Culture

Since the beginning of the coronavirus pandemic, scientists and physicians worldwide undertook enormous efforts to understand the disease caused by the virus. In their latest collaborative study, researchers from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and physicians from the University of Freiburg Medical Center unveil a novel feature of COVID-19 immunity, which could have implications for future therapies. The study points to the involvement of Interleukin 33, an important danger signal, when immune cells encounter Sars-CoV-2 for a second time.

"We started the study at a very early stage of the pandemic in 2020 when not much was known about the immune response post-infection", says Erika Pearce, group leader at the Max Planck Institute of Immunobiology and Epigenetics. "Our aim was to examine the development of immunity in people recovering from Covid-19."

Antibodies stick around

An infection with Sars-CoV-2 triggers a complex immune response necessary for the development of immunity to the virus. In simple terms, two linked branches of our immune system need to remember the virus to prevent reinfection, namely antibody-producing B cells and memory T cells. Understanding how this happens in Sars-CoV-2 infection is key for controlling the Covid-19 pandemic and critical for the success of the vaccination efforts.

For the study, the team examined blood samples of 155 individuals who mostly had mild disease. They measured the amount of antibodies against the SARS-CoV-2 spike protein and found that patients maintain high levels of antibodies more than two months after infection, indicating that they will likely be protected from re-infection. "We thought this was very encouraging, but we also wanted to understand better how the immune system would react to a second encounter with the virus," says Petya Apostolova, physician and researcher in the lab of Erika Pearce.

When the virus hits the second time

Effective immunity to a virus is reached when sufficient antibodies and memory T cells are present in the blood of a person who has recovered from the disease or has been vaccinated. To test how this happens after Covid-19, the team exposed blood cells from participants who had antibodies against Sars-CoV-2 to a portion of the virus. They observed that memory T cells had developed and quickly responded to viral proteins. "We measured a broad panel of molecules that our immune cells use to communicate with each other. It was most fascinating to us that of all these measurements, the amount of Interleukin 33 was the closest match to the amount of antibodies people had, and to the activation of their memory T cells," explains Apostolova. Interleukin 33 (IL-33) is released by cells that sense danger in their environment and has been previously linked to chronic lung disease. IL-33 can have beneficial effects by activating T cells and inducing antibody production, but it can also promote inflammation of the lung. For the first time, this study has linked IL-33 production to immunity to Sars-CoV-2.

"We believe that Interleukin 33, which is normally produced as an alarm-signal, could be an important link between protection and disease severity," says Cornelius Waller from the University of Freiburg Medical Center. Indeed, by analyzing public data of lung cells taken from patients during Sars-CoV-2 infection, the researchers were able to show that Interleukin 33 was produced in their lungs. However, identifying the implications of these findings also in the context of lung tissue damage after severe Covid-19 infections will require more investigation.

The group of researchers hopes this collaboration will continue. As Waller pointed out, "we were able to discover this much so quickly through this fantastic synergy between clinicians experienced in the care for Covid-19 patients and experts in the immunology field." The researchers hope that this study might pave the way to better understanding immunity to Sars-CoV-2 and other viral infections.

An international group of scientists led by the RIKEN Cluster for Pioneering Research have studied the chemical composition of 50 protoplanetary-disk forming regions in the Perseus Molecular Cloud, and found that despite being in the same cloud, the amounts of complex organic molecules they contain are quite different. Interestingly, the chemically rich young disks have similar compositions of organic molecules. These findings raise an important question: do solar-like systems share a common chemistry at birth?

It was once believed that complex organic molecules were rare in the universe, and that this rarity might be a reason we have not found evidence of life outside the earth. However, in the last two decades it has become clear that these molecules are common. According to Yao-Lun Yang, who led the research as a member of the Star and Planet Formation Laboratory in the RIKEN Cluster for Pioneering Research, and is now at the University of Virginia as a VICO Origins postdoctoral fellow, "Today, scientists have begun to systematically survey protoplanetary disks--disks where planets eventually form around a star--in the hope of determining how these molecules form, how common they are, and what impact they have on planetary systems."

Though scientists have looked at individual systems, there is little comparative data to understand these young stars as a group. The RIKEN-led group decided to use observations from the ALMA observatory in Chile, which thanks to its high resolution allows scientists to study chemical compounds in protoplanetary disks. The observations required more than three years to complete.

The group surveyed the emission from organic molecules at specific frequencies in very young disks. They looked at methanol and acetonitrile, as well as two larger molecules, methyl formate and dimethyl ether. They found that different regions had large variation in the abundance of methanol and acetonitrile, though intriguingly, the relative abundance between the two species was remarkably similar. According to Yang, "This implies that there is a common production mechanism of these two molecules, and this give us important hints on how they form in space." In addition, the abundances of methyl formate and dimethyl ether tended to be higher relative to methanol in denser regions, hinting that there is something about the denser conditions that allows them to be abundant. Their findings were published by the American Astronomical Society last week in The Astrophysical Journal.

According to Nami Sakai, leader of the Star and Planet Formation Laboratory, "This raises important questions regarding how special the chemical environment of the infant Solar system is. We will be able to answer this question in the future by examining the chemical evolution of the gas surrounding young protostars. We hope that such knowledge will be a base for understanding the origin of life on the Earth.

The unpopular guests are already here. Hazel-, alder- and elm tree pollen sweep in over us during the early spring months, with birch pollen following in May. Then grass follows in June-July before mugwort pollen closes the season in late summer. All leading to more and more people suffering.

Over fifty years, the proportion of young Danes who sneeze, rub itchy eyes or suffer a blocked nose because of pollen has grown from 7-8 per cent in the 1970s to 24 per cent today. And for asthma, the proportion has risen from 4 to 12 per cent during the same period. This is shown by a study of 53,000 Danish blood donors published by researchers from Aarhus University in collaboration with the Blood Bank at Aarhus University Hospital.

The lead author of the study, Susan Mikkelsen, is a PhD student at the Department of Clinical Medicine and a medical specialist in clinical immunology. She points to how the large blood donor study combines questionnaires and blood samples with the possibility of many follow-up studies:

"In the newly published study, 53,000 blood donors from all over the country born in the period from the 1950s and up until the turn of the millennium, completed a questionnaire on a tablet while donating blood," says Susan Mikkelsen, who works as a medical doctor at Department of Clinical Immunology at Aarhus University Hospital while completing her PhD dissertation.

"The blood from 25,000 of the participants has also been examined for antibodies against nine selected allergens, ranging from different types of pollen to animal hair and dust mites. In medical language, we say that the test participants who react by forming antibodies are 'sensitised'," she explains.

The blood samples show that the proportion of sensitised donors increases with the number of allergic disorders. For example, the researchers can see that ninety per cent of those who indicate that they have both asthma and allergic reactions in the nose and eyes, form antibodies.

On the other hand, the proportion of sensitised is only half as large for donors who grew up on a farm with animals, where they are exposed to a range of bacteria, fungi and pollen that might be protective against hypersensitivity.

Susan Mikkelsen also points out that the newly published study, which has been published in Clinical and Translational Allergy, is a so-called conservative research result which cannot be accused of exaggerating the problem - it most likely downplays it. The blood donors are in fact not representative random sample of the Danish population, as they are healthier, in particular the oldest blood donors, due to the requirement that a donor must be 'healthy' to give blood.

"For us, this means that the severe asthmatics aren't included when we calculate the proportion of allergy sufferers, because they simply aren't allowed to give blood. When every fifth blood donor nevertheless ticks the box as allergic and every tenth as asthmatic, this of course tells something about how hay fever and asthma are today very common diseases," says Susan Mikkelsen.

The latter is co-author Torben Sigsgaard's area of expertise. He is professor at the Department of Public Health and acknowledges that we in the Western world are becoming increasingly allergic. This was demonstrated already 15 years ago, for example in the Danish "Glostrup"' studies and the European Respiratory studies.

"Nevertheless, the current study contributes with important knowledge. The study shows, for example, that there is probably some way to go until we in Denmark reach the ceiling for how many people can become allergy sufferers, as the curve doesn't appear to be flattening out as we've seen it do in Switzerland, for example," says Torben Sigsgaard with reference to a theory that there is a maximum limit for how many people in a particular population group will, under the wrong circumstances, develop allergies. The theory is that the Swiss have now reached this maximum, but the specifics remain unclear. Torben Sigsgaard also points out that hay fever and asthma can be severe disorders - even though they are relatively common in Denmark.

"For some young sufferers, hay fever means that they have trouble completing exams, because the pollen season coincides with summer exams. We also know that some people completely opt out of social activities when the allergy is worst, because they think it's too disgusting and inconvenient to have their eyes and nose constantly running," says Torben Sigsgaard, who has many years of experience in the research field.

He emphasises that the large biobank with blood samples allows researchers to continue working with genetic analyses or studies connected to air pollution.

"The uniqueness of the study is that we can examine the participants' blood for biomarkers and genetic markers and compare the findings with environmental impacts, follow-up questionnaire surveys and the Danish registers. This makes it possible to look at the significance of genetic-environmental interaction on allergy and sensitisation. In addition, the repeated blood samples from each participant make it possible to study the immune system before symptom onset in participants with newly developed allergic symptoms," says Susan Mikkelsen.

"We're extremely grateful for the blood donors' contribution to the study. They make their blood samples available for research and thus facilitate our studies," she says.

Electrical batteries are increasingly crucial in a variety of applications, from integration of intermittent energy sources with demand, to unlocking carbon-free power for the transportation sector through electric vehicles (EVs), trains and ships, to a host of advanced electronics and robotic applications.

A key challenge however is that batteries degrade quickly with operating conditions. It is currently difficult to estimate battery health without interrupting the operation of the battery or without going through a lengthy procedure of charge-discharge that requires specialised equipment.

In work recently published by Nature Machine Intelligence, researchers from the Smart Systems Group at Heriot-Watt University in Edinburgh, UK working together with researchers from the CALCE group at the University of Maryland in the US developed a new method to estimate battery health irrespective of operating conditions and battery design or chemistry, by feeding artificial intelligence (AI) algorithms with the raw battery voltage and current operational data.

Darius Roman, the PhD student that designed the AI framework said: "To date, the progress of data-driven models for battery degradation relies on the development of algorithms that carry out inference faster. Whilst researchers often spend a considerable amount of time on model or algorithm development, very few people take the time to understand the engineering context in which the algorithms are applied. By contrast, our work is built from the ground up. We first understand battery degradation through collaborations with the CALCE group at the University of Maryland, where in-house degradation testing of batteries was carried out. We then concentrate on the data, where we engineer features that capture battery degradation, we select the most important features and only then we deploy the AI techniques to estimate battery health."

In addition, the researchers found that current data-driven models for battery health estimation do not consider model confidence. However, this is often critical for decision making to understand how the AI model came to a certain conclusion and whether the model can be trusted. In their work, the proposed AI model is capable of quantifying uncertainty in its predictions to better support operating decisions.

The developed framework scales up with new chemistries, including the new upcoming solid-state batteries, battery designs and operating conditions and has the potential to unlock new strategies of how batteries can and should be used.

Valentin Robu, from the Smart Systems Group said: "Batteries are increasingly critical to a variety of applications, from robotics to renewable energy integration. A key challenge in these domains is having an accurate, high-confidence estimates of battery state of health. Consider for example, a robotic asset operating in a remote environment such as deep subsea monitoring, where assuring the health of the battery deployed on the robot is mission-critical. Similarly, for energy applications, having an accurate estimate of the remaining useful lifetime of the battery is often critical to a project's economic viability."

A tiny protein of SARS-CoV-2, the coronavirus that gives rise to COVID-19, may have big implications for future treatments, according to a team of Penn State researchers.

Using a novel toolkit of approaches, the scientists uncovered the first full structure of the Nucleocapsid (N) protein and discovered how antibodies from COVID-19 patients interact with that protein. They also determined that the structure appears similar across many coronaviruses, including recent COVID-19 variants -- making it an ideal target for advanced treatments and vaccines. They reported their results in Nanoscale.

"We discovered new features about the N protein structure that could have large implications in antibody testing and the long-term effects of all SARS-related pandemic viruses," said Deb Kelly, professor of biomedical engineering (BME), Huck Chair in Molecular Biophysics and director of the Penn State Center for Structural Oncology, who led the research. "Since it appears that the N protein is conserved across the variants of SARS-CoV-2 and SARS-CoV-1, therapeutics designed to target the N protein could potentially help knock out the harsher or lasting symptoms some people experience."

Most of the diagnostic tests and available vaccines for COVID-19 were designed based on a larger SARS-CoV-2 protein -- the Spike protein -- where the virus attaches to healthy cells to begin the invasion process.

The Pfizer/BioNTech and Moderna vaccines were designed to help recipients produce antibodies that protect against the Spike protein. However, Kelly said, the Spike protein can easily mutate, resulting in the variants that have emerged in the United Kingdom, South Africa, Brazil and across the United States.

Unlike the outer Spike protein, the N protein is encased in the virus, protected from environmental pressures that cause the Spike protein to change. In the blood, however, the N protein floats freely after it is released from infected cells. The free-roaming protein causes a strong immune response, leading to the production of protective antibodies. Most antibody-testing kits look for the N protein to determine if a person was previously infected with the virus -- as opposed to diagnostic tests that look for the Spike protein to determine if a person is currently infected.

"Everyone is looking at the Spike protein, and there are fewer studies being performed on the N protein," said Michael Casasanta, first author on the paper and a postdoctoral fellow in the Kelly laboratory. "There was this gap. We saw an opportunity -- we had the ideas and the resources to see what the N protein looks like."

Initially, the researchers examined the N protein sequences from humans, as well as different animals thought to be potential sources of the pandemic, such as bats, civets and pangolins. They all looked similar but distinctly different, according to Casasanta.

"The sequences can predict the structure of each of these N proteins, but you can't get all the information from a prediction -- you need to see the actual 3D structure," Casasanta said. "We converged the technology to see a new thing in a new way."

The researchers used an electron microscope to image both the N protein and the site on the N protein where antibodies bind, using serum from COVID-19 patients, and developed a 3D computer model of the structure. They found that the antibody binding site remained the same across every sample, making it a potential target to treat people with any of the known COVID-19 variants.

"If a therapeutic can be designed to target the N protein binding site, it might help reduce the inflammation and other lasting immune responses to COVID-19, especially in COVID long haulers," Kelly said, referring to people who experience COVID-19 symptoms for six weeks or longer.

The team procured purified N proteins, meaning the samples only contained N proteins, from RayBiotech Life and applied them to microchips developed in partnership with Protochips Inc. The microchips are made of silicon nitride, as opposed to a more traditional porous carbon, and they contain thin wells with special coatings that attract the N proteins to their surface. Once prepared, the samples were flash frozen and examined through cryo-electron microscopy.

Kelly credited her team's unique combination of microchips, thinner ice samples and Penn State's advanced electron microscopes outfitted with state-of-the-art detectors, customized from the company Direct Electron, for delivering the highest-resolution visualization of low-weight molecules from SARS-CoV-2 so far.

"The technology combined resulted in a unique finding," Kelly said. "Before, it was like trying to look at something frozen in the middle of the lake. Now, we're looking at it through an ice cube. We can see smaller entities with many more details and higher accuracy."

Since 2016, a federal regulation has allowed nurse practitioners and physician assistants to obtain a waiver to prescribe buprenorphine, a medication used to treat opioid use disorder as a medication assisted treatment.

But a recent study by Indiana University researchers found the bill, called the Comprehensive Addiction and Recovery Act (CARA), has not greatly increased the amount of nurse practitioners prescribing buprenorphine, especially in states that have further restrictions. The study was published in Medical Care Research and Review.

"Nurse practitioners and physician assistants are an important workforce with a capacity to expand treatment access for those with substance use disorders," said Kosali Simon, co-author of the study and a Herman B. Wells Endowed Professor in IU's O'Neill School of Public and Environmental Affairs. "But we have found that efforts like CARA have been limited in actually utilizing this group, with nurse practitioners accounting for a relatively small proportion of buprenorphine prescriptions."

Buprenorphine is the only agonist medication for opioid addiction that can be prescribed by a qualified physician or nonphysician practitioner in an office-based setting. Simon said research has shown it is associated with significant decreases in relapse and overdose. However, the U.S. has a shortage of providers who have a waiver, known as an X waiver, from the Drug Enforcement Administration to prescribe buprenorphine outside of opioid treatment programs.

Through the Comprehensive Addiction and Recovery Act nurse practitioners and physician assistants to prescribe buprenorphine to up to 30 patients at a time for their first year, and after that, they can obtain authorization to prescribe to up to 100 patients. Some states mandate further restrictions though, including those that limit the authority of nurse practitioners to prescribe.

Kosali and a team of researchers from various universities used pharmacy claims data between January 2015 and September 2018 from Optum's deidentified Clinformatics DataMart to examine the impact of federal and state scope-of-practice regulations on nurse practitioner's buprenorphine prescribing.

At the county-level, researchers found the proportion of patients filling prescriptions written by nurse practitioners was low even after CARA: 2.7% in states that did not require physician oversight of nurse practitioners and 1.1% in states that did. While analyses in rural counties showed higher rates of buprenorphine prescriptions written by nurse practitioners, the study found rates were still considerably low - 3.7% in states with less restrictive regulations and 1.1% in other states.

Simon said since relatively few physicians have a waiver to prescribe, it can be difficult for nurse practitioners who must have physician oversight to find a waivered physician to oversee them. Some also face supervising physicians who are unsupportive of buprenorphine treatment.

"These results indicate that less restrictive scope-of-practice regulations are associated with greater nurse practitioner prescribing following CARA," Simon said. "The small magnitude of the changes indicates that federal attempts to expand treatment access through CARA have been limited. More is needed so people with substance use disorder have access to medication assistant treatment."

While state restrictions did not help, the researchers said there are more deterrents involved including insufficient training and education about opioid use disorder treatment, burdensome training time, lack of institutional and clinician peer support, poor care coordination and inadequate insurance reimbursement.

Researchers recommend relaxing state scope-of-practice requirements for nurse practitioners and addressing other practice-level and educational barriers that impede treatment access. Additionally, Simon said eliminating the need for an X waiver for all practitioners should be further considered to help address gaps in opioid use disorder care, especially in primary care settings and rural areas. Alternatively, current X waiver training requirements could be decreased for certain clinicians, including nurse practitioners and physician assistants, who have previously completed substance use disorder treatment training during residency.

A clean energy future propelled by hydrogen fuel depends on figuring out how to reliably and efficiently split water. That's because, even though hydrogen is abundant, it must be derived from another substance that contains it -- and today, that substance is often methane gas. Scientists are seeking ways to isolate this energy-carrying element without using fossil fuels. That would pave the way for hydrogen-fueled cars, for example, that emit only water and warm air at the tailpipe.

Water, or H2O, unites hydrogen and oxygen. Hydrogen atoms in the form of molecular hydrogen must be separated out from this compound. That process depends on a key -- but often slow -- step: the oxygen evolution reaction (OER). The OER is what frees up molecular oxygen from water, and controlling this reaction is important not only to hydrogen production but a variety of chemical processes, including ones found in batteries.

"The oxygen evolution reaction is a part of so many processes, so the applicability here is quite broad." -- Pietro Papa Lopes, Argonne assistant scientist

A study led by scientists at the U.S. Department of Energy's (DOE) Argonne National Laboratory illuminates a shape-shifting quality in perovskite oxides, a promising type of material for speeding up the OER. Perovskite oxides encompass a range of compounds that all have a similar crystalline structure. They typically contain an alkaline earth metal or lanthanides such as La and Sr in the A-site, and a transition metal such as Co in the B-site, combined with oxygen in the formula ABO3. The research lends insight that could be used to design new materials not only for making renewable fuels but also storing energy.

Perovskite oxides can bring about the OER, and they are less expensive than precious metals such as iridium or ruthenium that also do the job. But perovskite oxides are not as active (in other words, efficient at accelerating the OER) as these metals, and they tend to slowly degrade.

"Understanding how these materials can be active and stable was a big driving force for us," said Pietro Papa Lopes, an assistant scientist in Argonne's Materials Science division who led the study. "We wanted to explore the relationship between these two properties and how that connects to the properties of the perovskite itself."

Previous research has focused on the bulk properties of perovskite materials and how those relate to the OER activity. The researchers wondered, however, whether there was more to the story. After all, the surface of a material, where it reacts with its surroundings, can be completely different from the rest. Examples like this are everywhere in nature: think of a halved avocado that quickly browns where it meets the air but remains green inside. For perovskite materials, a surface that becomes different from the bulk could have important implications for how we understand their properties.

In water electrolyzer systems, which split water into hydrogen and oxygen, perovskite oxides interact with an electrolyte made of water and special salt species, creating an interface that allows the device to operate. As electrical current is applied, that interface is critical in kicking off the water-splitting process. "The material's surface is the most important aspect of how the oxygen evolution reaction will proceed: How much voltage you need, and how much oxygen and hydrogen you're going to be producing," Lopes said.

Not only is the perovskite oxide's surface different from the rest of the material, it also changes over time. "Once it's in an electrochemical system, the perovskite surface evolves and turns into a thin, amorphous film," Lopes said. "It's never really the same as the material you start with."

The researchers combined theoretical calculations and experiments to determine how the surface of a perovskite material evolves during the OER. To do so with precision, they studied lanthanum cobalt oxide perovskite and tuned it by "doping" the lanthanum with strontium, a more reactive metal. The more strontium was added to the initial material, the faster its surface evolved and became active for the OER -- a process the researchers were able to observe at atomic resolution with transmission electron microscopy. The researchers found that strontium dissolution and oxygen loss from the perovskite were driving the formation of this amorphous surface layer, which was further explained by computational modelling performed using the Center for Nanoscale Materials, a DOE Office of Science User Facility.

"The last missing piece to understand why the perovskites were active towards the OER was to explore the role of small amounts of iron present in the electrolyte," Lopes said. The same group of researchers recently discovered that traces of iron can improve the OER on other amorphous oxide surfaces. Once they determined that a perovskite surface evolves into an amorphous oxide, then it became clear why iron was so important.

"Computational studies help scientists understand reaction mechanisms that involve both the perovskite surface and the electrolyte," said Peter Zapol, a physicist at Argonne and study co-author. "We focused on reaction mechanisms that drive both activity and stability trends in perovskite materials. This is not typically done in computational studies, which tend to focus solely on the reaction mechanisms responsible for the activity."

The study found that the perovskite oxide's surface evolved into a cobalt-rich amorphous film just a few nanometers thick. When iron was present in the electrolyte, the iron helped accelerate the OER, while the cobalt-rich film had a stabilizing effect on the iron, keeping it active at the surface.

The results suggest new potential strategies for designing perovskite materials -- one can imagine creating a two-layer system, Lopes said, that is even more stable and capable of promoting the OER.

"The OER is a part of so many processes, so the applicability here is quite broad," Lopes said. "Understanding the dynamics of materials and their effect on the surface processes is how we can make energy conversion and storage systems better, more efficient and affordable."

KEELE, UK, April 9, 2021 -- This study builds upon two earlier published studies (Mold et al., 2020, Journal of Alzheimer's Disease Reports) from the same group. The new data, also published in the Journal of Alzheimer's Disease Reports, demonstrate that aluminum is co-located with phosphorylated tau protein, present as tangles within neurons in the brains of early-onset or familial Alzheimer's disease (AD). "The presence of these tangles is associated with neuronal cell death, and observations of aluminum in these tangles may highlight a role for aluminum in their formation," explained lead investigator Matthew John Mold, PhD, Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK.

The earlier research highlighted widespread co-localization of aluminum and amyloid-β in brain tissue in familial AD. The researchers used a highly-selective method of immunolabelling in the current study, combined with aluminum-specific fluorescence microscopy. Phosphorylated tau in tangles co-located with aluminum in the brain tissue of the same cohort of Colombian donors with familial AD were identified. "It is of interest and perhaps significance with respect to aluminum's role in AD that its unequivocal association with tau is not as easily recognizable as with amyloid-β. There are many more aggregates of aluminum with amyloid-β than with tau in these tissues and the latter are predominantly intracellular," remarked co-author, Professor Christopher Exley.

Per Dr. George Perry, Editor-in-Chief of Journal of Alzheimer's Disease, "Aluminum accumulation has been associated with Alzheimer's disease for nearly half a century, but it is the meticulously specific studies of Drs. Mold and Exley that are defining the exact molecular interaction of aluminum and other multivalent metals that may be critical to formation of the pathology of Alzheimer's disease."

"The new data may suggest that the association of aluminum with extracellular senile plaques precedes that with intracellular aggregates of tau. These relationships with both amyloid-β and tau may account for the high levels of aluminum observed in the brain tissue of donors with familial AD versus those without a diagnosis of neurodegenerative disease," said Dr Mold. "Tau and amyloid-beta are known to act in synergy to produce neurotoxicity in AD and our data provide new evidence for a role of aluminum in this process".

A new study using human genetics suggests researchers should prioritize clinical trials of drugs that target two proteins to manage COVID-19 in its early stages.

The findings appeared online in the journal Nature Medicine in March 2021.

Based on their analyses, the researchers are calling for prioritizing clinical trials of drugs targeting the proteins IFNAR2 and ACE2. The goal is to identify existing drugs, either FDA-approved or in clinical development for other conditions, that can be repurposed for the early management of COVID-19. Doing so, they say, will help keep people with the virus from being hospitalized.

IFNAR2 is the target for approved drugs often used by patients with relapsing forms of the central nervous system disorder multiple sclerosis. The researchers believe the most promising ACE2 therapy against COVID-19 is a drug that was developed before the pandemic began and has been evaluated in clinical trials to reduce inflammatory response in patients with severe respiratory disorders.

Dr. Juan P. Casas, a physician epidemiologist at the Veterans Affairs Boston Healthcare System, led the study. The research included collaborators from the University of Cambridge and the European Bioinformatics Institute in England, and Istituto Italiano di Tecnologia in Italy.

"When we started this project early last summer, most COVID-19 trials were being done on hospitalized patients," Casas explains. "Very few treatments were being tested to give to patients early in the natural history of the disease. However, as the availability of testing against coronavirus increased, an opportunity opened to identify and treat COVID-19 patients before they progress to more severe forms that require hospitalization.

"The problem we tried to overcome," he adds, "is how to identify if existing drugs, either approved or in clinical development for other conditions, can be repurposed for the early management of COVID-19. Most commonly used strategies for drug repurposing are based on pre-clinical studies, such as experiments in cells or animal models. However, those types of studies may have problems of reproducibility or difficulties in translating their findings to humans. That usually leads to higher rates of failure in clinical trials."

Casas and his team used genetics as the starting point to identify drugs that can be repurposed for treating COVID-19. Large-scale human genetic studies have been widely used to inform drug development programs, with some research identifying COVID-19 drug targets.

"The reason we used human genetics is as follows," says Casas, who is also a faculty member at Harvard Medical School. "Given that more than 90% of drugs target a human protein encoded by a gene, the opportunity is there to use genetic variants within those druggable genes as instruments to anticipate the effects that drugs targeting the same protein will have. In other words, genetic studies that used variants within druggable genes can be conceived as natural randomized trials."

To put things into perspective, he refers to a gene that encodes a protein called PCSK9. The protein is the target of a class of drugs called PCSK9 inhibitors, which are used to lower cholesterol and prevent cardiovascular disease. Researchers discovered that class of drugs because of studies showing that people carrying a certain variant within the PCSK9 gene tend to have high levels of cholesterol and are at greater risk for cardiovascular disease.

"That kind of genetic study was pivotal to identify the PSCK9 protein as a target for drug discovery," Casas says. "It's known that drug targets with human genetic support have a least twice the odds of success compare to the targets without human genetic support."

Building on these known benefits of human genetics for drug discovery, Casas and his team set out to identify all genes that encode proteins that served as targets for FDA-approved drugs or drugs in clinical development. They called this set of 1,263 genes the "actionable druggable genome." The genes were from two large genetic datasets that totaled more than 7,500 hospitalized COVID-19 patients and more than 1 million COVID-free controls.

By comparing the genetic profiles of the hospitalized patients and the controls, and looking at which drugs target which genes, the researchers were able to pinpoint the drugs most likely to prevent severe cases of COVID-19 that require hospitalization.

The two datasets were VA's Million Veteran Program (MVP), one of the world's largest sources for health and genetic information, and the COVID-19 Host Genetics Initiative, a consortium of more than 1,000 scientists from over 50 countries working collaboratively to share data and ideas, recruit patients, and disseminate findings.

"This study gets to the heart of why we built MVP," says Dr. Sumitra Muralidhar, director of the Million Veteran Program. "It demonstrates the potential of MVP to discover new treatments, in this case for COVID-19."

ACE2 is highly relevant to COVID-19 because the coronavirus uses that protein to enter human cells. The most promising ACE2 therapy against COVID-19 is the drug APN01, which mimics the protein. The drug works by confusing the coronavirus so it attaches to the drug instead of the ACE2 protein in the human cell. Positive evidence is emerging from small clinical trials on the effectiveness of APN01 in COVID-19 patients, especially those that are hospitalized. "Hence, if our genetic findings are correct, there's a need to test this strategy in clinical trials in COVID-19 outpatients," Casas says.

The IFNAR2 protein serves as the target for a drug family known as type-I interferons, one of which is interferon beta. That drug is approved for treating patients with a degenerative form of multiple sclerosis, a chronic disease that attacks the central nervous system and disrupts the flow of information within the brain and between the brain and the body. The researchers showed that people with a certain variant of IFNAR2 had less chance of being hospitalized due to COVID-19, compared to people without the variant.

Currently, Casas is early into planning a clinical trial to test the efficiency and safety of interferon beta in COVID-19 outpatients in VA. If his genetic findings are confirmed by a trial, he says the goal would be to prescribe the drug after people are diagnosed with COVID-19 but before their conditions require hospitalization.

Casas sees a continued need for drugs to treat people in the early phase of COVID-19, despite the ongoing worldwide vaccination campaigns.

"This is largely due to two reasons," he says. "First, it will take some time to achieve the high levels of vaccine coverage needed to create herd immunity. In addition, certain coronavirus variants are emerging that seem to lead to a reduced vaccine efficiency. We are not yet in the clear."

PHILADELPHIA - Psychosocial stress - typically resulting from difficulty coping with challenging environments - may work synergistically to put women at significantly higher risk of developing coronary heart disease, according to a study by researchers at Drexel University's Dornsife School of Public Health, recently published in the Journal of the American Heart Association.

The study specifically suggests that the effects of job strain and social strain -- the negative aspect of social relationships -- on women is a powerful one-two punch. Together they are associated with a 21% higher risk of developing coronary heart disease. Job strain occurs when a woman has inadequate power in the workplace to respond to the job's demands and expectations.

The study also found that high-stress life events, such as a spouse's death, divorce/separation or physical or verbal abuse, as well as social strain, were each independently linked with a 12% and 9% higher risk of coronary heart disease, respectively.

The Drexel study used data from a nationally representative sample of 80,825 postmenopausal women from the Women's Health Initiative Observational Study, which tracked participants from 1991 to 2015, to find better methods of preventing cancer, heart disease and osteoporosis in women. In the current follow-up study, Drexel researchers evaluated the effect of psychosocial stress from job strain, stressful life events and social strain (through a survey), and associations among these forms of stress, on coronary heart disease.

Nearly 5% of the women developed coronary heart disease during the 14-year, seven-month study. Adjusting for age, time at a job, and socioeconomic characteristics, high-stress life events were associated with a 12% increased coronary heart disease risk, and high social strain was associated with a 9% increased risk of coronary heart disease. Work strain was not independently associated with coronary heart disease.

Coronary heart disease, the leading cause of death in the United States, occurs with the heart's arteries become narrow and cannot bring sufficient oxygenated blood to the heart. The latest work builds on earlier studies linking psychosocial stress to coronary heart disease by finding out how job strain and social strain work together to compound disease risk.

"The COVID-19 pandemic has highlighted ongoing stresses for women in balancing paid work and social stressors. We know from other studies that work strain may play a role in developing CHD, but now we can better pinpoint the combined impact of stress at work and at home on these poor health outcomes," said senior author Yvonne Michael, ScD, SM, an associate professor in the Dornsife School of Public Health. "My hope is that these findings are a call for better methods of monitoring stress in the workplace and remind us of the dual-burden working women face as a result of their unpaid work as caregivers at home ."

The study's authors say that future studies should look at the effects of shift work on coronary heart disease and explore the effects of job demands according to gender.

"Our findings are a critical reminder to women, and those who care about them, that the threat of stress to human health should not go ignored," said lead author Conglong Wang, PhD, a recent Dornsife graduate who conducted the research while at Drexel. "This is particularly pertinent during the stressors caused by a pandemic."

Children may not be as infectious in spreading SARS-CoV-2 to others as previously thought, according to new University of Manitoba-led research in CMAJ (Canadian Medical Association Journal).

"Our findings have important public health and clinical implications," writes principal investigator Dr. Jared Bullard, associate professor, pediatrics/child health and medical microbiology/infectious diseases, Max Rady College of Medicine, University of Manitoba and associate medical director, Cadham Provincial Laboratory in Winnipeg, Manitoba. "If younger children are less capable of transmitting infectious virus, daycare, in-person school and cautious extracurricular activities may be safe to continue, with appropriate precautions in place, and with lower risk to child care staff, educators and support staff than initially anticipated."

Fourteen researchers from multiple disciplines at the University of Manitoba, Cadham Provincial Laboratory, Manitoba Health and Seniors Care and the Public Health Agency of Canada's National Microbiology Laboratory analyzed samples from 175 children and 130 adults in Manitoba infected with SARS-CoV-2 to see if there was a difference in infectiousness. Using cell cultures of nasopharyngeal swabs, they investigated viral loads in both groups to determine if children were more infectious.

"As an increasing number of jurisdictions consider whether in-school learning, daycares and extracurricular activities should continue or resume, a better understanding of the relative contributions of children and adolescents to SARS-CoV-2 transmission, when compared with adults, is essential," the authors write. "This is particularly important given the increased likelihood of asymptomatic infection in this group."

Tick-borne encephalitis is a disease just as nasty as it sounds. Once bitten by an infected tick, some people develop flu-like symptoms that resolve quietly but leave behind rampant neurological disease--brain swelling, memory loss, and cognitive decline. Cases are on the rise in Central Europe and Russia with some 10,000 incidents reported each year. Vaccines can provide protection, but only for a limited time. There is no cure.  

Now a new study describes antibodies capable of neutralizing the virus transmitted by tick bites. These so-called broadly neutralizing antibodies have shown promise in preventing TBE in mice and could inform the development of better vaccines for humans. Further, preliminary results suggest that the antibodies may not only prevent tick-borne encephalitis but even treat the condition, as well as the related Powassan virus emerging in the United States. 

Lead author Marianna Agudelo and colleagues in the laboratory of Rockefeller's Michel C. Nussenzweig examined nearly 800 antibodies obtained from individuals who had recovered from TBE or had been vaccinated to prevent infection. The most potent antibodies, designated VH3-48, turned out to be best suited to fend off future infections. They found that VH3-48 neutralized lab-grown varieties of the TBE virus, as well other tick-borne illnesses including the Langat, Louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. 

The researchers also showed that these powerful antibodies are not common; in fact, most of the antibodies produced by humans exposed to TBE virus are of inferior quality, with the coveted VH3-48 antibodies making only occasional appearances. Moreover, vaccinated patients in the study did not manage to develop any VH3-48 antibodies at all. "You'd expect the most prevalent antibodies to be the absolute best, but that is not what we found in TBE," Agudelo says. "This may explain how the virus tricks the immune system, misdirecting it into producing inferior antibodies." 

The discovery of VH3-48 provides hope for a more effective TBE vaccine. Current vaccines require three doses spaced over two years and only provide about five years of protection before a booster shot is required. Next-generation vaccines built around coaxing the body into producing the rare VH3-48 antibody could be more potent, require fewer booster shots, and also prove protective against a number of tick-borne viruses.  

"A vaccine like this would not just be more elegant, but also better focused," says Michel C. Nussenzweig, the Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology at Rockefeller. "Now that we have the structures of these antibodies, we know what to target in order to design more effective vaccines." 

Broadly neutralizing antibodies may also provide the first specific treatment for TBE. Nussenzweig, Agudelo, and colleagues found that mice infected with TBE recover after receiving antibody therapy, although it remains to be seen if this finding will translate to humans.

"The next step is a clinical trial with the antibodies," Nussenzweig says, "perhaps in Europe where there are many cases, to see whether we can ameliorate the symptoms of those suffering from encephalitis."

The CDC recently declared racism as a threat to public health. But when it comes to dismantling white supremacy in public health, action must be taken beyond issuing statements declaring racism a public health crisis, says Sirry Alang, associate professor of sociology and health, medicine, and society at Lehigh University. A new analysis from Alang and colleagues examines the three core functions of public health -- assessment, policy development and assurance -- and the ten recently revised essential public health services (EPHSs) to offer strategies public health can follow to dismantle white supremacy.

The article, "White Supremacy and the Core Functions of Public Health," by Alang and colleagues from the University of Minnesota School of Public Health was published in the American Journal of Public Health.

The researchers found that public health has contributed to structural racism and white supremacy, mentioning that health surveillance systems do not routinely collect data on racism, schools of public health are disproportionately white, and that research led by Black scholars is less likely to be funded than research led by their white counterparts.

"Public health research evaluates variation in the accessibility, effectiveness, and quality of health services by race. But the impact of racism and white supremacy on these outcomes are often ignored," Alang said.

To combat these challenges, the researchers suggest actions to take in response to public health's essential public health services.

Assessment

Under assessment, public health professionals are tasked with assessing and monitoring population health status, factors that influence health, and community needs and assets. Additionally, they are to investigate, diagnose and address health problems and hazards affecting the population.

The researchers suggest public health professionals consider tracking and reporting respondents' exposures to and experiences of police brutality and other indicators of structural racism and white supremacy, as well as investigate the complex mechanisms through which white supremacy shapes health outcomes.

Policy Development

Under policy development, tasks include communicating effectively to inform and educate people about improving health, strengthening communities and partnerships to improve health, creating and implementing policies that affect health, and utilizing legal and regulatory actions designed to improve and protect health.

The researchers encourage public health professionals to take action by educating public and policymakers on indicators of white supremacy and how it affects health, ensure equitable allocation of resources, and develop and enforce regulations and policies to dismantle practices that maintain structural racism and white supremacy.

Assurance

Under assurance, the essential public health services include ensuring an effective system that enables equitable access to services and care, building a diverse and skilled workforce, and improving and innovating public health functions.

The researchers recommend public health professionals acknowledge racist systems and advocate for antiracist policies, set clear expectations for education on equity, focus on antiracist methodologies and ensure the infrastructure for teaching, research and practice is grounded in critical race theory so that the implications of historical and contemporary manifestations of white supremacy are addressed.

"Public health can do better by ensuring that assessment includes data collection, monitoring and reporting of racism pertinent to the health of Black, Indigenous and people of color. Policy development must center the experiences of people most impacted by white supremacy. Assurance requires us to analyze the impact of white supremacy on training curricula, research funding and resources, racial composition of the healthcare workforce, and on health outcomes," wrote the researchers.

Moving forward, Alang says public health institutions have to develop and enforce regulations and policies to dismantle practices that maintain structural racism and white supremacy.

"Public health cannot address racial inequities in health outcomes without addressing white supremacy in the field itself--the discipline, profession and practice of public health, and public health schools," Alang explained. "The newly revised ten essential public health services now highlight equity, but to live up to our goal of equity, they must also tackle structural racism and its roots: white supremacy."

Scientists at the Victor Chang Cardiac Research Institute in Sydney have discovered a critical new gene that it is hoped could help human hearts repair damaged heart muscle after a heart attack.

Researchers have identified a genetic switch in zebrafish that turns on cells allowing them to divide and multiply after a heart attack, resulting in the complete regeneration and healing of damaged heart muscle in these fish.

It's already known that zebrafish can heal their own hearts, but how they performed this incredible feat remained unknown, until now. In research recently published in the prestigious journal, Science, the team at the Institute drilled down into a critical gene known as Klf1 that previously had only been identified in red blood cells. For the first time they discovered it plays a vital role in healing damaged hearts.

Dr Kazu Kikuchi, who led this world first research, said he was astonished by the findings.

"Our research has identified a secret switch that allows heart muscle cells to divide and multiply after the heart is injured. It kicks in when needed and turns off when the heart is fully healed. In humans where damaged and scarred heart muscle cannot replace itself, this could be a game-changer," Dr Kikuchi explains.

"With these tiny little fish sharing over 70% of human genes, this really has the potential to save many, many lives and lead to new drug developments."

The gene works by making remaining uninjured heart muscle cells more immature and changing their metabolic wiring. This allows them to divide and make new cells.

When the gene was removed, the zebrafish heart lost its ability to repair itself after an injury such as a heart attack, which pinpointed it as a crucial self-healing tool.

Professor Bob Graham, Head of the Institute's Molecular Cardiology and Biophysics Division, says they hope to utilise this world-first discovery, made in collaboration with the Garvan Institute of Medical Research, to transform the treatment of heart attack patients and other heart diseases.

"The team has been able to find this vitally important protein that swings into action after an event like a heart attack and supercharges the cells to heal damaged heart muscle. It's an incredible discovery," says Prof Graham.

"The gene may also act as a switch in human hearts. We are now hoping further research into its function may provide us with a clue to turn on regeneration in human hearts, to improve their ability to pump blood around the body."

Importantly, the team also found that the Klf1 gene played no role in the early development of the heart and that its regenerative properties were only switched on after a heart injury.

Professor Graham added: "This is clear evidence that the regeneration you get after a heart injury is not the same as what happens during the development of the heart but involves an entirely different pathway; an issue that has been debated for years."

Animals are remarkably diverse in their sleep and activity patterns due to foraging strategies, social behavior and their desire to avoid predators. With more than 3,000 types of cichlids, these freshwater fish may just be one of the most diverse species in the world. Lake Malawi alone, which stretches 350 miles through eastern Africa, is home to more than 500 cichlid species. They evolved from a few species that likely entered the lake about 3 million years ago and now display very different behaviors and inhabit well-defined niches throughout the lake.

So how is it possible that so many different species can coexist in this large tropical lake? Many factors have been considered including the multitude of ecological resources available, predation, and the ability of cichlid species to evolve highly specific courtship and feeding behavior. Despite the dramatic difference between day and nightlife, the way fish exploit different times of day has not been studied systematically.

Lake Malawi's cichlids are presumed to be active during the daytime, most likely to avoid predation, although this has never been investigated scientifically. By examining alterations in the circadian timing of activity and the duration of rest-wake cycles, researchers from Florida Atlantic University in collaboration with the University of Massachusetts Amherst, are the first to identify a single nocturnal species of a Malawi cichlid - the Tropheops sp. "red cheek."

The study, published in the Journal of Experimental Biology, reveals that nocturnal behavior in the red cheek, a member of a highly speciose and ecologically diverse lineage, was maintained when fish were provided shelter, but not under constant darkness, suggesting it results from acute response to light rather than an endogenous circadian rhythm. In addition, researchers discovered that nocturnality is associated with increased eye size after correcting for evolutionary history, suggesting a link between visual processing and nighttime activity.

Lake Malawi cichlids in the study exhibited substantial and continuous variation in activity levels and patterns, and closely related species differed markedly in activity. Findings suggest that circadian regulation of activity may provide a mechanism for niche exploitation in African cichlids. Researchers also identified diversity of locomotor behavior, and together, these results provide a system for investigating the molecular and neural basis underlying variation in nocturnal activity.

To examine the effects of ecological niche and evolutionary history on the regulation of locomotor activity and rest, researchers measured locomotor activity across the circadian cycle in 11 Lake Malawi cichlid species. The species were selected for diversity in habitat, behavior and lineage representation and included the near-shore rock-dwelling clade of Malawi cichlids (mbuna) as well as representative species from another major lineage within the lake. Prior to this study, the circadian regulation of activity and rest within a lineage that inhabits a shared environment was unknown.

"Given that Malawi cichlids exhibit an impressive magnitude of diversity in an array of anatomical and behavioral traits, we predicted that they may also exhibit high magnitudes and continuous variation in rest-activity patterns. We think these differences also extend to sleep and foraging behavior, providing a system to investigate how complex traits that are critical for survival evolve," said Alex Keene, Ph.D., lead author and a professor of biological sciences in FAU's Charles E. Schmidt College of Science, on the John D. MacArthur Campus at Jupiter. "Our finding that the timing and duration of rest and activity varies dramatically, and continuously, between populations of Lake Malawi cichlids raise the possibility that these differences play a critical role in the rapid speciation of this system."