Culture

Manipulating RNA can allow plants to yield dramatically more crops, as well as increasing drought tolerance, announced a group of scientists from the University of Chicago, Peking University and Guizhou University.

In initial tests, adding a gene encoding for a protein called FTO to both rice and potato plants increased their yield by 50% in field tests. The plants grew significantly larger, produced longer root systems and were better able to tolerate drought stress. Analysis also showed that the plants had increased their rate of photosynthesis.

"The change really is dramatic," said University of Chicago Prof. Chuan He, who together with Prof. Guifang Jia at Peking University, led the research. "What's more, it worked with almost every type of plant we tried it with so far, and it's a very simple modification to make."

The researchers are hopeful about the potential of this breakthrough, especially in the face of climate change and other pressures on crop systems worldwide.

"This really provides the possibility of engineering plants to potentially improve the ecosystem as global warming proceeds," said He, who is the John T. Wilson Distinguished Service Professor of Chemistry, Biochemistry and Molecular Biology. "We rely on plants for many, many things--everything from wood, food, and medicine, to flowers and oil--and this potentially offers a way to increase the stock material we can get from most plants."

Rice nudged along

For decades, scientists have been working to boost crop production in the face of an increasingly unstable climate and a growing global population. But such processes are usually complicated, and often result only in incremental changes.

The way this discovery came about was quite different.

Many of us remember RNA from high school biology, where we were taught that the RNA molecule reads DNA, then makes proteins to carry out tasks. But in 2011, He's lab opened an entire new field of research by discovering the keys to a different way that genes are expressed in mammals. It turns out that RNA doesn't simply read the DNA blueprint and carry it out blindly; the cell itself can also regulate which parts of the blueprint get expressed. It does so by placing chemical markers onto RNA to modulate which proteins are made and how many.

He and his colleagues immediately realized that this had major implications for biology. Since then, his team and others around the world have been trying to flesh out our understanding of the process and what it affects in animals, plants and different human diseases; for example, He is a co-founder of a biotech company now developing new anti-cancer medicines based on targeting RNA modification proteins.

He and Guifang Jia, a former UChicago postdoctoral researcher who is now an associate professor at Peking University, began to wonder how it affected plant biology.

They focused on a protein called FTO, the first known protein that erases chemical marks on RNA, which Jia found as a postdoctoral researcher in He's group at UChicago. The scientists knew it worked on RNA to affect cell growth in humans and other animals, so they tried inserting the gene for it into rice plants--and then watched in amazement as the plants took off.

"I think right then was when all of us realized we were doing something special," He said.

The rice plants grew three times more rice under laboratory conditions. When they tried it out in real field tests, the plants grew 50% more mass and yielded 50% more rice. They grew longer roots, photosynthesized more efficiently, and could better withstand stress from drought.

The scientists repeated the experiments with potato plants, which are part of a completely different family. The results were the same.

"That suggested a degree of universality that was extremely exciting," He said.

It took the scientists longer to begin to understand how this was happening. Further experiments showed that FTO started working early in the plant's development, boosting the total amount of biomass it produced.

The scientists think that FTO controls a process known as m6A, which is a key modification of RNA. In this scenario, FTO works by erasing m6A RNA to muffle some of the signals that tell plants to slow down and reduce growth. Imagine a road with lots of stoplights; if scientists cover up the red lights and leave the green, more and more cars can move along the road.

Overall, the modified plants produced significantly more RNA than control plants.

Modifying the process

The process described in this paper involves using an animal FTO gene in a plant. But once scientists fully understand this growth mechanism, He thinks there could be alternate ways to get the same effect.

"It seems that plants already have this layer of regulation, and all we did is tap into it," He said. "So the next step would be to discover how to do it using the plant's existing genetics."

He can imagine all sorts of uses down the road--and he's working with the university and the Polsky Center for Entrepreneurship and Innovation to explore the possibilities.

"Even beyond food, there are other consequences of climate change," said He. "Perhaps we could engineer grasses in threatened areas that can withstand drought. Perhaps we could teach a tree in the Midwest to grow longer roots, so that it's less likely to be toppled during strong storms. There are so many potential applications."

A new study showed that a wearable computer vision device can reduce collisions for both people who are blind or those who are visually impaired and using a long cane and/or guide dog by 37 percent, compared to using other mobility aids alone.

People who have visual impairments are at a significantly higher risk for collisions and falls. Commonly used mobility aids like long canes and guide dogs can offer benefits, but come with limitations in effectiveness and costs, respectively. While some electronic devices are marketed direct-to-consumer claiming to warn wearers of surrounding objects, there has been little evidence of their effectiveness in actual daily mobility settings. This is one of the first randomized-controlled trials to look at the potential benefit of the devices at home and outside of a controlled lab environment. The new study led by vision rehabilitation researchers at Mass Eye and Ear, a member of Mass General Brigham was published July 22 in JAMA Ophthalmology.

"Independent travel is an essential part of daily life for many people who are visually impaired, but they face a greater risk of bumping into obstacles when they walk on their own," said Gang Luo, PhD, an associate scientist at the Schepens Eye Research Institute of Mass Eye and Ear, and an associate professor of ophthalmology at Harvard Medical School. "Although many blind individuals use long canes to detect obstacles, collision risks are not completely eliminated. We sought to develop and test a device that can augment these everyday mobility aids, further improving their safety."

Vibrating wearable device prototype put to test

The experimental device used in the trial was created by Dr. Luo and colleagues in his vision rehabilitation lab, including the lead author Shrinivas Pundlik, PhD, who designed the computer vision algorithm. The device and data recording unit were enclosed in a sling backpack with a chest-mounted, wide-angle camera on the strap, and two Bluetooth-connected wristbands worn by the user. The camera is connected to a processing unit that captures images and analyzes collision risk based on the relative movement of incoming and surrounding objects in the camera's field of view. If an imminent collision is detected on the left or right side, the corresponding wristband will vibrate; a head-on collision will cause both wristbands to vibrate. Unlike other devices that simply warn of nearby objects whether or not a user is moving toward the objects, this device analyzes relative motion, warning only of approaching obstacles that pose a collision risk, and ignoring objects not on a collision course.

The new study included 31 blind and visually impaired adults who use either a long cane or guide dog (or both) to aid their daily mobility. After being trained to use the device, they used it for about a month at home in conjunction with their typical mobility device (mostly a long cane). The device was randomized to switch between active mode, in which the users could receive vibrating alerts for imminent collisions, and silent mode, in which the device still processed and recorded images, but did not give users any warning even if potential collisions were detected. The silent mode is equivalent to the placebo condition in many clinical trials testing drugs. The wearers and researchers would not know when the device modes changed during the testing and analysis. Collisions were analyzed by researchers from the recorded videos. The effectiveness of the device was evaluated by comparing collision incidents that occurred during active and silent modes. The study found that the collision frequency in active mode was 37 percent less than that in silent mode.

Providing a new option for the visually impaired

Long canes are one of the most effective and affordable mobility tools for a person who is blind or visually impaired, but they have limitations. Canes primarily detect hazards on the ground that are within reach; however, hazards above ground level are often missed. Additionally, the range of long cane sweeping can be restricted in busy environments, such as cities, in order avoid hitting nearby pedestrians. Guide dogs are highly effective, but hard to come by and cost-prohibitive for many, as training a guide dog typically costs $45,000-$60,000. A chest-mounted, collision-warning device could provide an option to help people avoid overhanging or moving obstacles that pose challenges to long cane users, Dr. Luo explained.

Alex Bowers, PhD, a clinical researcher and one of the co-authors of the paper, added that the video recording from the study also provides rich data about daily life mobility of people with visual impairments. This can, in turn help researchers better understand the challenges of collision detection in this population.

"Long canes are still very helpful and cost-effective tools that work well in many situations, but we hope a wearable device like this can fill in the gaps that the cane might miss, providing a more affordable, easier to obtain option than a guide dog," Dr. Bowers said. "The insights provided by our data can be valuable for improving mobility aid training."

Next, Dr. Luo and his team seek to leverage ongoing improvements in mobile processing power and cameras to make the device smaller and more cosmetically appealing. With additional funding, the team hopes that such a device could be submitted to the U.S. Food and Drug Administration for approval so that it could be commercially available for people with low vision.

"Dr. Luo and his team are making great contributions to supporting and ensuring travel independence in our low-vision community," said Joan W. Miller, MD, Chief of Ophthalmology at Mass Eye and Ear, Massachusetts General Hospital, and Brigham and Women's Hospital, and Chair of Ophthalmology and David Glendenning Cogan Professor of Ophthalmology at Harvard Medical School.

New European Union regulations on batteries could offer a huge boost to the global decarbonisation mission - but only if it leverages its political and economic weight to ensure a fairer global marketplace.

According to a team of scientists and researchers writing in Science, the new regulations, due to come into force from January 2022, have the potential to unify policy on approaches such as recycling, use of recycled raw materials, and creating a circular economy.

Contributing to the study were experts at Newcastle University, the University of Birmingham, Circular Energy Storage Research and Consulting, University of California, Davis and the National Institute of Clean and Low Carbon Energy (NICE) America Research.

The European Union is a significant market for Electric Vehicles globally, and the effects of its regulation will be felt by battery supply chains in many other countries, including the United Kingdom, even though it has left the European Union.

Although these rules are both necessary and welcome, whilst well-intentioned, the researchers argue, their effects are hard to predict and could result in a competitive disadvantage for European companies. This is because the EU must operate in the global marketplace where there is an imbalance between new and mature markets and uncertainty caused by the rapid rate of growth and innovation in the lithium-ion battery (LIB) market.

China, for example, has a well-developed LIB market, with relatively strict regulations around recycling and decarbonising the supply chain. In the US, in contrast, although electrification of transport has been declared a priority, legislation to promote a circular economy in the sector is lagging behind both China and the EU.

Dr Oliver Heidrich, of Newcastle University, led the study. He says: "Balancing the challenges of climate change, sustainability and competitiveness is a difficult task. Formal assessments along the supply and value chain from raw material extraction, achieving carbon reductions targets to final disposal are needed to ensure social, environmental and economic aspects are addressed successfully".

Companies that are able to comply with more stringent regulations have a big competitive advantage in these markets. This is particularly true in China where there are well-established, tougher domestic requirements. Companies in markets where there is ready access to both virgin and recycled materials - such as China and South Korea - are also likely to have an advantage over EU companies, where supply chains are less well-developed and may still rely on imported materials.

The US shares the EU's situation with a less developed supply chain, however battery makers will retain a higher degree of freedom to operate which can be crucial for innovation in both battery technology and electric mobility.

"While it is critical to ensure a high degree of sustainability in the battery supply chain we must not forget that the end game is a decarbonised and less polluting transportation sector," says Hans Eric Melin, of Circular Energy Storage Research and Consulting. "By raising the bar to a higher level than for almost any other product there is a significant risk that the European battery industry, which is well behind global leaders, will struggle to keep up with the required pace. This could limit automotive makers' ability to produce electric vehicles at the scale required by 2030 and might also cause distortion of innovation and a slow down of investments."

Global standards, argue the researchers, are the only way to make this essential supply chain both predictable and powerful. The new, advanced standards set out by the EU, together with its significant share of the EV market, could give it leverage to lead the way in setting such standards.

"The EU Battery Regulation has admirable intentions, but unintended consequences could be felt by manufacturers, recyclers and other actors across the world. Whilst difficult to achieve, and politically challenging, a co-ordinated, global approach would ensure a more rapid and effective transition to electric transport," says Dr Gavin Harper, of the University of Birmingham

The European market can provide significant leverage to set standards across the globe in order to stimulate innovation in the areas of cascaded use and recycling and serve as a steppingstone to more formal global standards. Policies and legislations that address environmental or social issues are very much needed and do need to consider the unintended consequences as much as the in-tended consequences

Newly-hatched pterosaurs may have been able to fly but their flying abilities may have been different from adult pterosaurs, according to a new study.

Pterosaurs were a group of flying reptiles that lived during the Triassic, Jurassic and Cretaceous Periods (228 to 66 million years ago). Due to the rarity of fossilised pterosaur eggs and embryos, and difficulties distinguishing between hatchlings and small adults, it has been unclear whether newly-hatched pterosaurs were able to fly.

Researchers from the Universities of Portsmouth and Bristol, along with palaeontologist Darren Naish, found that hatchling humerus bones were stronger than those of many adult pterosaurs, indicating that they would have been strong enough for flight.

In the study, published in Scientific Reports, the researchers modelled the flying abilities of hatchlings using previously obtained wing measurements from four established hatchling and embryo fossils from two pterosaur species, Pterodaustro guinazui and Sinopterus dongi. They also compared these wing measurements with those of adults from the same species and compared the strength of the humerus bone, which forms part of the wing, of three hatchlings with those of 22 adult pterosaurs.

Study co-author Dr Mark Witton from the University of Portsmouth said: "Although we've known about pterosaurs for over two centuries, we've only had fossils of their embryos and hatchlings since 2004. We're still trying to understand the early stages of life in these animals. One discussion has centred around whether pterosaurs could fly as hatchlings or, like the vast majority of birds and bats, they had to grow a little before they could take wing.

"We found that these tiny animals - with 25 cm wingspans and bodies that could neatly fit in your hand - were very strong, capable fliers. Their bones were strong enough to sustain flapping and take-off, and their wings were ideally shaped for powered (as opposed to gliding) flight. However, they would not have flown exactly like their parents simply because they were so much smaller: flight capabilities are strongly influenced by size and mass, and so pterosaur hatchlings, being hundreds of times smaller than their parents, were likely slower, more agile fliers than the wide-ranging, but less manoeuvrable adults."

Dr Liz Martin-Silverstone from the University of Bristol’s School of Earth Sciences said: “There have been several debates about whether juvenile pterosaurs could fly, but this is the first time it’s been studied through a more biomechanical point of view. It’s exciting to discover that even though their wings may have been small, they were built in a way that made them strong enough to fly.”

The researchers found that while hatchlings had long, narrow wings suited to long-distance flight, their wings were shorter and broader than those of adult pterosaurs, with a larger wing area relative to hatchling mass and body size. These wing dimensions may have made hatchlings less efficient than adult pterosaurs at long-distance travel, but may have resulted in them being more agile fliers, enabling them to suddenly change direction and speed.

The authors speculate that the agile flying style of hatchling pterosaurs may have enabled them to rapidly escape predators and made them better suited to chasing nimbler prey and flying amongst dense vegetation than adult pterosaurs.

Dr Witton said: "That gives us a lot to think about with regard to flying reptile ecology. How independent were the hatchlings from their parents? Did flight style influence habitat choices, and did these change as pterosaurs grew? There's still a lot to learn about the life histories of these animals, but we're confident that, whatever they were doing as they grew up, they were capable of flying from the moment they hatched."

A research team led by Wim Annaert (VIB-KU Leuven) uncovered the early assembly of gamma-secretase, a protein complex linked to numerous cellular processes including the development of Alzheimer's disease. In a first step, two dimeric subcomplexes are formed, which independently exit the ER and only afterwards assemble into a four-subunit complex. This 'buckle up' mechanism is thought to prevent premature assembly and activity. The new insights are very relevant, as gamma-secretase is an important potential therapeutic target for Alzheimer's and other conditions.

An enzyme complex involved in plaque production

Gamma-secretase is best known as the enzyme that cleaves the amyloid precursor protein, generating a small peptide called amyloid beta, the main constituent of the plaques found in the brains of people affected by Alzheimer's disease. Ever since the discovery of its implication in disease, gamma-secretase has been studied and tested as a potential therapeutic target, but its role in the body is much broader than producing amyloid.

We now know that gamma-secretase is a complex made up of four components, two of which have multiple homologues, resulting in variety of complexes with distinct subcellular distributions, providing a basis for substrate selectivity. All four gamma-secretase components are transmembrane proteins that are co-translationally inserted into the endoplasmic reticulum (ER). But how these four subunits get assembled in such stable enzyme complexes remained unknown until now.

Dissecting the assembly line

The Annaert lab at the VIB-KU Leuven Center for Brain & Disease Research is specialized in membrane trafficking and has a long track record of studying the gamma-secretase complex. By combining biochemistry and high-resolution imaging, they have now uncovered the early steps of the gamma-secretase assembly process.

"To dissect the assembly steps, we used a method developed by Randy Schekman of UC Berkeley (who won the Noble Prize in Medicine in 2013), and with whom we collaborated on this endeavor. This approach unveiled that in fact dimers of two out of the four subunits are formed in the ER, in this way preventing the premature breakdown of individual subunits," says Wim Annaert. "These dimers only get fully assembled into gamma-secretase complexes shortly thereafter, between ER-exit and their transition to the Golgi complex."

Only fully assembled complexes are transported through the Golgi onto their final destination in different cellular compartments.

Interestingly, the dimer assembly signature remains visible in the high-resolution structure of gamma-secretase, suggesting a 'buckle up model' for dimer assembly: one side of the dimers act as 'buckles', while the other side functions as the belt through interactions keeping the full complex in place.

"This 'buckle up' mechanism could prevent the untimely processing of substrates," says Annaert. "Given the broad range of substrates and pathways controlled by gamma-secretase -from developmental processes to cancer and Alzheimer, the precise tuning of this assembly process allows for further spatiotemporal regulation of gamma-secretase activity."

The insights are extremely relevant, as problems during complex assembly may also have a significant impact on the many physiological and pathological processes regulated by gamma-secretase.

In a new study, published recently in the journal Circulation Research, scientists discover how the production of protective molecules known as specialised pro-resolving mediators (SPM) is altered in patients with COVID-19.

The results suggest that treatments which increase SPM production, such as dexamethasone or SPM based drugs, could play a key role in limiting inflammation in these patients.

Currently there is little understanding around the mechanisms that lead to uncontrolled inflammation in patients with COVID-19.

The study found a link between decreased SPM blood levels and disrupted white blood cell responses in patients with a higher disease burden. The findings also revealed that dexamethasone, the first drug approved for treatment of patients with COVID-19, increased the levels of these protective molecules in these patients. Furthermore, treatment of white blood cells with SPM improved their function and reduced the expression of molecules linked to the spread of inflammation. Understanding these mechanisms will help provide new leads into the development of treatments to limit disease severity in patients with COVID-19.

This study offers a new insight into the disrupted biological processes that contribute to increased disease severity in COVID-19 patients. Results suggest that treatments which increase SPM production, such as dexamethasone or SPM based drugs, could play a key role in limiting inflammation in this patient group.

Jesmond Dalli, Professor in Molecular Pharmacology and Lipid Mediator Unit Director at Queen Mary University of London said: "The observation that dexamethasone increased the production of SPM was a surprising finding. This finding suggests that SPM may serve as biomarkers to determine the efficacy of this drug in limiting inflammation in patients with COVID-19. Another surprising finding was that blood levels of these molecules remained altered several weeks after resolution of clinical symptoms."

"Our results are the first to relate the impact that COVID-19 infections on immune responses and to explore the utility of using SPM to rectify white blood cell behaviour. Given the extensive body of literature demonstrating the protective role of these molecules in limiting inflammation in both viral and bacterial infections these results suggest that SPM and SPM-based therapeutics may be useful in the treatment of infections to limit inflammation without compromising the ability of the immune system to deal with the invading pathogen".

Mauro Perretti (Dean for Research, School of Medicine and Dentistry) said: "This study is a perfect example of a productive partnership between Barts and the London School of Medicine at Queen Mary and Barts NHS Trust, a partnership established in difficult circumstances yet successful thanks to the will and commitment of our scientists and clinicians. The paper presents world class data on how resolution pathways impact on COVID infection, opening opportunities for new therapies and new markers to predict patient outcome".

Alexandria, Va., USA - Jiachen Lin, Harvard School of Dental Medicine, Boston, Mass., USA., presented the poster "Burden of Oral Diseases in Emerging Countries: A Prediction Model" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021.

The goal of this study was to investigate the burden of oral diseases and predict trends by 2025 in the U.S. and emerging countries. Global Burden of Disease data from 1990-2017 was used to analyze the prevalence and disability-adjusted life years of oral diseases across the U.S., Brazil, Russia, India, China, Mexico, Indonesia, Nigeria and Turkey by gender and age groups (

In the prediction model, females and older adults had a higher burden of oral diseases. Notably, Nigeria was expected to continue with the lowest estimated oral diseases burden compared to the other countries. Although the U.S. had a relatively lower oral diseases burden than emerging countries, forecasts suggest a large increase of disability-adjusted life years attributed to oral diseases across all age groups.

These results provide insightful information for policymakers to identify effective oral health strategies and allocation of resources to decrease the burden of oral diseases among populations with purported higher and increasing burden of oral diseases in the next five years.

View this poster presentation in the IADR General Session Virtual Experience Platform.

View a PDF of this press release.

International Association for Dental Research

The International Association for Dental Research (IADR) is a nonprofit organization with over 10,000 individual members worldwide, with a mission to drive dental, oral and craniofacial research for health and well-being worldwide. To learn more, visit http://www.iadr.org.

Since early 2019, researchers have been recording and analysing marsquakes as part of the InSight mission. This relies on a seismometer whose data acquisition and control electronics were developed at ETH Zurich. Using this data, the researchers have now measured the red planet's crust, mantle and core - data that will help determine the formation and evolution of Mars and, by extension, the entire solar system.

Mars once completely molten

We know that Earth is made up of shells: a thin crust of light, solid rock surrounds a thick mantle of heavy, viscous rock, which in turn envelopes a core consisting mainly of iron and nickel. Terrestrial planets, including Mars, have been assumed to have a similar structure. "Now seismic data has confirmed that Mars presumably was once completely molten before dividing into the crust, mantle and core we see today, but that these are different from Earth's," says Amir Khan, a scientist at the Institute of Geophysics at ETH Zurich and at the Physics Institute at the University of Zurich. Together with his ETH colleague Simon Stähler, he analysed data from NASA's InSight mission, in which ETH Zurich is participating under the leadership of Professor Domenico Giardini.

No plate tectonics on Mars

The researchers have discovered that the Martian crust under the probe's landing site near the Martian equator is between 15 and 47 kilometres thick. Such a thin crust must contain a relatively high proportion of radioactive elements, which calls into question previous models of the chemical composition of the entire crust.

Beneath the crust comes the mantle with the lithosphere of more solid rock reaching 400-600 kilometres down - twice as deep as on Earth. This could be because there is now only one continental plate on Mars, in contrast to Earth with its seven large mobile plates. "The thick lithosphere fits well with the model of Mars as a 'one-plate planet'," Khan concludes.

The measurements also show that the Martian mantle is mineralogically similar to Earth's upper mantle. "In that sense, the Martian mantle is a simpler version of Earth's mantle." But the seismology also reveals differences in chemical composition. The Martian mantle, for example, contains more iron than Earth's. However, theories as to the complexity of the layering of the Martian mantle also depend on the size of the underlying core - and here, too, the researchers have come to new conclusions.

The core is liquid and larger than expected

The Martian core has a radius of about 1,840 kilometres, making it a good 200 kilometres larger than had been assumed 15 years ago, when the InSight mission was planned. The researchers were now able to recalculate the size of the core using seismic waves. "Having determined the radius of the core, we can now calculate its density," Stähler says.

"If the core radius is large, the density of the core must be relatively low," he explains: "That means the core must contain a large proportion of lighter elements in addition to iron and nickel." These include sulphur, oxygen, carbon and hydrogen, and make up an unexpectedly large proportion. The researchers conclude that the composition of the entire planet is not yet fully understood. Nonetheless, the current investigations confirm that the core is liquid - as suspected - even if Mars no longer has a magnetic field.

Reaching the goal with different waveforms

The researchers obtained the new results by analysing various seismic waves generated by marsquakes. "We could already see different waves in the InSight data, so we knew how far away from the lander these quake epicentres were on Mars," Giardini says. To be able to say something about a planet's inner structure calls for quake waves that are reflected at or below the surface or at the core. Now, for the first time, researchers have succeeded in observing and analysing such waves on Mars.

"The InSight mission was a unique opportunity to capture this data," Giardini says. The data stream will end in a year when the lander's solar cells are no longer able to produce enough power. "But we're far from finished analysing all the data - Mars still presents us with many mysteries, most notably whether it formed at the same time and from the same material as our Earth." It is especially important to understand how the internal dynamics of Mars led it to lose its active magnetic field and all surface water. "This will give us an idea of whether and how these processes might be occurring on our planet," Giardini explains. "That's our reason why we are on Mars, to study its anatomy."

Astronomers using two of the world's most powerful radio telescopes have made a detailed and sensitive survey of a large segment of our home galaxy -- the Milky Way -- detecting previously unseen tracers of massive star formation, a process that dominates galactic ecosystems. The scientists combined the capabilities of the National Science Foundation's Karl G. Jansky Very Large Array (VLA) and the 100-meter Effelsberg Telescope in Germany to produce high-quality data that will serve researchers for years to come.

Stars with more than about ten times the mass of our Sun are important components of the Galaxy and strongly affect their surroundings. However, understanding how these massive stars are formed has proved challenging for astronomers. In recent years, this problem has been tackled by studying the Milky Way at a variety of wavelengths, including radio and infrared. This new survey, called GLOSTAR (Global view of the Star formation in the Milky Way), was designed to take advantage of the vastly improved capabilities that an upgrade project completed in 2012 gave the VLA to produce previously unobtainable data.

GLOSTAR has excited astronomers with new data on the birth and death processes of massive stars, as well on the tenuous material between the stars. The GLOSTAR team of researchers has published a series of papers in the journal Astronomy & Astrophysics reporting initial results of their work, including detailed studies of several individual objects. Observations continue and more results will be published later.

The survey detected telltale tracers of the early stages of massive star formation, including compact regions of hydrogen gas ionized by the powerful radiation from young stars, and radio emission from methanol (wood alcohol) molecules that can pinpoint the location of very young stars still deeply shrouded by the clouds of gas and dust in which they are forming.

The survey also found many new remnants of supernova explosions -- the dramatic deaths of massive stars. Previous studies had found fewer than a third of the expected number of supernova remnants in the Milky Way. In the region it studied, GLOSTAR more than doubled the number found using the VLA data alone, with more expected to appear in the Effelsberg data.

"This is an important step to solve this longstanding mystery of the missing supernova remnants," said Rohit Dokara, a Ph.D student at the Max Planck Institute for Radioastronomy (MPIfR) and lead author on a paper about the remnants.

The GLOSTAR team combined data from the VLA and the Effelsberg telescope to obtain a complete view of the region they studied. The multi-antenna VLA -- an interferometer -- combines the signals from widely-separated antennas to make images with very high resolution that show small details. However, such a system often cannot also detect large-scale structures. The 100-meter-diameter Effelsberg telescope provided the data on structures larger than those the VLA could detect, making the image complete.

"This clearly demonstrates that the Effelberg telescope is still very crucial, even after 50 years of operation," said Andreas Brunthaler of MPIfR, project leader and first author of the survey's overview paper.

Visible light is strongly absorbed by dust, which radio waves can readily penetrate. Radio telescopes are essential to revealing the dust-shrouded regions in which young stars form.

The results from GLOSTAR, combined with other radio and infrared surveys, "offers astronomers a nearly complete census of massive star-forming clusters at various stages of formation, and this will have lasting value for future studies," said team member William Cotton, of the National Radio Astronomy Observatory (NRAO), who is an expert in combining interferometer and single-telescope data.

"GLOSTAR is the first map of the Galactic Plane at radio wavelengths that detects many of the important star formation tracers at high spatial resolution. The detection of atomic and molecular spectral lines is critical to determine the location of star formation and to better understand the structure of the Galaxy," said Dana Falser, also of NRAO.

The initiator of GLOSTAR, the MPIfR's Karl Menten, added, "It's great to see the beautiful science resulting from two of our favorite radio telescopes joining forces."

Around 470 million years ago, plants began to conquer the terrestrial surfaces. The first examples had a small axis terminated by a structure capable of forming spores, almost like current mosses. The appearance of plant organs mediated the explosive radiation of land plants, which shaped the surface of our planet and allowed the establishment of terrestrial animal life.

However, evolving such a diversity of organs, such as roots, leaves, or immobile gametes, requires coordinated genetic changes: rise of new genes, repurpose of genetic material, and development of new regulatory programs. In a study published in Nature Plants, a consortium between Europe - including the team led by GREEN-IT member and then IGC, now ITQB NOVA PI at the Plant Reproduction and Evolution Laboratory Jörg Becker - the United States and Singapore introduced an atlas that compiles gene expression data from ten different species of land plants - the largest collection to date. Focusing on the detailed analysis of the collected data, the team looked to identify novel and missing components involved in the formation of sex organs and cells. "Comparing data from such different species allowed us to distinguish genes that are important for the reproduction of all land plants from those that only matter for flowering plants", explains Jörg.

The comparative analysis of the atlases revealed that a large portion of the gene expression remained unchanged throughout evolution, when looking at equivalent organs from different species. The data also showed that the establishment of organs relies heavily on the repurpose of existing genetic material. "We saw that many groups of genes appeared long before the corresponding organ, and this tells us that they emerged through the repurpose of genetic material that already existed", explains the researcher.

The team also looked for patterns in the development of female and male gametes. "We were interested in comparing the first land plants, which have swimming sperm and need water for their reproduction, with plants with non-swimming sperm, which is inside the pollen grain and does not depend on water for its mobility", says Jörg. The team found that in contrast with female gametes, male gametes presented a high number and conservation of genes, indicating that male reproduction appears to be more specialized than female. Among them, proteins that regulate gene expression - transcription factors - and proteins responsible for transferring phosphate to other proteins - kinases-, potentially important for the making and function of pollen.

This work also allowed the establishment of the EVOREPRO database, a user-friendly online tool that allows the browsing and comparative analysis of the genomic and transcriptomic data derived from samples across thirteen members of the plant kingdom. This database may be a valuable resource for further studies and validation of key genes involved in organogenesis and land plants reproduction.

Plants are our greatest source of food and materials and the comprehension of their function is essential to be able to counteract the current strains that plague this resource and find long term sustainable solutions. "Knowing the genes important for the development and function of a specific organ gives us an indication of which genes to manipulate to elevate its function. We are looking for those that make sperm and egg development more heat resistant, for example, and for ways to overcome the fertilization barriers between different plant species to obtain superior quality hybrids," concludes Jörg.

A new study increases knowledge of the genetics behind aortic aneurysm, a disease that can spark life-threatening events like aortic dissections and ruptures.

University of Michigan Health-led researchers compared blood samples from more than 1,300 people who had a thoracic aortic aneurysm with more than 18,000 control samples, in partnership with U-M's Cardiovascular Health Improvement Project and its Michigan Genomics Initiative.

"After examining nearly the entire human genome for genetic changes that increase risk of aneurysm, we discovered a new change in the genetic code of a transcription factor, which means it controls many other genes," explained co-corresponding author Cristen Willer, Ph.D., a professor of cardiovascular medicine, internal medicine, human genetics and computational medicine and bioinformatics at University of Michigan Health.

Then, Willer's team collaborated with Minerva Garcia-Barrio, Ph.D., an assistant professor of internal medicine, to examine the role this gene played in smooth muscle cells, a component of aorta.

"We examined this gene in human cells and discovered that the transcription factor we identified is a key factor that gives instructions to cells about when to die and replenish," said co-lead author Tanmoy Roychowdhury, Ph.D., a research fellow in the Division of Cardiovascular Medicine.

The authors say future research might investigate whether slowing down this apoptosis, or cellular death, in aortic aneurysm could reduce the risk of a person experiencing an aortic dissection or rupture in the future.

Scientists at Cambridge and Leeds have successfully reversed age-related memory loss in mice and say their discovery could lead to the development of treatments to prevent memory loss in people as they age.

In a study published today in Molecular Psychiatry, the team show that changes in the extracellular matrix of the brain - 'scaffolding' around nerve cells - lead to loss of memory with ageing, but that it is possible to reverse these using genetic treatments.

Recent evidence has emerged of the role of perineuronal nets (PNNs) in neuroplasticity - the ability of the brain to learn and adapt - and to make memories. PNNs are cartilage-like structures that mostly surround inhibitory neurons in the brain. Their main function is to control the level of plasticity in the brain. They appear at around five years old in humans, and turn off the period of enhanced plasticity during which the connections in the brain are optimised. Then, plasticity is partially turned off, making the brain more efficient but less plastic.

PNNs contain compounds known as chondroitin sulphates. Some of these, such as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulphate, promote neuroplasticity. As we age, the balance of these compounds changes, and as levels of chondroitin 6-sulphate decrease, so our ability to learn and form new memories changes, leading to age-related memory decline.

Researchers at the University of Cambridge and University of Leeds investigated whether manipulating the chondroitin sulphate composition of the PNNs might restore neuroplasticity and alleviate age-related memory deficits.

To do this, the team looked at 20-month old mice - considered very old - and using a suite of tests showed that the mice exhibited deficits in their memory compared to six-month old mice.

For example, one test involved seeing whether mice recognised an object. The mouse was placed at the start of a Y-shaped maze and left to explore two identical objects at the end of the two arms. After a short while, the mouse was once again placed in the maze, but this time one arm contained a new object, while the other contained a copy of the repeated object. The researchers measured the amount of the time the mouse spent exploring each object to see whether it had remembered the object from the previous task. The older mice were much less likely to remember the object.

The team treated the ageing mice using a 'viral vector', a virus capable of reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs and found that this completely restored memory in the older mice, to a level similar to that seen in the younger mice.

Dr Jessica Kwok from the School of Biomedical Sciences at the University of Leeds said: "We saw remarkable results when we treated the ageing mice with this treatment. The memory and ability to learn were restored to levels they would not have seen since they were much younger."

To explore the role of chondroitin 6-sulphate in memory loss, the researchers bred mice that had been genetically-manipulated such that they were only able to produce low levels of the compound to mimic the changes of ageing. Even at 11 weeks, these mice showed signs of premature memory loss. However, increasing levels of chondroitin 6-sulphate using the viral vector restored their memory and plasticity to levels similar to healthy mice.

Professor James Fawcett from the John van Geest Centre for Brain Repair at the University of Cambridge said: "What is exciting about this is that although our study was only in mice, the same mechanism should operate in humans - the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age."

The team have already identified a potential drug, licensed for human use, that can be taken by mouth and inhibits the formation of PNNs. When this compound is given to mice and rats it can restore memory in ageing and also improves recovery in spinal cord injury. The researchers are investigating whether it might help alleviate memory loss in animal models of Alzheimer's disease.

The approach taken by Professor Fawcett's team - using viral vectors to deliver the treatment - is increasingly being used to treat human neurological conditions. A second team at the Centre recently published research showing their use for repairing damage caused by glaucoma and dementia.

Over the last few decades, neurodegenerative diseases became one of the top 10 global causes of death. Researchers worldwide are making a strong effort to understand neurodegenerative diseases pathogenesis, which is essential to develop efficient treatments against these incurable diseases. However, our knowledge about the basic molecular mechanisms underlying the pathogenesis of neurodegenerative diseases is still lacking. A team of researchers found out the implication of lysosomes in the spread of Parkinson's disease.

The accumulation of misfolded protein aggregates in affected brain regions is a common hallmark shared by several neurodegenerative diseases (NDs). Mounting evidence in cellular and in animal models highlights the capability of different misfolded proteins to be transmitted and to induce the aggregation of their endogenous counterparts, this process is called "seeding". In Parkinson's disease, the second most common ND, misfolded α-synuclein (α-syn) proteins accumulate in fibrillar aggregates within neurons. Those accumulations are named Lewy bodies.

α-syn fibrils spreads through TNTs inside lysosomes

In 2016, a team of researchers from the Institut Pasteur (Paris) and the French National Centre for Scientific Research (in French: CNRS, Centre national de la recherche scientifique) demonstrated that α- syn fibrils spread from donor to acceptor cells through tunneling nanotubes (TNTs). They also found out that these fibrils are transferred through TNTs inside lysosomes. "TNTs are actin-based membrane channels allowing the transfer of several cellular components including organelles between distant cells. Lysosomes are organelles normally deputed to the degradation and recycling of toxic/damaged cell material" describes Chiara Zurzolo, head of the Membrane Traffic and Pathogenesis Unit at the Institut Pasteur.

α-syn fibrils can modify lysosome shape and permeability to allow seeding and diffusion

Following this original discovery, researchers, now shed some light on how lysosomes participate in the spreading of α-syn aggregates through TNTs. "By using super-resolution and electron microscopy, we found that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. We demonstrated for the first time that α-syn fibrils induce the peripheral redistribution of the lysosomes thus increasing the efficiency of α-syn fibrils' transfer to neighbouring cells," continues Chiara Zurzolo. They also showed that α-syn fibrils can permeabilize the lysosomal membrane, impairing the degradative function of lysosomes and allowing the seeding of soluble α-syn, which occurs mainly in those lysosomes. Thus, by impairing lysosomal function α-syn fibrils block their own degradation in lysosomes, that instead become a hub for the propagation of the pathology.

BY IMPAIRING LYSOSOMAL FUNCTION Α-SYN FIBRILS BLOCK THEIR OWN DEGRADATION IN LYSOSOMES, THAT INSTEAD BECOME A HUB FOR THE PROPAGATION OF THE PATHOLOGY

This discovery contributes to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology. This information can be exploited to establish novel therapies to target these incurable diseases.

Replication of SARS-CoV-2, the virus responsible for COVID-19, depends on a series of interactions between viral proteins and different cellular partners such as nucleic acids (DNA or RNA). Characterizing these interactions is crucial to elucidate the process of viral replication and identify new drugs for treating COVID-19.

An interdisciplinary consortium of scientists from the Institut Pasteur, the Ecole Polytechnique, the Institut Curie, Inserm, the CNRS and the universities of Paris, Paris-Saclay, Bordeaux and Toulouse have demonstrated a specific interaction between a domain of a SARS-CoV-2 protein (Nsp3) and unusual DNA or RNA structures known as G-quadruplexes or G4s. "Using a broad range of experimental approaches, we characterized this interaction and revealed that this Nsp3 protein domain has a clear G4 propensity. We also showed that G4 ligands [chemical compounds that bind with G4s] prevent this interaction," explains Marc Lavigne, a scientist in the Department of Virology at the Institut Pasteur and coordinator of the G4-Covid19 project. These results were recently published in Nucleic Acids Research.

Potential therapeutic application patented

Alongside this study, some G4 ligands were developed by the co-authors* of the article. In a cellular system reproducing SARS-CoV-2 infection, the Institut Pasteur (Marc Lavigne, Hélène Munier-Lehmann, Jeanne Chiavarelli and Björn Meyer) demonstrated that these ligands, which prevent interaction between the SARS-CoV-2 protein and the G4 structure, exhibit antiviral activity.

These results pave the way for the use of G4-binding molecules as potent antiviral compounds (European patent 20 306 606.3 and Institut Pasteur DI 2020-59) and confirm the choice to target host-virus interactions in antiviral strategies.

The project received financial support from the Institut Pasteur (via the exceptional COVID-19 program, funded in part by donations), the French National Research Agency (ANR-Flash-Covid) and own funding from the various laboratories involved. It also involved the participation of several of the Institut Pasteur's technological platforms (PF-BMI, PF-3PR and PF-CCB).

When Alexander Flemming discovered a mould on a culture plate overgrown with bacteria in 1928, he did not expect to find one of the most widely used active substances: penicillin. Accidental discoveries and the identification of active ingredients from traditional remedies, such as the morphine of the opium poppy, have shaped the discovery of new medicines for a long time.

Modern drug discovery - from chance to system

Meanwhile, major developments in chemistry and molecular biology have been made that enable a systematic and targeted search for potential active substances in modern drug discovery. First, advances in the field of organic and especially combinatorial chemistry made it possible to produce huge substance libraries and test them for their pharmacological effect in high-throughput tests. Following technological advances like the sequencing of the human genome and the development of new methods in molecular biology enabled the identification of disease-related cellular processes and their molecular key players. This paved the way towards modern drug discovery, where large libraries of molecules are screened in a high-throughput manner for their influence on relevant target molecules, mostly proteins. Identified substances, so-called hits, are optimized in their chemical structure to lead structures that are already effective in small doses and are well absorbed and distributed in the body.

No effect without side effects

This target-based drug development is very successful in identifying new drug candidates that prevent the target proteins from functioning or interacting with other proteins. However, potential drug candidates are rarely specific and very often also act on related proteins that have a similar function or structure. "It is not uncommon that an initially promising drug candidate unexpectedly shows serious side effects in a later phase of its longstanding development, thus limiting or even preventing its clinical use," says Slava Ziegler.

In search of unknown bioactivities

In order to track down possible side effects during drug development, potential drug candidates are screened in assays for their effect on known protein classes, biological processes and certain cellular properties. However, these tests can only reflect the expected bioactivity since the number of known target molecules in the cell is limited. So-called profiling approaches now offer the possibility of detecting a wider spectrum of activity. These unbiased tests investigate the influence on hundreds of cellular or genetic parameters recorded in a substance's profile that is compared with profiles of reference substances with known effects.

When drug profiles match

In their latest study, the group of Herbert Waldmann and Slava Ziegler combined two of these profiling approaches to identify bioactive substances from a library of about 15000 natural product-inspired molecules and compared them with the profiles of known, active compounds. Applying the Cell Painting Assay, where functional areas of the cell are stained and then microscopically examined for changes, a large cluster of substances with similar profiles was identified. However, it was not possible to predict the mode of action of the cluster since the associated reference compounds had various activities or target molecules. With a subsequent search using proteome profiling, in which the quantities and thus the regulation of thousands of proteins was examined, the researchers were able to narrow down the cluster to a common activity - the modulation of cholesterol homeostasis - an unexpected biological activity for the most reference substances in the cluster.

Two birds with one stone: identifying new bioactivities and side effects

But how can substances with very different target molecules trigger the same effect? The researchers revealed that most of the compounds in the cluster accumulate in the lysosome, an organelle where cholesterol is stored temporarily for its further function in the cell. The lysosome has a lower pH value than the rest of the cell, and this is crucial for the functioning of the lysosomal digestive enzymes that process foreign and the cell's own biomolecules. In the lysosome, the substances from the cluster described increase the pH value and thus disrupt the function of this organelle and, in particular, the cholesterol balance of the cell. The fact that the compounds accumulate in the lysosome is not due to a specific target molecule in the lysosome but to their chemical and physical properties, which they have obtained through their structural optimization for improved solubility.

"Interestingly, disturbed cholesterol balance has already been linked to some drugs on the market, such as antipsychotics" notes Tabea Schneidewind, first author of the study. " With the combination of the two search strategies, we can kill two birds with one stone: unveil unknown side effects and identify new active substances and modes of action" says Slava Ziegler.

Targeting cholesterol homeostasis could possibly also disturb SARS-CoV-2 infections

Influencing cholesterol homeostasis seems to be a common feature of many compounds and should be taken into account when evaluating side effects of active substances. However, the observed activity is not per se undesired. Currently, drugs and compounds with known modes of action are being intensively studied for inhibition of SARS-CoV-2 infection of host cells, and many compounds of our cluster have been identified to suppress this process. Interestingly, membrane cholesterol and thus proper cholesterol homeostasis are crucial for Sars-CoV-2 infection as shown in several studies. Our data most likely explain the reason for the activity of these compounds against the virus: they alter cholesterol biosynthesis and localization in cells, which impairs Corona-Virus infection", says Slava Ziegler.