Culture

Washington, DC - January 22, 2021 - New research shows that non-steroidal anti-inflammatory drugs (NSAIDs) reduced both antibody and inflammatory responses to SARS-CoV-2 infection in mice. The study appears this week in the Journal of Virology, a publication of the American Society for Microbiology.

The research is important because "NSAIDs are arguably the most commonly used anti-inflammatory medications," said principal investigator Craig B. Wilen, Assistant Professor of Laboratory Medicine and Immunology, Yale University School of Medicine.

In addition to taking NSAIDs for chronic conditions such as arthritis, people take them "for shorter periods of time during infections, and [during] acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise," said Dr. Wilen. "Our work suggests that the NSAID meloxicam dampens the immune response to SARS-CoV-2 infection."

The research also suggests that the consequences of NSAID use during natural infection and vaccination should be evaluated in humans, said Dr. Wilen. "This data likely exists, particularly in the clinical trials for the vaccines, so it should be mined to see if it produces antibody responses in people."

"Taking NSAIDs during COVID-19 could be harmful or beneficial, depending on the timing of administration," said Dr.Wilen. The potent anti-inflammatory, dexamethasone (not an NSAID), is detrimental to COVID-19 sufferers when taken early in the infection, but beneficial when administered during later stages of COVID-19, said Dr. Wilen.

Similarly, NSAIDs' anti-inflammatory activity might be detrimental early in SARS-CoV-2 infection, because at this stage, inflammation is usually helpful. That changes at later stages of COVID-19, particularly if the patient undergoes an intense inflammation known as a cytokine storm. A cytokine storm is an immune response of inflammatory compounds that often occurs in COVID-19 patients, can lead to complications, need for the intensive care unit, and even death.

A reduction in neutralizing antibodies caused by NSAIDs might be benign, or it might blunt the immune system's ability to fight the disease during the early stages of infection. It could also reduce the magnitude and/or length of protection from either natural infection or vaccination, said Dr. Wilen.

The initial motivation to investigate NSAIDs' effect on COVID-19 "was a twitter thread, suggesting NSAIDs should not be used during COVID-19," said Dr. Wilen. "This seemed suspicious to us, so we wanted to investigate."

Dr. Wilen and his team expected that there would be little to no effect of NSAIDs on viral infection, which turned out to be correct.They also thought that NSAIDs would not significantly affect the antibody response to natural infection. "In fact, we initially didn't even carefully look at the antibody response, because we didn't expect it to be altered by NSAIDs. This turned out to be wrong, said Dr. Wilen.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

At least 1 in 3 COVID-19 cases asymptomatic

Analysis makes a case for widespread testing to identify those who may unwittingly spread the virus

A review of 61 studies and reports comprising more than 1.8 million people confirms that at least 1 in 3 people infected with the SARS-CoV-2 virus do not have any symptoms. These findings build on a June 2020 review of a more limited data set, which also found that a significant proportion of infections were asymptomatic. The review is published in Annals of Internal Medicine.

The authors from Scripps Research reviewed studies and reports from around the world, including two
massive serosurveys in England and Spain that tested the presence of SARS-CoV-2 antibodies in hundreds of thousands of people. In both studies, about one-third of individuals tested positive for the virus but never experienced symptoms.

According to the authors, these findings suggest that widespread at-home testing to include even those without symptoms could help to identify those who may unwittingly spread the virus, as about half of new infections are believed to be caused by people who are either presymptomatic or asymptomatic. Determining how effective vaccines are at preventing asymptomatic infection will also be important. The authors note that it was just about one year ago--on January 24, 2020--that the first asymptomatic case of COVID-19 was documented, but largely ignored. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-6976.

Media contacts: A PDF for this article is not yet available. Please click the link to read the full text. The lead author, Eric J. Topol, MD, can be reached through Anna Anderson at aanders@scripps.edu.

There isn't much in Kamchatka, a remote peninsula in northeastern Russia just across the Bering Sea from Alaska, besides an impressive population of brown bears and the most explosive volcano in the world.

Kamchatka's Shiveluch volcano has had more than 40 violent eruptions over the last 10,000 years. The last gigantic blast occurred in 1964, creating a new crater and covering an area of nearly 100 square kilometers with pyroclastic flows. But Shiveluch is actually currently erupting, as it has been for over 20 years. So why would anyone risk venturing too close?

Researchers from Washington University in St. Louis, including Michael Krawczynski, assistant professor of earth and planetary sciences in Arts & Sciences and graduate student Andrea Goltz, brave the harsh conditions on Kamchatka because understanding what makes Shiveluch tick could help scientists understand the global water cycle and gain insights into the plumbing systems of other volcanoes.

In a recent study published in the journal Contributions to Mineralogy and Petrology, researchers from the Krawczynski lab looked at small nodules of primitive magma that were erupted and preserved amid other materials.

"The minerals in these nodules retain the signatures of what was happening early in the magma's evolution, deep in Earth's crust," said Goltz, the lead author of the paper.

The researchers found that the conditions inside Shiveluch include roughly 10%-14% water by weight (wt%). Most volcanoes have less than 1% water. For subduction zone volcanoes, the average is usually 4%, rarely exceeding 8 wt%, which is considered superhydrous.

Of particular interest is a mineral called amphibole, which acts as a proxy or fingerprint for high water content at known temperature and pressure. The unique chemistry of the mineral tells researchers how much water is present deep underneath Shiveluch.

"When you convert the chemistry of these two minerals, amphibole and olivine, into temperatures and water contents as we do in this paper, the results are remarkable both in terms of how much water and how low a temperature we're recording," Krawczynski said.

"The only way to get primitive, pristine materials at low temperatures is to add lots and lots of water," he said. "Adding water to rock has the same effect as adding salt to ice; you're lowering the melting point. In this case, there is so much water that the temperature is reduced to a point where amphiboles can crystallize."

The enzyme that makes RNA from a DNA template is altered to slow the production of ribosomal RNA (rRNA), the most abundant type of RNA within cells, when resources are scarce and the bacteria Escherichia coli needs to slow its growth. Researchers used cryo-electron microscopy (cryo-EM) to capture the structures of the RNA polymerase while in complex with DNA and showed how its activity is changed in response to poor-growth conditions. A paper describing the research led by Penn State scientists appears January 22, 2020 in the journal Nature Communications.

"RNA polymerase is an enzyme that produces a variety of RNAs using information encoded in DNA," said Katsuhiko Murakami, professor of biochemistry and molecular biology at Penn State and the leader of the research team. "This is one of the key steps in the central dogma of molecular biology: transferring genetic information from DNA to RNA, which in turn often codes for protein. It's required for life and the process is basically shared from bacteria to humans. We are interested in understanding how the structure of RNA polymerase is changed for modulating its activity and function, but it's been difficult to capture using traditional methods like X-ray crystallography, which requires crystallizing a sample to determine its structure."

RNA polymerase functions by binding to specific DNA sequences called "promoters" found near the beginning of genes that are going to be made into RNA. To understand the structure and function of the polymerase during this interaction, researchers need to capture the polymerase while it is bound to the promoter DNA, but the interaction can be very unstable at some promoters. Crystallography can only capture RNA polymerase bound to a promoter if the complex is very stable, but for ribosomal RNA promoters this interaction tends to be unstable so that the polymerase can quickly escape to begin making the RNA. To see these interactions the researchers turned to cryo-EM, a method that allows them to visualize the structure of macromolecules in solution.

"When you talk about RNA, most people think about messenger RNA (mRNA), which is the template for making proteins," said Murakami. "But the most abundant type of RNA in cells doesn't actually code for protein. Ribosomal RNA is the major structural component of the ribosome, which is the cellular machinery that builds proteins using messenger RNAs as templates. Ribosomal RNA synthesis accounts for up to 70 percent of total RNA synthesis in E. coli cells."

When a cell divides, which E. coli can do every twenty minutes in nutrient-rich growth conditions, it needs to provide the two resulting daughter cells with enough ribosomes to function, so it is continually making ribosomal RNAs.

"If you do some back-of-the-envelope calculations, an E. coli cell needs to make around 70,000 ribosomes every 20 minutes," said Murakami. "This means RNA polymerase starts ribosomal RNA synthesis every 1.7 seconds from each ribosomal RNA promoter. So, the polymerase has to bind the ribosomal RNA promoter transiently in order to quickly move onto the ribosomal RNA synthesis step. This is not an ideal for a crystallographic approach, but in a cryo-EM study, we could capture this interaction and, in fact, see different several stages of the interaction in a single sample."

The researchers were able to determine the three-dimensional structures of the RNA polymerase-promoter complex at two different stages. One when the DNA was still "closed," before the two strands of the DNA molecule are separated allowing access to the template strand (they refer to this as a closed complex), and one when the DNA was "open" (called an open complex) and primed for RNA synthesis to begin.

"We found a large conformational change in part of the polymerase called the ? (sigma) factor when it binds to promoter DNA, which has never been observed before" said Murakami. "This change opens a gate that allows the DNA to enter a cleft in the polymerase and form the open complex quickly."

When E. coli needs to slow its growth due to limited resources, two molecules--a global transcription regulator called DksA and a bacterial signaling molecule called ppGpp, bind directly with the polymerase to reduce production of ribosomal RNA. The research team investigated how the binding of these two factors alters the conformation of the polymerase and affects its activity in a promoter-specific manner.

"DksA and ppGpp binding to the polymerase alters its conformation, which prevents the opening of a gate and therefor the polymerase has to follow an alternative pathway to form the open complex," said Murakami. "This is not an ideal pathway for the ribosomal RNA promoter and thus slow its activity. It's exciting to see these conformational changes to the polymerase that have direct functional consequences. We couldn't do this without the cryo-EM, so I'm very thankful to have access to this technology here at Penn State for optimizing experimental conditions for preparing cryo-EM specimens before sending them to the National Cryo-EM Facility at NCI/NIH for high-resolution data collections. We are going to be able to continue to analyze cellular components and complexes that were previously inaccessible."

TAMPA, Fla. (January 22, 2021)- The pressing concern posed by rising sea levels has created a critical need for scientists to precisely predict how quickly the oceans will rise in coming centuries. To gain insight into future ice sheet stability and sea-level rise, new research from an international team led by University of South Florida geoscientists is drawing on evidence from past interglacial periods when Earth's climate was warmer than today.

Using deposits in the caves of the Mediterranean island of Mallorca, known as phreatic overgrowths on speleothems, to reconstruct past sea level stands, the team was able to determine that the vertical extent of these unique deposits corresponds with the amplitude of the fluctuating water table, said author USF geosciences Professor Bogdan Onac. That determination now is providing scientists with a way to precisely measure past sea levels.

Working with colleagues at the University of New Mexico, University of Balearic Islands and Columbia University, the researchers' findings were published in Scientific Reports. In their project, the geosciences team documented the position and timing of sea level during key time intervals over the past 6.5 million years for which global mean sea-level estimates have been highly uncertain.

Their results contribute to the understanding of past warm periods to gain insight into the magnitude and frequency of sea level rise, which is critical for scientists' ability to forecast and make recommendations on adapting to future global warming.

The team expanded upon their research previously published in Nature, by investigating samples between 800,000 and 6.5 million years old. Using deposits from several of the Mallorcan caves and applying numerical and statistical models to estimate the corrections for glacial isostatic adjustment and long?term uplift, they translated the local sea level estimates into global mean sea level (GMSL).

Their results show that during key time events, such as Pliocene-Pleistocene Transition, when the Earth underwent a major transition from the warm climates of the Pliocene to the Pleistocene ice ages, the GMSL stood at 6.4 meters. During the beginning and the end of the Mid?Pleistocene Transition the sea level was at ?1.1 meter and 5 meters respectively.

"Overall, our results support that sea level dropped significantly after the Pliocene," said USF doctoral alum Oana Dumitru, the study's lead author who is now a postdoc at Columbia University's Lamont-Doherty Earth Observatory.

The authors also show that local sea level before and at the onset of the Messinian Salinity Crisis, a major geological event during which the Mediterranean Sea became partly to nearly dry of water, was at approximately 33 meters above present level. These estimates may offer starting points for assessing whether sea-level drawdown in the Western Mediterranean happened gradually or rapidly, the researchers said.

"Our estimates are important snapshots of sea level still stands, but additional sea level index points will be useful to yield more context for our results," the team wrote in their journal article. "By providing direct estimates of sea level using POS as robust proxies, this work advances our understanding of sea level position during several past warm periods. These results therefore contribute to efforts of studying past warm periods to gain insight into the magnitude and frequency of sea level rise."

Collective research to date regarding nutrients found in the leaves of contemporary cycad species has been inconsistent as far as data collection and narrow in scope, according to a University of Guam-led literature review published on Nov. 19 in Horticulturae journal.

Understanding nutrient accumulation within cycads is essential to effective horticultural management, and more importantly, conservation of this plant group, which is highly prized within the horticulture trade and also threatened worldwide.

"Cycads comprise the most threatened group of plants worldwide, but they are also one of the least studied plant groups," said Benjamin Deloso, a cycad specialist with the University of Guam and lead author of the study. "Most of the disciplines of cycad research are only now accumulating enough peer-reviewed literature to enable organized global reviews, such as this one."

The effort to compile and summarize peer-reviewed literature on the subject was undertaken by scientists from Guam, Florida, the Philippines, Thailand, and the Micronesian Island of Yap -- each of whom also co-authored some of the articles cited in the review.

They concluded that in order to draw more reliable comparisons among studies of cycad leaf nutrition, future research should include:

More taxa
The literature reviewed represented only 13% of the world's cycad species. More species need to be added to the published database to increase relevance of the results.

More plants in their natural habitats
The number of cycad species from which native habitat data were obtained was an unusually low 4% of the 358 described species. Most of the reviewed publications reported data from botanic garden settings, which have been shown to artificially change the concentration of cycad leaf nutrients.

The influence of season
In the few studies that factored in the season, the results found that leaf nutrients varied among male and female plants and plants of different provenances, indicating future research should take season into account.

The influence of insect herbivory
Many cycad taxa co-evolved with leaf-eating insects, while others are threatened by non-native pests, yet only one study in the review factored in and noted the influence of insect herbivory on cycad leaf nutrients.

The influence of biotic and abiotic factors
Perhaps the greatest benefit of the review was the explanation of biotic and abiotic factors that have been shown to influence cycad leaf nutrient relations. Future studies can now be designed to ensure research methods include measurements of plant size, leaf age, level of shade, position of leaflets within the compound leaf, and the concentrations of nutrients within the soils of the root zone -- all factors that influence leaf nutrient concentrations.

Furthermore, the sampling and analytical methods were highly disparate among the studies.

"One of our main points was that the protocols for sampling leaf tissue to determine nutrient concentrations of cycad leaves have not been homogeneous among the various research agendas," Deloso said. "This compromised our ability to unequivocally determine any canonical trends in the results."

Discoveries based on data review

Despite the disparities in research methods, the review of published research revealed that cycad leaf nitrogen and phosphorus concentrations exceeded the global mean for these elements in all seed-bearing plants. According to the authors, the cyanobacteria endosymbionts that inhabit cycad roots provide additional nitrogen for the cycad to exploit. These cyanobacterial endosymbionts are absent from many other plant groups, which may help explain these findings.

Deloso said the findings of this first-ever literature review on the topic of leaf nutrition in cycads are key moving forward with cycad research.

"Among my co-authors were the world's three leading authorities for Guam's native cycad, Cycas micronesica. This tree is one of the many endangered cycad species, and these experts are crucial sources of knowledge to inform future conservation decisions," he said.

Even at the start of the COVID-19 pandemic last year, people around the world became more fearful of what could happen to them or their family.

A new Flinders University study of 1040 online participants from five western countries published in PLOS ONE explores people's response to the stresses of the escalating pandemic, finding more than 13% of the sample had post-traumatic stress disorder (PTSD) related symptoms consistent with levels necessary to qualify for a clinical diagnosis.

With ongoing economic and social fallout, and death toll of more than 2 million, the team of psychology researchers warn more needs to be done to cope with the potential short and long-term spike in PTSD cases resulting from the pandemic - as well as related mental health problems such as anxiety, depression, psychosocial functioning, etc.

"While the global pandemic does not fit into prevailing PTSD models, or diagnostic criteria, our research shows this ongoing global stressor can trigger traumatic stress symptoms," says lead researcher Associate Professor Melanie Takarangi, from Flinders Psychology.

"We found that traumatic stress was related to future events, such as worry about oneself or a family member contracting COVID-19, to direct contact with the virus, as well as indirect contact such as via the news and government lockdown - a non-life threatening event," says co-author Victoria Bridgland, who is undertaking a PhD studying the triggers of PTSD.

PTSD is a set of reactions, including intrusive recollections such as flashbacks, that can develop in people exposed to an event that threatened their life or safety (e.g., sexual assault, natural disaster).

"Our findings highlight the need to focus on the acute psychological distress - including the perceived emotional impact of particular events - associated with COVID-19 and build on other research from the past year that demonstrates the damaging psychological impact of COVID-19 on mental health," says Ms Bridgland.

Comprehensive long-term documentation of COVID-19 related traumatic stress reactions will allow health professionals to help people who could otherwise fall through the cracks, the research team concludes.

The online survey examined a range of responses to common post-traumatic stress symptoms, such as repeated disturbing and unwanted images, memories or thoughts about the COVIC-19 pandemic.

COVID-19's psychological fallout has been dubbed the "second curve," predicted to last for
months to years, the paper notes.

"Notably, while most of our participants reported experiencing some form of
psychological distress and 13.2% of our sample were likely PTSD positive when anchoring
symptoms to COVID-19, only 2% of our total sample reported they had personally tested positive to COVID-19, and only 5% reported that close family and friends had tested positive.

"It therefore seems likely that the psychological fallout from COVID-19 may reach further than the medical fallout," the paper concludes.

Marine microalgae-based cellular agriculture is a promising new way to sustainably produce plant-based 'meat' and healthy 'superfoods' for the future.

Researchers at Flinders University's Centre for Marine Bioproducts Development (CMBD) in Australia are responding to growing interest from consumers looking for healthier, more environmentally friendly, sustainable and ethical alternatives to animal proteins.

Marine microalgae, single-cell photosynthetic organisms from the ocean could be the solution to the world's meat protein shortage, says CMBD director Flinders University Professor Wei Zhang, who is also co-leading a bid to establish a national Marine Bioproducts Cooperative Research Centre (MB-CRC) in Australia.

The CRC's mission is to find ways to develop the third-generation of Australian high-value marine bioindustry (as opposed to the first-generation of fisheries and the second-generation of aquaculture) and transform Australia's emerging marine bioproducts sector into a globally competitive industry.

The Centre's focus will be on industry and market-driven innovations to improve both the supply chain and value chain to deliver costs savings, improved production and competitive capacity for Australia to access high value marine bioproducts markets across the globe.

"Our research spans the entire value chain, from microalgae cultivation and circular advanced biomanufacturing to the development of high-value functional food," Professor Zhang says.

"Microalgae come in a diverse range of nutritional profiles and advanced cultivation strategies can be developed for tuning microalgae to produce protein-, oil- and carbohydrate-dominant types that can be processed into a broad range of functional foods, including healthy cell patties, chips, pastes, jams and even caviar."

Two freshwater microalgal products currently on the market are the high protein Chlorella and Spirulina varieties used in the production of foods such as green pasta, drinks and beverages.

Marine species are of significant interest as they do not require scarce freshwater and crop land. Their unique nutritional profiles such as their high DHA and EPA content (long chain omega 3 fatty acids) are essential for infant and brain development and cardiac health.

Bioreactors for upscaling upscaled aquatic production of photosynthetic microalgae can also help to combat greenhouse gas emissions and climate change. One 90 x 90 x 210 cm (3 x 3 x 7 ft) bioreactor unit can absorb up to 400 times more carbon dioxide than the same footprint of trees.

Using sunlight, certain varieties of microalgae create oxygen and convert carbon dioxide into organic carbon (protein, carbohydrates, pigments, fats and fibres), just like plants, but do not require valuable arable land for their production.

"They are therefore often called the rainforests of the oceans," says Associate Professor Kirsten Heimann, senior lecturer in biotechnology at Flinders University.

"Using sunlight, photosynthetic microalgae create oxygen and convert carbon dioxide into organic carbon (protein, carbohydrates, pigments, fats, fibres, and micronutrients), just like plants, but do not require valuable arable land for their production.

This means microalgae can be sustainably harvested and converted into eco-friendly superfoods," she says. "Putting one and one together, microalgae and innovative production and processing could help to service the world's booming population and growing demand for sustainable protein production," she says.

Along with research into processing techniques, the CMBD team is also investigating the use of waste or harvested seaweed for biodegradable plastics production, another sustainable solution to non-degradable petroleum-based plastics.

Food insecurity spiked among residents living in two predominantly African American neighborhoods during the first weeks of the coronavirus pandemic, far outpacing food insecurity observed among the general U.S. population during the same period, according to a new RAND Corporation study.

Following residents of two Pittsburgh low-income African American neighborhoods characterized as food deserts since 2011, the study found that the pandemic increased the number of people facing food insecurity by nearly 80%.

Similar to United States national trends, food insecurity among residents had been improving consistently since 2011. However, the study found that those gains were erased by the pandemic, with the disparities between the predominantly African American residents and U.S. population at the highest levels seen over the past decade.

The findings are published online by the American Journal of Public Health.

"In a short period of time, the coronavirus pandemic has magnified preexisting racial and ethnic disparities in food security," said Tamara Dubowitz, the study's lead author and a senior policy researcher at RAND, a nonprofit research organization. "While food insecurity is linked to a wide variety of health problems, these disparities reflect larger systemic issues including structural racism."

The study involved residents of the Hill and Homewood neighborhoods in Pittsburgh that have been the focus of a long-running research project investigating the influence that diet, access to food and other items have on residents' health and wellbeing.

Both of the neighborhoods are primarily African American and low income. A group of residents of both areas have been surveyed about their access to healthy food on several occasions since 2011.

For the latest study, RAND researchers surveyed a group of 605 residents from the neighborhoods during March, April and May 2020, asking about how the pandemic was affecting their access to food. Researchers have been following the residents since 2011.

The study found that the number of residents reporting food insecurity increased from 20.7% in 2018 to 36.9% in 2020 -- a nearly 80 percent rise. Previous research had shown that food insecurity had been falling in the two neighborhoods since 2011.

Among those surveyed, participation in the Supplemental Nutrition Assistance Program or SNAP (52.2%) and food bank use (35.9%) did not not change significantly during the early weeks of the coronavirus pandemic.

"This finding suggests that existing safety nets may need more support in order to reach those with emerging needs," Dubowitz said. "Lack of reported use could be due to difficulties with SNAP enrollment, problems accessing food banks in the early days of the pandemic or feelings of stigma related to participating in such programs."

What The Study Did: This randomized clinical trial compares the effects of three doses of bamlanivimab monotherapy (700 vs 2,800 vs 7,000 mg) vs combination bamlanivimab and etesevimab vs placebo on change in day 11 severe acute respiratory syndrome coronavirus 2 viral load in patients with mild to moderate COVID-19.

Authors: Daniel M. Skovronsky, M.D., Ph.D., of Eli Lilly and Company in Indianapolis, 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.2021.0202)

Editor's Note: The articles includes conflict 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.

Genetic inheritance affects the likelihood of developing breast cancer. Some genes are already known to increase cancer risk; other genes are suspected to be involved, but not to what extent. It is crucial to clarify this issue to improve prevention since it opens the way to more personalised follow-up and screening programs. A large international consortium, which includes the Spanish National Cancer Research Centre (CNIO), has studied 34 putative susceptibility genes on samples from 113,000 female breast cancer cases and controls, and its results confirm the importance of nine of them.

The study "defines the genes most clinically useful for inclusion on panels for breast cancer risk prediction (...), to guide genetic counselling," the authors write in the New England Journal of Medicine (NEJM).

This is the most ambitious study carried out to date to shed light on the role of heredity in breast cancer, one of the most common cancers today - one out of every eight women will have it at some point in their lives.

250 researchers from dozens of institutions in more than 25 countries participated in the genetic analysis. One-third of the samples were analysed at the CNIO, with the participation of Javier Benítez, Anna González-Neira and Ana Osorio. Groups from seven other Spanish institutions also participated in the study.

Osorio, from the CNIO Human Genetics Group, stresses the importance of the information provided by this study when monitoring breast cancer patients and their families. "Genetic tests are already done on people with a family history of the disease, but in those tests we can only analyse genes of which we are certain that they affect the risk. Now we have more information, and we can improve the genetic counselling of patients and their families," the CNIO researcher says.

Low- and moderate-risk genes

It has been known for some time that the risk of developing breast cancer depends partly on genetic inheritance, but determining exactly which genes increase this risk, and how much, remains a major challenge.

The genes that confer high risk when mutated, BRCA1 and BRCA2, were already identified in the mid-1990s. Having mutations in these genes confers a cumulative risk of around 70% of developing breast cancer by the age of 80, and a risk of 40% and 20% of developing ovarian cancer for carriers of mutations in BRCA1 and BRCA2, respectively. It was this strong effect that made it possible to identify these genes in families with a high incidence of cancer.

Today, genetic diagnosis alerts many patients' family members, who can then act at very early stages of cancer or even prevent its appearance. But the BRCA genes explain only a small part of all cases. In the vast majority of cases, genes are involved that confer a lower risk and that may interact with each other or with other genetic and environmental factors, which can modify the risk.

In recent years, a number of studies have identified dozens of such candidate genes that increase the risk of breast cancer to some degree, but these studies were done with relatively few patients and their results were not conclusive. It was the aim of the study now published to improve this knowledge by determining precisely which genes are involved, and to what extent they affect the risk to develop which subtype of tumour.

"Genetic testing for breast cancer susceptibility is widely used, but for many genes the evidence for association with breast cancer is weak," the authors write in NEJM, adding that the risk estimates are imprecise and that cancer subtype-specific risk estimates are lacking altogether.

"The most clinically useful genes"

The study is the result of the European project BRIDGES (Breast Cancer Risk after Diagnostic Gene Sequencing), in which the CNIO participates. The study was based on the analysis of 34 known or suspected breast cancer susceptibility genes in DNA samples from 60,400 women who had developed breast cancer and 53,400 healthy women.

The results pinpoint nine genes for which there is solid evidence of their involvement in the disease: ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D and TP53. For some of these genes, this was already known, but for others, such as RAD51C and D and BARD1, their involvement was not so well established. For all genes, more precise risk estimates can now be calculated and these estimates are tailored for each tumour subtype.

On the other hand, the study shows that about fifteen of the genes that have been used so far in some tests "are not indicative of an increased risk" for breast cancer and should therefore not be taken into account, at least at this time, in risk estimates.

However, the authors remind us that the probability of developing breast cancer is not determined by genes alone. Other risk factors such as age, hormonal history and environmental factors also play a role, which in turn are influenced by the genetic background.

"In fact," points out González-Neira, Head of the Human Genotyping - CEGEN Unit at the CNIO, "it is been already working on mathematical models that integrate current knowledge about all these factors and their interaction, which make possible to provide a good estimate of the adjusted risk for each woman and thus individualise clinical management".

The final objective is to improve prevention with much more personalised screening programmes than those currently available. Implementation of such precision medicine protocols in breast cancer will improve early diagnosis and reduce morbidity and mortality rates for this disease.

When university campuses sent students, staff and faculty members home in March, Padmini Rangamani, a professor at the University of California San Diego, suddenly found herself running her research lab remotely, teaching her classes online, and supervising her two children, ages 10 and 13, who are also learning online.

To deal with the stress the situation created, Rangamani turned to a support network of fellow female faculty members around the United States. They chatted and texted and eventually decided to write a scholarly article with recommendations for all other female principal investigators in academia.

The article, "Ten simple rules for women principal investigators during a pandemic," was published October 2020 in PLOS Computational Biology. It's perhaps important to note that despite its title, the article is careful to say that the cardinal rule is that there are no rules. So all 10 points outlined are in fact suggestions. Also despite its title, Rangamani says most of the 10 points outlined in the publication can apply to all caregivers juggling work and caregiving during the pandemic.

"Without in-person school or daycare, and without after-school programs, there is really no way for caregivers to function at full capacity at work," Rangamani said.

In addition, such concerns have not been discussed openly in the workplace, the authors felt. Their real fear is then that talent nurtured through the years will be lost in one fell swoop--and their main goal is to try and change this. Rangamani and fellow co-authors want to normalize conversations about juggling work and family obligations. "If you want to say 'I can't meet at this time, because I need to be on a Zoom with my kids, that doesn't mean you're not serious about your job or not doing your job well," she said. "We want to reduce this perception bias."

This is particularly important to maintain equity and diversity within an organization, Rangamani added. "We need to be extremely vigilant to ensure that those who are particularly vulnerable do not exit the system," she said. Single parents, those who are taking care of elderly parents and relatives, and parents whose children have special services are especially at risk, she added. "The intense pressure of being 'on' all the time is simply not realizable right now."

While the paper outlines some changes that can be made at a campus-wide or even university system level, Rangamani is focused on a smaller scale: an office or a department for example. It is much easier to get these smaller groups together and have genuine conversations about what the individual needs are and what can be done to get our colleagues through this intensely difficult period without sacrificing quality or fairness.. "There are measures you can take at the grassroots level," she said.

In order to normalize these conversations about work-life balance Rangamani hopes that leadership will empower those who hesitate to ask for help to do so.
Here are the 10 suggestions that the paper outlines to cope during the pandemic:

Find a peer group of women to provide professional support.
"The authors are all members of an online group for women PIs in biomedical engineering, which has historically served as a sounding board for professional concerns. We have found that maintaining these connections has been essential over the course of our careers and are even more important during this quarantine period."

Say no to requests to do anything outside of your main responsibilities
"If you can't do them now, you can offer a time when you might be able to do them; the requesting party will need to recognize that your future schedule could go through upheaval as surges of the disease hit different areas and restrictions change. "

Drop something
"True, your house might not be as clean as you would like, and you may be eating more frozen pizza than you normally would tolerate. Remember that you are not the only person accepting this as your "new normal." We can't forget that the goal during a pandemic is survival--if you are keeping yourself physically and mentally healthy, you are more than succeeding."

When you have energy to do more than the minimum, use it to support women and underrepresented groups
"We recognize that advocacy of this nature is a privilege, and not everyone is able to do so safely. If you are in the position to support women and underrepresented groups and have the energy, pick a cause and lean into it. Also, recognize that this action can take many forms, some of which may be a better fit for your individual situation."

Remember, you know yourself best
"You know the things that have historically helped you relieve stress. Make a list of 10 of them. Some of them may not be an option during quarantine (oh, how some of us miss writing in coffee shops). But for those that are an option, try to do 1 of them every now and then."

It's OK to push back
"Perpetuating the myth that we can all work to the same degree (or better!) than we did a few months ago is very damaging to many women PIs. When you hear statements such as "everyone is writing more grants now" and "since we have more time, let's have a virtual conference about this topic," it's more than OK to push back that this is not your reality, regardless of the reason."

Remember, you have some flexibility to make your own schedule
"If there are pockets of time where you find yourself able to focus better than others, do your best to protect them. Block these times on your calendar--both in the near future and in the upcoming months by declining invitations for extraneous responsibilities."

Whatever help you can get, take it
"Perhaps your kids are old enough that they can even help with some of your work--1 of the authors tried (unsuccessfully) to engage her son in doing analysis on ImageJ (NIH, Bethesda, Maryland). Another purchased a 3D printer and recruited her daughter to help print parts for an OpenSPIM setup."

Do your best to remember that others are struggling too--be empathetic and work to build a community
"We suggest that each situation is approached with empathy, while maintaining your standards and accountability. For example, empathy may mean that when you assign a task to a group member or staff, you ask them whether the timeline is feasible. If it's not, that may be a sign that in the future you should aim to give them more advance notice. If a pattern of not completing work continues, it is then time to ask for an explanation. Recognize that just as no one is fully aware of your situation, you are not completely aware of your colleague's situation."

Don't lose your sense of humor
"We know, there is nothing funny about this situation. Many of us have needed or will need space to grieve deeply. However, our experience is that where you can share a laugh, you should."

Rangamani herself does her best to implement some of these suggestions. She prioritizes the well-being of her own research group over other zoom meetings; protects her research time; and does not schedule meetings at lunch time, if she can help it.

"While there is a light at the end of the tunnel in the form of vaccines," Rangamani also notes, "this global health crisis may be a once-in-a-lifetime opportunity for the academy to take a close look at how we can empower our vulnerable colleagues and make policy changes to change our culture for the better."

The authors put rule, or rather suggestion, 10 in practice, by including a list of humorous rules and tips in a supplemental file.

"Service expectations are now completely fulfilled by raising scientifically literate humans of our own and science communication by way of family conversations, Facebook and Twitter debates," they write.

Tsukuba, Japan -- How valuable are earmuffs? The answer to this simple question can depend. What brand are they? Are they good quality? What is the weather like? Given the choice between earmuffs and suntan lotion, most people would choose to have the earmuffs on a cold winter day and the lotion on a sunny day at the beach. This ability to place different values on objects depending on the environmental context is something that we do all the time without much thought or effort. But how does it work? A new study led by Assistant Professor Jun Kunimatsu at the University of Tsukuba in Japan and Distinguished Investigator Okihide Hikosaka at the National Eye Institute (NEI) in the United States has discovered the part of the brain that allows this type of learning to occur.

"Value and reward are known to be encoded in the part of the brain called the basal ganglia," explains Dr. Hikosaka. "We set out to identify the specific neuronal circuits underlying environment-based value learning."

To find the answer, the researchers first taught monkeys a kind of "Where's Waldo" game in which they searched scenes for embedded objects that gave them rewards. Looking at the objects could lead big or small rewards depending on the background scene in which they were embedded. After the monkeys learned this game using many objects and many backgrounds, they were able to routinely make eye movements to the big rewards and avoid looking at the small rewards, even when the background scenes were switched suddenly.

The final output from the basal ganglia controls motor movements, in this case eye movements. The team hypothesized that a certain kind of brain cell called fast-spiking neurons were responsible for the successful learning of their game. To test this idea, they used a drug to temporarily block input from these cells to different parts of the basal ganglia just when monkeys were trying to learn the associations between objects, backgrounds, and values. They found that when input to the tail end of the striatum--a part of the basal ganglia-- was blocked, it prevented monkeys from learning new scene-based associations, but did not prevent them from performing well when they were given scenes and objects that they had already learned.

The findings could have applications in clinical research. "Reduced input from fast-spiking neurons has been observed in some clinical conditions," says Dr. Kunimatsu, "including Tourette syndrome and Huntington's disease, both of which are accompanied by deficits in skill learning that could be related to an inability to learn environment-based values."

The results of a study led by Northern Arizona University and the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, suggest the immune systems of people infected with COVID-19 may rely on antibodies created during infections from earlier coronaviruses to help fight the disease.

COVID-19 isn't humanity's first encounter with a coronavirus, so named because of the corona, or crown-like, protein spikes on their surface. Before SARS-CoV-2 -- the virus that causes COVID-19 -- humans have navigated at least 6 other types of coronaviruses.

The study sought to understand how coronaviruses (CoVs) ignite the human immune system and conduct a deeper dive on the inner workings of the antibody response. The published findings, "Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with endemic human coronaviruses," appear today in the journal Cell Reports Medicine.

"Our results suggest that the COVID-19 virus may awaken an antibody response that existed in humans prior to our current pandemic, meaning that we might already have some degree of pre-existing immunity to this virus." said John Altin, an assistant professor in TGen's infectious disease branch and the study's senior author.

This knowledge could help researchers design new diagnostics, evaluate the healing powers of convalescent plasma, develop new therapeutic treatments and -- importantly -- help design future vaccines or monoclonal antibody therapies capable of protecting against mutations that may occur in the COVID-19 virus.

The researchers used a tool called PepSeq to finely map antibody responses to all human-infecting coronaviruses. PepSeq is a novel technology being developed at TGen and NAU that allows for the construction of highly diverse pools of peptides (short chains of amino acids) bound to DNA tags. When combined with high-throughput sequencing, these PepSeq molecule pools allow for deep interrogation of the antibody response to viruses.

"The data generated using PepSeq allowed for broad characterization of the antibody response in individuals recently infected with SARS-CoV-2 compared with those of individuals exposed only to previous coronaviruses that now are widespread in human populations," said Jason Ladner, the study's lead author and an assistant professor in NAU's Pathogen and Microbiome Institute.

Besides SARS-CoV-2, researchers examined the antibody responses from two other potentially deadly coronaviruses: MERS-CoV, which caused the 2012 outbreak in Saudi Arabia of Middle East Respiratory Syndrome; and SARS-CoV-1, the first pandemic coronavirus that caused the 2003 outbreak in Asia of Severe Acute Respiratory Syndrome. All three are examples of coronaviruses that infect animals, but evolved to make people sick and became new human pathogens.

In addition to characterizing antibodies that recognize SARS-CoV-2, they also examined the antibody responses of four older coronaviruses: alphacoronavirus 229E; alphacoronavirus NL63; betacoronavirus OC43; and betacoronavirus HKU1. These so called "common" coronaviruses are endemic throughout human populations, but usually are not deadly and cause mild upper respiratory infections similar to those of the common cold.

By comparing patterns of reactivity against these different coronaviruses, the researchers demonstrated that SARS-CoV-2 could summon immune system antibodies originally generated in response to past coronavirus infections. This cross-reactivity occurred at two sites in the SARS-CoV-2 Spike protein; the protein on the surface of virus particles that attaches to ACE2 proteins on human cells to facilitate cell entry and infection.

"Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous coronavirus exposures, and which have potential to raise broadly-neutralizing antibodies. We further demonstrate that these cross-reactive antibodies preferentially bind to endemic coronavirus peptides, suggesting that the response to SARS-CoV-2 at these regions may be constrained by previous coronavirus exposure," said Altin, adding that more research is needed to understand the implications of these findings.

The findings could help explain the widely varying reactions COVID-19 patients have to the disease; from mild to no symptoms, to severe infections requiring hospitalization, and often resulting in death. It's also possible that differences in the pre-existing antibody response identified by this study could help to explain some of the difference in how severely COVID-19 disease manifests in old versus young people, who will have different histories of infections with the common coronaviruses.

"Our findings raise the possibility that the nature of an individual's antibody response to prior endemic coronavirus infection may impact the course of COVID-19 disease," Ladner said.

Also contributing to this study were: City of Hope National Medical Center, Walter Reed National Military Medical Center, Vitalant Research Institute, Sanford Burnham Prebys Medical Discovery Institute, Norwegian University of Science and Technology, St. Olavs Hospital and Encodia Inc.

Former undergraduate computer science student Zane Fink is named a co-author of the study. "Zane helped a lot with the design of the assays used and he wrote custom analysis software," said Ladner. Fink, who graduated from NAU in Spring 2020, is now pursuing a PhD in computer science at the University of Illinois.

Funding for this study was provided by the National Institutes of Health and the State of Arizona Technology and Research Initiative Fund.

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About Northern Arizona University
Northern Arizona University is a higher-research institution providing exceptional educational opportunities in Arizona and beyond. NAU delivers a student-centered experience to its nearly 30,000 students in Flagstaff, statewide and online through rigorous academic programs in a supportive, inclusive and diverse environment. Dedicated, world-renowned faculty help ensure students achieve academic excellence, experience personal growth, have meaningful research opportunities and are positioned for personal and professional success.

About TGen, an affiliate of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is affiliated with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases: CityofHope.org. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.

Media Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
syozwiak@tgen.org

As scientists increasingly rely on eyewitness accounts of earthquake shaking reported through online systems, they should consider whether those accounts are societally and spatially representative for an event, according to a new paper published in Seismological Research Letters.

Socioeconomic factors can play a significant if complex role in limiting who uses systems such as the U.S. Geological Survey's "Did You Feel It?" (DYFI) to report earthquake shaking. In California, for instance, researchers concluded that DYFI appears to gather data across a wide socioeconomic range, albeit with some intriguing differences related to neighborhood income levels during earthquakes such as the 1989 Loma Prieta, the 1994 Northridge and 2018 Ridgecrest earthquakes.

In India, by contrast, stark gaps in literacy and urban versus rural communities can lead to gaps in self-reported earthquake accounts though DYFI, write Susan Hough of the USGS and Stacey Martin of Australian National University.

Previous studies have looked at the reasons why people respond to DYFI, including a 2016 publication by Sum Mak and Danijel Schorlemmer. But socioeconomic differences in who reports earthquake shaking "is a factor we haven't thought enough about, even though it is shaping the data sets that are available, especially outside of the United States" said Hough.

Intensity data gleaned from DYFI are used to develop ShakeMap representations of ground motion in places with sparse instrumentation. ShakeMap in turn informs the Prompt Assessment of Global Earthquakes for Response (PAGER) system that provides crucial rapid information for earthquake response.

"The end result is that we are relying on unrepresentative [DYFI] data to flesh out ShakeMaps for large global earthquakes," Hough noted. "If the data are limited and unrepresentative, PAGER may not give emergency managers a good indication of where to direct their resources."

"I know many who take the DYFI observations from outside the United States at face value without any scrutiny and made the incorrect assumption that that's all there is to the story," Martin added. "As we've shown in this study, that would be a really inappropriate assumption."

Representation can also come into play when scientists rely on archival accounts to study historic earthquakes. Hough described the potential impact of unrepresentative earthquake reports in an earlier study when she and her colleague Morgan Page found a letter published in an Arkansas newspaper that helped to re-locate an 1882 earthquake within the Choctaw Nation in southeastern Oklahoma. The single chance account has helped seismologists better understand historical seismicity in Oklahoma, but there are still many "unknown unknowns" about earthquakes in the region during and after the 1882 event because Native American accounts are unavailable, Hough said.

When Hough and Martin compared DYFI responses with ZIP code average household income for the three California earthquakes, the researchers uncovered some complex and intriguing trends. For the Northridge earthquake, for instance, relatively affluent areas were more likely to contribute strong shaking reports, and strong shaking levels from poorer areas may be underrepresented in the DYFI data.

The researchers found that in India, DYFI reports skewed heavily toward urban individuals and depended strongly on a region's literacy rates. In some cases, the difference between DYFI self-reports and accounts gathered through traditional means such as local press accounts was significant. For the 2015 Gorkha earthquake, for instance, 74% of DYFI responses were from urban areas, while only 34% of traditional accounts were from urban centers.

"Being Indian, I know firsthand that there are disparities on numerous fronts in my country," said Martin. "Nonetheless the stark contrast in urban and rural DYFI reports from India for the three earthquakes that were analyzed for this study was still surprising to me. I did not anticipate that the social disparities would show up in something as seemingly far removed as earthquake felt reports."

Further development of online systems will potentially make them more inclusive; for example, including online surveys in multiple languages, and designing easy-to-use apps. It also remains important, the researchers said, to survey earthquake effects using media reports, which the study showed tend to be more inclusive in India.

Hough noted that the geoscience community is grappling with how underrepresentation affects its workforce, but studies like this show how underrepresentation "is actually an issue for science itself."

"You can connect the dots, I think," she said. "If you don't have a diverse community of scientists, you don't have people who are asking the right questions."