Culture

BATON ROUGE, LOUISIANA, May 11, 2020--A microscopic algae ("microalgae") could provide a complete and sustainably sourced supplemental diet to boost the robustness of managed honey bees, according to research just published by Agricultural Research Service (ARS) scientists in the journal Apidologie .

Poor nutrition in honey bees is often an underlying factor in colony losses because malnutrition amplifies the detrimental effects of parasites, pathogens, and pesticides. Habitat loss, decreases in flowering plant diversity and large tracts of crop monoculture (cultivation of a single crop over a large area) all can potentially contribute to lessening natural pollen sources, which provide bees essential nutrition.

Now, research by ARS entomologists Vincent Ricigliano and Michael Simone-Finstrom has shown that the microalgae Arthrospira platensis (commonly called spirulina) has a nutritional profile that closely resembles pollen. Spirulina is a part of family of blue-green algae, which are single-celled organisms that exist individually or in chains or groups.

Ricigliano and Simone-Finstrom found that spirulina is rich in essential amino acids and lipids required by bees, with levels matching those found in tested pollen samples.

The two scientists are both with the ARS Honey Bee Breeding, Genetics, and Physiology Research Laboratory in Baton Rouge, Louisiana.

"Our work is a pioneering first look into the nutritional and functional properties of a single microalga and how well it corresponds to what is needed in a complete pollen substitute for the honey bee," explained Ricigliano.

In addition to being rich in essential amino acids necessary for protein synthesis, immune function and colony growth in honey bees, spirulina also contains prebiotics that support the growth of healthy gut bacteria.

Commercial beekeepers have become increasingly reliant on artificial pollen substitute diets to nourish colonies during periods of pollen scarcity as well as to bolster colony size before they fulfill pollination service contracts.

Currently available commercial diets for bees usually incorporate a variety of ingredients such as soy, yeast, wheat, lentils and milk proteins in an effort to supply balanced nutrition. These artificial diets are sometimes deficient in essential macronutrients (proteins, lipids, prebiotic fibers), micronutrients (vitamins, minerals), or antioxidants.

"So the need to scientifically improve the efficacy of pollen substitutes can be considered vital to modern beekeeping and we need to think about how we can do it in a sustainable way," Ricigliano said.

Microalgae can be sustainably grown on a large scale with a minimal amount of water and few chemical inputs. It can even be grown in places where soybeans and other crops cannot be grown.

"All it takes are shallow ponds, nutrient salts and sunlight to produce highly nutritious microalgae," said Ricigliano.

Now, the researchers are testing the microalgae diet in a field setting to make sure the diet is attractive to bees and supports colony growth. The excellent nutrition profile of spirulina suggests that there are likely other microalgae that could serve honey bees well, Simone-Finstrom pointed out.

"We have also begun development of new microalgae strains to address other aspects of bee health, including targeted nutrition strategies," Ricigliano added

(Philadelphia, PA) - The vast majority of cells in the human body contain tiny power plants known as mitochondria that generate much of the energy cells use for day-to-day activities. Like a dynamic renewable resource, these little power plants are constantly dividing and uniting in processes called fission and fusion. The balance between fission and fusion is critical for health - especially cardiovascular health.

Now, in new research, scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) have uncovered a novel mechanism by which abnormalities in mitochondrial fission in endothelial cells - the cells that line the inner surface of blood vessels - contribute to inflammation and oxidative stress in the cardiovascular system. They further show how the fission-fusion balance can be stabilized to lower inflammation using salicylate, the main active ingredient in everyday pain-relieving drugs like aspirin.

The groundbreaking research was published online May 11 in the journal Hypertension.

"It was already known that in cardiovascular disease the function of endothelial cells and mitochondria are impacted by inflammation, but we were unsure whether there was a link between the two," explained Satoru Eguchi, MD, PhD, FAHA, Professor of Physiology and Professor in the Cardiovascular Research Center, Sol Sherry Thrombosis Research Center, and Center for Metabolic Disease Research at LKSOM.

In endothelial cells, chronic inflammation causes mitochondria to become smaller and fragmented. This damaging process is mediated by a molecule known as dynamin-related protein 1 (Drp1). Normally, Drp1 plays a helpful role in maintaining fission-fusion balance. When cells are stressed by inflammation, however, it steps up fission activity, resulting in mitochondrial fragmentation.

"How Drp1 acts to increase mitochondrial fragmentation when endothelial cells are inflamed has been unclear," Dr. Eguchi said. "But we wondered whether it might interact with nuclear factor (NF)-κB, which oversees the regulation of inflammatory processes and is involved in endothelial dysfunction."

In endothelial cells, Dr. Eguchi and colleagues stimulated inflammatory pathways that produced mitochondrial fragmentation. They then examined the effects of blocking Drp1 activity and expression. These experiments showed that in cells, Drp1 inhibition suppresses mitochondrial fission, NF-κB activation, and inflammation. Reductions in fission and inflammation were also observed in cells following NF-κB inhibition, as well as in follow-up studies in mice genetically engineered to have less Drp1.

The researchers next determined whether the anti-inflammatory drug salicylate could also reduce mitochondrial fragmentation. Salicylate works by blocking the activity of multiple inflammatory molecules, including NF-κB. As anticipated, in mice, treatment with salicylate attenuated inflammation and mitochondrial fragmentation via its effects on NF-κB and downstream pathways.

"Our findings suggest that salicylate may be able to maintain the balance between mitochondrial fission and fusion under inflammatory conditions," Dr. Eguchi said. "This observation could have real clinical impact, since salicylate is already used in aspirin and related pain-relievers."

In future work, Dr. Eguchi plans to explore the influence of aging and other factors on Drp1 and mitochondrial fission in endothelial cells.

"Mitochondrial function declines with aging, but we also know that exercise and diet influence this process. How these factors come together mechanistically to impact vascular health is not fully understood," Dr. Eguchi explained.

MAY 11, 2020 -- Microorganisms living inside and on our body play a crucial role in both the maintenance of our health and the development of disease. Now researchers at UTSA have uncovered evidence about the importance of maintaining physical distance to minimize the spread of microbes among individuals.

The scientists observed monkeys in the wild to understand what role genetics, diet, social groupings and distance in a social network play when it comes to the microbes found inside an animal's gut.

"Social microbial transmission among monkeys can help inform us about how diseases spread. This has parallels to our current situation in which we are trying to understand how social distancing during the COVID 19 pandemic and future disease outbreaks may influence disease transmission," said Eva Wikberg, an assistant professor in UTSA's Department of Anthropology who studies the interaction between ecology, behavior and genetics in primates.

The gut microbiome refers to all the microorganisms inhabiting the digestive tract, starting with the stomach and ending with the colon. Over the past decade the microbiome has come under more scientific focus because it's believed that an unhealthy gut microbiome can lead to obesity, impaired immune function, weakened parasite resistance and even behavioral changes.

However, researching microbiomes is difficult because of the variation in microbial composition between individuals. One long-standing question is whether this variation is driven by genetic makeup, diets or social environments.

This research inquiry has been especially hard in wild populations because of the lack of detailed data necessary to tease apart the myriad factors that shape the microbiome.

To find an answer, Wikberg and fellow researchers studied the fecal matter of 45 female colobus monkeys that congregated in eight different social groups in a small forest by the villages of Boabeng and Fiema in Ghana. The scientists saw major differences among social groups' gut microbiomes.

However, individuals from different groups that were more closely connected in the population's social network had more similar gut microbiomes. This discovery indicates that microbes may be transmitted during occasional encounters with members of other social groups.

A similar setting may be when people come into one-meter proximity of each other at a store. Being in close proximity or accidentally brushing up against someone else may be all it takes to transmit certain microbes.

This study suggests that microbes transmitted this way help the colobus monkeys digest the leaves in their diet. However, further research is needed to investigate whether this type of transmission yields health benefits, which could explain why different social groups occasionally have friendly between-group encounters.

"Studies of wild animals can teach us a lot about the importance of using interventions, such as social distancing, to ensure a safer community during this pandemic," said Wikberg.

Even before the coronavirus pandemic wreaked havoc with the nation's food supply and economy, one in seven adults between the ages of 50 and 80 already had trouble getting enough food because of cost or other issues, a new poll finds.

The percentage who said they'd experienced food insecurity in the past year was even higher among those in their pre-Medicare years, and those who are African-American or Latino. Older adults with lower household incomes and lower levels of education were also more likely to say they had had trouble getting food.

Yet only a third of those with food affordability issues were receiving government food aid for people with low incomes, called SNAP benefits or "food stamps." And less than 2% of those over 60 have received free meals served at senior centers or delivered to their home by programs like Meals on Wheels.

Disruptions to food supply chains, employment and social services from COVID-19 may have worsened disparities, say the experts who designed the poll.

The new results come from the National Poll on Healthy Aging, carried out by the University of Michigan Institute for Healthcare Policy and Innovation with support from AARP and Michigan Medicine, U-M's academic medical center. It involved a national sample of more than 2,000 adults aged 50 to 80 who answered a range of questions about their food security in December 2019.

"These data suggest an important opportunity, which is likely even more urgent now, to connect older adults with resources they may not know about, and to explore public policies that could improve access," says Cindy Leung, Sc.D., M.P.H., a member of IHPI and assistant professor of nutritional sciences at the U-M School of Public Health who worked on the poll.

Julia Wolfson, Ph.D., M.P.P., an assistant professor of health management and policy at the School of Public Health, notes the striking differences the poll reveals between those who said they hadn't experienced food insecurity in the past year, and those who had. "Food-insecure older adults were three times more likely to say they were in fair or poor physical health, and nearly five times as likely to say they were in fair or poor mental health," she says.

Older adults with recent experiences of food insecurity were also twice as likely to say their diet was fair or poor. This could have further implications for their long-term health.

"Access to nutritious food and health status are closely linked, yet this poll reveals major disparities in that access," says Preeti Malani, M.D., the poll's director and a professor of internal medicine at Michigan Medicine. "Even as we focus on preventing the spread of coronavirus, we must also ensure that older adults can get food that aligns with any health conditions they have, so we don't exacerbate diabetes, hypertension, digestive disorders and other conditions further."

"This research reaffirms that many older adults struggle to afford the food they need, and are not using available food and nutrition assistance programs," says Alison Bryant, Ph.D., senior vice president of research for AARP. "The current crisis makes it even more urgent to ensure that our most vulnerable populations can access the nutrition they need."

Options for increasing food security after 50

Malani notes that because of COVID-19 and temporary closures of senior centers and other places that served meals, the federal program that supports Meals on Wheels and community food services for older adults has freed up money for more home delivery of meals. And new programs to feed older adults have started at the federal and state levels.

For instance, the state of Michigan has established an expanded program for meal delivery thanks to the newly flexible funds. An online form, available through the state COVID-19 website, acts as the central intake site.

Similarly, the U.S. Department of Agriculture, which oversees the Supplemental Nutrition Assistance Program or SNAP, has allowed states to apply for emergency waivers to make it easier for people to qualify for the program, or to stay on it.

AARP Foundation has provided grants to multiple programs that aim to reduce food insecurity, including Food on the Move, The Campus Kitchens Project and funding for states to help seniors apply for nutrition assistance. In light of the coronavirus crisis, AARP recently called for Congress and USDA to provide a temporary increase in the maxiumum benefit and minimum monthly benefit for SNAP.

The National Poll on Healthy Aging results are based on responses from a nationally representative sample of 2,048 adults aged 50 to 80 who answered a wide range of questions online. Questions were written, and data interpreted and compiled, by the IHPI team. Laptops and Internet access were provided to poll respondents who did not already have them.

In a new multi-center study of U.S. women with newly diagnosed invasive breast cancer, Mount Sinai researchers have shown that insulin resistance is one factor mediating part of the association between race and poor prognosis in the disease. The findings were published in Breast Cancer Research on Tuesday, May 12.

Despite improvements in breast cancer diagnosis and treatment, black women with breast cancer continue to have worse prognoses on average than white women. Breast cancer prognoses also tend to be worse in patients with insulin resistance, a common condition that occurs when metabolic cells in the body don't respond adequately to insulin, causing the pancreas to make more insulin to maintain normal glucose levels. Insulin resistance is an important component of obesity, prediabetes, and type 2 diabetes. Patients with these conditions also tend to have more aggressive breast cancer subtypes and increased mortality.

"Given that obesity and diabetes epidemics disproportionately affect minority populations, it is important to understand the relationship of hyperinsulinemia, insulin resistance, and increased insulin receptor (IR) signaling on the progression of breast cancer," explained lead author Emily J. Gallagher, MD, PhD, Assistant Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai. Dr. Gallagher specializes in onco-endocrinology, the treatment of endocrine complications of oncology treatments. "Understanding these relationships could explain the different patterns of disease seen in different racial groups and help to identify patients who would benefit from targeted therapy," she says.

This is the first cross-sectional study to examine in detail insulin resistance as a factor associated to the disparities in breast cancer prognosis between black women and white women. The study included 515 women with a newly diagnosed breast cancer; about 83 percent of the subjects were white and 17 percent black. The Mount Sinai team evaluated the women for insulin resistance, metabolic syndrome--a cluster of conditions that occur together and may include high blood pressure or high blood sugar--and obesity to investigate whether insulin is a key mechanistic link in the association between these metabolic conditions and breast cancer aggressiveness. Samples of breast cancer tissue were examined to assess the role of insulin receptor and insulin-like growth factor receptor expression in disparities in breast cancer prognoses between the racial groups.

The researchers found that insulin resistance was more prevalent in black women with invasive breast cancer than in white women and that insulin resistance mediated part of the effect of race on prognosis. Additionally, the team found that tumors from black women had a higher expression of the insulin receptor, which is what insulin binds to in the tumors. Tumors with a worse prognosis had higher expression of the insulin receptor.

"Our results raise a number of questions for future research and patient care. It will be important in future studies to explore whether lowering insulin levels or targeting IR signaling will improve breast cancer disparities," said co-senior investigator Nina Bickell, MD, PhD, MPH, Associate Director of Community Engaged and Equity Research of The Tisch Cancer Institute and Co-Director of the Center for Health Equity and Community Engaged Research at the Icahn School of Medicine at Mount Sinai.

Degenerative diseases such as Alzheimer's often involve complex interactions between multiple proteins and other biomolecules. Understanding these interactions using existing imaging technologies is difficult because of insufficient resolution and the impossibility of simultaneously detecting many different proteins.

In a recent interdisciplinary study, a research team led by Professors Dae Won Moon and Su-Il In from Daegu Gyeongbuk Institute of Science and Technology developed an innovative approach that extends the applications of the technique 'secondary-ion mass spectrometry' from its original purpose in the semiconductor industry to the biomedical imaging field. Secondary-ion mass spectrometry allows one to analyze the composition of surfaces and offers very high resolution. Using this technology to image proteins was impossible--until now.

In this novel approach, different metal oxide nanoparticles are individually attached to antibodies that bind to specific target proteins. The mass spectrometer can easily detect these nanoparticles even at low irradiation doses, which leaves the cell tissue intact and allows for multiple analyses on the same cells. Through this approach, it is theoretically possible to analyze tens of proteins simultaneously. This vastly surpasses existing fluorescence-based approaches, which allow for the simultaneous imaging of around four proteins.

The researchers used their method to compare the distribution of proteins in the brain tissue of mice that were either healthy or had Alzheimer's. They showed that valuable insight could be gained from observing multiplex protein distributions in the 'hippocampus' section of the brain and demonstrated how these differed between healthy and diseased mice.

Achieving these results required combining knowledge from many disciplines. Prof. Moon remarks, "For me, a special highlight of this work is the collaboration of many researchers from different backgrounds, such as chemists, nano-particle experts, medical doctors, and biologists. It was not easy and took a long time, but it was exciting to see the progress. We can now visualize multiple proteins on cell membranes with a spatial resolution of 300 nanometers." He expects this new imaging approach to become an important tool to deepen our understanding on degenerative diseases. "The proposed technique could be used to figure out the early stages of Alzheimer's disease, in turn allowing for early detection and treatment," he states, hopefully.

The UC San Diego researchers who developed algae-based flip-flops and surfboards are at it again. This time they are advancing their brand of renewable and biodegradable materials for use in other products like coated fabrics, patent leather and adhesives, with some foodie flare, too--flavors and fragrances.

The latest research by Michael Burkart, Stephen Mayfield and Robert Pomeroy--online in Green Chemistry, a journal of the Royal Society of Chemistry--outlines their efforts to develop methods for producing microalgae-based polyols--monomer units for polyurethane polymers--that can be used to make polyurethane foams with waste oils from algae biomass.

Many researches consider algae one of the best renewable resources for replacing fossil fuels and battling global warming without impacting food supplies. But unlike vegetable oils, the oil from algae contains small organic contaminants, like photosynthetic pigments and other cofactors that can complicate their use.

The team chose to work with oil from the green microalgae Nannochloropsis salina, a common source of omega-3 fatty acids that are sold as dietary supplements. The leftover oils, more than 70-percent, are typically either thrown away or burned, but the UC San Diego researchers found a better use for them. They developed a process to purify and convert this waste stream into azelaic acid, a building block for flexible polyurethanes. Wanting to "use the whole buffalo," they also converted the co-product heptanoic acid into a food flavoring and fragrance.

"We showed that we could take waste products from algae-based omega-3 oil production and convert those into valuable and renewable polyurethane foams. These have all kinds of commercial applications, from flip-flops and running shoe soles, to mattresses and yoga mats. In addition, we prepared a flavoring molecule from the remaining co-product that is valued at over $500 per kilogram," said Burkart referring to the team's paper, "Co-production of flexible polyurethanes and renewable solvent from a microalgae oil waste stream."

To start the work, the research team, which included scientists from Division of Physical Sciences, the Division of Biological Sciences and the California Center for Algae Biotechnology at UC San Diego, first found a scalable, cost-effective pathway to improve the purity of algae oil using simple physical methods along with saponification. This is a process by which oils react with sodium or potassium hydroxide to produce glycerol and a fatty acid salt, or soap.

In addition to the fatty acids, Mayfield explained that the team identified multiple contaminants in the waste oil. "Unlike plants, which store mainly triacyglycerides, or vegetable oil, in their seeds, microalgae contain a variety of metabolic components that are insoluble in water but freely soluble in the algae oil when extracted. The presence of these pigments inhibits downstream reaction efficiency, therefore their removal is a key process in the production of renewable chemicals from algae oil."

According to the scientists, their scalable process can be performed on oils from multiple algal species, to produce valuable monomers--molecules that take part in a chain reaction to form polymers--for a highly sustainable source of bio-based plastics. The study included an exploration of the economic value of the team's methodology. According to Pomeroy, they chose the N. salina as a strain for growing algae in large scale because of its established high production of eicosapentaenoic acid (EPA), a valuable omega-3 oil, and the ability of scientists to grow the strain for high biomass content.

"This study indicates that an algae-sourced waste stream has both the practical and economic potential to support material production of polyurethanes," said Burkart. "We are already working with major shoe companies to turn these into commercial products that people will want to buy. We are finding that consumers are concerned about all of the petroleum-based plastic waste we are generating as a society, and our team is rapidly developing solutions for future products. Stay tuned!"

Kyoto, Japan -- 'Like a frog stared down by a snake', goes an old Japanese expression, descrbing an animal petrified with fear.

However, it now seems that this freeze in action may not be about fear at all, but rather a delicate waiting game of life and death.

A new report from researchers at Kyoto University's Graduate School of Science shows that this common interaction is all about patience, with each animal waiting for and anticipating its opponent's actions.

"When predator and prey face each other, it is generally thought that the initiator has the advantage that would mediate successful capture or escape," explains Nozomi Nishiumi, corresponding author of the report published in the Canadian Journal of Zoology.

"However, in cases involving snakes and frogs, they occasionally move extremely slowly -- or almost not at all. It looks like they purposely avoid taking preemptive action."

Nishiumi, together with colleague Akira Mori, examined how the animals' behaviors affected the consequences of their interaction by focusing specifically on the kinematics of the snakes' strikes and the frogs' flight behavior.

The team analyzed the movement patterns of the Japanese striped snake, Elaphe quadrivirgata, and the black-spotted pond frog, Pelophylax nigromaculatus, both in the field and in staged encounter experiments.

"In the staged encounters we wanted to look at the disadvantages of preemptive actions by analyzing the kinematic characteristics of each animal's movements," explains Nishiumi.

"The field observations, on the other hand, were designed to follow the consequences of the animals' actions and survival."

The team found that the counteractions of each animal were often effective because the initiator's actions were difficult to change once started. For example, if the snake initiated a strike action first, the frog would evade the attack because the trajectory of the strike could not be changed mid-movement, allowing the frog to escape safely while the snake spent time resetting its lunge posture.

Alternatively, if the frog first attempted an escape, the snake would start lunging immediately, and occasionally be able to adjust its strike direction in anticipation of the frog's direction of movement.

"The efficacy of this waiting tactic depends on the distance between them: the closer they are the less likely the counteraction succeeds," continues Nishiumi.

"In this regard, when approaching this critical distance, the animals appropriately switch their behaviors from waiting to taking action."

These results suggest that a game of patience occurs between the animals, providing insight on predicting the decision-making of predators and prey.

A simple saliva test developed by QUT biomedical scientists has detected early throat cancer in a person who had no symptom and no clinical signs of cancer.

In what is believed to be a world-first, the non-invasive test picked up HPV-DNA in a saliva sample from an infected healthy person. Persistent human papillomavirus (HPV) infection is now the leading cause of cancers in the oropharynx (tonsils and tongue base area of the throat).

"The series of saliva tests raised the alert and detected an early cancer before the person had any symptoms," said QUT Faculty of Health's Associate Professor Chamindie Punyadeera, who, with Dr Kai Tang, developed the test.

"This enabled removal of the tonsil which had a 2mm cancer in it, by straightforward local surgery alone.

"The incidence of high-risk human papillomavirus (HPV)-driven throat cancers is on the rise in developed countries and, unfortunately, it is often discovered only when it is more advanced, with patients needing complicated and highly impactful treatment.

"In the US, HPV-driven throat cancers have surpassed cervical cancers as the most common cancer caused by HPV but unlike cervical cancer, up until now, there has been no screening test for this type of oropharyngeal cancer."

Professor Punyadeera said the discovery was made during an HPV-prevalence study which included 665 healthy individuals.

"To take the test all the person has to do is give a salivary oral rinse sample. When the test shows HPV-16 DNA, it is repeated and if the presence of HPV-16 is persistent over a period of time we would be suspicious that there may be underlying cancer.

"The person whom we reported in this study had been consistently HPV-16 DNA positive for 36 months, with a steadily rising count of HPV-16 DNA after testing at 6, 12 and 36 months.

"The patient was found to have a 2mm squamous cell carcinoma in the left tonsil, treated by tonsillectomy. This has given our patient a high chance of cure with very straightforward treatment.

"Since the surgery, the patient has had no evidence of HPV-16 DNA in his saliva."

Professor Punyadeera said this was the first-ever case of histologically confirmed diagnosis of an asymptomatic, hidden throat cancer, diagnosed with a saliva screening test and that wider validation studies were required to confirm this finding.

"The presence of this pattern of elevated salivary HPV-DNA must be fully evaluated, as it may provide the critical marker for early cancer detection.

"We now have the promise of a screening test for oropharynx cancer and there is an urgent need to undertake a major study to validate this test and the appropriate assessment pathway for people with persisting salivary HPV-DNA."

Tsukuba, Japan - Allergies can significantly affect health and quality of life. While allergen immunotherapy provides long-lasting therapeutic relief to people suffering from environmental allergies, the therapy can last several years and requires large amounts of allergen. Now, researchers from the University of Tsukuba developed a novel system that enables the mass production of the major birch pollen allergen Bet v 1 in plant leaves in just a matter of days. In a new study published in Frontiers in Plant Science, they showed that their system not only produces large amounts of Bet v 1, but the purified protein was also highly reactive towards the IgE antibodies in sera from individuals with birch pollen allergy.

"The idea of allergen immunotherapy is to desensitize the body's response to the allergen by exposing patients to it in gradually increasing amounts," says corresponding author of the study Professor Kenji Miura. "Because a significant drawback is the difficult, expensive and low-yield production of allergens, our goal was to develop a new system that allows for the rapid and massive production of allergens that can be used in the clinical setting."

To achieve their goal, the researchers turned to their previously established "Tsukuba system," which makes use of a method called agroinfiltration. They first introduced the gene for Bet v 1 into a specific type of bacteria called Agrobacterium tumefaciens and let them grow. They then immersed leaves of the plant Nicotiana benthamiana into the bacterial solution to bring the bacteria into close contact with the plant, so the bacteria could transfer the Bet v 1 gene to plant cells, which in turn started producing the protein. To test the quality of their product, the researchers also produced the protein in Brevibacillus brevis, which is a standard bacterial host for protein production.

"We were able to purify 1.2mg of Bet v 1 protein from 1g leaves in just 5 days," explains Professor Miura. "This is a relatively large amount that is otherwise difficult to achieve using standard methods. Our next goal was to test whether our protein was immunogenic, which is a prerequisite for immunotherapy."

The researchers isolated sera from individuals with birch pollen allergy and mixed them with Bet v 1 protein purified from plants and bacteria. In both cases, the researchers were able to show that Bet v 1-specific IgE from the patients' sera, which is the antibody causing the allergy, was strongly reactive to their proteins.

"These are striking results that show how functional allergens can be produced in a fast and efficient way," says Professor Miura. "Given that immunotherapy requires 5-20μg allergen per treatment over several years, our findings could offer an opportunity to significantly improve allergen immunotherapy."

Evidence from a large study of several thousand patients shows that men have higher concentrations of angiotensin-converting enzyme 2 (ACE2) in their blood than women. Since ACE2 enables the coronavirus to infect healthy cells, this may help to explain why men are more vulnerable to COVID-19 than women.

The study, published in the European Heart Journal [1] today (Monday), also found that heart failure patients taking drugs targeting the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), did not have higher concentrations of ACE2 in their blood.

Dr Adriaan Voors (MD-PhD), Professor of Cardiology at the University Medical Center Groningen (The Netherlands), who led the study, said: "Our findings do not support the discontinuation of these drugs in COVID-19 patients as has been suggested by earlier reports."

Some recent research suggested that RAAS inhibitors might increase concentrations of ACE2 in plasma - the liquid part of blood - thereby increasing the risk of COVID-19 for cardiovascular patients taking these drugs. The current study indicates that this is not the case, although it looked only at ACE2 concentrations in plasma, not in tissues such as lung tissue. In addition, the study cannot provide definitive evidence on the effects of RAAS inhibitors in patients with COVID-19. Its conclusions are mainly restricted to heart failure patients, and the patients did not have COVID-19, so the researchers cannot provide a direct link between the course of the disease and ACE2 plasma concentrations.

Prof Voors said: "ACE2 is a receptor on the surface of cells. It binds to the coronavirus and allows it to enter and infect healthy cells after it is has been modified by another protein on the surface of the cell, called TMPRSS2. High levels of ACE2 are present in the lungs and, therefore, it is thought to play a crucial role in the progression of lung disorders related to COVID-19."

Prof Voors and his colleagues were already studying differences in markers of disease in the blood between men and women before the coronavirus outbreak. The results became available soon after the pandemic began.

The first author of the study, Dr Iziah Sama from UMC Groningen, said: "When we found that one of the strongest biomarkers, ACE2, was much higher in men than in women, I realised that this had the potential to explain why men were more likely to die from COVID-19 than women."

The researchers measured ACE2 concentrations in blood samples taken from two groups of heart failure patients from 11 European countries [2]. There were 1485 men and 537 women in the first group, the index cohort, which was designed to test the researchers' hypotheses and research questions. Then the researchers validated their findings in a second group of 1123 men and 575 women, the validation cohort.

The median (average) age of the participants in the index cohort was 69 years for men and 75 years for women, and in the validation cohort it was 74 and 76 years, respectively.

When the researchers looked at a number of clinical factors that could play a role in ACE2 concentrations, including the use of ACE inhibitors, ARBs and mineralocorticoid receptor antagonists (MRAs), as well as a history of chronic obstructive pulmonary disease, coronary artery by-pass graft and atrial fibrillation, they found that male sex was the strongest predictor of elevated ACE2 concentrations. In the index cohort, ACE inhibitors, ARBS and MRAs were not associated with greater ACE2 plasma concentrations, and in the validation cohort, ACE inhibitors and ARBs were associated with lower ACE2 concentrations, while MRAs were only weakly associated with higher concentrations.

"To the best of our knowledge, this is the first substantial study to examine the association between plasma ACE2 concentrations and the use of blockers of the renin-angiotensin-aldosterone system in patients with cardiovascular disease. We found no evidence that ACE inhibitors and ARBs were linked to increased ACE2 concentrations in plasma. In fact, they predicted lower concentrations of ACE2 in the validation cohort, although we did not see this in the index cohort," said Prof Voors.

"The effect of MRAs on ACE2 concentrations is not clear, as the weak increase in concentrations in the validation cohort was not seen in the index cohort. Our findings do not suggest that MRAs should be discontinued in heart failure patients who develop COVID-19. They are a very effective treatment for heart failure and the hypothetical effects on viral infection should be weighed carefully against their proven benefits," he said.

ACE2 is found not only in the lungs, but also the heart, kidneys and the tissues lining blood vessels, and there are particularly high levels in the testes. The researchers speculate that its regulation in the testes might partially explain higher ACE2 concentrations in men, and why men are more vulnerable to COVID-19.

Other limitations of the study include the fact that the researchers only measured concentrations of ACE2 in plasma, not in tissues, so they cannot be sure that concentrations in the blood are similar to those seen in tissues; it is the ACE2 in the lung tissues that are thought to be important for viral infection of the lungs, not ACE2 concentrations in the blood.

In an accompanying editorial [3], Professor Gavin Oudit, from the University of Alberta, Canada, and Professor Marc Pfeffer, from Brigham and Women's Hospital, Harvard Medical School, USA, write: "When faced with the rapidly expanding COVID-19 pandemic and in the absence of definitive data, the results of Sama et al obtained in heart failure patients in the pre-COVID-19 period offer supporting evidence to continue ACE inhibitors or ARBs in patients at risk for SARS-CoV-2 infection. However, this field is moving so rapidly that we now have two observational studies of ARB/ACE inhibitor use in hospitalized COVID-19 patients showing no augmented risk to COVID-19 patients and even suggesting possible benefit."

The study is one of several research papers, clinical reviews, editorials and discussion papers on COVID-19 and cardiovascular disease to be published in a special issue of the European Heart Journal on Thursday 14 May. [4]

Asgard archaea, proposed as a new archaeal superphylum, are currently composed of five phyla Lokiarchaeota, Thorarchaeota, Odinarchaeota, Heimdallarchaeota, and Helarchaeota. Since Asgard archaea contain abundant eukaryotic signature proteins and form a monophyletic group with eukaryotes in a phylogenetic tree, they are regarded as the closest relatives of Eukarya and have therefore attracted increasing research interests, although the debate about the evolutionary relationship is ongoing. In the past several years, metagenome-assembled genomes (MAGs) enabled us to decipher the metabolic capabilities of Asgard archaea, and the most recent isolation and transcriptomic analysis of Lokiarchaeota provided further insights into their metabolic capabilities. However, since no comprehensive information about the in situ activity of these Asgard archaea has been compiled so far, our understanding of these phylogenetically and evolutionally important archaea is based on prediction, and thus, severely limited.

In the present study, Cai and his colleagues sampled coastal sediments from different depth layers, where they identified abundant Lokiarchaeotal and Thorarchaeotal 16S rRNA genes, for deep metagenomic and metatranscriptomic sequencing (totally 2.3 Tbp). Finally, they recovered 15 Asgard archaeal MAGs with genome completeness >75%, covering almost all phyla (except Odinarchaeota). Notably, the Heimdallarchaeota lineage is composed of three robust subclades including two previously known branches i.e. Heimdall-MHVG and Heimdall-AAG, with high branch support values. Phylogenetic analysis of a 16S rRNA gene (1152 bp) found in the remaining Heimdallarchaeota-like MAGs showed that it formed a new monophyletic branch with an identity below 74% to 16S rRNA genes of other Asgard archaeal phyla. Thus, they propose this lineage as a new phylum named Gerdarchaeota, after Gerd, the Norse goddess of fertile soil, because these Asgard archaea genomes were obtained from organic-rich coastal environments. Genomic analyses predict that Gerdarchaeota are facultative anaerobes in utilizing both organic and inorganic carbon. Nevertheless, unlike their closest relatives Heimdallarchaeota, Gerdarchaeota have genes encoding for cellulase and enzymes involved in the tetrahydromethanopterin-based Wood-Ljungdahl pathway. Another interesting they found is that Gerdarchaeota MAGs lack the key enzyme G1PDH for archaeal lipid biosynthesis, but contain the bacterial/eukaryal-type G3PDH for synthesis of bona fide bacterial lipids, which might explain the eukaryogenesis.

Since diverse Asgard MAGs (6 phyla) were identified in different sedimental depth layers, Cai and his colleagues further investigated their in situ activities through metatranscriptomics to predict their ecological roles. They detected high expression levels of genes encoding extracellular peptidases, ABC transporter, and the enzyme sets for the conversion of amino acids to acetyl-CoA in both surface and subsurface coastal sediments, implying that Asgard archaea might be essential participants in the degradation of these substrates. Also, the presence of transcripts for ethanol metabolism (alcohol dehydrogenase, aldehyde ferredoxin oxidoreductase), suggesting that ethanol might be another substrate or product. It is intriguing to note that they also identified the expressed gene set for aerobic respiration in Gerdarchaeota, Heimdallarchaeota-AAG and Heimdallarchaeota-MHVG, including the key transcript of cytochrome c oxidase (belonging to Gerdarchaeota) indicates that these Asgard archaea might participate aerobically in organic matter degradation in surface sediments. Although the Asgard archaea phyla co-inhabit the same sediment layers, distinct ecological roles are played by a given phylum. For example, unlike Heimdallarchaeota-AAG and Heimdallarchaeota-MHVG, Gerdarchaeota contain and expressed genes for autotrophy and cellulose degradation.

The phrase 'the uplift of the Tibetan Plateau' is often used to link various phenomena (e.g. monsoon dynamics and biodiversity evolution) but in this review Spicer and colleagues bring together diverse lines of evidence to show that the concept of an extensive low-relief Tibet, rising in its entirety as a result of the India-Eurasia collision, is false, and the product of overly simplistic modelling. The orogeny of the Tibetan region (Tibet, The Himalaya and the Hengduan Mountains) dates back approximately 200 million years, long before the arrival of India, and was the product of earlier Gondwanan tectonic block collisions that produced a complex of mountain chains and valleys. The authors explain why previous stable isotope and fossil-based estimates of past surface heights were often contradictory; isotopes tend to record the height of mountain crests, while the fossils are more indicative of where sediments accumulate in valley bottoms. The isotopic bias towards uplands means that even valleys appear as uplands at the height of the bounding mountains and so appear as an elevated plateau, a result confirmed by isotope-enabled climate modelling. By combining well-dated multiple paleoaltimetric methods a better understanding of past topography emerges.

The formation of a complex topography, and in places thickened crust, before the arrival of India suggests that the formation of the Tibetan Plateau was not only due to the India-Eurasia collision and this has important implications for the amount of crustal shortening and the size of 'greater India' before collision.
Previous work pointed to a rise of eastern Tibet and the Hengduan Mountains in the Miocene, but recent radiometric re-dating of key sites shows the region was elevated before plateau formation and the rise of the Himalaya. Uplift began in the Eocene in large part due to extrusion of parts of Tibet beginning as early as ~ 52 Ma and extended into the early Oligocene, with landscape dissection through the expansion of river drainages taking place in the Miocene (subject to the dating being correct) as the monsoons strengthened.

The Himalaya began to rise in the Eocene, but only crested the pre-existing Gangdese mountains that already formed a 4-5 km high 'wall' along southern Tibet after the mid Miocene. North of the Gangdese, along the Bangong-Nujiang Suture south of the Tangula mountains, a deep ancient east-west aligned great central valley existed until early in the Neogene (approximately 23 million years ago) and later in its history was internally-drained. Numerous fossil finds show lakeside sub-tropical vegetation in this valley remained below 2.3 km above sea level for much of its history, the valley floor only rising in the Neogene to form today's flat plateau through ongoing tectonic compression from India and sediment infilling. 'Uplift' in geology relates to the rise of rocks and work done against gravity, so the infilling of basins by sediment to contribute to the formation of a low-relief surface means that Tibet was never 'uplifted' as a plateau, nor was that rise solely a consequence of the India-Eurasia collision.

Herpes simplex virus (HSV1) infections are initiated at mucosal surfaces where the virus infects epithelial cells. When HSV1 spreads from the peripheral nerves and into the central nervous system, it can infect the brain and cause herpes simplex encephalitis, a rare disease with high mortality if left untreated. In most cases, the innate immune system prevents HSV1 brain infection, but HSV1 is sometimes able to evade the brain's defenses. A research team from Aarhus University, University of Oxford, and University of Gothenburg, led by first author Chiranjeevi Bodda in Søren Paludan's lab, discovered a molecular mechanism that helps HSV1 infect the brain, which they present in a study that will be published May 8 in the Journal of Experimental Medicine (JEM).

The stimulator of interferon genes (STING) protein plays an important role in immunity, and it is activated by a virus's DNA during viral infection. STING initiates a cascade of cellular actions that help fight the invader. Those initial efforts include gene activation and production of cytokine proteins such as type I interferon (IFN) that boost the immune response. "HSV1 has evolved multiple mechanisms to evade the host cells' induction of type I IFN," Bodda explains, "but how HSV1 evades the type I IFN response in the brain were not well understood."

The research team worked to identify proteins encoded in HSV1's genome that promoted HSV1's immune evasion in the brain. They infected mouse brain cells grown in culture with HSV1 mutants that were missing key genes, or whose gene activity was altered, and found that a HSV1 containing a mutated VP1-2 gene showed increased innate immune responses. Mice showed a similarly robust immune response against HSV1 with mutant VP1-2. This indicated that normal VP1-2 suppresses immunity.

The key difference between normal VP1-2 and the mutant VP1-2 was the mutant lacked its ability to remove a post-translational modification, called ubiquitin, from other proteins inside host cells after it infects them. Ubiquitin is one of several post-translational modifications known to modulate the STING cascade's immune response. The team found that VP1-2 was targeting the STING activity in brain immune cells, known as microglia. The team further showed that VP1-2 can directly remove STING ubiquitination, which prevented STING from being activated for signaling. "Before this study there was no knowledge on viruses altering ubiquitin in the brain's immune response," Paludan says.

"Our study shows that HSV1 targets STING ubiquitination in the brain to promote viral infection and potentially progression to herpes simplex encephalitis," Bodda says. "A drug that inhibits the virus's ability to remove ubiquitin could allow brain cells to mount an efficient antiviral response against HSV1. This could especially benefit immunocompromised patients with severe HSV1 brain infection, particularly in cases that are resistant to the standard acyclovir treatment."

Paludan adds that though the study focuses on herpesviruses, there are parallels to the coronavirus and relevance to the COVID-19 pandemic. "Our results lead us to hope that if we can prevent viruses from blocking STING, then we can prevent the virus from replicating. That could pave the way for new principles for treatment of herpes, influenza and also the coronavirus."

Scientists from the University of Groningen have developed a method that combines different resolution levels in a computer simulation of biological membranes. Their algorithm backmaps a large-scale model that includes features, such as membrane curvature, to its corresponding coarse-grained molecular model. This has allowed them to zoom in on toxin-induced membrane budding and to simulate a full-sized mitochondrial lipid membrane. Their approach, which was published in the journal Nature Communications on 8 May, opens the way to whole-cell simulations at a molecular level.

Molecular dynamics simulations are a powerful tool to study the movements and interactions of atoms and molecules. However, in many biological processes, large-scale changes in, for example, membrane shape are important. 'These shape changes are of fundamental importance to the cell's functioning,' explains Siewert-Jan Marrink, Professor of Molecular Dynamics at the University of Groningen. 'However, the time and length scale of these membrane shape changes are too large for simulations at a molecular resolution.'

Challenging

Even though an increase in computing power allows more complex and longer simulations, cell structures such as mitochondria are still beyond reach. That is why the Molecular Dynamics group has developed an algorithm that links large-scale changes to molecular level simulations. For mitochondria, they started with an electron micrograph density map. The densities were translated into lipid structures and these were used as the input for a molecular dynamics simulation with the Coarse Grain (CG) Martini force field, previously developed by Marrink.

'The difficult part is to place the lipids in the correct orientation in this density map, which is especially challenging in bent areas,' adds Wria Pezeshkian, a postdoctoral researcher in Marrink's team and co-author of the paper. The algorithm allows users to add different kinds of lipids to the membrane, at a realistic packing level. Using this approach, Marrink and his colleagues were able to simulate the entire lipid membrane of a mitochondrion for two nanoseconds. Pezeshkian: 'This structure contained more than five million lipids, which meant that the simulation had to deal with 80 million particles as each lipid molecule consists of multiple particles.'

Triangles

Considering the size and shape, this simulation's complexity is larger than any simulation performed previously. 'A simulation of microseconds would have been possible but, as we had no information on the localization of the proteins in the mitochondrial membrane, it only contained lipids and is therefore unstable,' explains Marrink. Adding this extra complexity to the simulation is certainly possible and is currently in progress.

Instead of a density map, the input for the system could also be a continuum model, which represents the membrane surface as triangles made up of nodes that are connected by 'springs'. Such a model can calculate forces generated by membrane deformation. Backmapping lipids and toxin proteins onto the corresponding parts of this model allowed Marrink and his colleagues to zoom in on molecular behaviour in the stalk of a membrane bud that was induced by the joint action of many toxins.

Synthetic cell

'Our final goal is to simulate an entire eukaryotic cell and zoom in on specific parts of this object,' says Marrink. This is currently out of reach, although the current system already allows simulation of large objects inside a cell, such as the endoplasmic reticulum or the Golgi apparatus. 'And we could probably simulate a red blood cell.'

A simple synthetic cell may soon be within reach. Marrink is involved in a project aimed at creating a synthetic cell and being able to simulate processes such as cell division would help its design. 'We would really like to know which lipids and proteins could play a role in cell constriction during division.'