Culture

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."

Fusarium Head Blight (FHB), also known as scab, is a significant disease of small grain cereals, such as wheat and barley, that impacts farmers around the world. The disease has been reducing acreage and increasing the price of wheat production in the United States since the early 1990s, which in turn increases costs for downstream producers, such as millers and brewers.

The disease is caused by a fungus that produces heat-stable trichothecene mycotoxins, which help the disease spread. To stop the spread, plant breeders are working to develop cultivars with improved resistance to FHB. A team of plant pathologists primarily based at Rutgers University recently generated wheat overexpressing two non-specific lipid transfer proteins and found that this enhanced protection against the fungus and led to a reduction of one of the major mycotoxins.

"We found that the AtLTp4.4 protein, from the large gene family of nsLTPs, had both antifungal and antioxidant properties," said John McLaughlin. "This is the first study to show that nsLTPs have dual functions and the first study to explore how these functions contribute to FHB-resistance in wheat."

The discovery that genes like nsLTPs can improve FHB-resistance in wheat adds to the catalog of genes that plant breeders can use in their breeding programs. This discovery also opens new research avenues for McLaughlin and his colleagues.

"We are exploring if nsLTP overexpression in barley can impact FHB resistance and if the increase of nsLTPs in the grain improves the antioxidant properties of malt," said McLaughlin. "Additionally, nsLTPs are predicted to improve beer shelf life and flavor stability, and we will be testing that."

Their research also highlights the need to better understand the connection between the induction of reactive oxygen species and mycotoxin production/accumulation in small grain cereals as the scientists found that application of trichothecenes to wheat leaf tissue and the accumulation of reactive oxygen species, independent of the fungus, can be significantly impacted by the overexpression of nsLTPs.

"Our research shows that gain-of-function mutants can be used to enhance plant disease resistance, and our article shows some of the techniques involved to explore the mechanisms of disease resistance," McLaughlin added.

What started as the preliminary analysis of routine laboratory data has since evolved into the largest-ever study of viral load levels in patients with SARS-CoV-2. A team of researchers from Charité - Universitätsmedizin Berlin have now analyzed the PCR samples of more than 25,000 persons with COVID-19. Working under the leadership of Prof. Dr. Christian Drosten, the team determined the viral loads of each individual sample and used their results to estimate levels of infectiousness. The research, which has been published in Science*, provides a clear idea of the infectiousness of the disease in different age groups and at different levels of disease severity. It also provides new insights into the B.1.1.7 variant.

According to the reproductive number (R 0), a person infected with SARS-CoV-2 will, on average, transmit their infection to three to five other people. While it is a useful metric in an epidemiological setting, 'R 0' does not lend itself to estimating the risk of transmission at the individual or group level. Once normal social and environmental factors are removed from the equation, individuals can differ markedly in terms of their infectiousness and the length of time during which they actively shed the virus.

To better understand and estimate infectiousness in specific groups of individuals, a team led by Prof. Dr. Christian Drosten, Director of Charité's Institute of Virology and a researcher at the German Center for Infection Research (DZIF), analyzed the PCR samples of more than 25,000 COVID-19 cases in order to determine their 'viral loads'. A sample's viral load - the total number of copies of the SARS-CoV-2 genome contained in the sample - provides a rough estimate of the quantity of virus present in a patient's throat and, as such, is a useful metric for estimating an individual's infectiousness. To further improve their estimates, the researchers also applied findings regarding the minimum viral load threshold typically required for the successful isolation of SARS-CoV-2 in cell culture (where isolation indicates the presence of infectious virus). Sequential samples were available for more than 4,300 of the cases studied. Using these to track throat viral load data over time, the researchers were able to model the typical development of viral loads over the course of the infection. The researchers then looked for significant differences in their data, specifically in relation to different age groups, disease severity and virus variants.

No notable differences in viral load levels were recorded among SARS-CoV-2-positive individuals aged between 20 and 65 years, the average throat swab sample containing approximately 2.5 million copies of the SARS-CoV-2 genome. Viral loads were found to be lowest in very young children (0 to 5 years). Levels started at approximately 800,000 copies of the viral genome, increased with age, and approached adult levels in older children and adolescents.

"While these numbers look very different at first glance, it is crucial to remember that viral load results are shown on a logarithmic scale," says Prof. Drosten. "The differences in viral loads found in the youngest children are, in fact, barely below the threshold at which we would normally consider them clinically relevant. Crucially, one also has to understand how we arrive at these values and take this into account when interpreting them." Highlighting the differences in the methodology of sample collection between children and adults, the virologist adds: "Children's swabs are significantly smaller in size and collect less than half the sample quantity normally available for PCR testing. Moreover, the level of discomfort involved with the procedure means that deep nasopharyngeal swabs are often replaced with simple throat swabs. This of course further reduces the amount of viral material collected. For this reason, we fully expect that, in children, the same level of viral replication will produce lower viral load results during PCR testing."

When comparing peak viral loads in laboratory samples, the researchers estimated levels of infectivity in the youngest children (0 to 5 years) to be at approximately 80 percent of that found in adults. As previously, values for school-aged children and adolescents were found to be approaching adult values. "This shows that viral loads are not directly proportional to infectivity and cannot be converted directly," explains Prof. Drosten. He adds: "Even these data-based estimates of infectivity have to be corrected upwards because of the different methods of sample collection used in children. All of this forms part of a clinical virologist's overall assessment. My initial assumption, that all age groups have roughly the same level of infectivity, has been confirmed, both by this and by other studies."

A symptom-based comparison confirmed observations previously made in COVID-19 cases, namely that even asymptomatic individuals can have very high viral loads. Individuals who required hospitalization were found to have higher viral loads than others over the entire course of the disease. Based on their new models of viral load courses over time, the researchers estimate that individuals infected with SARS-CoV-2 reach peak viral load levels in their throats as early as 1 to 3 days before the onset of symptoms.

Approximately 9 percent of the COVID-19 cases tested showed extremely high viral loads of one billion copies per sample or higher. More than a third of these potentially highly infectious individuals had either no symptoms or only mild symptoms. "These data provide a virological foundation for the notion that a minority of infected individuals cause the majority of all transmissions," explains Prof. Drosten. He adds: "The fact that this includes so many people without any relevant symptoms underlines the importance of pandemic control measures such as social distancing and mandatory mask-wearing."

In samples collected from individuals infected with the B.1.1.7 ('UK' or 'British') variant, average viral loads were found to be increased by a factor of ten, while laboratory-based estimates of infectivity were increased by a factor of 2.6. To arrive at these data, the researchers took viral load data from approximately 1,500 cases infected with B.1.1.7 and compared them with data from approximately 1,000 people infected with other variants who had been tested at the same testing centers, outpatient departments and clinical wards around the same time. Prof. Drosten adds: "Laboratory studies may not as yet be in a position to provide a definitive explanation, but one thing is clear: B.1.1.7 is more infectious than other variants."

The researchers plan to continue their work on viral loads throughout the course of the pandemic. They hope to gain insights into the changes which occur as new variants arise as the virus adapts to increasing levels of population immunity.

LA JOLLA--(May 25, 2021) One of the many effects of aging is loss of muscle mass, which contributes to disability in older people. To counter this loss, scientists at the Salk Institute are studying ways to accelerate the regeneration of muscle tissue, using a combination of molecular compounds that are commonly used in stem-cell research.

In a study published on May 25, 2021, in Nature Communications, the investigators showed that using these compounds increased the regeneration of muscle cells in mice by activating the precursors of muscle cells, called myogenic progenitors. Although more work is needed before this approach can be applied in humans, the research provides insight into the underlying mechanisms related to muscle regeneration and growth and could one day help athletes as well as aging adults regenerate tissue more effectively.

"Loss of these progenitors has been connected to age-related muscle degeneration," says Salk Professor Juan Carlos Izpisua Belmonte, the paper's senior author. "Our study uncovers specific factors that are able to accelerate muscle regeneration, as well as revealing the mechanism by which this occurred."

The compounds used in the study are often called Yamanaka factors after the Japanese scientist who discovered them. Yamanaka factors are a combination of proteins (called transcription factors) that control how DNA is copied for translation into other proteins. In lab research, they are used to convert specialized cells, like skin cells, into more stem-cell-like cells that are pluripotent, which means they have the ability to become many different types of cells.

"Our laboratory previously showed that these factors can rejuvenate cells and promote tissue regeneration in live animals," says first author Chao Wang, a postdoctoral fellow in the Izpisua Belmonte lab. "But how this happens was not previously known."

Muscle regeneration is mediated by muscle stem cells, also called satellite cells. Satellite cells are located in a niche between a layer of connective tissue (basal lamina) and muscle fibers (myofibers). In this study, the team used two different mouse models to pinpoint the muscle stem-cell-specific or niche-specific changes following addition of Yamanaka factors. They focused on younger mice to study the effects of the factors independent of age.

In the myofiber-specific model, they found that adding the Yamanaka factors accelerated muscle regeneration in mice by reducing the levels of a protein called Wnt4 in the niche, which in turn activated the satellite cells. By contrast, in the satellite-cell-specific model, Yamanaka factors did not activate satellite cells and did not improve muscle regeneration, suggesting that Wnt4 plays a vital role in muscle regeneration.

According to Izpisua Belmonte, who holds the Roger Guillemin Chair, the observations from this study could eventually lead to new treatments by targeting Wnt4.

"Our laboratory has recently developed novel gene-editing technologies that could be used to accelerate muscle recovery after injury and improve muscle function," he says. "We could potentially use this technology to either directly reduce Wnt4 levels in skeletal muscle or to block the communication between Wnt4 and muscle stem cells."

The investigators are also studying other ways to rejuvenate cells, including using mRNA and genetic engineering. These techniques could eventually lead to new approaches to boost tissue and organ regeneration.

Extra funding should be made available for early years care in the wake of the pandemic, researchers say.

Experts at the University of Leeds, University of Oxford and Oxford Brookes University have made the call after assessing the benefits of early childhood education and care (ECEC) for children under three during COVID-19.

They found children who attended childcare outside the home throughout the first UK lockdown made greater gains in language and thinking skills, particularly if they were from less advantaged backgrounds.

And now they are making several policy recommendations including

- A sustainable funding model for nursery provision

- Promotion of funded places in target areas where take-up is low

- Removal of administrative barriers to the take-up of places

Dr Catherine Davies, Associate Professor in Language Development in the School of Languages, Cultures and Societies, who co-authored the study, said: "Our data clearly show that children from all backgrounds benefit from attending childcare for all or part of the week. Their cognitive skills become stronger, which will help them in their later learning and development, too. Government investment in sustainable, high-quality early years education and care is crucial so that all families can access this support."

Part of a nationally-funded project on Social Distancing and Development, the aim of the study was to analyse the impact of attending childcare - and of missing out - on children from different backgrounds, and to provide evidence for policymakers planning for further lockdowns and disruptions to early education and care.

The researchers worked with 189 UK families with children aged 8 to 36 months old during spring and winter 2020, when nurseries were closed to all children except those of critical workers or those classed as vulnerable. Between March and June 2020, nursery attendance dropped to less than 10% of usual levels. This was followed by an extended period of quarantine measures, reduced attendance, and disruption to sessions.

The families answered questions about their use of formal childcare such as nursery and childminders before, during and between lockdowns, informal childcare from family members or friends, and about their income, level of education, occupation and neighbourhood. Parents completed surveys about the number of words that their child said or understood, and their child's early thinking skills, or executive functions - the control of attention, behaviour and emotion. They followed up six months later, reporting again on their child's language ability and thinking skills.

Parents were asked to record their child's understanding and use of words across categories such as animals, vehicles and food. They were also asked how often their child exhibited different behaviours, and then played games designed to elicit skills such as waiting, finding, and sorting.

The team then explored associations between time spent at ECEC, the families' socioeconomic background, and children's growth in language and thinking skills.

Their findings showed that a child who regularly attended ECEC one day per week during the pandemic could be expected to understand an average of 24 more new words over the Spring-Winter 2020 period compared with their peers, while a child regularly attending two days could be expected to understand 48 more new words than their peers over the same period, and so on. This effect was greater among children from less affluent backgrounds. Overall, the results suggest that those children who could not attend nursery were disadvantaged by the social distancing measures.

In addition, children from all backgrounds who continued to attend nursery displayed boosted growth in thinking skills.

Study co-author Dr Alexandra Hendry, a research fellow at the University of Oxford, said: "Lower-income families have been disproportionately impacted by infections, deaths, unemployment, and mental ill-health during the pandemic - all stressors which are likely to negatively affect home interactions with children. We have demonstrated that early childhood education and care boosts these children's vocabulary skills, and all children's thinking skills.

"Solid abilities in these areas are likely to have cascading positive effects as children move through their preschool years and beyond. To maintain these benefits for child development and for levelling inequalities, properly-funded, high-quality early childhood education and care is crucial."

The project lead for the Social Distancing and Development Study, Dr Nayeli Gonzalez-Gomez, Senior Lecturer in Psychology at Oxford Brookes University, noted "Our findings add to the evidence base that providing access to properly-funded, safe, and high-quality early childhood education and care may be a way to level some of the inequalities experienced by children from less privileged background, while still benefiting all children."

The paper, Early Childhood Education and Care (ECEC) during COVID-19 boosts growth in language and executive function, is published in Infant and Child Development.

The research was funded by the Economic and Social Research Council as part of its rapid response to COVID-19.

Royal College of Speech and Language Therapists' chief executive Kamini Gadhok MBE says: "This important research provides clear evidence that young children from disadvantaged backgrounds have been disproportionately affected by the COVID-19 pandemic, with a worrying impact on their language development.

"Given the importance of language skills for young people's life chances, it's imperative that governments across all four nations put support for children's communication and language development at the centre of education recovery plans. This must include action and funding in the early years which supports pre-school settings to work in partnership with speech and language therapists."

Research Study Key Takeaways:

Ridesharing can reduce a passenger's risk of being a target of sexual assault by providing a more reliable and timely transportation option for traveling to a safer place.

The entry of Uber into a city contributes to a 6.3% reduction in rape incidents.

A 1% increase in Uber pickups in a neighborhood translates to a more than 3% decrease in the likelihood of sexual assaults.

CATONSVILLE, MD, May 24, 2021 - Contrary to portraits painted in popular media, new research involving ridesharing services shows they provide an additional level of protection for potential sexual assault victims, particularly in neighborhoods with inadequate public transportation or in circumstances that are more prone to sex crimes.

The study, "The Deterrent Effect of Ride-sharing on Sexual Assault and Investigation of Situational Contingencies," published in the INFORMS journal Information Systems Research, found the entry of Uber into a city in the United States contributes to a 6.3% reduction in rape incidents.

"Even a 1% increase in Uber pickups in a neighborhood translates to a more than 3% decrease in the likelihood of sexual assaults," said Jiyong Park of the University of North Carolina at Greensboro.

The study was conducted by Park alongside Min-Seok Pang of Temple University, Junetae Kim of the National Cancer Center Korea and Byungtae Lee of the Korea Advanced Institute of Science and Technology.

This research investigates the relationship between ridesharing and sexual assault, which has been a controversial, but underexplored topic in public debates on the sharing economy and ridesharing. This study is the first to present systematic empirical evidence that a ridesharing platform can provide a viable means to prevent sexual crimes under certain circumstances.

"Ridesharing can reduce a passenger's risk of being a target of sexual assault by providing a more reliable and timely transportation option for traveling to a safer place," said Park. "Moreover, ridesharing contributes to a more significant reduction in the likelihood of rape occurrences in neighborhoods with limited transportation accessibility, such as the city's outskirts and neighborhoods where a higher percentage of the population is non-Caucasian."

The study also found that ridesharing is more effective in deterring sexual crime in riskier circumstances, such as around alcohol-serving establishments on weekend nights or when the probability of crime occurrences increases.

"Despite the common misconception due to popular media stories, our work proves that digital platforms can be leveraged to solve societal challenges by matching supply and demand closely for relevant services, which calls for spatiotemporal investigations of granular-level data in designing platform businesses and devising policy instruments," concluded Park.

Has your heart ever started to race at the thought of an upcoming deadline for work? Or has the sight of an unknown object in a dark room made you jump? Well, you can probably thank your amygdala for that.

The small almond-shaped brain structure is central to how we perceive and process fear. As we start to learn to associate fear with cues in our environment, neuronal connections within the amygdala are dynamically altered in a process called synaptic plasticity. Although this physiological mechanism is important for facilitating fear learning, it has mostly been studied in the context of excitatory neurons within the amygdala. Far less is known about the role inhibitory cells play.

In a recent publication in Cell Reports, MPFI scientists from the Bolton Lab delve deeper into a specialized portion of inhibitory circuitry in the amygdala, known as the apical intercalated cell cluster (apITC). Characterizing this small but distinctive cluster of cells, the Bolton Lab has discovered rich connectivity and a rather unique ability to modulate plasticity in the amygdala.

"What really grabbed our attention was the fact that relatively little was known about apITC function or connective circuitry," explains Douglas Asede, Ph.D., first author and former postdoc in the Bolton Lab. "When working with a relatively unknown brain area, it's a game of inputs and outputs. First, you have to identify what connects with the neuron cluster and what it connects to, then evaluate what functional role that circuitry plays."

The Bolton Lab began its investigation by characterizing and functionally testing the incoming connections to the apITC. First, the team utilized a highly specialized technique called monosynaptic tracing to selectively identify the upstream presynaptic partners. Once identified, the researchers used a combination of presynaptic optogenetic stimulation (light activation) and postsynaptic electrophysiology to verify that the connections were functional.

"We were able to unravel a number of diverse inputs for this unique cell cluster, ranging from areas important for memory such as the entorhinal cortex to sensory processing regions such as the thalamus," explains Dr. Asede. "Among this diversity, two notable inputs from the thalamus stood out because of their relative strength compared to other connections we tested as well as their origin in thalamic regions known for their involvement in fear learning."

The strong connections to the apITC originated from two areas of the thalamus, the medial geniculate nucleus (MGm) and the posterior intralaminar nucleus (PIN). Previous work has shown the MGm and PIN to be important processing centers for auditory and somatosensory information, respectively. In the context of fear learning, inputs from the thalamus send fear-related sensory information to the amygdala, which then integrates and associates fear with particular cues from the environment.

To examine whether this sensory information flow through the apITC was important for fear learning, MPFI scientists studied the changes in these synaptic connections in mice directly after behavioral training. A group of mice underwent classical fear conditioning and behavior-driven changes and were then evaluated using pre and post-synaptic markers for plasticity. Interestingly, the team found significant signs of synaptic strengthening in the sensory inputs to the apITC after fear learning when compared to control animals.

"Typically, when synapses are important to a particular behavior, their connections are strengthened during learning, so our results really highlighted the importance of these sensory connections in fear learning," notes Dr. Asede.

The LA is a region of the amygdala that is strongly associated with fear learning, fear-related sensory integration, and the formation of fear-based memories. The Bolton Lab used simultaneous electrical stimulation of thalamic sensory inputs and optogenetic stimulation of apITC cell inputs to the LA to reveal that activation of apITC acts as a gate to reduce incoming sensory-driven responses in the LA.

"Armed with the understanding that apITC is important for sensory gating and fear learning, we next looked at what type of downstream connections the apITC makes to give us a clue about possible functions the cluster has in the amygdala fear circuitry."

Classically it's been thought that inhibitory cells within the brain make very short-range, downstream connections, acting to dynamically modify circuits within their own local environments. Using axonal reconstruction, the Bolton Lab identified that while most apITC connections are local axon collaterals to neighboring apITCs or project to a close region within the amygdala called the lateral amygdala (LA). Surprisingly, they also identified a subset of relatively long-range connections to more distant brain structures, challenging classical thinking on inhibitory circuits.

"The apITC is one of several clusters of inhibitory neurons that surround the amygdala like a
net. Each cluster has a unique role in regulating emotional processing in the amygdala by gating specific inputs," notes Mclean Bolton, Ph.D. and Research Group Leader at MPFI. "The ITCs have receptors for many neuromodulators such as dopamine, opiates, and oxytocin so they may function as a barometer for sensing internal state and modifying emotions accordingly. This makes them a potential target for therapies to treat anxiety and PTSD, so understanding how each cluster contributes to amygdala function is important."

CHICAGO, May 24, 2021--More than a year after COVID-19 appeared in the U.S., dentists continue to have a lower infection rate than other front-line health professionals, such as nurses and physicians, according to a study published online ahead of the June print issue in the Journal of the American Dental Association. The study, "COVID19 among Dentists in the U.S. and Associated Infection Control: a six-month longitudinal study," is based on data collected June 9 - Nov. 13, 2020.

According to the study, based on the number of dentists with confirmed or probable COVID-19 infections over more than six months, the cumulative infection rate for U.S. dentists is 2.6%. The monthly incidence rate varied, ranging from 0.2% to 1.1% per month. By comparison, in June 2020, the cumulative COVID-19 prevalence rate for other U.S. health professionals ranged from 3.3% (Chicago-based hospital physicians) to 35.3% (U.S. based emergency medicine services).

"We're pleased to see that dentists have demonstrated continued low monthly incidence of disease despite several regional and national COVID-19 rate spikes during the study period," said American Dental Association (ADA) Science and Research Institute Chief Executive Officer Marcelo Araujo, D.D.S., M.S., Ph.D., the senior author of the report.

Dr. Araujo added, "This study shows high rates of pre-appointment screening of patients and appropriate infection control measures throughout the study period, demonstrating that adhering to very strict protocols for enhanced infection control helps protect their patients, their dental team and themselves."

In addition to Dr. Araujo, other authors of the report include researchers from the ADA Science and Research Institute and Health Policy Institute based in Chicago, as well as Maria L Geisinger, D.D.S., M.S. with University of Alabama at Birmingham in Birmingham, Ala., and Effie Ioannidou, D.D.S., M.D.S., with the University of Connecticut in Farmington, Conn., and a member of the ADA Council on Scientific Affairs.

This study is a continuation of the first large-scale report of incidence rates of COVID-19 among dentists in the U.S published in October 2020. The present six-month longitudinal study aimed to:

Determine the cumulative prevalence rate of COVID-19 among dentists;

Calculate the monthly incidence rate for the same population over the course of the study; and

Assess the level of engagement in specific infection control practices among dentists over a six-month period of time.

The results of this present study, as well as the earlier study, show that prevalence and incidence rates among dentists continue to be very low when compared to the population as a whole and to other health care professionals.

"This study reinforces that the dental care sector is up and running safely," said Chief Economist and Vice President of the ADA Health Policy Institute Marko Vujicic, Ph.D. "Nowhere is this proof point more evident than by the fact that more than 90% of patients surveyed indicate they have already visited the dentist or soon will."

The authors plan future research projects on the barriers and facilitators to wearing Personal Protective Equipment (PPE) according to CDC recommendations, and levels of protection against COVID-19 provided by different levels of PPE use and infection control procedures.

Researchers at Lund University in Sweden have developed an algorithm that combines data from a simple blood test and brief memory tests, to predict with great accuracy who will develop Alzheimer's disease in the future. The findings are published in Nature Medicine.

Approximately 20-30% of patients with Alzheimer's disease are wrongly diagnosed within specialist healthcare, and diagnostic work-up is even more difficult in primary care. Accuracy can be significantly improved by measuring the proteins tau and beta-amyloid via a spinal fluid sample, or PET scan. However, those methods are expensive and only available at a relatively few specialized memory clinics worldwide. Early and accurate diagnosis of AD is becoming even more important, as new drugs that slow down the progression of the disease will hopefully soon become available.

A research group led by Professor Oskar Hansson at Lund University have now shown that a combination of relatively easily acccessible tests can be used for early and reliable diagnosis of Alzheimer's disease. The study examined 340 patients with mild memory impairment in the Swedish BioFINDER Study, and the results were confirmed in a North American study of 543 people.

A combination of a simple blood test (measuring a variant of the tau protein and a risk gene for Alzheimer's) and three brief cognitive tests that only take 10 minutes to complete, predicted with over 90% certainty which patients would develop Alzheimer's dementia within four years. This simple prognostic algorithm was significantly more accurate than the clinical predictions by the dementia experts who examined the patients, but did not have access to expensive spinal fluid testing or PET scans, said Oskar Hansson.

"Our algorithm is based on a blood analysis of phosphylated tau and a risk gene for Alzheimer's, combined with testing of memory and executive function. We have now developed a prototype online tool to estimate the individual risk of a person with mild memory complaints developing Alzheimer's dementia within four years", explains Sebastian Palmqvist, first author of the study and associate professor at Lund University.

One clear advantage of the algorithm is that it has been developed for use in clinics without access to advanced diagnostic instruments. In the future, the algorithm might therefore make a major difference in the diagnosis of Alzheimer's within primary healthcare.

"The algorithm has currently only been tested on patients who have been examined in memory clinics. Our hope is that it will also be validated for use in primary healthcare as well as in developing countries with limited resources", says Sebastian Palmqvist.

Simple diagnostic tools for Alzheimer's could also improve the development of drugs, as it is difficult to recruit the suitable study partcipants for drug trials in a time- and cost-effective manner.

"The algorithm will enable us to recruit people with Alzheimer's at an early stage, which is when new drugs have a better chance of slowing the course of the disease", concludes Professor Oskar Hansson.