Culture

WEHI researchers have discovered a key differentiation process that provides an essential immune function in helping to control cancer and infectious diseases.

The research, published in Science Immunology, is the first to show a new factor - DC-SCRIPT - is required for the function a particular type of dendritic cell - called cDC1 - that is essential in controlling the immune response to infection.

Led by WEHI Professor Stephen Nutt, Dr Michael Chopin and Mr Shengbo Zhang, it defines the role for a new regulatory protein - DC-SCRIPT - in producing dendritic cells.

At a glance

WEHI researchers have uncovered a key step in the formation of a particular type of dendritic cell - called cDC1 - in controlling the immune response to infection.

The research highlights the importance of DC-SCRIPT in the production of effective dendritic cells.

Through gaining a better understanding of how dendritic cells are produced, researchers hope to be able to determine a way of directing the body to produce large numbers of dendritic cells, to enable it to better fight off cancer and infections.

DC-SCRIPT essential in the production of cancer-fighting cells

Dendritic cells are immune cells that activate 'killer' T cells, which are vital for clearing viral infections and for triggering a response to cancer tumours.

Through gaining a better understanding of how this process works, researchers hope to be able to determine a way of directing the body to produce large numbers of dendritic cells, to enable it to better fight off cancer and infections.

Professor Nutt said the research paper highlighted the importance of DC-SCRIPT in the production of effective dendritic cells.

"What we found, is that without this new factor, the cells develop poorly, and their capacity to fight infection and cancer, or to clear a parasite, is diminished," he said.

"The next stage of our research is to try and work out how we can get the body to produce these particular dendritic cells, cDC1s, in large volumes in order to boost the body's natural tumour response."

Harnessing the body's natural response to infection

Dr Chopin said he was confident cDC1s held the clues to improving immunity to viruses and tumours.

"This paper clearly shows DC-SCRIPT is one of the regulators of dendritic cell production. As a result of this study, we're now focussed on ways we could harness this to increase dendritic cell production," he said.

"We now have a biomarker to follow when we expand this elusive cell type, which we will continue to test in pre-clinical models."

This research lays the foundation for future studies into dendritic cell production and their clinical applications in response to tumours.

"We have generated new tools, allowing us to trace these cells within the tumour and observe how they behave in the tumour environment," Dr Chopin said.
This work was made possible with funding from the National Health and Medical Research Council and the Victorian Government.

What The Study Did: This survey study examined the career development, productivity, childcare needs and likelihood of leaving the workforce among employees at an academic medical center during the COVID-19 pandemic.

Authors: Angela Fagerlin, Ph.D., of the University of Utah in Salt Lake City, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.3997)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Extended surges in the South and West in the summer and early winter of 2020 resulted in regional increases in excess death rates, both from COVID-19 and from other causes, a 50-state analysis of excess death trends has found. Virginia Commonwealth University researchers' latest study notes that Black Americans had the highest excess death rates per capita of any racial or ethnic group in 2020.

The research, publishing Friday in the Journal of the American Medical Association, offers new data from the last 10 months of 2020 on how many Americans died during 2020 as a result of the effects of the pandemic -- beyond the number of COVID-19 deaths alone -- and which states and racial groups were hit hardest.

The rate of excess deaths -- or deaths above the number that would be expected based on averages from the previous five years -- is usually consistent, fluctuating 1% to 2% from year to year, said Steven Woolf, M.D., the study's lead author and director emeritus of VCU's Center on Society and Health. From March 1, 2020, to Jan. 2, 2021, excess deaths rose a staggering 22.9% nationally, fueled by COVID-19 and deaths from other causes, with regions experiencing surges at different times.

"COVID-19 accounted for roughly 72% of the excess deaths we're calculating, and that's similar to what our earlier studies showed. There is a sizable gap between the number of publicly reported COVID-19 deaths and the sum total of excess deaths the country has actually experienced," Woolf said.

For the other 28% of the nation's 522,368 excess deaths during that period, some may actually have been from COVID-19, even if the virus was not listed on the death certificates due to reporting issues.

But Woolf said disruptions caused by the pandemic were another cause of the 28% of excess deaths not attributed to COVID-19. Examples might include deaths resulting from not seeking or finding adequate care in an emergency such as a heart attack, experiencing fatal complications from a chronic disease such as diabetes, or facing a behavioral health crisis that led to suicide or drug overdose.

"All three of those categories could have contributed to an increase in deaths among people who did not have COVID-19 but whose lives were essentially taken by the pandemic," said Woolf, a professor in the Department of Family Medicine and Population Health at the VCU School of Medicine.

The percentage of excess deaths among non-Hispanic Black individuals (16.9%) exceeded their share of the U.S. population (12.5%), reflecting racial disparities in mortality due to COVID-19 and other causes of death in the pandemic, Woolf and his co-authors write in the paper. The excess death rate among Black Americans was higher than rates of excess deaths among non-Hispanic white or Hispanic populations.

Woolf said his team was motivated to break down this information by race and ethnicity due to mounting evidence that people of color have experienced an increased risk of death from COVID-19.

"We found a disproportionate number of excess deaths among the Black population in the United States," said Woolf, VCU's C. Kenneth and Dianne Wright Distinguished Chair in Population Health and Health Equity. "This, of course, is consistent with the evidence about COVID-19 but also indicates that excess deaths from some conditions other than COVID-19 are also occurring at higher rates in the African American population."

Surges in excess deaths varied across regions of the United States. Northeastern states, such as New York and New Jersey, were among the first hit by the pandemic. Their pandemic curves looked like a capital "A," Woolf said, peaking in April and returning rapidly to baseline within eight weeks because strict restrictions were put in place. But the increase in excess deaths lasted much longer in other states that lifted restrictions early and were hit hard later in the year. Woolf cited economic or political reasons for decisions by some governors to weakly embrace, or discourage, pandemic control measures such as wearing masks.

"They said they were opening early to rescue the economy. The tragedy is that policy not only cost more lives, but actually hurt their economy by extending the length of the pandemic," Woolf said. "One of the big lessons our nation must learn from COVID-19 is that our health and our economy are tied together. You can't really rescue one without the other."

According to the study's data, the 10 states with the highest per capita rate of excess deaths were Mississippi, New Jersey, New York, Arizona, Alabama, Louisiana, South Dakota, New Mexico, North Dakota and Ohio.

Nationally, Woolf expects the U.S. will see consequences of the pandemic long after this year. For example, cancer mortality rates may increase in the coming years if the pandemic forced people to delay screening or chemotherapy.

Woolf said future illness and deaths from the downstream consequences of the devastated economy could be addressed now by "bringing help to families, expanding access to health care, improving behavioral health services and trying to bring economic stability to a large part of the population that was already living on the edge before the pandemic." Among other research, his team's 2019 JAMA study of working-age mortality underscores the importance of prioritizing public health measures like these, he said.

"American workers are sicker and dying earlier than workers in businesses in other countries that are competing against America," Woolf said. "So investments to help with health are important for the U.S. economy in that context just as they are with COVID-19."

Derek Chapman, Ph.D., Roy Sabo, Ph.D., and Emily Zimmerman, Ph.D., of VCU's Center on Society and Health and the School of Medicine joined Woolf as co-authors on the paper published Friday, "Excess Deaths From COVID-19 and Other Causes in the United States, March 1, 2020, to January 2, 2021."

Their study also confirms a trend Woolf's team noted in an earlier 2020 study: Death rates from several non-COVID-19 conditions, such as heart disease, Alzheimer's disease and diabetes, increased during surges.

"This country has experienced profound loss of life due to the pandemic and its consequences, especially in communities of color," said Peter Buckley, M.D., dean of the VCU School of Medicine. "While we must remain vigilant with social distancing and mask-wearing behaviors for the duration of this pandemic, we must also make efforts to ensure the equitable distribution of care if we are to reduce the likelihood of further loss of life."

Based on current trends, Woolf said the surges the U.S. has seen might not be over, even with vaccinations underway.

"We're not out of the woods yet because we're in a race with the COVID-19 variants. If we let up too soon and don't maintain public health restrictions, the vaccine may not win out over the variants," Woolf said. "Unfortunately, what we're seeing is that many states have not learned the lesson of 2020. Once again, they are lifting restrictions, opening businesses back up, and now seeing the COVID-19 variants spread through their population.

"To prevent more excess deaths, we need to hold our horses and maintain the public health restrictions that we have in place so the vaccine can do its work and get the case numbers under control."

What The Study Did: This study updates an analysis of deaths in the United States in 2020, including deaths due to COVID-19 as well as all other causes.

Authors: Steven H. Woolf, M.D., M.P.H., of the Virginia Commonwealth University School of Medicine in Richmond, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2021.5199)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

People who radicalize to extremist ideologies often are triggered by negative life events or exposure to propaganda, and those who escape from extreme groups frequently are aided by an individual or group that intervenes to help them reject the philosophy, according to a new RAND Corporation study.

Expanding access to mental health care, creating opportunities for exposure to diverse cultural groups and media literacy education all are important strategies that may aid the battle against extremism, according to researchers. However, harsh law enforcement actions often are unproductive in changing people's extremist beliefs.

The RAND study describes personal accounts based on interviews with more than two dozen former white supremacists, Islamic extremists and their family members about what leads people to join extremist groups and, at least in some cases, leave these groups and their radical ideologies.

"Terrorism and ideologically-inspired violence represent persistent and serious threats to the security of the United States," said Ryan Andrew Brown, the study's lead author and a senior social scientist at RAND, a nonprofit research organization. "By better understanding the pathways individuals take to radicalization, we can improve our prevention and deradicalization strategies."

The study is one of the first public reports to incorporate the experiences of white supremacists, Islamic extremists and their family members to look for common factors and signs along the pathway to radicalization.

Events such as the Jan. 6 attack on the U.S. Capitol underscore a growing threat to America's national security posed by homegrown terrorism and ideologically inspired violence. Domestic attacks have maintained a steady and growing pace in recent years, foreshadowing recent events.

The RAND study is based on interviews about 32 people who became radicalized -- 24 white supremacists and 8 Islamic extremists. Those interviewed included 24 former extremists, 10 family members and two friends. To recruit study participants, the team worked with Parents for Peace and Beyond Barriers, two organizations that work with former members of radical extremist organizations and family members who have assisted with deradicalization efforts.

The study provides findings across four areas: background characteristics of radical extremists, pathways to radicalization, deradicalizing and leaving organizations, and participant perspectives on mitigation strategies.

The RAND interviews highlight several factors that may contribute to individuals becoming radicalized, including facing financial instability, mental health challenges such as trauma and PTSD, and social factors such as victimization and marginalization.

In more than half of the cases, a "re-orienting" event was described that prompted an individual to reconsider previously accepted views and embrace extremist ideologies. These events included a gun possession charge, rejection by the military, a friend's suicide and an extended period of unemployment.

In a majority of cases, individuals described consuming propaganda during radicalization, especially online materials, but also music and books.

In seven cases (4 white supremacist, 3 Islamic extremist), recruitment involved top-down action by recruiters from radical organizations. In 18 cases (15 white supremacist, 3 Islamic extremist), recruitment involved "bottom-up" entry in which individuals radicalize on their own and then sought membership in extremist organizations.

"It may be difficult to observe noticeable changes in individuals until they are radicalized and those changes often are a surprise to their family," Brown said. "It is only after the radicalization takes place that family members and friends may understand what has happened."

Individuals in the RAND study said they also benefited socially while participating in extremist groups, most notably finding friends and developing a sense of camaraderie and friendship that was previously missing in their lives. Some noted a new sense of power.

The most commonly mentioned factor for exiting a group was a sense of disillusionment and burnout. Hypocrisy or other negative behaviors by group members were often cited as reasons for these feelings.

Individuals or groups helped 22 of the individuals in the RAND sample to exit extremist groups, with such interventions most often conducted intentionally. The interventions included diverse cultural and demographic exposures, providing emotional support, and providing pathways to financial and/or domestic stability.

In half of those cases, the intervention was orchestrated and conducted by an institution, including religious groups, law enforcement, and secular nonprofits. Twenty-two of the 32 cases also described processes of self-driven exit from extremism, in which former extremists sought their own paths out of groups and ideologies.

A majority of the study participants also indicated that they experienced interventions that had failed, most often efforts that had been initiated by family members. Punitive interventions by law enforcement also often led to paradoxical effects of increased extremism.

"Our work suggests that the punitive approach should be used sparingly because it seldom ends radicalization and frequently has negative consequences for community members," Brown said.

The RAND study provides recommendations that community organizations and researchers should pursue in the future to strengthen both practice and understanding of what works.

Those recommendations include expanding community based mental health services in areas at risk for radicalization and exploring whether interventions based on an addiction treatment model can help deter radicalization.

Community organizations also should consider ways to expand exposure to diverse populations, help at-risk families recognize and react to signs of extremism, and improve ways to present deradicalization messages at the right time and place.

Researchers should work to better identify geographic and demographic hot spots for radicalization, develop educational and outreach efforts to help recognize and address the signs of radicalization, and explore social network approaches to deradicalization.

ITHACA, NY, April 2, 2021 - A team of researchers from the Boyce Thompson Institute (BTI) has discovered a distinct group of bacteria that may help fungi and plants acquire soil nutrients. The findings could point the way to cost-effective and eco-friendly methods of enriching soil and improving crop yields, reducing farmers' reliance on conventional fertilizers.

Researchers know that arbuscular mycorrhizal (AM) fungi establish symbiotic relationships with the roots of 70% of all land plants. In this relationship, plants trade fatty acids for the fungi's nitrogen and phosphorus. However, AM fungi lack the enzymes needed to free nitrogen and phosphorus from complex organic molecules.

A trio of BTI scientists led by Maria Harrison, the William H. Crocker Professor at BTI, wondered whether other soil microbes might help the fungi access those nutrients. In a first step towards examining that possibility, the team investigated whether AM fungi associate with a specific community of bacteria. The research was described in a paper published in The ISME Journal on March 1.

The team examined bacteria living on the surfaces of long filament-like structures called hyphae, which the fungi extend into the soil far from their host plant. On hyphae from two species of fungi, the team discovered highly similar bacterial communities whose composition was distinct from those in the surrounding soil.

"This tells us that, just like the human gut or plant roots, the hyphae of AM fungi have their own unique microbiomes," said Harrison, who is also an adjunct professor in Cornell University's School of Integrative Plant Science. "We're already testing a few interesting predictions as to what these bacteria might do, such as helping with phosphate acquisition."

"If we're right, then enriching the soil for some of these bacteria could increase crop yields and, ultimately, reduce the need for conventional fertilizers along with their associated costs and environmental impacts," she added.
Her co-researchers on the study were former BTI scientists Bryan Emmett and Véronique Lévesque-Tremblay.

Among the fungi

In the study, the team used two species of AM fungi, Glomus versiforme and Rhizophagus irregularis, and grew them in three different types of soil in symbiosis with Brachypodium distachyon, a grass species related to wheat. After letting the fungus grow with the grass for up to 65 days, the researchers used gene sequencing to identify bacteria sticking to the hyphae surfaces.

The team found remarkable consistency in the makeup of bacterial communities from the two fungal species. Those communities were similar in all three soil types, but very different from those found in soil away from the filaments.
The function of these bacteria is not yet clear, but their composition has already sparked some interesting possibilities, Harrison said.

"We predict that some of these bacteria liberate phosphorus ions in the immediate vicinity of the filaments, giving the fungus the best chance to capture those ions," Harrison said. "Learning which bacteria have this function could be key to enhancing the fungi's phosphate acquisition process to benefit plants."

Harrison's group is investigating the factors that control which bacteria assemble on the filaments. Harrison thinks the AM fungi may secrete molecules that attract these bacteria, and in turn, the bacterial communities may influence which molecules the fungus secretes.

Highway patrol

Among the hyphae microbiomes were members of Myxococcales and other taxa that include "bacterial predators" that kill and eat other bacteria by causing them to burst and release their contents.

These predators move by gliding along surfaces so "the fungal filaments could serve as linear feeding lanes," said Emmett, who is currently a research microbiologist for the U.S. Department of Agriculture's Agricultural Research Service in Ames, Iowa. "Many soil bacteria appear to travel along fungal hyphae in soil, and these predators may make it a more perilous journey."
While not every member of those taxa on the filaments may be predatory, Harrison's group plans to investigate how and why those putative predators assemble there. "It's possible that the actions of predatory bacteria make mineral nutrients available to everyone in the surrounding soil - predators and fungi alike," she said.

Infectious diseases are a leading cause of global mortality. During an infection, bacteria experience many different stresses -- some from the host itself, some from co-colonizing microbes and others from therapies employed to treat the infection. In this arms race to outwit their competition, bacteria have evolved mechanisms to stay alive in the face of adversities. One such mechanism is the stringent response pathway. Understanding how the activation of the stringent response pathway is controlled can provide clues to treat infection.

In new research published this week online in the journal Proceedings of the National Academy of Sciences, former Carnegie Mellon University graduate student Surya D. Aggarwal and his advisor, Associate Professor of Biological Sciences Luisa Hiller, observed that the deletion of a gene involved in surface remodeling caused a stress-dependent growth defect in a human pathogen that could not easily be explained. Deciphering the biological mechanism underlying this defect led to an international collaboration between Carnegie Mellon, the Universidade NOVA de Lisboa (Portugal) and the University of Warwick (UK). The joint effort combined the Carnegie Mellon team's expertise in pathogenesis with that of Assistant Professor Sergio Filipe of the Universidade NOVA de Lisboa and the University of Warwick Associate Professor Adrian Lloyd's work in the composition and biosynthesis of bacterial cell walls and associated biochemical processes.

"This has been one of the most fun and exciting projects in my career," said Hiller.

The joint project established that transfer RNAs (tRNAs) serve as a crucial component in the control of the activation of the stringent response pathway. tRNAs play a critical role in translation: they help to decode the genetic information into amino acids, the building blocks of proteins.

However, sometimes they can make a mistake, where the tRNA carrier and the amino acid building block are mismatched, rendering the combination toxic. In stressful conditions, tRNAs make more errors and accumulation of these errors is a trigger for the stringent response. This biological process is akin to the malfunction of a machine in an assembly line that results in flaws in the final manufactured product.

Many bacteria display a thick cell wall on their surface. Amino acids are a key component of this structure, and this research revealed that a protein involved in the addition of amino acids to this cell wall, the MurM enzyme, displays a strong preference for the tRNA loaded with mismatched building blocks. By diverting these toxic blocks towards cell wall synthesis and away from translation, MurM serves as a quality control manager who ensures that the flow line remains error-free and the manufacturing process can continue unabated.

In the absence of MurM, cells under stress activate the stringent response more easily than the parental strain. These findings suggested that MurM serves as a gatekeeper of this stress response pathway.

"It is highly rewarding when suddenly intriguing observations are explained by a simple and clear model," Filipe said. "The proposal that the cell wall can be used to divert the accumulation of toxic compounds is quite exciting. I wonder what other surprises will come from the study of the bacterial cell surface".

"To explore this further, we drew parallels between the bacteria we study and other species that do not encode MurM", said Aggarwal, who is now a postdoctoral fellow at NYU Langone Medical Center. In most domains of life, including human cells, the pathological consequences of these toxic tRNAs are mitigated by AlaXp, an enzyme that also corrects the defect by decoupling the tRNA from the incorrectly coupled building block.

However, Streptococcus pneumoniae, the bacteria in this study, as well as multiple other bacteria with thick cell walls, do not encode AlaXp. Aggarwal adds, "We wanted to test whether artificially introducing an additional gatekeeper in the form of AlaXp to pneumococcal cellular machinery would allow the flow line to remain functional even in the absence of MurM. This line of investigation set us on a road to test whether the stress-dependent growth defects we observed were attributable to the protein's role in preventing accumulation of toxic tRNAs."

The validation was a joint effort. The research at CMU employed genetic tools to decouple the role of the MurM in the architecture of the cell wall from its role in correcting toxic carrier-building block pairs. The work at Warwick made use of biochemical tools to reveal the underlying processes that render MurM optimal to correct the toxic molecules, while studies in Lisbon captured how the correction activity of the MurM enzyme impacts cell wall architecture. To quote Lloyd: "This international consortium was able to focus disparate yet connected areas of expertise to determine how previously considered disparate areas of microbial biochemistry collaborate to enable a crucial pathogen to navigate the stresses it endures during infection. This work provides a step change in our understanding of the resilience of bacteria as they cause infection."

The study suggests that MurM is an alternative evolutionary solution to the challenge of these toxic tRNAs. These findings implicate cell wall synthesis in the survival of bacteria as they encounter unpredictable and hostile conditions in the host. The association between cell wall synthesis and translational fidelity is likely to be active in many other pathogens, implicating these findings in the biology of many other pathogens.

This collaborative work sets the framework for future work exploring the molecular connection between two fundamental cell processes, translation and cell wall synthesis, and stress responses. Moreover, the pivotal position of the stringent response in survival to stresses and to antibiotics, suggests these findings will also shed light on pathways associated with bacterial drug resistance, a major challenge for this century.

James McKerrow, MD, PhD, dean of the Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego, has long studied neglected tropical diseases -- chronic and disabling parasitic infections that primarily affect poor and underserved communities in developing nations. They're called "neglected" because there is little financial incentive for pharmaceutical companies to develop therapies for them.

One of these neglected diseases is Chagas disease, the leading cause of heart failure in Latin America, which is spread by "kissing bugs" carrying the parasite Trypanosoma cruzi. These parasites produce an enzyme called cruzain that helps them replicate and evade the human immune system. McKerrow's research team looks for inhibitors of cruzain -- small molecules that might form the basis for new anti-parasitic medicines. One particularly effective cruzain inhibitor is called K777.

Then, in the spring of 2020, the COVID-19 pandemic began to sweep through the United States. Researchers quickly reported that SARS-CoV-2, the coronavirus that causes COVID-19, can't dock on and infect human cells unless a human enzyme called cathepsin L cleaves the virus' spike protein.

And it just so happens that cathepsin L looks and acts a lot like cruzain.

In a study published March 31, 2021 by ACS Chemical Biology, McKerrow and team show that low concentrations of K777 inhibit cathepsin L can reduce SARS-CoV-2's ability to infect four host cell lines, without harming the cells.

"Since K777 inhibits a human enzyme, not the virus itself, it's our hope that it's less likely the virus will evolve resistance against it," said McKerrow, co-senior author of the study with Thomas Meek, PhD, of Texas A&M University.

K777 wasn't equally effective in all cell lines. That's likely because not all cell lines produced the same amount of cathepsin L or the same amount of ACE2, the host cell receptor that the virus' spike protein uses to latch onto cells after it's cleaved by cathepsin L. The inhibitor was best at preventing SARS-CoV-2 infection in the cells that produced the most cathepsin L and ACE2.

The cell lines tested were derived from African green monkey kidney epithelium, human cervical epithelium and two types of human lung epithelium. While an important research tool, cell lines such as these are not necessarily representative of patients. They are easy to grow and manipulate in research laboratories because they are cancer cells, but that also means their molecular features likely differ from the average person's healthy lung or cervical cells.

"We were surprised at just how effective K777 is in blocking viral infection in the lab," McKerrow said. "Yet under usual circumstances it would be impractical and unlikely that we ourselves would be able to move the compound so quickly into clinical trials. We're fortunate that an 'entrepreneur-in-residence' program here at UC San Diego has helped bridge that gap."

Selva Therapeutics, a privately held biotechnology company, has licensed K777 from UC San Diego. In parallel with this study, the company has also found that the experimental therapeutic prevented lung damage in COVID-19 animal models and was well-tolerated by people who participated in a Phase I clinical trial to assess safety. Selva is planning a Phase IIa clinical trial in non-hospitalized COVID-19 patients for late 2021.

Many people with COVID-19 experience mild disease and can recover at home with supportive care to help relieve their symptoms. Currently, severe cases of COVID-19 may be treated with the antiviral drug remdesivir, approved by the U.S. Food and Drug Administration (FDA) for use in hospitalized patients, or a medication that has received emergency use authorization from the FDA, such as monoclonal antibodies. Worldwide, more than 124 million people have been diagnosed with COVID-19 and 2.72 million have died from the infection.

A novel mechanism has been identified that might explain why a rare mutation is associated with familial Alzheimer's disease in a new study by investigators at the University of Chicago. The paper, published on April 2 in the Journal of Experimental Medicine, characterizes a mutation located in a genetic region that was not previously thought be pathogenic, upending assumptions about what kinds of mutations can be associated with Alzheimer's Disease.

Alzheimer's, a neurodegenerative disease that currently affects more than 6 million Americans, has been characterized by the accumulation of A? peptides into plaques in the spaces between neurons in the brain. These A? peptides are generated when a larger precursor protein, APP, is cleaved into smaller fragments as APP transits through different cellular compartments.

Most mutations that have previously been associated with Alzheimer's lie either within or just next to a region of the APP gene that codes for the eventual A? peptide fragment. However, while the mutation studied by the research team is located in the APP gene, itis quite far from the area where previously characterized mutations are found. The mutation, S198P, was first found in two patients affected by Alzheimer's, and raised eyebrows due to its distance from known disease-associate mutations.

"This mutation, which is not in the region of APP that codes for the A? fragment, was so interesting because it was so far away from where all the other mutations are normally located," said senior author Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago, "Thus it was not clear how this mutation might be contributing to the pathology of the disease."

The investigators, led by Xulun Zhang, Ph.D., a Research Professional in the Sisodia lab, examined how S198P could affect A? peptide production by studying both cultured cells and mice. They found that the presence of the S198P mutation resulted in both cultured cells and mice having elevated levels of A? peptides. To further understand why S198P caused elevated A? levels, the authors looked at different steps of the APP-to-A? production pipeline.

Using cultured cells, the authors found that S198P causes APP to fold more quickly, allowing A? peptides to be produced from mature APP more quickly than from APP that did not contain the S198P mutation. "The rapid folding enhances the egress of APP through the cellular compartments where A? is made, allowing faster production of the A? peptide" said Sisodia. Mice harboring S198P also had more plaques causes by A? accumulation, reinforcing the likelihood that the mutation does indeed contribute to disease.

However, like with many other mutations, the presence of S198P is not a guarantee that Alzheimer's will develop. "This variant is only partially penetrant," said Sisodia, meaning that not every person with S198P will go on to develop Alzheimer's. Similar to mutations in the breast cancer genes BRCA1/2, S198P influences only the probability that an affected person will develop Alzheimer's.

"Geneticists would argue that this is not a pathogenic mutation because you can find this mutation in unaffected people, but this is a complex disease and studying these rare variants uncovers new biology," said Sisodia.

The fact that S198P is located so far away from previously characterized mutations underscores that there is much to still be understood about Alzheimer's. "A lot of mutations that have been described for the past 20 years have been dismissed because they don't look like they follow the normal rules. We need to pay attention to these rare variants because they open up new areas of investigation to completely decipher this disease," said Sisodia.

Though effective treatments for Alzheimer's still remain in development, Sisodia believes his group's findings argue for a renewed focus on A? peptides. "Failures in clinical trials have led some people to think that maybe A? has nothing to do with this disease, but these results clearly support a role for A? in disease pathogenesis. I hope this revives people's notions about the importance of A? in Alzheimer's."

The identification of S198P's mechanism has led Sisodia to plan to go back to other overlooked mutations and investigate them as well. "There are all these other rare variants that were seemingly benign according to other people, but we know from clinical studies that they too drive Alzheimer's pathology and clinical phenotypes," said Sisodia. "We figured out S198P, great! Now let's move on to all these other variants!"

In a new study, researchers identify three clinical COVID-19 phenotypes, reflecting patient populations with different comorbidities, complications and clinical outcomes. The three phenotypes are described in a paper published this week in the open-access journal PLOS ONE 1st authors Elizabeth Lusczek and Nicholas Ingraham of University of Minnesota Medical School, US, and colleagues.

COVID-19 has infected more than 18 million people and led to more than 700,000 deaths around the world. Emergency department presentation varies widely, suggesting that distinct clinical phenotypes exist and, importantly, that these distinct phenotypic presentations may respond differently to treatment.

In the new study, researchers analyzed electronic health records (EHRs) from 14 hospitals in the midwestern United States and from 60 primary care clinics in the state of Minnesota. Data were available for 7,538 patients with PCR-confirmed COVID-19 between March 7 and August 25, 2020; 1,022 of these patients required hospital admission and were included in the study. Data on each patient included comorbidities, medications, lab values, clinic visits, hospital admission information, and patient demographics.

Most patients included in the study (613 patients, or 60 percent) presented with what the researchers dubbed "phenotype II." 236 patients (23.1 percent) presented with "phenotype I," or the "Adverse phenotype," which was associated with the worst clinical outcomes; these patients had the highest level of hematologic, renal and cardiac comorbidities (all p

The authors conclude that phenotype-specific medical care could improve COVID-19 outcomes, and suggest that future research is needed to determine the utility of these findings in clinical practice.

The authors add: "Patients do not suffer from COVID-19 in a uniform matter. By identifying similarly affected groups, we not only improve our understanding of the disease process, but this enables us to precisely target future interventions to the highest risk patients."

PHILADELPHIA - A team led by scientists in the Perelman School of Medicine at the University of Pennsylvania has identified nine potential new COVID-19 treatments, including three that are already approved by the Food and Drug Administration (FDA) for treating other diseases.

The team, whose findings were published in Cell Reports, screened thousands of existing drugs and drug-like molecules for their ability to inhibit the replication of the COVID-19-causing coronavirus, SARS-CoV-2. In contrast to many prior studies, the screens tested the molecules for anti-coronaviral activity in a variety of cell types, including human airway-lining cells that are similar to the ones principally affected in COVID-19.

Of the nine drugs found to reduce SARS-CoV-2 replication in respiratory cells, three already have FDA approval: the transplant-rejection drug cyclosporine, the cancer drug dacomitinib, and the antibiotic salinomycin. These could be rapidly tested in human volunteers and COVID-19 patients.

The experiments also shed light on key processes the coronavirus uses to infect different cells and found that the antiviral drug remdesivir, which has an FDA Emergency Use Authorization for treating COVID-19, does appear to work against the virus in cell-culture tests on respiratory cells, whereas hydroxychloroquine does not.

"Our discoveries here suggest new avenues for therapeutic interventions against COVID-19, and also underscore the importance of testing candidate drugs in respiratory cells," said co-senior author Sara Cherry, PhD, a professor of Pathology and Laboratory Medicine and scientific director of the High-Throughput Screening (HTS) Core at Penn Medicine.

Study collaborators included co-senior authors David Schultz, PhD, technical director of the HTS Core, and Holly Ramage, PhD, assistant professor of microbiology & immunology at Thomas Jefferson University.

Although great progress has been made in the development of vaccines and treatments for the SARS-CoV-2 coronavirus, there is still much room for improvement. In the United States, the only antiviral COVID-19 treatments that have received FDA Emergency Use Authorization -- remdesivir and several anti-SARS-CoV-2 antibody preparations -- are expensive and far from 100 percent effective.

For their screening project, Cherry and colleagues assembled a library of 3,059 compounds, including about 1,000 FDA-approved drugs and more than 2,000 drug-like molecules that have shown activity against defined biological targets. They then tested all of these for their ability to significantly inhibit SARS-CoV-2 replication in infected cells, without causing much toxicity.

Initially, they performed antiviral screens using cell types they could grow easily in the lab and infect with SARS-CoV-2, namely African Green Monkey kidney cells, and a cell line derived from human liver cells. With these screens, they identified and validated several compounds that worked in the monkey kidney cells, and 23 that worked in the human liver cells. Hydroxychloroquine, which is used as a malaria drug, and remdesivir, were effective in both cell types.

Since SARS-CoV-2 is mainly a respiratory virus and is thought to initiate infections via airway-lining cells, the researchers sought a respiratory cell type that they could infect experimentally with the virus. They eventually identified a suitable cell line, Calu-3, that is derived from human airway-lining cells. They used these respiratory-derived cells to test the antiviral compounds identified through the human liver cell screen, and found that only nine had activity in the new cells. The nine did not include hydroxychloroquine. (Remdesivir worked in the Calu-3 cells but was not included in the list because it is already in use against COVID-19.)

By identifying different sets of drugs that work in different cell types, the researchers also shed light on the mechanisms SARS-CoV-2 uses to gain entry to cells. The findings suggest that in kidney and liver cells, the virus uses a mechanism that can be disrupted, for example, by hydroxychloroquine; yet the virus appears to use a different mechanism in respiratory cells, thus explaining hydroxychloroquine's lack of success in those cells -- and in COVID-19 clinical trials.

The nine antivirals active in respiratory cells did include salinomycin, a veterinary antibiotic that is also being investigated as an anticancer drug; the kinase enzyme inhibitor dacomitinib, an anticancer drug; bemcentinib, another kinase inhibitor now being tested against cancers; the antihistamine drug ebastine; and cyclosporine, an immune suppressing drug commonly used to prevent the immune rejection of transplanted organs.

The study highlights cyclosporine as particularly promising, as it appears to works against SARS-CoV-2 in respiratory and non-respiratory cells, and via two distinct mechanisms: inhibiting cell enzymes called cyclophilins, which the coronavirus hijacks to support itself, and suppressing the potentially lethal inflammation of severe COVID-19.

"There may be important benefits to the use of cyclosporine in hospitalized COVID-19 patients, and ongoing clinical trials at Penn and elsewhere are testing that hypothesis," Cherry said.

Within southeast Michigan's Middle Eastern and North African community, those who worry about deportation or believe they've been treated unfairly are likely to face more adverse conditions associated with poor health, including food insecurity and financial distress.

The MENA people who face several of these barriers are also more likely to report chronic illness and mental health issues as well as worse overall health.

That's according to a new study by the University of Michigan Rogel Cancer Center, the University of Michigan School of Public Health, and the Arab Community Center for Economic and Social Services.

"There are numerous health disparities for the MENA community that are not that different from other racial and ethnic groups where we're trying to close the gap," says Minal R. Patel, Ph.D., M.P.H., an associate professor of health behavior and health education at the U-M School of Public Health and a member of the Rogel Cancer Center. "The data show us that this is an important population where we should be focusing our efforts to address health needs."

This is the latest in a series of papers based on data from an extensive survey designed to better understand the population within one of the geographic areas the Rogel Cancer Center aims to serve. The researchers paid special attention to MENA people because metro Detroit is home to one of the United States' largest MENA communities, with about 210,000 residents hailing from Lebanon, Egypt, Syria, Iraq, Yemen and other Arab countries.

Previous state surveys had revealed significant health disparities for the MENA population, similar to what Michigan's African-American and Hispanic groups experience. However, Patel and her research team knew more specific data was needed to determine MENA people's unmet health needs as well as the impact that discrimination has on their health.

Through questionnaires distributed in community venues -- including grocery stores, mosques, and health care clinics -- to about 400 people who identified as MENA, researchers found that almost 60% of respondents felt they had experienced discrimination. Close to half did not believe the government was trying to improve life for Arab-Americans. Although fewer people worried about deportation or thought they had been treated unfairly, those who did often faced more adverse conditions associated with poor health, such as food insecurity.

More unmet health needs were also found among people who were not born in the United States (58% of the study's sample); who had lived in America for fewer years; who spoke Arabic at home; and who were from Egypt, Syria, or Yemen -- countries with unstable political environments and high poverty rates.

Public health researchers and media outlets alike have previously called attention to the physical and mental toll of immigration-related concerns on Latino immigrants. Patel says this data illustrates how the MENA people fit into that discussion.

"We were able to highlight that even though we don't share a border with a Middle Eastern country, we still have a sizeable population right next door to us that have concerns about immigration," Patel says. "This is another community where we can bring in that national conversation and think about how it is specifically impacting health."

Among risk factors that limit optimal health in the MENA population, transportation issues for health care visits, food insecurity, and financial strain were the most common, followed by unemployment and unstable housing.

Patel said she was surprised at the prevalence of food insecurity in particular given the number of grocery stores and restaurants in areas with large concentrations of the MENA population.

"When you drive through Dearborn, where much of the survey took place, it doesn't look like the makeup of your typical food desert," Patel says. "So we need to unpack that. Food insecurity is multidimensional, and the availability of food is only one component."

Overall, experiencing more risk factors for poor health, e.g., food insecurity and unemployment and unstable housing, was linked with more chronic diseases, including cancer, diabetes, high blood pressure, depression and heart conditions. In addition, mental health and general health were poorer for the people who faced multiple societal conditions that limit optimal health.

This survey was conducted in 2019, and Patel says all the issues discussed have likely worsened for the MENA community since then due to the increased stressors of the pandemic.

Washington, April 2, 2021--The Organisation for Economic Co-operation and Development (OECD) will release a new PISA report on student growth mindset on Thursday, April 8 at 5:00 a.m. ET, followed by a press conference held in collaboration with the American Educational Research Association (AERA) and the Yidan Prize Foundation at 10:30 a.m. ET.

The new report "Sky's the limit: Growth mindset, students, and schools in PISA" provides analyses on student growth mindset, a concept much discussed in the current field of psychology. Growth mindset is the belief that someone's ability and intelligence can be developed over time. PISA collected international comparable data on "growth mindset" from nearly 80 countries/economies for the first time in 2018. The report sheds lights on how educators, policy makers and researchers can further support the potential of students around the world.

Edward Ma (Yidan Prize Foundation), Carol Dweck (Stanford University), and Andreas Schleicher (OECD) will open the press conference to discuss the findings, which will be followed by Q&A with reporters, moderated by Tony Pals (AERA) on April 8, 10:30 - 11:30 a.m. ET. This event is organized as a part of the 2021 AERA Virtual Annual Meeting.

Waiting for your turn can be frustrating, especially when it comes to COVID-19 vaccinations. But prioritizing who receives the limited supply of vaccines available saves lives and reduces spread of infection, according to a study published today in the journal PNAS from the University of California, Davis.

While there is mostly universal agreement that older people should be prioritized, debates are currently underway about prioritizing a variety of other groups. Still others argue against targeting at all.

"Prioritization has benefits because people differ in at least two key ways -- their risk of infection and the likelihood of serious consequences from infection," said senior author Michael Springborn, a UC Davis professor in the Department Environmental Studies and an economist focused on environmental risk, including infectious disease. "We know that front-line essential workers have less capacity to socially distance and thus an elevated risk, while seniors are more seriously impacted by infection. Accounting for this substantially increases the benefits of vaccination."

For the study, the researchers modeled COVID-19 transmission rates and the optimal allocation of an initially limited vaccine supply in the U.S. under a variety of scenarios. They found that deaths, years of life lost and infections were between 17 to 44 percent lower when vaccinations targeted vulnerable populations -- particularly seniors and essential workers -- rather than an alternative approach where everyone is equally likely to be vaccinated.

"We also found that in regions where there was a faster increase in infections, and where there is less masking and social distancing occurring, targeting was even more important in avoiding those outcomes," said lead author Jack Buckner, a Ph.D. candidate in the UC Davis Graduate Group in Ecology.

ESSENTIAL CONSIDERATIONS

Building on the standard approach in modeling analyses to account for age groups, the study is the first to include front-line essential workers as their own category. In doing so, the researchers identified that such workers should be a vaccination priority along with or shortly after seniors. Policies that target based on both age and essential worker status substantially outperformed those that consider age only.

Prioritizing essential workers versus seniors depends on the conditions. For instance, when there is a good supply of effective vaccines and the outbreak is relatively under control, targeting essential workers first to help reduce overall spread can be ideal. But if vaccine supply is limited and cases and deaths are surging, targeting seniors and the most vulnerable directly may be the better strategy.

Previous studies have assumed that a given prioritization strategy remains constant over time. This study uniquely allows for prioritization to evolve as conditions change, such as when more people in certain groups become vaccinated.

"There is a substantial value to prioritization, at least for the first few months of the vaccine rollout," Springborn said.

"Once a large proportion of the most vulnerable people or the most likely to be exposed have been vaccinated, it becomes less important who gets it," said Buckner.

STILL MUCH TO LEARN

The authors say that while the scientific community and public have learned a lot about SARS-CoV-2, the virus that causes COVID-19, there are still many uncertainties to address. This includes how well vaccines impede transmission, how much individuals will relax their protective measures as vaccinations progress, and how durable immunity will be given the rise of new variants.

The authors took a general approach that is adaptable for future disease outbreaks.

"The analytic approach put forward in this study to assess the optimal dynamic allocation of vaccines adds to the methodological toolkit with applications beyond the COVID-19 pandemic," said study author Gerardo Chowell, a professor of epidemiology and biostatistics at Georgia State University.

DEPRIVATION among society at large is 'driving' Covid-19 disparities among minority ethnic groups - predominantly South Asian and Black African or Caribbean populations - and could be considered the main cause of disproportionate infection rates, hospitalisation and deaths experienced by these populations, according to new analysis from the University of Leicester.

The study, supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) comes a day after a government-commissioned review concluded race and racism have become less important factors in explaining social disparities in the UK.

Researchers at the University of Leicester used UK Biobank data of 407,830 South Asian, Black and White individuals to model a hypothetical intervention whereby 50 per cent of the general population were lifted out of material deprivation status (the 'grade' of deprivation was measured by the highly regarded Townsend score that is made up of four domains: unemployment, non-car ownership, non-home ownership and household overcrowding).

By moving the 50 per cent most deprived in the general population sample out of material deprivation, over 80 per cent of the extra, 'excess' risk of Covid-19 outcomes for South Asian and Black populations was eliminated.

Even just by moving 25 per cent of the sample out of deprivation, between 40-50 per cent of additional risk to South Asian and Black populations was alleviated.

The striking results of this large, unprecedented analysis dispute several existing studies, some of which maintain that poorer health among ethnic minority populations could be the driving factor for Covid-19 disparities.

Cameron Razieh, Lead author of the analysis and Epidemiologist at the University of Leicester specialises in ethnic minority health conditions. He explains:-

"The method of analysis we used in this study upholds that inequalities in health or health behaviours in people living with high deprivation are, in the most part, the result of the high deprivation itself.

"If we take this as truth, then we can conclude that high levels of deprivation are helping drive Covid-19 ethnic disparities. Reducing deprivation within the whole population could therefore play a pivotal role in reducing ethnic inequalities in Covid-19 outcomes observed in South Asian and Black communities."

Professor Kamlesh Khunti, joint senior author of the study who also works as Director of the UK NIHRApplied Research CollaborationsEast Midlands (ARC EM) said:-

"Material deprivation is a universal underpinning determinant of health inequalities within and between populations.

"Quantifying the extent to which material deprivation reduces risk is important but even more imperative is to now ask how we can reduce social inequality and increase social mobility.

"There is a rapidly closing window to use research evidence such as this to give those most in need a fighting chance to better manage their health."

Joint senior author Tom Yates, Professor of physical activity, sedentary behaviour and health at the University of Leicester added:-

"The data from this study calls for improved assistance to be provided to the poorest communities.

"In what we hope is the final stretch of this pandemic we must now pull together - backed by research - to ensure that for those most at risk of Covid-19 outcomes, there is still light at the end of this very long tunnel.

"History may judge harshly if we do not get this right despite the evidence elucidated."