Culture

Free, circulating vitamin D levels in the blood may be a better predictor of future health risks in aging men, according to a study being presented at e-ECE 2020. These data suggest the free, precursor form of vitamin D found circulating in the bloodstream is a more accurate predictor of future health and disease risk, than the often measured total vitamin D. Since vitamin D deficiency is associated with multiple serious health conditions as we get older, this study suggests that further investigation into vitamin D levels and their link to poor health may be a promising area for further research.

Vitamin D deficiency is common in Europe, especially in elderly people. It has been associated with a higher risk for developing many aging-related diseases, such as cardiovascular disease, cancer and osteoporosis. However, there are several forms, or metabolites, of vitamin D in the body but it is the total amount of these metabolites that is most often used to assess the vitamin D status of people. The prohormone, 25-dihydroxyvitamin D is converted to 1,25-dihydroxyvitamin D, which is considered the active form of vitamin D in our body. More than 99% of all vitamin D metabolites in our blood are bound to proteins, so only a very small fraction is free to be biologically active. Therefore the free, active forms may be a better predictor of current and future health.

Dr Leen Antonio from University Hospitals Leuven in Belgium and a team of colleagues investigated whether the free metabolites of vitamin D were better health predictors, using data from the European Male Ageing Study, which was collected from 1,970 community-dwelling men, aged 40-79, between 2003 and 2005. The levels of total and free metabolites of vitamin D were compared with their current health status, adjusting for potentially confounding factors, including age, body mass index, smoking and self-reported health. The total levels of both free and bound vitamin D metabolites were associated with a higher risk of death. However, only free 25-hydroxyvitamin D was predictive of future health problems and not free 1,25-dihydroxyvitamin D.

Dr Antonio explains, "These data further confirm that vitamin D deficiency is associated with a negative impact on general health and can be predictive of a higher risk of death."

As this is an observational study, the causal relationships and underlying mechanisms remain undetermined. It was also not possible to obtain specific information about the causes of death of the men in the study, which may be a confounding factor.

"Most studies focus on the association between total 25-hydroxyvitamin D levels and age-related disease and mortality. As 1,25-dihydroxyvitamin D is the active form of vitamin D in our body, it was possible it could have been a stronger predictor for disease and mortality. It has also been debated if the total or free vitamin D levels should be measured. Our data now suggest that both total and free 25-hydroxyvitamin D levels are the better measure of future health risk in men," says Dr Antonio

Dr Antonio and her team are currently finalising the statistical analysis and writing a manuscript on these findings.

Japan and the U.S. have seen an increase in percutaneous coronary intervention (PCI) procedures, which is driven primarily by a rise in elective PCIs in Japan compared to non-elective in the U.S., according to a study in the Journal of the American College of Cardiology. Since adoption of large-scale PCI trial results vary internationally, the study sought to analyze large national registries in both countries to illuminate international variation in PCI practice as a foundation for further quality improvement.

In a study looking at NCDR CathPCI Registry data in the U.S. and J-PCI registry data in Japan, researchers from the Japanese Association of Cardiovascular Intervention and Therapeutics in Tokyo and several U.S.-based hospitals, compared temporal trends in procedural volume, patient characteristics, pre-procedural testing, procedural characteristics and quality metrics in the U.S. and Japan between 2013 and 2017.

Researchers found that PCI volume increased by 15.8% in the U.S.--from 550,872 in 2013 to 637,650 in 2017--primarily due to an increase in non-elective PCIs. In Japan, PCIs increased by 36%--from 181,750 in 2013 to 247,274 in 2017--primarily due to an increase in elective PCIs. Elective PCI rates were more than two-fold greater in Japan (72.7%) than in the U.S. (33.8%).

Data also showed the ratio of non-elective vs. elective PCI and the performance of non-invasive stress testing in stable disease was lower in Japan than in the U.S. Computed tomography angiography was more commonly used in Japan.

Plant protein foods--like lentils, beans, and nuts--can provide vital nutrients using a small fraction of the land required to produce meat and dairy. By shifting to these foods, much of the remaining land could support ecosystems that absorb CO2, according to a new study appearing in the journal Nature Sustainability.

In their study, the researchers analyzed and mapped areas where extensive production of animal-sourced food, which requires 83 percent of Earth's agricultural land, suppresses native vegetation, including forests.

The study highlights places where changing what people grow and eat could free up space for ecosystems to regrow, offsetting our CO2 emissions in the process.

"The greatest potential for forest regrowth, and the climate benefits it entails, exists in high- and upper-middle income countries, places where scaling back on land-hungry meat and dairy would have relatively minor impacts on food security," says Matthew Hayek, the principal author of the study and an assistant professor in New York University's Department of Environmental Studies.

Burning fossil fuels for energy emits CO2, warming the planet. When warming reaches 1.5 °C (2.7 °F) above pre-industrial levels, more severe impacts like droughts and sea level rise are expected. Scientists describe how much fossil fuel we can burn before hitting that limit using the global "carbon budget."

According to the authors' findings, vegetation regrowth could remove as much as nine to 16 years of global fossil fuel CO2 emissions, if demand for meat were to drastically plummet in the coming decades along with its massive land requirements. That much CO2 removal would effectively double Earth's rapidly shrinking carbon budget.

"We can think of shifting our eating habits toward land-friendly diets as a supplement to shifting energy, rather than a substitute," says Hayek. "Restoring native forests could buy some much-needed time for countries to transition their energy grids to renewable, fossil-free infrastructure."

In their report, the authors emphasize that their findings are designed to assist locally tailored strategies for mitigating climate change. Although meat consumption in many countries today is excessive and continues to rise, raising animals remains critical in some places.

These considerations will be important as countries attempt to develop their economies sustainably, according to Colorado State University's Nathan Mueller, one of the study's co-authors.

"Land use is all about tradeoffs," explains Mueller, an assistant professor in the Department of Ecosystem Science and Sustainability and the Department of Soil and Crop Sciences. "While the potential for restoring ecosystems is substantial, extensive animal agriculture is culturally and economically important in many regions around the world. Ultimately, our findings can help target places where restoring ecosystems and halting ongoing deforestation would have the largest carbon benefits."

Recent proposals to cover much of Earth's surface in forests have generated controversy as a climate solution. Physically planting upward of a trillion trees would require a substantial physical effort. Additionally, poor planning could encourage uniform tree plantations, limit biodiversity, or deplete dwindling water in dry areas. Lastly, challenges lie in finding enough land to keep trees safe from logging or burning in the future, releasing stored carbon back into the atmosphere as CO2.

However, the researchers kept these potential problems in mind when devising their study.

"We only mapped areas where seeds could disperse naturally, growing and multiplying into dense, biodiverse forests and other ecosystems that work to remove CO2¬ for us," Hayek says. "Our results revealed over 7 million square kilometers where forests would be wet enough to regrow and thrive naturally, collectively an area the size of Australia."

Technological fixes for climate change may soon be on the horizon, like machinery that removes CO2 directly from the atmosphere or power plant exhaust pipes. Placing too much confidence in these technologies could prove dangerous, however, according to study co-author Helen Harwatt, a fellow of the Harvard Law School.

"Restoring native vegetation on large tracts of low yield agricultural land is currently our safest option for removing CO2," says Harwatt. "There's no need to bet our future solely on technologies that are still unproven at larger scales."

But the benefits of cutting back on meat and dairy reach far beyond addressing climate change.

"Reduced meat production would also be beneficial for water quality and quantity, wildlife habitat, and biodiversity," notes William Ripple, a co-author on the study and a professor of ecology at Oregon State University.

Recent events have also shone a spotlight on the importance of healthy ecosystems in preventing pandemic diseases with animal origins, such as COVID-19.

"We now know that intact, functioning ecosystems and appropriate wildlife habitat ranges help reduce the risk of pandemics," Harwatt adds. "Our research shows that there is potential for giving large areas of land back to wildlife. Restoring native ecosystems not only helps the climate; when coupled with reduced livestock populations, restoration reduces disease transmission from wildlife to pigs, chickens, and cows, and ultimately to humans."

When historian Frederick Jackson Turner presented his famous thesis on the US frontier in 1893, he described the "coarseness and strength combined with acuteness and acquisitiveness" it had forged in the American character.

Now, well into the 21st century, researchers led by the University of Cambridge have detected remnants of the pioneer personality in US populations of once inhospitable mountainous territory, particularly in the West.

A team of scientists algorithmically investigated how landscape shapes psychology. They analysed links between the anonymised results of an online personality test completed by over 3.3 million Americans, and the "topography" of 37,227 US postal - or ZIP - codes.

The researchers found that living at both a higher altitude and an elevation relative to the surrounding region - indicating "hilliness" - is associated with a distinct blend of personality traits that fits with "frontier settlement theory".

"The harsh and remote environment of mountainous frontier regions historically attracted nonconformist settlers strongly motivated by a sense of freedom," said researcher Friedrich Götz, from Cambridge's Department of Psychology.

"Such rugged terrain likely favoured those who closely guarded their resources and distrusted strangers, as well as those who engaged in risky explorations to secure food and territory."

"These traits may have distilled over time into an individualism characterised by toughness and self-reliance that lies at the heart of the American frontier ethos" said Götz, lead author of the study.

"When we look at personality across the whole United States, we find that mountainous residents are more likely to have psychological characteristics indicative of this frontier mentality."

Götz worked with colleagues from the Karl Landsteiner University of Health Sciences, Austria, the University of Texas, US, the University of Melbourne in Australia, and his Cambridge supervisor Dr Jason Rentfrow. The findings are published in the journal Nature Human Behaviour.

The research uses the "Big Five" personality model, standard in social psychology, with simple online tests providing high-to-low scores for five fundamental personality traits of millions of Americans.

The mix of characteristics uncovered by study's authors consists of low levels of "agreeableness", suggesting mountainous residents are less trusting and forgiving - traits that benefit "territorial, self-focused survival strategies".

Low levels of "extraversion" reflect the introverted self-reliance required to thrive in secluded areas, and a low level of "conscientiousness" lends itself to rebelliousness and indifference to rules, say researchers.

"Neuroticism" is also lower, suggesting an emotional stability and assertiveness suited to frontier living. However, "openness to experience" is much higher, and the most pronounced personality trait in mountain dwellers.

"Openness is a strong predictor of residential mobility," said Götz. "A willingness to move your life in pursuit of goals such as economic affluence and personal freedom drove many original North American frontier settlers."

"Taken together, this psychological fingerprint for mountainous areas may be an echo of the personality types that sought new lives in unknown territories."

The researchers wanted to distinguish between the direct effects of physical environment and the "sociocultural influence" of growing up where frontier values and identities still hold sway.

To do this, they looked at whether mountainous personality patterns applied to people born and raised in these regions that had since moved away.

The findings suggest some "initial enculturation" say researchers, as those who left their early mountain home are still consistently less agreeable, conscientious and extravert, although no such effects were observed for neuroticism and openness.

The scientists also divided the country at the edge of St. Louis - "gateway to the West" - to see if there is a personality difference between those in mountains that made up the historic frontier, such as the Rockies, and eastern ranges e.g. the Appalachians.

While mountains continue to be a "meaningful predictor" of personality type on both sides of this divide, key differences emerged. Those in the east are more agreeable and outgoing, while western ranges are a closer fit for frontier settlement theory.

In fact, the mountainous effect on high levels of "openness to experience" is ten times as strong in residents of the old western frontier as in those of the eastern ranges.

The findings suggest that, while ecological effects are important, it is the lingering sociocultural effects - the stories, attitudes and education - in the former "Wild West" that are most powerful in shaping mountainous personality, according to scientists.

They describe the effect of mountain areas on personality as "small but robust", but argue that complex psychological phenomena are influenced by many hundreds of factors, so small effects are to be expected.

"Small effects can make a big difference at scale," said Götz. "An increase of one standard deviation in mountainousness is associated with a change of around 1% in personality."

"Over hundreds of thousands of people, such an increase would translate into highly consequential political, economic, social and health outcomes."

In a significant advance, UC San Francisco Weill Institute for Neurosciences researchers working towards a brain-controlled prosthetic limb have shown that machine learning techniques helped an individual with paralysis learn to control a computer cursor using their brain activity without requiring extensive daily retraining, which has been a requirement of all past brain-computer interface (BCI) efforts. 

"The BCI field has made great progress in recent years, but because existing systems have had to be reset and recalibrated each day, they haven't been able to tap into the brain's natural learning processes. It's like asking someone to learn to ride a bike over and over again from scratch," said study senior author Karunesh Ganguly, MD, PhD, an associate professor in the UCSF Department of Neurology. "Adapting an artificial learning system to work smoothly with the brain's sophisticated long-term learning schemas is something that's never been shown before in a person with paralysis."

The achievement of "plug and play" performance demonstrates the value of so-called ECoG electrode arrays for BCI applicartions. An ECoG array comprises a pad of electrodes about the size of a post-it note that is surgically placed on the surface of the brain. They allow long-term, stable recordings of neural activity and have been approved for seizure monitoring in epilepsy patients. In contrast, past BCI efforts have used "pin-cushion" style arrays of sharp electrodes that penetrate the brain tissue for more sensitive recordings but tend to shift or lose signal over time. In this case, the authors obtained investigational device approval for long-term chronic implantation of ECoG arrays in paralyzed subjects to test their safety and efficacy as long-term, stable BCI implants. 

In their new paper, published September 7, 2020 in Nature Biotechnology , Ganguly's team documents the use of an ECoG electrode array in an individual with paralysis of all four limbs (tetraplegia). The participant is also enrolled in a clinical trial designed to test the use of ECoG arrays to allow paralyzed patients to control a prosthetic arm and hand, but in the new paper, the participant used the implant to control a computer cursor on a screen. 

The researchers developed a BCI algorithm that uses machine learning to match brain activity recorded by the ECoG electrodes to the user's desired cursor movements. Initially, the researchers followed the standard practice of resetting the algorithm each day. The participant would begin by imagining specific neck and wrist movements while watching the cursor move across the screen. Gradually the computer algorithm would update itself to match the cursor's movements to the brain activity this generated, effective passing control of the cursor over to the user. However, starting this process over every day put a severe limit on the level of control that could be achieved. It could take hours to master control of the device, and some days the participant had to give up altogether. 

The researchers then switched to allow the algorithm to continue updating to match the participant's brain activity without resetting it each day. They found that the continued interplay between brain signals and the machine learning-enhanced algorithm resulted in continuous improvements in performance over many days. Initially there was a little lost ground to make up each day, but soon the participant was able to immediately achieve top level performance. 

"We found that we could further improve learning by making sure that the algorithm wasn't updating faster than the brain could follow -- a rate of about once every 10 seconds," said Ganguly, a practicing neurologist with UCSF Health and the San Francisco Veterans Administration Medical Center's Neurology & Rehabilitation Service. "We see this as trying to build a partnership between two learning systems -- brain and computer -- that ultimately lets the artificial interface become an extension of the user, like their own hand or arm."

Over time, the participant's brain was able to amplify patterns of neural activity it could use to most effectively drive the artificial interface via the ECoG array, while eliminating less effective signals -- a pruning process much like how the brain is thought to learn any complex task, the researcher say. They observed that the participant's brain activity seemed to develop an ingrained and consistent mental "model" for controlling the BCI interface, something that had never occurred with daily resetting and recalibration. When the interface was reset after several weeks of continuous learning, the participant rapidly re-established the same patterns of neural activity for controlling the device -- effectively retraining the algorithm to its former state.

"Once the user has established an enduring memory of the solution for controlling the interface, there's no need for resetting," Ganguly said. "The brain just rapidly convergences back to the same solution."

Eventually, once expertise was established, the researchers showed they could turn off the algorithm's need to update itself altogether, and the participant could simply begin using the interface each day without any need for retraining or recalibration. Performance did not decline over 44 days in the absence of retraining, and the participant could even go days without practicing and see little decline in performance. The establishment of stable expertise in one form of BCI control (moving the cursor) also allowed researchers to begin "stacking" additional learned skills -- such as "clicking" a virtual button -- without loss of performance.

Such immediate "plug and play" BCI performance has long been a goal in the field, but has been out of reach because the "pincushion-style" electrodes used by most researchers tend to move over time, changing the signals seen by each electrode. Also, because these electrodes penetrate brain tissue, the immune system tends to reject them, gradually impairing their signal. ECoG arrays are less sensitive than these traditional implants, but their long-term stability appears to compensate for this shortcoming. The stability of ECoG recordings may be even more important for long-term control of more complex robotic systems such as artificial limbs, a key goal of the next phase of Ganguly's research.

"We've always been mindful of the need to design technology that doesn't end up in a drawer, so to speak, but which will actually improve the day-to-day lives of paralyzed patients," Ganguly said. "These data show that ECoG-based BCIs could be the foundation for such a technology." 

Sharks' non-bony skeletons were thought to be the template before bony internal skeletons evolved, but a new fossil discovery suggests otherwise.

The discovery of a 410-million-year-old fish fossil with a bony skull suggests the lighter skeletons of sharks may have evolved from bony ancestors, rather than the other way around.

Sharks have skeletons made cartilage, which is around half the density of bone. Cartilaginous skeletons are known to evolve before bony ones, but it was thought that sharks split from other animals on the evolutionary tree before this happened; keeping their cartilaginous skeletons while other fish, and eventually us, went on to evolve bone.

Now, an international team led by Imperial College London, the Natural History Museum and researchers in Mongolia have discovered a fish fossil with a bony skull that is an ancient cousin of both sharks and animals with bony skeletons. This could suggest the ancestors of sharks first evolved bone and then lost it again, rather than keeping their initial cartilaginous state for more than 400 million years.

The team published their findings today in Nature Ecology & Evolution.

Lead researcher Dr Martin Brazeau, from the Department of Life Sciences at Imperial, said: "It was a very unexpected discovery. Conventional wisdom says that a bony inner skeleton was a unique innovation of the lineage that split from the ancestor of sharks more than 400 million years ago, but here is clear evidence of bony inner skeleton in a cousin of both sharks and, ultimately, us."

Most of the early fossils of fish have been uncovered in Europe, Australia and the USA, but in recent years new finds have been made in China and South America. The team decided to dig in Mongolia, where there are rocks of the right age that have not been searched before.

They uncovered the partial skull, including the brain case, of a 410-million-year-old fish. It is a new species, which they named Minjinia turgenensis, and belongs to a broad group of fish called 'placoderms', out of which sharks and all other 'jawed vertebrates' - animals with backbones and mobile jaws - evolved.

When we are developing as foetuses, humans and bony vertebrates have skeletons made of cartilage, like sharks, but a key stage in our development is when this is replaced by 'endochondral' bone - the hard bone that makes up our skeleton after birth.

Previously, no placoderm had been found with endochondral bone, but the skull fragments of M. turgenensis were "wall-to-wall endochondral". While the team are cautious not to over-interpret from a single sample, they do have plenty of other material collected from Mongolia to sort through and perhaps find similar early bony fish.

And if further evidence supports an early evolution of endochondral bone, it could point to a more interesting history for the evolution of sharks.

Dr Brazeau said: "If sharks had bony skeletons and lost it, it could be an evolutionary adaptation. Sharks don't have swim bladders, which evolved later in bony fish, but a lighter skeleton would have helped them be more mobile in the water and swim at different depths.

"This may be what helped sharks to be one of the first global fish species, spreading out into oceans around the world 400 million years ago."

Hundreds of innovators, research pioneers, clinicians, industry leaders and policy makers from all around Europe are united by a vision of how to revolutionize healthcare. In two publications - a perspective article in the journal Nature and the LifeTime Strategic Research Agenda - they now present a detailed roadmap of how to leverage the latest scientific breakthroughs and technologies over the next decade, to track, understand and treat human cells throughout an individual's lifetime.

The LifeTime initiative, co-coordinated by the Max Delbrueck Center of Molecular Medicine in the Helmholtz Association (MDC) in Berlin and the Institut Curie in Paris, has developed a strategy to advance personalized treatment for five major disease classes: cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases. The aim is a new age of personalized, cell-based interceptive medicine for Europe with the potential of improved health outcomes and more cost-effective treatment, resulting in profoundly changing a person's healthcare experience.

Earlier detection and more effective treatment of diseases

To form a functioning, healthy body, our cells follow developmental paths during which they acquire specific roles in tissues and organs. But when they deviate from their healthy course, they accumulate changes leading to disease which remain undetected until symptoms appear. At this point, medical treatment is often invasive, expensive and inefficient. However, now we have the technologies to capture the molecular makeup of individual cells and to detect the emergence of disease or therapy resistance much earlier.

Using breakthrough single-cell and imaging technologies in combination with artificial intelligence and personalized disease models will allow us to not only predict disease onset earlier, but also to select the most effective therapies for individual patients. Targeting disease-causing cells to intercept disorders before irreparable damage occurs will substantially improve the outlook for many patients and has the potential of saving billions of Euros of disease-related costs in Europe.

A detailed roadmap for implementing LifeTime

The perspective article "The LifeTime initiative and the future of cell-based interceptive medicine in Europe" and the LifeTime Strategic Research Agenda (SRA) explain how these technologies should be rapidly co-developed, transitioned into clinical settings and applied to the five major disease areas. Close interactions between European infrastructures, research institutions, hospitals and industry will be essential to generate, share and analyze LifeTime's big medical data across European borders. The initiative's vision advocates ethically responsible research to benefit citizens all across Europe.

According to Professor Nikolaus Rajewsky, scientific director of the Berlin Institute for Medical System Biology at the Max Delbrueck Center for Molecular Medicine and coordinator of the LifeTime Initiative, the LifeTime approach is the way into the future: "LifeTime has brought together scientists across fields - from biologists, to clinicians, data scientists, engineers, mathematicians, and physicists ¬- to enable a much improved understanding of molecular mechanisms driving health and disease. Cell-based medicine will allow doctors to diagnose diseases earlier and intercept disorders before irreparable damage has occurred. LifeTime has a unique value proposition that promises to improve the European patient's health."

Dr. Geneviève Almouzni, director of research at CNRS, honorary director of the research center from Institut Curie in Paris and co-coordinator of the LifeTime Initiative believes that the future with LifeTime offers major social and economic impact: "By implementing interceptive, cell-based medicine we will be able to considerably improve treatment across many diseases. Patients all over the world will be able to lead longer, healthier lives. The economic impact could be tremendous with billions of Euros saved from productivity gains simply for cancer, and significantly shortened ICU stays for Covid-19. We hope EU leaders will realize we have to invest in the necessary research now."

CINCINNATI - As the world scrambles to control the growing COVID-19 coronavirus pandemic, new research in Nature Structural & Molecular Biology shows viruses also play a key evolutionary role in mammals' ability to reproduce and survive.

Scientists in the Cincinnati Children's Perinatal Institute and at Azabu University in Japan obtained their data by studying laboratory mice and human germline cells.

In two separate papers appearing in the same edition of the journal, they reveal two distinct and fundamental processes underlying germline transcriptomes. They also show that species-specific transcriptomes are fine-tuned by endogenous retroviruses in the mammalian germline

Germline transcriptomes include all the messenger RNA in germline cells, which contain either the male or female half of chromosomes passed on as inherited genetic material to offspring when species mate. This means that germline transcriptomes define the unique character of sperm and egg to prepare for the next generation of life.

Although the studies are separate they complement one another, according to Satoshi Namekawa, PhD, principal investigator on both papers and a scientist in the Division of Reproductive Science at Cincinnati Children's.

"One paper, Maezawa and Sakashita et al., explores super-enhancers, which are robust and evolutionally conserved gene regulatory elements in the genome. They fuel a tightly regulated burst of essential germline genes as sperm start to form," Namekawa said.

"The second study, Sakashita et al., involves endogenous retroviruses that act as another type of enhancer - gene regulatory elements in the genome - to drive expression of newly evolved genes. This helps fine tune species-specific transcriptomes in mammals like humans, mice, and so on.

Clinical Relevance

Together the studies have significant potential ramifications for clinical practice, according to study authors, who include a multi-disciplinary mix of developmental biologists, bioinformaticians and immuno-biologists. Dysregulation of gene expression in the formation of male sperm is closely associated with male infertility and birth defects.

Viruses, especially endogenous retroviruses (ERVs) that are an inherent part of mammalian biology, can dramatically influence gene expression, investigators report. ERVs are molecular remnants of retroviruses that infect the body and over time incorporate into the genome.

"What we learn from our study is that, in general, viruses have major roles in driving evolution," Namekawa explained. "In the long-term, viruses have positive impacts to our genome and shape evolution."

Super-Enhancer Switch

The study, Maezawa and Sakashita et al., combined biological testing of mouse models and human germline cells with computational biology, including genome-wide profiling of gene regulatory elements in germline cells.

Those tests revealed that the the genome-wide reorganization of super-enhancers drives bursts of germline gene expression after germ cells enter meiosis, a specialized form of cell division that produces the haploid genome of germ cells.

The study further demonstrates the molecular process through whichsuper-enhancer switching takes place in germ cells. Super-enhancers are regulated by two molecules that act as gene-burst control switches - the transcription factor A-MYB and SCML2, a critical silencing protein in sperm formation.

TEs and Jumping Genes

Endogenous retroviruses are a group of transposable elements (TEs), mobile genetic elements that account for approximately 40-50 percent of a given mammalian genome. Also referred to as "jumping genes," TEs have long been considered genetic threats because transposition can be harmful if, for example, the process disrupts protein-coding genes.

Building on findings from the 1950s that TEs can function as genetic regulatory elements, Namekawa and his collaborators (Sakashita et al.) produced data showing that ERV-driven mechanisms help fine tune species-specific transcriptomes.

In rodents with type 2 diabetes, a single surgical injection of a protein called fibroblast growth factor 1 can restore blood sugar levels to normal for weeks or months. Yet how this growth factor acts in the brain to generate this lasting benefit has been poorly understood.

Clarifying how this occurs might lead to more effective diabetes treatments that tap into the brain's inherent potential to ameliorate the condition.

"Until recently, the brain's ability to normalize elevated blood sugar levels in diabetic animals was unrecognized," said Dr. Michael Schwartz, professor of medicine at the University of Washington School of Medicine and co-director of the UW Medicine Diabetes Institute. "By interrogating cellular and molecular responses induced in the hypothalamus by a brain peptide called fibroblast growth factor 1, our international teams' latest findings chart a path towards a more complete understanding how this effect is achieved.

"These insights," he said, "may one day inform therapeutic strategies for inducing sustained diabetes remission, rather than simply lowering blood sugar levels on a day-to-day basis as current treatments do."

Type 2 diabetes affects 10% of the U.S. population. It is closely tied to obesity and causes serious health problems including heart disease, vision loss, kidney failure, dementia, difficult-to-cure infections, and nerve damage. It also increases the risk of needing amputations. Control of blood sugar levels can prevent these problems, but is often hard to achieve and becomes an ongoing struggle for many patients.

In two companion papers in the Sept. 7 editions of Nature Communications and Nature Metabolism, international teams of researchers describe the intricate biology of the brain's response to fibroblast growth factor 1. The first team describes robust cellular responses that appear to safeguard brain-signaling pathways critical to keeping blood sugar in check.

A second team, containing some of the same researchers, made discoveries about extracellular matrix assemblies called "perineuronal nets" that enmesh groups of neurons involved in blood sugar control. The investigators learned that fibroblast growth factor 1 repairs perineuronal nets that have been damaged by diabetes. This response is required for diabetes remission to be sustained.

Dr. Tunes Pers, of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen in Denmark, and diabetes and obesity researcher Dr. Michael Schwartz at UW Medicine in Seattle were senior authors of the Nature Communications report. The lead authors from their labs were Dr. Marie Bentsen and Dr. Dylan Rausch.

The international team of scientists that they assembled began by detailing changes of gene expression induced by fibroblast growth factor 1 treatment across diverse brain cell types located in the hypothalamus. This small region of the brain regulates many body functions, including levels of blood sugar, hunger, food intake, and energy use and storage.

The scientists found that glial cells, which not only provide structural support but also help to organize and regulate neurocircuit activity, responded more intensely than did neurons, brain cells known for electrical transmission of information.

The researchers also observed enhanced interactions between astrocytes and a subset of neurons that make agouti-related protein (called Agrp neurons). Astrocytes are abundant, star-shaped glial cells that nourish neurons and support their electrical transmissions. Agrp neurons are essential components of the melanocortin signaling system, a brain circuit crucial to control of feeding, body weight and blood sugar.

Excessive activation of Agrp neurons is known to dampen melanocortin signaling. This effect has been linked to diabetes development in people and rodents. The researchers noted that prohibiting melancortin signaling after fibroblast growth factor 1 injection into the brain prevents sustained diabetes remission.

Among other cell types that responded robustly to fibroblast growth factor 1 are tanycytes, elongated, nutrient-sensing glial cells found only in the hypothalamus. Their contributions to normalizing of glucose levels require additional study.

The paper published in Nature Metabolism looked at structures that the scientists called "the previously unrecognized participants" in the mechanism behind fibroblast growth factor 1's ability to induce diabetes remission.

These are the perineuronal nets that enmesh blood sugar-regulating neurons in the hypothalamus, including Agrp neurons. The lead author of this paper is Kim Alonge, acting instructor in medicine at the UW School of Medicine. The senior author is Michael Schwartz.

Perineuronal nets promote neurocircuit stability by enmeshing neurons and girding the connections between them. The researchers wanted to know if obesity-related diabetes is associated with structural changes in these perineuronal nets, and whether those could be treated.

The research team noted that in the Zucker Diabetes Fatty rat model of type 2 diabetes, these nets are scarce in the hypothalamus compared to rats with normal blood sugar levels, Yet in other parts of the brain the nets are normal.

This loss of perineuronal nets was rapidly reversed following a single injection of fibroblast growth factor 1 into the brain. The ability of fibroblast growth factor 1 to ameliorate diabetes was hampered by removing the nets through enzymatic digestion. In contrast, intact perineuronal nets are not required for fibroblast growth factor 1 to affect food intake.

These finding identify perineuronal nets as key targets for sustained diabetes remission induced by the action of fibroblast growth factor 1. The researchers speculate that perhaps these nets help to constrain the activity of Agrp neurons and thereby pump up melanocortin signaling.

The researchers plan to continue to try to bridge the gap between the cellular (and extracellular) responses to fibroblast growth factor 1 and the normalization of blood sugar levels. This, they hope, may ultimately uncover novel strategies for achieving sustained diabetes remission in patients.

Patients with autoimmune inflammation of their thyroid may be at greater risk of developing anxiety, according to a study being presented at e-ECE 2020. The study found that people with anxiety may also have inflammation in their thyroid gland that can be reduced by taking the non-steroidal anti-inflammatory, ibuprofen. These findings suggest that thyroid function may play an important role in the development of anxiety disorders and that thyroid inflammation should be investigated as an underlying factor in psychiatric disorders, such as anxiety.

At present, up to 35% of the young population (25-60 years) in developed countries have an anxiety disorder. Anxiety can have a severe impact of people's quality of life and ability to work and socialise, and anti-anxiety medication does not always have a lasting effect. Current examinations for anxiety disorders usually focus on dysfunction of the nervous system and do not take into account the role of the endocrine system.

The thyroid gland produces the hormones thyroxine (T4) and triiodothyronine (T3) that are essential for regulating heart, muscle and digestive function, brain development and bone maintenance. Autoimmune inflammation in the thyroid occurs when our bodies wrongly produce antibodies that attack the gland and causes damage. Recent studies indicate that anxiety disorders can be associated with the dysfunction of the thyroid gland. Therefore, it is important to understand how this may contribute to anxiety, so that patients can be treated more effectively.

Dr Juliya Onofriichuk from Kyiv City Clinical Hospital investigated thyroid function in 29 men (average age 33.9) and 27 women (average age 31.7) with diagnosed anxiety, who were experiencing panic attacks. Ultrasounds of their thyroid glands assessed thyroid function and levels of thyroid hormones were measured. The patients with anxiety showed signs of inflammation of their thyroid glands but their function was not affected, with thyroid hormone levels all within the normal range, although slightly elevated. They also tested positive for antibodies directed against the thyroid. Treatment for 14 days with ibuprofen and thyroxine reduced thyroid inflammation, normalised thyroid hormone levels and reduced their anxiety scores.

"These findings indicate that the endocrine system may play an important role in anxiety. Doctors should also consider the thyroid gland and the rest of the endocrine system, as well as the nervous system, when examining patients with anxiety," Dr Onofriichuk explains.

This knowledge could help patients with anxiety receive more effective treatment that improves thyroid function and could have a long-term positive effect on their mental health. However, sex and adrenal gland hormones were not taken in to account in this study, and these can also have a serious effect on anxiety.

Dr Onofriichuk now plans to conduct further research that examines the levels of thyroid, sex and adrenal hormones (cortisol, progesterone, prolactin, oestrogen and testosterone) in patients with dysfunctional thyroid glands and anxiety disorders. This research aims to help understand more clearly the role of the endocrine system in the development of anxiety and could lead to better management of anxiety disorders.

COVID-19 patients can suffer long-term lung and heart damage but, for many, this tends to improve over time, according to the first, prospective follow-up of patients infected with the coronavirus, presented at the European Respiratory Society International Congress. [1]

Researchers in the COVID-19 'hot spot' in the Tyrolean region of Austria recruited consecutive coronavirus patients to their study, who were hospitalised at the University Clinic of Internal Medicine in Innsbruck, the St Vinzenz Hospital in Zams or the cardio-pulmonary rehabilitation centre in Münster, Austria. In their presentation to the virtual congress today (Monday), they reported on the first 86 patients enrolled between 29 April and 9 June, although now they have over 150 patients participating.

The patients were scheduled to return for evaluation six, 12 and 24 weeks after their discharge from hospital. During these visits, clinical examinations, laboratory tests, analysis of the amounts of oxygen and carbon dioxide in arterial blood, lung function tests, computed tomography (CT) scans and echocardiograms were carried out.

At the time of their first visit, more than half of the patients had at least one persistent symptom, predominantly breathlessness and coughing, and CT scans still showed lung damage in 88% of patients. However, by the time of their next visit 12 weeks after discharge, the symptoms had improved and lung damage was reduced to 56%. At this stage, it is too early to have results from the evaluations at 24 weeks.

"The bad news is that people show lung impairment from COVID-19 weeks after discharge; the good news is that the impairment tends to ameliorate over time, which suggests the lungs have a mechanism for repairing themselves," said Dr Sabina Sahanic, who is a clinical PhD student at the University Clinic in Innsbruck and part of the team that carried out the study, which includes Associate Professor Ivan Tancevski, Professor Judith Löffler-Ragg and Dr Thomas Sonnweber in Innsbruck.

The average age of the 86 patients included in this presentation was 61 and 65% of them were male. Nearly half of them were current or former smokers and 65% of hospitalised COVID-19 patients were overweight or obese. Eighteen (21%) had been in an intensive care unit (ICU), 16 (19%) had had invasive mechanical ventilation, and the average length of stay in hospital was 13 days.

A total of 56 patients (65%) showed persistent symptoms at the time of their six-week visit; breathlessness (dyspnoea) was the most common symptom (40 patients, 47%), followed by coughing (13 patients, 15%). By the 12-week visit, breathlessness had improved and was present in 31 patients (39%); however, 13 patients (15%) were still coughing

Tests of lung function included FEV1 (the amount of air that can be expelled forcibly in one second), FVC (the total volume of air expelled forcibly), and DLCO (a test to measure how well oxygen passes from the lungs into the blood). These measurements also improved between the visits at six and 12 weeks. At six weeks, 20 patients (23%) showed FEV1 as less than 80% of normal, improving to 18 patients (21%) at 12 weeks, 24 patients (28%) showed FVC as less than 80% of normal, improving to 16 patients (19%) at 12 weeks, and 28 patients (33%) showed DLCO as less than 80% of normal, improving to 19 patients (22%) at 12 weeks.

The CT scans showed that the score that defines the severity of overall lung damage decreased from eight points at six weeks to four points at twelve weeks. Damage from inflammation and fluid in the lungs caused by the coronavirus, which shows up on CT scans as white patches known as 'ground glass', also improved; it was present in 74 patients (88%) at six weeks and 48 patients (56%) at 12 weeks.

At the six-week visit, the echocardiograms showed that 48 patients (58.5%) had dysfunction of the left ventricle of the heart at the point when it is relaxing and dilating (diastole). Biological indicators of heart damage, blood clots and inflammation were all significantly elevated.

Dr Sahanic said: "We do not believe left ventricular diastolic dysfunction is specific to COVID-19, but more a sign of severity of the disease in general. Fortunately, in the Innsbruck cohort, we did not observe any severe coronavirus-associated heart dysfunction in the post-acute phase. The diastolic dysfunction that we observed also tended to improve with time."

She concluded: "The findings from this study show the importance of implementing structured follow-up care for patients with severe COVID-19 infection. Importantly, CT unveiled lung damage in this patient group that was not identified by lung function tests. Knowing how patients have been affected long-term by the coronavirus might enable symptoms and lung damage to be treated much earlier and might have a significant impact on further medical recommendations and advice."

In a second poster presentation to the Congress [3], Ms Yara Al Chikhanie, a PhD student at the Dieulefit Santé clinic for pulmonary rehabilitation and the Hp2 Lab at the Grenoble Alps University, France, said that the sooner COVID-19 patients started a pulmonary rehabilitation programme after coming off ventilators, the better and faster their recovery.

Patients with severe COVID-19 can spend weeks in intensive care on ventilators. The lack of physical movement, on top of the severe infection and inflammation, leads to severe muscle loss. The muscles for breathing are also affected, which weakens the breathing capacity. Pulmonary rehabilitation, which involves physical exercises and advice on managing symptoms, including shortness of breath and post-traumatic stress disorder, is crucial for helping patients to recover fully.

Ms Al Chikhanie used a walking test to evaluate the weekly progress of 19 patients [4] who had spent an average of three weeks in intensive care and two weeks in a pulmonary ward before being transferred to the Dieulefit Santé clinic for pulmonary rehabilitation. Most were still unable to walk when they arrived, and they spent an average of three weeks in rehabilitation. The walking test measured how far the patients could walk in six minutes. At the beginning, they were able to walk an average of 16% of the distance that, in theory, they should be able to walk normally if healthy. After three weeks of pulmonary rehabilitation, this increased to an average of 43%, which was a significant gain but still a serious impairment.

Ms Al Chikhanie said: "The most important finding was that patients who were admitted to pulmonary rehabilitation shortly after leaving intensive care, progressed faster than those who spent a longer period in the pulmonary ward where they remained inactive. The sooner rehabilitation started and the longer it lasted, the faster and better was the improvement in patients' walking and breathing capacities and muscle gain. Patients who started rehabilitation in the week after coming off their ventilators progressed faster than those who were admitted after two weeks. But how soon they can start rehabilitation depends on the patients being judged medically stable by their doctors. Despite the significant improvement, the average period of three weeks in rehabilitation wasn't enough for them to recover completely.

"These findings suggest that doctors should start rehabilitation as soon as possible, that patients should try to spend as little time as possible being inactive and that they should enrol with motivation in the pulmonary rehabilitation programme. If their doctors judge it to be safe, patients should start physical therapy exercises while still in the hospital's pulmonary ward."

Thierry Troosters, who was not involved in the study, is President of the European Respiratory Society and Professor in Rehabilitation Sciences at KU Leuven, Belgium. He said: "Anecdotal evidence has been emerging since the start of the COVID-19 pandemic that many patients suffer debilitating long-term after-effects from the coronavirus. Dr Sahanic's presentation is important because it is one of the first, comprehensive prospective follow-ups of these patients and shows the serious, long-term impact of COVID-19 on the lungs and heart. It is sobering to hear that more than half of the patients in this study showed damage to their lungs and hearts 12 weeks after hospital discharge, and that nearly 40% were still suffering from symptoms such as breathlessness. The good news, however, is that patients do improve and this surely will help the rehabilitation process, as discussed in the second presentation.

"Ms Al Chikhanie's research complements this information and shows how essential it is for patients to start pulmonary rehabilitation as soon as they are physically able to do so. This is why rehabilitation can also be started in the ward, if programmes are adapted to the capabilities of the patient. This is perfectly in line with a recent statement of our Society where we also advocate for tailored rehabilitation. It is clear from both these studies that rehabilitation, including physical and psychologic components, should be available for patients as soon as possible and it should continue for weeks if not months after they have been discharged from hospital in order to give patients the best chances of a good recovery. Governments, national health services and employers should be made aware of these findings and plan accordingly." [5]

A research group led by Prof. XUE Tian from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS), collaborating with Prof. WU Qian form Beijing Normal University and Prof. WANG Xiaoqun from Institute of Biophysics of CAS, provided a comprehensive transcriptomic atlas based on 119520 single cells of retina of human and macaque at different ages.

This work, which provides valuable basic for the molecular regulation of aging progression and related diseases, was published in National Science Review on August 25th 2020.
Vision is the most important perception for humans and animals. The human retina is a specialized light-sensitive tissue of neurons, glia, and nourishing blood vessels. Different cell in the retina convert the incoming light into electrochemical signals and then relay to the brain for visual formation. However, as people age, the function of the retina deteriorates and the risk of various aging related diseases increases. Thus, it is necessary to understand the aging process and underlying complexities of the retina to help rescuing age-related retinal diseases.

Researchers collected 119520 cell transcriptomes of human and macaque retina from young to old. Firstly, by comparing the human and macaque retinal cell composition and regional molecular differences, researchers found that though rods of humans and macaques can be both divided into two subtypes by MYO9A expression, the proportion of MYO9A- cells varied between the two species.

Later, researchers then compared the macular area with the peripheral area of the retina. The results showed that there were significant differences in gene expression in macular area and peripheral area between Muller Glia (MG) and Cone.

Researchers used the aging database to fit the macular and peripheral regions of the retina and calculate the aging curves of the two regions. The results showed that the degree of senescence in macular area was higher than that in peripheral area, which was consistent with the high expression of MGs in peripheral area.

In addition, studies have found that rods are significantly damaged in the aging process, especially MYO9A- rod cells are more likely to reduce in the aging process.

Finally, they generated a dataset showing the cell-type and region-specific gene expression associated with 55 types of human retinal disease.

This study is the first international report on the single-cell transcriptome atlas of retinal in human and non-human primates, which not only systematically analyzes the molecular characteristics of various cell types in the human retina during the aging process, but also reveals the regional and cell subtype specific evolution of retinal aging.

As the flu season approaches, a strained public health system may have a surprising ally -- the common cold virus.

Rhinovirus, the most frequent cause of common colds, can prevent the flu virus from infecting airways by jumpstarting the body's antiviral defenses, Yale researchers report Sept. 4 in the journal The Lancet Microbe.

The findings help answer a mystery surrounding the 2009 H1N1 swine flu pandemic: An expected surge in swine flu cases never materialized in Europe during the fall, a period when the common cold becomes widespread.

A Yale team led by Dr. Ellen Foxman studied three years of clinical data from more than 13,000 patients seen at Yale New Haven Hospital with symptoms of respiratory infection. The researchers found that even during months when both viruses were active, if the common cold virus was present, the flu virus was not.

"When we looked at the data, it became clear that very few people had both viruses at the same time," said Foxman, assistant professor of laboratory medicine and immunobiology and senior author of the study.

Foxman stressed that scientists do not know whether the annual seasonal spread of the common cold virus will have a similar impact on infection rates of those exposed to the coronavirus that causes COVID-19.

"It is impossible to predict how two viruses will interact without doing the research," she said.

To test how the rhinovirus and the influenza virus interact, Foxman's lab created human airway tissue from stem cells that give rise to epithelial cells, which line the airways of the lung and are a chief target of respiratory viruses. They found that after the tissue had been exposed to rhinovirus, the influenza virus was unable to infect the tissue.

"The antiviral defenses were already turned on before the flu virus arrived," she said.

The presence of rhinovirus triggered production of the antiviral agent interferon, which is part of the early immune system response to invasion of pathogens, Foxman said.

"The effect lasted for at least five days," she said.

Foxman said her lab has begun to study whether introduction of the cold virus before infection by the COVID-19 virus offers a similar type of protection.

What The Article Says: A hospitalist charts his emotional journey in this narrative essay from when once brightly colored signs declared hospital workers as heroes to now when the signs have faded and the steady and intense work of helping patients with COVID-19 has seemingly become mundane.

Authors: Bernard E. Trappey, M.D., of the University of Minnesota in Minneapolis, is the author.

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

(doi:10.1001/jama.2020.17249)

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

A trial of a simple yet effective surgery has led Australian experts to promote it as an option to specialists around the world for managing difficult obstructive sleep apnoea (OSA) cases.

After rigorous evaluation of the surgery, excellent outcomes were shown in sleep apnea patients who had been unable to use continuous positive pressure airway (CPAP) treatment, with patients achieved relief from snoring and disrupted sleep and experienced improved general health. according to a new report in the Journal of the American Medical Association (JAMA).

Almost 1 billion people are estimated to have OSA globally, with the main treatment CPAP tolerated by only half of those who try it. Almost 30% of people with OSA wake up very easily with light sleep and other problems caused by minor airway narrowing.

The multi-level surgical technique combining a new version of palate surgery with a low risk tongue procedure to create an improved airway resulted in a substantial reduction in the number of night-time apnoea events and improvements in daytime sleepiness and quality of life. After removing any tonsils, the palate is repositioned and the tongue treated to open up the airway and reduce obstruction.

Flinders University's Emeritus Professor Doug McEvoy says the surgery offers promise to millions of people around the world who suffer from obstructive sleep apnoea but cannot adapt to using a CPAP mask or similar device each night.

"This trial is the result of extensive prior research into the surgical treatment of sleep apnoea and gives new hope to people who, without treatment, would each day continue to feel sleepy and depressed and may have their lives cut short by the detrimental effects of long-term interrupted sleep," says Professor McEvoy.
Lead author University of Wollongong Professor Stuart MacKay, who will give further details of the surgical clinical trial at the global online European Respiratory Society congress on 7 September and in a JAMA podcast, says about half of

patients prescribed CPAP treatment are not using it consistently long term.

"It's very exciting to see so many patients getting a better night's sleep with reduced snoring and less health risk after this surgery, " says Professor MacKay.

The paper, 'Effect of Multilevel Upper Airway Surgery vs Medical Management on the Apnea-Hypopnea Index and Patient-Reported Daytime Sleepiness Among Patients with Moderate or Severe Obstructive Sleep Apnea: The SAMS Randomized Clinical Trial' (2020) is due to be published by JAMA on September 4.