that is expressed in our brain, called microRNA-132, we came across a rather unexpected observation. This molecule, which we had previously found to be decreased in the brain of Alzheimer's patients, seemed to regulate homeostasis of neural stem cells in the central nervous system". Back then, Alzheimer's was thought to be a disease affecting only mature neuronal cells, so at first glance this finding did not seem to explain a possible role of microRNA-132 in the progression of Alzheimer's.

In this study, the researchers set out to address whether microRNA-132 can regulate adult hippocampal neurogenesis in healthy and Alzheimer's brains. Using distinct Alzheimer's mouse models, cultured human neural stem cells and post-mortem human brain tissue, they discovered that this RNA molecule is required for the neurogenic process in the adult hippocampus. "Decreasing the levels of microRNA-132 in the adult mouse brain or in human neural stem cells in a dish impairs the generation of new neurons. However, restoring the levels of microRNA-132 in Alzheimer's mice rescues neurogenic deficits and counteracts memory impairment related to adult neurogenesis", Sarah Snoeck, technician in the group of Salta, explains.

These results provide a proof-of-concept regarding the putative therapeutic potential of bringing about adult neurogenesis in Alzheimer's. Salta: "Our next goal is to systematically assess the efficacy and safety of targeting microRNA-132 as a therapeutic strategy in Alzheimer's disease".

Swedish and Danish journalists describe their role as monitorial to a greater extent than journalists from other Nordic countries. Journalists from Norway and Iceland state they have the least experience of political influence and thus differ from Finnish journalists. This is shown by a new comparative study published by Nordicom at the University of Gothenburg.

In a new study, researchers examine the similarities and differences in Nordic journalists' perceptions of the role of journalists and different kinds of influence on journalistic work. They also compare the Nordic perceptions with journalists in the rest of Europe. The study is based on survey data from the Worlds of Journalism Study, which is the largest comparative journalism study ever conducted. The study covers 67 countries around the world, including all Nordic countries.

"We have directly comparable data from Nordic and European countries, which is rare. When we combine analysis of these data with our concept of journalistic style, we can present a more holistic and nuanced view of Nordic journalists' professional values and working conditions than previous studies", says Jari Väliverronen, researcher in journalism at Tampere University and one of the researchers behind the study.

Many similarities between Sweden and Denmark

Danish and Swedish journalists are generally the most similar in the study and are distinguished by a strong identification with the monitorial role of journalists.

"Danish and Swedish journalists consider to a greater extent their monitorial role in relation to, for example, politics to be important, but at the same time, they also emphasise the importance of objectivity", says Jan Fredrik Hovden, professor of media studies at the University of Bergen and the other researcher behind the study.

The main difference between the countries is the experience of external influences. The Swedes experience the strongest financial impact on their work, while the Danes feel they are most influenced by organisational factors, such as strong pressure from the newsrooms.

Clear Nordic differences

In a European context, journalists from the Nordic countries are relatively similar to each other, with comparatively low levels of perceived political and economic influence.

"The fact that the Nordic countries are relatively similar in a European comparison indicates that national media systems have a strong impact on journalists' professional roles and perceived influences. Within the Nordic region, on the other hand, there are clear differences, and several different journalistic styles emerge", says Väliverronen.

The most important differences within the Nordic region are related to journalists' relations to the political field, on one hand, and the strength of their perceived editorial autonomy and external influences, on the other. Norwegian and Icelandic journalists distance themselves to a greater extent from politics and have a more market-oriented style; this is especially true for Icelandic journalists. Finnish journalists, on the other hand, appear to be more oriented towards their local community, and also feel most strongly influenced by politics, compared with the other Nordic countries.

Over a year after the novel coronavirus cemented its grip on the world, much of the conversation surrounding the disease remains simple: how many people died and how many survived?

But researchers at Michigan Medicine say a devastating side effect lurks, underreported, between those extremes - the loss of ability caused by the virus.

In a study published in the journal PM&R, investigators found that 45% of patients hospitalized for COVID-19 experienced significant functional decline after being discharged.

"Rehabilitation needs were really, really common for these patients," says lead author Alecia K. Daunter, M.D., a pediatric physiatrist at Michigan Medicine. "They survived, but these people left the hospital in worse physical condition than they started. If they needed outpatient therapy or are now walking with a cane, something happened that impacted their discharge plan."

The team of researchers reviewed charts of nearly 300 adult patients hospitalized for COVID-19 at Michigan Medicine during the pandemic's first wave between March and April 2020. They analyzed patients' discharge locations, therapy needs at the time of release and if they needed durable medical equipment or other services.

Of survivors who experienced functional decline, 80% were referred for additional therapy after being discharged. Nearly 20% of all patients lost so much ability, they were not able to live independently after their release.

"These patients may have needed to move to a subacute facility, or they might have needed to move in with a family member, but they were not able to go home," Daunter says. "This has a massive impact on patients and their families - emotionally and physically."

The study period occurred in the pandemic's infancy, as health care providers sought best practices to minimize exposures and manage patient overflow. As a result, 40% of patients never had a rehabilitation evaluation while hospitalized. That likely means, Daunter explains, that the number of patients losing ability is underreported.

"Physicians and others in the health care system were working appropriately to discharge patients," she says. "They needed to keep patients safe while maximizing available beds and minimizing exposure to staff. I think that contributed to many people not being assessed by a therapist or PM&R physician. So, the things we do to in the hospital to maximize functioning, like mobility interventions and assessing activities of daily living were, not happening as often."

COVID-19 can systematically damage various organ systems, causing neurological and musculoskeletal impairments. Michigan Medicine recently opened two clinics to address the growing population of "long COVID" patients.

However, the virus' effect on daily functioning is not frequently described, which, given the magnitude of the current public health crisis, can't be ignored any longer, says Edward Claflin, M.D., a Michigan Medicine physiatrist and co-author of the paper.

"These results help to highlight the true impact of the COVID-19 disease on our patients," Claflin says. "They fill in that gap in knowledge about how patients with COVID recover and what kind of rehabilitation needs they have."

The "first wave" study is a snapshot look at acute therapy needs during a time when knowledge of the unique virus was even more limited. The team hopes for additional research examining the long-term effects COVID has on functionality. However, health systems can use the current data to optimize rehabilitation evaluations and prepare resources for this underserved population, Daunter says.

"These problems are frequent, and the stakes are pretty high if we miss them, or allow them to progress during hospitalization," she says. "Some of these people were working and many were living independently. To lose that level of function is meaningful. We want to make sure we're addressing those needs, not just looking at the black and white, survival or death."