Culture

CHAPEL HILL, N.C. -- A new study published in Science confirms that SARS-CoV-2 has mutated in a way that's enabled it to spread quickly around the world, but the spike mutation may also make the virus more susceptible to a vaccine.

The new strain of coronavirus, called D614G, emerged in Europe and has become the most common in the world. Research at the University of North Carolina at Chapel Hill and the University of Wisconsin-Madison shows the D614G strain replicates faster and is more transmissible than the virus, originating in China, that spread in the beginning of the pandemic.

There were bright spots in the study findings: While the D614G strain spreads faster, in animal studies it was not associated with more severe disease, and the strain is slightly more sensitive to neutralization by antibody drugs.

The study published Nov. 12 provides some of the first concrete findings about how SARS-CoV-2 is evolving.

"The D614G virus outcompetes and outgrows the ancestral strain by about 10-fold and replicates extremely efficiently in primary nasal epithelial cells, which are a potentially important site for person-to-person transmission," said Ralph Baric, professor of epidemiology at the UNC-Chapel Hill Gillings School of Global Public Health and professor of microbiology and immunology at the UNC School of Medicine.

Baric has studied coronaviruses for more than three decades and was integral in the development of remdesivir, the first FDA-approved treatment for COVID-19.

Researchers believe the D614G strain of coronavirus dominates because it increases the spike protein's ability to open cells for the virus to enter. These crown-like spikes give the coronavirus its name.

The D614G mutation causes a flap on the tip of one spike to pop open, allowing the virus to infect cells more efficiently but also creating a pathway to the virus' vulnerable core.

With one flap open, it's easier for antibodies -- like the ones in the vaccines currently being tested -- to infiltrate and disable the virus.

For the recent study, Baric Lab researchers -- including first author Yixuan J. Hou -- worked in collaboration with Yoshihiro Kawaoka and Peter Halfmann, both virologists on faculty at the University of Wisconsin-Madison.

"The original spike protein had a 'D' at this position, and it was replaced by a 'G,'" Kawaoka said. "Several papers had already described that this mutation makes the protein more functional and more efficient at getting into cells."

That earlier work, however, relied on a pseudotyped virus that included the receptor-binding protein but was not authentic. Using reverse genetics, Baric's team replicated a matched pair of mutant SARS-CoV-2 viruses that encoded D or G at position 614 and compared basic property analysis using cell lines, primary human respiratory cells, and mouse and hamster cells.

Kawaoka and Halfmann contributed their unique coronavirus study model, which uses hamsters. The University of Wisconsin-Madison team -- including Shiho Chiba, who ran the hamster experiments -- performed replication and airborne transmission studies with both the original virus and the mutated version created by Baric and Hou.

They found that the mutated virus not only replicates about 10 times faster -- it's also much more infectious.

Hamsters were inoculated with one virus or the other. The next day, eight uninfected hamsters were placed into cages next to infected hamsters. There was a divider between them so they could not touch, but air could pass between the cages.

Researchers began looking for replication of the virus in the uninfected animals on day two. Both viruses passed between animals via airborne transmission, but the timing was different.

With the mutant virus, the researchers saw transmission to six out of eight hamsters within two days, and to all the hamsters by day four. With the original virus, they saw no transmission on day two, though all of the exposed animals were infected by day four.

"We saw that the mutant virus transmits better airborne than the [original] virus, which may explain why this virus dominated in humans," Kawaoka said.

The researchers also examined the pathology of the two coronavirus strains. Once hamsters were infected, they presented essentially the same viral load and symptoms. (The hamsters with the mutated strain lost slightly more weight while sick.) This suggests that while the mutant virus is much better at infecting hosts, it doesn't cause significantly worse illness.

Researchers caution that the pathology results may not hold true in human studies.

"SARS-CoV-2 is an entirely new human pathogen and its evolution in human populations is hard to predict," Baric said. "New variants are continually emerging, like the recently discovered mink SARS-CoV-2 cluster 5 variant in Denmark that also encodes D614G.

"To maximally protect public health, we must continue to track and understand the consequences of these new mutations on disease severity, transmission, host range and vulnerability to vaccine-induced immunity."

DALLAS - Nov. 12, 2020 - UT Southwestern researchers have discovered a mechanism that cells use to degrade microRNAs (miRNAs), genetic molecules that regulate the amounts of proteins in cells.

The findings, reported online today in Science, not only shed light on the inner workings of cells but could eventually lead to new ways to fight infectious diseases, cancer, and a bevy of other health problems.

Scientists have long known that genes contain the instructions for making every protein in an organism's body. However, various processes regulate whether different proteins are produced and in what amounts. One of these mechanisms involves miRNAs, small pieces of genetic material that break down complementary pieces of messenger RNA (mRNA) in cells, preventing the mRNA sequence from being translated into proteins.

Since the discovery of miRNAs in 1993, researchers have amassed a wealth of knowledge about the hundreds of different miRNA molecules and their targets as well as mechanisms that control their production, maturation, and roles in development, physiology, and disease. However, explains Joshua Mendell, M.D., Ph.D., professor and vice chair of the department of molecular biology at UTSW, and postdoctoral fellow Jaeil Han, Ph.D., very little was known about how cells dispose of miRNAs when they're finished using them.

"As long as miRNA molecules stick around in a cell, they reduce the production of proteins from their target mRNAs," explains Mendell, a Howard Hughes Medical Institute (HHMI) investigator and member of the Harold C. Simmons Comprehensive Cancer Center. "So understanding how cells get rid of miRNAs when they are no longer needed is pivotal for fully appreciating how and when they do their jobs."

To answer this question, Mendell, Han, and their colleagues harnessed CRISPR-Cas9, a gene-editing tool that recently won the 2020 Nobel Prize in Chemistry for two scientists who developed it. By serving as "molecular scissors," Mendell says, this system can cut out individual genes, allowing researchers to explore their functions.

In a human cancer cell line known as K562, the researchers used CRISPR-Cas9 to target most of the 20,000 protein-coding genes in the human genome, looking for any that caused a normally short-lived miRNA known as miR-7 to linger in cells. Their search turned up at least 10 genes that are needed to degrade this miRNA.

The researchers learned that the proteins encoded by these genes come together in cells to form a larger assembly known as a ubiquitin ligase, which functions to tag other proteins for destruction. This particular ubiquitin ligase had never been described before, Mendell says, but like other ubiquitin ligase complexes, it appears to mark proteins destined for degradation. However, rather than tag miR-7 itself, further investigation showed that this complex instead tags a protein called Argonaute, which ferries miRNAs through cells.

Once the Argonaute protein attached to miR-7 is targeted for degradation, this miRNA is left naked in the cell - a state that triggers cells to destroy the miRNA using RNA-degrading enzymes.

The research team found that this ubiquitin ligase complex is key for degrading not only miR-7 in K562 cells, but also a variety of other miRNAs in other cell types and species. These results suggest that this mechanism for miRNA decay acts broadly to control the levels of miRNAs during animal development and across tissues. Because other studies have shown that abnormal levels of various miRNAs are associated with a variety of diseases and infections, finding ways to control miRNA degradation - either to eradicate problematic miRNAs in cells or hold on to beneficial ones - could represent a new way to treat these conditions.

"For over a decade, researchers have been searching for mechanisms through which cells degrade miRNAs," says Han. "Now that we've discovered new cellular machinery that can accomplish this, we will be able to apply this discovery to better understand how miRNAs are regulated and, we hope, eventually develop new therapies."

Philadelphia, November 12, 2020 - Osteoarthritis (OA), a widely acknowledged cause of disability that affects patients' quality of life and has significant economic impact through healthcare costs and loss of earnings. In a novel study researchers have identified cytoplasmic localized histone deacetalyse 6 (HDAC6) as a promising therapeutic target to postpone development of and possibly treat OA using the HDAC6 inhibitor Tubastatin A. They report their results in The American Journal of Pathology, published by Elsevier.

"Because chondrocytes are the only resident cells in articular cartilage, the steady state of these cells is important to maintain joint function," explained lead investigator Weiyang Gao, MD, Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China. "In various OA diseases, chondrocytes undergo a series of pathophysiologic changes, leading to the loss of chondrocytes, which can impair mitochondrial function and extracellular matrix synthesis (ECM) to promote the progression of OA."

Investigators detected the variations in expression level of HDAC6 after destabilization of the medial meniscus (DMM)-induced mouse OA model. They dissected the knee cartilage tissue of two-week-old mice to obtain primary chondrocytes. HDAC6 was up-regulated after OA and peaked at four weeks post-DMM. Thus, they constructed primary chondrocytes overexpressing HDAC6 by transfection of plasmid.

Their results indicate that overexpression of HDAC6 causes mitochondrial dysfunction and promotes reactive oxygen species production, leading to ECM degradation. However, the administration of the selective HDAC6 inhibitor Tubastatin A reversed the effect caused by HDAC6 overexpression in vitro and further postponed the progression of OA in vivo by ameliorating the degradation of cartilage and improving the microenvironment and function of the joint, suggesting that HDAC6 may be a target for delaying and managing OA with Tubastatin A.

"To our knowledge this is the first study to show that the expression level of HDAC6 is up-regulated in chondrocytes during the OA process and that the up-regulated expression of HDAC6 is associated with mitochondrial disfunction and ECM degradation," commented Dr. Gao. "Our results show that HDAC6 is a potential target for treatment of OA and supports the administration of Tubastatin A to treat OA."

OA is an inflammatory disease characterized by increased degradation of cartilage tissue in the joint due to overproduction of enzymes degrading the extracellular matrix. It is the most common joint disorder in the United States and is highly prevalent around the world. Among US adults 60 years of age and older the prevalence of symptomatic knee OA is approximately 10 percent in men and 13 percent in women. Chondrocytes are the only resident cells of articular cartilage, and the steady state of their intracellular environment is of great significance for maintaining the articular cartilage morphology.

Women who experience sexual violence combined with other forms of intimate partner violence suffer greater damage to their health and are much more likely to attempt suicide, according to a study led by researchers at the University of Bristol's Centre for Academic Primary Care published today [12 November] in the International Journal of Epidemiology .

Intimate partner violence - psychological, physical or sexual violence perpetrated by a current or former partner - is the most common form of violence experienced by women worldwide.

The study, conducted in collaboration with the World Health Organization (WHO) and University of Melbourne, found that all types of intimate partner violence were associated with long-lasting damage to health but combinations that included sexual violence were more common and markedly more damaging to women's physical and mental health.

Researchers analysed data from the WHO multi-country study on women's health, which has information from 16 different sites in 11 different countries on over 21,000 women who have ever had a partner. This new analysis assessed different combinations of psychological, physical and sexual intimate partner violence and their impacts on health.

They found that over 15 per cent of ever-partnered women had experienced a combination of intimate partner violence that included sexual violence. Those who had experienced this in the last year were ten times more likely to attempt suicide than those who had not. Women who had experienced multiple forms of abuse were also more likely to experience difficulty walking, difficulty with daily activities, pain or discomfort, poor memory or concentration, dizziness, and vaginal discharge, and to be taking sleeping pills or painkillers.

Study lead, Dr Lucy Potter a GP and NIHR In-Practice Clinical Research Fellow at the University of Bristol's Centre for Academic Primary Care, said: "We know intimate partner violence is damaging to health. What this study adds is the recognition of the profound harm caused by multiple forms of abuse, particularly when it includes sexual violence, and how we do not see this when all forms of abuse are lumped together as one experience. Practitioners and policy makers must appreciate the diversity of experience of intimate partner violence to tailor support appropriately.

"We also found that these health impacts persist over a year after the abuse ends. So, effective prevention and early intervention are vital to the health of individuals and families and health systems."

Senior author, Professor Gene Feder from the University of Bristol's Centre for Academic Primary Care, said: "Violence against women is a violation of human rights that damages their and their children's physical and mental health, with substantial health care and societal costs. It is an important cause of ill health among women globally and an indicator for Goal 5 - Gender Equality and Women and Girls' Empowerment - of the United Nations' Sustainable Development Goals.

"This study, analysing the impact of different types and combinations of intimate partner violence, shows the severe health impact when these include sexual or psychological abuse. These types of abuse are often not recognised by health care providers."

For years, researchers have known through numerous studies that hearing and other sensory systems of adults and children who have autism differ from children or adults without autism.

Now, University of Miami and Harvard Medical School researchers who explored responses to the standard hearing test administered to millions of newborns around the world, are closing in on a way to detect early indicators of autism--perhaps as early as at birth.

Published in the journal Autism Research, the findings could inform additional research and pave the way for evaluations that can better identify newborns with elevated autism risk by using standard hearing tests. The researchers note that such tests are already regularly and widely used to screen newborns for hearing loss. The tests work by measuring auditory brainstem response (ABR), which gauges how well a baby's inner ear and brain respond to sound.

"We're not at the point just yet where we're telling clinicians to use ABR testing as a determinant for autism in babies," said study co-author Elizabeth Simpson, an associate professor in the College of Arts and Sciences' Department of Psychology, whose research focuses on understanding infant social cognitive development. "But we are saying that this study presents a promising direction in how ABR testing can be used as a method for precise autism detection at birth."

"The importance for diagnosing autism early during infant and child development, when interventions can have the most impact, cannot be overstated," said the study's lead author Oren Miron, a research associate in the Department of Biomedical Informatics at Harvard Medical School. "Any additional tool that could clarify diagnostic clues would be invaluable in that regard."

For the study, researchers analyzed large datasets of Florida infants who were screened for hearing impairments with ABR tests. Usually conducted in hospital maternity wards, the tests make computer recordings of the auditory nerve activity of babies who are exposed to sounds transmitted by electrodes placed on their scalps. The test sound is very mild and can be performed while the infants sleep.

The research team analyzed nearly 140,000 auditory recordings from babies born in Florida and matched the data with records from the Florida Department of Education indicating children with developmental disabilities. Ultimately, they found that newborns who were later diagnosed with autism had slower brain responses to sounds during their ABR tests.

"Within the dataset we used from the Department of Education records of children who had autism, we saw how many we could match up from the ABR test screenings," Simpson said. "We located 321 children who had ABR test screenings taken when they were newborns and who were later diagnosed with autism by preschool age."

With additional investigation, researchers hope to add additional layers to the ABR screenings so that doctors can use them not only to better understand a newborn's hearing and risk for autism, but potentially other developmental problems--like speech, language impairment, and Sudden Infant Death Syndrome--that could arise later.

"We know autism spectrum disorder is connected to how children process sound, so even if the child's hearing is normal, it can still be processed differently," Simpson added. "With better understanding of how ABR testing can be used to identify at-risk babies, we can flag children who might be at risk."

An international team including chemists from RUDN University suggested an economically feasible and environmentally friendly method to synthesize surfactants. The new compounds can become an eco-friendly alternative to traditional chemicals used in oil production, skincare products manufacture, and in the pharmaceutical industry to transport drugs to diseased body tissues. The work was published in the Journal of Molecular Liquids.

Surfactants are common both in the industry and in our everyday life. They are used as bases for detergents, added to lubricants and construction materials (concrete mixes, cement, and drilling fluids), and protect equipment from corrosion. The most effective of them are gemini surfactants that contain two hydrophilic (water-attracting) groups. However, there also "pseudo" gemini surfactants that have one hydrophilic and one hydrophobic (water-resistant) group of atoms bound together. An international team of chemists including partners from RUDN University synthesized several new "pseudo" gemini surfactants and confirmed that their performance characteristics were on par with the existing compounds. The new synthesis method is quite cost-efficient, works at room temperature, and does not require expensive reagents.

"The creation of cheap methods for the synthesis of gemini surfactants with satisfactory performance characteristics can be a turning point for the chemistry of detergents. We focused both on the development of synthetic methods and on studying the properties of new compounds," said Fedor Zubkov, a PhD, and an Assistant Professor at the Department of Organic Chemistry, RUDN University.

To create new compounds, the chemists used six common higher fatty acids: capric, lauric, myristic, palmitic, stearic, and oleic acid. The hydrophilic properties of the new surfactants came from amines synthesized based on two affordable reagents--hexamethylenediamine and epoxypropene. To obtain a surfactant, the team dissolved an amine and one one the acids (at the ratio 1:2) in acetone at room temperature and then concentrated the solvent. The final products looked like viscous yellow liquids. The molecules of the surfactants were formed due to electrostatic interaction between oxygen atoms in the carboxylic groups of the acids and amino groups in the amine.

The team at RUDN University conducted a thorough study of the properties of the new compounds and paid special attention to the key characteristic of surfactants--their ability to reduce the superficial tension of solutions and form micelles. It is this property that makes surfactants usable in the skincare industry. The lowest superficial tension values (up to 20 mN/m) were registered for the surfactant based on myristic acid. By this parameter, the new surfactant is almost identical to fluorine-containing ones that are often used in the industry. However, unlike them, the new compound is more environmentally friendly. Weaker chemical bonds make it biodegradable and therefore unlikely to be accumulated in the environment.

Other important characteristics of surfactants are foam formation and foam stability. Five out of six new surfactants formed foam in a water solution, and in the case of two of them (based on lauric and myristic acids), the volume of produced foam exceded the volume of the initial solution 3 to 4 times. The compounds based on palmitic and stearic acids produced less foam, but it was more stable and lasted up to three days. These and other characteristics of the new compounds make them promising for the skincare industry, medicine, anti-corrosion treatment of construction and industrial facilities, and oil recovery increase.

"Gemini surfactants and their synthesis are a burning issue for modern chemistry, as they can potentially replace traditional monomeric surfactants and make the chemical industry move environmentally friendly," added Fedor Zubkov.

The United States may have set itself up for the spread of a pandemic without even knowing it.

According to new research from the McKelvey School of Engineering at Washington University in St. Louis, pollution may bear part of the blame for the rapid proliferation in the United States of SARS-CoV-2, the virus responsible for the spread of COVID-19.

The research, from the lab of Rajan Chakrabarty, associate professor in the Department of Energy, Environmental & Chemical Engineering, was published online ahead of print in the journal Science of The Total Environment.

When it comes to how ill someone gets after contracting COVID-19, medical professionals believe that a person's health -- having certain medical conditions, for example -- can play a vital role. When it comes to how fast the virus can spread through the community, it turns out the health of the environment is directly correlated to the basic reproduction ratio R0, which denotes the expected number of people each sick person can infect.

The reproduction ratio R0 of COVID-19 associates directly with the long-term ambient PM2.5 exposure levels. And the presence of secondary inorganic components in PM2.5 only makes things worse, according to Chakrabarty.

"We checked for more than 40 confounding factors," Chakrabarty said. Of all of those factors, "There was a strong, linear association between long-term PM2.5 exposure and R0."

PM2.5 refers to ambient particles with a diameter of 2.5 micrometers or less; at that size, they can enter a person's lungs and cause damage. For this reason, PM2.5 can be detrimental to respiratory health. But how this relates to the spread of COVID-19 through a population had yet to be explored.

Chakrabarty and his graduate student Payton Beeler, both aerosol researchers who have done previous coronavirus modeling, became interested in the relationship after two papers were published in quick succession. First, a July paper in the journal Science found that levels of susceptibility to COVID-19 is a driving factor for the pandemic; it is more important than temperature, which researchers initially thought might play an outsized role.

Then in August, research published in the Journal of Infection found that the highest number of cases of COVID-19 with severe illness were in places with higher pollution levels.

"I was thinking, why, in the majority of the U.S. states, have we had such a rapid spread of the virus?" Chakrabarty said. Particularly in the earlier stages of the pandemic. "We wanted to confine our study to the point in time when the shutdown was in place. For the most part, people did remain confined from early March until the end of April."

The team decided to look at places where R0 was greater than one -- that's the point at which one person can spread an illness to more than one person, and the illness takes off. In those places, they looked at 43 different factors -- including population density, age distribution, even time delays in states' stay-at-home orders.

Then, using pollution estimates across the U.S. between 2012 and 2017 published by Randall Martin, professor in the Department of Energy, Environmental & Chemical Engineering, the team looked for any relationships.

Modeling revealed an increase of almost 0.25 in R0 corresponding to a 10% increase in sulfate, nitrogen dioxide and ammonium, or SNA composition and an increase of 1 μg/m3 in PM2.5 mass concentrations, respectively.

They found these linear correlations to be strongest in places where pollution levels were well below National Ambient Air Quality Standards (NAAQS), the levels of air pollutants that are considered safe for humans.

"Annual mean PM2.5 national standards are set at or below 12 micrograms per cubic meter, below that you are supposed to be safe," Chakrabarty said. "What we saw, the correlation we're seeing is well below that standard." In fact, they saw a rapid increase in R0 when PM2.5 exposure levels were below 6 micrograms per cubic meter.

Chakrabarty hypothesizes this initial increase in R0, which is followed by a plateau once levels hit 6 micrograms per cubic meter, is a result of initial changes in condition; when the air is free of PM2.5 , an individual is unaffected. The initial exposure is the catalyst for change in lung health resulting in a change from non-susceptibility to susceptibility, which is reflected in the increasing R0.

And although there was no direct correlation between black carbon -- a.k.a. soot -- and R0, researchers did find a connection.

"Our collaborators at Saint Louis University suggested a mediation/moderation statistical approach," a detailed analysis that looks at the way additional variables affect the outcome of the initial relationship. In this case, researchers looked at soot's effect on R0, considering SNA's effect.

"We found black carbon acts as a kind of catalyst. When there is soot present, PM2.5 has more of an acute effect on lung health, and therefore on R0."

The mediation/moderation study was not superfluous -- one of the common ways people are exposed to SNA is through pollution emitted from cars and coal-fired power plants. Both of which also emit soot.

"Although decades of strict air quality regulations in the U.S. have resulted in significant reductions of nitrogen dioxide levels," the authors wrote in the paper's conclusion, "recent reversal of environmental regulations which weaken limits on gaseous emissions from power plants and vehicles threaten the country's future air quality scenario."

"Instead of working to resolve this issue, these reversals may be setting us up for another pandemic," Chakrabarty said.

Inspired by work on infants, researchers at the Eötvös Loránd University (ELTE ) investigated whether dogs' behaviors are guided by human displays of preference or by the animals' own choices. They found that dogs' looking times, but not fetching behavior, were influenced by the owner's expression of preference. Although the studies did not demonstrate that dogs override their own preferences for an object, the results suggested that the owners' expressed preference was perceived by the dogs and guided their perceptual focus.

Studies on animal cognition deepen our understanding of the human mind's evolution and help inform policy makers in the production of legislation around animal keeping. Whether dogs have any idea that their humans have thoughts and emotions of their own, is one of the hot topics in dog research. The answer could have interesting implications, but it has been challenging to find a decisive way to test it so far.

„There is no shortage of attempts to unveil the putative mind-reading abilities of dogs" says Dr. Ádám Miklósi, head of the Department of Ethology at Eötvös Loránd University, Budapest, „but no single study has been convincing enough on its own, so over the years we have broken down the big question into smaller, more tangible goals."

One of these goals has been to investigate how dogs respond to expressions signaling the preferences of humans. A new study published in Frontiers in Psychology follows up on previous efforts in this direction. „We knew that dogs respond to humans signalling their preference, but in previous studies, the dogs' own priorities were not accounted for. In particular, we did not know how conflicting preferences between the dogs and the owner influence the behavior of dogs." says Eniko Kubinyi, leading author of the study, senior researcher at Eötvös Loránd University. „18-month-old children recognize that their own preference might differ from that of others and they understand how desire can be inferred from emotional expressions, but 14-month-olds do not. We wanted to test where dogs are on this scale."

The researchers first tested a subset of dogs on their spontaneous preference for either a dog toy or a bracelet. The toy was without exception the more desirable object. Next, owners displayed happy expressions towards the bracelet and made disgusted faces towards the toy. Then the owner asked the dog to fetch, without providing additional guiding cues. All dogs fetched the toy, indicating that their own choice was not overcome by the emotional expressions of the owner. "Thus dogs either are not able to distinguish between their own and the owners' preference or they failed to inhibit the "wrong" response" explains Flóra Szánthó, co-author.

The researchers decided to dig deeper. „Fetching was clearly not a good choice to measure dogs' sensitivity to others' preferences for several reasons" notes Kubinyi, „since their own favorite object was in reach, the dogs had little incentive to factor in the owner's choice in their responses. We assumed that if the same objects were out of reach, they would stimulate what appears to be "showing" behavior in the dogs and they would direct more attention towards their owners' pick, thereby also weakening the affordance provided by their preferred object." To test this hypothesis, the researchers decided to put the objects up on the laboratory's windowsill where the dogs could not reach them.

Fifty-one dogs were assigned to one of two experimental groups: a matching/congruent condition where owners displayed happy expressions towards the toy and made disgusted faces towards the bracelet, and a non-matching/incongruent condition, where owners showed happiness toward the bracelet and disgust toward the toy. After the emotion display, the toy and the bracelet were placed out of reach and the researchers now measured how much time the dogs looked at each object. "In this case", says Ivaylo Iotchev, postdoc at Eötvös Loránd University, and co-author, "the dogs looked at the favored toy when their owner had previously responded to it with a happy face. In the other group they looked the same amount of time at the bracelet and the toy."

The demonstration of the owners' preference affected the dogs' behavior. „It is not certain that this influence is the result of inferred and shared representations" warns Kubinyi. "We have not found conclusive evidence that dogs, similarly to one and a half.year-old toddlers, understand the subjectivity of the desire, i.e., that different people can have different attitudes toward the same object. If they indeed infer the owner's preference, they might not understand fetching as an act of offering an object to a human, or response inhibition, an important aspect of cognitive control, was not sufficiently strong to overwrite the animals' own preference." What is certain, is that this study is the first to show that dogs are sensitive to their owners' choice even though they prefer to fetch their favorite toy when it is in reach."

URBANA, Ill. ­­- Food insecurity in America is reaching an all-time high during the COVID-19 pandemic. But large regional differences exist in the severity of the impact.

Experts project over 50 million Americans will be food insecure in 2020, including about 17 million children, says Craig Gundersen, ACES distinguished professor in the Department of Agricultural and Consumer Economics at the University of Illinois.

Gundersen estimated food insecurity using Map the Meal Gap, an interactive model he developed for Feeding America, a nationwide network of more than 200 food banks in the U.S. For the current report, he combined MMG data with projected unemployment numbers.

"One of the key things about COVID-19 is how there's differential impacts across the country and by demographic groups. People with college education generally have not seen much of an impact on either unemployment rates or incomes. However, people in lower-wage jobs tend to be impacted a lot more," Gundersen states. "We would expect greater impact of COVID-19 in areas with a high concentration of service industry jobs."

The report finds the hardest hit states are the same as before the pandemic - Mississippi, Arkansas, Alabama, Louisiana, and New Mexico ­- but with higher rates. Jefferson County, Mississippi, has the highest food insecurity rate, 30.4%, in the country.

However, the pandemic disproportionately affected other states. For example, Nevada jumped from 20th to eighth highest food insecurity rate by state.

"Areas like Nevada, which has a strong emphasis on the service industry and tourism, will have substantially higher rates of increase in food insecurity than areas with fewer service sector workers," Gundersen says.

These findings can help direct relief efforts, he notes.

"Resources should continue to be directed towards those areas with greater needs before, during, and after COVID-19. But we also have to recognize that during the pandemic situation there are areas of the country, such as Nevada, which may need more emergency assistance in the near term," Gundersen says.

"Furthermore, some of these jobs may not come back; tourism may be permanently down in the United States. So these impacts could also have longer term ramifications," he concludes.

LOS ANGELES (Nov. 12, 2020) -- Older adults who joined group exercise classes experienced decreased loneliness and social isolation, according to a new Cedars-Sinai study conducted before the COVID-19 pandemic. The classes have continued virtually since March, and early results suggest the online versions are also effective.

Seniors face increased risk for developing serious health issues or even death if they lack social connections or feel alone. Loneliness is connected to higher rates of depression, anxiety and suicide. Experts say social isolation can have the same impact on an older person's health as smoking 15 cigarettes a day.

Both loneliness and social isolation are widespread issues in the U.S., where more than a third of adults 45 and older feel lonely and nearly a quarter of those 65 and older are socially isolated, according to the National Academies of Sciences, Engineering, and Medicine. But few studies have examined the most effective ways to improve social connectedness among seniors.

"As the demographics of our country shift, more people are living alone than ever before," said the study's lead author, Allison Moser Mays, MD, a Cedars-Sinai geriatrician. "The number of adults over the age of 65 in the U.S. is expected to reach more than 70 million by 2030 - double what it is now. We need sustainable ways to help this burgeoning population thrive as they age, or there will be widespread consequences."

Mays and her co-investigators partnered with local community groups to enroll participants in evidence-based exercise and health management classes for people over 50 at nine sites in Los Angeles neighborhoods with a known concentration of low-income older adults. All locations - which included libraries, senior centers and recreation centers - were accessible for those with mobility limitations and had access to parking and public transit.

The study tracked 382 participants ages 52 to 104 from July 2018 through March 2020, when the pandemic forced the classes to move online. Some people were referred by their Cedars-Sinai physician during an office visit. Others found the program through community outreach.

All participants met with a health coach who assessed their needs and helped them select one of four courses, which research has shown improve other aspects of health: Arthritis Exercise, EnhancedFitness, Tai Chi for Arthritis, and Chronic Disease Self-Management. The three exercise classes proved the most popular, and individuals had to attend at least one session to be included in the study.

Participants completed questionnaires about their social connections and loneliness prior to starting their course and after six months. At the end of that period, investigators found a 6.9% decrease in loneliness and a 3.3% improvement in social connectedness, after adjusting for age, gender and other characteristics. The study was published in the American Journal of Geriatric Psychiatry.

"These classes had already been shown to reduce the risk of falls in seniors, and this was the first demonstration that they also reduce social isolation, to the best of our knowledge," Mays said.

The Leveraging Exercise to Age in Place (LEAP) classes have been supported by a three-year grant from the AARP Foundation. Cedars-Sinai has adopted the successful programming under the Community Engagement Department.

"The results of this study are very exciting because we've provided a model that other health systems can easily replicate by integrating evidence-based programs in the community with their organizations. They don't need to reinvent the wheel," said senior study author Sonja Rosen, MD, chief of Geriatric Medicine at Cedars-Sinai. "The health coach is the key ingredient because they make sure that nobody falls through the cracks."

The health coach has been especially crucial since the pandemic began when classes moved online and participants sometimes have needed help figuring out how to log on to the platform. That effort has been paying off.

Of the 59 participants who continued with the virtual workouts, there has not been a statistically significant change in loneliness or social isolation one month after stay at home orders began, according to data Mays presented over the weekend at the Gerontological Society of America's annual meeting. The investigators will analyze further data as the classes continue. They're also piloting another program that pairs older adults with younger participants for one-on-one workout sessions online.

"Cedars-Sinai treats more patients over the age of 80 than any other academic health system in the country," Rosen said. "We're really at the epicenter of this growing population of older adults and figuring out the best ways to care for them so they can successfully age in place."

Rosen said efforts like the LEAP program helped Cedars-Sinai earn its designation as an Age-Friendly Health System Committed to Care Excellence earlier this year. The distinction, which highlights care tailored to older adults, is part of a national initiative of The John A. Hartford Foundation and the Institute for Healthcare Improvement, in partnership with the American Hospital Association and the Catholic Health Association of the United States.

CHARLOTTE, N.C. - NOV. 12, 2020 - A new comprehensive study from UNC Charlotte's Urban Institute, College of Health and Human Services and School of Social Work shows an effective approach to ending chronic homelessness that helps those in need and benefits communities.

The Housing First Charlotte-Mecklenburg initiative, an innovative multi-sector collaboration that's been working to end chronic homelessness in Charlotte for five years, has placed more than 1,000 people in the Charlotte community in stable housing. This is the largest and most comprehensive local effort to address chronic homelessness. Nationwide, on any given night, more than 550,000 Americans are experiencing homelessness, and this research could offer guidance to cities around the U.S. struggling with this issue.

"The Housing First Charlotte-Mecklenburg effort led to major housing wins during a time of increasing housing scarcity, and the vast majority of those who were able to access housing through the effort did not return to emergency shelters," said Lori Thomas, associate professor at UNC Charlotte's School of Social Work and Director of Research and Faculty Engagement at the UNC Charlotte Urban Institute.

Thomas has completed an evaluation of the first phase of the program, the most rigorous and in-depth study to date in Charlotte and one of the few reports in the country that examines a community's overall response to chronic homelessness. Findings highlighted in Thomas' research may have a significant impact throughout the country in other cities working to expand Housing First programs such as Atlanta, Denver, San Francisco and Washington, D.C.

Key findings from the first phase of the Housing First program include:

Housing First works. Almost three-quarters of study participants housed through the Housing First program either retained their housing or moved into other housing during the study period. That means a large majority of people who get housed, stay housed.

Housing First impacts participants. Clients who gained housing showed reductions in trauma, mental illness and substance use. Additionally, housed participants scored significantly higher on standardized overall quality of life indicators.

Housing First impacts the community. People who were housed were less likely to be arrested or visit the emergency department. Additionally, the average number of visits to the Mecklenburg County Health Departments and the average number of nights spent in emergency shelters all decreased.

Costs of housing are partially offset through other community services. Based on the changes in service utilization, there is a $2.54 reduction in community services for every $10 invested in housing first permanent supportive housing. This savings reduces the average annual cost of housing first permanent supportive housing from $17,256 to $12,688.

There were also lessons learned that can improve the initiative. Among those:

Housing First participants experienced persistent and worsening food insecurity. Rates of food insecurity remained high for clients who gained housing. Research suggests people might have more difficulty accessing food once they gain housing, perhaps because they do not have transportation to free resources where they previously got food, or because they now live in a "food desert."

Housing First participants continued to report poor perceptions of physical health. The impact of years without housing and access to preventative care, as well as the fact that the majority of study participants have two or more disabilities, may account for this finding.

Housing First and the focus on homelessness highlighted the need for better coordination, representation and communication among stakeholders across various sectors (government, nonprofit, academic and business). Additionally, the initiative drove home the need to connect homelessness to the community-wide affordable housing challenges facing Charlotte and Mecklenburg.

"With the release of the Housing First Evaluation report, we are able to share information with the community about the results and impact of a public-private, community initiative to end chronic homelessness," said Stacy Lowry, director of community support services for Mecklenburg County. "In addition to outcomes, this report also provides an in-depth analysis of the initiative, itself. By looking at the relationship between outcomes and process, Charlotte-Mecklenburg can use this report to expand and strengthen existing efforts to prevent and end homelessness as well as inform new, systemic solutions to address complex problems comprehensively and effectively."

HOUSTON - (Nov. 12, 2020) - "Position 4" didn't seem important until researchers took a long look at a particular peptide.

That part of the peptide drawn from a SARS-CoV virus turned out to have an unexpected but significant influence on how it stably binds with a receptor central to the immune system's ability to attack diseased cells.

In a study published by the Proceedings of the National Academy of Sciences, researchers at Rice University's Brown School of Engineering and the University of Texas MD Anderson Cancer Center revealed models at atomic resolution that detail not only the binding but also, for the first time, the unbinding mechanisms that underlie a key component of the immune system.

They say better understanding of the entire mechanism could lead to advancements in immunotherapy that boosts the body's ability to fight disease.

Rice computer scientist Lydia Kavraki, alumnus Jayvee Abella and postdoctoral researcher Dinler Antunes, led the study.

"Finding good targets to trigger a protective immune response is very challenging, especially in cancer research," Antunes said. "The fact that this particular peptide was predicted not to bind to HLAs (human leukocyte antigens) by sequence-based methods highlights a blind spot in our current prediction capacity.

"By incorporating structural analysis, we can detect the contribution of these secondary interactions to peptide binding and stability, hopefully enabling us to find better targets for antiviral vaccine development and T-cell-based cancer immunotherapy," he said.

The researchers used their simulations to illuminate details of how the intracellular SARS peptide, QFKDNVILL, binds to an MHC receptor protein known as HLA-A?24:02, primarily at dominant anchors on both ends of the peptide (at positions 2 and 9) and presents them for inspection to the immune system's T cells.

Stable binding of a peptide and MHC is a prerequisite to the activation of T cells, which look for peptides not normally found in healthy cells. If the peptide and protein don't bind, the T cell is not prompted to attack.

"That much was known from previous studies of the bound and unbound states of many such complexes," Kavraki said. "What they didn't capture was the intermediate states and the transitions that lead from one state to another, especially the unbinding.

"I think this is the only analysis that shows the unbinding of peptides from the MHC with atomic resolution," Kavraki said. "Other peptides have similar characteristics and we think they would have similar behaviors."

All of these interactions were revealed in great detail through Markov state models that analyze how systems change over time. In this case, the models revealed the importance of secondary sites that support the peptide's primary anchors. That's where position 4 stood out.

"There are the main, canonical anchors that people know, but there are these secondary interactions that contribute to the binding and the stability," Antunes said. "These are harder to capture, but in this study, it seems that position 4 plays a very important role. When you mutate it, it affects the behavior of the peptide as it unbinds from the molecule."

The researchers modeled mutations of the MHC to see how they would influence binding and found they supported the importance of position 4 to the stability of the complex.

"Our computational approach was able to make predictions on the effect of mutations that are then experimentally verified," said co-author Cecilia Clementi, a former Rice professor who recently became Einstein Professor of Physics at the Free University of Berlin.

The researchers developed a two-stage process to simplify the computational complexity of atom-scale analysis of large molecules. The first stage used a technique called umbrella sampling to accelerate the initial exploration of the molecules. The second, exploratory stage used adaptive sampling, in which simulations are driven to accelerate the construction of the Markov model.

"The challenge is that these MHCs are pretty large systems for computational chemists to simulate," said Abella, whose research on the topic formed much of his doctoral thesis. "We had to make some approximations and leverage advances in these classes of methods to move forward.

"We're not the first one to study unbinding, but what characterizes our work over others is that we keep full atomic resolution in our simulations," he said. "Other works use a technique known as a Markov chain Monte Carlo, whereas we use molecular dynamics, which lets us incorporate time into our computation to capture the kinetics."

Their methods can be applied to other peptide-MHC complexes with existing 3D models. "This was, in some sense, a feasibility study to show we can use molecular dynamics and build a Markov state model of a system this size," Abella said.

The researchers also noted the study's relevance to the current fight against COVID-19, as the SARS peptide they viewed, QFKDNVILL, is highly similar to the NFKDQVILL peptide in SARS-CoV-2, with the same binding pockets in positions 2, 4 and 9.

"These results suggest that both peptides can bind to HLA-A*2402 and provide targets for anti-viral T-cell responses, which are of great interest in light of the current pandemic," said co-author Gregory Lizée, a professor in the Department of Melanoma Medical Oncology at MD Anderson. "But these results also shed light on many other potential immune targets, including those of other viruses and even human cancers."

Kavraki noted that experimental work by longterm collaborator Lizée and Kyle Jackson, a graduate research assistant at Lizée's lab who produced the mutant proteins, were critical to validate their simulations. Kavraki's own lab won a National Science Foundation (NSF) Rapid Response Research grant to help identify fragments of SARS-CoV-2 viral proteins as possible targets for vaccine development.

MADISON, Wis. -- Researchers have discovered a previously unknown way that pancreatic cells decide how much insulin to secrete. It could provide a promising new target to develop drugs for boosting insulin production in people with Type 2 diabetes.

In a pair of papers recently published in Cell Metabolism, scientists from the University of Wisconsin-Madison and their colleagues point to an overlooked enzyme known as pyruvate kinase as the primary way pancreatic beta cells sense sugar levels and release the appropriate amount of insulin.

From several proof-of-concept experiments in rodents and on human pancreatic cells, the team found that drugs stimulating pyruvate kinase not only increase the secretion of insulin but have other metabolically protective effects in the liver, muscle and red blood cells. The findings suggest that activating pyruvate kinase could be a new way to increase insulin secretion to counter Type 2 diabetes, but more research would be required before any new treatments were available.

"Too much insulin can lower blood sugar to dangerous levels, and too little insulin can lead to diabetes," says Matthew Merrins, a professor of medicine at the UW School of Medicine and Public Health who led the work. "The question we're asking here is: How do nutrients like glucose and amino acids turn on beta cells in the pancreas to release just the right amount of insulin?"

The work was accomplished by carefully dissecting the paradoxical timing of key biochemical events in the prevailing understanding of how pancreatic beta cells respond to nutrients in the blood. The researchers point to a new, richer model to understand how this important process is controlled that resolves these inconsistencies.

For decades, scientists believed that mitochondria, the energy generators in cells, initiated insulin secretion. It was a natural explanation, because mitochondria produce the high-energy molecule ATP, in the process depleting ATP's low-energy version, ADP. The drop in ADP stimulates calcium -- the ultimate trigger to release stored insulin.

But the timing didn't make sense. Mitochondria are most active after insulin secretion has already begun, not before. Plus, mitochondria would stall out before exhausting enough ADP to trigger insulin secretion.

A clue to solving these apparent paradoxes came from studies in the 1980s on heart muscle cells. At the time, scientists found that the enzyme pyruvate kinase -- which converts sugar into energy, independently of mitochondria -- could also severely deplete ADP. This process happens near ADP-sensing proteins involved in insulin release in the pancreas. Maybe, Merrins' team thought, the pancreas took advantage of this proximity to fine-tune the release of insulin.

In initial experiments, the researchers supplied sugar and ADP to sections of pancreatic cells containing pyruvate kinase. The enzyme gobbled up both components, depleting ADP. Because pyruvate kinase was located near the ADP-sensing protein that triggers insulin secretion, it had a big effect.

"That's one of the important concepts in our paper: the location of metabolism is critical to its function," says Merrins.

Using mouse and human pancreatic islets, the clusters of cells that release insulin, the researchers tried stimulating pyruvate kinase activity. Drugs that activate the enzyme quadrupled the release of insulin, but only when there was enough sugar around -- a sign that pyruvate kinase can't be forced to release too much insulin.

"Pyruvate kinase doesn't change how much fuel comes into the cell, it just changes how that fuel is used," says Merrins. "Drugs that active pyruvate kinase strongly boost insulin secretion without causing too much insulin release that can lead to hypoglycemia."

In all, they discovered evidence of a more complex way in which pancreatic beta cells decide when and how much insulin to release, akin to a two-cycle engine. In the first cycle, blood sugar gets processed by pyruvate kinase, depleting ADP. Mitochondria keep the process going by feeding pyruvate kinase even more material, which causes ADP levels to crash, ultimately stimulating enough calcium entry into the cell to release insulin.

In the second cycle, mitochondria switch from feeding pyruvate kinase with material to producing the high-energy molecule ATP, which is needed to fully release insulin. Then the process resets.

In the companion study, led by Merrins' colleagues at Yale University, the researchers examined how pyruvate kinase activators affected metabolism in healthy and obese rats. In a series of experiments, they found that activating pyruvate kinase increased both insulin secretion and insulin sensitivity while improving sugar metabolism in liver and red blood cells. Such treatments could be helpful for people with Type 2 diabetes, who don't produce enough insulin and have dysfunctional sugar metabolism as a result.

"The therapeutic idea here is we could rewire metabolism to more efficiently trigger insulin secretion while improving the function of other organs at the same time," says Merrins.

Little is understood about how cilia, the tiny hairlike organelles that in humans are often the first lines of defense against pathogens in our lungs and respiratory tracks and even help push sperm along, move in coordination. New research from USC scholars identifies the mechanisms in play for cilia to work effectively and productively to push particles and fluid along, which is especially important given their critical role in health and in even ensuring reproduction.

Given the difficulty of accessing cilia in locations such as the lung, brain, and reproductive tract, researchers often study aquatic microorganisms to get insight into cilia motion because the structure of cilia is conserved across species. In a healthy body, motile cilia coordinate with each other to achieve specific modes of motion, so they can direct fluid flows in a certain direction (without coordinated movement of cilia in the lung for example, lung tissues risk buildup of bacteria and viruses). USC researchers performed computational experiments to better understand how cilia transition between different modes of coordination such as rowing together in the same direction versus moving in different directions. The researchers found that these changes in movement direction occur in one of two ways: changing the level of in sync activity between cilia or shifting the activity level of the cilia. Results were published in Physical Letters Review.

This is critical, says Eva Kanso, the Zohrab A. Kaprielian Fellow in Engineering and professor of Aerospace and Mechanical Engineering, because cilia, in mammalian tissue, are in places like the upper respiratory tracts, where they form the first line of defense against environmental particles, viruses and bacteria--thus making understanding how they work all the more important. Cilia can force mucus to be pushed from the lungs or help sperm move along the reproductive tract to meet with an egg.

"When cilia are not coordinated, each is moving in a different direction. Their purpose is to push fluids and if every cilium is working against every other cilium, they won't be able to achieve this in a consistent, coherent manner," Kanso said.

But beyond coordination, Kanso said, the next biggest consideration is how cilia transition from one coordinated mode of motion to the next. "The fate of the cell is dependent on these transitions."

The environment could also play a role. In the lungs, a shift in the environment--perhaps the result of diseased tissue--could trigger a shift in the activity level of the cilia. As a result, the cilia may be less coordinated and this transition to an uncoordinated state could be detrimental to the health of the lung. Without appropriate motion sweeping harmful bacteria and particles out of the lung, it may build up within the lung. In turn, this could change the cilia's environment, causing a feedback loop that continues to suppress normal cilia function, Kanso said.

Kanso said that the study also suggests that the level of coupling between cilia can change transitional behavior--and this could change the progression of certain diseases, for example lung disease. Given this, her team is hoping to translate the tools and techniques they acquire from a broader study of ciliary beds to a collaboration with Dr. Amy Ryan, assistant professor, and Dr. Janna Nawroth, senior research scientist, both at the Keck School of Medicine at USC.

The study Kanso and post-doctoral scholar Yi Man, conducted focused on the interaction of a pair of cilia. In the future, they hope to look at a whole ciliary bed, with the hopes of further understanding not only how cilia function, but also the greater implications for how their coordination reflects on the health of an organism.

"The long-term vision is that maybe there will be some way to not just look at individual cilia but grow ciliated tissue--for instance based on a swab of human cells--and to look at its coordination. How well the cells coordinate could be used as a diagnostic tool to better understand how far a disease has progressed and what a patient's prognosis is," Kanso said.

Current research and applications in the field of artificial intelligence (AI) include several key challenges. These include: (a) A priori estimation of the required dataset size to achieve a desired test accuracy. For example, how many handwritten digits does a machine have to learn before being able to predict a new one with a success rate of 99%? Similarly, how many specific types of circumstances does an autonomous vehicle have to learn before its reaction will not lead to an accident? (b) The achievement of reliable decision-making under a limited number of examples, where each example can be trained only once, i.e., observed only for a short period. This type of realization of fast on-line decision making is representative of many aspects of human activity, robotic control and network optimization.

In an article published today in the journal Scientific Reports, researchers show how these two challenges are solved by adopting a physical concept that was introduced a century ago to describe the formation of a magnet during a process of iron bulk cooling.

Using a careful optimization procedure and exhaustive simulations, a group of scientists from Bar-Ilan University has demonstrated the usefulness of the physical concept of power-law scaling to deep learning. This central concept in physics, which arises from diverse phenomena, including the timing and magnitude of earthquakes, Internet topology and social networks, stock price fluctuations, word frequencies in linguistics, and signal amplitudes in brain activity, has also been found to be applicable in the ever-growing field of AI, and especially deep learning.

"Test errors with online learning, where each example is trained only once, are in close agreement with state-of-the-art algorithms consisting of a very large number of epochs, where each example is trained many times. This result has an important implication on rapid decision making such as robotic control," said Prof. Ido Kanter, of Bar-Ilan's Department of Physics and Gonda (Goldshmied) Multidisciplinary Brain Research Center, who led the research. "The power-law scaling, governing different dynamical rules and network architectures, enables the classification and hierarchy creation among the different examined classification or decision problems," he added.

"One of the important ingredients of the advanced deep learning algorithm is the recent new bridge between experimental neuroscience and advanced artificial intelligence learning algorithms," said PhD student Shira Sardi, a co-author of the study. Our new type of experiments on neuronal cultures indicate that an increase in the training frequency enables us to significantly accelerate the neuronal adaptation process. "This accelerated brain-inspired mechanism enables building advanced deep learning algorithms which outperform existing ones," said PhD student Yuval Meir, another co-author.

The reconstructed bridge from physics and experimental neuroscience to machine learning is expected to advance artificial intelligence and especially ultrafast decision making under limited training examples as to contribute to the formation of a theoretical framework of the field of deep learning.