Culture

A general practitioner, wife and mother has recounted her experience with COVID-19 which saw her stay in hospital 150 days and become one of the first patients to be treated with extracorporeal membrane oxygenation (ECMO), special equipment that completely takes over the function of the lungs and is a last resort option.

The self-written case report, which appears in the journal Anaesthesia Reports (a journal of the Association of Anaesthetists) is by Dr Anushua Gupta, who works as a general practitioner in Stockport, Greater Manchester, UK. It is thought to be the first patient-written account of ECMO to treat COVID-19 to appear in the medical literature.

Extracorporeal membrane oxygenation was introduced as a centrally commissioned NHS service following the H1N1 influenza pandemic ten years ago, and there are five centres that provide it in England. It involves the removal of deoxygenated venous blood, the addition of oxygen (and removal of carbon dioxide) outside the body and return of the now oxygenated venous blood to the patient. It requires specialist staff, advanced equipment and more space, yet it might provide more time for patients to potentially respond to treatment during the acute phase of their illness.

Dr Gupta explains: "I remained in hospital for 150 days, 34 of which I spent on ECMO. I have no recollection of my time on ECMO, but liberation from it was not the end of my story; I had to overcome numerous physical and mental challenges during recovery and rehabilitation. I hope my story is read by others who are recovering from COVID-19 or critical illness more generally, and that it provides hope that one can return towards a normal way of life and the challenges of rehabilitation can be overcome."

She was infected in the first wave of the pandemic, sometime during March 2020, around 2 weeks after her 40th birthday. On April 1, she was admitted to Wythenshawe Hospital, and on April 4 she suddenly deteriorated with severe breathlessness and due to low oxygen levels started to experience "visual hallucinations of a black-winged figure". She was transferred to ICU for tracheal intubation and mechanical ventilation, requiring a medically-induced coma with no guarantee of survival.

"My worst fears were coming true. I telephoned my husband Ankur, and asked to see our daughter Ariana - just 18 months old at that time - on a videocall, as I thought that I would never get to see her again," she recalls. "I feared that I would never get to fulfil the dream that my husband and I had of living into old age together. However, I had to remain composed for the sake of my husband, who likewise had to be strong for our daughter." She was sedated later that night, not knowing she would remain in a coma for the next two months.

It was sheer coincidence that the hospital where Dr Gupta was admitted is North West England's centre for ECMO, but her case had to be assessed on her chances of survival like any other patient. Doctors decided on April 13 to put her on ECMO, which was required for 34 days. On May 13, just 4 days before being weaned from ECMO, she began to show improvement. She went on to have a tracheostomy to help her breathing on May 23 and her sedatives were gradually reduced.

Dr Gupta then details her long battle to recover from the disease, both for the remaining time in hospital and after being discharged on September 1, 2020. "My daughter has been my driving force, underpinning my determination to get better. My husband, who held the fort when I was not there, has continued to support me in every way," she explains.

She suffered multiple lung complications, swallowing difficulties and completely lost her voice due to the length of time in ICU, which she has gradually recovered from thanks to extensive support from speech and language therapists, although she remains hoarse at times. She also explains that early on after the sedatives were weaned off, "I couldn't sit upright without support, I could not feed myself, brush my teeth or hair, wash myself or even hold a pen; like a baby in its first year of life. I had to be moved by hoist for two months despite being completely awake and alert. In that time, with immense input from the physiotherapy team, I mustered the physical and mental strength to slowly be able to pull myself to stand up using a special device called a rota stand. It took a further few weeks to progress to taking my first few steps. I learned that one can certainly not underestimate the vital role of rehabilitation following critical care."

She also received extensive psychological support to help deal with the anxiety of separation from her daughter and family, and also the trauma of her physical recovery, learning various coping strategies including meditation.

She concludes: "My recovery is by no means complete. I have significant changes to my lungs. It remains unknown whether those changes are reversible. I still get breathless, but this is improving, and my exercise tolerance is getting better too. I was suffering significantly with pains in multiple joints for many months. I feel this may well be what others have described as 'long-COVID'. However, this is also improving, and I am getting fitter and more active. My liver function has improved but is not quite normal. My mental health is much better. I try to keep a very positive outlook on life, and I feel like I have been given a second chance."

Researchers at Michigan Medicine found that people with venom allergies are much more likely to suffer mastocytosis, a bone marrow disorder that causes higher risk of fatal reactions.

The team of allergists examined approximately 27 million United States patients through an insurance database - easily becoming the nation's largest study of allergies to bee and wasp stings, or hymenoptera venom. The results, published in the Journal of Allergy and Clinical Immunology, revealed mastocytosis in fewer than 0.1% of venom allergy patients - still near 10 times higher than those without allergies.

"Even though there is mounting interest, mast cell diseases are quite understudied; there are probably many people who go through life as some sort of 'medical mystery,' unaware of that diagnosis," says lead investigator Charles Schuler, M.D., a clinical assistant professor of allergy and immunology at Michigan Medicine. "One way to find them is to find people with a venom allergy. This research strongly supports that and will help us more properly treat these patients."

A life-threatening reaction to a bee sting can often be the first manifestation of mastocytosis. It's the most common anaphylaxis trigger in that patient population.

While mastocytosis diagnoses are more prevalent in U.S. venom allergy patients, the numbers are significantly higher in Europe, says Cem Akin, M.D., senior author and clinical professor of allergy and immunology at Michigan Medicine.

"This suggests that there may be differences in sensitization patterns to bee and wasp venoms between Europe and the U.S.," Akin says. "However, the European numbers may be overestimated due to referral and patient selection bias, as most of the centers publishing on the topic are referral facilities for mastocytosis. While Michigan Medicine is one of the world's largest referral centers for mastocytosis, we also have a large population of patients we follow for venom allergy."

The study included a five-year analysis of patients with history of severe venom allergy who underwent venom desensitization immunotherapy at Michigan Medicine. The research team found that elevated levels of tryptase, a chemical secreted by allergy cells, may predict if a person is at higher risk for reaction to immunotherapy.

"This study helps us account for the side effects or adverse outcomes associated with our current therapy," Schuler says. "Knowing this, allergists can be more watchful during sessions and watch for systemic reactions."

This study started out as a Michigan Medicine quality assurance project, and the paper is now the most comprehensive analysis of incidence of hymenoptera venom allergy and mastocytosis in the country, says James Baldwin, M.D., chief of Michigan Medicine's division of allergy and clinical immunology.

"It creates a picture of the burden of these conditions," Baldwin says. "It will inform both future research and public policy decisions in the field moving forward."

When a person views a familiar image, even having seen it just once before for a few seconds, something unique happens in the human brain.

Until recently, neuroscientists believed that vigorous activity in a visual part of the brain called the inferotemporal (IT) cortex meant the person was looking at something novel, like the face of a stranger or a never-before-seen painting. Less IT cortex activity, on the other hand, indicated familiarity.

But something about that theory, called repetition suppression, didn't hold up for University of Pennsylvania neuroscientist Nicole Rust. "Different images produce different amounts of activation even when they are all novel," says Rust, an associate professor in the Department of Psychology. Beyond that, other factors—an image's brightness, for instance, or its contrast—result in a similar effect.

In a paper published in the Proceedings of the National Academy of Sciences, she and postdoctoral fellow Vahid Mehrpour, along with Penn research associate Travis Meyer and Eero Simoncelli of New York University, propose a new theory, one in which the brain understands the level of activation expected from a sensory input and corrects for it, leaving behind the signal for familiarity. They call it sensory referenced suppression.

The visual system

Rust's lab focuses on systems and computational neuroscience, which combines measurements of neural activity and mathematical modeling to figure out what's happening in the brain. One aspect relates to the visual system. "The big central problem of vision is how to get the information from the world into our heads in an interpretable way. We know that our sensory systems have to break it down," she says.

It's a complicated process, greatly simplified here for clarity: Information comes into the eye via the rods and cones. It travels neuron by neuron through a stack of brain areas that make up the visual system and finally to a visual brain area called the IT cortex. Its 16 million neurons activate in different patterns depending on what's being viewed, and the brain must then interpret the patterns to understand what it's seeing.

"You get one pattern for a specific face. You get a different pattern for 'coffee cup.' You get a different pattern for 'pencil,'" Rust says. "That's what the visual system does. It builds the world back up to help you decipher what you're looking at."

In addition to its role in vision, activation of the IT cortex is also thought to play a role in memory. Repetition suppression, the old theory, relies on the idea that there's an activation threshold that gets crossed: More neural activity tells the brain the image is novel, less indicates one that's previously seen.

Because several factors affect the total amount of neural activity, also called spikes, in the IT cortex, the brain can't discern what's specifically causing the reaction. It could be memory, image contrast, or something else altogether, Mehrpour says. "We propose a new idea that the brain corrects for the changes caused by these other factors, in our case contrast," he says. After that calibration, what remains is the isolated brain activation for familiarity. In other words, the brain understands when it is viewing something that it has previously seen.

Long-term implications

To draw this conclusion, the researchers presented sequences of grayscale images to two adult male rhesus macaques. Every image appeared exactly twice, the first time as novel, the second time as familiar, in a range of high- and low-contrast combinations. Each viewing lasted precisely half a second. The animals were trained to use eye movements to indicate whether an image was new or familiar, disregarding the contrast levels.

As the macaques performed this memory task, the researchers recorded neural activity in the IT cortex, measuring the spikes for hundreds of individual neurons, a unique method that differs from those that measure proxies of neural activity averaged across 10,000 neurons firing. Because Rust and colleagues wanted to understand the neural code, they needed information for individual neurons.

Using a mathematical approach, they deciphered the patterns of spikes that accounted for how the macaques could distinguish memory from contrast. This ultimately confirmed their hypothesis. "Familiarity and contrast both change the overall firing rate," Rust says. "What we're saying is the brain can tease apart and isolate one from the other."

In the future, better understanding this process could have applications for artificial intelligence, Mehrpour says. "If we know how the brain represents and rebuilds information in memory in the presence of changes in sensory input like contrast, we can design AI systems that work in the same way," he says. "We could potentially build machines that work in the same way that our brain does."

Beyond that, Rust says that down the line the findings could have implications for treating memory-impairing diseases like Alzheimer's. "By understanding how memory in a healthy brain works, you can lay the foundations to develop preventions and treatments for the memory-related disorders plaguing an aging population."

But for any of this to come to pass, it will be crucial to keep digging, she says. "To get this right, we have to understand the memory signal that's driving behavior." This work brings neuroscientists one step closer.

The combination of a carb-heavy diet and poor oral hygiene can leave children with early childhood caries (ECC), a severe form of dental decay that can have a lasting impact on their oral and overall health.

A few years ago, scientists from Penn's School of Dental Medicine found that the dental plaque that gives rise to ECC is composed of both a bacterial species, Streptococcus mutans, and a fungus, Candida albicans. The two form a sticky symbiosis, known scientifically as a biofilm, that becomes extremely virulent and difficult to displace from the tooth surface.

Now, a new study from the group offers a strategy for disrupting this biofilm by targeting the yeast-bacterial interactions that make ECC plaques so intractable. In contrast to some current treatments for ECC, which use antimicrobial agents that can have off-target effects, potentially harming healthy tissues, this treatment uses an enzyme specific to the bonds that exist between microbes.

"We thought this could be a new way of approaching the problem of ECCs that would intervene in the synergistic interaction between bacteria and yeast," says Geelsu Hwang, an assistant professor in Penn Dental Medicine and senior author on the study, published in the journal mBio. "This offers us another tool for disrupting this virulent biofilm."

The work builds off findings from a 2017 paper by Hwang and colleagues, including Hyun (Michel) Koo of Penn Dental Medicine, which found that molecules call mannans on the Candida cell wall bound tightly to an enzyme secreted by S. mutans, glycosyltransferases (Gftb). In addition to facilitating the cross-kingdom binding, Gftb also contributes to the stubbornness of dental biofilms by manufacturing gluelike polymers called glucans in the presence of sugars.

While some cases of ECC are treated with drugs that kill the microbes directly, potentially reducing the number of pathogens in the mouth, this doesn't always effectively break down the biofilm and can have off-target effects on "good" microbes as well as the soft tissues in the oral cavity.

Hwang and colleagues wanted to try a different approach that would directly target the insidious interaction between yeast and bacteria and opted to target the mannans in the Candida cell surface as a point of contact.

Using three different mannan-degrading enzymes, they applied each to a biofilm growing on a tooth-like surface in a human saliva medium and left it for five minutes. Following the treatment, they noted that the overall biofilm volume was reduced. Using powerful microscopy, they also observed drastic reductions in the biofilm thickness and interactions between bacteria and yeast. The pH of the surrounding medium was higher when exposed to the enzymes, indicating an environment that is not as acidic and thus less conducive to tooth decay.

They also measured how easy it was to break up the biofilm after treatment, using a device that applies a stress, akin to tooth brushing.

"The biofilm structure was more fragile after the enzyme treatment," Hwang says. "We were able to see that the biofilms were more easily removed."

To confirm the mechanism of their approach--that the mannan-degrading enzymes were weakening the binding between yeast and bacteria--the team used atomic-force microscopy to measure the bonds between Candida and Gftb. The therapy, they found, reduced this binding force by 15-fold.

Finally, they wanted to get a sense of how well-tolerated these enzymes would be when used in the oral cavity, especially since children would be the patient group targeted.

Applying the enzymes to human gingival cells in culture, they found no harmful impact, even when they used a concentrated form of the enzymes. In addition, they observed that the treatment didn't kill the bacteria or yeast, a sign that it could work even if the microbes developed mutations that would lend them resistance against other types of therapies.

The researchers kept the application time relatively short at five minutes though they hope to see activity in an even shorter time, like the two minutes that is recommended for tooth brushing. Hwang says they may consider a non-alcohol-based mouthwash with these enzymes added that could be used by children as a preventive measure against ECC.

The researchers hope to continue pursuing this possibility with additional follow up, including testing these enzymes in an animal model. With more successes, they aim to add another tool for fighting the public health threat of ECC.

In studying COVID-19 testing and positivity rates in West Virginia between March and September 2020, West Virginia University researchers found disparities among Black residents and residents experiencing food insecurity.

Specifically, the researchers found communities with a higher Black population had testing rates six times lower than the state average, which they argue could potentially obscure prevalence estimates. They also found that areas associated with food insecurity had higher levels of testing and a higher rate of positivity.

"This could mean that public health officials are targeting predominately rural areas to keep tabs on how the pandemic will unfold in isolated communities within higher food insecurity," said Brian Hendricks, a research assistant professor with the West Virginia University School of Public Health's Department of Epidemiology and Biostatistics.

Hendricks said a unique element of this research is the Census-level data. While there are 55 counties in West Virginia, there are 484 Census tracts, which allowed the researchers to hone in on individual communities, almost on a scale of 1 to 100. This allowed researchers to compare testing and positivity rates with demographic data such as income level, sex, race, etc. "This is community-level modeling," Hendricks said. "We're doing something at a very granular level. Most modeling is at a county-level or above."

Among tracts included in the spatial analysis, Hendricks and his team identified 14 Census tracts which had among the state's highest percent Black/African American populations and testing disparities (defined as one or less tests per 1,000 people), contained within the cities of Fairmont, Wheeling, Bluefield, Beckley, Huntington, Dunbar and Charleston. These findings are in line with the study's overall findings of more testing occurring in higher food insecure locations with lower percent of the population identifying as Black/African American.

Hendricks said the team wanted to look at rurality and racial disparities, as adverse impacts of socio-economic and racial inequalities are oftentimes worsened in rural areas. Rural communities often have less access to healthcare, higher levels of food insecurity and poverty, and observe overall higher prevalence of pre-existing conditions, which can impact severity of COVID-19 infection.

The researchers incorporated a measure called the area deprivation index, which is essentially a scoring comprised of 17 socio-economic indicators, which indicates the extent which a community is vulnerable compared to other communities in the state. In addition to income, the measure controls for percent blue collar workers, household crowding, households with plumbing and transportation, and etc.

Before the vaccine was readily available, social distancing was the major defense against the virus.

"However, not all communities can socially distance equally," Hendricks said. "That was the motivating fire behind this paper -- where are these disparities?"

Recognizing this issue early in the pandemic, the West Virginia National Guard, the West Virginia Department of Health and Human Resources, and local health departments began holding targeted testing events. A COVID-19 Advisory Commission on African American Disparities was also formed.

While rural Black/African Americans have historically utilized health care at lower rates than their white counterparts due to medical mistrust, access to care, and a myriad of other factors, the article concludes by stating further research is needed to determine the underlying barriers restricting coronavirus testing among Black communities, and to better understand the role food insecurity in isolated areas has on risk of COVID-19 infection.

"This paper is making traction, already informing what do we do next," Hendricks said. For example, a subsequent grant was awarded which focused on putting more testing in vulnerable communities.

Scientists have long thought that there was a direct connection between the rise in atmospheric oxygen, which started with the Great Oxygenation Event 2.5 billion years ago, and the rise of large, complex multicellular organisms.

That theory, the "Oxygen Control Hypothesis," suggests that the size of these early multicellular organisms was limited by the depth to which oxygen could diffuse into their bodies. The hypothesis makes a simple prediction that has been highly influential within both evolutionary biology and geosciences: Greater atmospheric oxygen should always increase the size to which multicellular organisms can grow.

It's a hypothesis that's proven difficult to test in a lab. Yet a team of Georgia Tech researchers found a way -- using directed evolution, synthetic biology, and mathematical modeling -- all brought to bear on a simple multicellular lifeform called a 'snowflake yeast'. The results? Significant new information on the correlations between oxygenation of the early Earth and the rise of large multicellular organisms -- and it's all about exactly how much O2 was available to some of our earliest multicellular ancestors.

"The positive effect of oxygen on the evolution of multicellularity is entirely dose-dependent -- our planet's first oxygenation would have strongly constrained, not promoted, the evolution of multicellular life," explains G. Ozan Bozdag, research scientist in the School of Biological Sciences and the study's lead author. "The positive effect of oxygen on multicellular size may only be realized when it reaches high levels."

"Oxygen suppression of macroscopic multicellularity" is published in the May 14, 2021 edition of the journal Nature Communications. Bozdag's co-authors on the paper include Georgia Tech researchers Will Ratcliff, associate professor in the School of Biological Sciences; Chris Reinhard, associate professor in the School of Earth and Atmospheric Sciences; Rozenn Pineau, Ph.D. student in the School of Biological Sciences and the Interdisciplinary Graduate Program in Quantitative Biosciences (QBioS); along with Eric Libby, assistant professor at Umea University in Sweden and the Santa Fe Institute in New Mexico.

Directing yeast to evolve in record time

"We show that the effect of oxygen is more complex than previously imagined. The early rise in global oxygen should in fact strongly constrain the evolution of macroscopic multicellularity, rather than selecting for larger and more complex organisms," notes Ratcliff.

"People have long believed that the oxygenation of Earth's surface was helpful -- some going so far as to say it is a precondition -- for the evolution of large, complex multicellular organisms," he adds. "But nobody has ever tested this directly, because we haven't had a model system that is both able to undergo lots of generations of evolution quickly, and able to grow over the full range of oxygen conditions," from anaerobic conditions up to modern levels.

The researchers were able to do that, however, with snowflake yeast, simple multicellular organisms capable of rapid evolutionary change. By varying their growth environment, they evolved snowflake yeast for over 800 generations in the lab with selection for larger size.

The results surprised Bozdag. "I was astonished to see that multicellular yeast doubled their size very rapidly when they could not use oxygen, while populations that evolved in the moderately oxygenated environment showed no size increase at all," he says. "This effect is robust -- even over much longer timescales."

Size -- and oxygen levels -- matter for multicellular growth

In the team's research, "large size easily evolved either when our yeast had no oxygen or plenty of it, but not when oxygen was present at low levels," Ratcliff says. "We did a lot more work to show that this is actually a totally predictable and understandable outcome of the fact that oxygen, when limiting, acts as a resource -- if cells can access it, they get a big metabolic benefit. When oxygen is scarce, it can't diffuse very far into organisms, so there is an evolutionary incentive for multicellular organisms to be small -- allowing most of their cells access to oxygen -- a constraint that is not there when oxygen simply isn't present, or when there's enough of it around to diffuse more deeply into tissues."

Ratcliff says not only does his group's work challenge the Oxygen Control Hypothesis, it also helps science understand why so little apparent evolutionary innovation was happening in the world of multicellular organisms in the billion years after the Great Oxygenation Event. Ratcliff explains that geologists call this period the "Boring Billion" in Earth's history -- also known as the Dullest Time in Earth's History, and Earth's Middle Ages -- a period when oxygen was present in the atmosphere, but at low levels, and multicellular organisms stayed relatively small and simple.

Bozdag adds another insight into the unique nature of the study. "Previous work examined the interplay between oxygen and multicellular size mainly through the physical principles of gas diffusion," he says. "While that reasoning is essential, we also need an inclusive consideration of principles of Darwinian evolution when studying the origin of complex multicellular life on our planet." Finally being able to advance organisms through many generations of evolution helped the researchers accomplish just that, Bozdag adds.

University of California scientists have discovered genetic data that will help food crops like tomatoes and rice survive longer, more intense periods of drought on our warming planet.

Over the course of the last decade, the research team sought to create a molecular atlas of crop roots, where plants first detect the effects of drought and other environmental threats. In so doing, they uncovered genes that scientists can use to protect the plants from these stresses.

Their work, published today in the journal Cell, achieved a high degree of understanding of the root functions because it combined genetic data from different cells of tomato roots grown both indoors and outside.

"Frequently, researchers do lab and greenhouse experiments, but farmers grow things in the field, and this data looks at field samples too," said Neelima Sinha, a UC Davis professor of plant biology and the paper's co-author.

The data yielded information about genes that tell the plant to make three key things.

Xylem are hollow, pipe-like vessels that transport water and nutrients from the roots all the way up to the shoots. Without transport in xylem, the plant cannot create its own food via photosynthesis.

"Xylem are very important to shore up plants against drought as well as salt and other stresses," said lead study author Siobhan Brady, a professor of plant biology at UC Davis.

In turn, without plant mineral transport in xylem, humans and other animals would have fewer vitamins and nutrients essential for our survival. In addition to some typical players needed to form the xylem, new and surprising genes were found.

The second key set of genes are those that direct an outer layer of the root to produce lignin and suberin. Suberin is the key substance in cork and it surrounds plant cells in a thick layer, holding in water during drought.

Crops like tomatoes and rice have suberin in the roots. Apple fruits have suberin surrounding their outer cells. Anywhere it occurs, it prevents the plant from losing water. Lignin also waterproofs cells and provides mechanical support.

"Suberin and lignin are natural forms of drought protection, and now that the genes that encode for them in this very specific layer of cells have been identified, these compounds can be enhanced," said study co-author Julia Bailey-Serres, a UC Riverside professor of genetics.

"I'm excited we've learned so much about the genes regulating this moisture barrier layer. It is so important for being able to improve drought tolerance for crops," she said.

Genes that encode for a plant's root meristem also turned out to be remarkably similar between tomato, rice, and Arabidopsis, a weed-like model plant. The meristem is the growing tip of each root, and it's the source of all the cells that make up the root.

"It's the region that's going to make the rest of the root, and serves as its stem cell niche," said Bailey-Serres. "It dictates the properties of the roots themselves, such as how big they get. Having knowledge of it can help us develop better root systems."

Brady explained that when farmers are interested in a particular crop, they select plants that have features they can see, such as bigger, more attractive fruits. Much more difficult is for breeders to select plants with properties below ground they can't see.

"The 'hidden half' of a plant, below ground, is critical for breeders to consider if they want to grow a plant successfully," Brady said. "Being able to modify the meristem of a plant's roots will help us engineer crops with more desirable properties."

Though this study analyzed only three plants, the team believes the findings can be applied more broadly.

"Tomato and rice are separated by more than 125 million years of evolution, yet we still see similarities between the genes that control key characteristics," said Bailey-Serres. "It's likely these similarities hold true for other crops too."

Bottom Line: The U.S. Preventive Services Task Force (USPSTF) recommends that adults ages 45 to 75 be screened for colorectal cancer, lowering the age for screening that was previously 50 to 75. The USPSTF also recommends that clinicians selectively offer screening to adults 76 to 85 years of age. Colorectal cancer is the third leading cause of cancer death for both men and women in the United States. In 2016, 26% of eligible adults had never been screened and nearly one-third were not up to date with screening in 2018. The USPSTF routinely makes recommendations about the effectiveness of preventive care services and this statement replaces its 2016 recommendation.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2021.6238)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

CLEVELAND - According to new study results, a team of researchers led by Cleveland Clinic's Thaddeus Stappenbeck, M.D., Ph.D., have found that a diet high in fat and sugar is associated with impaired intestinal immune cell function in mice. The findings, published in Cell Host & Microbe, provide novel insights into pathways linking obesity and disease-driving gut inflammation, and have implications for developing targets to treat inflammatory bowel diseases (IBD) in patients.

Using data from more than 900 patients, the researchers found that elevated body mass index is associated with abnormal Paneth cells among patients with Crohn's disease and non-IBD patients.

Paneth cells are a type of anti-inflammatory immune cell found in the intestines that helps to protect against microbial imbalances and infectious pathogens. Dysfunction of these cells is driven by a combination of genetic mutations and environmental factors. Dr. Stappenbeck and others have previously linked Paneth cell dysfunction to gut changes indicative of IBD in preclinical models and a subset of Crohn's disease patients from multiple cohorts around the world.

"With this understanding, we set out to investigate whether diet-induced obesity--specifically caused by a diet high in fat and sugar, or a 'western diet'--is one of the environmental factors that can lead to impaired Paneth cell function," said Dr. Stappenbeck, chair of Lerner Research Institute's Department of Inflammation & Immunity.

The researchers compared the effects of a western diet versus a standard diet. The team's western diet contained about 40 percent fat and an elevated level of simple carbohydrates, which better resembles the diet of an average U.S. adult than regimens prescribed in other preclinical studies.

After eight weeks, the group that ate the western diet had more abnormal Paneth cells than the group that ate a standard diet. In the western diet group, other changes become apparent two months after the Paneth cell defects, including increased gut permeability, where bacteria and toxins can enter the gut and which is well-linked with chronic inflammation. Notably, however, switching to a standard diet from the western diet completely reversed the Paneth cell dysfunction.

"When we started to look into large-scale datasets for the specific mechanisms that might connect the high-fat, high-sugar diet with the Paneth cell dysfunction, a secondary bile acid called deoxycholic acid caught our attention," said Dr. Stappenbeck.

Deoxycholic acid is a metabolic byproduct of intestinal bacteria. Researchers found that consuming a western diet increased the bile acid in a region of the intestines called the ileum and, as a result, increased the expression of two downstream molecules, farnesoid X receptor (FXR) and type I interferon (IFN).

"For the first time, we showed how coordinated elevation of FXR and type I IFN signals in multiple cell types contribute to Paneth cell defects in response to a diet high in fat and sugar. In previous research, stimulating FXR has shown to help treat other diseases, including fatty liver disease, so we are hopeful that with additional research we can interrogate how the combination of elevated FXR and IFN signals can be targeted to help treat diet-induced gut infections and chronic inflammation."

Dr. Stappenbeck also explained that while the team was interested to learn that changing the diet regimen reversed the pathological changes, more research would be needed to determine if these changes also occur in patients.

Researchers have identified specific influenza targets that could be used to better protect Indigenous people from experiencing severe influenza disease through a universal, T cell-based vaccine.

In a collaboration with Monash Biomedicine Discovery Institute, Menzies School of Health Research and CQUniversity, Peter Doherty Institute for Infection and Immunity (Doherty Institute) researchers took a deep-dive look into how the immune system can protect Aboriginal and Torres Strait Islander people from severe influenza disease.

"We know that some populations are at high risk from severe influenza, and these include Indigenous people globally," said University of Melbourne Professor Katherine Kedzierska, Laboratory Head at the Doherty Institute.

"As many as 10 to 20 per cent of Aboriginal and Torres Strait Islander people died of influenza during the 1919 pandemic, compared to less than one per cent mortality rate in non-Indigenous Australians. Hospitalisation and morbidity rates were also higher for Aboriginal and Torres Strait Islander people during the 2009 H1N1 pandemic.

"Similarly, high adult mortalities (up to 100 per cent) were reported in some isolated Alaskan villages. Our research aims to harness immune responses to protect these high-risk populations."

The research team particularly focused on killer T cells and proteins called HLAs, important in determining immune responses to different pathogens.

HLA proteins vary across individuals and ethnicities. A specific HLA protein, named HLA-A*24:02, can be linked to more severe (or even fatal) outcomes of influenza. It is also highly prevalent in Aboriginal and Torres Strait Islander people, as well as many other Indigenous populations around the world.

Using state-of-the-art antigen discovery technology at Monash University, Professor Anthony Purcell and Dr Patricia Illing identified small fragments of influenza (peptide antigens) that were subsequently screened by Dr Luca Hensen, a research officer at the Doherty Institute, who identified which of these fragments formed protective targets for killer CD8 T cells that are presented by HLA-A*24:02.

"We propose that a universal influenza vaccine could be developed using these targets to promote optimal killer CD8 T cell response in the context of HLA-A*24:02," Dr Hensen said.

"This could provide much better global protection and help prevent severe influenza disease and death in populations who are at higher risk."

Co-author, Associate Professor Steven Tong, Royal Melbourne Hospital Infectious Diseases Physician and Co-Lead of the Clinical Research Discipline at the Doherty Institute, said other factors that contribute to poorer outcomes in Indigenous populations need to be considered, including higher rates of chronic diseases and the importance of social determinants of health.

"These findings are a significant step forward in understanding the immune profile of Aboriginal and Torres Strait Islander people and enable us to put that in context with the other determinants contributing to a higher risk of severe influenza. It is critical that future T cell-based influenza vaccines are designed to also protect ethnic populations who experience a high burden of disease," Associate Professor Tong said.

CQUniversity researcher, Professor Adrian Miller, of the Jirrbal people of North Queensland, said Aboriginal and Torres Strait Islander people were some of the most vulnerable when it came to influenza.

"The spread of influenza poses particular risks for isolated Indigenous communities," Professor Miller said.

"We hope that the findings from this research ultimately lead to a universal flu vaccine that will also protect Indigenous populations."

This project looked at samples from 127 participants from the LIFT (Looking Into influenza T-cell immunity) cohort based in the Northern Territory.

Manufactured in a new process based on crystalline materials, these low-loss mirrors promise to open up completely new application areas, for example in optical respiratory gas analysis for early cancer detection or the detection of greenhouse gases. This work will be published in the current issue of the journal Optica.

In 2016 researchers at the LIGO laser interferometer succeeded in the first direct observation of gravitational waves, which had originally been predicted by Albert Einstein in 1916. A significant contribution to the observation of this wave-like propagation of disturbances in space-time, which was rewarded with the Nobel Prize a year later, was provided by the laser mirrors of the kilometer-long interferometer assembly. Optimization of these mirrors for extremely low optical absorption losses was a key advancement in realizing the sensitivity necessary to make such measurements. "Low-loss mirrors are a key technology for many different research fields," explains Oliver H. Heckl, head of the Christian Doppler Laboratory for Mid-IR Spectroscopy and Semiconductor Optics, "They are the link for such diverse research fields as cancer diagnosis and gravitational wave detection."

In fact, comparable mirror properties are also promising technological breakthroughs for significantly more practical applications. This includes, among other things, sensitive molecular spectroscopy, i.e. the detection of the smallest amounts of substances in gas mixtures - a research focus of the Christian Doppler Laboratory (CDL). Examples can be found in the early detection of cancer through the detection of the smallest concentrations of marker molecules in the breath of patients, or in the precise detection of methane leaks in large-scale natural gas production systems in order to limit the contribution of such greenhouse gases to climate change.

Unlike the experiments at LIGO, however, such investigations are conducted much further outside the visible light spectrum, in the mid-infrared range. In this wavelength region, also known as the "fingerprint region", many structurally similar molecules are clearly distinguishable on the basis of their characteristic absorption lines. Therefore, it is a longstanding wish of the photonics community, to realize similarly low loss levels in this technically challenging wavelength range.

This is exactly what the team led by Oliver H. Heckl has now achieved in an international cooperation. In this case, low loss means that the new type of mirror absorbs less than 10 out of a million photons. For comparison: A commercially available bathroom mirror "destroys" around ten thousand times more photons, and even the mirrors used in top research have ten to a hundred times higher losses.

This drastic improvement was made possible through the use of a completely new optical coating technology: First, single-crystal stacks of high-purity semiconductor materials are deposited via an epitaxial growth process. These monocrystalline multilayers are then transferred via a proprietary bonding process onto curved silicon optical substrates, completing the mirrors that were tested at both the CDL and NIST. This unique "crystalline coating" technology was developed and carried out by the industrial partner of the Christian Doppler Laboratory, Thorlabs Crystalline Solutions. This company was originally founded under the name Crystalline Mirror Solutions (CMS) in 2013 as a spin-off from the University of Vienna by Garrett Cole and Markus Aspelmeyer. CMS was acquired by Thorlabs Inc. in December 2019. This industry collaboration was made possible, with the support of the Federal Ministry for Digital and Economic Affairs, via the internationally unique model of the Christian Doppler Research Association (CDG) to promote application-oriented basic research. A research group led by Adam Fleisher from the National Institute for Standards and Technology (NIST) in Gaithersburg, Maryland (USA), which is renowned for precision measurements, also played a key role in this success. Georg Winkler, co-author of the current study expresses his enthusiasm: "Precise measurement technology is much more than just pedantry. Wherever you can take a closer look by an order of magnitude, you usually discover completely new phenomena, just think of the invention of the microscope and telescope!"

In fact, this assessment has already proven true in the detailed characterization of the new mirrors themselves, when a previously unknown effect of polarization-dependent absorption was discovered in the semiconductor layers and theoretically explored by collaborator Prof. Hartwin Peelaers at the University of Kansas. "These results open up great opportunities regarding further refinement of these mirrors ", co-author Lukas Perner is delighted: "Thanks to the extremely low losses can we now further optimize the bandwidth and reflectivity."

With this in mind, the project partners are already working on a further improvement of the technology: Expansion of the optical bandwidth of the mirrors will allow them to be used efficiently with so-called optical frequency combs. This will enable the analysis of particularly complex gas mixtures with unprecedented accuracy.

Spintronics is an emerging technology for manufacturing electronic devices that take advantage of electron spin and its associated magnetic properties, instead of using the electrical charge of an electron, to carry information. Antiferromagnetic materials are attracting attention in spintronics, with the expectation of spin operations with higher stability. Unlike ferromagnetic materials, in which atoms align along the same direction like in the typical refrigerator magnets, magnetic atoms inside antiferromagnets have antiparallel spin alignments that cancel out the net magnetization.

Scientists have worked on controlling the alignment of magnetic atoms within antiferromagnetic materials to create magnetic switches. Conventionally, this has been done using a 'field-cooling' procedure, which heats and then cools a magnetic system containing an antiferromagnet, while applying an external magnetic field. However, this process is inefficient for use in many micro- or nano- structured spintronics devices because the spatial resolution of the process itself is not high enough to be applied in a micro- or nano-scale devices.

"We discovered that we can control the antiferromagnetic state by simultaneously applying mechanical vibration and a magnetic field," says Jung-Il Hong of DGIST's Spin Nanotech Laboratory. "The process can replace the conventional heating and cooling approach, which is both inconvenient and harmful to the magnetic material. We hope our new procedure will facilitate the integration of antiferromagnetic materials into spintronics-based micro- and nano-devices."

Hong and his colleagues combined two layers: a cobalt-iron-boron ferromagnetic film on top of an iridium manganese antiferromagnetic film. The layers were grown on piezoelectric ceramic substrates. Combined application of mechanical vibration and a magnetic field allowed the scientists to control the alignments of magnetic spins repeatedly along any direction desired.

The team aims to continue the search and development of new magnetic phases beyond conventionally classified magnetic materials. "Historically, new material discovery has led to the development of new technologies," says Hong. "We want our research work to be a seed for new technologies."

In today's plants, photorespiration dissipates some of the energy produced by photosynthesis and releases CO2. It begins when the enzyme RuBisCO acts on oxygen instead of carbon dioxide and creates toxic side-products requiring costly recycling reactions. The detoxification process uses up fixed carbon and wastes energy, thus strongly limiting agricultural productivity.

Scientists generally pursue two approaches to minimizes the deleterious effects of photorespiration: mimic the carbon concentrating mechanism of C4 plants or introduce new metabolic pathways to bypass the photorespiration.

Researchers led by Andreas Weber from Heinrich Heine University Düsseldorf and Tobias Erb from the Max Planck Institute for terrestrial Microbiology have developed a solution that synergistically couples photorespiration and C4 metabolism, connecting two of the main targets in plant metabolism. Within the EU-funded project Gain4Crops (http://www.gain4crops.eu), they have turned a photorespiration bypass route, the recently discovered BHAC, into a carbon strengthening mechanism in C3 plants. The team has introduced enzymes from the microbial BHAC pathway in a model plant, Arabidopsis thaliana, where they successfully convert a product of photorespiration into the source of a synthetic C4 cycle and without dissipating carbon, nitrogen, or energy.

After a successful plant transformation, gas exchange measurement and metabolites profiling confirmed that the plant conserves nitrogen and accumulates signature C4 metabolites. The Arabidopsis model showed no gain in the amount of CO2 assimilated via photosynthesis at the expense of the CO2 released by photorespiration; but, as the team pointed out, several bottlenecks might be responsible for masking the full potential of the BHAC pathway.

To fully appreciate the gain in carbon fixed and ultimately in yield, the pathway needs to be improved by identified other targets via kinetic and genomic scale metabolic models. Indeed, prototyping in many model organisms, like Arabidopsis, allows identifying shortcomings before moving to a target crop, thus speeding up the development process. For example, the Gain4crops project plans to test the newly discovered pathway in a set of model organisms of increasing cellular and anatomical complexity before moving to its final target: the sunflower.

Overall this study represents the first proof of concept for carbon-concentrating mechanisms in C3 plant that dependent on photorespiration, coupling the solution with the problem, and creating opportunities for improved agricultural productivity in the future. Furthermore, higher photosynthetic crops might become a valuable tool in the face of climate change thanks to their climate resilience and reduced consumption of resources.

Agriculture needs to keep pace with a growing population on a planet in a short supply of resources and with changing environmental conditions. "Improving sustainability is probably the biggest challenge of the 21st century, and, even if there is no single silver bullet, the combination of different solutions might bring an effective improvement," says Andreas Weber. And in the quest for more sustainable agriculture, agriculture that uses less land and resources engineered crops that tackle photorespiration might be part of the solution.

In a recent research, researchers led by Prof. ZHANG Haimin from the Institute of Solid State Physics of the Hefei Institutes of Physical Science (HFIPS) realized the synthesis of Mo single atoms anchored on activated carbon (Mo-SAs/AC) by the formed Mo-Ox bonds. The result was published on Chemical Communications.

According to the researchers, this new oxygen-coordinated molybdenum single atom catalyst was proved efficient to electrosynthesis of ammonia. The O-coordinated environment in this study, different from N-coordinated environment reported before, provided the sites to anchor Mo single atoms and form Mo-Ox sites, which could be used as the active centers for the adsorption and activation of N2, resulting in high nitrogen reduction reaction (NRR) activity.

"We have been curious about the key to the high NRR catalytic activity," said GENG Jing, first author of the study, "then we found the Mo-Ox site in the catalyst."

In this research, the surface-rich oxygen functional groups of pre-treated activated carbon played an important role in capturing the Mo precursor, forming Mo-O coordination to anchor Mo atoms as the catalytic active sites.

As a result, in Na2SO4 electrolyte, the Mo-SAs/AC can produce ammonia and attain a faradaic efficiency with high stability and good durability.

This work would be very helpful for designing and developing oxygen-coordinated single atom NRR electrocatalysts for high efficiency electrosynthesis of ammonia.

This work was financially supported by the National Key R&D Program of China, the Natural Science Foundation of China, the China Postdoctoral Science Foundation, and the HFIPS Director's Fund.

A new software tool developed by Earlham Institute researchers will help bioinformaticians improve the quality and accuracy of their biological data, and avoid mis-assemblies. The fast, lightweight, user-friendly tool visualises genome assemblies and gene alignments from the latest next generation sequencing technologies.

Called Alvis, the new visualisation tool examines mappings between DNA sequence data and reference genome databases. This allows bioinformaticians to more easily analyse their data generated from common genomics tasks and formats by producing efficient, ready-made vector images.

First author and post-doctoral scientist at the Earlham Institute Dr Samuel Martin in the Leggett Group, said: "Typically, alignment tools output plain text files containing lists of alignment data. This is great for computer parsing and for being incorporated into a pipeline, but it can be difficult to interpret by humans.

"Visualisation of alignment data can help us to understand the problem at hand. As a new technology, several new alignment formats have been implemented by new tools that are specific to nanopore sequencing technology.

"We found that existing visualisation tools were not able to interpret these formats; Alvis can be used with all common alignment formats, and is easily extensible for future ones."

A key feature of the new command line tool is its unique ability to automatically highlight chimeric sequences - weak links in the DNA chain. This is where two sequences - from different parts of a genome or different species - are linked together by mistake to make one, affecting the data's accuracy.

Chimera sequences can be problematic for bioinformaticians when identifying specific DNA. The chimera formation can physically happen to the DNA molecules during either sequencing library preparation, during the sequencing process on some platforms, and by assembly tools when trying to piece together a genome.

During the development of the tool, the team compared genome assemblies with and without using Alvis chimera detection. The vector image (example_contigalignment.pdf) produced shows an example output, where the intuitive tool tracks all reads it recognises as chimeras.

"Although chimeric sequences don't make up a large proportion of samples, they can have a significant effect, so we have to be careful that we have identified them during analysis," said Dr Martin.

"In the Alvis diagram example of chimera data, each rectangle across the page represents a read, and the coloured blocks inside them represent alignments. Most chimeras are easy to see because their alignments are different colours, meaning they map to different genomes. Others are more subtle because both alignments are to the same genome, but different regions."

The Alvis tool can pinpoint visualisation of only chimeric sequences for further inspection, and output numerical data describing the chimeras. This demonstrates that by applying the tool and then bioinformatically splitting the chimeras, the quality of the assemblies is significantly improved.

Accessed over 600 times since being made available at the beginning of March this year, Dr Martin, adds: "We hope that Alvis continues to be useful to other researchers working with, for example, nanopore sequencing; improving their understanding of their data by visualising alignments,''.

"Alignments are so fundamental to bioinformatics that it could be of use to anyone working with long read sequencing data, as well as alignments generated by sequencing data from short-read platforms. The diagrams that Alvis generates can be easily exported to directly use in publications, demonstrated in our study already."

The paper "Alvis: a tool for contig and read ALignment VISualisation and chimera detection" is published in BMC Bioinformatics.