Culture

A year into the COVID-19 pandemic, mass vaccinations have begun to raise the tantalizing prospect of herd immunity that eventually curtails or halts the spread of SARS-CoV-2. But what if herd immunity is never fully achieved - or if the mutating virus gives rise to hyper-virulent variants that diminish the benefits of vaccination?

Those questions underscore the need for effective treatments for people who continue to fall ill with the coronavirus. While a few existing drugs show some benefit, there's a pressing need to find new therapeutics.

Led by The University of New Mexico's Tudor Oprea, MD, PhD, scientists have created a unique tool to help drug researchers quickly identify molecules capable of disarming the virus before it invades human cells or disabling it in the early stages of the infection.

In a paper published this week in Nature Machine Intelligence, the researchers introduced REDIAL-2020, an open source online suite of computational models that will help scientists rapidly screen small molecules for their potential COVID-fighting properties.

"To some extent this replaces (laboratory) experiments, says Oprea, chief of the Translational Informatics Division in the UNM School of Medicine. "It narrows the field of what people need to focus on. That's why we placed it online for everyone to use."

Oprea's team at UNM and another group at the University of Texas at El Paso led by Suman Sirimulla, PhD, started work on the REDIAL-2020 tool last spring after scientists at the National Center for Advancing Translational Sciences (NCATS) released data from their own COVID drug repurposing studies.

"Becoming aware of this, I was like, 'Wait a minute, there's enough data here for us to build solid machine learning models,'" Oprea says. The results from NCATS laboratory assays gauged each molecule's ability to inhibit viral entry, infectivity and reproduction, such as the cytopathic effect - the ability to protect a cell from being killed by the virus.

Biomedicine researchers often tend to focus on the positive findings from their studies, but in this case, the NCATS scientists also reported which molecules had no virus-fighting effects. The inclusion of negative data actually enhances the accuracy of machine learning, Oprea says.

"The idea was that we identify molecules that fit the perfect profile," he says. "You want to find molecules that do all these things and don't do the things that we don't want them to do."

The coronavirus is a wily adversary, Oprea says. "I don't think there is a drug that will fit everything to a T." Instead, researchers will likely devise a multi-drug cocktail that attacks the virus on multiple fronts. "It goes back to the one-two punch," he says.

REDIAL-2020 is based on machine learning algorithms capable of rapidly processing huge amounts of data and teasing out hidden patterns that might not be perceivable by a human researcher. Oprea's team validated the machine learning predictions based on the NCATS data by comparing them against the known effects of approved drugs in UNM's DrugCentral database.

In principle, this computational workflow is flexible and could be trained to evaluate compounds against other pathogens, as well as evaluate chemicals that have not yet been approved for human use, Oprea says.

"Our main intent remains drug repurposing, but we're actually focusing on any small molecule," he says. "It doesn't have to be an approved drug. Anyone who tests their molecule could come up with something important."

An abnormal build up of carbohydrates -- sugars and starches -- in the kernels and leaves of a mutant line of corn can be traced to one misregulated gene, and that discovery offers clues about how the plant deals with stress.

That is the conclusion of Penn State researchers whose previous study discovered the Maize ufo1 gene responsible for creating the mutant corn line. They now are assessing its effects and potential for inclusion in breeding new lines of corn better able to thrive in a warming world. The finding of higher sugar levels in plant tissues in their latest study is just another aspect for plant geneticists to consider.

"This discovery has implications for food security and breeding new crop lines that can better deal with a changing climate -- with corn, there is still a lot to be done," said Surinder Chopra, professor of maize genetics in the College of Agricultural Sciences. "In fact, there is a great deal of genetic and phenotypic diversity in corn, and we can use that diversity and ask the question, 'How is the ufo1 gene distributed in the existing 10,000 germplasm lines?'"

Can plant geneticists select for some of that diversity and incorporate the ufo1 gene to improve corn? That is the question Chopra is trying to answer, starting with this new study that found elevated sugar levels in seeds and leaves of the mutant corn line.

What traits can be improved in corn with the ufo1 gene's help?

"Certainly, stress tolerance, but also likely seed development, which has implications in seed yield as well as improved biomass," Chopra said. "And we would like to develop a better plant type that could grow in more dense culture, yet still be more productive. And finally, we need to look at resiliency and sustainability. Can we breed corn lines that get the same amount of yield with lower fertilizer inputs and need less water?"

Chopra started research on the Maize ufo1 gene because of its association with an orange/red pigmentation in the mutant corn line. Celebrated maize geneticist Charles Burnham, at the University of Minnesota, identified this conspicuous ufo1 mutant circa 1960. Another well-known maize geneticist, Derek Styles, with the University of Victoria, Canada, a student of Burnham's, then chose the name, which stands for "unstable factor for orange."

In 1997, Styles sent Chopra seeds for the mutant line. Since then, he introgressed its genes into an inbred line maintained by his research group at Penn State. In 2019, Chopra solved the genetic mystery behind ufo1.

However, it turns out that the gene controls many plant characteristics beyond pigmentation. Still, ufo1 is just one gene, and it is not functioning alone in the corn genome, Chopra noted.

There are more than 30,000 genes in the maize plant, so it is important to learn how ufo1 interacts with other genes before plant geneticists could use it in breeding a new type of crop, he added. "In order to go to the breeding aspect, we first need to learn how this gene actually functions," Chopra said. "We need to learn about how it partners with proteins, and learning about those protein interactions will be the goal of future research."

But for now, this study revealed how accumulation of sugars in corn seed is modified in the presence or absence of the ufo1 gene, according to Debamalya Chatterjee, doctoral student in agronomy, who spearheaded the research.

"Down the road, we could use this knowledge of the ufo1 gene in breeding, to perform better crosses that make more resilient and more productive hybrids, where sugars and starches are in balance," he said.

The researchers took a step in that direction today (May 3) when they published their findings in Plant Physiology, reporting that the maize ufo1 mutant gene affects cell differentiation, influences carbohydrate and hormone accumulation in the plant, and modulates expression patterns of essential genes involved in corn seed development.

All plant materials analyzed in the study were grown during 2016-2020 summers at the Russell E. Larson Agricultural Research Center, Rock Springs, and in greenhouse and plant growth chamber facilities at Penn State's University Park campus. Inbreds and genetic stocks were obtained from the Maize Genetics Cooperation Stock Center managed by the U.S. Department of Agriculture's Agricultural Research Service.

May 3, 2021

Using social values for profit cheapens them, a new study cautions.

Toronto - Businesses sometimes align themselves with important values such as a clean environment, feminism, or racial justice, thinking it's a win-win: the value gets boosted along with the company's bottom line.

But be careful, warns new research from the University of Toronto's Rotman School of Management.

Using these values primarily for self-interested purposes such as profit or reputation can ultimately undermine their special status and erode people's commitment to them.

"It sets a different norm for appropriate use of the value," says research author Rachel Ruttan, an assistant professor of organizational behaviour and human resources at the Rotman School, who co-authored the study with Loran Nordgren, a professor of management and organizations at the Kellogg School of Management. "These are things that we are supposed to pursue as ends in themselves and this is shifting how people might think about that."

In multiple studies using hundreds of participants, Dr. Ruttan found that people exposed to more self-interested uses of "sacred" values not only demonstrated diminished regard for those values subsequently but were less willing to donate to causes that supported them.

A social media post wishing "Happy Earth Day," from NASCAR, the stock car racing organization, reduced people's subsequent respect for the annual environmental protection event, compared to a similar post from a group dedicated to ecological conservation. In another study, participants aware of a 2015 "paid patriotism" scandal, where the National Football League was revealed to have accepted money from the U.S. military for game-day flag presentations and the honouring of military members, showed less concern for patriotic displays than those unaware of the case.

Participants in yet another study were less likely to donate to an environmental cause after reading about a fictional report in which many organizations had launched pro-environmental campaigns in pursuit of profits.

Typically, values that are obviously under threat trigger people's moral outrage, such as when money intended to promote workplace diversity is reallocated to cover other expenses. But that impulse isn't switched on when the value appears to be at least superficially supported -- even if it's really being leveraged for a very different purpose. That less pure use gets subtly normalized and is how the value's status ends up corrupted, says Prof. Ruttan.

Still, it is possible for an organization to associate itself with social values and not diminish them, she says. But organizations must show "legitimate commitment" toward the value. She points to the example of an environmentally branded clothing company that discourages customers from purchasing replacements for its jackets, offering to repair their worn ones instead.

"That is a real commitment to sustainability, where they're actively taking on a cost," says Prof. Ruttan.

Consumers, meanwhile, should think critically about the campaigns they see and resist taking automatic cues from them about how to think about the values these campaigns appear to promote.

"Grassroots action is still important and upholding our own commitment to these causes is still very valuable in the face of all of this information," says Prof. Ruttan.

TORONTO - Scientists at the Krembil Brain Institute, part of University Health Network (UHN), in collaboration with colleagues at the Centre for Addiction and Mental Health (CAMH), have used precious and rare access to live human cortical tissue to identify functionally important features that make human neurons unique.

This experimental work is among the first of its kind on live human neurons and one of the largest studies of the diversity of human cortical pyramidal cells to date.

"The goal of this study was to understand what makes human brain cells 'human,' and how human neuron circuitry functions as it does," says Dr. Taufik Valiante, neurosurgeon, scientist at the Krembil Brain Institute at UHN and co-senior author on the paper.

"In our study, we wanted to understand how human pyramidal cells, the major class of neurons in the neocortex, differ between the upper and bottom layers of the neocortex," says Dr. Shreejoy Tripathy, a scientist with the Krembil Centre for Neuroinformatics at CAMH and co-senior author on this study.

"In particular, we wanted to understand how electrical features of these neurons might support different aspects of cross-layer communication and the generation of brain rhythms, which are known to be disrupted in brain diseases like epilepsy."

With consent, the team used brain tissue immediately after it had been removed during routine surgery from the brains of patients with epilepsy and tumours. Using state-of-the-art techniques, the team was then able to characterize properties of individual cells within slices of this tissue, including visualizations of their detailed morphologies.

"Little is known about the shapes and electrical properties of living adult human neurons because of the rarity of obtaining living human brain tissue, as there are few opportunities other than epilepsy surgery to obtain such recordings," says Dr. Valiante.

To keep the resected tissue alive, it is immediately transferred into the modified cerebrospinal fluid in the operating room then taken directly into the laboratory where it is prepared for experimental characterization.

It is rare to study human tissue because accessing human tissue for scientific inquiries requires a tight-knit multidisciplinary community, including patients willing to participate in the studies, ethicists ensuring patient rights and safety, neurosurgeons collecting and delivering samples, and neuroscientists with necessary research facilities to study these tissues.

After initial analysis, members of the Krembil Centre for Neuroinformatics used further large-scale data analysis to identify the properties that distinguished neurons in this cohort from each other. These properties were then compared to those from other centres doing similar work with human brain tissue samples, including the Allen Institute for Brain Sciences in Seattle, Washington.

Noted in the team's findings:

A massive amount of diversity among human neocortical pyramidal cells

Distinct electrophysiological features between neurons located at different layers in the human neocortex

Specific features of deeper layer neurons enabling them to support aspects of across-layer communication and the generation of functionally important brain rhythms

The teams also found notable and unexpected differences between their findings and similar experiments in pre-clinical models, which Dr. Tripathy believes is likely reflective of the massive expansion of the human neocortex over mammalian and primate evolution.

"These results showcase the notable diversity of human cortical pyramidal neurons, differences between similarly classified human and pre-clinical neurons, and a plausible hypothesis for the generation of human cortical theta rhythms driven by deep layer neurons," says Dr. Homeira Moradi Chameh, a scientific associate in Dr. Valiante's laboratory at Krembil Brain Institute and lead author on the study.

In total, the team was able to characterize over 200 neurons from 61 patients, reflecting the largest dataset of its kind to-date and encapsulating almost a decade's worth of painstaking work at UHN and the Krembil Brain Institute.

"This unique data set will allow us to build computational models of the distinctly human brain, which will be invaluable for the study of distinctly human neuropathologies," says Dr. Scott Rich, a postdoctoral research fellow in Dr. Valiante's laboratory at the Krembil Brain Institute and co-author on this work.

"For instance, the cellular properties driving many of the unique features identified in these neurons are known to be altered in certain types of epilepsy. By implementing these features in computational models, we can study how these alterations affect dynamics at the various spatial scales of the human brain related to epilepsy, and facilitate the translation of these 'basic science' findings back to the clinic and potentially into motivations for new avenues in epilepsy research."

"This effort was only possible because of the very large and active epilepsy program at the Krembil Brain Institute at UHN, one of the largest programs of its kind in the world and the largest program of its kind in Canada," says Dr. Valiante.

LUGANO, Switzerland, 3 May 2021 - As breast cancer becomes a largely curable disease, with more than 70% of women surviving at least 10 years after diagnosis across most of Europe thanks to early detection and treatment, (1) the quality of life after cancer has become an important aspect of the patient journey - one that may be inadequately addressed with current standards of follow-up. A study presented at the ESMO Breast Cancer 2021 Virtual Congress (2) has shown that breast cancer survivors differ widely in the burden of symptoms they experience after the end of treatment and thereby revealed an unmet need for tailored approaches to follow-up care. (3)

Lead author Kelly de Ligt from the Netherlands Cancer Institute in Amsterdam explained the rationale for the study: "Follow-up programmes are different in each country. In the Netherlands, for instance, breast cancer survivors have an annual visit with their treating physician for a follow-up period of five years, or 10 years if they are young. Previous studies had assessed side-effects experienced after the end of treatment as independent items, but in reality, survivors usually experience multiple symptoms that can add up and weigh heavily on their daily life. We wanted to measure the overall burden on their health-related quality of life and see if any patterns emerged that would better inform us on which individuals require active symptom management."

Women who had been surgically treated with or without adjuvant treatment for breast cancer stages I to III were selected between one and five years after diagnosis from the Netherlands Cancer Registry, which contains comprehensive information about diagnosis and treatment for all cancer patients in the Netherlands. A total of 404 participating survivors were questioned about their experienced burden for fatigue, nausea, pain, shortness of breath, insomnia, appetite, constipation, diarrhoea, as well as emotional and cognitive symptoms.

Analysis of their answers allowed the identification of three main subgroups of breast cancer survivors experiencing low, intermediate and high symptom burdens respectively. "In the low-burden group, to which almost a third of patients belonged, women were less affected compared to the average found among a representative sample of 1,300 women of the general population in the Netherlands, who filled out the same questionnaire," de Ligt elaborated. "I was pleasantly surprised to find that so many survivors were doing as well or even better than the average Dutch woman." A further 55% of study participants were classed in the intermediate-burden subgroup, which had similar results to the general population, though their scores for fatigue, insomnia and cognitive symptoms were slightly worse.

Within the high-burden subgroup, meanwhile, de Ligt was alarmed by the results observed: "This was the smallest group, only 15% of our population, but nonetheless, one in six women in our study had worse scores than the general population for all symptoms - and the differences, ranging between 15 and 20 percentage points, were large enough to be considered not just statistically significant, but clinically relevant as well," she explained. According to de Ligt, these findings confirm the necessity for personalised approaches to the follow-up of cancer patients, some of whom still require special attention as late as five years after diagnosis.

The study results further showed that patients with comorbidities such as heart disease and diabetes were more likely to experience a high symptom burden. "This association was so strong in our analysis that we were not able to link the level of symptom burden patients reported with the type of therapy they had received. However, because we measured symptom burden and comorbidities at the same time in the study, we cannot draw conclusions from these findings alone," de Ligt added. "Future research should attempt to measure patients' health-related quality of life through Patient Reported Outcome Measures (PROMs) before the start of treatment for breast cancer and afterwards to allow us to measure the effect of the therapy."

Nadia Harbeck, LMU University Hospital of Munich, Germany, a breast cancer expert not involved in the study, commented: "As a clinician, I was surprised that the analysis revealed no associations between the treatments patients had received and the burden-related subgroup they belonged to, because I would think that any therapy we administer - for example having just surgery plus radiotherapy versus undergoing an extensive course of systemic treatment both before and after the surgery - does have an impact on the symptom burden patients experience over the five-year follow-up period. Gathering data from a larger group of women could help us to gain more insight, and it would be interesting to see this study reproduced in other countries to ascertain whether there are also cultural and social factors impacting patients' answers."

She added: "In my experience, some patients could do without the quarterly visits to their outpatient practitioner, which are part of the standard follow-up protocol in Germany, while others do need that regular interaction with a physician. It is not always easy to distinguish between them initially, because when I see my patients right after treatment, they are so busy returning to their normal lives that a lot of the physical and emotional burden they feel is not there yet or is suppressed. In addition, some patients are not naturally communicative about their personal experience with the disease. This new data shows that if we specifically assessed women's needs in this respect at different stages in their follow-up journey, we could adapt the care we offer not just to their risk of recurrence, but also to their physical and mental state over time. The gynaecologists, family doctors and nurses who help us in follow-up care should be made aware of these findings."

The important role of outpatient healthcare providers in breast cancer patients' post-treatment journey is confirmed by another study which has revealed that among 621 breast cancer patients treated at Oulu University Hospital in Finland, between 2003 and 2013, only a minority (25%) of cancer relapses were detected during pre-planned control visits. (4) More than half of the 95 cases of recurrence were identified as a result of patients contacting their physician about a new symptom they were experiencing, most commonly pain.

"It is essential to reinforce the message to patients that if they feel anything unusual, they should mention it without delay to a medical professional, along with the information that they are a breast cancer survivor, to ensure that any connection with the cancer is not missed - especially when a lot of time has passed since the initial diagnosis," Harbeck emphasised. "As anticancer therapies have become more effective, the pattern of metastasis has changed over the years and can affect any organ, so there is not just one main symptom or area of the body to be attentive to. Patients therefore need to be well-informed and must be made to feel comfortable about contacting their physician outside of their planned consultations if necessary."

A research team from the Institut de Neurociències at the Universitat Autònoma de Barcelona (INc-UAB) has showed that inhibition through a drug of the Tac2 neuronal circuit, involved in the formation of the memory of fear, has opposite effects on the ability to remember aversive events in mice according to sex: it is reduced in male mice and increased in female mice.

Is the first time that a drug has been shown to produce this opposite effect on the memory of male and female mice. The study also evidences that opposing molecular mechanisms and behaviours can occur in memory formation depending on sex. The study has been published in Nature Communications.

The research group on Translational mechanisms of the memory of fear led by Raül Andero, professor and researcher at ICREA, has been studying the functioning of fear memory for years to find treatments for pathologies associated with traumatic experiences, such as post-traumatic stress and phobias.

The research team had identified that the Tac2 circuit, located in the amygdala, could be temporarily blocked by the effect of a drug they are studying. This drug, called Osanetant, was able to reduce the capacity to recall traumatic events in male mice. In the study published now, they discovered that this same drug produces the opposite effect in female mice, increasing their fear memory.

This opposite effect is explained by the fact that, in blocking the Tac2 pathway, the drug interacts with the neuronal receptors of two sex hormones: testosterone in males and estrogen in females. In addition, it has been observed that hormonal fluctuations during the oestrous cycle in female mice, equivalent to the menstrual cycle in women, vary the effects of the drug on the ability to remember aversive events.

''These results demonstrate the ability that hormones have to modulate the formation of fear memories, and show the need to consider sex differences and hormonal cycles in the design of pharmacological treatments for psychiatric disorders'', says Antonio Florido, INc-UAB predoctoral researcher and first author of the article.

In the field of neurosciences, only one study in females is published for every 5.5 done in males. And research on Tac2 pathway has also been done mostly in males so far.

"Understanding how and why memory processes differ between sexes is key to designing treatments for fear disorders, especially considering that women are the ones who most often present these types of disorders. Some drugs that are already used may not have the expected effects on them", says Raül Andero, the study coordinator. "Our findings may help raise awareness of the need to do research differentiating by sex and promote basic and clinical studies that include the female sex", he adds.

The drug studied is not new, but it is safe for use in humans. However, at the moment it is not being used to treat any disease. Dr. Andero's group is now investigating its potential use in treating fear disorders differently by sex.

In this research, which has been carried out in collaboration with other INc-UAB research groups and the Hospital del Mar Medical Research Institute (IMIM), scientists show the importance of personalized medicine. "Mental health drugs that we have today, not only for memory-related disorders, are not specific enough and may be causing contrary effects to those desired", they conclude.

Diatoms are tiny unicellular plants -- no bigger than half a millimeter -- which inhabit the surface water of the world's oceans where sunlight penetration is plenty. Despite their modest size, they are one of the world's most powerful resources for removing carbon dioxide (CO2) from the atmosphere. They currently remove, or "fix," 10-20 billion metric tons of CO2 every year by the process of photosynthesis. But not much is known about which biological mechanisms diatoms use, and whether these processes might become less effective with rising ocean acidity, temperatures, and, in particular, CO2 concentrations. A new study in Frontiers in Plant Science shows that diatoms predominantly use one pathway to concentrate CO2 at the vicinity of carbon fixing enzyme and that this continues to operate even at higher CO2 concentrations.

"We show that marine diatoms are super smart in fixing atmospheric CO2 even at the present-day level of CO2 -- and the variability in surface seawater CO2 levels did not impact the gene expression and abundance of the five key enzymes used in carbon fixation," says the group leader of the study, Dr Haimanti Biswas from the National Institute of Oceanography-CSIR (Council of Scientific and Industrial Research), India. "This answers a key question about how marine diatoms may respond to the future increase in atmospheric CO2 levels."

The plant kingdom has evolved a wide range of mechanisms for concentrating CO2 from the air, or water, and transforming it into organic carbon. In this way, plants convert CO2 into glucose and other carbohydrates, which they use as building blocks and energy storage. But these different mechanisms have varied strengths and weaknesses. Somewhat ironically, the only carbon-fixing enzyme, RuBisCO, is notoriously inefficient at fixing CO2 and hence plants need to keep CO2 levels high In the vicinity of this enzyme.

To better understand which mechanism diatoms use to concentrate CO2, Biswas and her collaborators, Drs Chris Bowler and Juan Jose Pierella Karluich from the Institut de Biologie de I'Ecole Normale Supérieure, Paris, France, mined a data set from the Tara Oceans research expedition. The international Tara expedition collected marine plankton samples from around the world over several years (2009 to 2013). These included more than 200 metagenomes (which show the abundance of the genes responsible for the five key enzymes) and over 220 metatranscriptomes (showing expression of the genes for the five key enzymes) from diatoms of different size classes.

Biswas and her collaborators were particularly interested in how often the genes of five key carbon-fixing enzymes are present, and whether there were any differences in their abundance and expression levels depending on location and conditions. Across all of the samples measured, one enzyme was roughly ten times more abundant than any of the other enzymes. This enzyme -- called carbonic anhydrase -- is especially informative because it also confirms that diatoms are actively pumping in dissolved CO2 inside the cell, as opposed to biochemically transforming CO2 first.

The team also observed complex different patterns of the key enzymes' gene expression, which varied depending on latitude and temperature. The researchers hope to learn more using new datasets from more widely-traveled future expeditions.

"So far, our study indicates that despite variability in CO2 levels, these tiny autotrophs are highly efficient in concentrating CO2 inside the cell," says Biswas. "That's the probable reason for their ability to fix nearly one-fifth of the global carbon fixation on earth."

The legacy of systemic racism in the U.S impacts psychosis risk at the individual and neighborhood level, according to a definitive review published online today. Researchers examined U.S. based evidence connecting social and environmental factors with outcomes relating to psychotic experiences, including schizophrenia.

The review examined potential risk factors and influence of structural racism within three key areas. These included disparities in neighborhoods; trauma and stress experienced at both collective and individual levels; and complications experienced around pregnancy.

Disparities in U.S. neighborhoods perpetuate disadvantage for racially minoritized communities through inequitable access to healthcare, healthy foods, education and employment opportunities, and safe housing, the authors note. These disadvantages are associated with cumulative stress and, some research suggests, heightened risk for psychosis.

A history of trauma is common among people with schizophrenia and more than 85% report at least one adverse childhood experience. Research has associated multiple trauma experiences with increased risk of psychosis. Among people experiencing psychosis, rates of trauma and adversity are significantly higher in marginalized racial groups compared to white people.

Several obstetric complications have been associated with increased risk for psychotic disorders, such as infections, maternal stress and an increase in maternal inflammation. Black women in the U.S. are at substantially increased risk for many obstetric complications compared to white women.

"Being a particular race in and of itself is not the determinant; the systematic racism that constructs the social milieu makes it relevant," the authors conclude.

"Our review suggests the legacy of structural racism in the U.S. is a fundamental cause of racial inequities in social determinants of psychosis," said lead author Deidre M. Anglin, Ph.D., with City College of New York, City University of New York. "Funding priorities, training, and intervention development in North American psychiatry must shift to reflect this evidence."

New research has shown that COVID-19 infections in healthcare workers during the first wave of the pandemic provided an accurate sample of the general population, suggesting that data from healthcare workers could be used to estimate the severity of future viruses more quickly.

The study, led by researchers from RCSI University of Medicine and Health Sciences in collaboration with IBM Research, is published in PLOS ONE.

The researchers analysed the infection data from healthcare workers and the progression of the first wave of the COVID-19 outbreak using the reported daily infection numbers in Ireland. Using similar data in four other countries (Germany, UK, South Korea and Iceland), computer models showed how the disease progressed in different countries related to their approach to testing, tracing and lockdown restrictions.

Healthcare workers in Ireland made up 31.6% of all test-confirmed infections while only representing 3% of the population. However, the researchers found that the healthcare worker data closely related to that of the entire population after using software to create a more accurate picture of how widespread the disease was.

This suggests that governments could use data from only healthcare workers to inform decisions on whether to implement restrictions, wide-scale testing and contact tracing for future viruses.

"As we have seen with the COVID-19 pandemic, implementing countermeasures early can save lives and reduce the spread of the disease," said RCSI Professor of Chemistry Donal O'Shea, who led the work.

"However, wide-scale testing can take time to set up, delaying decisions and costing lives. While the healthcare population is no longer an accurate sample of the general population for COVID-19 due to different vaccination rates, governments could use data from their healthcare worker population to make informed decisions on what measures to implement earlier when future viruses emerge."

The research noted that very few nations were able to set up effective systems that tested the entire population, carried out contact tracing and quarantined those infected with COVID-19.

"Setting up wide-scale testing systems for healthcare workers is much easier than setting up a similar programme for everyone since the infrastructure for testing for diseases is always in place in healthcare settings," said Dr Dan Wu, honorary lecturer in the RCSI Department of Chemistry and first author on the paper.

"A screening programme that tested all healthcare workers would have the additional benefit of catching asymptomatic spread of the disease since all healthcare workers would be tested. If governments could catch highly infectious diseases and implement countermeasures early, this could possibly prevent new viruses from erupting into another epidemic/pandemic."

Scientists have revealed how an antibiotic of 'last resort' kills bacteria.

The findings, from Imperial College London and the University of Texas, may also reveal a potential way to make the antibiotic more powerful.

The antibiotic colistin has become a last resort treatment for infections caused by some of the world's nastiest superbugs. However, despite being discovered over 70 years ago, the process by which this antibiotic kills bacteria has, until now, been something of a mystery.

Now, researchers have revealed that colistin punches holes in bacteria, causing them to pop like balloons. The work, funded by the Medical Research Council and Wellcome Trust, and published in the journal eLife, also identified a way of making the antibiotic more effective at killing bacteria.

Colistin was first described in 1947, and is one of the very few antibiotics that is active against many of the most deadly superbugs, including E. coli, which causes potentially lethal infections of the bloodstream, and Pseudomonas aeruginosa and Acinetobacter baumannii, which frequently infect the lungs of people receiving mechanical ventilation in intensive care units.

These superbugs have two 'skins', called membranes. Colistin punctures both membranes, killing the bacteria. However, whilst it was known that colistin damaged the outer membrane by targeting a chemical called lipopolysaccharide (LPS), it was unclear how the inner membrane was pierced.

Now, a team led by Dr Andrew Edwards from Imperial's Department of Infectious Disease, has shown that colistin also targets LPS in the inner membrane, even though there's very little of it present.

Dr Edwards said: "It sounds obvious that colistin would damage both membranes in the same way, but it was always assumed colistin damaged the two membranes in different ways. There's so little LPS in the inner membrane that it just didn't seem possible, and we were very sceptical at first. However, by changing the amount of LPS in the inner membrane in the laboratory, and also by chemically modifying it, we were able to show that colistin really does puncture both bacterial skins in the same way - and that this kills the superbug. "

Next, the team decided to see if they could use this new information to find ways of making colistin more effective at killing bacteria.

They focussed on a bacterium called Pseudomonas aeruginosa, which also causes serious lung infections in people with cystic fibrosis. They found that a new experimental antibiotic, called murepavadin, caused a build up of LPS in the bacterium's inner skin, making it much easier for colistin to puncture it and kill the bacteria.

The team say that as murepavadin is an experimental antibiotic, it can't be used routinely in patients yet, but clinical trials are due to begin shortly. If these trials are successful, it may be possible to combine murepavadin with colistin to make a potent treatment for a vast range of bacterial infections.

Akshay Sabnis, lead author of the work also from the Department of Infectious Disease, said: "As the global crisis of antibiotic resistance continues to accelerate, colistin is becoming more and more important as the very last option to save the lives of patients infected with superbugs. By revealing how this old antibiotic works, we could come up with new ways to make it kill bacteria even more effectively, boosting our arsenal of weapons against the world's superbugs."

University of South Australia researchers have identified an enzyme that may help to curb chronic kidney disease, which affects approximately 700 million people worldwide.

This enzyme, NEDD4-2, is critical for kidney health, says UniSA Centre for Cancer Biology scientist Dr Jantina Manning in a new paper published this month in Cell Death & Disease.

The early career researcher and her colleagues, including 2020 SA Scientist of the Year Professor Sharad Kumar, have shown in an animal study the correlation between a high salt diet, low levels of NEDD4-2 and advanced kidney disease.

While a high salt diet can exacerbate some forms of kidney disease, until now, researchers did not realise that NEDD4-2 plays a role in promoting this salt-induced kidney damage.

"We now know that both a high sodium diet and low NEDD4-2 levels promote renal disease progression, even in the absence of high blood pressure, which normally goes hand in hand with increased sodium," says Dr Manning.

NEDD4-2 regulates the pathway required for sodium reabsorption in the kidneys to ensure correct levels of salt are maintained. If the NEDD4-2 protein is reduced or inhibited, increased salt absorption can result in kidney damage.

Even people on a low salt diet can get kidney damage if they have low levels of NEDD4-2 due to genetic variations or mutations in the gene.

Prof Kumar says the long-term goal is to develop a drug that can increase NEDD4-2 levels in people with chronic kidney disease (CKD).

"We are now testing different strategies to make sure this protein is maintained at a normal level all the time for overall kidney health," Prof Kumar says.

"In diabetic nephropathy - a common cause of kidney disease - levels of NEDD4-2 are severely reduced. This is the case even when salt is not a factor."

The study also revealed a surprising finding: that the high salt diet induced kidney disease is not always due to high blood pressure.

"In a lot of cases, kidney disease is exacerbated by hypertension, so we wanted to investigate that link in our study. In fact, we found the complete opposite - that a high salt diet caused excessive water loss and low blood pressure. This is significant because it means that kidney disease can also happen in people who don't have high blood pressure," Dr Manning says.

A 2020 Lancet paper estimated that about 700 million people - or 10 per cent of the world's population - suffer from chronic kidney disease, which represents a 29 per cent increase in the past 30 years.

The huge spike in CKD is mainly attributed to a global obesity epidemic in recent decades, leading to diabetes, one of the leading causes of chronic kidney disease along with high blood pressure.

World Health Organization statistics reveal a 300 per cent increase in diabetes between 1980 and 2014, making it one of the top 10 causes of death worldwide and showing the gravity of the problem facing scientists trying to tackle kidney disease.

"Obesity and lifestyle are two main factors driving chronic kidney disease but there are other things at play as well," says Dr Manning. "Acute kidney injuries, drugs taken for other conditions, high blood pressure and a genetic predisposition can also cause it."

Pioneering neural recordings in patients with Parkinson's disease by UC San Francisco scientists lays the groundwork for personalized brain stimulation to treat Parkinson's and other neurological disorders.

In a study published May 3rd in Nature Biotechnology, UCSF Weill Institute for Neurosciences researchers implanted novel neurostimulation devices that monitor brain activity for many months, with and without deep brain stimulation (DBS) therapy. Pairing the brain recordings with wearable monitors of movement, they identified patterns of brain activity corresponding to specific movement abnormalities associated with Parkinson's. Their research provides the first evidence, during normal activities of daily living, for a long-held hypothesis that Parkinson's symptoms are related to erratic brain wave patterns, and demonstrate how DBS restores order to patient brain waves.

"We can record hundreds of hours of brain wave activity wirelessly as patients go about normal activities," said Philip Starr, MD, PhD, the Dolores Cakebread Professor of Neurological Surgery at UCSF and senior author of the study. "It allows us, really for the first time, to understand the brain activity behind specific neurological problems as they occur in the real world."

Parkinson's disease is a degenerative neurological disorder that causes slow movement (bradykinesia), trouble walking, and tremors, as well as symptoms unrelated to movement. According to the Parkinson's Foundation, some 60,000 Americans are diagnosed with Parkinson's disease every year. The exact cause of Parkinson's is not known, but all patients show decreased levels of dopamine - a neurotransmitter that regulates motivation in the brain.

It's long been suspected that erratic brain wave patterns also play a role in triggering Parkinson's symptoms. Previous research in monitoring brain wave activity of Parkinson's patients has been limited to short periods in clinical settings. This greatly limits the amount of data available for analysis - providing a limited glimpse of patient brain activity which cycles and changes throughout the day.

Starr and study lead author Ro'ee Gilron, PhD, a postdoctoral scholar in the Department of Neurological Surgery, sought to get a more complete picture. They implanted small sensors that measure electrical activity into the subthalamus and motor cortex brain areas of five patients with Parkinson's disease. These sensors were connected to pulse generators enabled to sense brain activity. This allowed for continuous recording of brain activity while patients went about their daily routine.

Months of recordings produced a massive amount of data. To sort through it all, the researchers developed an algorithm to compare brain wave activity with data recorded from movement-sensing devices that patients wore on their wrists. They discovered that periods of dyskinesia (excessive movement induced by medications) and bradykinesia corresponded with exaggerated brain waves in specific frequency bands, both in the subthalamus and in motor cortex.

After months of recording and analysis, the researchers went further and measured the effect of DBS on the patients. DBS delivers electrical impulses into the brain and has long been used to ameliorate the symptoms of Parkinson's disease, though why it worked was not previously understood. This study demonstrated that deep brain stimulation appears to improve Parkinson's symptoms by regulating patients' erratic brain wave patterns, partly by suppressing lower frequency waves that inhibit movement, and regulating higher frequency waves that promote movement.

Previous studies using implanted recording systems could not record the effects of active stimulation on brain wave activity because the electrical signals created by stimulation caused recording interference. In the new study, Gilron and colleagues developed a workaround using the same principal used in noise cancelling headphones. By offsetting the electrical waves created by stimulation, the researchers could make the signals cancel each other out, allowing for accurate recording of brain waves by the recording lead.

"This is the first time we've been able to measure the effect of continuous stimulation on brain waves," said Gilron. "We've done deep brain stimulation in hundreds of thousands of patients before without any way to monitor the immediate effect. It was like trying to treat blood pressure without measuring it."

These broad findings help clarify some underlying factors in Parkinson's Disease, but every Parkinson's patient will likely have their own unique brain wave fluctuations. The researchers say that this is exactly why continuous neural recording is so crucial to successful treatment. The massive dataset accumulated from patient recordings helps to reveal the most minute brain wave patterns that correlate with Parkinson's symptoms. With proper analysis, onset of Parkinson's symptoms could be anticipated, and brain wave patterns corrected when symptoms manifest.

"It's like the Hubble Space Telescope," said Gilron. "We could view the night sky before it, but Hubble allowed us to see much greater detail and volume and it led to unique discoveries. I hope that this technique will as well."

The next step for the researchers is a randomized clinical trial including 10 patients. The researchers believe that this will greatly accelerate individualized treatments for Parkinson's disease because new algorithms to identify symptom patterns can be tested immediately, as opposed to the years and sometimes decades involved in developing new medications.

The findings also have potential beyond Parkinson's disease, the researchers say. Numerous neurological disorders related to erratic brain wave activity like epilepsy, chronic depression and chronic pain could likely be treated in the same way -- through real-time monitoring of brain activity and personalized neuromodulation.

"We're looking at the Parkinson's population as a way to develop this platform," said Starr. "Hopefully this will be utilized in disorders where we currently don't have any effective stimulation therapies."

Blood may seem like a simple fluid, but its chemistry is complex. When too much potassium, for instance, accumulates in the bloodstream, patients may experience deadly irregular heart rhythms.

Cardiovascular scientists at Virginia Tech's Fralin Biomedical Research Institute at VTC are studying why.

In a new study, published in Pflügers Archiv European Journal of Physiology, the research team led by Steven Poelzing, associate professor at the institute, describes how subtle changes in potassium, calcium, and sodium levels regulate heartbeats.

Poelzing says that the results could help researchers and physicians understand the nuances of cardiac arrythmias, as well as a group of genetic disorders that impact sodium channel function, such as Brugada syndrome.

The scientists elevated blood potassium in guinea pigs, creating a condition called hyperkalemia, which causes some of the heart's key electrical conduits, sodium channels, to shut down. Next, they increased calcium levels and observed the heart muscle cells pressing closer together. This miniscule motion - spanning mere nanometers - helps preserve electrical conduction in the heart.

"We know the heart is extremely sensitive to changes in blood electrolyte levels, but until recently we didn't have a great picture of how the heart's molecular landscape is remodeled, and how these muscle cells adapt," said Poelzing, who is also an associate professor in the Virginia Tech College of Engineering's department of biomedical engineering and mechanics.

Heart muscle cells primarily pass electrical signals via a network of protein bridges called gap junctions and sodium channels. These pathways let nutrients and positively charged minerals flow between cells. When there are too many positively charged potassium ions in the blood, however, the cells get overstimulated and temporarily block signaling channels.

"This can be dangerous when sodium channels get stuck in a half-closed state. The cell isn't dying, but it's not as electrically active as it once was. This can cause dangerous heart arrythmias and sudden cardiac death," Poelzing said.

When the heart's core electrical pathways falter, heart muscle cells press closer together, allowing them to sense subtle electric fields generated by neighboring cells. This secondary form of cell-to-cell signaling is known as ephaptic coupling.

"Ephaptic coupling appears to address the effects of a functional loss of sodium channels, in this case caused by high potassium, and helps keep the current flowing properly across the heart muscle," Poelzing said.

Over the course of the eight-year study, Poelzing's team tested different concentrations of sodium and calcium to treat the electrical defects associated with high potassium to see how the heart would respond. They discovered that increasing sodium and calcium levels together greatly reduced the distances between cells, providing a substantial improvement in cardiac conduction.

In the clinic, human patients with hyperkalemia who develop abnormal heart rhythms are administered intravenous calcium gluconate. Poelzing's findings help explain why elevating calcium levels under these certain clinical conditions is beneficial.

"What surprised me is that such small changes in electrolyte values have such dramatic effects," said Ryan King, the study's first author and a postdoctoral research associate in the lab of Scott Johnstone, an assistant professor at the Fralin Biomedical Research Institute. "The ranges of sodium, calcium, and potassium we used in this study are not exaggerated, extreme ionic conditions that you'd never find in a clinical setting. They're all within ranges that could show up in metabolic blood panels."

Boston, MA (May 2, 2021) - A new study, presented today at the AATS 101st Annual Meeting, finds that AATS Foundation fellowships support success in academic surgery career tracks. The AATS Foundation has two primary grant funding mechanisms: the AATS Foundation Scholarship and the Surgical Investigator Award. The study looked at publications, citations, NIH funding, and leadership position of awardees, among other factors.

Results show that recipients of both the AATS Surgical Investigator award and the Foundation Scholarship demonstrate sustained scholarship with peer reviewed publications and a high rate of receiving one or more NIH grants. The AATS grants place individuals on a career path for academic surgery with impressive scholastic contributions and ascending to leadership positions.

The AATS Foundation Grant has been awarded to 42 individuals. Awardees have a median of 4,733 citations. During the four-year window following the award, awardees published a median of 23 manuscripts, with a median of 364 citations. Subsequent NIH grant funding was attained by 44 percent of awardees, who al; secured 2-3 additional NIH grants. The majority of awardees - 89 percent - have been promoted, with most holding either a clinical directorship or a division chief position.

The Surgical Investigator award has been awarded to 24 surgeons. In the four-year window since the grant was awarded, recipients generated a media of 37 publications with a media of 632 citations. 26 percent secured NIH funding, of which all attained second and third NIH grants. Half of the awardees obtained an academic promotion.

"There's a narrative within academic medicine that surgery is too time consuming to allow for research, and the data here shows that there are real opportunities for surgical researchers that yield results," said Edgar Aranga-Michel, MD/PhD candidate at University of Pittsburgh - CMU. "The AATS fellowships are a success factor that support a career in academic surgery.

Boston, MA (May 2, 2021) - A new study, presented today at the AATS 101st Annual Meeting, found that heart transplantation using donation after cardiac death (DCD) with normothermic regional perfusion (NRP) is feasible in the United States. Broader application of DCD heart transplantation has the potential to increase cardiac allograft availability by 20-30 percent. Over a one-year period, from January 2020 to January 2021, eight heart transplants were performed using cardiopulmonary bypass (CPB) for immediate regional reperfusion and cardiac unloading to accomplish optimal myocardial salvage. All hearts were successfully resuscitated and weaned from CPB with no inotropic support and all were accepted for transplantation. Post-transplant cardiac function was excellent in all recipients.

Improving the number and quality of organs available for transplantation is a key objective that improves outcomes for patients. The DCD process has been used with success in the United Kingdom, Belgium and Australia. This study is the first to measure outcomes in the United States.

"Our study addresses an important concept - the relative shortage of donors and the need for organs," explained Dr. Nader Moazami, Surgical Director of Heart Transplantation and Mechanical Circulatory Support at NYU Langone Health. "The DCD process taps into potential donors that have been used in the past for abdominal transplants but not for cardiac patients. We are excited about expanding the potential donor pool in the United States."

Preliminary data shows that DCD heart transplant with CPB allows immediate reperfusion and complete unloading of the heart, correction of metabolic derangements and real-time in-situ assessment of the heart prior to acceptance. Post-transplant cardiac function has been excellent in all cases with excellent early survival. This approach is readily adoptable for more widespread use, and will increase donor availability in the United States. During the study, six livers and 14 kidneys were recovered from the same donors, which could indicate success in increasing organ availability for non-cardiac patients as well.

Because the DCD process allows surgeons to resuscitate and assess the organ better before transplantation, the strategy should improve outcomes for patients. "This is the first study of DCD-NRP transplantation in the United States, and we already have many patients at least six months out from the transplant experiencing positive results," explained Deane Smith, MD, Assistant Professor of Cardiothoracic Surgery and Surgical Director of the Adult ECMO Program at NYU Langone Health. "Using traditional methods, there is not an effective way to assess the heart on the pump, but using DCD-NRP, we can measure cardiac output and hemodynamics before a decision is made to accept the heart, and hopefully we will improve the quality of the other organs.