Culture

On May 5, 2020, news broke about a reportedly more contagious variant of SARS-CoV-2--the virus that causes COVID-19--based on a preliminary paper posted to the preprint server bioRxiv. The preprint stated that a variant of the virus with a particular mutation leading to an amino acid change, D614G, in its spike protein was "more transmissible" than other forms and represented an "urgent concern" for containment and vaccine development. But in the days that followed, criticisms of these assertions surfaced. On July 2, the journal Cell published a revised and peer-reviewed version of the paper that offers additional experimental and clinical data about the D614G variant suggesting that it may be more infectious, but concludes that we still cannot be certain about whether the variant makes SARS-CoV-2 more transmissible or leads to more severe disease.

"We could see at the time of our initial preprint submission that the G614 variant was becoming the predominant form globally, but we could not differentiate between three broad possibilities that might explain a fitness advantage," says lead author Bette Korber, a laboratory fellow at Los Alamos National Laboratory whose research prior to her work on COVID-19 focused on the search for an HIV vaccine. "The added experiments in the published study point to enhanced infectivity due to the spike protein change as the favored hypothesis. But infectiousness and transmissibility are not always synonymous, and we hope others will study these viruses in greater detail with wild-type virus in natural infection settings and varied target cells."

"The Korber et al. paper has changed pretty considerably from what I saw in their preprint," says Nathan Grubaugh, a virologist at the Yale School of Public Health not affiliated with Korber's team and the lead author of a Preview contextualizing the paper, also published in Cell. "The in vitro data strengthened the clinical findings, both of which suggest that viruses containing the D614G mutation may be able to replicate to higher levels in human cells. But what we cannot say is that it is more transmissible or leads to more severe disease. Essentially, we don't know if this has had any meaningful impact on the COVID-19 pandemic."

While coronaviruses generally have low rates of mutation, Korber and her colleagues were concerned that even small mutations to SARS-CoV-2 could hinder efforts to understand and fight the virus. "We knew from our direct experience in the HIV field that in some cases, a single amino acid change can have a major phenotypic impact," she says. To that end, the team worked to develop a publicly available data-analysis pipeline that could mine SARS-CoV-2 sequences made available on the Global Initiative for Sharing All Influenza Data (GISAID) database to help scientists explore potentially interesting mutations. They quickly identified the D614G variant as something to pay attention to: its key amino acid change from aspartic acid (D) to glycine (G) occurred on a protein that's crucial to how the virus infects human cells--and it was rapidly becoming the dominant version of the virus around the world.

The preprint of the paper focused on the development of this tool and offered an analysis of the global prevalence of the G variant of the virus. This analysis suggested that the G variant took over nearly everywhere it was introduced, which the team argued meant that it was outcompeting the D variant: it was better at jumping from human to human. Criticisms of the preprint argued that this conclusion overstated the results of the analysis, that the preprint lacked experimental evidence to show that the G variant was better at infecting human cells, and that the authors had ignored other possible explanations for its spread, such as the founder effect, where a mutation happens to land in an environment more suited to it becoming the dominant form.

To address these concerns and those of the peer reviewers, the researchers further segmented their geographic analysis in order to look at changes in the frequency of the D and G variants in all regions at country, state or province, and county or city levels. They added the dates of stay-at-home orders in various regions to their analysis to show that the G variant often continued to take over a region even after travel became restricted, limiting the possibility that it was simply being repeatedly imported. There was also more data available: approximately 30,000 global SAR-CoV-2 sequences to work with when the paper underwent revision after peer review as opposed to approximately 6,000 at the time the preprint was submitted. "The richer dataset supported our original observations and gave us more confidence in the results," Korber says. "We now show that in almost every case, G614 increased. There were very few exceptions to this pattern, and we characterize two of them, Iceland and Santa Clara county in California, in detail in the paper."

The researchers were also able to obtain additional clinical data (they looked at 999 patients from the United Kingdom as compared to 470 in the preprint) to show that patients infected with the G variant of the virus had higher levels of viral RNA, which is sometimes correlated with a higher viral load in the body. There was no difference in hospitalization outcomes for patients with one variant versus the other.

Perhaps most importantly, the revised paper now contains the results of two independently conducted sets of experimental studies to assess the infectivity of the G variant based out of the labs of Erica Ollmann Saphire at La Jolla Institute for Immunology and David Montefiori at Duke University. The researchers engineered versions of the virus with the glycine amino acid substitution and then tested how effectively they could infect human cells in a dish. "Virus particles containing the G form of spike on their surface were approximately 3-6 times more infectious," says Montefiori. "Because the only difference between the two sets of virus particles was D versus G at position 614, the increased infectivity can be directly attributed to the D614G mutation." He does note that there are limitations to these findings: the researchers weren't able to use wild-type viruses and did not study the respiratory system cells that SARS-CoV-2 naturally target. There are also other factors involved in real-life transmission of a virus from person to person that may not be accounted for. Despite the limitations, he says the findings are exciting because "they provide a possible biological explanation for the rapid spread of the G form of the virus across the globe."

"It seems likely that it's a fitter virus," agrees Saphire. Her lab was also able to show that antibodies from six people in the San Diego area who had already recovered from COVID-19 were just as effective at neutralizing both the D and G variants. She notes that the San Diegans were infected at a time when both D and G viruses circulated, so the team can't be sure which type the people were infected with, but their findings still show that a higher concentration of antibodies isn't needed to neutralize the new, apparently "fitter" variant despite the higher levels of viral RNA it produced. "That's good news," she says. "Human convalescent sera can neutralize the new virus just as well or perhaps just a bit better." This result suggests that for this particular variant, treatments and vaccines already in development--which are overwhelmingly focused on the spike protein and often based on the original version of the virus sequenced in Wuhan--could still be just as effective.

Korber and her colleagues are still glad they posted the preprint when they did. "We carefully weighed our options," Korber says. "These experimental assays were not easy to develop, and it seemed they were weeks or possibly months away at the time we published the preprint--this assessment turned out to be correct. It seemed important to get the G614 variant immediately into the queue for further study, and we feel our preprint accelerated efforts to enable comparisons of the D614 and G614 spike variants. We and others have now resolved that there is an apparent difference in infectivity between the two variants, and we were able to join in a new collaborative effort to this end that was enabled in part by the preprint."

"Computational analysis of sequence changes is always faster than wet lab experimentation," Saphire says. "Although coronaviruses have some proofreading capacity, mutations can emerge, and vigilance, surveillance, and continued study of the virus will be key to ensuring that the drugs, antibodies, and other interventions under development remain effective. This is the reason the pipeline was set up: to detect mutations that could be important in time to make the needed reagents, grow the necessary viruses, and do the experiments to understand if there is an effect."

"The global expansion of G614, whether through natural selection or chance, means that this variant now is the pandemic," notes Grubaugh in his Preview. Still, he argues that for the general public, these results don't really change much. "Mutation and evolution are natural parts of pandemics and viruses being viruses," he says. "Some of these can slightly change how a virus 'behaves,' but they are not switches that can make a virus suddenly an existential threat.

"While there are still important studies needed to determine if this will influence drug or vaccine development in any meaningful way, we don't expect that D614G will alter our control measures or make individual infections worse," he adds. "It's more of a live look into science unfolding: an interesting discovery was made that potentially touches millions of people, but we don't yet know the full scope or impact. We only just learned about this virus about six months ago, and we'll learn a lot more in the next six months."

Researchers have shown that a variation in the viral genome of Covid-19 improved its ability to infect human cells and helped it become the dominant strain circulating around the world today.

The study, published today in the journal Cell, shows the variation is more infectious in cell cultures under laboratory conditions. The variant, named 'D614G', makes a small but effective change in the 'spike' glycoprotein that protrudes from the surface of the virus, which it uses to enter and infect human cells.

The D614G variant of Covid-19 quickly took over as the dominant strain soon after it first appeared, with geographic samples showing a significant shift in viral population from the original, to the new strain of the virus.

Researchers from the Los Alamos National Laboratory in New Mexico and Duke University in North Carolina, partnered with the University of Sheffield's Covid-19 Genomics UK research group to analyse genome samples published on GISAID, an international resource for sharing genome sequences among researchers worldwide.

Dr Thushan de Silva, Senior Clinical Lecturer in Infectious Diseases at the University of Sheffield, led analysis of data from Sheffield. He said: "We have been sequencing SARS-CoV-2 strains in Sheffield since early in the pandemic and this allowed us to partner with our collaborators to show this mutation had become dominant in circulating strains. The full peer-reviewed study published today confirms this, and also that the new D614G genome mutation variant is also more infectious under laboratory conditions.

"Data provided by our team in Sheffield suggested that the new strain was associated with higher viral loads in the upper respiratory tract of patients with Covid-19, meaning the virus's ability to infect people could be increased.

"Fortunately at this stage, it does not seem that viruses with D614G cause more severe disease."

Dr Bette Korber, from the Los Alamos National Laboratory in New Mexico, was the lead author of the study. She said: "It is possible to track SARS-CoV-2 (Covid-19) evolution globally because researchers worldwide are rapidly making their viral sequence data available through the GISAID viral sequence database. Currently tens of thousands of sequences are available through this project, and this enabled us to identify the emergence of a variant that has rapidly become the globally dominant form."

New supporting experiments, more extensive sequencing and clinical data, and improved statistical models have been published today in full at Cell, however the researchers are keen to stress that further laboratory analysis in live cells needs to be done to determine the full implications of the mutation.

"It's remarkable to me," commented Dr Will Fischer, from Los Alamos National Laboratory and an author on the study. "That this increase in infectivity was detected by careful observation of sequence data alone, and that our experimental colleagues could confirm it with live virus in such a short time."

LOS ALAMOS, N.M., July 2, 2020-- Research out today in the journal Cell shows that a specific change in the SARS-CoV-2 coronavirus virus genome, previously associated with increased viral transmission and the spread of COVID-19, is more infectious in cell culture. The variant in question, D614G, makes a small but effective change in the virus's 'Spike' protein, which the virus uses to enter human cells.

Bette Korber, a theoretical biologist at Los Alamos National Laboratory and lead author of the study, noted, "The D614G variant first came to our attention in early April, as we had observed a strikingly repetitive pattern. All over the world, even when local epidemics had many cases of the original form circulating, soon after the D614G variant was introduced into a region it became the prevalent form."

Geographic information from samples from the GISAID COVID-19 viral sequence database enabled tracking of this highly recurrent pattern, a shift in the viral population from the original form to the D614G variant. This occurred at every geographic level: country, subcountry, county, and city.

Two independent lines of experimental evidence that support these initial results are included in today's paper. These additional experiments, led by Professor Erica Ollmann Saphire, Ph.D., at the La Jolla Institute, and by Professor David Montefiori, Ph.D., at Duke University, showed that the D614G change increases the virus's infectivity in the laboratory. These new experiments, as well as more extensive sequence and clinical data and improved statistical models, are presented in the Cell paper. More in vivo work remains to be done to determine the full implications of the change.

The SARS-CoV-2 virus has a low mutation rate overall (much lower than the viruses that cause influenza and HIV-AIDS). The D614G variant appears as part of a set of four linked mutations that appear to have arisen once and then moved together around the world as a consistent set of variations.

"It's remarkable to me," commented Will Fischer of Los Alamos, an author on the study, "both that this increase in infectivity was detected by careful observation of sequence data alone, and that our experimental colleagues could confirm it with live virus in such a short time."

Fortunately, "the clinical data in this paper from Sheffield showed that even though patients with the new G virus carried more copies of the virus than patients infected with D, there wasn't a corresponding increase in the severity of illness," said Saphire, who leads the Gates Foundation-supported Coronavirus Immunotherapy Consortium (CoVIC).

Korber noted, "These findings suggest that the newer form of the virus may be even more readily transmitted than the original form - whether or not that conclusion is ultimately confirmed, it highlights the value of what were already good ideas: to wear masks and to maintain social distancing."

Research partners from Los Alamos National Laboratory, Duke University, and the University of Sheffield initially published work on this analysis on the bioRxiv site in an April 2020 preprint. That work also included observations of COVID-19 patients from Sheffield that suggested an association of the D614G variant with higher viral loads in the upper respiratory tract.

"It is possible to track SARS-CoV-2 evolution globally because researchers worldwide are rapidly making their viral sequence data available through the GISAID viral sequence database", Korber said. Currently tens of thousands of sequences are available through this project, and this enabled Korber and the research team to identify the emergence of the D614G variant.

GISAID was established to encourage collaboration among influenza researchers, but early in the epidemic the consortium established a SARS-CoV-2 database, which soon became the de facto standard for sharing outbreak sequences among researchers worldwide.

Syracuse, N.Y. - A new study published recently in "BMC Pediatrics" shows a connection between the time of the month when low-income families receive their Supplemental Nutrition Assistance Program (SNAP) benefits and the number of emergency room visits due to injuries to children from those families.

Childhood injuries are the leading cause of illness and death in the United States, resulting in an estimated 9.2 million emergency department visits and $17 billion in medical costs annually. For preschoolers, it is the leading cause of disability.

Researchers linked administrative data for SNAP and Medicaid in the state of Missouri from January 2010 to December 2013. They explored monthly patterns in the association between SNAP receipt and ER claims due to childhood injury for children age 0-5 and examined if these patterns are sensitive to the timing of SNAP benefits.

The result: Families that receive benefits later in the month have fewer ER visits, likely because they can afford to feed their families at the end of the calendar month when other resources run low.

The study, "Childhood injuries and food stamp benefits: an examination of administrative data in one US state," was published June 17 by BMC Pediatrics. Colleen Heflin, professor of public administration and international affairs at Syracuse University's Maxwell School of Citizenship and Public Affairs and senior research associate in its Center for Policy Research, is author of the study.

"Our study suggests that childhood injuries, the leading cause of mortality and morbidity in the United States, can be reduced by disbursing SNAP benefits later in the month instead of at the beginning of the calendar month," Heflin said. "Previous work suggests that childhood injuries are associated with parenting practices and child behavior problems, which are also correlated with maternal stress and income.

"Simply put, low-income households may find it harder to avoid childhood injuries while coping with food insecurity," Heflin said. "This work provides one more to a long list of reasons it is important to support federal food assistance programs such as SNAP."

The researchers chose Missouri because unlike most states that disburse SNAP benefits within the first 10?days of the calendar month, Missouri pays SNAP benefits between the first 22 days of the month, based on the recipient's birthdate and last name.

The researchers said there is no evidence that childhood injuries connected to the timing of SNAP benefits are caused by parents.

"I think that food insecure parents are probably distracted by worrying about how to feed their families and not able to fully focus on their children who may be acting out because they are hungry," Heflin said. "It's more about how many things parents can juggle at one time in a home with food insecurity."

During March 2020, 27.3 million individuals in 19 million households received SNAP benefits. The Families First Coronavirus Response Act allowed states greater flexibility in administering the program, the ability to provide an emergency supplement to benefits, and school meal replacement benefits to households with children. Many states were approved for these changes to their SNAP program through the end of June.

New Rochelle, NY, July 2, 2020--The Editor-in-Chief of Human Gene Therapy, the first journal devoted to the field of gene therapy, and one of the world's leading experts on gene therapy have co-authored a new editorial, Moving Forward After Two Deaths in a Gene Therapy Trial of Myotubular Myopathy, in response to the news of two deaths in a now-halted gene therapy clinical trial.

The editorial, published in Human Gene Therapy, is co-authored by James M. Wilson, MD, PhD, director of the Gene Therapy Program at the University of Pennsylvania and former Editor Human Gene Therapy Clinical Development, and Editor-in-Chief Terry Flotte, MD, who is also the Dean of the University of Massachusetts School of Medicine.

The editorial is in response to the recent report of the deaths of two children receiving high doses of a gene therapy vector (AAV8) in a Phase I trial for X-linked myotubular myopathy (MTM). The news "is a tragic reminder of how difficult it is to predict outcomes in first-in-human studies," the authors wrote.

The sponsor of this clinical study is Audentes Therapeutics, which was acquired by Japan's Astellas Pharma in 2019. Wilson and Flotte say preclinical studies had been very promising. But in the ongoing trial, three patients were given a three-fold higher dose than other participants; they all experienced severe hepatotoxicity, which proved fatal in two of these subjects.

Wilson and Flotte note that some signs of toxicity have been reported in other AAV trials over the past year or two, including trials for spinal muscular atrophy and Duchenne muscular dystrophy, which are being run by companies such as Solid Bio, Sarepta, and Pfizer. Fortunately, all the affected subjects in these trials have recovered.

In early 2018, Wilson published a landmark paper in Human Gene Therapy describing severe toxicity in nonhuman primates infused with high doses of AAV.

Although data are limited at present, Wilson and Flotte suggest the deaths of the MTM trial "more closely resembles those of the [non-human primate] studies rather than those of the [Duchenne] trials." One possibility the authors discuss is the role of antibodies to AAV that either pre-exist or accumulate following vector infusion.

With much more work needed to understand immune-mediated gene therapy vector toxicities, Wilson and Flotte conclude that "the early clinical development of gene therapy vectors may require an iterative process, especially if unexpected toxicities are observed." Additional studies in preclinical models should help evaluate the variables associated with immune response.

The MTM trial is on hold while authorities investigate further; the fate of the candidate therapy is unclear.

"Whether this product can be revived is unclear, the fact remains that patients with MTM and many other rare genetic diseases have no treatments," the authors state. "It is imperative that the scientific community work together with full transparency and cooperation to learn from these tragedies to assure that we can deliver safe and effective treatments to individuals living with rare genetic diseases such as MTM."

FINDINGS

UCLA scientists have identified a new function for histones, the spool-shaped proteins that regulate gene expression and serve as anchors for strands of DNA to wrap around.

The researchers discovered that histones act as an enzyme that catalyzes the transfer of electrons from a molecule to a metal, converting copper into a form that can be used by the cells.

The finding refutes earlier theories that copper in the body spontaneously converts into a form that cells can utilize. Instead, histones facilitate the use of copper in the presence of oxygen. This enables copper to reach its cellular destinations and protein targets, including proteins in mitochondria, the cell's power source.

The absence of enzyme activity in histones impairs many cellular processes, such as mitochondrial respiration, which depends on copper to function.

METHOD

The scientists blended biochemistry and molecular biology approaches while using baker's yeast as a model cell to show that histones bind to copper and convert it to a usable form. The team duplicated the experiment in a test tube and within living cells.

IMPACT

The study suggests that the presence of histones in an ancestor of eukaryotes -- cells that contain a nucleus -- played an essential role some 2 billion years ago in the evolution of history's first eukaryotic cell, giving rise to a vast diversity of humans, animals, plants and fungi.

The new findings could deepen scientists' understanding of the evolution of eukaryotes. Given the importance of chromatin and copper to human health, the UCLA discovery also could provide insights into how disease develops in a variety of human conditions, from cancer to mitochondrial diseases and neurodegenerative disorders.

WASHINGTON--People with endocrine disorders may see their condition worsen as a result of COVID-19, according to a new review published in the Journal of the Endocrine Society.

"We explored the previous SARS outbreak caused by the very similar virus SARS-CoV-1 to advise endocrinologists involved in the care of patients with COVID-19," said Noel Pratheepan Somasundaram of the National Hospital of Sri Lanka in Colombo, Sri Lanka. "The virus that causes COVID-19--SARS-CoV-2--binds to the ACE2 receptor, a protein which is expressed in many tissues. This allows the virus to enter endocrine cells and cause the mayhem associated with the disease."

SARS-CoV-2 can cause loss of smell and gain entry to the brain. In past coronavirus infections such as the SARS epidemic in 2003, many patients developed a post-viral syndrome with fatigue. This could in part be caused by adrenal insufficiency, a condition where the adrenal glands do not make enough cortisol, as a result of damage to the pituitary system. During the SARS epidemic, patients who developed adrenal insufficiency typically recovered within one year.

"Testing for cortisol deficiency and treating patients with steroids may become a vital treatment strategy," Somasundaram said. "Very recent studies have demonstrated lowered mortality in severely-ill patients with COVID-19 treated with the steroid dexamethasone."

COVID-19 also could lead to new cases of diabetes and worsening of existing diabetes. The SARS-CoV-2 virus attaches to ACE2, the main entry point into cells for coronavirus, and disrupts insulin production, causing high blood glucose levels in some patients. The authors highlight the need for strict glucose monitoring in patients with COVID-19 as a measure to maximize recovery.

"People with vitamin D deficiency may be more susceptible to coronavirus and supplementation could improve outcomes, though evidence on the subject is mixed," Somasundaram said.

If there's one myth that has persisted through the years without much evidence, it's this: multiply your dog's age by seven to calculate how old they are in "human years." In other words, the old adage says, a four-year-old dog is similar in physiological age to a 28-year-old person.

But a new study by researchers at University of California San Diego School of Medicine throws that out the window. Instead, they created a formula that more accurately compares the ages of humans and dogs. The formula is based on the changing patterns of methyl groups in dog and human genomes -- how many of these chemical tags and where they're located -- as they age. Since the two species don't age at the same rate over their lifespans, it turns out it's not a perfectly linear comparison, as the 1:7 years rule-of-thumb would suggest.

The new methylation-based formula, published July 2 in Cell Systems, is the first that is transferrable across species. More than just a parlor trick, the researchers say it may provide a useful tool for veterinarians, and for evaluating anti-aging interventions.

"There are a lot of anti-aging products out there these days -- with wildly varying degrees of scientific support," said senior author Trey Ideker, PhD, professor at UC San Diego School of Medicine and Moores Cancer Center. "But how do you know if a product will truly extend your life without waiting 40 years or so? What if you could instead measure your age-associated methylation patterns before, during and after the intervention to see if it's doing anything?" Ideker led the study with first author Tina Wang, PhD, who was a graduate student in Ideker's lab at the time.

The formula provides a new "epigenetic clock," a method for determining the age of a cell, tissue or organism based on a readout of its epigenetics -- chemical modifications like methylation, which influence which genes are "off" or "on" without altering the inherited genetic sequence itself.

Epigenetic changes provide scientists with clues to a genome's age, Ideker said -- much like wrinkles on a person's face provide clues to their age.

Ideker and others have previously published epigenetic clocks for humans, but they are limited in that they may only be accurate for the specific individuals on whom the formulas were developed. They don't translate to other species, perhaps not even to other people.

Ideker said it was Wang who first brought the dog idea to him.

"We always look at humans, but humans are kind of boring," he said. "So she convinced me we should study dog aging in a comparative way."

To do that, Ideker and Wang collaborated with dog genetics experts Danika Bannasch, DVM, PhD, professor of population health and reproduction at UC Davis School of Veterinary Medicine, and Elaine Ostrander, PhD, chief of the Cancer Genetics and Comparative Genomics Branch at the National Human Genome Research Institute, part of the National Institutes of Health. Bannasch provided blood samples from 105 Labrador retrievers. As the first to sequence the dog genome, Ostrander provided valuable input on analyzing it.

Dogs are an interesting animal to study, Ideker said. Given how closely they live with us, perhaps more than any other animal, a dog's environmental and chemical exposures are very similar to humans, and they receive nearly the same levels of health care. It's also important that we better understand their aging process, he said, as veterinarians frequently use the old 1:7 years ratio to determine a dog's age and use that information to guide diagnostic and treatment decisions.

What emerged from the study is a graph that can be used to match up the age of your dog with the comparable human age (see figure: go.ucsd.edu/2Ze8ZCd). The comparison is not a 1:7 ratio over time. Especially when dogs are young, they age rapidly compared to humans. A one-year-old dog is similar to a 30-year-old human. A four-year-old dog is similar to a 52-year-old human. Then by seven years old, dog aging slows.

"This makes sense when you think about it -- after all, a nine-month-old dog can have puppies, so we already knew that the 1:7 ratio wasn't an accurate measure of age," Ideker said.

According to Ideker, one limitation of the new epigenetic clock is that it was developed using a single breed of dog, and some dog breeds are known to live longer than others. More research will be needed, but since it's accurate for humans and mice as well as Labrador retrievers, he predicts the clock will apply to all dog breeds.

Next, the researchers plan to test other dog breeds, determine if the results hold up using saliva samples, and test mouse models to see what happens to their epigenetic markers when you try to prolong their lives with a variety of interventions.

Meanwhile, Ideker, like many other dog owners, is looking at his own canine companion a little differently now.

"I have a six-year-old dog -- she still runs with me, but I'm now realizing that she's not as 'young' as I thought she was," Ideker said.

New research published today in the Journal of Physiology shows that 12 weeks of easy-to-administer passive stretching helps improve blood flow by making it easier for your arteries to dilate and decreasing their stiffness.

Passive stretching differs from active stretching in that the former involves an external force (another person or gravity) stretching you, whereas active stretching is performed on your own. The changes they observed in blood vessels could have implications for diseases, including the number one global killer, heart disease.

Researchers at the University of Milan assigned 39 healthy participants of both sexes to two groups. The control group didn't undergo any stretching. The experimental group performed leg stretches 5 times a week for 12 weeks. Researchers evaluated the effect of passive stretching on the blood flow locally and in the upper arm. They found that the arteries in both the lower leg and upper arm had increased blood flow and dilation when stimulated, along with decreased stiffness.

Both of these changes may have implications for diseases such as heart disease, stroke and diabetes as they are characterized by changes in blood flow control, due to an impaired vascular system.

If this study is replicated in patients with vascular disease, it could indicate whether or not this training method could serve as a new drug-free treatment for improving vascular health and reducing disease risk, especially in people with lower mobility.

Moreover, stretching may also be used during hospitalisation or after surgical interventions, in order to preserve the vascular health when patients have low mobility. It can be also performed at home by carers or family members.

Emiliano Ce, an author on the paper said:

This new application of stretching is especially relevant in the current pandemic period of increased confinement to our homes, where the possibility of performing beneficial training to improve and prevent heart disease, stroke and other conditions is limited.

Why do you like the music you do? You would think that it is because of the music itself. But that's only half the story. Surprisingly, the other half of the story doesn't have much to do with music at all. A new Big Data study from Bar-Ilan University and Columbia Business School found that the musician's personality plays a large role, as well, in listener preferences.

The study, published today in the Journal of Personality and Social Psychology, was conducted by team of psychologists from four major universities and led by Zuckerman Scholar and musician Dr. David Greenberg, from the Interdisciplinary Department of Social Sciences and Department of Music at Bar-Ilan University, and Assistant Professor at Columbia Business School Dr. Sandra Matz. By analyzing the public personas of famous musicians and bands, and the personality traits of their fans, the team showed that people prefer the music of artists whose public personalities are similar to their own - an experience they've dubbed the "self-congruity effect of music."

In three separate studies of more than 80,000 people, the researchers looked at several factors: persona ratings of 50 of the most famous musicians in the Western world, listener reactions to actual musical stimuli, and the lyrics in the artists' music. The musicians studied were diverse, ranging from Paul McCartney, Bob Dylan, Elton John, Whitney Houston, The Rolling Stones to Beyoncé, Coldplay, Dave Matthews Band, Maroon 5, Taylor Swift, and Ozzy Osbourne.

The results from the three studies show that the fit in personality between the listener and the musician predicts musical preferences similar to the fit for gender, age, and even the audio features of music. It's important to note that the perceived personality or public "persona" of the musicians were measured--not their actual personalities. The findings are a major advance in this area of research and show that musical preferences are driven by social, psychological and group dynamics.

The findings highlight the social powers of music and how music gives fans a sense of pride and belonging to a social world. Even more, the results shed light on the evolutionary origins of music, which say that music evolved as a way to communicate groups characteristics which helped tribes determine whether or not to cooperate with each other.

Dr. David Greenberg, a Zuckerman Scholar at Bar-Ilan University in Israel, an honorary research associate at Cambridge University in England, and a professional musician, says, "In today's world, where social divisions are increasing, our studies are showing us how music can be a common denominator to bring people together."

Dr. Sandra Matz, Assistant Professor at Columbia Business School, says, "The findings can pave the way for a new approaches for record companies or music management to target and build audiences."

Dr. H. Andrew Schwartz, Assistant Professor at Stony Brook University, says, "The findings can be applied to situations involving mental health. For example, in times of stress and uncertainty, listeners can seek music of artists with similar personalities to themselves and feel understood and a sense of connectedness."

Durham, NC - Plastic pollution is a critical environmental issue facing the world today, yet the impact of all the microplastics (MPs) and nanoplastics (NPs) that have seeped into the food and beverage supply on human health is an "undervalued avenue of research," according to the team behind a revealing new study released today in STEM CELLS. This study outlines the new platform researchers designed that allowed them to investigate the potentially harmful effects of MPs and NPs. The results show not only how these particles can impact a developing infant's health, but also may open novel ways to study this prevalent type of pollution and its contributions to the origin of various diseases.

From 1950 to now, plastic production has increased nearly 200-fold to the current 350 million tons, according to a study published last June in Science of The Total Environment. As of 2018, approximately 6.9 billion tons had become waste, with 79 percent of that accumulated in the natural environment.

"Assuming that only 15 percent of their total caloric intake is from plastic-packaged nutrients, it was calculated that the average person consumes up to 121,000 MP particles per year, while people who drink bottled water consume an additional 90,000 MP. And these numbers don't account for particulates that enter our bodies through occupational exposure (such as construction, boating or the bath and shower industries) and other means. So you can see this number has the potential to increase substantially," said Miodrag Stojkovic, Ph.D., DVM. Dr. Stojkovic is corresponding author of the international study, led by researchers from the Medical Fertility Hospital, Leskovac, Serbia, and Faculty of Medical Sciences, University of Kragujevac, Serbia, and currently is affiliated with Massachusetts Eye and Ear, Harvard Medical School in Boston.

Few studies have investigated the potentially harmful effects of MPs/NPs on early human development and health. To further complicate things, the plethora of plastic types, particle sizes and the lack of a reliable model makes studying the impact of rising environmental plastic pollution on human health a real challenge.

"Adding to that," Dr. Stojkovic said, "no clear definition or regulation of MPs/NPs exists on an international basis."

All this led Dr. Stojkovic and his colleagues to develop a new platform that would enable them, for the first time, to estimate gene changes and signaling pathways that might be altered in response to the exposure of pre-implantation human embryos and human induced pluripotent stem cells (iPSCs) to plastic particles. They focused their work on nanoparticles shed by one of the most prevalent types of plastics used in food and beverage packaging -- polystyrene.

To begin, they analyzed human iPSC growth media that was persistently exposed to plastic (storage bottles, dishes, pipettes and tips, laboratory air and lab coats) using pyrolysis-gas chromatography/mass spectrometry (PyGC/MS). The PyGC/MS analysis excluded the additional presence of any known polymer. Next, they exposed thawed early human expanded blastocysts and human iPSCs to nano- (40 nm) and micro- (200 nm) polystyrene items and examined the effects. And lastly, the researchers used the HiPathia method -- a model that allows the estimation of how changes in the expression of genes affect signaling circuits and consequent cell functional decisions -- to enable them to detect any disease mechanisms and predict relevant clinical outcomes.

The collective data from these analyses showed that NPs alter genes that are connected to eye development, cardiac malformations and ischemia.

"Taken together, results obtained with our embryo- and stem cell-based platform and polystyrene NPs clearly demonstrate that an understanding of bio-NP interactions and the implications on human health is, more than ever, of utmost importance, especially in this era of increased environmental plastic pollution and the presence of microscopic plastic particles in the air, soil, food, beverages, and tap water," Dr. Stojkovic said. "We also believe that the study findings make a strong call for an urgent action by scientific and policymaking authorities to create regulatory measures that might lessen NPs' impact, especially given that our platform deciphers the links between environmental and intracellular pollutions, and origin of detrimental diseases."

"This outstanding report provides a sobering look at the effects of plastic nanoparticles on human stem cells. It has been known that these particles are problematic, but this is the first report, to my knowledge, to provide mechanistic, detailed data on how polystyrene nanoplastics affect human iPSCs and embryonic cells," said Jan Nolta, Editor-in-Chief of STEM CELLS. "This platform will be very useful for future studies evaluating the negative effects of different types of plastic nanoparticle contaminants."

The combination of ceftolozane with tazobactam broadens the range of antibiotic therapy in adults with severe infections of the lungs, the urinary tract, the renal pelvis and the abdominal cavity. In view of the increasing resistance development in bacteria, this drug combination is therefore an important additional treatment option.

The German Institute for Quality and Efficiency in Health Care (IQWiG) now investigated in four early benefit assessments whether ceftolozane/tazobactam not only offers a broadening of the treatment options in severe infections of the different organs, but also an added benefit in comparison with individual antibiotic therapy, which takes the respective resistance situation into account.

The result: There are no informative studies for such a comparison, particularly, as the local and individual resistance situation was not sufficiently considered in the approval studies. In the overall consideration, there was therefore no proof of advantages or disadvantages of ceftolozane/tazobactam on the basis of the available data.

Comparison was too narrow and provided no hint of added benefit

To avoid the development of resistances, antibiotics should be used as specifically as possible, i. e. depending on the local pathogen spectrum and the individual pathogen sensitivity. The local resistance situation also has to be taken into account, as the spread of resistant germs can vary greatly from place to place.

The approval studies underlying the four drug manufacturer dossiers are principally high-quality randomized controlled trials (RCTs). However, they only compared the new drug combination in the therapeutic indications for lungs and abdominal cavity, and for urinary tract and renal pelvis only with one other antibiotic each - without showing relevant differences between the intervention and the control groups. This very restricted comparison does not concur with the much broader treatment options specified as suitable therapy according to the appropriate comparator theapy. It can also not be inferred from the study data that the local resistance situation in the respective study centres and the individual resistance situation after pathogen detection were sufficiently taken into account.

"This is very regrettable," says Thomas Kaiser, Head of IQWIG's Drug Assessment Department, "because the development of new antibiotics is principally necessary and very welcome. However, to draw conclusions on the added benefit, we need studies that consider the local and individual resistance situation adequately. Unfortunately, this was not the case in the studies presented."

However, a comparison with further treatment options under consideration of the local pathogen spectrum, the resistance profile, the risk of infection with multi-resistant pathogens, and the pathogen sensitivity on the basis of an antibiogram offers promising opportunities for proof of an added value of new antibiotics.

Overall, no hint of an added benefit of ceftolozane/tazobactam could be derived in comparison with the appropriate comparator therapy; an added benefit is therefore not proven.

No advantage of ceftolozane/tazobactam can be inferred from in vitro data

The sensitivity or resistance of a pathogen for different antibiotics can be studied outside a concrete treatment situation, i. e. in the laboratory (in vitro). It is principally conceivable to derive an advantage of a new antibiotic on the basis of in vitro data if the new drug shows high efficacy, whereas the drugs hitherto available in the therapeutic indication show (almost) no efficacy.

The in vitro data in the manufacturer dossier are incomplete, however, as not all available drugs were assessed. Furthermore, the analyses of these in vitro data show that several tested drugs are effective in the investigated pathogens and are a possible treatment option besides ceftolozane/tazobactam.

G-BA decides on the extent of added benefit

The dossier assessments are part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the dossier assessments, the G-BA conducts commenting procedures and makes decisions on the extent of the added benefit.

More English-language information will be available soon (extracts of the dossier assessments as well as easily understandable information on informedhealth.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.

Physicists at Martin Luther University Halle-Wittenberg (MLU) and Lanzhou University in China developed a simple concept that could improve significantly magnetic-based data processing. Using ultrashort electric pulses in the terahertz range, data can be written, read and erased very quickly. This would make data processing faster, more compact and energy efficient. The researchers confirmed their theory by running complex simulations and the results were published in the journal NPG Asia Materials.

Magnetic data storage is indispensable for storing securely the huge amount of data generated every day, for instance through social networks. Once stored, the information can still be retrieved after many years. Charge-based data storage used for example in mobile phones is much more short-lived when there is no energy supply. Traditional magnetic hard drives and components have disadvantages of their own, due to the moving mechanical parts and the need for magnetic fields which makes them more power consuming and relatively slow when reading and writing data.

"We were after a fast and energy-efficient alternative," explains Professor Jamal Berakdar from the Institute of Physics at MLU. He and his colleagues from Lanzhou University came up with a simple idea. By using ultrashort pulses in the terahertz range, information could be written in magnetic nano-vortices and retrieved within picoseconds. Theoretically, this renders possible billions of read and write operations per second without the need for magnetic fields. "With the appropriately shaped pulses the data can be processed very quickly at low energy cost," says Berakdar. The new concept is based on existing terahertz and magnetism technologies. "It exploits advances in electric pulse generation and nanomagnetism."

So far, the method has been tested in computer simulations. "In recent years there have been fantastic advances in generating and controlling electrical pulses," says Berakdar. Therefore, it makes sense to explore new ways to apply these pulses to data storage. The concept presented by the researchers offers a simple tool for controlling magnetic nano-vortices and can therefore be directly utilised for new storage technologies.

Currently we are facing a dementia epidemic, estimations showing that by 2050 approximately 131 million people will be affected. Every 7 seconds a patient is diagnosed worldwide. Because the common forms of dementia occur in the elderly, delaying the onset or worsening of the cognitive impairment could translate into a significant reduction of the incidence of the disease. Estimations have shown that of the huge number of cases expected by 2050, roughly 23 million could be avoided if the onset of the disease could be delayed by 2 years. Despite the ambition to identify a disease modifying therapy or a cure for dementia by 2025 set by the G8 dementia summit in 2013, the findings so far are not very encouraging.

To date there is growing evidence of the association of vascular risk factors like hypertension, high cholesterol levels or diabetes mellitus with cognitive impairment and Alzheimer's disease. Unfortunately, simply managing these risk factors had little effect in reducing the incidence of dementia. These factors, however, strongly increase the risk of a patient to suffer an ischemic stroke and incident stroke approximately doubles the risk of dementia. From the study of Saver published in 2006 we know that "each hour in which treatment fails to occur the brain loses as many neurons as it does in 3.6 years of normal aging".

These neuronal losses occur through ischemic necrosis in the core of the infarction, but may be prolonged up to 2 weeks after the ischemic insult in the penumbral area surrounding the ischemic core through another type of cell loss, namely apoptosis. In initiating apoptosis oxidative species have a major role. Several authors have shown consistent increases in oxidative stress after an ischemic stroke. As the authors pointed out in a previous study, oxidative stress increases mainly after cardioembolic stroke, followed by lacunar stroke, with a less prolonged burst of generation of oxidative species following thrombotic stroke.

There is a considerable overlap between the oxidative stress-induced pathogenesis in ischemic stroke and Alzheimer's disease including mitochondrial dysfunction (the mitochondria being the main generators of energy in the cells), calcium overload of the cells, activation of different destructive enzymes by the excess intracellular calcium, aberrant gene transcription and expression, induction of autophagy (a process by which cells degrade their own cytoplasmic proteins and organelles) and activation of inflammatory responses.

Despite promising results of antioxidant molecules in animal models of ischemic stroke, human clinical trials were disappointing possibly due to late administration and incorrect selection of patients. However, in a study published in 2019 edaravone (an antioxidant molecule) given within 48 hours after endovascular revascularization in acute ischemic stroke was associated with greater functional independence at hospital discharge, lower in-hospital mortality and reduced intracranial hemorrhage after admission in a study which enrolled over 10,000 patients. More recently in a report presented at the International Stroke Conference 2020, nerinetide or NA1, a molecule which reduces endogenous nitric oxide (also an oxidative species) generated inside the cell during ischemia, improved the outcome of ischemic stroke patients who underwent endovascular thrombectomy. Unfortunately, NA1 interacted with alteplase, limiting its efficiency in patients who were also thrombolysed.

Antioxidants have been evaluated also in degenerative diseases, Alzheimer's disease included, with promising results in animal models but inconclusive results in clinical trials. Therapeutic strategies are hampered by the dual role of oxidative species in the organism. On one hand, increased ROS production contributes to age-related chronic conditions and on the other, oxidant species function as signaling molecules in pathways that are critical for cell survival. However, based on the compelling evidence of the implication of oxidative stress in AD pathogenesis and of the pivotal role of mitochondria, molecules acting as mitochondria-targeted antioxidants show promise in animal models of neurodegenerative diseases, improve mitochondrial function after coronary ischemia/reperfusion in rats, and some have already been developed into drugs used in clinical trials in type 2 diabetic patients.

In view of the implication of oxidative stress in the genesis of AD pathology, the authors hypothesize that with aging, in the presence of well-established vascular risk factors, and possibly with a genetic contribution, AD pathology develops slowly without clinically overt cognitive impairment. However, after a stroke there is a sudden burst in oxidative stress which accelerates the pathogenesis of dementia and leads to clinically obvious cognitive impairment. If this hypothesis would be proven the reason for reaching antioxidant treatment in acute ischemic stroke would be reinforced. Further studies in this direction with long follow-up periods would be needed. Nonetheless, in view of the high incidence and prevalence of the disease, the results could be rewarding.

Men are more likely than are women to be seen as "brilliant," finds a new study measuring global perceptions linked to gender. The work concludes that these stereotyped views are an instance of implicit bias, revealing automatic associations that people cannot, or at least do not, report holding when asked directly.

The research, which appears in the Journal of Experimental Social Psychology, was conducted by scientists at New York University, the University of Denver, and Harvard University.

"Stereotypes that portray brilliance as a male trait are likely to hold women back across a wide range of prestigious careers," observes Daniel Storage, an assistant professor in the University of Denver's Department of Psychology and the paper's lead author.

"Understanding the prevalence and magnitude of this gender-brilliance stereotype can inform future efforts to increase gender equity in career outcomes," adds Andrei Cimpian, an associate professor in NYU's Department of Psychology and the paper's senior author.

Previous work by Cimpian and his colleagues has suggested that women are underrepresented in careers where success is perceived to depend on high levels of intellectual ability (e.g., brilliance, genius), including those in science and technology.

Less understood are the factors that explain this phenomenon. To address this, the new Journal of Experimental Social Psychology study explored the potential impact of stereotypes. For example, perhaps the qualities of genius and brilliance are associated in people's minds with men more than with women--and, as a result, women are less encouraged to pursue these fields--or the atmosphere of these fields is less welcoming to women.

However, accurately measuring stereotyping is a challenge. People are often reluctant to admit they have stereotypes, so asking directly about these beliefs is unlikely to provide an accurate measure of whether they endorse the idea that brilliance is more common among men than it is among women.

To overcome this methodological obstacle, the researchers adopted a test that is geared to measure stereotyping indirectly. Here, the aim is to capture implicit stereotypes--or the automatic associations that come to mind between certain traits (e.g., brilliance) and certain groups (e.g., men). This is in contrast to explicit stereotyping, in which we knowingly and verbally ascribe traits to groups of people.

The team employed a long-established tool, the Implicit Association Test (IAT), which measures the degree of overlap between concepts (e.g., brilliant and male) without explicitly asking subjects whether or not they hold stereotyped views.

The IAT is essentially a speeded sorting task. In the study, participants saw a series of stimuli (such as a picture of a woman or the word "brilliant") on a computer screen and were asked to sort them into two categories by pressing either the E or the I key on their keyboard. For example, in some trials participants were asked to press E if they saw a stimulus that is related to either the category male or the trait brilliant. On other trials, the sorting rule was different. For example, the gender categories were swapped such that participants had to press E if they saw a stimulus that is related to either the category female or the trait brilliant.

The logic of the IAT, the authors explain, is as follows: If brilliant is more associated with male than with female in people's minds, then participants will be faster to sort the stimuli when brilliant and male are paired with the same response key--because the stereotype makes these two concepts seem like they "go together"--than when brilliant and female are paired.

Across a series of five studies, which included U.S. women and men, U.S. girls and boys (ages 9 and 10), and women and men from 78 other countries, the researchers consistently found evidence for an implicit stereotype associating brilliance with men more than with women. The magnitude of this stereotype was striking as well--for example, it was similar in strength to the implicit stereotype that associates men more than women with careers (and women more than men with the family), which was identified in earlier work.

The team also gauged explicit stereotypes, directly asking subjects whether they believed that men are more brilliant than women. In marked contrast to the implicit stereotyping measures, subjects reported disagreeing with this idea--and, in one study, explicitly associated the quality of being "super smart" with women more than with men. The finding is consistent with previous scholarship showing that people are unlikely admit to stereotyping, reinforcing the importance of measuring such perceptions through more subtle means.

Tessa Charlesworth, a doctoral student at Harvard University and co-author of the paper, notes that "a particularly exciting finding from this work is that, if anything, people explicitly say that they associate women with brilliance. Yet implicit measures reveal a different story about the more automatic gender stereotypes that come to mind when thinking about brilliance."