Culture

To splice or not to splice...

In an article published in the journal RNA, Karan Bedi, a bioinformatician in Mats Ljungman's lab, Department of Radiation Oncology at the University of Michigan Medical School, investigated the efficiency of splicing across different human cell types. The results were surprising in that the splicing process appears to be quite inefficient, leaving most intronic sequences untouched as the transcripts are being synthesized. The study also reports variable patterns between the different introns within a gene and across cell lines, and it further highlights the complexity of how newly transcripts are processed into mature mRNAs.

Several processes take place to produce mature mRNAs that then can be exported to the cytoplasm and used as a template for protein synthesis. After initiation of transcription and the go-ahead of elongation to produce the pre-mRNA, introns need to be spliced out and the protein-coding exons connected. At first, pre-mRNA is made as a complementary sequence of the DNA but with slightly different chemistry and includes all the introns. Then the spliceosome machinery, made up of about 300 proteins, assembles "co-transcriptionally" at each intron junction as the RNA emerges from its synthesis. "Splicing is an incredibly complex process because of the great number of proteins involved that repeatedly need to assemble and disassemble at each junction. Also, the speed at which transcription generates RNA is quite fast so the splicing process has to be well organized. Many steps can go wrong and lead to various pathologies, which is why it is so important to have a better understanding of how splicing happens and how it is regulated," said Bedi.

The team started their study by analyzing the large set of Bru-seq data that the Ljungman lab has accumulated over the last 10 years and settled on six cell lines that had deep enough data for a comprehensive analysis of splicing efficiencies genome-wide. The Bru-seq technology was developed in the Ljungman lab and is based on the selective capturing of newly synthesized RNA tagged with bromouridine. Once collected, the nascent Bru-labeled RNAs were sequenced at the University of Michigan Advanced Genomics Core, and Bedi used a custom-designed computational analysis pipeline to analyze the splicing efficiencies across these data sets.

"You have to be able to use samples with a sufficient read-depth to analyze the splicing efficiencies at the junctions between introns and exons," explained Bedi. To do so, he combined sequencing data from many experiments.

In addition to the 300 proteins that remove the introns, other regulating factors participate in the splicing process. The authors identified a number of RNA-binding proteins that have been shown to have variable degrees of binding to introns, or the exon, or to the junction between them.

Bedi concluded his interview with a puzzling question opened for investigation: to have a protein, the cell needs mRNAs that are properly spliced. Why, then, would the cell waste so much energy into making RNAs that are imprecisely spliced? Ljungman points out that the inclusion of introns in our genes has served an important purpose during the evolution of higher eukaryotes in that it allowed for an increased protein diversity by the "re-shuffling" of the coding exon sequences. "If splicing was fully accurate and efficient every time, the diversity of protein-coding sequences would be much lower and thus, we believe, evolution must have shaped a certain degree of 'sloppiness' into the splicing process. Our study is the most comprehensive study of co-transcriptional splicing genome-wide to date and it clearly documents the variability of the splicing process across genes and cell types," added Ljungman.

Splicing is an area of research where much is still to be explored and discovered. Fundamental biology questions and technology development go hand in hand to find answers that contribute to the understanding of the splicing process and for the development of cures for various diseases caused by aberrant splicing.

Mats Ljugman is Professor of Radiation Oncology and of Environmental Health Sciences, and director of the Bru-Seq lab. He is also co-director of the University of Michigan Center for RNA Biomedicine of which the Bru-Seq lab is one of its two core facilities. Areas of expertise of this lab are RNA isolation, cDNA library preparation, and sequencing data analysis. The Bru-Seq lab serves researchers from the University of Michigan, and other institutions in the United States and around the world.

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer's disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer's. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson's disease, six for stroke and one for amyotrophic lateral sclerosis (ALS). The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published July 8 in the journal Nature Neuroscience.

Scientists have worked for decades to develop treatments for Alzheimer's by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don't fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

"In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer's disease," said principal investigator Carlos Cruchaga, PhD, the Reuben Morriss III Professor of Neurology and a professor of psychiatry. "Using Alzheimer's disease samples, we've been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer's."

The scientists focused on protein levels in the brain, cerebrospinal fluid and blood plasma of people with and without Alzheimer's disease. Some of the proteins were made by genes previously linked to Alzheimer's risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

"They are FDA-approved, and all of the safety data on the drugs is available," said Cruchaga, . "With what is already known about the safety of these drugs, we may be able to jump directly to clinical trials."

Cruchaga said the team's focus on protein levels in key tissues has certain advantages over prior efforts to identify genes linked to Alzheimer's.

"The classic genetic studies of Alzheimer's have attempted to correlate genetic mutations with disease, but we know that genes carry the instructions to build proteins and that diseases such as Alzheimer's occur when those protein levels get too high or too low," Cruchaga explained. "To understand the biology of Alzheimer's disease, we should look at proteins rather than only at genes."

As an example, Cruchaga pointed to the APOE gene, which was first linked to Alzheimer's risk decades ago. But even after all this time, it still has not clear how that gene contributes to the disease.

"In this study, we were able to see that APOE alters levels of several proteins in brain tissue and CSF," Cruchaga said. "We also saw changes in proteins linked to another gene called TREM2 that was associated with Alzheimer's risk more recently. Understanding how the protein levels are affected by these risk genes is helping us to identify pathways that lead to disease."

Past research has helped identify about 50 genetic signals linked to Alzheimer's, but only a handful of the genes responsible for those signals have been found. Cruchaga said that focusing on protein levels in tissue may help reveal what's happening with the other 40-plus genetic signals that appear to be connected to Alzheimer's risk.

The researchers analyzed proteins and genes from brain tissue, cerebrospinal fluid and blood plasma from samples gathered from 1,537 people in the U.S. The samples are stored at the Knight Alzheimer's Disease Research Center at Washington University. Half of the samples came from people with a clinical diagnosis of Alzheimer's disease; the other half came from study participants who are considered cognitively normal.

The researchers measured protein levels in the samples from the brain, CSF and plasma. Using statistical techniques, they then connected the protein levels to disease. There were 274 proteins linked to disease in study subjects' CSF, 127 in blood plasma and 32 in brain tissue.

They applied those findings and machine learning techniques to distinguish among the protein differences and zero in on some of the proteins that contribute to damage that leads to Alzheimer's.

"We have targets -- although I'm not saying all of these targets are going to work or that all of the compounds we identified are going to stop the progress of the disease -- but we have a real hypothesis," Cruchaga said. "And we expect it may be possible to move from these genetic studies into real clinical trials quickly. That's a big jump."

*Note: this paper is being presented at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) and is being published in The Lancet Microbe. Please credit both the congress and the journal in your stories*

A new study presented at this year's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) and published in The Lancet Microbe, shows that antibodies generated by CoronaVac, an inactivated COVID-19 vaccine, work less well against the P.1 Brazil (Gamma) variant.

It also suggests that the P.1 variant may be able to reinfect individuals who previously had COVID-19.

The SARS-CoV-2 virus spike protein is the primary target of neutralising antibodies - antibodies that block the entry of the virus into cells - including those induced by vaccines. The emergence of variants with multiple mutations in this protein has raised concerns that neutralising antibody responses, and so the effectiveness of vaccination programmes, could be compromised.

The P.1 variant was discovered in Manaus, Brazil, in early January 2021 and has 15 unique mutations. Previous studies have found evidence that it can escape neutralisation by antibodies. However, most of these studies used modified viruses and there is little information on the ability of the wild-type P.1 variant, with a complete set of mutations, to evade neutralising antibodies in individuals previously infected with COVID-19 or vaccinated with an inactivated vaccine.

Dr Jose Luiz Proença-Módena, Laboratory of Emerging Viruses, University of Campinas, Brazil, and colleagues, studied the sensitivity of the P.1 variant to neutralising antibodies present in the serum of 53 individuals who had been vaccinated and 21 who had been previously infected with SARS-CoV-2.

The results were compared with those for a B lineage virus, one of the dominant strains in Brazil before the emergence of the P.1 variant.

The vaccinated group was made up of 18 individuals who had received a single dose and 20 who had received two doses of the CoronaVac inactivated vaccine during the Brazilian vaccination programme, plus 15 participants who had received two doses during a trial.

CoronaVac is one of the main vaccines in Brazil's national immunisation programme and has been approved for emergency use in Brazil, China, Columbia, Indonesia, Mexico and Turkey. Previous research from Brazil has shown it to be 50.7% effective at preventing symptomatic infections.

All the blood samples from individuals with past infections had high concentrations of SARS-CoV-2-specific antibodies. Tests showed the P.1 variant to be less sensitive to these antibodies than the B lineage virus. Antibody concentrations needed to be around nine times higher to neutralise the P.1 variant than the B lineage virus.

Antibodies from vaccinated individuals were also less efficient at neutralising the P.1 variant than the B lineage virus. The antibodies from almost all of the people who had one dose of the vaccine (20-23 days earlier) as part of the immunisation programme and all of those who had two doses in the trial (134-260 days earlier) had no detectable effect on the P.1 variant.

In contrast, the P.1 variant was still sensitive to the antibodies in the plasma of those who had two doses in the immunisation programme (second dose 17-38 days earlier) but to a lesser extent than the B lineage virus.

The authors say: "This study shows that antibodies present in the plasma of people with a history of COVID-19 or individuals vaccinated with CoronaVac were less efficient at neutralising P.1 variant isolates than a B lineage isolate.

"Neutralising antibodies are an important component of the immune response against SARS-CoV-2. Therefore, the capacity of the P.1 variant to evade antibodies present in the plasma of CoronaVac-immunised individuals suggests that the virus can potentially circulate in vaccinated individuals - even in areas with high vaccination rates."

They add: "Our results also suggest that the P.1 variant can escape from neutralising antibody responses generated by previous SARS-CoV-2 infection and thus reinfection might be possible.

"Consequently, continued and enhanced genetic surveillance of SARS-CoV-2 variants worldwide, paired with plasma neutralising antibody assays is required to guide updates of immunisation programmes.

"However, a phase 3 clinical trial showed that CoronaVac can protect against severe COVID-19 and death. Therefore, neutralising antibodies might not be the only contributing factor - the T-cell response may also play an important role in reducing disease severity."

A new UBC Sauder School of Business study shows that depending on how employees understand their boss' motivation, employees can feel anger or guilt, and consequently, react differently to abusive supervision.

Former Apple CEO Steve Jobs was a famously harsh corporate leader, one who pushed his employees to extremes to achieve the company's lofty aims.

But while many aspiring leaders still believe that the "tough love" approach is effective, a new study from UBC Sauder shows that, even when abusive leadership is meant to push employees to new heights, it can land them in deep lows in the long term.

Abusive supervision -- which includes behaviours like yelling at employees, giving them the silent treatment, or putting them down in front of their coworkers -- has long been linked with psychological distress, increased turnover and decreased performance.

But a key question hadn't been properly examined: do employees respond differently when their supervisor's abuse is motivated by different reasons?

For the study, titled The Whiplash Effect: The (Moderating) Role of Attributed Motives in Emotional and Behavioral Reactions to Abusive Supervision, researchers conducted three studies on three continents.

For the first, which involved 1,000 soldiers and officers in the Chinese military, subordinates filled out surveys about the supervision they experienced, the emotions they felt, and how they responded.

The second was a laboratory experiment that involved 156 students and employees at a large American university. There, participants were given different roles as subordinates in a consulting firm, and were subjected to different forms of supervision -- some abusive and some non-abusive -- and were given hints about their supervisors' motivations.

They were also given the opportunity to participate in deviant behaviours against the supervisor, or engage in more positive "organizational citizenship behaviours," or OCBs (helpful actions that go beyond an employee's contract, such as assisting a co-worker with a project, or participating in workplace charity drives).

A third study had 325 employees and supervisors at a Swedish luxury car company fill out daily surveys for three weeks -- for the subordinates, about the abusive supervision they experienced and the emotions they felt, and for the supervisors, about the OCBs and deviant behaviours they observed.

Across all three studies, the researchers found that when employees think their supervisors' abusive actions are motivated by a desire to inflict harm, they are more likely to feel angry.

When subordinates believe their leaders are prodding employees to improve performance, however, they are more likely to feel guilt.

"When you feel like your supervisor is pushing you really hard, it's abusive, and you feel angry. But when they want to motivate you and improve your performance, employees have a strong feeling of guilt," explains UBC Sauder Assistant Professor Lingtao Yu (he, him, his), who named the study after the Oscar-winning film Whiplash, which follows an abusive band teacher and a student he's pushing to extremes.

"They think, 'Maybe there is a gap between what I do and what they expect. Maybe there's room for me to improve.'"

Those different emotions, in turn, lead to different behaviours. Employees who feel their bosses are "out to get them" are more likely to engage in devious or destructive behaviours and less likely to engage in more positive organizational citizenship behaviours, or OCBs.

Those who feel their leaders are pushing them to do better are less likely to act deviously and more drawn to positive corporate behaviours.

"People feel there's something they've done, or that they haven't done enough, so it's not entirely attributed to the other person. They may take some responsibility," explains Professor Yu, who coauthored the study with University of Minnesota Professor Michelle Duffy.

"So, guilt will actually trigger more prosocial behaviors, because the employee wants to do something to rebuild the relationship with the supervisor."

The findings are especially important given that, according to previous research, a third of U.S. employees are estimated to experience abusive supervision, and 45 percent of Europeans can recall an instance when they were either the target of supervisory abuse or observed it.

The study also found people's feelings of guilt don't last, so Professor Yu emphasizes that while the results-driven form of abusive supervision can sometimes have short-term benefits, in the long run it simply doesn't pay -- especially since abusive leadership can cost companies millions in lawsuits, health expenses, and productivity loss.

"Even if you have good intentions, you still want to be more mindful about your leadership behaviour -- and there are many other tools you can use to stimulate your employees' performance," he says. "Abusive leadership should not be the one you choose."

More than a third of coal miners and former coal miners suffering from black lung disease struggle with depression, and more than one in 10 has recently considered suicide, a new study finds.

The study is believed to be the first to examine mental-health issues in a large population of coal miners in the United States. Based on the troubling results, the researchers are calling for more mental health resources and treatment for current and former miners. They also are urging further study of potential contributors to the problem, including social determinants of health, substance use and workplace safety.

"Although coal mining is on the decline, the rates of black lung in Southwest Virginia continue to increase. Coal miners in Central Appalachia face disparities in health related to a range of complex social, economic, occupational and behavioral factors," said researcher Drew Harris, MD, a pulmonary medicine expert at UVA Health. "This study highlights the unrecognized crisis of mental illness in miners that warrants urgent attention, resources and expanded care."

Miners' Mental Health

Harris serves as the medical director of the Black Lung Clinic at Southwest Virginia's Stone Mountain Health Services, the only federally funded black lung clinic in Virginia. Black lung is a progressive lung illness caused by inhaling toxic coal and rock dust within coal mines. The dust literally blackens the insides of the lungs and leaves patients struggling to breathe. This devastating disease has few treatment options and is increasingly being diagnosed in Central Appalachian coal miners: Out of more than 1,400 coal miners X-rayed in the last year at Stone Mountain, more than 15% had progressive massive fibrosis, the most severe form of black lung.

To gauge the mental wellbeing of black-lung patients, Harris and his colleagues reviewed data collected at the clinic since 2018 assessing patients for anxiety, depression and post-traumatic stress disorder (PTSD).

More than 2,800 miners voluntarily completed a mental-health survey. The average age was 66; 99.6% were white; and 99.7% were male.

Of the participants:

883 patients, or 37.4%, reported symptoms consistent with major depressive disorder.

1,005 patients, or 38.9% had clinically significant anxiety.

639 patients, or 26.2%, had symptoms of PTSD.

295 patients, or 11.4%, had considered suicide in the last year. (For comparison, this figure is only 2.9% among Virginia men overall.)

"These rates of mental illness far exceeded those documented in coal mining populations internationally," the researchers write in a new scientific paper outlining their findings.

Rates skewed highest among sicker patients who required supplemental oxygen to help them breathe. Among that group, 47.7% reported anxiety; 48.5% reported depression; and 15.9% reported considering suicide.

The researchers note that depression and other mental-health issues not only affect patients' quality of life but can reduce the likelihood they will stick with their medications.

"The rates of mental illness identified in this large population of U.S. coal miners is shocking," Harris said. "Improved screening and treatment of mental illness in this population is an urgent, unmet need that warrants urgent action."

Evidence from an ancient eggshell has revealed important new information about the extreme climate change faced by human early ancestors.

The research shows parts of the interior of South Africa that today are dry and sparsely populated, were once wetland and grassland 250,000 to 350,000 years ago, at a key time in human evolution.

Philip Kiberd and Dr Alex Pryor, from the University of Exeter, studied isotopes and the amino acid from ostrich eggshell fragments excavated at the early middle Stone Age site of Bundu Farm, in the upper Karoo region of the Northern Cape. It is one of very few archaeological sites dated to 250,000 to 350,000 in southern Africa, a time period associated with the earliest appearance of communities with the genetic signatures of Homo sapiens.

This new research supports other evidence, from fossil animal bones, that past communities in the region lived among grazing herds of wildebeest, zebra, small antelope, hippos, baboons and extinct species of Megalotragus priscus and Equus capensis, and hunted these alongside other carnivores, hyena and lions.

After this period of equitable climate and environment the eggshell evidence - and previous finds from the site - suggests after 200,000 years ago cooler and wetter climates gave way to increasing aridity. A process of changing wet and dry climates recognised as driving the turnover and evolution of species, including Homo sapiens.

The study, published in the South African Archaeological Bulletin, shows that extracting isotopic data from ostrich eggshells, which are commonly found on archaeological sites in southern Africa, is a viable option for open-air sites greater than 200,000 years old. The technique which involves grinding a small part of the eggshell, to a powder allows experts to analyse and date the shell, which in turn gives a fix on the climate and environment in the past.

Using eggshell to investigate past climates is possible as ostriches eat the freshest leaves of shrubs and grasses available in their environment, meaning eggshell composition reflects their diet. As eggs are laid in the breeding season across a short window, the information found in ostrich eggshell provides a picture of the prevailing environment and climate for a precise period in time.

Bundu Farm, where the eggshell was recovered is a remote farm 50km from the nearest small town, sitting within a dry semi-desert environment, which supports a small flock of sheep. The site was first excavated in the late 1990's the site with material stored at the McGregor Museum, Kimberley (MMK). The study helps fill a gap in our knowledge for this part of South Africa and firmly puts the Bundu Farm site on the map.

Philip Kiberd, who led the study, said: "This part of South Africa is now extremely arid, but thousands of years ago it would have been Eden-like landscape with lakes and rivers and abundant species of flora and fauna. Our analysis of the ostrich eggshell helps us to better understand the environments in which our ancestors were evolving and provides an important context in which to interpret the behaviours and adaptations of people in the past and how this ultimately led to the evolution of our species'.

Eight pieces of salmon-based maki, nigiri or sashimi or maki unagi (eel) is the safest combination of sushi for adult and adolescent populations. That is one of the findings of TecnATox (Centre for Environmental, Food and Toxicological Technology), a joint research group from the URV and the Pere Virgili Health Research Institute (IISPV), which has analysed the presence of arsenic and various heavy metals in sushi. The consumption of sushi has increased significantly since the start of the 21st century, as has the number of restaurants offering it throughout the region. Although eating fish is recommended because of its high nutritional value, it can also lead to exposure to contaminants, such as heavy metals. Likewise, rice is a food that provides many nutrients and fibre and is low in fat, but it too can be source of pollutants such as arsenic.

The research group analysed the concentrations of various toxic elements (cadmium, nickel, lead, mercury, inorganic arsenic and methylmercury) and iodine in a hundred pieces of sushi, specifically those known as sashimi (raw fish), maki (a seaweed roll stuffed with rice, raw fish or other ingredients) an nigiri (balls of rice with fish or seafood on top). The researchers also calculated dietary exposure to all of these contaminants in various population groups (infants, adolescents and adults) and evaluated the risks to health.

The main results show a significantly higher concentration of inorganic arsenic in maki and nigiri, compared to sashimi, a finding associated with the presence of rice. They also show higher levels of mercury and methylmercury in sushi that contains tuna due to the bioaccumulation and biomagnification of this metal.

The research group also wanted to determine how consumption of this foodstuff varied in different groups of the population. They examined an average intake of 8 pieces of sushi in adults and adolescents and an average intake of 3 pieces in infants and found an increase in exposure to nickel and lead, although this remained within safe established levels. "The most worrying finding concerns methylmercury, a highly neurotoxic compound, for which there was an estimated exposure of 0.242 μg per kg of bodyweight in adolescents, a value higher than the safe daily limit established by the European Food Safety Authority (EFSA)", explained Montse Marquès, one of the researchers who worked on the study. By the same token, although not as high as in adolescents, the exposure levels calculated for adults and infants also suggest a relatively high intake of methylmercury.

Finally, the results were analysed as a whole to determine which combinations of sushi do not represent a risk. "We recommend that people combine 8 pieces of salmon-based maki, nigiri or sashimi or maki containing unagi (eel) and limit their consumption of any type of sushi containing tuna", warned Marquès.

The researchers stressed that the amounts of sushi analysed constitute only one of the five recommended meals a day. This means that the consumption of other foods throughout the day may also lead to exposure to certain toxic elements, such as arsenic (present in rice and rice-based foods), mercury (present in tuna and swordfish) or nickel (present in vegetables, pulses and cereals).

Due to its nutritional benefits, the researchers still recommend the consumption of sushi, but they also stress the need to do so in moderation in order to minimise the intake of certain food toxins.

The rationale for the research is in the fact that despite the high number of recognized Indigenous groups who are struggling to maintain their languages, cultures, and identities in Russia, there is little research done on the matters of cultural and linguistic revitalization. This study sought to address this gap by exploring the views of two Indigenous groups, Karelian and Mari, on the development of their Indigenous languages and educational strategies to protect and revive their languages. The study relied on in-depth one-on-one interviews with 20 participants, ten from each Indigenous group.

The findings show that despite older generations' relative proficiency and interest in their respective Indigenous languages, motivation to master them is fading among younger Indigenous populations. There is also a lack of opportunities to learn the languages including informal settings despite protections within the federal legal system. The participants identified three reasons for the rapid decrease of language speakers which include assimilation of the Indigenous groups, differences in rural and urban development, and globalization.

We singled out three areas where the research results can be implemented. First, those responsible for education policy for the country's indigenous population can draw on the findings of the study to develop educational initiatives. Second, the study design can be used to conduct similar studies with a different sample. Third, the results of qualitative research will be used to design a tool for quantitative research on the problems of this project.

During the project, the team members held a number of meetings with overseas colleagues and agreed to start developing the design of a collaborative study planned for 2022-2023. The purpose of the future research is to conduct a comparative analysis of the ways of adapting the UN Declaration on Indigenous Peoples and the national educational laws adopted on its basis (including laws for cultural and linguistic revival) in Russia, Mexico, Taiwan, Bolivia, Australia, and Canada.

A pioneering cultivation strategy that recreates a mangrove environment in the lab has enabled identification of novel bacteria residing in Red Sea mangroves and will help improve understanding of mangrove ecosystem stability, resilience and sustainability.

Mangroves are highly productive, dominant coastal ecosystems that line between 60-70 percent of the world's tropical and subtropical coastlines. They harbor diverse microbial communities thought to make up 80 percent of the ecosystem's biomass. Many of the microbial species, families and taxa are unknown to science.

The cultivation strategy was developed by a team of KAUST researchers, including Fatmah Sefrji and Ramona Marasco.

"Red Sea mangroves are particularly interesting because they represent an extreme and unique version of mangrove environments that are exposed to stressful conditions, including high temperatures, salinity and oligotrophy," says Sefrji. "These environmental stresses exert a strong selective force on the mangrove's microbial communities and so favor the presence of unique species and families."

The team's key challenge was to recreate the mangrove environment in the lab so that they could grow the bacteria in their natural setting. They moved portions of the mangrove sediment and seawater to lab-based growth chambers because in artificial media, it is nearly impossible to reproduce all the molecules, such as nutrients and vitamins, and the molecular cross-communication that are necessary for healthy microbial growth.

"It is difficult to successfully cultivate so-called 'microbial dark matter'-- the environmental microorganisms that are unknown to science and have never been cultured before," says Marasco. "There are so many molecules and parameters important for the growth of a given microbial species from a particular setting."

Once the growth chambers were set up, the team cultivated the resident microbial communities by feeding them regularly with nutrients taken from the natural mangrove environment. They then analyzed the genotypes and phenotypes of selected bacterial isolates, discovering a series of new species, and even taxa. Two papers highlight the first two organisms new to science, the bacterium Mangrovivirga cuniculi (new family Mangrovivirgaceae) and a new bacterial strain called Kaustia mangrovi.

"Both organisms grow in the presence of relatively high salinity and temperature and in the pH range typical of mangrove sediment on the Red Sea," says Sefrji. "Despite their similar physiology, each bacterial isolate showed unique physical and biochemical characteristics, confirmed also by the analysis of their genomes."

The researchers hope the identification of these organisms will contribute to a wider understanding of mangroves and provide insight into effective ways of protecting these unique ecosystems, particularly in light of climate change. The ability to cultivate Red Sea mangrove bacteria at scale could have significant implications, and not just for mangroves themselves.

"Cultivating members of a microbial community adapted to the variable and harsh conditions of the Red Sea may represent an important source of metabolites and enzymes for future biotechnological applications," says Marasco. "For example, bacteria that promote plant growth could boost mangrove seedling establishment, while others could confer salt tolerance to cereal crops. We are actively characterizing our novel strains for such capacities."

Researchers at The University of Queensland, working to gain a better understanding of how brain cells work, have discovered the underlying mechanism of a rare genetic mutation that can cause epilepsy.

Dr Victor Anggono from UQ's Queensland Brain Institute said his team made the ground-breaking findings while researching nerve cell communications, which are an important process in normal brain function.

''We're both excited and astounded to make such an important contribution to the field of cellular and molecular neuroscience,'' Dr Anggono said.

He stressed that the mutation was extremely rare, with only one reported case in the world to date.

Dr Anggono's team studied protein structures, called receptors, that are attached to cell surfaces to make the discovery.

''It turns out that this particular mutation causes receptors in brain cells to behave differently, resulting in an imbalance in brain cell communication - and that can lead to disorders,'' he said.

''For example, cells that talk too much are associated with epilepsy and unwanted cell death - while cells that talk too little have negative impacts on learning and memory.

''There are also many examples of other mutations in the same gene that are known to be associated with epilepsy.

''What we know is that this receptor is critical for brain function and can lead to epilepsy when its function is misregulated.

''The findings point the way for further research to understand and potentially treat similar mutations.''

The imbalance in brain cell communications is also believed to be involved in neurological conditions including Alzheimer's disease and autism spectrum disorders.

Dr Anggono said the research provided a springboard for developing personalised medicines to target the mutation.

''Receptor blockers which have been approved by the US Food and Drug Administration (FDA), are already available for human treatment, but the challenge is to find the right ones and see how patients respond,'' he said.

Interim data from a phase 3 trial of a COVID-19 vaccine developed in China (CoronaVac) suggests that two doses offer 83.5% protection against symptomatic COVID-19.

The preliminary findings, published in The Lancet and presented at this year's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), indicate that CoronaVac induces a robust antibody response. No severe adverse events or deaths were reported among the more than 10,000 trial participants in Turkey, with most adverse events mild and occurring within 7 days of an injection. However, more research is needed to confirm vaccine efficacy in the long term, in a more diverse group of participants, and against emerging variants of concern.

CoronaVac uses an inactivated whole virus. When people receive the vaccine, their immune system attacks the harmless form of the virus by producing antibodies to fight it off, leading to immunity. Developed by Sinovac Life Sciences, the vaccine - which can be stored and transported at 2-8°C - has been approved for emergency use in 22 countries, and has been in phase 3 trials since mid-2020 in Brazil, Indonesia, Chile, and Turkey. In this trial, participants were given two 3μg doses of CoronaVac 14 days apart.

To date, interim efficacy and safety results of phase 3 trials have been reported for 8 COVID-19 vaccines: University of Oxford/AstraZeneca, Gam-COVID-Vac, Moderna, Pfizer, Janssen, Novavax, and two inactivated vaccines developed by Sinopharm. [1]

Lead author Professor Murat Akova, from Hacettepe University Medical School, Turkey, said: "In order to bring the COVID-19 pandemic under control, the world needs every single dose of safe and effective vaccines, and our results add important evidence of the safety and effectiveness of inactivated-virus vaccines. One of the advantages of CoronaVac is that it does not need to be frozen, making it easier to transport and distribute. This could be particularly important for global distribution, as some countries may struggle to store large amounts of vaccine at very low temperatures." [2]

Between September 14, 2020, and January 5, 2021, 10,218 adults between 18 and 59 years were randomly assigned to receive two doses of the vaccine (6,650) or a placebo (3,568). The trial was conducted across 24 centres in Turkey. The average age of the participants was 45 years and 5,907 (58%) were male.

After the first dose, 87 participants in the vaccine group and 98 in the placebo group were excluded. The most common reasons for exclusion in the vaccine group were returning a positive COVID-19 test (60) and withdrawing from the study (11). The most common reasons in the placebo arm were unblinding before the second dose (45) and returning a positive COVID-19 test (35). A further 4 participants in the vaccine group were excluded after the second dose as they were aged over 59 years.

In total, 10,029 participants (6,559 in the vaccine group and 3,470 in the placebo group) were included in the efficacy analysis, and 10,214 participants (not including the 4 excluded who were over 59 years) were included in the safety analysis.

In total, 150 COVID-19 cases were confirmed by PCR after an average follow-up of 43 days, an incidence rate of 123 cases per 1,000 people per year. From 14 days after the second dose, 9 cases of symptomatic COVID-19 were confirmed in the vaccine group, an incidence rate of 32 cases per 1,000 people per year. In the placebo group, 32 cases were reported, an incidence rate of 192 cases per 1,000 people per year. Following analysis, the authors estimate that this is equivalent to a vaccine efficacy of 83.5%.

Analysis of immune responses induced by the vaccine involved a sample of 1,413 participants (981 from the vaccine group and 432 from the placebo group). CoronaVac induced an antibody response among 90% (880/981) of those who received the vaccine. The authors note that antibody response decreased with increasing age in men and women.

Adverse reactions were analysed using data from 10,214 participants (6,646 in the vaccine group and 3,568 in the placebo group). The incidence of adverse events in those who received the vaccine was relatively low at 19% (1,259/6,646). The incidence in the placebo group was 17% (603/3,568).

A total of 3,845 adverse effects were reported in 1,862 participants. Most of the reported adverse effects (90% [3,469/3,845]) were mild, and included fatigue, pain at the injection site, and myalgia. No severe adverse events or fatalities were recorded during the study period, and only 6 participants (

The authors acknowledge that the analysis included a short follow-up period and involved a relatively young and low-risk population. Further data is needed on the duration of protection, and safety and efficacy of the vaccine in elderly people, adolescents and young children, and those with chronic diseases. Data on the effectiveness of CoronaVac against variants of concern is also required. Study participants received doses 14 days apart, whereas community immunisation has involved a 28-day interval. While it has been claimed that 28-day immunisation schemes lead to better immunogenicity, the longer the interval, the higher the chances of contracting COVID-19 before getting fully immunised.

The phase 3 trial results published today follows an earlier phase 1/2 trial that reported on the safety and immunogenicity of CoronaVac in healthy children and adolescents. [3]

Writing in a linked Comment, Dr Maheshi N Ramasamy and Dr Lucy Jessop of the University of Oxford, UK, and the National Immunisation Office of the Health Service Executive, Ireland, respectively (who were not involved in the study), said: "Tanriover and colleagues' findings suggest that two doses of CoronaVac have robust efficacy (within the WHO target product profile for SARS-CoV-2 vaccines) and acceptable tolerability when administered with a 14-day interval. CoronaVac is also available as single-dose vials, which improves ease of administration and reduces wastage." They continue, echoing the authors' acknowledgement that further research is needed, saying: "... CoronaVac is another useful tool in the global fight against COVID-19, although more data are needed on its efficacy against emerging variants and on its duration of protection across different age groups and geographical settings and in the presence of comorbidities."

While the UK was in lockdown, certain species of captive amphibians became more visible, a new study suggests.

The COVID-19 pandemic forced the closure of zoos across the UK for several months from March 2020, with gradual re-openings from summer into autumn and winter.

These closures provided a team of researchers, from the University of Exeter and WWT Slimbridge Wetland Centre, a unique opportunity to study the effect of visitor presence on several species of amphibian at Slimbridge.

The project assessed the number of individuals of six species - common toad, common frog, smooth newt, pool frog, golden mantella and golden poison dart frog - visible to observers while their exhibit was closed, when it partially reopened to more staff and when it reopened to visitors.

"Amphibians responded to the lack of people at the wetland centre differently," said lead author Dr Paul Rose.

"Some species of amphibian were more likely to be on view when there were smaller numbers of visitors at their enclosure.

"These differences are probably related to the specific camouflage or anti-predation tactics of certain species, with aposematic frogs (toxic, brightly coloured species) being less impacted by visitor presence but cryptic (camouflaged species) being less visible when the public were around."

For example, the study found the camouflaged species of common toads were most likely to be on view when the centre was in lockdown compared to when visitors returned. They also showed the most significant decline in visibility from lockdown to when more staff returned to the centre.

These findings show it may be beneficial to offer more cover and camouflage opportunities for captive common toads, in a way that allows the toads to feel hidden but can still be viewed by visitors.

The results of the study can also be used help inform husbandry, collection planning and provide a useful benchmark for further, more complex, welfare assessment measures.

Led by the London School of Hygiene & Tropical Medicine (LSHTM), in partnership with the World Health Organization (WHO) and Avenir Health, the research team carried out a systematic review and meta-analysis of syphilis prevalence among MSM between 2000 to 2020, drawing on data from 275 studies involving more than 600,000 study participants across 77 countries.

The worldwide prevalence of syphilis among MSM was 15x higher than most recent estimates for men in the general population (7.5% versus 0.5%). Researchers further estimated the prevalence across eight regions of the Sustainable Development Goals (SDG) and six regions of the WHO. Latin America and the Caribbean region had the highest prevalence of syphilis (10.6%), whereas Australia and New Zealand had the lowest (1.9%). There is, therefore, an urgent need to quantify the burden of syphilis in this high-risk group.

Syphilis is a sexually transmitted infection (STI) caused by the bacterium Treponema pallidum. When diagnosed, syphilis is easily treated with penicillin. One study found that annual screening and treatment of at least 62% of sexually active MSM is necessary to achieve local elimination.

Dr Matthew Chico, Associate Professor at LSHTM and lead author, said: "Men tend to be disadvantaged when it comes to syphilis testing and treatment. Women are routinely screened for syphilis at their first antenatal care visit, and are offered testing at family planning services. Men in general do not have the same number of contacts with the health system as women, and MSM face additional barriers due to stigma and shaming.

"As diseases go, syphilis is terribly deceptive. In the primary and secondary stages of infection, skin lesions, such as chancre or rash, may present, only to then disappear as if the person has been cured. Unfortunately, without treatment, the bacterium will slowly invade internal organs, and can lead to physical deformity, loss of vision, dementia, and even death. There is no good reason for this to happen. We have effective treatment."

Dr Motoyuki Tsuboi, from LSHTM and the study's first author, said: "The Global Health Sector Strategy of the WHO has an ambitious target to reduce global syphilis incidence by 90% between 2018 and 2030. We hope our findings - the first global prevalence estimates of syphilis among MSM - will serve as a catalyst for action."

In this new study, pooled estimates of syphilis among MSM were highest (8.7%) in regions where HIV prevalence is more than 5%. Lower-middle income countries also had a high burden (8·7%). Countries with low-income status had the lowest syphilis prevalence estimates among MSM (3.8%). Syphilis prevalence estimates were high among studies exclusively involving male sex workers, transgender women, and transgender women sex workers.

Among studies conducted from 2000 to 2009 and 2010 to 2020, global syphilis prevalence was estimated to be 8·9% and 6·6% respectively. However, four of eight SDG regions - Europe and Northern America, Latin America and the Caribbean, Oceania [excluding Australia and New Zealand]) - showed higher estimates between 2015 and 2020 than 2010 and 2014.

Dr Tsuboi said: "Syphilis prevalence among MSM is unacceptably high at the global and SDG regional levels, particularly in lower-middle, upper-middle, and high-income countries, where cases appear to be increasing and where HIV prevalence is high. Urgent action is needed."

The researchers say that it is difficult to know if syphilis prevalence among MSM will be altered by the COVID-19 pandemic. While there is evidence the pandemic has impacted MSM sexual activity, there have also been reports that MSM have experienced difficulty accessing STI testing and treatment due to COVID-19, potentially translating into fewer syphilis cases being diagnosed, treated and removed from the MSM population.

Eloise Stonborough, Associate Director of Policy and Research at Stonewall, (she/her) said: "Sexually transmitted infections, including syphilis, can cause severe health problems if untreated. These figures provide an important insight into the increased prevalence of syphilis infections for men who have sex with men. It's important that everyone, including LGBTQ+ people and those at higher risk, is supported to understand how to protect themselves against syphilis and other sexually transmitted infections.

"It's also vital that healthcare services are inclusive and welcoming of all lesbian, gay, bi, trans and queer people, so everyone feels comfortable getting the help and support they need."

The authors acknowledge limitations of the study, including the fact that Eastern and South-Eastern Asia contributed 55% of the global data points, most of which were from China where the prevalence of syphilis among MSM was slightly higher than the overall global total. This has the effect of slightly skewing upward the pooled prevalence estimates. Another limitation is that one-third of the data points relied on convenience sampling.

When you pour cream into a cup of coffee, the viscous liquid seems to lazily disperse throughout the cup. Take a mixing spoon or straw to the cup, though, and the cream and coffee seem to quickly and seamlessly combine into a lighter color and, at least for some, a more enjoyable beverage.

The science behind this relatively simple anecdote actually speaks to a larger truth about complex fluid dynamics and underpins many of the advancements made in transportation, power generation, and other technologies since the industrial era--the seemingly random chaotic motions known as turbulence play a vital role in chemical and industrial processes that rely on effective mixing of different fluids.

While scientists have long studied turbulent fluid flows, their inherent chaotic natures have prevented researchers from developing an exhaustive list of reliable "rules," or universal models for accurately describing and predicting turbulence. This tall challenge has left turbulence as one of the last major unsolved "grand challenges" in physics.

In recent years, high-performance computing (HPC) resources have played an increasingly important role in gaining insight into how turbulence influences fluids under a variety of circumstances. Recently, researchers from the RWTH Aachen University and the CORIA (CNRS UMR 6614) research facility in France have been using HPC resources at the Jülich Supercomputing Centre (JSC), one of the three HPC centres comprising the Gauss Centre for Supercomputing (GCS), to run high-resolution direct numerical simulations (DNS) of turbulent setups including jet flames. While extremely computationally expensive, DNS of turbulence allows researchers to develop better models to run on more modest computing resources that can help academic or industrial researchers using turbulence's effects on a given fluid flow.

"The goal of our research is to ultimately improve these models, specifically in the context of combustion and mixing applications," said Dr. Michael Gauding, CORIA scientist and researcher on the project. The team's recent work was just named the distinguished paper from the "Turbulent Flames" colloquium, which happened as part of the 38th International Symposium on Combustion.

Starts and stops

Despite its seemingly random, chaotic characteristics, researchers have identified some important properties that are universal, or at least very common, for turbulence under specific conditions. Researchers studying how fuel and air mix in a combustion reaction, for instance, rely on turbulence to ensure a high mixing efficiency. Much of that important turbulent motion may stem from what happens in a thin area near the edge of the flame, where its chaotic motions collide with the smoother-flowing fluids around it. This area, the turbulent-non-turbulent interface (TNTI), has big implications for understanding turbulent mixing.

While running their DNS calculations, Gauding and his collaborator, Mathis Bode from RWTH Aachen, set out to specifically focus on this some of the subtler, more complex phenomena that take place at the TNTI.

Specifically, the researchers wanted to better understand the rare but powerful fluctuations called "intermittency" - an irregular process happening locally but with very high amplitude. In turbulent flames, intermittency enhances the mixing and combustion efficiency but too much can also extinguish the flame. Scientists distinguish between internal intermittency, which occurs at the smallest scales and is a characteristic feature of any fully developed turbulent flow, and external intermittency, which manifests itself at the edge of the flame and depends on the structure of the TNTI.

Even using world-class HPC resources, running large DNS simulations of turbulence is computationally expensive, as researchers cannot use assumptions about the fluid motion, but rather solve the governing equations for all relevant scales in a given system--and the scale range increases with the "strength" of turbulence as power law. Even among researchers with access to HPC resources, simulations oftentimes lack the necessary resolution to fully resolve intermittency, which occurs in thin confined layers.

For Bode and Gauding, understanding the small-scale turbulence happening at the thin boundary of the flame is the point. "Our simulations are highly resolved and are interested in these thin layers," Bode said. "For production runs, the simulation resolution is significantly higher compared to similar DNS simulations to accurately resolve the strong bursts that are connected to intermittency."

The researchers were able to use the supercomputers JUQUEEN, JURECA, and JUWELS at JSC to build a comprehensive database of turbulence simulations. For example, one simulation was run for multiple days on the full JUQUEEN module, employing all 458,752 compute cores during the centre's "Big Week" in 2019, simulating a jet flow with about 230 billion grid points.

Mixing and matching

With a better understanding of the role that intermittency plays, the team takes data from their DNS runs and using it to improve less computationally demanding large eddy simulations (LES). While still perfectly accurate for a variety of research aims, LES are somewhere between an ab initio simulation that begins with no assumptions and a model that has already baked in certain rules about how fluids will behave.

Studying turbulent jet flames has implications for a variety of engineering goals, from aerospace technologies to power plants. While many researchers studying fluid dynamics have access to HPC resources such as those at JSC, others do not. LES models can often run on more modest computing resources, and the team can use their DNS data to help better inform these LES models, making less computationally demanding simulations more accurate. "In general, present LES models are not able to accurately account for these phenomena in the vicinity of the TNTI," Gauding said.

The team was able to scale its application to take full advantage of JSC computing resources partially by regularly participating in training events and workshops held at JSC. Despite already being able to leverage large amounts of HPC power, though, the team recognizes that this scientific challenge is complex enough that even next-generation HPC systems capable of reaching exascale performance--slightly more than twice as fast as today's fastest supercomputer, the Fugaku supercomputer at RIKEN in Japan--may not be able to fully simulate these turbulent dynamics. However, each computational advancement allows the team to increase the degrees of freedom and include additional physics in their simulations. The researchers are also looking at using more data-driven approaches for including intermittency in simulations, as well as improving, developing, and validating models based on the team's DNS data.

Faba beans are an excellent source of food protein, but about 4% of the world's population are afflicted by favism, which renders them sensitive to the faba bean anti-nutrients vicine and convicine. Now, an international research team has identified the VC1 gene as responsible for the production of these compounds.

Faba beans have actually been a source of food protein since pre-historic times, but a fraction of the population, mostly from warm southern regions, cannot tolerate them. Pythagoras and his followers avoided them, and Roman priests of Jupiter associated them with death. Today, we know that faba beans produce the anti-nutrients vicine and convicine, which cause a risk for favism - a condition arising from damage to red blood cells - for susceptible individuals.

Among legumes - the pod-producing family of plants to which pea, chickpea and soybean also belong - faba beans have the second-highest yield globally. They also have the highest seed protein content of the starch-containing legumes and out-perform soybean in cool climates. Faba beans are consequently a prime protein source for facilitating a global switch to a plant-based diet, considered necessary for significant reductions in carbon emissions.

The VC1 gene is responsible for vicine-convicine content

However, when people deficient in a specific enzyme eat a large portion of uncooked faba beans, vicine and convicine can induce abnormal breakdown of red blood cells. The resultant hemolytic anemia, known as favism, has inevitably limited the potential use of faba beans. Although there are a number of faba bean varieties with low levels of vicine and convicine, the gene responsible for this trait was previously unknown.

Now, the scientists have identified the gene responsible for vicine-convicine content. What is more, they have identified the specific mutation within this gene that causes the reduction in synthesis. They found that all faba bean varieties with a low vicine-convicine content, descended from a single accession found in a genebank, had two nucleotides - the "letters" that make up DNA - inserted within the VC1 gene. This insertion disrupts the VC1 function and is the only known genetic source of low vicine and convicine content.

Stig U. Andersen, one of project leaders, says, "Working across disciplines to integrate biochemical and molecular genetic data was key to finally unveiling the genetic source of low vicine and convicine."

The work has been published in Nature Plants and it paves the way for the complete description of the biosynthetic pathway of vicine and convicine, and ultimately for breeding, production and commercial use of faba bean varieties totally free from these anti-nutritional compounds.

The team, comprising leading scientists from Denmark, Finland, Germany, the UK and Canada, are already looking to the future. Fernando Geu-Flores, who led the work, says:

"Now that we understand where these anti-nutrients come from, we can attempt to breed them out completely, thus contributing to food safety and sustainability."