Culture

Scientists at Sanford Burnham Prebys have gained a deeper insight into the intricacies of autophagy, the process in which cells degrade and recycle cellular components. The findings, published in Current Biology, describe how the "trash bags" in a cell--called autophagosomes--are tagged to direct their movement to the cellular "recycling plants" where waste is processed. The research opens new paths to understanding the relationship between autophagy and age-related diseases such as cancer and neurological disorders.

"Our latest study identifies how a chemical modification (phosphate-related tag) of a key autophagosome component, the protein called LCB3, helps direct the transport of autophagosomes within the cell in the right direction," says Malene Hansen, Ph.D., professor at Sanford Burnham Prebys and senior author of the study. "We previously reported that LCB3, which is found on the surface of autophagosomes, needs to be tagged for autophagy to function effectively. Now we have a better understanding of how tagging happens and how important it is for autophagosome movement."

In addition to their own laboratory studies, the Hansen lab worked with colleagues in the lab of Sandra Encalada, Ph.D., at the Scripps Research Institute, San Diego, leaders in the field of transport of cellular components in neurons. Those investigations showed that blocking the chemical modification of the LC3B protein disrupted the efficient transport of autophagosomes toward the cellular recycling plants.

"Waste transport in a cell is like moving garbage trucks down a highway," says Jose Luis Nieto-Torres, Ph.D., a postdoc in the Hansen laboratory and first author of the study. "Together with our collaborators, we studied the process in nerve cells because they are long and flat, which helps us observe the directional aspects of transport, a critical aspect for waste recycling via autophagy.

"We clearly saw that if phosphate tagging of LC3B was hampered, autophagosomes, or the trash bags filled with waste, failed to move in the direction of lysosomes--cell's recycling plant. This is potentially very harmful to the health of a cell. It's somewhat analogous to what would happen if a garbage truck didn't pick up your trash--your waste could accumulate, become scattered in the neighborhood and create a health hazard."

As a next step, the researchers want to figure out which waste products are selected for recycling and how a cell determines when to start moving the waste.

"My lab's research efforts are focused on the relationship between aging and autophagy," concludes Hansen. "Based on this discovery, we have a new, potential entry point to modulate the activity of recycling in a cell, which may prove relevant to understanding the diminished functions of autophagy that are known to occur in aging cells. Such insights could ultimately lead to new drug targets to combat age-related diseases as well as potential diagnostic markers to assess autophagy 'health,' an important goal for the future."

What The Study Did: Researchers describe the local transmission pattern of SARS-CoV-2 in Valencia, the third most populated city in Spain.

Authors: Carolina Romero García, M.D., Ph.D., of the University General Hospital, European University, in Valencia, Spain, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2021.13818)

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

CHICAGO --- Scientists have long known the brain's hippocampus is crucial for long-term memory. Now a new Northwestern Medicine study has found the hippocampus also plays a role in short-term memory and helps guide decision-making.

The findings shed light on how the hippocampus contributes to memory and exploration, potentially leading to therapies that restore hippocampal function, which is impacted in memory-related aging and neurodegenerative diseases such as dementia, the study authors said.

In the study, scientists monitored participants' brain activity and tracked their eye movements while looking at different complex pictures. The scientists discovered that as we visually scan our environment and absorb new information, our hippocampus becomes activated, using short-term memory to better process new visual information to help us rapidly reevaluate situations.

How our memory helps us scan new environments

Imagine walking down the street and noticing an awkwardly parked car on your neighbor's lawn. Maybe you quickly dismiss it and move on. But when you see an ambulance and fire truck approaching your location, you connect the dots and look back to see the scene of an accident. By using short-term memory to guide where you look, the hippocampus allows you to reexamine the car and form a lasting memory of the accident.

"At any given moment, your brain rapidly initiates eye movements that you are typically unaware of," said corresponding author James Kragel, a postdoctoral research fellow at Northwestern University Feinberg School of Medicine. "Our findings suggest the hippocampus uses memory to inform where your eyes look, thereby priming the visual system to learn and reevaluate our environment on the fly.

"If you didn't look back and see the crash, you might not encode that important information, but in using short-term memory retrieval, you can tie those clues together and remember details that cue bigger memories. It all comes down to building connections among these disparate elements that allow you to remember them later in a much easier way."

The study will be published June 18 in the journal Science Advances.

"These findings emphasize that although hippocampal-dependent memory is typically considered a thing of the past, in fact, it operates in the moment to optimize our behavior and decision-making," said senior study author Joel Voss, associate professor of medical social sciences, neurology, and psychiatry and behavioral sciences at Feinberg. "This is key to understanding hippocampal function and developing effective treatments for memory disorders."

"It is as if you are using your memory to plan for what to expect, and then when it mismatches with what is actually unfolding, your hippocampus gets activated to reevaluate and update your current perception of what is going on," Kragel said.

Tracking eye movements to learn more about memory

The study was conducted on patients with epilepsy who were undergoing neurosurgical monitoring at Northwestern Memorial Hospital to localize the source of their seizures. They had electrodes implanted in their brains to map seizure-related brain activity. During their stay in the epilepsy-monitoring unit, participants performed a memory task in which they studied lists of complex scenes with multiple people and objects (e.g. someone sitting at a park bench with food on the table, things happening in the background) followed by a memory test.

During the test, the participants indicated whether a presented scene was old or new. Throughout the task, the authors simultaneously recorded eye movements and neural activity to link hippocampal activity to memory-guided behaviors.

When studying a scene for the first time, participants often returned their gaze to a location they had just viewed hundreds of milliseconds prior. These "revisitation" eye movements enhanced spatiotemporal memory for scenes (remembering where an object was located or the sequence in which something happened). Brain recordings revealed the brain networks involved in generating these "revisitations," as hippocampal activity shifted just before their execution. Increases in brain activity followed revisitations, which Kragel believes may form a lasting memory of the scene and its elements.

"This shows that the hippocampal contribution to memory unfolds over just hundreds of milliseconds during ongoing behavior, which is surprising given that the timecourse of its involvement, typically seen in long-term memory retrieval, is usually thought to be days to years," Voss said.

Identifying the causes of human neurodegenerative diseases is a global research priority, warranting frequent reviews of the accumulating knowledge. In doing just that, biologists from the Plant Physiology Laboratory at the University of Guam and neuroscientists from the Experimental Medicine Program at The University of British Columbia have published an update on the reputed environmental toxins that have been suspected of being involved in mammal neurodegeneration. Their summary was published in April in the book Spectrums of Amyotrophic Lateral Sclerosis, which is available online from the publisher Wiley Blackwell.

A decades-long search for a dementia-causing toxin

Interest in the correlations between environmental toxins and neurodegeneration focused the world's magnifying glass on the island of Guam in the 1950s due to an unexpected increase in cases of neurodegenerative cases among the indigenous CHamoru population. The specific condition that temporarily affected Guam is known as amyotrophic lateral sclerosis-parkinsonism dementia (ALS-PDC) and known locally by the CHamoru term lytico-bodig.

A focus on this isolated cluster of cases led to decades of pursuit of causal toxins found in seeds of Guam's native cycad tree. These seeds were components of the local cuisine at the time, and increased reliance on this form of food starch during World War II was a plausible hypothesis to explain the increase in neurodegeneration cases shortly after the war.

Several factors likely coalesce

An ebb and flow of sequential disappointments has evolved since the 1950s because the identification of a single causal cycad toxin remains elusive.

But these disappointments have been countered by successes. It is now understood that several factors likely coalesce into a synchronized perfect storm to generate an unusual increase in localized neurodegenerative cases, such as what temporarily happened on Guam. These co-factors may include exposure to high doses of the environmental toxin by the most susceptible gender with the most susceptible genes at the most susceptible age, followed by a latency period before the neuronal damage begins to express itself.

The UOG-UBC collaboration has lasted more than two decades, and various members of the team have authored more than 100 journal articles on various aspects of cycad biology during that time. The toxicology of Guam cycad seeds was the subject of 14 of these publications.

"When I began collaborating with UOG, we had the benefit of building on the foundation of decades of research from Guam," said co-author Christopher Shaw, UBC neuroscientist. "We used the fact that no plant scientist had been directly involved in any of the previously published research to secure funds to revisit various issues concerning cycad seed toxins."

Difference between acute and slow-acting toxins

One of the many confusing aspects of this research is that acute toxins, which cause immediate poison reactions following cycad seed ingestion, are distinct from slow-acting toxins, which lead to neurodegeneration.

"The distinctions between these two forms of toxins are often confused, and scientists are constantly reminding the public that many years need to elapse after the exposure to a slow plant toxin before negative health outcomes develop," said Benjamin Deloso, a cycad biologist with UOG.

Claims of cyanide poisoning inaccurate

Another benefit from the marathon pursuit of the causal cycad toxin is that an enormous body of literature has developed that uncovered which biomolecules are not at play.
"This is how science works," Shaw said. "The aggressive empirical look at each candidate toxin was justified and refined the development of superseding hypotheses that were vigorously tested."

For example, cassava roots contain sugar-based molecules that liberate cyanide after ingestion by mammals, and cycad seeds contain similar molecules, but cycad seeds contain no free cyanide and the identified sugar-based cycad molecules in cycads are incapable of liberating toxic levels of cyanide following ingestion by mammals. The meticulous research revealed the claims of cyanide as a potential cycad toxin and that cycad seed consumption could cause cyanide poisoning were inaccurate.

"Throwing around fear-mongering buzzwords, like cyanide, is a classic example of a repetition of false information in order to drive a personal agenda," Deloso said. "There are even petitions being circulated that falsely claim that cycad plants contain cyanide in attempts to force retail nurseries to stop selling cycad plants to pet owners."

The research team contends that scientists are not immune from the mistake of repeating these sorts of false claims about cycads. This tends to happen when scientists get their information from the gray literature or online encyclopedia style websites that are not vetted by cycad experts.

The authors hope that one outcome of their new publication is a decline in the spread of false information about cycad poisoning, as these untruthful statements damage the international community's attempts to improve cycad conservation.

The population on Earth is increasingly growing and people are expected to live longer in the future. Thus, better and more reliable therapies to treat human diseases such as Alzheimer's and cardiovascular diseases are crucial. To cope with the challenge of ensuring healthy ageing, a group of international scientists investigated the potential of biosynthesising several polyamines and polyamines analogues with already known functionalities in treating and preventing age-related diseases.

One of the most interesting molecules to study was spermidine, which is a natural product already present in people's blood and an inducer of autophagy that is an essential cellular process for clearing damaged proteins, e.g., misfolded proteins in brain cells that can cause Alzheimer's. When people get older the level of spermidine in the blood decrease and dietary supplements, or certain food products are needed to maintain a stable and high level of spermidine in the blood. However, those products are difficult to produce with traditional chemistry due to their structural complexity and extraction of natural resources is neither a commercially viable nor a sustainable approach.

Therefore, the researchers instead decided to open their biochemical toolbox and use classical metabolic engineering strategies to engineer the yeast metabolism to produce polyamines and polyamines analogues.

"This group of molecules has huge potential in addressing important societal challenges and it seemed logical to try and produce them with the help of biology," emphasises Jiufu Qin, Senior Researcher at The Novo Nordisk Foundation Center for Biosustainability, DTU.

Solid vantage point

The team of scientists explored seven biosynthetic routes that synthesises spermidine from arginine or ornithine and by employing flux balance analysis they could estimate the maximum theoretical yield of each pathway.

After establishing the most efficient pathway for spermidine and systematically engineering the cellular metabolism of yeast they managed to ultimately reach a production of spermidine at titers 2.3 gram per liter on lab scale. An initial result that proves the potential of utilising nature's large and diverse reservoir of biochemical tools to push forward products that can meet the challenges of population ageing and a lack of sufficient food supplies.

"We expect that our studies lay the groundwork for fermentation-based manufacture of diverse polyamines and polyamine analogues to further unlock this field's potential for pharmacological and agricultural applications, "says Jens Nielsen, Professor at Chalmers University of Technology and CEO at BioInnovation Institute.

But all that glitter is not gold and an obstacle such as low enzyme activity causing feedback regulation and thereby compromising the product yield still needs to be overcome.

Hit the nail on the head

Even though the strain might need to be improved further, scale-up towards commercial production is already ongoing since the current titers are deemed sufficient for initialising production.

The company Chrysea Labs has been established based on this scientific study and the company has a mission of developing healthy lifespan nutritional interventions by ameliorating the natural occurring anti-ageing mechanism autophagy that recycle the cellular process, which is critical for maintaining cell health, renewal and survival.

Since the market is expected to grow in the coming years and only a few competitors are currently present in the field there might be a window of opportunity for Chrysea Labs to be a frontrunner in ensuring healthy ageing.

That is the conclusion of new research published in the journal Geriatrics, which examined studies on several "telehealth" applications - smartphone apps used by patients and healthcare professionals to manage their condition.

Researchers found that smartphone apps and telehealth initiatives have the potential to improve the effectiveness and efficiency of healthcare systems and patients' quality of life in relation to pain management

The authors also emphasise that user involvement in development and construction of smartphone apps and telehealth initiatives is vital to enhance acceptability and usability.

However, the study also advised that enhanced systems, policies and procedures are needed in order to prevent unethical use of health data across the health system.

According to the United Nations, the global population of over 65s is growing at a faster rate than any other age group. The population of older adults is expected to be at 1.5 billion by 2050.

Co-author Dr Antonio Bonocaro, Senior Lecturer in Adult and Acute Care Nursing at Anglia Ruskin University (ARU), said: "Chronic pain is a significant cause of disability. The current COVID-19 pandemic has severely impacted normal healthcare delivery, making it harder for people to physically access services, and even in normal times, healthcare services are under increasing strain.

"Our research found there is considerable potential for apps to actively support older people with their pain management and also improve communication with health professionals when physical services are unobtainable. They are cheap, informal, and popular.

"However, telehealth apps are mostly produced without getting users involved in the developmental process. The need for information sharing, education, and self-administration of pain relief is almost completely neglected.

"Data protection is a big concern for patients. The importance of data privacy and confidentiality should be acknowledged, and encryption and password-protected access to any data is important."

Footprints from at least six different species of dinosaur - the very last dinosaurs to walk on UK soil 110 million years ago - have been found in Kent, a new report has announced.

The discovery of dinosaur footprints by a curator from Hastings Museum and Art Gallery and a scientist from the University of Portsmouth is the last record of dinosaurs in Britain.

The footprints were discovered in the cliffs and on the foreshore in Folkestone, Kent, where stormy conditions affect the cliff and coastal waters, and are constantly revealing new fossils.

Professor of Palaeobiology, David Martill, said: "This is the first time dinosaur footprints have been found in strata known as the 'Folkestone Formation' and it's quite an extraordinary discovery because these dinosaurs would have been the last to roam in this country before becoming extinct.

"They were walking around close to where the White Cliffs of Dover are now - next time you're on a ferry and you see those magnificent cliffs just imagine that!"

The footprint fossils formed by sediment filling the impression left behind when a dinosaur's foot pushes into the ground, which then preserves it.

The footprints are from a variety of dinosaurs, which shows there was a relatively high diversity of dinosaurs in southern England at the end of the Early Cretaceous period, 110 million years ago.

They are thought to be from ankylosaurs, rugged-looking armoured dinosaurs which were like living tanks; theropods, three-toed flesh-eating dinosaurs like the Tyrannosaurus rex; and ornithopods, plant-eating 'bird-hipped' dinosaurs so-called because of their pelvic structure being a little bit similar to birds.

Philip Hadland, Collections and Engagement Curator at the Hastings Museum and Art Gallery is lead author on the paper. He said: "Back in 2011, I came across unusual impressions in the rock formation at Folkestone. They seemed to be repeating and all I could think was they might be footprints.

"This was at odds with what most geologists say about the rocks here, but I went looking for more footprints and as the tides revealed more by erosion, I found even better ones. More work was needed to convince the scientific community of their validity, so I teamed up with experts at the University of Portsmouth to verify what I'd found."

Most of the findings are isolated footprints, but one discovery comprises six footprints - making a 'trackway', which is more than one consecutive print from the same animal.

This trackway of prints are similar in size to an elephant footprint and have been identified as likely to be an Ornithopodichnus, of which similar, but smaller-sized footprints have also been found in China from the same time period.

The largest footprint found - measuring 80 cm in width and 65 cm in length - has been identified as belonging to an Iguanodon-like dinosaur. Iguanodons were also plant-eaters, grew up to 10 metres long and walked on both two legs or on all fours.

Professor Martill said: "To find such an array of species in one place is fascinating. These dinosaurs probably took advantage of the tidal exposures on coastal foreshores, perhaps foraging for food or taking advantage of clear migration routes."

In the Late Cretaceous period, this part of Kent, and indeed much of the United Kingdom was beneath a shallow sea, but this study also shows unequivocally that the Folkestone Formation was inter-tidal.

Mr Hadland said: "Aside from finding that dinosaurs went to the seaside just like their modern relatives the birds, we have also found new evidence that changes the interpretation of the geology of the Folkestone Formation strata.

"It just goes to show that what has been previously published about the geology of an area isn't always correct and new insights can be made. There is also the potential for almost anyone to make a discovery that adds to scientific knowledge from publicly accessible geological sites."

The paper is published in Proceedings of the Geologists' Association and some of the footprints are currently on display at Folkestone Museum.

Biologists have identified a family of algae as a living missing link in the microscopic domain.

Over the course of evolutionary time, marine microorganisms have undergone an immense range of diversification. This applies in particular to the group known as dinophytes. Also known as dinoflagellates, these unicellular algae can account for a significant fraction of the phytoplankton in the oceans, and their ecological and economic significance is correspondingly high. A team of researchers led by Ludwig-Maximilians-Universitaet (LMU) in Munich biologist Professor Marc Gottschling now reports the identification of a missing link between the two major phylogenetic groups of dinophytes, which sheds new light on the evolution of these organisms.

Many dinophytes are characterized by a bipartite protective structure called a theca, which consists of cellulosic plates synthesized in specialized vesicles that lie immediately below the plasma membrane. The patterning of the plates is often species- and group specific. In the new study, Gottschling and his colleagues focused on a monoclonal dinophyte strain that had been assigned to the Cladopyxidaceae. Using a combination of morphological analysis by electron microscopy and genetic characterization (by ribosomal RNA sequencing), they discovered - much to their surprise - that its phylogenetic position reveals it to be a 'missing link' between the two major groups of thecate dinophytes - the Gonyaulacales and the Peridiniales. In addition, the study showed that this dinophyte represents a new genus and species, which they named Fensomea setacea in honor of the micropaleontologist Robert A. Fensome.

"Missing links have made many important contributions to the understanding of evolution," Gottschling points out. "Among the best known examples among macrofauna are the Urvogel Archaeopteryx and the coelacanth (Latimeria). But the recognition and documentation of a living missing link in the microscopic domain is also highly significant." Up to now, the Cladopyxidaceae have been classified within the Gonyaulacales, while other Dinophyceae with a comparable hyposome were assigned to the Peridiniales." Thanks to the recognition of this missing link, we have now shown that these are misaassignments," says Gottschling. Based on our work the two large groups can now be morphologically defined in a more coherent manner, which clarifies their evolutionary history. The modern Cladopyxidaceae are most probably quite similar to the last common ancestor of all dinophytes, which originated about 200 million years ago. They are the last suvivors of a group that was much more abundant during the times of the dinosaurs."

One in six women and one in twelve men in Austria suffers from some form of IBS - therefore around one million people in all. Using currently available techniques, it is only possible to diagnose IBS by a process of elimination. Most people suffering from irritable bowel syndrome only go to their doctor when they have severe symptoms such as constipation, diarrhoea, abdominal pain, or a change in bowel motion. Researchers from the Department of Medicine III of the Medical University of Vienna and the University of Vienna have now shown that, in most cases, IBS is associated with bacterial biofilms in the gut that are visible under endoscopic examination.

"For the first time, we have managed to identify a cause of irritable bowel syndrome and, at the same time, show how this disease can be more accurately diagnosed, classified and assessed," says Christoph Gasche, Head of the Laboratory for Molecular Gastroenterology at Medical University of Vienna and leader of the study funded by the Austrian Science Fund (FWF) and Vienna Science and Technology Fund (WWTF), which has now been published in the leading journal Gastroenterology and came into being in collaboration with MedUni Vienna microbiologist Athanasios Makristathis, David Berry and Markus Muttenthaler (University of Vienna), as well as Timo Rath (Friedrich Alexander University, Erlangen).

According to the study, people who have taken a lot of medication over the course of their lives, so that the balance of their gut flora has been disrupted, are more likely to be affected by bacterial biofilms. Another interesting subgroup is patients who have previously had organ transplants. Gasche explains: "Certain drugs, such as proton pump inhibitors, can upset the balance of the bacterial ecosystem. The bacteria then go into survival mode. To give themselves a better chance of surviving this stress, they band together for safety and form biofilms, a sort of protective space that makes them resistant to antibiotics and other environmental toxins."

In total, more than 1,000 colonoscopies were performed in a multi-centre study, and it was found that two thirds of those who had IBS symptoms also had biofilms in their small or large intestine. However, these mucosal biofilms are also found in one third of patients with ulcerative colitis.

This bacterial matrix, which can be reticular or even planar, adheres like a thin layer on the mucosal lining of the gut - not unlike dental plaque in caries - thereby impairing its functions and, hence, that of the gut. "Up until now, it has always been assumed in investigations that this sticky film is made up of residues of impurities in the gut, which were difficult to eliminate," says Gasche. "However, we have now been able to show that this is where the bacterial matrix adheres." A revolutionary discovery for the lead authors of the study, Maximilian Baumgartner und Michaela Lang, on a par "with the discovery of the rod-shaped bacterium Helicobacter pylori, which permanently changes the gastric environment."

Irrigation might help, biofilms as a new characteristic of IBS

In many cases it is possible to wash away these biofilms in the large intestine using an endoscopic "spray gun". Future studies will show whether this alleviates the IBS symptoms. Also, this technique cannot (as yet) be used to remove biofilms from the small intestine, where they also frequently occur. In a new project funded by Vienna Science and Technology Fund (WWTF), the MedUni Vienna experts are therefore already investigating how the new findings about these biofilms can be used in future to generally remove them or even to prevent them from forming in the first place. But one conclusion can already be drawn from the study results: "Biofilms reflect an imbalance in the gut flora, could well explain the symptoms of IBS patients and, hence, give rise to new therapeutic approaches," say the researchers.

Due to sample size limitations, previous studies of DMARD use and COVID-19 outcomes have combined several different rheumatic diseases and medications, and investigated a single outcome- for example, the risk of hospitalization. EULAR has given financial support to a global project collecting information on SARS-CoV-2 infection in people with rheumatic diseases. The COVID-19 Global Rheumatology Alliance physician-reported registry launched in March 2020 to collect data on adults with rheumatic disease and confirmed or presumptive COVID-19.

This analysis from Jeffrey Sparks, Zachary Wallace, and colleagues aimed to investigate the associations between baseline use of biologic or targeted synthetic DMARDs with a range of poor COVID-19 outcomes specifically in people with rheumatoid arthritis (RA). The treatments included were abatacept, rituximab, JAK inhibitors (JAKi), interleukin-6 inhibitors (IL-6i), ortumornecrosis factor inhibitors (TNFi). The outcomes were scored on a scale of one to four for COVID-19 severity: 1) no hospitalization, 2) hospitalization without oxygen need, 3) hospitalization with any oxygen need or ventilation, or 4) death. The authors used an analysis to compare each drug class toTNFi.

Of 1,673 people with RA taking b/tsDMARDs when they developed COVID-19, 498 (34.3%) were hospitalized and 112 (6.7%) died. Rituximab users were more likely than TNFi users to have interstitial lung disease(ILD;11.6% versus1.7%) and history of cancer (7.1%versus2.0%); JAKi users were more likely than TNFi users to be obese (17.3%versus9.0%). After propensity score matching, the authors found that rituximab was strongly associated with greater odds of having a worseCOVID-19outcome compared to TNFi. Among rituximab users, 42 (18.8%) died compared to 27 (3.3%) of TNFi users. JAKi use was also associated with greater odds of having a worse COVID-19 severity. People taking abatacept orIL-6ididnot have worseCOVID-19 severity compared to TNFi. Overall, the results were similar in the sensitivity analysis and after excluding cancer or ILD.

Since the abstract was submitted, Sparks adds that the database was refreshed so the numbers have all changed and the sample size is bigger. The main findings are consistent with the initial submission.

Similar results regarding rituximab have been found in the French RMD cohort. Avouac and colleagues reported findings on behalf of a consortium of contributors, includingFAI2R,SFR,SNFMI,SOFREMIP,CRI, and IMIDIATE. Of 1,090peopleincludedwith rheumatic diseases - mainly RA -137 developed severeCOVID-19disease (12.6%). After adjusting for potential confounding factors, severe disease was confirmed to be more frequent in patients receiving rituximab. People who developed severeCOVID-19hadreceived rituximab infusion more recently compared to people with mild or moderate infection.

In this cohort, 89 people cohort died-an overall death rate of 8.2%. Death rate was numerically higher in people receiving rituximab(20.6%) compared to those not(7.4%),and the subgroup of untreated patients with diseases eligible for rituximab therapy (9.9%).However, after adjusting for confounding factors, the risk of death was not significantly increased in people treated with rituximab, although the length of hospital stay was markedly longer in people treated with rituximab compared to both untreated groups.

Results so far from these registriesof people with RA and COVID-19show that baseline use of rituximab or JAKiis associated with worse severity of COVID-19 compared to TNFi use. The elevated odds for poor COVID-19 outcomes in people taking rituximab highlights the urgent need for strategies to limit their risk, such as optimal vaccination timing. The global alliance finding that JAKi are associated with poor COVID-19 outcomes is novel, and needs to be reproduced in other studies.

Climate warming plays a larger role than plant genes in influencing the number and identity of fungal species on oak leaves, especially in autumn. Recently published in the journal New Phytologist, this research by ecologists sheds light on how warming and tree genes affect the dynamics of fungal communities across the season.

"One of our major findings was that elevated temperature decreased the number of fungal species and changed their community composition, especially in the late season" says Maria Faticov, a researcher at the Department of Ecology, Environment and Plant Sciences (DEEP) at Stockholm University.

Plants host thousands of microscopic organisms and leaves are no exception. Leaves harbour a large diversity of microorganisms including fungi, bacteria and, less frequently, archaea. Fungi are among the most diverse groups of microorganisms living on leaves. Some of these microscopic fungi cause disease, others can promote plant growth and defend leaves against biotic and abiotic stresses, and still others play an important role in leaf senescence and decomposition.

Climate is one of the main factors influencing fungal development, either directly or indirectly, by triggering plant defences.

"From earlier studies, we know that the number of fungal species and their abundance change as leaves age and the season progresses from spring to autumn. What we do not know is what role climate warming and plant genetic variation play in shaping fungal communities across the growing season" says Ayco Tack, associate professor at the Department of Ecology, Environment and Plant Sciences, Stockholm University.

To answer this question, researchers took on a challenging project - they built 6 identical cages in a field to the north of Stockholm, each cage the size of a small living room. Scientists put 132 young oak trees into the cages that represented 5 different genotypes. Half of the cages were heated from May to October using ceramic heaters. The remaining ones were left as control and did not have heaters in them. The temperature in the heated cages was increased by ca 2°C to mimic the global temperature increase predicted by scientists to occur by the end of the century. Researchers collected leaves in the early, middle and late growing season and used DNA sequencing to find out which fungi had colonised the leaves. This way they could compare the changes in fungal community structure between the control and warming treatment and also among oak genotypes.

"We observed that fungal community composition drastically changed from spring to autumn, with yeasts increasing in relative abundance and fungal pathogens decreasing. Interestingly, while experimental warming had a major impact on the fungal community, oak genotype explained only a minor part of the variation in the number of fungal species and their composition" says Maria Faticov.

These findings suggest that warming is one of the most important environmental factors shaping fungal community development during the growing season and emphasizes how profound the effects of ongoing climate change may be to plant health and ecosystem functioning.

Researchers did not link the observed change in fungal community structure under warming with plant health and ecosystem functioning. More detailed long-term experiments are needed to predict how changes in the fungal community under climate warming will influence the plants they live on and their surrounding environment.

"In future studies, it will be interesting to investigate how these changes in the number of fungal species and their abundances under warmer climate impact such important processes as plant health, leaf senescence and litter decomposition" says Maria Faticov.

Scientists have developed a new technique that could revolutionise medical imaging procedures using light.

A team of physicists, led by Dr David Phillips from the University of Exeter, have pioneered a new way in which to control light that has been scrambled by passage through a single hair-thin strand of optical fibre. These ultra-thin fibres hold much promise for the next generation of medical endoscopes - enabling high-resolution imaging deep inside the body at the tip of a needle.

Conventional endoscopes are millimetres wide and have limited resolution - so cannot be used to inspect individual cells. Single optical fibres are approximately 10x narrower and can enable much higher-resolution imaging - enough to examine the features of individual cells directly inside living tissue. It is normally only possible to view cells once they have been taken outside the body and placed in a microscope.

The catch is that we can't directly look through optical fibres, as they scramble the light sent through them. This problem can be solved by first calibrating an optical fibre to understand how it blurs images, and then using this calibration information as a key to decipher images from the scrambled light. Earlier this year, Dr Phillips' group developed a way to measure this key extremely rapidly, in collaboration with researchers from Boston University in the USA, and the Liebniz Institute of Photonic Technologies in Germany [paper: Compressively sampling the optical transmission matrix of a multimode fibre, published in Light: Science and Applications, April 21st 2021].

However, the measured key is very fragile, and easily changes if the fibre bends or twists, rendering deployment of this technology in real clinical settings currently very challenging. To overcome this problem, the Exeter based team have now developed a new way to keep track of how the image unscrambling key changes while the fibre is in use. This provides a way to maintain high resolution imaging even as a single fibre based micro-endoscope flexes. The researchers achieved this by borrowing a concept used in astronomy to see through atmospheric turbulence and applying it to look through optical fibres. The method relies on a 'guide-star' - which in their case is a small brightly fluorescing particle on the end of the fibre. Light from the guide-star encodes how the key changes when the fibre bends, thus ensuring imaging is not disrupted.

This is a key advance for the development of flexible ultra-thin endoscopes. Such imaging devices could be used to guide biopsy needles to the right place, and help identify diseased cells within the body.

Dr Phillips, an Associate Professor in the Physics and Astronomy department at the University of Exeter, said: "We hope that our work brings the visualisation of sub-cellular processes deep inside the body a step closer to reality - and helps to translate this technology from the lab to the clinic."

The latest work is in collaboration with researchers at the Liebniz Institute of Photonic Technologies in Germany, and the Brno Insititute of Scientific Instruments in the Czech Republic. The project was made possible with funding from the Royal Academy of Engineering and the Royal Society in the UK, the European Research Council, and the Chinese Scholarship Council.

Memory effect assisted imaging through multimode optical fibres is published in Nature Communications on Friday, June 18th 2021

RA is an inflammatory autoimmune disease that causes pain, swelling and stiffness in the joints. It can also cause fatigue, and the underlying inflammation may affect other body systems. Dementia is a symptom of damage to the brain, which can be caused by a number of different diseases - for example, Alzeimer's. Symptoms include memory loss, difficulty concentrating, confusion, and mood changes. It is not known what causes all types of dementia, but it is it thought that some of the damage could be caused by other underlying diseases. Heart failure happens when the heart becomes weak or stiff, and is not able to pump blood around the body properly. People with heart failure may be breathless even when at rest, feel very tired, and have swollen ankles or legs.

Heart failure is one of the most common cardiovascular conditions in people with RA, and previous studies have suggested that people with RA are twice as likely to develop heart failure as people in the general population without RA. For dementia, previous studies have delivered mixed results about the pattern of cognitive impairment and dementia in people with RA compared to the general population- with some showing increased odds, while others show the reverse. Furthermore, existing studies have not evaluated trends in incidence of dementia or heart failure to see if the risks have changed over time.

Two groups at the Mayo Clinic, USA have run population-based studies in Minnesota to assess the incidence of dementia or heart failure over time in people with RA, and compared to the general population.

Vanessa Kronzer and colleagues assessed the incidence of dementia over time in people with RA and compared it to that seen in the general population. Medical record data were collected for 895 people diagnosed with RA between 1980 and 2009. All individuals were followed until death, migration, or31st December2019to see if they went on to develop dementia. The 10-year cumulative incidence of dementia in people diagnosed during the1980s, 1990s, and 2000s was 12.7%, 7.2%, and 6.2%, respectively - showing a clear decline and markedly lower cumulative incidence of dementia for people diagnosed with RA in the2000s compared with the1980s. For 880 people in the general population without RA, the10-year cumulative incidence of dementia in the 1980s, 1990s, and 2000swas 9.3%,5.0%, and7.1%, respectively. Overall, the risk of dementia in RA patients was significantly higher than in people without RA. When subdivided by decade, the risk of dementia in people diagnosed with RA was higher than non-RA comparators in the 1980s and 1990s-but notthe2000s.

Elena Myasoedova and colleagues used the same methods to look at the trends of heart failure in 905 people diagnosed with RA between 1980 and 2009, and followed until death, migration, or31stDecember2019.The 10-year cumulative incidence of heart failure in people diagnosed with RA in the1980s, 1990s, and 2000s was 8.5%,10.8%, and7.1%, respectively. These results show there was no difference in incidence of heart failureinthe1990s and 2000s compared tothe1980s.For903 people in the general population without RA over the same time period the incidence of heart failure was 7.4%,7.5%,and 7.3%.When comparing the risk of heart failure in people with and without RA, those diagnosed with RA in the 2000s had no excess risk of heart failure compared to the general population. This finding is in contrast to the 2-fold excess risk seen in people diagnosed with RA in the1980s, and around1.5-fold increased risk in 1990s.

Further studies should investigate these association, and look at the role of inflammation, autoimmunity, and anti-rheumatic treatments in the risk of dementia and heart failure.

Uveitis occurs in up to 20% of children with JIA, although this varies depending on the specific type of JIA that each child has. Jens Klotsche and colleagues shared new data at the 2021 EULAR congress analysing the risk of uveitis events after discontinuing disease-modifying antirheumatic drugs (DMARD) in children with one of two JIA categories: extended oligoarthritis and rheumatoid factor (RF)-negative polyarthritis.

The data for the analysis came from two ongoing biologic registers: the German Biologics in Pediatric Rheumatology (BiKeR) registry, and the Juvenile arthritis Methotrexate/Biologics long-term Observation (JuMBO) study. Adverse events and reports about uveitis events during treatment and after discontinuation of DMARDs were collected. A total of 2,041children with RF-negative polyarthritis or extended oligoarthritis were included. About half of the patients were enrolled in BiKeR when they started taking etanercept (n=1,137;55.7%), followed by 635 (31.1%) patients starting methotrexate monotherapy, or adalimumab (n=198, 9.7%). A history of uveitis was reported for 11.7%of children at enrolment in BiKeR.

Children with uveitis had a lower age at JIA onset in comparison to patients without uveitis. A total of 142 recurrent uveitis events were reported in 93 children, and for 27 children this was an incident uveitis reported during follow-up, with 19 uveitis flares reported for patients after the age of 18.

Uveitis events were reported significantly more often in the first 24 months after methotrexate discontinuation, and in the first 3 months after biological DMARD discontinuation (adalimumab and etanercept). Children with amethotrexate dose of 10 mg/m²or less at last intake had a higher likelihood for uveitis events. Overall, the longer the time since DMARD discontinuation the fewer uveitis events occurred.

This is the first prospective study to look at the risk of uveitis after DMARD withdrawal. The findings show uveitis relapses are common. Patients who stop DMARD therapy are at high risk for uveitis within the first 3-24 months after discontinuation. Rheumatologists and ophthalmologists should be aware about this risk, which should lead to regular uveitis screening after DMARD withdrawal.

Fruit flies have found at least two solutions to the problem of sorting their sex chromosomes: a matter of life and death.

Sex determination in animals often depends on the unequal segregation of specific chromosomes. Female cells generally possess two X chromosomes, while male cells contain one X and one Y chromosome. The latter, which is inherited from the male parent, has far fewer genes than the X. In the fruit fly Drosophila, male cells make up for the fact that they have only one X chromosome by boosting the level of expression of all of its genes by a factor of 2. This phenomenon, which is known as dosage compensation, requires that the X chromosome in males be regulated differently from all the others. A team of molecular biologists at Ludwig-Maximilians-Universitaet (LMU) in Munichs Biomedical Center led by Professor Peter Becker has now shown that, over the course of 40 million years, members of the genus Drosophila have discovered at least two different ways of making this vital distinction.

"In light of the significance of dosage compensation, one might expect that the principles behind the specific recognition of the X chromosome in males would be highly conserved," says Becker. "In other words, the process should work in essentially the same way in all Drosophila species. However, when we compared the two species Drosophila melanogaster and Drosophila virilis, we discovered, to our surprise, that they use distinct mechanisms for this purpose." Significantly, the primary components involved in dosage compensation - the proteins MSL2 and CLAMP, together with the non-coding RNA roX - are found in both species. So their last common ancestor presumably possessed the genes that code for these products.

The two species diverged about 40 million years ago, and since then they have evolved in parallel. The new study shows that, during this period, the mediators of dosage compensation and their binding sites on the X chromosome have evolved in different ways. As a result, the relative influence of, and the interactions between, the components have changed. Among other things, in D. melanogaster the copy numbers of certain DNA sequences on the X chromosome have increased. In parallel, the DNA-binding domain of the MSL2 protein has acquired the ability to recognize these sequences, and they now play a critical role in the recognition of the X chromosome in this species.

In D. virilis, on the other hand, these sequences have not been amplified. Their recognition by MSL2 therefore depends on its interaction with the CLAMP protein to a much greater extent than in the case of D. melanogaster - even though the CLAMP protein can also bind to many sequences on the other chromosomes. "We assume that the non-coding roX RNA inhibits the binding of MSL2 at these sites", says Becker. The study has therefore uncovered a new role for this RNA. Up until now, researchers had assumed that roX comes into play not at the level of sequence recognition, but at a later stage in the dosage compensation process.

These findings have interesting evolutionary implications. "As the sex chromosomes continue to diversify, the emergence of alternative but equally effective solutions to the problem of balancing the activity of the genome demonstrates that evolution is not a deterministic process," Becker points out.