Culture

A University of Florida study of middle-aged and older adults finds those who unknowingly carry methicillin-resistant Staphylococcus aureus, or MRSA, on their skin are twice as likely to die within the next decade as people who do not have the bacteria.

"Very few people who carry MRSA know they have it, yet we have found a distinct link between people with undetected MRSA and premature death," said the study's lead author Arch G. Mainous III, Ph.D., a professor in the department of health services research, management and policy at the UF College of Public Health and Health Professions, part of UF Health, the university's academic health center.

The findings suggest that routine screening for undetected MRSA may be warranted in older people to prevent deaths from infection.

A third of Americans carry Staphylococcus aureus, or staph, on their skin or in nasal passages. About 1% of those people, or more than 3 million people, carry MRSA, the staph strain that is hard to treat and resistant to many antibiotics. Unless MRSA carriers develop an infection or are tested for the bacteria, they may not even know they carry it. Previous research has found that a quarter of people who carry MRSA without an active infection, known as colonized MRSA, for a year or more will eventually develop a MRSA infection.

"MRSA can be part of normal body flora, but it can lead to infection when immune systems are compromised, especially in people who are hospitalized, have underlying disease, or after antibiotic use," said Mainous, also vice chair for research in the UF College of Medicine's department of community health and family medicine.

A Centers for Disease Control and Prevention report showed that in 2017, 119,000 Americans experienced a staph bloodstream infection and nearly 20,000 died. Hospitalized patients with colonized MRSA may be particularly vulnerable to developing an infection during a hospital stay or after discharge. Wounds, surgical incisions and use of medical devices, such as catheters, may also lead to MRSA infection among carriers.

For the study, which appears in the Journal of the American Board of Family Medicine, researchers analyzed data from the 2001-2004 National Health and Nutrition Examination Survey, a large, nationally representative study that combines survey questions with laboratory testing, including nasal swabs to test for the presence of MRSA. The researchers linked data on participants ages 40-85 with data from the National Death Index to track deaths over an 11-year period. Researchers adjusted for factors including gender, race and ethnicity, health insurance, poverty-income ratio, hospitalization in the previous 12 months, and doctor diagnosis of heart disease, diabetes and asthma.

They found the mortality rate among participants without MRSA was about 18%, but among those with colonized MRSA, the mortality rate was 36%. Participants who carried staph bacteria on their skin, but not MRSA, did not have an increased risk for premature death.

Some states and hospital systems require MRSA testing for patients before hospital admission, but policies for testing and treatment of colonized MRSA, which may include use of topical or oral antibiotics, are highly variable from hospital to hospital, Mainous said.

"Without a uniform strategy, we are missing an opportunity to help prevent deaths caused by MRSA," Mainous said. "Maybe we should know who is carrying MRSA."

DETROIT - A study published in the Journal of Occupational and Environmental Medicine from researchers at Henry Ford Health System has found that Henry Ford's early implementation of a universal mask policy in the COVID-19 pandemic was associated with reducing the risk of healthcare workers at Henry Ford acquiring COVID-19.

Through retrospective analysis of an internal hospital quality metric reporting analytics database that was not associated with electronic medical records, researchers discovered a correlation between the implementation of Henry Ford's universal mask policy and a significant drop in the rate at which its Healthcare workers tested positive for SARS-CoV-2. As COVID-19 diagnoses and hospitalizations across the State of Michigan continued to rise through late March 2020, the cases among Henry Ford's healthcare workers began to fall. By the time the first peak in COVID-19 cases occurred in the general population, the rate of cases among Henry Ford healthcare workers was already trending downward.

"This research reinforces the fact that mask wearing is effective in reducing the risk of acquiring COVID-19 and validated our decision early on to implement the universal mask policy, not only to protect our team members, but also to ensure they are able to care for members of the community who had contracted COVID-19," said Steven Kalkanis, M.D., CEO of Henry Ford Medical Group. "At Henry Ford Health System, our universal mask policy issued on March 26, 2020 ensured all staff, both clinical and non-clinical, received surgical or procedural masks and mandated that staff wear a mask at work while also following all other personal protective equipment requirements. Our hope is that the findings of this study continue to encourage members of the community to wear a mask in line with Centers for Disease Control and Prevention recommendations."

Healthcare workers have a threefold increased risk of reporting testing positive for SARS-CoV-2, the virus that causes COVID-19, compared to the general population, according to a study published in Lancet Public Health. As of March 22, 2021, the Centers for Disease Control and Prevention (CDC) has reported more than 450,000 SARS-CoV-2 infections among healthcare workers in the U.S. since the onset of the pandemic, and nearly 1,500 COVID-19 related deaths among healthcare workers.

From March 12 - August 10, 2020, 19.2% of healthcare workers at Henry Ford were symptomatic for COVID-19 and underwent SARS-CoV-2 testing. Before March 28-30 - the single changepoint in the data when the rate of new cases began to trend downward - the odds of a tested healthcare worker having a positive SARS-CoV-2 test result doubled every 4.5 - 7.5 days. After March 30, the odds of a tested healthcare worker having a positive result reduced by half every 10.5 - 13.5 days.

"This effort would not have been possible without the leadership of our executive team, including our president and CEO Wright Lassiter, III, Dr. Steven Kalkanis, chief clinical officer Dr. Adnan Munkarah, and chief operating officer Bob Riney," said Dee Dee Wang, M.D., Director of Structural Heart Imaging at Henry Ford Hospital and principal investigator of the study. "At a time when much was unknown about the novel coronavirus, this initiative truly helped keep our healthcare workers safe. I would also like to acknowledge Dr. Betty Chu, our associate chief clinical officer and chief quality officer; Dr. William O'Neill, director of our Center for Structural Heart Disease; Dr. Geehan Suleyman, medical director of Infection Control; Dr. Marcus Zervos, chief of our Infectious Disease division; and so many others who were instrumental in the creation and successful implementation of our universal mask policy."

With the arrival of COVID-variants in the community, even with COVID-19 vaccines now being rolled out, healthcare workers and community members should remain vigilant and continue to wear a mask in accordance with CDC recommendations.

Henry Ford is providing onsite expertise and oversight for the vaccine administrations, medical care and operations at the Ford Field mass vaccination site. Vaccines administered at Ford Field are in addition to Michigan's regular statewide vaccine allotment. Key facts to know:

- Will operate seven days a week from 8 a.m. - 8:30 a.m. for eight weeks

- The U.S. Air Force will provide vaccination support

- 68 vaccination pods will be set up on the Concourse at Ford Field. Vaccinations are open to those who meet the Michigan Department of Health and Human Services vaccine guidelines.

Registration and appointment scheduling are being managed by Meijer. People may register in the following ways:

- Online at clinic.meijer.com/register/CL2021

- Text EndCOVID to 75049

- Call the State of Michigan COVID hotline at 888-535-6136 (Press 1) Monday-Friday 8 a.m. - 5 p.m. and Saturday/Sunday 8 a.m. - 1 p.m.

Researchers from Queens University, Boston University, University of Toronto, University of Rochester, and Treasury Board Secretariat, Government of Canada published a new paper in the Journal of Marketing that tests a simple, no-cost intervention that can double registration rates, thus helping communities gradually increase the number of prospective donors.

The study, forthcoming in the Journal of Marketing, is titled "Increasing Organ Donor Registrations with Behavioral Interventions: A Field Experiment" and is authored by Nicole Robitaille, Nina Mazar, Claire I. Tsai, Avery M. Haviv, and Elizabeth Hardy.

Current statistics on organ donation point to an ever-increasing demand, yet inadequate supply of available donors. For example, in the United States, there are over 113,000 individuals currently on the transplant waiting list and 22 people die each day waiting. And the gap between those needing transplants and those receiving them continues to widen. With thousands currently waiting for organ transplants, the need for donors is urgent. One way to address the ever-growing demand is to increase the number of individuals registered to donate. While the vast majority of people support organ donation, many do not take the steps to register.

Low registration rates are especially common in countries with explicit consent registration policies--that is, individuals must opt in to become organ donors--compared to countries with presumed consent policies--where individuals are organ donors by default but can opt out. Although some suggest changing the default may be a promising intervention, the impact on actual donations has been mixed due to, among other things, uncertainties about a deceased person's donation preferences.

Furthermore, changing registration policies involves implementation challenges and ethical considerations surrounding informed consent. To date, most jurisdictions have maintained their existing policies, thus prompting the question, what can be done within explicit consent systems to improve organ donor registration rates? Prior research provides a good understanding of predictors of organ donation attitudes and intentions, yet little is known about how to increase actual registrations.

To address these limitations, the research team conducted a field experiment in the Province of Ontario to test behavioral marketing interventions targeting information and altruistic motives in an effort to increase new organ donor registrations in a prompted choice context. Along with the interventions, the researchers streamlined the registration process (i.e., intercepting customers at the time of decision, handing out promotional materials upon arrival for customers to consider while waiting) and updated the design of the registration form to increase the saliency of their interventions (i.e., a simplified form printed on cardstock using colored accents).

The researchers say that "Our paper contributes to the limited evidence for low-cost and scalable solutions to increase organ donor registrations within the current explicit consent systems. Our field experiment demonstrates how intercepting customers with promotional materials at the right time (an information brochure and perspective-taking prompts), along with other process and design improvements, can increase new organ donor registrations" says Robitaille. Specifically, Tsai points out, "the best-performing condition, prompting perspective-taking through reciprocal altruism ("If you needed a transplant would you have one? If so, please help save lives and register today.") significantly increased actual registration rates from 4.1% in the control condition to 7.4%, an 80% increase."

Hardy add that "We were able to do so without imposing on the freedom of individuals, raising ethical concerns (i.e., changing defaults), or passing new legislation." Haviv illustrates the potential impact of their findings, saying "Assuming that everything held constant over time and we introduced our best performing intervention (reciprocal altruism) together with our process and design improvements Ontario-wide, we could expect roughly 225,000 additional new registrations annually. Given that one donor can save up to eight lives, and enhance 75 others, such an increase could make a meaningful impact on the lives of many."

Mazar concludes with "By leveraging behavioral science to design our interventions, this research contributes to understanding how to reduce the intention-action gap in the context of organ donation, improve public policy, and enhance social welfare."

Scientists at the Institute for Integrated Cell-Material Sciences (iCeMS) and colleagues in Japan have revealed molecular mechanisms involved in eliminating unwanted cells in the body. A nuclear protein fragment released into the cytoplasm activates a plasma membrane protein to display a lipid on the cell surface, signalling other cells to get rid of it. The findings were published in the journal Molecular Cell.

"Every day, ten billion cells die and are engulfed by blood cells called phagocytes. If this didn't happen, dead cells would burst, triggering an auto-immune reaction," explains iCeMS biochemist Jun Suzuki, who led the study. "It is important to understand how dead cells are eliminated as part of our body's maintenance."

Scientists already know that dead cells display an 'eat me' signal on their surface that is recognized by phagocytes. During this process, lipids are flipped between the inner and outer parts of the cell membrane via a variety of proteins called scramblases. Suzuki and his team have already identified several of these lipid-scrambling proteins, but some of their activation mechanisms have been unclear.

To solve this, the team used an array of screening approaches to study the scrambling protein called Xkr4. The broad aim was to single out the genes that are active during cell death and to specifically zoom in on Xkr4 and its associated proteins to understand how they interact.

"We found that a nuclear protein fragment activates Xkr4 to display the 'eat me' signal to phagocytes," says iCeMS cell biologist Masahiro Maruoka, the first author of the study.

Specifically, the scientists found that cell death signals lead to a nuclear protein, called XRCC4, getting cut by an enzyme. A fragment of XRCC4 leaves the nucleus, activating Xkr4, which forms a dimer: the linking of identical pieces into configurations. Both XRCC4 binding and dimer formation are necessary for Xkr4 to ultimately transfer lipids on the cell surface to alert phagocytes.

Xkr4 is only one of the scrambling proteins. Others are activated much faster during cell death. The team now wants to understand when and why the Xkr4 pathway is specifically activated. Since it is strongly expressed in the brain, it is likely important for brain function. "We are now studying the elimination of unwanted cells or compartments in the brain to understand this process further," says Maruoka.

Presents a brief overview of the eight COVID-19 editorials published in DMPHP over the past year and using them as a framework to follow the evolution of the Pandemic over time. A review of the salient epidemiological and clinical dimensions of COVID-19 over time is given as well as a discussion of the medical and public health impacts of the disease and the interventions and policies put in place to contain and mediate the virus.

The concluding discussion questions the validity of the criteria used in selection of priority groups for vaccination in the US and notes that had a uniform program supporting the immunization of all over age 65 (accounting for 80% of COVID-19 deaths), the most lives would be spared while simultaneously cutting across all socio-economic and ethnic groups. Continuing this line of reasoning globally would provide an opportunity for the US to reburnish its humanitarian image through a vaccine diplomacy initiative with a goal to vaccinate the over 65 of every nation. To date, almost 500 million doses of vaccine have been administered; had they been targeted to the over 65 global population of some700 million, we would be well on our way to a return to the old normal.

How do different parts of the body communicate? Scientists at St. Jude are studying how signals sent from skeletal muscle affect the brain.

The team studied fruit flies and cutting-edge brain cell models called organoids. They focused on the signals muscles send when stressed. The researchers found that stress signals rely on an enzyme called Amyrel amylase and its product, the disaccharide maltose.

The scientists showed that mimicking the stress signals can protect the brain and retina from aging. The signals work by preventing the buildup of misfolded protein aggregates. Findings suggest that tailoring this signaling may potentially help combat neurodegenerative conditions like age-related dementia and Alzheimer's disease.

"We found that a stress response induced in muscle could impact not only the muscle but also promote protein quality control in distant tissues like the brain and retina," said Fabio Demontis, PhD, of St. Jude Developmental Neurobiology. "This stress response was actually protecting those tissues during aging."

The Environmental Protection Agency (EPA) is underestimating methane emissions from oil and gas production in its annual Inventory of U.S. Greenhouse Gas Emissions and Sinks, according to new research from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). The research team found 90 percent higher emissions from oil production and 50 percent higher emissions for natural gas production than EPA estimated in its latest inventory.

The paper is published in the journal Atmospheric Chemistry and Physics.

The research team, led by Joannes Maasakkers, a former graduate student at SEAS, developed a method to trace and map total emissions from satellite data to their source on the ground.

"This is the first country-wide evaluation of the emissions that the EPA reports to the United Nations Framework Convention on Climate Change (UNFCC)," said Maasakkers, who is currently a scientist at the SRON Netherlands Institute for Space Research.

Currently, the EPA only reports total national emissions to the UNFCC. In previous research, Maasakkers and his collaborators, including Daniel Jacob, the Vasco McCoy Family Professor of Atmospheric Chemistry and Environmental Engineering at SEAS, worked with the EPA to map regional emissions of methane from different sources in the US. That level of detail was used to simulate how methane moves through the atmosphere.

In this paper, the researchers compared those simulations to satellite observations from 2010-2015. Using a transport model, they were able to trace the path of emissions from the atmosphere back to the ground and identify areas across the US where the observations and simulations didn't match up.

"When we look at emissions from space, we can only see how total emissions from an area should be scaled up or down, but we don't know the source responsible for those emissions," said Maasakkers. "Because we spent so much time with the EPA figuring out where these different emissions occur, we could use our transport model to go back and figure out what sources are responsible for those under- or over-estimations in the national total."

The biggest discrepancy was in emissions from oil and natural gas production.

The EPA calculates emission based on processes and equipment. For example, the EPA estimates that a gas pump emits a certain amount of methane, multiplies that by how many pumps are operating across the country, and estimates total emissions from gas pumps.

"That method makes it really hard to get estimates for individual facilities because it is hard to take into account every possible source of emission," said Maasakkers. "We know that a relatively small number of facilities make up most of the emissions and so there are clearly facilities that are producing more emissions than we would expect from these overall estimates."

The researchers hope that future work will provide more clarity on exactly where these emissions are coming from and how they are changing.

"We plan to continue to monitor U.S. emissions of methane using new high-resolution satellite observations, and to work with the EPA to improve emission inventories," said Jacob.

"It's important to understand these emissions better but we shouldn't wait until we fully understand these emissions to start trying to reduce them," said Maasakkers. "There are already a lot of things that we know we can do to reduce emissions."

The immune systems of all vertebrates contain specialized cells, called T cells, that play a fundamental role in protecting against fungal, bacterial, parasitic and viral infections. T cells use 'molecular sensors' called T cell receptors (TCRs) on their surface that can detect and eliminate the invading pathogens. For most of the past four decades, it was considered that there were only two T cell lineages, αβ and γδ T cells, characterized by their cell surface expressed αβ and γδ TCRs, respectively.

In a paper published today in Science, an international team of scientists at the University of New Mexico (US), Monash University (Australia), and the US National Institutes of Health, has defined a novel T cell lineage, called γμ T cells, found only in marsupials (e.g. kangaroos and opossums) and monotremes (e.g. duckbill platypus).

Evidence for the γμ TCR came with the discovery of genes encoding the TCRμ protein whilst analyzing the first complete marsupial genome, that of the South American opossum Monodelphis domestica. Oddly, distinct from conventional αβ and γδ TCRs, TCRμ was predicted to share similarity with the antibodies.

Using the Australian Synchrotron, the scientists at Monash University obtained a detailed three-dimensional image of the opossum γμTCR architecture that was unique and distinct from αβ or γδ TCRs. Noteworthy was the presence of an additional single antibody-like segment called Vμ domain with an architecture resembling to nanobodies, a unique type of antibodies. This discovery raises the possibility that γμ T cells recognize pathogens using novel mechanisms, distinct from conventional T cells.

"The discovery of a nanobody like structure in the γμ TCR has the potential to expand the immunology 'toolbox'. Indeed, nanobodies discovered in the camel family (e.g. alpacas) have recently attracted considerable interests for their development as research and diagnostic tools and more importantly as immunotherapeutics in humans to combat cancer and viral infections such as COVID-19. Marsupials may offer an alternative source of nanobodies, one that is smaller, easier and cheaper to maintain than llamas or alpacas." said Monash University Dr Marcin Wegrecki from the Biomedicine Discovery Institute, co-first author on the paper.

"Our findings further illustrate the value of exploring the world's biodiversity for novelty beyond the standard animal research models, such as laboratory mice. Modern genomic tools applied to many species have opened the door to the myriad of immunological solutions to fighting pathogens that evolution has produced." said Prof Robert Miller from the University of New Mexico, co-lead author on the paper.

"Many in-roads have been made in understanding the immune systems of humans and mice leading to the development of novel immunotherapeutic approaches enabling humans to combat highly pathogenic viruses. However, much less is understood on how immunity operates in other species that, in some cases, have been decimated by wildlife diseases. Ultimately our work may guide the development of veterinary approaches (e.g. novel vaccines) that will contribute to wildlife conservation." said Dr Jérôme Le Nours from Monash Biomedicine Discovery Institute, co-lead author on the paper.

"This is a prime example of curiosity driven science leading to unexpected and transformative findings." Le Nours stated.

Renewable energy demand and consumption is at an all-time high in the United States.

Shrub willow - a quick-growing woody crop - can be an excellent source of renewable bioenergy. The crop is harvested and turned into wood chips, which can be used for heat, mulch, animal bedding, biochar, and biofuel.

In a new study, researchers grew shrub willow on a semi-commercial scale to better understand the nuances of this bioenergy crop. The research was published in Agronomy Journal, a publication of the American Society of Agronomy.

"We learned and developed key know-hows that we can transfer to industry partners interested in this crop," says Armen Kemanian. Kemanian is a member of the American Society of Agronomy and is the lead author of the study.

Insights include determining which willow varieties to plant and how to best handle planting and harvesting.

"Starting a willow crop can be expensive," says Kemanian. "It also requires a perfectly choreographed operation to keep costs low and yields high."

But shrub willow also offers several advantages as a bioenergy crop.

"Shrub willow thrives in wetter areas with cold winters and mild summers," says Kemanian. That makes the crop well-suited to New England and parts of the upper Midwest.

Other bioenergy crops, such as switchgrass, grow better in areas of the U.S. with warmer summers.

According to Kemanian, "Shrub willow can be part of a geographically diverse combination of bioenergy crops."

One important quality of shrub willow is its ability to store a tremendous amount of carbon. That's beneficial because when there is more carbon stored in plants, there is less carbon in the atmosphere.

When the carbon is in the atmosphere as carbon dioxide, it can be a harmful greenhouse gas. But when the carbon is in the plant, it doesn't pose a risk to the environment.

Shrub willow also has tremendous genetic variability. That's important for breeding key crop characteristics, such as pest resistance.

"The study found that planting a mixture of willow varieties is critically important," says Kemanian.

That's because some highly productive willow varieties attract pests, like the willow leaf beetle. Surrounding these high-yield willow varieties with beetle-resistant varieties can slow down the pests.

"This is a different strategy compared to growing annual crops," explains Kemanian.

Annuals can be replanted every year. In contrast, shrub willow can be harvested every two to four years for more than 20 years. "Growing different varieties together is critical," says Kemanian.

The relatively long lifespan of willow crops also means that planning is vitally important.

"Harvest costs account for a large fraction of total operation cost over the life cycle of willow crops," says Kemanian.

The study established that a well-designed field is easier to harvest. That might seem obvious, but some of the findings are counterintuitive.

For example, while yields are important, seeking the highest possible yield per unit area is not the most critical parameter when planning willow planting schemes.

"Designing fields and plantings so that harvest machinery traffic is efficient is more important," says Kemanian.

However, the study also found that - at least on semi-commercial scales - actual willow yields could be lower than the expected yield potential.

"Willow thrives in productive soils," says Kemanian. "Rocky soils can increase planting and harvest cost and lower yields."

Researchers suggest that when it comes to growing shrub willow, the harvestable crop isn't the only valuable outcome for farmers.

"We should also monetize the ecosystem services that willow provides," says Kemanian.

These services include storing carbon, hosting pollinators, reducing water runoff, and retaining nutrients - such as nitrogen - in the soil.

"Willow can play a significant role in improving our most intensely farmed land," says Kemanian. "We just need to take advantage of the synergies between animal production and crop production."

But quantifying the ecosystems services of willow at a large scale remains complicated. "We can tackle this challenge with computer modeling," says Kemanian. "That's something our team is doing right now."

Other next steps include monitoring for pest outbreaks with unmanned aerial vehicles (UAVs). These UAVs could also be used to detect and control pests efficiently and economically.

"Ultimately, we think willow can play a role in regenerative and climate-smart agriculture," says Kemanian.

SILVER SPRING, Md. - As concern has grown over COVID-19 variants and their implications for how well COVID-19 vaccines will protect against the virus, researchers have proposed a method to examine instances of SARS-COV-2 infections in people who have received a COVID-19 vaccine.

Genomic sieve analysis of these so-called "breakthrough" SARS-CoV-2 infections in COVID vaccine trials is a critical tool to identify viral mutations associated with vaccine failure and to predict how vaccination impacts the virus' evolution.

Dr. Morgane Rolland, Chief of Viral Genetics for the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research, and Dr. Peter Gilbert, biostatistician and professor at the Vaccine and Infectious Disease and Public Health Sciences Divisions at Fred Hutchinson Cancer Research Center, described the strategy in a recent publication in PLOS Pathogens.

"No vaccine is 100 percent effective, so even in clinical trials for the highly effective COVID vaccines being rolled out now, some of the trial volunteers who received the vaccine experienced breakthrough infections," explained Rolland. "Sieve analysis compares those breakthrough viruses to those that infected the placebo group to help pinpoint which variants are evading the vaccine-induced immune response and inform efforts to improve COVID vaccines."

Gilbert added, "Think of the vaccine as a sieve and different variants as pebbles poured into the sieve: the vaccine will block some variants but allow others to pass through, and sieve analysis learns which variants make it through."

Sieve analysis allows scientists to recognize evolutionary patterns that will be key to infer how SARS-CoV-2 might adapt to widely used vaccines and predict how virus evolution could eventually impact vaccine efficacy. The paper's authors note SARS-CoV-2 is relatively slow to mutate, meaning it's unlikely current vaccines will be rendered obsolete soon, but increased vigilance is needed in the months until a majority of the population has been vaccinated to stem spread of concerning variants.

"The variants that emerged in the past two months highlight the need for next generation vaccines," said Rolland. "Conducting sieve analysis of samples obtained through vaccine trials is an efficient way to determine how future vaccines should be designed."

Scientists at Sinai Health say they have discovered a new pathway that controls dangerous overreactions in a body's immune system, including deadly forms of hyper-inflammation.

In new findings out today in the journal Science, researchers at the Lunenfeld-Tanenbaum Research Institute (LTRI) detail how a protein known as WAVE2, a protein expressed in all immune cells, plays a critical role in maintaining immune system balance.

As part of the research, scientists knocked out, or turned off, WAVE2 in a subset of immune cells in mice, which led to severe autoimmunity and inflammation, as well as an inability to mount an immune response to a viral infection.

The study's senior author, Dr. Kathy Siminovitch, said they also found that another protein, known as mTOR, became overly active in the absence of WAVE2, putting the immune system into overdrive and leading to immune cell exhaustion.

"Much like Goldilocks, a proper immune response requires such a delicate balance," said Dr. Siminovitch, senior investigator at the LTRI and Canada Research Chair in the Mechanisms Regulating Immunologic Disease. "You have to get it just right. By developing a mouse strain in which T cells, key players in immunity, lack WAVE2, we have shown that this protein is absolutely required for balanced immune responses."

How to keep the immune system from going into overdrive has been a key question for medical experts as they continue to grapple with the devastating effects of COVID-19 pandemic, particularly on the elderly population.

Patients over the age of 65 are at a higher risk of developing severe COVID-19, partly due to a phenomenon called "cytokine storm" where the immune system overacts and damages organs.

"The pandemic has starkly illuminated the critical importance of immune balance and the severe consequences of disrupting such balance," said Siminovitch. "It has also highlighted the importance of fundamental research, which has taken us where we are today in understanding the virus and having treatment and prevention strategies in hand."

For years, Dr. Siminovitch has been exploring the genetic and molecular mechanisms that regulate and maintain balance across the immune system. In previous work, she helped trace the complex molecular steps that turn a rare gene mutation into Wiskott-Aldrich syndrome, which impairs the immune system of boys, and can lead to death at a very young age.

Dr. Siminovitch said they would like to expand their research to look at how the WAVE2-mTOR pathway may contribute to specific autoimmune, inflammatory and other conditions, such as Alzheimer's disease.

"Understanding how to achieve this kind of control in immunity is really important," said Dr. Siminovitch. "This research opens the door to new ways of restoring that balance through the development of new therapeutics that target the WAVE2- mTOR pathway."

The evolving science of wisdom rests on the idea that wisdom's defined traits correspond to distinct regions of the brain, and that greater wisdom translates into greater happiness and life satisfaction while being less wise results in opposite, negative consequences.

Scientists have found in multiple studies that persons deemed to be wiser are less prone to feel lonely while those who are lonelier also tend to be less wise. In a new study, published in the March 25, 2021 issue of the journal Frontiers in Psychiatry, researchers at University of California San Diego School of Medicine take the connection between wisdom, loneliness and biology further, reporting that wisdom and loneliness appear to influence -- and/or be influenced by -- microbial diversity of the gut.

The human gut microbiota is comprised of trillions of microbes -- bacteria, viruses, fungi -- that reside within the digestive tract. Researchers have known for a while about the "gut-brain axis," which is a complex network that links intestinal function to the emotional and cognitive centers of the brain.

This two-way communication system is regulated by neural activity, hormones and the immune system; alterations can result in disruptions to stress response and behaviors, said the authors, from emotional arousal to higher-order cognitive abilities, such as decision-making.

Past studies have associated gut microbiota with mental health disorders including depression, bipolar disorder and schizophrenia, as well as personality and psychological traits regarded as key, biologically based components of wisdom. Recent research has connected the gut microbiome to social behavior, including findings that people with larger social networks tend to have more diverse gut microbiotas.

The new Frontiers in Psychiatry study involved 187 participants, ages 28 to 97, who completed validated self-report-based measures of loneliness, wisdom, compassion, social support and social engagement. The gut microbiota was analyzed using fecal samples. Microbial gut diversity was measured in two ways: alpha-diversity, referring to the ecological richness of microbial species within each individual and beta-diversity, referring to the differences in the microbial community composition between individuals.

"We found that lower levels of loneliness and higher levels of wisdom, compassion, social support and engagement were associated with greater phylogenetic richness and diversity of the gut microbiome," said first author Tanya T. Nguyen, PhD, assistant professor of psychiatry at UC San Diego School of Medicine.

The authors said that the mechanisms that may link loneliness, compassion and wisdom with gut microbial diversity are not known, but observed that reduced microbial diversity typically represents worse physical and mental health, and is associated with a variety of diseases, including obesity, inflammatory bowel disease and major depressive disorder.

A more diverse gut microbiota may be less susceptible to invasion by outside pathogens, which could contribute to and help promote better resilience and stability of the community.

"It is possible that loneliness may result in decreased stability of the gut microbiome and, consequently, reduced resistance and resilience to stress-related disruptions, leading to downstream physiological effects, such as systemic inflammation," the authors wrote.

"Bacterial communities with low alpha-diversity may not manifest overt disease, but they may be less than optimal for preventing disease. Thus, lonely people may be more susceptible to developing different diseases."

The relationship between loneliness and microbial diversity was particularly strong in older adults, suggesting that older adults may be especially vulnerable to health-related consequences of loneliness, which is consistent with prior research.

Conversely, the researchers said that social support, compassion and wisdom might confer protection against loneliness-related instability of the gut microbiome. Healthy, diverse gut microflora may buffer the negative effects of chronic stress or help shape social behaviors that promote either wisdom or loneliness. They noted that animal studies suggest that gut microbiota may influence social behaviors and interactions, though the hypothesis has not been tested in humans.

The complexity of the topic and study limitations, such as the absence of data about individuals' social networks, diet and degree of objective social isolation versus subjective reports of loneliness, argue for larger, longer studies, wrote the authors.

"Loneliness may lead to changes in the gut microbiome or, reciprocally, alterations of the gut milieu may predispose an individual to become lonely," said Dilip V. Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences at UC San Diego School of Medicine and senior author of the paper. "We need to investigate much more thoroughly to better understand the phenomenon of the gut-brain axis."

An analysis of adult human brain tissue reveals over 900 proteins tied to epilepsy. The brain disorder, estimated to afflict more than 3 million Americans, is mostly known for symptoms of hallucinations, dreamlike states, and uncontrolled, often disabling bodily seizures.

Led by researchers at NYU Grossman School of Medicine, the study examined molecular differences among the brains of 14 epilepsy patients and another group of 14 adults of similar age and gender who did not have the disease.

Study results showed that altered levels of brain proteins predominated in the hippocampus, a structure located deep inside the skull and responsible for memory and learning. However, some 134 proteins were significantly changed in both the hippocampus and frontal cortex, the front third of the brain, which is also responsible for controlling thought and body movements. Most of the changed proteins were tied to genes in charge of protein production and linked to epilepsy in much smaller, earlier studies, but four of the 20 most-altered proteins had never previously been associated with the disorder.

One particular protein, researchers say, stood out as the most significantly depleted across all brain regions. Called G Protein Subunit 1, or GNB1, the protein is known to play an important role in dozens of biological reactions, or pathways, involved in nerve growth and communication throughout the brain, but they say its precise role in epilepsy remains unclear.

Despite decades of research, researchers say, the causes of epilepsy remains unknown. Dozens of drugs are used to control seizures by targeting known protein weaknesses, excesses, or deficiencies, and the "electrical storms" they trigger in the brain, but fail in one-third of patients to do so.

Publishing in the journal Brain Communications online March 9, the new investigation focused on regions of the frontal cortex and hippocampus that previous imaging and neurological studies had identified as most impacted by seizures.

"Our analysis identifies hundreds of potential new treatment targets for epilepsy, focusing on areas of the brain mostly damaged by the disease," says study co-senior investigator Orrin Devinsky, MD, a professor in the departments of Neurology, Neuroscience and Physiology, Neurosurgery, and Psychiatry at NYU Langone Health.

"While our results point to the hippocampus as the brain region most vulnerable in epilepsy, further research is needed to confirm if this region is the primary source of the illness from which damage spreads out across other brain regions, as well as how epilepsy is mutually tied to other disorders, such as dementia and depression," says Devinsky, who also serves as director of the Comprehensive Epilepsy Center at NYU Langone.

"Of particular interest, these findings suggest that the G Protein Subunit 1 brain pathways are a strong target for new epilepsy therapies," says study co-senior author Thomas Wisniewski, MD.

Wisniewski, the Gerald J. and Dorothy R. Friedman Professor in the Department of Neurology and director of the Center for Cognitive Neurology at NYU Langone, says GNB1 pathways are already the target of more than a dozen drugs, such as nabilone and prazosine, used to treat conditions other than epilepsy, including nausea and high blood pressure.

Wisniewski says the NYU Langone team has plans to create a database that depicts "the brain landscape" of epilepsy protein and gene targets. They also plan initial clinical studies to determine how existing GNB1-altering medications may prevent or treat the disorder.

Researchers from Charité - Universitätsmedizin Berlin and the Francis Crick Institute have developed a mass spectrometry-based technique capable of measuring samples containing thousands of proteins within just a few minutes. It is faster and cheaper than a conventional blood count. To demonstrate the technique's potential, the researchers used blood plasma collected from COVID-19 patients. Using the new technology, they identified eleven previously unknown proteins which are markers of disease severity. The work has been published in Nature Biotechnology*.

Thousands of proteins are active inside the human body at any given time, providing its structure and enabling reactions which are essential to life. The body raises and lowers the activity levels of specific proteins as required, including when responding to external factors such as pathogens and drugs. The detailed patterns of the proteins found inside cells, tissues and blood samples can therefore help researchers to better understand diseases or make diagnoses and prognoses. In order to obtain this 'protein fingerprint', researchers use mass spectrometry, a technology known to be both time-consuming and cost-intensive. 'Scanning SWATH', a new mass-spectrometry-based technology, promises to change this. Developed under the leadership of Prof. Dr. Markus Ralser, Director of Charité's Institute of Biochemistry, this technology, which is much faster and cost-effective than previous methods, enables researchers to measure several hundred samples per day.

"In order to speed up this technology, we changed the mass spectrometer's electric fields. The data produced are of such extreme complexity that humans can no longer analyze them," explains Einstein Professor Prof. Ralser, who is also a Group Leader at the Francis Crick Institute in London. He adds: "We therefore developed computer algorithms that are based on neural networks and which use these data to extract the relevant biological information. This enables us to identify thousands of proteins in parallel and greatly reduces measuring timescales. Fortunately, this method is also more precise."

This high-throughput technology has a broad range of potential applications, ranging from basic research and large-scale drug development to the identification of biological markers (biomarkers), which can be used to estimate an individual patient's risk. The technology's suitability for the latter was demonstrated by the researchers' study on COVID-19. As part of this research, the team analyzed blood plasma samples from 30 Charité inpatients with COVID-19 of varying degrees of disease severity, comparing the protein patterns obtained with those of 15 healthy individuals. The actual measurements conducted on individual samples only took a few minutes.

The researchers were able to identify a total of 54 proteins whose serum levels varied according to the severity of COVID-19. While 43 of these proteins had already been linked to disease severity during earlier studies, no such relationship had been established for 11 of the proteins identified. Several of the previously unknown proteins associated with COVID-19 are involved in the body's immune response to pathogens which increases clotting tendency. "In the shortest of timeframes, we discovered protein fingerprints in blood samples which we are now able to use to categorize COVID-19 patients according to severity of disease," says one of the study's lead authors, Dr. Christoph Messner, who is a researcher at Charité's Institute of Biochemistry and the Francis Crick Institute. He continues: "This type of objective assessment can be extremely valuable, as patients will occasionally underestimate the severity of their disease. However, in order to be able to use mass spectrometry analysis for the routine categorization of COVID-19 patients, this technology will need to be refined further and turned into a diagnostic test. It may also become possible to use rapid protein pattern analysis to predict the likely course of a case of COVID-19. While the initial findings we have collected are promising, further studies will be needed before this can be used in routine practice."

Prof. Ralser is convinced that mass spectrometry-based investigations of the blood could one day complement conventional blood count profiles. "Proteome analysis is now cheaper than a complete blood count. By identifying many thousands of proteins at the same time, proteomic analysis also produces far more information. I therefore see enormous potential for widespread use, for instance in the early detection of diseases. We will therefore continue to use our studies to develop proteome technology for this type of application."

Tel-Aviv, ISRAEL - March 25, 2021 - Wild Biotech, a preclinical stage drug discovery & development company emerging out of stealth mode, today announces the publication of its first major paper, which appears in the journal Science. The study mapped the gut microbiota of animals in the wild on an unprecedented scale, adding millions of potentially novel microbiome-based therapeutics for human diseases to the company's already massive database. Wild will use these findings to first tap its database for targets in inflammatory, immune and gastrointestinal diseases.

"For the study, we collected gut microbiota from almost 200 species of animals in the wild, covering diverse classes, feeding behaviors, geographies, and traits," said Neta Raab, Co-founder & Chief Executive Officer at Wild Biotech. "Using de novo metagenome assembly, we constructed and functionally annotated a database of over 5,000 microbial genomes from those animals covering more than 1,200 bacterial species - 75% of which were previously unknown."

Animals in the wild exhibit extraordinary feats of survival. Some, from hyenas and jackals to Tasmanian devils, subsist on rotting, pathogen-infected and toxic food while remaining immune to disease - possible due, in part, to their gut microbiota. While the understanding of the diversity and functions within these ecosystems is poor, the microbial composition, diversity, and functional content of animals' microbiota have known associations with animal taxonomy, diet, activity, social structure and lifespan. "These are clues which we could tap into in order to discover entirely new agents to treat human diseases," Raab said.

The findings reported in Science add 30 million genes - each representing a potentially new therapeutic agent - to Wild's unique database of animal microbiota, which now comprises hundreds of animal species and 100 million genes. "The majority of that genomic material is novel, and our database introduces thousands of previously undescribed species into the bacterial tree of life," Raab said.

Wild applies cutting-edge AI tools to decipher the therapeutic potential of its database and identify proteins, peptides, bacteriophages, and other agents with direct activity on targets in human diseases. The company's database is unique because, unlike microbes found in the ocean or soil, the gut microbiota of animals is the most relevant and directly translatable to human therapeutics.

Wild Biotech's database and AI tools are complemented by high-throughput synthetic biology to validate microbiome-derived agents and accelerate them into preclinical testing, and the high quality of the data extracted from microbial genomes enables the company to directly synthesize and test agents. For example, in the Science study the team synthesized a panel of previously-undescribed enzymes from carrion eater microbiota and showed that they operate on a range of microbial toxins, suggesting a mechanism that detoxifies carrion for its safe consumption by the host animal.

The company has also identified in its database over 2,000 CRISPR/Cas genome editing systems, of which approximately one third does not belong to any known CRISPR/Cas family.

"Intractable diseases require new thinking on intervention. Wild has built a revolutionary approach and the tools to explore its novel data sets, unlike any other company," said Dr. John Baldoni, leading pharmaceutical industry expert and advisor to Wild. "You must have the data in order to do the computational work. Because of their highly evolved and relevant library, they are able to look at millions of interactions quickly, within days, and screen and target logical therapeutic areas. Wild's approach enables a translatable workflow from its microbiome data to molecular mechanisms associated with complex diseases."

"We are balancing innovation and clinical evidence to screen many millions of interactions with specific targets associated with human diseases," said Raab. "We are very excited about the extraordinary potential hidden in this database for identifying entirely novel approaches to treat disease."