Culture

Scientists have produced a tomato enriched in the Parkinson's disease drug L-DOPA in what could become a new, affordable source of one of the world's essential medicines.

The development of the genetically modified (GM) tomato has implications for developing nations where access to pharmaceutical drugs is restricted.

This novel use of tomato plants as a natural source of L-DOPA also offers benefits for people who suffer adverse effects - including nausea and behavioral complications - of chemically synthesised L-DOPA .

Tomato - was chosen as a widely cultivated crop that can be used for scaled up production and potentially offering a standardised and controlled natural source of L-DOPA .

The John Innes Centre led team modified the tomato fruit by introducing a gene responsible for the synthesis of L-DOPA in beetroot where it functions in the production of the pigments betalains.

L-DOPA is produced from tyrosine, an amino acid found in many foods. The research team inserted a gene encoding a tyrosinase, an enzyme that uses tyrosine to build molecules such as L-DOPA . This elevated the level of L-DOPA specifically in the fruit part of the plant and led to higher yields than those associated with L-DOPA production in the whole plant.

The levels achieved in the tomato fruit - 150mg of L-DOPA per kg of tomatoes - were comparable those observed in other L-DOPA accumulating plants - without some of the known drawbacks that have hampered plant metabolic production of the drug previously.

The aim now is to create a production pipeline where L-DOPA is extracted from the tomatoes and purified into the pharmaceutical product.

Professor Cathie Martin (FRS), corresponding author of the study explains: "The idea is that you can grow tomatoes with relatively little infrastructure. As GMOs (genetically modified organisms) you could grow them in screen houses, controlled environments with very narrow meshes, so you would not have pollen escape through insects.

"Then you could scale up at relatively low cost. A local industry could prepare L-DOPA from tomatoes because it's soluble and you can do extractions. Then you could make a purified product relatively low tech which could be dispensed locally."

Parkinson's disease is a growing problem in developing countries where many people cannot afford the daily $2 price of synthetic L-DOPA .

L-DOPA is an amino acid precursor of the neuro-chemical dopamine and is used to compensate for the depleted supply of dopamine in Parkinson's disease patients.

Also known as Levodopa, L-DOPA has been the gold standard therapy for Parkinson's disease since its establishment as a drug in 1967. It is one of the essential medicines declared by the World Health Organisation (WHO) and its market value is in the hundreds of billions of dollars.

The most common form of the drug is produced by chemical synthesis, but natural sources are also available. Only a few plants have been reported to contain measurable quantities of the molecule, mainly in seeds.

The most studied is the velvet bean, Mucuna pruriens, which contains up to 10% L-DOPA in its seeds. But this is problematic because the plant is covered in urticating hairs that contain mucunian that can cause irritation and allergic reactions in field workers who harvest the crop. The beans themselves cause elevated levels of tryptamines that can cause hallucinations in Parkinsons disease patients.

"We have demonstrated that the use of the tyrosinase-expressing tomatoes as a source of L-DOPA is possible. It's a further demonstration of tomato as a strong option for synthetic biology. Additionally, there were surprising beneficial effects including improvement in shelf-life and raised levels of amino-acids that we can investigate," says first author Dr Dario Breitel.

Bacteria is all around us--not just in bathrooms or kitchen counters, but also inside our bodies, including in tumors, where microbiota often flourish. These "small ecologies" can hold the key to cancer drug therapies and learning more about them can help development new life-saving treatments.

What happens when different strains of bacteria are present in the same system? Do they co-exist? Do the strongest survive? In a microbial game of rock-paper-scissors, researchers at the University of California San Diego's BioCircuits Institute uncovered a surprising answer. Their findings, titled "Survival of the weakest in non-transitive asymmetric interactions among strains of E. coli," appeared in a recent edition of Nature Communications.

The research team consisted of Professor of Bioengineering and Molecular Biology Jeff Hasty; Michael Liao and Arianna Miano, both bioengineering graduate students; and Chloe Nguyen, a bioengineering undergraduate. They engineered three strains of E. coli (Escherichia coli) so that each strain produced a toxin that could kill one other strain, just like a game of rock-paper-scissors.

When asked how the experiment came about, Hasty commented, "In synthetic biology, complex gene circuits are typically characterized in bacteria that are growing in well-mixed liquid cultures. However, many applications involve cells that are restricted to grow on a surface. We wanted to understand the behavior of small engineered ecologies when the interacting species are growing in an environment that is closer to how bacteria are likely to colonize the human body."

The researchers mixed the three populations together and let them grow on a dish for several weeks. When they checked back they noticed that, across multiple experiments, the same population would take over the entire surface--and it wasn't the strongest (the strain with the most potent toxin). Curious about the possible reasons for this outcome, they devised an experiment to unveil the hidden dynamics at play.

There were two hypotheses: either the medium population (called "the enemy of the strongest" as the strain that the strongest would attack) would win or the weakest population would win. Their experiment showed that, surprisingly, the second hypothesis was true: the weakest population consistently took over the plate.

Going back to the rock-paper-scissor analogy, if we assume the "rock" strain of E.coli has the strongest toxin, it will quickly kill the "scissor" strain. Since the scissor strain was the only one able to kill the "paper" strain, the paper strain now has no enemies. It's free to eat away at the rock strain slowly over a period of time, while the rock strain is unable to defend itself.

To make sense of the mechanism behind this phenomenon, the researchers also developed a mathematical model that could simulate fights between the three populations by starting from a wide variety of patterns and densities. The model was able to show how the bacteria behaved in multiple scenarios with common spatial patterns such as stripes, isolated clusters and concentric circles. Only when the strains were initially distributed in the pattern of concentric rings with the strongest in the middle, was it possible for the strongest strain to take over the plate.

It is estimated microbes outnumber human cells 10 to 1 in the human body and several diseases have been attributed to imbalances within various microbiomes. Imbalances within the gut microbiome have been linked to several metabolic and inflammatory disorders, cancer and even depression. The ability to engineer balanced ecosystems that can coexist for long periods of time may enable exciting new possibilities for synthetic biologists and new healthcare treatments. The research that Hasty's group is conducting may help lay the foundation to one day engineer healthy synthetic microbiomes that can be used to deliver active compounds to treat various metabolic disorders or diseases and tumors.

Vice Chancellor for Research Sandra Brown said, "Bringing together molecular biology and bionengineering has allowed discovery with the potential to improve the health of people around the world.  This is a discovery that may never have occurred if they weren't working collaboratively. This is another testament to the power of UC San Diego's multidisciplinary research."

Researchers have discovered a new superhighway network to travel through the Solar System much faster than was previously possible. Such routes can drive comets and asteroids near Jupiter to Neptune's distance in under a decade and to 100 astronomical units in less than a century. They could be used to send spacecraft to the far reaches of our planetary system relatively fast, and to monitor and understand near-Earth objects that might collide with our planet.

In their paper, published in the Nov. 25 issue of Science Advances, the researchers observed the dynamical structure of these routes, forming a connected series of arches inside what's known as space manifolds that extend from the asteroid belt to Uranus and beyond. This newly discovered "celestial autobahn" or "celestial highway" acts over several decades, as opposed to the hundreds of thousands or millions of years that usually characterize Solar System dynamics.

The most conspicuous arch structures are linked to Jupiter and the strong gravitational forces it exerts. The population of Jupiter-family comets (comets having orbital periods of 20 years)
as well as small-size solar system bodies known as Centaurs, are controlled by such manifolds on unprecedented time scales. Some of these bodies will end up colliding with Jupiter or being ejected from the Solar System.

The structures were resolved by gathering numerical data about millions of orbits in our Solar System and computing how these orbits fit within already-known space manifolds. The results need to be studied further, both to determine how they could be used by spacecraft, or how such manifolds behave in the vicinity of the Earth, controlling the asteroid and meteorite encounters, as well as the growing population of artificial man-made objects in the Earth-Moon system.

Membrane technology is widely used in various water treatment processes such as water desalination, sewage treatment, and advanced water treatment for producing clean tap water. The membrane filtration technology is a method that can significantly improve water quality and has been suggested as an alternative that can radically prevent larvae in the tap water that has become a widespread issue in Korea recently. However, the current membrane technology suffers from a rapid performance reduction due to the accumulation of bacterial adhesion on the membrane surface and the growth of microbial cells, leading to high maintenance costs.

The Korea Institute of Science and Technology (KIST) reported that the research team led by Dr. Jeehye Byun and Director Seok Won Hong from Water Cycle Research Center developed a membrane material that self-cleans biological contaminants through irradiation of sunlight. According to the team, the newly developed membrane material is expected to significantly reduce the cost of membrane management as the membrane can be reused after just 10 minutes of sunlight irradiation.

Water treatment membranes require periodic cleaning as the contaminants are accumulated on the membrane surface after water filtration. Currently, used membranes require to be cleaned with harsh chemicals for more than six hours at least once a week, which results in fairly high operating cost and damages the membranes due to the chemicals.

As a way to address these issues, the researchers at KIST firmly conjugated a visible-light-responsive photocatalyst to the water treatment membrane surface. This surface-modified photocatalytic membrane can fully decompose contaminants accumulated on the surface when irradiated with visible light, thereby easily cleaning the membrane. In particular, it displayed outstanding performance by removing 99.9% of bacteria, such as Escherichia coli and Staphylococcus aureus, and viruses, such as MS2 bacteriophage, accumulated on the membrane surface in less than an hour of light treatment. According to the team, the developed membrane can treat not only microbial cells but also organic contaminants such as dye solutions and heavy metals. Further, it showed the advantage of maintaining performance even after repeating the tests more than 10 times.

"Our research revealed that the efficiency of the water treatment processes can be improved by conjugating the photocatalytic technology and the water treatment membrane technology," Dr. Jeehye Byun from KIST said. "Based on these research results, we will endeavor to develop next-generation membranes that can lead the water treatment membrane market."

An interim analysis from the Swedish Drug-Elution Trial in Peripheral Arterial Disease (SWEDEPAD) has now been presented. It shows that, for patients with lower limb occlusive arterial disease, paclitaxel-coated balloons and stents do not bring about the rise in mortality previously reported. The study, led by the University of Gothenburg and published in The New England Journal of Medicine (NEJM), is expected to resonate internationally.

Peripheral arterial disease (PAD) is common, especially in older people, and causes poor blood circulation. The condition entails stenoses or occlusions of the arteries in the leg. This often causes severe pain, ulcers, and a high risk for lower limb amputation.

The most common treatment is endovascular balloon dilatation, sometimes combined with insertion of stents, small metal-mesh tubes that reinforce the vessel wall and prevent elastic recoil. The procedure, using a catheter inserted into the femoral artery in the groin, is minimally invasive -- that is, performed with the least possible surgical trauma to the body.

What the researchers did, as described in the current report, was to compare patients randomly assigned to undergo either dilation of the blood vessel with conventional devices, without any drug coating, or with the more expensive drug-coated devices, all of them using paclitaxel as coating agent. With data on approximately 2,300 patients included to date, the study is by far the largest of its kind in the world.

The finding, that mortality rates in the two different groups do not differ, is expected to be highly influential. The question of a possible increase in mortality among patients treated with paclitaxel coated balloons and stents has been a subject of lively debate in recent years.

In December 2018, a meta-analysis of all previous randomized studies was published by Dr Katsanos and co-workers. Surprisingly, the article reported increased mortality among patients who had received treatment with paclitaxel-eluting balloons and stents compared to control patients.

The use of these products then declined sharply all over the world and the U.S. Food and Drug Administration (FDA) was among the organizations that urged caution in using them. In the subsequent discussion, the 2018 results were called in question; but until now no randomized study sufficiently large to settle the matter has been carried out.

The first author of the NEJM article, and also chair of the steering group of this study, is Joakim Nordanstig, associate professor of vascular surgery at Sahlgrenska Academy, University of Gothenburg, and senior vascular surgeon at the Sahlgrenska University Hospital.

"We're proud and pleased that we in this way were able to provide a solution to the tricky clinical dilemma that arose when long-term patient safety relating to the treatment with paclitaxel-coated balloons and stents was called into question," Nordanstig says.

"Above all, our results are important for all the patients who are living with PAD and are facing a lower limb arterial procedure. Drug-eluting balloons and stents have been used widely around the world, and currently represent the most promising technique we have for preventing postoperative recurrence of stricture in the dilated artery. That kind of recurrent stricture is by far the most important limitation of invasive interventions in PAD, and it's something that affects a lot of patients," he continues.

"It's also hugely gratifying that Swedish vascular surgery and interventional radiology, working really well together, have truly been able to help solve an international treatment dilemma. Our study is definitely a team effort, and all the vascular surgeons, interventional radiologists and vascular and radiology nurses in Sweden who've taken part can stand a bit taller today."

The corresponding author, and also the principal investigator of SWEDEPAD, Mårten Falkenberg, professor of vascular interventions at Sahlgrenska Academy, adds that the study is funded mainly by the Swedish Research Council. It is carried out within the framework of Swedvasc (Sweden's National Quality Registry for Vascular Surgery), which is administered by the Uppsala Clinical Research Center (UCR) at Uppsala University. UCR is where the study platform was developed and the data processing has taken place. Scientists at UCR have previously conducted several studies of a similar design, and the collaboration between the University of Gothenburg and UCR has been a success factor.

"It's unusual for an interim analysis to be published in the world's top-ranking medical journal. The reason for it is that, in all probability, our finding -- although it's a negative one and thus doesn't demonstrate any differences between the treatment groups -- solves a medical dilemma with major clinical and financial implications world-wide," Falkenberg says.

"With this convincing and reassuring result, we've resumed our study, and a further 1,400 patients are now to be included. When it's all complete, we expect to be able to show whether the new technique, using drug-eluting balloons and stents, improves the outcomes that are most important for patients with peripheral arterial disease; decreased amputation rate and improved quality of life, as this still remains to be proven", Mårten Falkenberg concludes.

The mummified remains of ancient Egyptians hold many secrets, from the condition of the bodies to the artifacts placed within the burial garments. Now a team of researchers has found a way to unwrap those secrets, without unraveling the mummies themselves.

Three years ago, researchers from Northwestern University, in preparation for an exhibit on campus, carefully transported a 1,900-year-old mummy to the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE’s Argonne National Laboratory. There scientists used powerful X-ray beams to peer inside the layers of linen and resin to examine the 2,000-year-old bones and objects buried within.

“Such synergy between high technology and archaeology highlights what is possible when typical research boundaries are crossed.” — Marc Walton, Northwestern University’s Center for Scientific Studies in the Arts and McCormick School of Engineering

The results of this experiment, the first time an intact mummy was examined using X-ray diffraction techniques, were recently published in the Journal of the Royal Society Interface. The examinations confirmed several details about the mummy — the body belonged to a child of about five years old, most likely a girl, and was buried with what appears to be a scarab amulet of calcite, a sacred object meant to spiritually protect the body on its passage to the afterlife.

“We knew there were objects within the mummy, and we wanted to find out which materials were present,” said Stuart Stock, research professor of cell and molecular biology at Northwestern University’s Feinberg School of Medicine and the first author on the paper. “Short of opening the mummy, there’s no way other than X-ray diffraction to identify those materials.”

Ancient Egyptians believed it was important to preserve dead bodies in as lifelike a manner as possible. The extensive process they used is called mummification, and it involved removing all moisture from the body before wrapping the deceased in many layers of linens sealed with resin. Egyptians began mummifying the dead around 2,600 B.C, according to the Smithsonian Institution, and continued for more than 2,000 years.

Experts dated this particular mummy back to the Roman era (beginning in 30 B.C.). It was discovered in Hawara, Egypt and excavated in 1911, eventually making its way to the library of the Garrett-Evangelical Theological Seminary on Northwestern’s Evanston, Illinois campus. In 2018, the mummy became the centerpiece of an exhibition on campus, joining a series of Roman-Egyptian mummy portraits, representations of people embalmed within mummies that were excavated from areas near Hawara.

In preparation for the exhibit, Stock was asked to conduct research on the contents. He began by imaging it with a medical computed tomography (CT) scanner, which provided a roadmap of sorts for his work at the APS. The CT scan, Stock said, showed the team exactly where to aim the powerful X-ray beams generated by the APS, allowing them to complete their X-ray experiments in 24 hours.

“Without the CT scan to refer to, this literally would have taken two weeks,” Stock said.

The Northwestern team had the help of APS physicist and group leader Jonathan Almer of Argonne’s X-ray Science division, a co-author on the paper. Almer leads the scientific team at Beamline 1-ID, which makes use of high-energy X-rays that can penetrate larger samples. Even so, Almer said, this was one of the largest objects measured at the APS — more than three feet long, weighing roughly 50 pounds.

“This proves that we can find a needle in a haystack,” Almer said. “Often our research is looking for micron-level objects in a millimeter-sized sample. This was a scaling-up of work we do every day, and it shows that we can experiment with and see within a wide range of size scales.”

Also important, Almer noted, was that the X-ray beams could peer inside the mummy without damaging it. This non-invasive method, combined with the earlier CT scan, revealed several pieces of information that would not have been possible to determine otherwise.

The young girl’s skeleton, Stock said, is well preserved and shows no signs of trauma, meaning the child likely died of disease. While Stock and his colleagues were not able to conclusively determine the sex of the mummy, he said that evidence points to it being female, which would match the portrait discovered with the mummy. X-rays detected several small pins holding areas of the linen together, and Stock said he was able to determine they were made of modern metals, probably added 20 years ago as part of exhibiting the mummy.

Most surprising, Stock said, was the amulet (called Inclusion F in the paper), which turned out to be made of calcite, a carbonate mineral. While it is not unheard of for these amulets to be made of calcite, he said, it is rare, and knowing the composition will allow scientists to trace it to a time and place of origin.

Marc Walton, co-director of the Center for Scientific Studies in the Arts and research professor of materials science and engineering at Northwestern’s McCormick School of Engineering, worked with colleagues to place the mummy in a social and historical context for the 2018 exhibition, and was the scientist who brought Stock aboard the project. He said this study shows how an archaeological object can inspire new scientific directions.

“Not only does this work provide historians with data on the composition of the mummy, its burial conditions, and, therefore, its biography, but the complexity of the composite object pushed the authors to innovate new methods of synchrotron-based X-ray diffraction,” he said. “Such synergy between high technology and archaeology highlights what is possible when typical research boundaries are crossed.”

Stock said that while this method of examining the interiors of mummies may not be widely used in the future, given the logistical challenges, it may help scientists answer questions that otherwise would remain mysteries.

“It may be the only way to get out important information without disturbing the mummies,” he said.

Researchers from the Laboratory for Atmospheric and Space Physics (LASP) at the University of Colorado Boulder are diving into the dusty environment that surrounds the sun--a search that could help to reveal how planets like Earth come into being.

The pursuit comes by way of NASA's Parker Solar Probe, a pioneering mission that has taken scientists closer to Earth's home star than any spacecraft to date. Over two years, the probe has circled the sun six times, hitting maximum speeds of roughly 290,000 miles per hour.

In the process, the Parker team has learned a lot about the microscopic grains of dust that lie just beyond the sun's atmosphere, said David Malaspina, a space plasma physicist at LASP. In new research, for example, he and his colleagues discovered that the densities of these bits of rock and ice seem to vary wildly over the span of months--not something scientists were expecting.

"Every time we go into a new orbit, and we think we understand what we're seeing around the sun, nature goes and surprises us," said Malaspina, also an assistant professor in the Department of Astrophysical and Planetary Sciences.

He will present the group's results Tuesday, Dec. 8 at the 2020 virtual fall meeting of the American Geophysical Union (AGU).

Malaspina said that dust can give researchers an unexpected, and tiny, window into the processes that formed Earth and its neighboring planets more than 4.5 billion years ago.

"By learning how our star processes dust, we can extrapolate that to other solar systems to learn more about planet formation and how a cloud of dust becomes a solar system," he said.

Solar Dyson

The area just around the sun, a hot and radiation-rich environment, is often dustier than you might imagine, Malaspina said. It contains more grains of dust by volume than most other open expanses of space in the solar system. That's because the star, through gravity and other forces, pulls dust toward it from millions to billions of miles away, a bit like a vacuum cleaner.

But this vacuum cleaner is imperfect. As dust particles get closer to the sun, its radiation pushes on them more and more--some of those grains of dust will begin to blow in the other direction and can even fly out of the solar system entirely. The Wide-Field Imager for Parker Solar Probe (WISPR) instrument suite onboard the spacecraft found the first evidence for the existence of this dust-devoid region, known as the dust-free zone, more than 90 years after it was predicted.

"What you get is this really interesting environment where all of these particles are moving inward, but once they reach the near-sun environment, they can be blown away," Malaspina said.

Since launching in 2018, Parker Solar Probe--built and operated by the Johns Hopkins Applied Physics Laboratory, which also leads the mission for NASA--has flown to within about 11.6 million miles of the Sun's surface.

On each of Parker's orbits around the sun, the spacecraft collided with thousands of grains of dust. Many of these particles vaporize on the spot, creating a small burst of charged particles that the probe can detect using the five antennae that are part of its FIELDS Experiment. LASP plays an important role in this experiment, which is led by the University of California, Berkeley. Think of it like studying insect populations by counting the splatters on your car's windshield.

"You get a small puff of plasma," Malaspina said. "By looking at these spikes, we can understand how many dust impacts we're getting hit by."

New mysteries

Malaspina and his colleagues were originally hoping to use those puffs to pinpoint where exactly the solar system's inward-flying dust becomes outward-flying dust. But they stumbled on something puzzling in the process: The concentrations of dust that the team recorded seemed to vary by as much as 50% between Parker's six orbits around the Sun.

"That's really interesting because the timescale that it takes for dust to move in toward the Sun is thousands to millions of years," Malaspina said. "So how do we get variation in just three or four months?"

This dusty environment, in other words, may be a lot more complicated and fast-shifting than scientists previously thought. Malaspina said that the team will need to wait for Parker to complete more orbits to know exactly what's happening. He's just excited to be part of this once-in-a-lifetime chance to run a finger along the Sun's dusty shelves.

"This is the only in-situ measurement we are going to get for a long time in the inner solar system," Malaspina said. "We're trying to make the best of it and learn as much as we can."

Many proteins are required to maintain the structure, and to preserve the genetic integrity, of DNA. Sliding clamps are proteins that increase the efficiency of DNA replication. Without these proteins, cells would not be able to carry out continuous DNA synthesis, and organisms, from bacteria to humans, would not survive.

Sliding clamps are ring-shaped proteins that encircle DNA and bind to the DNA polymerase, the enzyme that performs the actual DNA replication. They effectively organize and orient the DNA and its ancillary proteins so as to enable replication. Sliding clamps are oligomeric proteins; they are made up of more than one identical copy of individual proteins called monomers.

The bacterial E. coli clamp, called beta, is made up of two identical monomers. Human cells contain clamps called PCNA, which are made up of three identical monomers. Strong intermolecular forces between these identical monomers ensure that the rings are stable in solution and do not fall off the DNA during replication.

The self-assembly of the monomers of sliding clamps into a stable doughnut-shape ring is controlled by ionic and other intermolecular forces. It is known that assembly of these structures can be influenced by the presence of salts, but other forms of molecular control over this self-assembly are not well understood. In an effort to understand the molecular basis for clamp self-assembly, associate Professor Marcia Levitus from School of Molecular Sciences and co-workers have now found that these protein doughnuts assemble in previously-unknown ways when exposed to molecules that bacteria typically use to tolerate high levels of salt in the environment.

Specifically, potassium glutamate (KGlu) and glycine betaine are found to promote self-assembly of beta and PCNA clamps into structures containing many doughnuts stacked face-to-face. These structures resemble tubes of doughnuts, and are only observed in the presence of compounds that cells produce when they need to tolerate high salt concentrations in the growing medium.

Their research, which has just been published in the Biophysical Journal, is a result of a long-standing collaboration with Professor Linda Bloom who works in the department of biochemistry and molecular biology, University of Florida.

"In this study we examine non-Coulombic effects on the self-assembly properties of sliding clamps," explained Levitus. "We determined relative diffusion coefficients of two sliding clamps using fluorescence correlation spectroscopy. Although so far we worked with two sliding clamps, our results suggest that our findings are not specific to these proteins and may be generalizable to a wide range of protein-protein interactions." Levitus is also part of the Biodesign Center for Single Molecule Biophysics.

Cells accumulate glutamate and related molecules under stress, and so formation of high-order protein assemblies under these conditions has important biological implications. Specifically, this would represent a mechanism by which the presence of stressor compounds in the cell could control DNA replication.

During the opening ceremonies of the 2018 Winter Olympics, held in PyeongChang, South Korea, Russian hackers launched a cyberattack that disrupted television and internet systems at the games. The incident was resolved quickly, but because Russia used North Korean IP addresses for the attack, the source of the disruption was unclear in the event's immediate aftermath.

There is a lesson in that attack, and others like it, at a time when hostilities between countries increasingly occur online. In contrast to conventional national security thinking, such skirmishes call for a new strategic outlook, according to a new paper co-authored by an MIT professor.

The core of the matter involves deterrence and retaliation. In conventional warfare, deterrence usually consists of potential retaliatory military strikes against enemies. But in cybersecurity, this is more complicated. If identifying cyberattackers is difficult, then retaliating too quickly or too often, on the basis of limited information such as the location of certain IP addresses, can be counterproductive. Indeed, it can embolden other countries to launch their own attacks, by leading them to think they will not be blamed.

"If one country becomes more aggressive, then the equilibrium response is that all countries are going to end up becoming more aggressive," says Alexander Wolitzky, an MIT economist who specializes in game theory. "If after every cyberattack my first instinct is to retaliate against Russia and China, this gives North Korea and Iran impunity to engage in cyberattacks."

But Wolitzky and his colleagues do think there is a viable new approach, involving a more judicious and well-informed use of selective retaliation.

"Imperfect attribution makes deterrence multilateral," Wolitzky says. "You have to think about everybody's incentives together. Focusing your attention on the most likely culprits could be a big mistake."

The paper, "Deterrence with Imperfect Attribution," appears in the latest issue of the American Political Science Review. In addition to Wolitzky, the authors are Sandeep Baliga, the John L. and Helen Kellogg Professor of Managerial Economics and Decision Sciences at Northwestern University's Kellogg School of Management; and Ethan Bueno de Mesquita, the Sydney Stein Professor and deputy dean of the Harris School of Public Policy at the University of Chicago.

The study is a joint project, in which Baliga added to the research team by contacting Wolitzky, whose own work applies game theory to a wide variety of situations, including war, international affairs, network behavior, labor relations, and even technology adoption.

"In some sense this is a canonical kind of question for game theorists to think about," Wolitzky says, noting that the development of game theory as an intellectual field stems from the study of nuclear deterrence during the Cold War. "We were interested in what's different about cyberdeterrence, in contrast to conventional or nuclear deterrence. And of course there are a lot of differences, but one thing that we settled on pretty early is this attribution problem." In their paper, the authors note that, as former U.S. Deputy Secretary of Defense William Lynn once put it, "Whereas a missile comes with a return address, a computer virus generally does not."

In some cases, countries are not even aware of major cyberattacks against them; Iran only belatedly realized it had been attacked by the Stuxnet worm over a period of years, damaging centrifuges being used in the country's nuclear weapons program.

In the paper, the scholars largely examined scenarios where countries are aware of cyberattacks against them but have imperfect information about the attacks and attackers. After modeling these events extensively, the researchers determined that the multilateral nature of cybersecurity today makes it markedly different than conventional security. There is a much higher chance in multilateral conditions that retaliation can backfire, generating additional attacks from multiple sources.

"You don't necessarily want to commit to be more aggressive after every signal," Wolitzky says.

What does work, however, is simultaneously improving detection of attacks and gathering more information about the identity of the attackers, so that a country can pinpoint the other nations they could meaningfully retaliate against.

But even gathering more information to inform strategic decisions is a tricky process, as the scholars show. Detecting more attacks while being unable to identify the attackers does not clarify specific decisions, for instance. And gathering more information but having "too much certainty in attribution" can lead a country straight back into the problem of lashing out against some states, even as others are continuing to plan and commit attacks.

"The optimal doctrine in this case in some sense will commit you to retaliate more after the clearest signals, the most unambiguous signals," Wolitzky says. "If you blindly commit yourself more to retaliate after every attack, you increase the risk you're going to be retaliating after false alarms."

Wolitzky points out that the paper's model can apply to issues beyond cybersecurity. The problem of stopping pollution can have the same dynamics. If, for instance, numerous firms are polluting a river, singling just one out for punishment can embolden the others to continue.

Still, the authors do hope the paper will generate discussion in the foreign-policy community, with cyberattacks continuing to be a significant source of national security concern.

"People thought the possibility of failing to detect or attribute a cyberattack mattered, but there hadn't [necessarily] been a recognition of the multilateral implications of this," Wolitzky says. "I do think there is interest in thinking about the applications of that."

A mysterious small marine reptile dating from 150 million years ago has been identified as a new species that may have been capable of diving very deeply. The well-preserved specimen was found in a Late Jurassic deep marine deposit along the English Channel coastline in Dorset, England.

The aquatic reptile has been determined to be part of the group known as ichthyosaurs, which were streamlined marine predators from the Late Jurassic period, according to paleontologist Megan L. Jacobs, a Baylor University doctoral candidate in geosciences and co-author of a study published in the journal PLOS ONE.

"This ichthyosaur has several differences that makes it unique enough to be its own genus and species," Jacobs said. "New Late Jurassic ichthyosaurs in the United Kingdom are extremely rare, as these creatures have been studied for 200 years. We knew it was new almost instantly, but it took about a year to make thorough comparisons with all other Late Jurassic ichthyosaurs to make certain our instincts were correct. It was very exciting to not be able to find a match."

The specimen, estimated to have been about 6 feet long, was discovered in 2009 by fossil collector Steve Etches MBE after a cliff crumbled along the seaside. He found it encased in a slab that would originally have been buried 300 feet deep in a limestone seafloor layer. The specimen since has been housed in The Etches Collection Museum of Jurassic Marine Life in Kimmeridge, Dorset. Jacobs named it Thalassodraco etchesi, meaning "Etches sea dragon" after Etches.

"Now that the new sea dragon has been officially named, it's time to investigate its biology," said study co-author David Martill, Ph.D., professor of paleontology at the University of Portsmouth in Portsmouth, United Kingdom. "There are a number of things that make this animal special."

Investigating the Differences

"This animal was obviously doing something different compared to other ichthyosaurs. One idea is that it could be a deep diving species, like sperm whales," Jacobs said. "The extremely deep rib cage may have allowed for larger lungs for holding their breath for extended periods, or it may mean that the internal organs weren't crushed under the pressure. It also has incredibly large eyes, which means it could see well in low light. That could mean it was diving deep down, where there was no light, or it may have been nocturnal."

With the deep rib cage, the creature would have looked very barrel-like, she said. Given its comparatively small flippers, it may have swum with a distinctive style from other ichthyosaurs.

The specimen's hundreds of tiny teeth would have been suited for a diet of squid and small fish, and "the teeth are unique by being completely smooth," Jacobs said. "All other ichthyosaurs have larger teeth with prominent striated ridges on them, so we knew pretty much straight away this animal was different."

Changes Through History

Ichthyosaurs originated as lizard-like creatures living on land and slowly evolved into the dolphin/shark-like creature found as fossils. Their limbs evolved into flippers, most of them very long or wide.

"They still had to breathe air at the surface and didn't have scales," Jacobs said. "There is hardly anything actually known about the biology of these animals. We can only make assumptions from the fossils we have, but there's nothing like it around today. Eventually, to adapt to being fully aquatic, they no longer could go up onto land to lay eggs, so they evolved into bearing live young, tail first. There have been skeletons found with babies within the mother and also ones that were actually being born."

Thalassodraco etchesi is closely related to Nannopterygius, a widespread genus of ichthyosaurs which inhabited Late Jurassic seas across Europe, Russia and the Arctic around 248 million years ago before becoming extinct around 90 million years ago. The largest ichthyosaurs, found in North America, had skulls nearly 16 feet long.

Jacobs said that the new specimen likely died from old age or attack by predators, then sank to the seafloor.

"The seafloor at the time would have been incredibly soft, even soupy, which allowed it to nose-dive into the mud and be half buried," she said. "The back end didn't sink into the mud, so it was left exposed to decay and scavengers, which came along and ate the tail end. Being encased in that limestone layer allowed for exceptional preservation, including some preserved internal organs and ossified ligaments of the vertebral column."

"It's excellent that new species of ichthyosaurs are still being discovered, which shows just how diverse these incredible animals were," Martill said.

Tsukuba, Japan - Consumers worldwide are demanding greener energy sources; therefore, optimizing the performance and economic viability of solar cells is an important research focus. Improving the efficiency of perovskite solar cells has been a particular priority; however, less emphasis has been placed on understanding what makes the cell performance deteriorate. Now, recent findings from researchers at the University of Tsukuba provide a microscopic-level study of perovskite solar cells to address the knowledge gap.

Organic-inorganic hybrid perovskites are attractive materials for use in solar cells because they are easy and cheap to prepare and absorb light over a wide range of wavelengths. Solar cells that use perovskite layers as the photoactive material are continually being improved, with a particular focus on their power conversion efficiency (PCE), which can now exceed 25%.

However, focusing on improving PCEs alone could be causing researchers to miss the significant steps forward that might result from a more detailed understanding of the underlying mechanisms. For example, the question of what causes the performance of perovskite solar cells to deteriorate is an important one that has not been comprehensively answered.

External factors such as oxygen and moisture in the air are known to compromise perovskite layers. However, the internal changes that affect the performance of cells are not as well understood. The researchers have therefore probed the deterioration mechanism using electron spin resonance (ESR) spectroscopy.

"We carried out ESR spectroscopy on perovskite solar cells while they were in use, which gave us a real-time picture of the molecular-level changes," study corresponding author Professor Kazuhiro Marumoto explains. "Specifically, we observed the charges and defects, and related spin states, in the solar cell layers while the current-voltage characteristics of the solar cells were being measured. This allowed us to understand the relationships between these factors."

This in-depth investigation of perovskite solar cells in operation showed that changes in the spin states result from changes in hole transport as well as the formation of interfacial electric dipole layers. It was therefore concluded that cell deterioration could be prevented by improving charge mobility in the hole transport material and preventing electric dipole layer formation.

"Establishing that changes in spin states are correlated with device performance has significantly broadened our understanding of perovskite solar cells," Professor Marumoto says. "We hope that our findings will provide a valuable new starting point for the continued development of solar cells and help accelerate the reality of cost-effective green energy."

Only 40 per cent of forests are considered to have high ecological integrity, according to a new global measure, the Forest Landscape Integrity Index.

The Index was created by 47 forest and conservation experts from across the world, including Professor James Watson of The University of Queensland and the Wildlife Conservation Society.

"This extremely fine-scale analysis of the ecological integrity of the world's forests has found that only 17.4 million square kilometres of Earth's remaining forests - or 40 per cent of them - are considered to have high integrity," Professor Watson said.

"And just 27 per cent of this area is found in nationally designated protected areas.

"High integrity forests are those which contain high levels of biodiversity, provide high quality ecosystem services and are more resilient to climate change.

"Many of our remaining forests have been heavily impacted by a variety of human activities, including logging, fires, hunting, wildlife exploitation and edge effects.

"These actions damage forest integrity.

"By protecting and expanding forests with high integrity, we can help slow the impacts of climate change, preserve biodiversity, protect the rights of indigenous peoples and local communities and prevent future pandemics."

Professor Watson said the index was a result of rapid advances in remote sensing, big data and cloud computing.

"The use of this index is critical in allowing us to locate Earth's remaining intact forests and ensure that they are better protected but also hold nations to account for how they treat their forests," he said.

"We show how critical some countries are, including Canada, Brazil, Democratic Republic of Congo, Papua New Guinea and Australia, in sustaining the world's last large intact forests.

"The fine-scale nature of the map will also allow land managers to plan activities more effectively and to monitor change over time."

Dr Hedley Grantham, lead author of the study and WCS's Director of Conservation Planning, said the study's results were fundamental to talks at the Convention on Biological Diversity.

"The current draft of the post-2020 Global Biodiversity Framework wisely proposes targets relating to ecosystem integrity and there has been active discussion about how this can be quantified and monitored," Dr Grantham said.

"Using this index, we can now set ambitious policy goals to improve the integrity of forests globally."

Luxembourg, 9 December 2020 - At an online European Parliament workshop hosted by Sirpa Pietikäinen, MEP (Finland), Alzheimer Europe launched a new report "Dementia as a European Priority - A Policy Overview" which takes stock of dementia policy at an EU level and sets out recommendations for future priorities across Europe.

As the European Union is about to agree a new long-term budget and the details of the EU4Health and Horizon Europe programmes are being finalised, Alzheimer Europe reflects on the place of dementia as a political priority in Europe in recent years. This includes the different ways in which dementia policy and research have been supported by the three institutions of the EU, as well as some of the high-profile coordination and research projects which have been made possible as a result of EU funding.

In the report, Alzheimer Europe also highlights some of its key activities in campaigning for change, as well as the work it has coordinated and participated in, along with its national member associations, to raise the profile of the condition and build an evidence base to make the case for the prioritisation of dementia.

Despite the progress made and the knowledge generated, the report highlights that people living with dementia continue to face a number of challenges. These challenges, which concern wider society too, include the increase in the number of people living with dementia (estimated to double by 2050) and the societal and economic cost of dementia.

As a result, the report sets out a number of recommendations for the EU, outlining specific areas in which dementia should be prioritised across international, health, research and social policy.

Recommendations include:

Prioritising dementia research in EU Research Programmes (including Horizon Europe), providing a fair allocation of resources and funding for existing programmes and better coordination between programmes

Prioritising dementia within policies relating to chronic diseases, mental health and ageing, both at an EU and national level

Supporting Member States to work towards the implementation of the World Health Organization's Global Action Plan on Dementia 2017-2025

Recognising dementia as a disability and including dementia in disability policies.

Commenting on the publication of the report, Alzheimer Europe's Executive Director, Jean Georges, stated:

"Alzheimer Europe has worked with its members over the past three decades to ensure that dementia is a political priority at the European level. The policy landscape has changed dramatically during this time and we have seen considerable progress as both national governments and the EU have given dementia greater prominence within their health and research policies."

"However, there is much still to do. The European Union and its Member States are on the cusp of historic deals on the EU budget, a greatly expanded Health Programme and the forthcoming Horizon Europe research programme. If we are to build on the knowledge, experience and progress gained in recent years, it is vital that dementia remain a political priority at a European level across health, research and social policy."

Researchers led by University of Warwick find that precarity - in employment, personal circumstances, social status - is among the biggest factors in affecting whether patients use antibiotics correctly

Whereas poverty did not have an impact, precarity pushed up to 1 in 2 people into inappropriate antibiotic use, suggesting that this could be a challenge in higher income as well as in developing countries

Research demonstrates that individuals cannot always be blamed for misuse of antibiotics, and that better sustainable development policy is needed

Efforts to improve security of livelihoods globally could also help tackle anti-microbial resistance as a side-effect

Patients living in precarious circumstances are less likely to use antibiotics appropriately according to a new study from the University of Warwick, suggesting that efforts to improve conditions for those with little security in their livelihoods could have an unexpected benefit in helping to tackle antimicrobial resistance globally.

The findings add to evidence that focus should shift from influencing individuals' efforts to combat anti-microbial resistance to supporting sustainable development policy that tackles the contributing factors.

The research, published in the journal BMJ Global Health and funded by the Economic and Social Research Council (ESRC), part of UK Research and Innovation, provides comprehensive analysis of how patients accessed and used healthcare, and is the first study to quantitatively examine the relationship between precarity and antibiotic use.

Precarity refers to personal circumstances dominated by uncertainty, whether that is in employment, your personal life or social status. Those in precarious circumstances are limited in their ability to plan ahead, and deprived of safety nets, social support, economic certainty and flexibility. It is not necessarily about being poor: although this study looked at low to middle income countries, precarity can also be a problem in higher income countries.

Using statistical analysis, the researchers were able examine the impact of socioeconomic factors, such as precarity, poverty and marginalisation, on their use of antibiotics to treat their illness. They found that patients in precarious circumstances had a chance of up to 51% of using antibiotics without advice from a medical professional or for inappropriate illnesses - compared to 17% for an average patient.

Lead author Dr Marco Haenssgen, from the Warwick Institute of Advanced Study and the Department of Global Sustainable Development, argues that this behaviour is understandable as when living in precarious circumstances individuals are engaged in a constant balancing act.

Dr Haenssgen, Assistant Professor in Global Sustainable Development, said: "You have to balance your health, your economic life, feed your family, go to school; these are all competing priorities.

"Antibiotics have become such a staple of healthcare that they have become what some people see as a 'quick fix' solution. When people are in precarious circumstances and deprived of social support, if they can find a quick fix to keep them going they will use it, and then it could become problematic."

In many low to middle income countries, patients often have to travel long distances to access healthcare services, something they may not be able to easily arrange or afford. Even in more economically developed areas, employment can be less secure and social networks can be eroded.

Antimicrobial resistance occurs when microbes become resistant to antibiotics, threatening their effectiveness. Human antibiotic use is known to be a main driver of this process, and policies to combat anti-microbial resistance have therefore typically focused on clinical factors and promoting individual responsibilities. However, the researchers argue that the impact of socioeconomic factors such as precarity are being underestimated.

Dr Haenssgen said: "You cannot always blame the individual for misuse of antibiotics. Often, we find ourselves in living conditions that provoke problematic behaviours, which means that if you want to improve antibiotic use you need to improve those living conditions.

"If we can improve situations of precarity then we have a good start for future interventions. We have a very substantial facet of the problem that is continuously disregarded and where potentially we have a lot of gains to realise.

"Antimicrobial resistance is a massive global health problem, it can potentially overturn what global health is. Many of the past gains that we have had in infectious disease control and prevention are potentially being undone by antimicrobial resistance."

The study focused on five local communities across rural Thailand and Lao People's Democratic Republic and surveyed 2066 residents on recent illnesses they had experienced and how they sought healthcare support for it. This provided the researchers with a rich dataset on 1421 illness episodes that they could analyse to determine what healthcare patients seek, if any, whether they were able to access suitable healthcare, and when these occur in the timeline of their illness.

Today, a clinician can order a blood test to check a patient's cholesterol or hemoglobin A1c levels -- biomarkers that help predict an individual's risk of cardiovascular disease or diabetes, respectively. But despite decades of advances in the understanding of Alzheimer's disease (AD), a blood test for predicting its risk remains elusive. Imaging scans of the brain and lumbar punctures that collect cerebrospinal fluid can offer diagnoses, but such tests are expensive and cumbersome for patients. Two years ago, investigators at Brigham and Women's Hospital reported the development of a blood test for a fragment of the protein tau, a hallmark of AD. Now, that test for levels of N-terminal fragment of tau (NT1) has been evaluated in participants in the Harvard Aging Brain Study (HABS), a cohort of cognitively normal, older adults who are followed closely over time. In Nature Communications, the authors report that baseline NT1 levels in the blood were highly predictive of the risk of cognitive decline and AD dementia.

"Our findings indicate that measuring a tau fragment in plasma can help predict which elderly people are likely to decline and how quickly they are likely to decline," said corresponding author Dennis Selkoe, MD, co-director of the Ann Romney Center for Neurologic Diseases. "We're excited because there are currently no commercially available blood tests to predict risk of AD in still-healthy individuals. Having such a blood test allows us to better screen people for enrollment in AD prevention trials and represents progress toward diagnostic tests for AD in medical care."

Selkoe cautions that a commercial test for routine clinical care likely remains several years away. But for clinical trials that seek to evaluate preventive treatments for AD, such as the large-scale clinical trials led by co-author Reisa Sperling, MD, MMSc, director of the Center for Alzheimer Research and Treatment at the Brigham NT1 levels could be measured before a participant enrolls in a the trial, and potentially also as a longitudinal measure to assess treatment response. The test ultimately represents a far less costly and less invasive alternative to imaging and lumbar punctures.

The current study, led by first author Jasmeer Chhatwal, MD, PhD, now an attending physician and scientist in the Massachusetts General Hospital Department of Neurology, evaluated the predictive value of NT1 among 236 cognitively normal participants in HABS. Participants were on average 74 years old when they entered HABS and were followed for an average of five years. Blood samples were collected in the first year.

The research team found that higher levels of NT1 in blood samples taken at the beginning of the trial were strongly associated with future clinical progression. The team divided participants into those with high, medium and low NT1 levels, finding that for the group with the highest levels, the risk of advancing to mild cognitive impairment (MC I) or AD dementia was 2.4-fold. NT1 levels predicted decline across multiple areas of memory, including episodic memory -- remembering specific events or experiences such as a person's birthday or a family visit -- and also predicted how fast the participant's cognition would decline. Imaging data showed that higher baseline NT1 blood levels were associated with elevated brain levels of β-amyloid plaques and the accumulation of tangles of tau -- both classical signs of AD.

The authors note that relatively few participants in HABS progressed to AD, an important limitation of this cohort. They found that another brain protein -- known as NfL -- which has been studied by other groups, may also be associated with cognitive decline, especially among people who already show signs of cognitive deficits. NfL was a less strong predictor than NT1 in the study.

"The NT1 tau fragment may be a reflection of damage to neurons and synapses, allowing us to use blood samples to detect what is happening in a patient's brain years before they begin experiencing symptoms," said Selkoe. "This could give us an invaluable window of time in which to evaluate interventions for preventing cognitive decline and AD dementia."