Brain

LA JOLLA--(February 17, 2021) In structural biology, some molecules are so unusual they can only be captured with a unique set of tools. That's precisely how a multi-institutional research team led by Salk scientists defined how antibodies can recognize a compound called phosphohistidine--a highly unstable molecule that has been found to play a central role in some forms of cancer, such as liver and breast cancer and neuroblastoma.

These insights not only set up the researchers for more advanced studies on phosphohistidine and its potential role in cancer, but will also enable scientists to manipulate the shape and atomic makeup of the antibodies' binding sites in order to design ever more efficient antibodies in the future. The study was published in the Proceedings of the National Academy of Sciences on February 5.

"We are excited that these new antibody structures reveal novel principles of antigen binding. Now we can redesign these antibodies and engineer their properties to make them more efficient," says Tony Hunter, Renato Dulbecco Chair and American Cancer Society Professor at Salk and the paper's senior author. "This work may also provide other scientists with phosphohistidine antibodies that better suit their research purposes."

Amino acids are joined together in precise sequences to form proteins, and several of them can undergo chemical transformations that can change the activity of the protein for better or worse. One such transformation is a process called phosphorylation, when a compound called phosphate is added to an amino acid, changing its shape and charge. Previously, Hunter showed that phosphorylation on the amino acid tyrosine can drive cancer progression, a discovery that led to numerous anticancer drugs. More recently, Hunter turned his attention to phosphorylation of the amino acid histidine (which creates phosphohistidine), suspecting that the process might also play a role in human disease.

Hunter developed a suite of antibodies able to bind to phosphohistidine in proteins, and used chemically stabilized phosphohistidine analogues to develop a series of monoclonal antibodies that could recognize these forms. The next step was to understand exactly how the antibodies are able to bind to phosphohistidine. This led Hunter to collaborate with Ian Wilson, the Hansen Professor of Structural Biology at the Scripps Research Institute and a world-renowned expert in using protein crystallography to define antibody structures, to study the structures of the phosphohistidine antibodies.

"My long-term colleague Tony and I have been collaborating on this project for the past seven years," says Wilson. "We have obtained new insights into how antibodies can evolve to recognize phosphates linked to proteins, which is very satisfying."

To find out how phosphohistidine is recognized, they needed to image their antibodies in the act of binding the phosphohistidine, and so formed crystals between each antibody bound to a phosphohistidine peptide.

"To understand the molecular interactions between the antibodies and phosphohistidine, we needed to look at them in great detail," says first author Rajasree Kalagiri, a Salk postdoctoral researcher and expert in X-ray crystallography. "Once we got the antibodies to form crystals, we bombarded those crystals with X-rays to obtain a diffraction pattern. We then applied methods that transform the diffraction pattern into a three-dimensional electron density map, which was then used to discern the atomic structure of the antibodies."

The two types of antibody crystal structures solved by the team revealed exactly how different amino acids are arranged around the phosphohistidine to bind it tightly. Their five structures more than double the number of phospho-specific antibody structures previously reported, and provide insights into how antibodies recognize both the phosphate and the linked histidine. They also reveal at a structural level how the two types of antibody recognize different forms of phosphohistidine, and this will allow the scientists to engineer improved antibodies in the future.

A University of Sydney-led international team of scientists has revealed the shape of one of the most important molecular machines in our cellsthe glutamate transporter, helping to explain how our brain cells communicate with one another.

Glutamate transporters are tiny proteins on the surface of all our cells that shut on and off the chemical signals that have a big role in making sure all cell-to-cell talk runs smoothly. They are also involved in nerve signalling, metabolism and learning and memory.

The researchers captured the transporters in exquisite detail using cryogenic electron microscopy (cryo-EM), showing they look like a 'twisted elevator' embedded in the cell membrane.

This world-first discovery opens a whole new field of possibility, studying if defects in the transporters could be the reason behind neurological diseases such as Alzheimer's disease.

The results of the research have been published in Nature.

"The first time I saw the image was amazing. It revealed so much about how this transporter works and explained years of previous research," says PhD student Ichia Chen who was lead author on the study.

--A multitasking transporter---

The researchers were able to 'photograph' the structure of the glutamate transporter, by analysing thousands of images trapped in a thin layer of ice using cryo-EM, a highly sensitive microscope that made this research possible.

Cryo-EM can make visible what is invisible to the naked eye, using electron beams to photograph biological molecules.

The results also confirm suspicions the researchers had for some time that the glutamate transporters were multi-taskers.

"Using Cryo-EM, we have uncovered for the first time just how these transporters can multitask - carrying out the dual functions of moving chemicals (like glutamate) across the cell membrane while also allowing water and chloride ions to move through at the same time,"said senior author Professor Renae Ryan from the School of Medical Sciences, Faculty of Medicine and Health.

"These molecular machines use a really cool twisting, elevator-like mechanism to move their cargo across the cell membrane. But they also have an additional function where they can allow water and chloride ions to move across the cell membrane. We have been studying these dual functions for quite some time, but we could never explain how the transporters did this until now. Using a combination of techniques including cryo-EM and computer simulations, we captured this rare state, where we can observe both functions happening at the same time."

"Understanding how the molecular machines in our cells work enables us to interpret defects in these machines in disease states and also gives us clues as to how we might target these machines with therapeutics,"says Professor Ryan.

---Key to bridging the gap in diseases---

Mapping out in detail the structure of the glutamate transporter could be a crucial tool for researchers in understanding how our bodies work ,and the mechanism behind some diseases.

Defects in the glutamate transporter have been linked to many neurological diseases such as Alzheimer's disease and stroke.

This includes rare diseases such as episodic ataxia, a disease that impacts movement and causes periodic paralysis, caused by an uncontrolled leak of chloride through the glutamate transporter in brain cells.

"Understanding the glutamate transporter structure, which controls the normal flow of chloride, could help design drugs that can 'plug up' the chloride channel in episodic ataxia," says co-lead author Dr Qianyi Wu.

---Result of teamwork ---

The paper was the result of seven years of work from researchers in Australia and the United States.

The work also highlights the importance and potential of high-resolution microscopy to understanding biological processes.

"We are really excited to use the new Glacios Cryo-EM at the Sydney Microscopy and Microanalysis facility, University of Sydney. Having access to this microscope 'in house' will accelerate our research and our understanding of these important molecular machines," says Dr Josep Font, co-senior author of the study.

Geologists have developed a new theory about the state of Earth billions of years ago after examining the very old rocks formed in the Earth's mantle below the continents.

Assistant Professor Emma Tomlinson from Trinity College Dublin and Queensland University of Technology's Professor Balz Kamber have just published their research in leading international journal, Nature Communications.

The seven continents on Earth today are each built around a stable interior called a craton, and geologists believe that craton stabilisation some 2.5 - 3 billion years ago was critical to the emergence of land masses on Earth.

Little is known about how cratons and their supporting mantle keels formed, but important clues can be found in peridotite xenoliths, which are samples of mantle that are brought to the Earth's surface by erupting volcanoes.

Dr Tomlinson, from Trinity's School of Natural Sciences, said:

"Many rocks from the mantle below old continents contain a surprising amount of silica - much more than is found in younger parts of the mantle."

"There is currently no scientific consensus about the reason for this."

The new research, which looks at the global data for mantle peridotite, comes up with a new explanation for this observation.

The research used a new thermodynamic model to calculate that the unusual mineralogy developed when very hot molten rock-- greater than 1700 °C - interacted with older parts of the mantle and this caused the growth of silica-rich minerals.

"For more than 1 billion years, from 3.8 to 2.5 billion years ago, volcanoes also erupted very unusual lavas of very low viscosity - lava that was very thin, very hot and often contained variable levels of silica," Dr Tomlinson added.

"Our modelling suggests that the unusual lavas were in fact the molten rocks that interacted with the mantle at great depth and this interaction resulted in the variable level of silica."

Professor Kamber, QUT, said:

"Both the silica-rich rocks in the deep mantle and the low viscosity volcanic rocks stopped being made by the Earth some 2.5 billion years ago. This timing is the boundary between the Archaean and Proterozoic eons - one of the most significant breaks in Earth's geological timescale."

What caused this boundary remains unknown, but the research offers a new perspective.

Professor Kamber added:

"This may have been due to a change in how the mantle was flowing. Once the mantle started slowly turning over all the way down to the core (2,900 km), the very high temperatures of the Archaean eon were no longer possible."

To provoke more interest and excitement for students and lecturers alike, a professor from Florida Atlantic University's College of Engineering and Computer Science is spicing up the study of complex differential mathematical equations using relevant history of algebra. In a paper published in the Journal of Humanistic Mathematics, Isaac Elishakoff, Ph.D., provides a refreshing perspective and a special "shout out" to Stephen Colbert, comedian and host of CBS's The Late Show with Stephen Colbert. His motivation? Colbert previously referred to mathematical equations as the devil's sentences and an unnatural commingling of letters and numbers - with the worst being the quadratic equation - an infernal salad of numbers, letters and symbols.

In response to Colbert's hilarious and satirical observations of mathematical equations, Elishakoff, lead author and a distinguished research professor in the Department of Ocean and Mechanical Engineering, suggests that mathematics education needs to be enlivened so that students will recognize that this discipline is not merely a necessary evil, but a vibrant, exciting and fascinating subject.

"Of course we know that Stephen Colbert was joking. However, as an avid fan of his show and a reader of his book, we have heard that 90 percent of every joke is truth - or 'truthiness' - a term ingeniously coined by Colbert himself," said Elishakoff. "One means of eliminating boredom and apathy in the classroom is presentation of mathematics in its historical context."

All joking aside, Elishakoff says that introducing the elements of history into the classroom will make the experience more meaningful and lively to encourage a deeper learning experience. In particular, history of differential equations will show students that not unlike themselves, famous mathematicians also have made mistakes. History also helps students see clearly that what seemed "impossible" to a great mathematician is now quite possible and straightforward.

"Building on the mistakes, confusions, and frustrations of mathematicians sensitizes both students and teachers," said Elishakoff. "Another potential benefit of using history of mathematics lies in sensitizing the teacher to possible difficulties of students' understanding; and may yield clues on how to respond and help the student overcome these obstacles. In addition, history can provide a feeling, for example, for how standards of rigor evolved."

In his research, Elishakoff views mathematics of the past as common heritage and values its serious study for its own sake. However when teaching mathematics, the history coming into the classroom is often supportive rather than central. He suggests introducing some of the historical examples in his published paper into the classroom.

"When students make an analogous mistake, they are in good company, committing for example, the mistake of the famous Greek mathematician Heron. The fact that students make this mistake 2,000 years after Heron lived is not that important," said Elishakoff. "Somehow this fact consoles them as it were, and spurs them to do better. They do not feel lonely in making the mistake. 'Don't worry,' I tell a student. If Heron of Alexandria was allowed to make a mistake, you are entitled to make it, too. The difference is that you can correct it and try to avoid it in the future."

In one of his courses, Elishakoff conducts a simple test to check the knowledge retained by his students from differential equations. It turns out that most never got the subject and only one or two students could solve simple differential equations.

"I continuously try to develop various materials to cure the mathematical state of students who possibly suffered as a result of dull and uninspired teaching to potentially put unhappy memories behind them," said Elishakoff. "Young learners of mathematics share a common experience with the greatest creators of mathematics: hitting a wall, meaning, first frustration, then struggle, and finally, enlightenment and elation."

Preliminary results of Elishakoff's research incorporating mathematics of the past as a heritage appear to be extremely encouraging.

"Understanding complicated differential equations is an integral component of almost every discipline in engineering and computer science," said Stella Batalama, Ph.D., dean of the College of Engineering and Computer Science. "Professor Elishakoff has identified an innovative and effective method to generate interest, increase confidence, provide encouragement and make a difficult subject more fun for our students as well as other students across the country."

Research teams from Ruhr-Universität Bochum (RUB) and the University of Copenhagen have therefore developed an approach that can predict the optimal composition and confirm its accuracy with high-throughput experiments. They report in the journal Angewandte Chemie International Edition of 28. December 2020.

Much less expensive elements than previous catalysts

Many electrochemical reactions go through several steps. Each should be optimized on a catalyst surface if possible, but different requirements apply to each step. "Since previous catalysts usually had only one optimized functionality, one could only make the best compromise possible, and energy losses could not be avoided," explains Professor Wolfgang Schuhmann from the Center for Electrochemistry at RUB. With complex solid solutions, several functionalities can be realized simultaneously on one catalyst surface, overcoming this limitation. However, this only happens when at least five different elements are combined. There are millions of possibilities in which percentage ratios the respective elements can be combined. The previous challenge of searching for a strategy to find optimal properties seems to be answerable with this class of materials. Now the task is to find out which combination fulfills the goal in the best possible way. "Incidentally, this may also be possible with much more favorable elements than with previous catalysts," Schuhmann emphasizes.

Make and check predictions

In their work, the research teams present an approach that offers guidance among the countless possibilities. "We have developed a model that can predict the activity for oxygen reduction as a function of composition, thus enabling calculation of the best composition," explains Professor Jan Rossmeisl from the Center for High Entropy Alloy Catalysis at University of Copenhagen.

The team from Bochum provided the verification of the model. "We can use a combinatorial sputtering system to produce material libraries where each point on the surface of the support has a different composition and there are different but well-defined gradients in each direction," explains Professor Alfred Ludwig from the Chair of New Materials and Interfaces at RUB. Using a scanning droplet cell, the catalytic properties of 342 compositions on a material library are then automatically measured to identify activity trends.

"We found that the original model did not yet do justice to the complexity and still made imprecise predictions. Therefore, we revised it and had it tested again experimentally," says Dr. Thomas Batchelor from the Copenhagen team, who was a visiting scientist at RUB as part of the collaboration. This time, prediction and experimental measurement showed excellent agreement, which was confirmed by further material libraries.

This strategy allows the complex mechanisms at the surfaces, which consist of five chemical elements, to be identified, leaving most of the screening effort to the computer. "If the model turns out to be universally applicable to all element combinations and also to other reactions, one of the currently biggest challenges of this catalyst class would be realistically met," the team said.

WASHINGTON -- Researchers have developed an extremely sensitive miniaturized optical fiber sensor that could one day be used to measure small pressure changes in the body.

"Our new pressure sensor was designed for medical applications and overcomes many of the issues of using silica-based fibers," said research team leader Hwa-Yaw Tam from The Hong Kong Polytechnic University. "It is sensitive enough to measure pressure inside lungs while breathing, which changes by just a few kilopascals."

The researchers describe their new optical fiber sensor in The Optical Society (OSA) journal Optics Letters. The sensor, which is based on a fiber Bragg grating (FBG) inscribed into a fiber made from a new polymer called Zeonex, was able to detect pressure changes of just 2 kilopascals.

"Our FBG sensor could be used in various medical applications because, in addition to its biocompatibility, the fiber is chemically inert and also not sensitive to moisture," said Tam. "Our ultimate objective is to use these types of sensors to monitor various parameters -- including pressure, temperature and strain -- inside animals and people."

Making a polymer sensor

Many fiber optic sensors are based on FBGs, tiny periodic microstructures that can be inscribed onto a fiber. When pressure rises the fiber stretches slightly, increasing the grating period in a way that changes its refractive index and shifts the light output toward the red end of the spectrum. Similarly, a decrease in pressure produces a blue shift.

Making an FBG sensor from a traditional silica optical fiber is not ideal for medical applications, especially those involving long-term use in the body, because these fibers exhibit a relatively high stiffness and can be brittle. FBGs embedded in silica fibers also have limited sensitivity to small pressure changes because the material does not stretch and contract very easily. Although polymer optical fibers have been developed, they tend to absorb water -- which can affect measurements -- and are not very easy to inscribe with an FBG.

To overcome these hurdles, the researchers turned to the advanced polymer Zeonex. This new material is not only chemically inert and works well in the aqueous environments like those found in the body, but also exhibits a higher light shift in response to a pressure change compared to silica fibers. Although substances called dopants are often used to make materials with different refractive indexes for the inner core and outside cladding of fibers, the researchers simplified the fabrication process by using different grades of Zeonex to make a single-material fiber.

"Eliminating the use of dopants allows the optical fibers to be fabricated with good reproducibility," said Tam. "We were able to use an excimer laser to easily inscribe the FBG and to add a side hole that runs parallel to the core. The side hole enhanced the pressure measurement sensitivity and significantly reduced lag, therefore providing better measurement accuracy."

High-resolution, reproducible readings

To demonstrate the new sensor, the researchers compared its performance with a traditional polymer-based sensor of a similar design. The sensors were placed inside a chamber, where the pressure was manually increased and decreased step by step above and below the atmospheric pressure. The corresponding light shift was monitored in real time for both sensors.

They found that the Zeonex-based sensors with the side-hole design produced a response that was linear, repeatable and had negligible lag or errors. The tests showed that the sensor can be used for low pressure measurement up to 50 kilopascals above or below atmospheric pressure with a resolution of 2.0 kilopascals. The sensitivity of the pressure measurement is increased by 80% compared to a traditional polymer-based sensor.

"The pressure sensor is most useful in conditions where the change in pressure is in the order of few kilopascals above and below the atmospheric pressure," said Tam. "It could be useful for low pressure sensing in medical and high-altitude environments as well as for detecting pressure changes in gaseous containers."

The researchers are now working to further reduce the sensor's response time, which is currently few tens of seconds. They also want to expand the sensor to measure other physical and chemical parameters such as pH and to functionalize the probe so that it can detect the pressure of a particular gas.

WASHINGTON -- When people pause before replying to a question, even for just a few seconds, their answers are perceived to be less sincere and credible than if they had replied immediately, according to research published by the American Psychological Association.

And the longer the hesitation, the less sincere the response appears.

"Evaluating other people's sincerity is a ubiquitous and important part of social interactions," said lead author Ignazio Ziano, PhD, of Grenoble Ecole de Management. "Our research shows that response speed is an important cue on which people base their sincerity inferences."

The research was published in the Journal of Personality and Social Psychology.

Researchers conducted a series of experiments involving more than 7,500 individuals from the United States, the United Kingdom and France. Participants either listened to an audio snippet, viewed a video or read an account of a person responding to a simple question (e.g., did they like a cake a friend made or had they stolen money from work). In each scenario, the response time varied from immediate to a 10-second delay. Participants then rated the sincerity of the response on a sliding scale.

Across all 14 experiments, participants consistently rated delayed responses as less sincere regardless of the question, whether it was a harmless one about cake or a more serious one about committing a crime.

A few conditions reduced this effect, the researchers found. For example, if the answer was considered socially undesirable, such as saying, "No, I don't like it" when a friend asks if you like their cake, response speed did not seem to matter much; the answer was considered sincere whether it was fast or slow. The researchers also found that if people thought a slower response was due to mental effort (for instance, having to think back if you had stolen candy 10 years ago), response speed had a smaller effect.

The findings have wide implications, according to Ziano. "Whenever people are interacting, they are judging each other's sincerity. These results can be applied to a wide range of interactions, going from workplace chit-chat to couples and friends bickering," he said. "Further, in job interviews and in court hearings and trials, people are often tasked with judgments of sincerity. Here, too, response speed could play a part."

For example, he said, imagine a hiring manager asking two job candidates, named Ann and Barb, whether they really know the programming language Javascript, as they claim. Ann says yes immediately, while Barb replies yes after three seconds.

"Our results suggest that in this situation, the hiring manager is more likely to believe Ann than Barb, and therefore more likely to hire Ann," said Ziano. "In general, whenever there is a response that requires an answer, such as in a job interview, delayed responses can be perceived as less sincere."

Another area where response time may be important is jury reactions to testimony in court.

"It would be unfair for the responder, such as a crime suspect, if the response delay was misattributed to thought suppression or answer fabrication when it was in fact caused by a different factor, such as simply being distracted or thoughtful," said Ziano.

The final experiment found that explicitly instructing participants to ignore delayed response reduced, but did not completely remove, the effect of delayed response on judgment of sincerity or guilt.

"Nevertheless, our research shows that, on the whole, a fast response seems to be perceived as more sincere, while a response that is delayed for even a couple of seconds may be considered a slow lie," said Ziano.

Atropisomers are a class of stereoisomers (chemical compounds that differ in spatial arrangement of atoms) arising from restricted rotation around a single bond and have various applications in chemistry. To date, most research on atropisomers has focused on "biaryl atropisomers" (due to the rotational restriction around a carbon-carbon bond), but it is also possible for atropisomers to arise from rotational restrictions around a nitrogen-carbon (N-C) bond. These N-C axially chiral compounds are found in various natural products and bioactive compounds and thus have promising applications in medicine and agriculture. Furthermore, these are known to be useful as chiral building blocks and chiral ligands.

Of course, before researchers can take advantage of any such applications, they need to develop a feasible method for synthesizing it. "Although a number of bioactive compounds and natural products possessing an N-C axially chiral structure have recently been found, no efficient synthetic method was known," notes Professor Osamu Kitagawa from Shibaura Institute of Technology (SIT), Japan. To address this problem, Prof. Kitagawa and his team have spent the past few decades developing efficient methods for the synthesis of N-C axially chiral compounds. In a paper recently published in Accounts of Chemical Research, Prof Kitagawa summarizes his team's achievements since 2002.

In 2001, Prof. Kitagawa's group started investigating a never-before-attempted catalytic asymmetric synthesis of ortho-tert-butyl anilides and other N-C axially chiral compounds. In 2005, they found that reacting achiral secondary ortho-tert-butylanilides with 4-iodonitrobenzene in the presence of a chiral palladium (Pd) catalyst (catalytic enantioselective aromatic amination) resulted in the highly enantioselective (asymmetric) synthesis of N-C axially chiral N-arylated ortho-tert-butylanilides. They next experimented with adapting this intermolecular N-arylation reaction for use in intramolecular reactions, and their efforts led to the synthesis of compounds called "N-C axially chiral lactams" (which had high optical purities). Importantly, these reactions represented the first enantioselective syntheses of N-C axially chiral compounds with a chiral catalyst.

The investigators continued their work by using chiral Pd-catalyzed intramolecular N-arylations to achieve the enantioselective syntheses of N-C axially chiral quinoline-4-one and phenanthridin-6-one derivatives. They also used various chiral Pd-catalyzed reactions to prepare optically active N-C axially chiral compounds called N-(2-tert-butylphenyl)indoles, 3-(2-bromophenyl)quinazolin-4-ones, and N-(2-tert-butylphenyl)sulfonamides. Prof Kitagawa's research has led to the successful synthesis of potentially useful compounds, such as an N-C axially chiral mebroqualone that acts as an agonist of specific receptors present in the brain, called "GABA receptors" (and has potential therapeutic properties).

In fact, since 2005, the enantioselective synthesis of N-C axially chiral compounds has become a topic of considerable interest to chemists outside of Prof. Kitagawa's research team. For example, the literature on the synthesis of axially chiral anilides with catalytic enantioselective aromatic aminations dates back to 2005, with a research paper by Prof. Kitagawa's team, but since then, other research groups have published more than 70 original papers concerning highly enantioselective synthesis of various N-C axially chiral compounds using chiral catalysts. Further, the team's 2010 paper on the catalytic enantioselective synthesis of N-C axially chiral indoles represented an important contribution to the development of axially chiral indole chemistry, and various research groups have since developed catalytic asymmetric syntheses for various indole derivatives that include a C?C chiral axis or an N-C chiral axis. Prof. Kitagawa himself sees his laboratory's work as having important applications to "the synthesis of optically active drug compounds and natural products with N-C axial chirality."

In conclusion, Prof. Kitagawa's research team has succeeded in devising catalytic enantioselective syntheses of N-C axially chiral compounds. This work has inspired other research teams to make further contributions in the same field and has led to workable synthetic pathways for bioactive compounds with potential medicinal value. Prof Kitagawa predicts that the catalytic asymmetric synthesis of N-C axially chiral compounds will continue to draw attention, thanks to the potential uses of such compounds across a broad range of fields.

Many steep valleys in the European Alps show the relicts of large rockslides, during which several hundreds of million cubic metres of rocks get instable, collapse and impact everything on their path. "For most of these, we still do not know how they are caused, because these rockslides occurred long before the start of written history in the region about 1000 years ago," says Patrick Oswald, PhD student at the Department of Geology of the University of Innsbruck and lead author of the study. "Curiously, many of these ancient rockslides occurred together in clusters, meaning they are found in small regions and have a rather comparable age". This enigmatic pattern has puzzled researchers over the last decades and fuelled some intense debates. Some experts propose that abrupt climate shifts can degrade rock slopes towards unstable conditions, whereas others think that strong earthquake shaking is the main driver. Such problems are notoriously difficult to solve, as the object of study - the rock slope - has collapsed and cannot be investigated anymore. Therefore, the research team decided to turn the perspective around and searched underwater for answers to these questions. "The different sediment layers that are deposited year after year on the bottom of our lakes and oceans provide long-term information on climatic and ecological conditions, but also record the disturbances induced by strong earthquake shaking that happened long ago, in the prehistoric past," says Michael Strasser, head of the Sedimentary Geology working group at the Department of Geology and the Austrian Core Facility for scientific core analysis at the University of Innsbruck.

Severe prehistoric earthquakes

The geologists focused on two of the most massive rockslides of Tyrol, the Tschirgant and the Fernpass. "Instead of investigating the remnants of these rockslides in the landscape, we drilled into the muddy sedimentary archives on the bottom of the lakes Piburgersee and Plansee in the region and searched for specific traces that could tell us when strong earthquakes took place," explains Jasper Moernaut from the Department of Geology, head of the project this study is based on, "Tyrol on Shaky Slopes". "By comparing the earthquake and rockslide reconstructions for the past 10,000 years, we can evaluate whether these relate to each other, or not." By applying state-of-the-art techniques, such as hydroacoustic profiling of the lake's subsurface or computer-tomography scans of the 8 m long sediment cores, the researchers found two different types of earthquake traces in the sediments: Strong seismic shaking has deformed surficial sediments on the bottom of the lakes and also triggered numerous underwater mud avalanches. By radiocarbon dating of organic matter in the cores, this research discovered ten prehistorical earthquakes during the past 10,000 years. The ground shaking associated to these earthquakes was stronger than for those that have struck the region in the past ~1000 years. "Through a painstaking evaluation of historical earthquake reports and comparison with the sedimentary imprints in the lakes, we estimated the earthquake magnitudes to be M5.5 to 6.5," says Christa Hammerl, a historical seismologist at the Austrian Central Institute for Meteorology and Geodynamics. "As the earthquakes in the Eastern Alps occur at only a few kilometres depth, such earthquakes can produce considerable damage on infrastructure and the natural landscape."

Rockslide clusters triggered by earthquakes

Strikingly, the ages of two extraordinary strong earthquakes coincide very well with those of multiple large rockslides around 3,000 and 4,100 years ago. This age coincidence let the geologists deduce that extreme seismic shaking ultimately triggered the rockslides at these times, solving the debate on the cause of rockslide clusters in the region. Since then, no large rockslides or such extraordinary strong earthquakes struck the area. The results also indicate that a close succession of at least five severe earthquakes preceded the rock slope collapses at about 3,000 years ago. "Therefore, we propose that seismic shaking cannot only trigger rockslides, but can also gradually degrade the rock slopes towards their critical tipping point," explains Michael Strasser. "With all this new information, the challenge now lies in its implementation for better assessing future earthquake and rockslide hazards in the densely populated Alpine valleys. An adequate mitigating of such low probability but high impact events forms a big challenge. Knowledge about these past events can help better understand earthquake occurrence and provide key information for assessing future earthquake- and rockslide hazard."

From 2015 to 2019, public school districts in the United States invested nearly $5 billion to upgrade their Wi-Fi networks, according to EducationSuperHighway. However, in the age of COVID-19-mandated virtual learning, millions of K-12 students still lack the minimal connectivity at home for digital learning.

In a new study from the University of Notre Dame, researchers quantify how school district connectivity increases test scores, but underscore the dark side of technology -- increased behavior problems.

A $600,000 increase in annual internet access spending produces a financial gain of approximately $820,000 to $1.8 million, alongside losses from disciplinary problems totaling $25,800 to $53,440, according to new research from Yixing Chen, an assistant professor of marketing at Notre Dame's Mendoza College of Business. His paper "Investigating the Academic Performance and Disciplinary Consequences of School District Internet Access Spending," which appeared in the February issue of the Journal of Marketing Research, also shows the academic gain is larger for schools in counties with better home access to high-speed internet.

Internet access improves students' academic performance, which is associated with higher future income potential. Meanwhile, disciplinary problems leading to students' removal from the classroom incur administrative costs per expulsion, funding losses due to lower average daily attendance rates and operations costs for alternative education programs.

The team compiled data from more than 9,000 public schools in Texas from 2000 to 2014, including internet access spending, 11 academic performance indicators and 47 types of school disciplinary problems. They also supplemented the public data with surveys of 3,924 parents.

Empirical evidence about the downside of school internet is lacking, although there is an ongoing debate on the regulation of school internet access. On the one hand, the concerns by schools and policy advocates about children's access to obscene or harmful content over the internet led to implementation of the Children's Internet Protection Act. On the other hand, there is a serious concern that zealously limiting internet access can undermine learning outcomes.

Chen, who specializes in the social impact of marketing, advises districts not to blindly spend big money on tech, but to think strategically and consider how they will manage the fallout.

"Our research shows high-speed internet serves as an information superhighway to learning opportunities and to negative behaviors such as cyber-bullying," he said. "Therefore, we should reimagine the boundaries of open school internet access and strengthen internet safety training in our curricula."

Despite goals to close the classroom connectivity gap, parents, school districts and policymakers struggle to quantify the impact of internet access spending, and Chen says his team's study -- one of the first marketing studies on education -- provides a roadmap for schools to evaluate the payoffs of their institutional spending and underscores why bridging the digital divide needs to be done carefully.

"School district administrators can use our findings to effectively communicate to parents the tangible value of their internet access spending," Chen said. "The positive synergy between this and household internet access suggests districts' efforts to incentivize and help parents obtain access can be a good way to help their students, but must be coupled with better strategies for mitigating any negative unintended consequences."

This study was part of Chen's doctoral dissertation, which was selected as the winner of the 2021 John A. Howard/AMA Doctoral Dissertation Award. Co-authors include Vikas Mittal from Rice University and Shrihari Sridhar from Texas A&M University.

Extending this study, Chen is building a benchmark database of U.S. public schools' performance metrics, finance, school characteristics and neighborhood characteristics. He has also established a research collaboration between Notre Dame and GreatSchools, a K-12 nonprofit, to help public schools with strategic planning.

Crocodiles are resilient animals from a lineage that has survived for over 200 million years. Skilled swimmers, crocodiles can travel long distances and live in freshwater to marine environments. But they can't roam far overland. American crocodiles (Crocodylus acutus) are found in the Caribbean and Pacific coasts of the Neotropics but they arrived in the Pacific before Panama existed, according to researchers from McGill University.

Over 3 million years ago, the formation of the Isthmus of Panama altered global ocean circulation, connecting North and South America and establishing the Caribbean Sea. This resulted in widespread mixing of species on the continent and separation in the seas. On land, mammals from North America such as mammoths, sabre-toothed cats, horses, and camels invaded South America, and strange mammals like giant ground sloths, armadillos, and opossums from South America invaded North America. This event is known as the Great American Interchange, and the opposite happened in the seas, where new species of corals, clams, and fishes evolved in the separated Pacific and Caribbean waters.

The question a group of McGill and Panamanian researchers asked was: how distant are the Pacific and Caribbean populations from each other and does it match the geological record? Researchers have long suspected that American crocodiles living on the Pacific coast should have diverged genetically enough from Caribbean populations to become unique species.

"We assumed we would detect significant genetic differences between Pacific and Caribbean crocodile populations that were isolated for the past 3 million years," thought José Avila-Cervantes, a recent PhD graduate of McGill University under the supervision of Professor Hans Larsson.

Capturing crocodiles

To test this, Avila-Cervantes captured and took blood samples of crocodiles from several populations living on both coasts of Panama. Back at McGill University, he sequenced their genomes to look for small variations in their DNA. He used the genetic differences to estimate how much evolutionary divergence and gene flow existed between populations. With this information, the team found that Pacific and Caribbean crocodile populations have been separated for only about 100,000 years.

"This time of separation is a far cry from the 3 million years we were expecting," said Professor Larsson, Director of the Redpath Museum at McGill. "But it did match the last interglacial period of the Ice Age."

Glacial and interglacial cycles in the Ice Age mark periods of peak polar glaciations separated by relatively warm times. These warm times caused sea levels to rise over 100 meters globally compared to present-day levels. Using the record of Ice Age sea levels, Avila-Cervantes was able to reconstruct what Panama would have looked like during these peak cold and warm periods of the Ice Age.

Coastal movements explained

"It surprised us to see that during the warm inter-glacial periods, most of Panama was underwater with the coasts separated by brackish lagoons, small rivers, and thin stretches of land," said Avila-Cervantes. "These are the reasons why we think crocodiles were able to pass from coast to coast freely and explain why their oldest genetic signature of separation coincides with this time." A second younger signature of genetic separation is timed to about 20,000 years ago and coincides with the last glaciation cycle that they found made Panama about twice as wide as it is today, and probably a good barrier for these crocodiles. "This is one of the first studies to implicate Ice Age glaciation-interglaciation cycles with the evolution of a tropical organism."

Yet the researchers discovered there is some genetic divergence between the populations on each coast despite the frequent inter-glaciations, and this diversity is at risk due to habitat destruction from human development. "It was difficult to find any population living on the Pacific coast near the Panama Canal," said Avila-Cervantes.

One of the best-preserved populations is in the middle of the Panama Canal on the Barro Colorado Island Nature Monument. "Preserving the population around this island may be our best chance to preserve the unique genetic signatures of Panamanian American crocodiles," said Professor Larsson. "Our study not only highlights the resilience of crocodiles to ancient climate changes and their great capacity to survive large geological events, but also their vulnerability to our voracious need to modify their environments."

About this study

"Effect of the Central American Isthmus on gene flow and divergence of the American crocodile (Crocodylus acutus)" by Jose Avila-Cervantes, Carlos Arias, Miryam Venegas-Anaya, Marta Vargas, Hans C.E. Larsson, and W. Owen McMillan was published in the journal Evolution.

Irvine, Calif., Feb. 16, 2021 -- A radioactive bone cement that's injected into bone to provide support and local irradiation is proving to be a safer alternative to conventional radiation therapy for bone tumors, according to a study led by University of California, Irvine researchers.

The study shows that this brachytherapy cement can be placed into spinal bones to directly irradiate tumors without harming the spinal cord, and the radioactive material will stay localized in the bones, which promises to virtually eliminate side effects.

Lead researcher Joyce Keyak, UCI professor of radiological sciences, presented the results at the 2021 annual meeting of the Orthopaedic Research Society, which was held virtually Feb. 12-16.

Cancers that begin in the breast, prostate, lung, thyroid, kidney and other locations can spread to and erode bones, most commonly in the spine. Further complicating matters, normal radiation treatments for this problem can threaten the spinal cord and weaken the bones already compromised by the tumor's erosion, increasing the risk of fracture.

Currently, multiple sessions of external beam radiation are used to treat cancer that has spread to the spine. This radiation causes unpleasant side effects (nausea, vomiting and diarrhea) and passes through the spinal cord, which often delays and limits treatment.

"Brachytherapy cement could be used without delay in a convenient, one-step, minimally invasive treatment to irradiate tumors," Keyak said, "and would not irradiate the spinal cord or limit future treatment options."

In animal and computational studies, the researchers evaluated the short-term safety of injecting brachytherapy cement into vertebrae; the possible migration of radioactivity into blood, urine or feces; the dose rate outside the injection site; and the radiation dose from phosphorus-32 emissions to the spinal cord and soft tissue.

At 17 weeks post-injection, physical examinations were all normal and no activity was detected in blood, urine or feces. The researchers found no evidence of the P-32 isotope in the circulating blood, no changes in blood work related to radioactivity and no neurological deficits.

"This localized treatment for bone tumors stays localized, and we did not see any effects outside the bone," Keyak said. "This is important because traditional radiation therapy causes adverse effects such as nausea, vomiting and diarrhea."

Bringing brachytherapy bone cement into being

Keyak and Dr. Harry Skinner, an orthopedic surgeon with St. Jude Heritage Medical Group, created the brachytherapy cement by infusing a common product of their trade, bone cement, with radioactive material already used in other treatments.

The brachytherapy bone cement does not have the same side effects as traditional radiation therapy, Keyak noted, because the injection directly targets the tumor and radiation doesn't pass through other organs, such as the intestines or stomach. Previous studies also revealed that it can immediately reduce pain in the spine, potentially getting patients off strong painkillers that could carry additional side effects.

Normally, a bone cancer patient needs 10 or more sessions of radiation therapy. But with the brachytherapy bone cement, Keyak said, a single injection can provide an equivalent, targeted tumor treatment with significantly less threat to the spinal cord and nerves.

"You can have this procedure and be done with it," she said. "And you can do it when tumors are smaller to prevent further bone and spinal cord damage, while limiting the pain and side effects that patients often feel."

Keyak and Skinner have started a company, Bone-Rad Therapeutics, for their product and have licensed its intellectual property (four patents and one pending patent).

The next step, Keyak said, will be more animal studies, followed by an application for a clinical trial.

A cloud simulation that captures the development and evolution of clouds based on atmospheric physical processes is more accurate than other models.

"Our model describes atmospheric conditions and thermodynamic processes as well as the fluid dynamics that govern the motion of air in the atmosphere," says Torsten Hädrich, a KAUST Ph.D. student in the international research team. "This allows us to simulate cloud phenomena more realistically than previous methods."

The model can take known atmospheric information at any time, such as temperature, humidity and wind, and simulate cloud formation, which is used for "nowcasting" of imminent cloud phenomena.

"For example, our model is able to simulate the formation of cumulonimbus clouds by considering varying temperature gradients in the atmosphere," says Hädrich. "The gradients lead to temperature inversions at certain altitudes, which are responsible for the characteristic flattened top of cumulonimbus clouds. We can also model different types of supercell thunderstorms, which has not been addressed previously."

The model was developed by KAUST's Hädrich and Dominik Michels in collaboration with researchers from Adam Mickiewicz University in Poland, the University of New Mexico in the U.S. and Google AI.

To create the model, the team had to resolve a number of physical processes, such as condensation and evaporation, and the complex interplay of physical quantities, such as temperature and humidity, within the simulation.

"Our main challenge was then to determine which parameters contribute to the formation of specific cloud types. We were able to define the physical parameters in our simulation in such a way that we could create specific cloud formations without specific knowledge," Hädrich says.

ANN ARBOR, Mich. - A third of parents say the COVID-19 pandemic has made it difficult to get dental care for their children, a new national poll suggests.

But some families may face greater challenges than others. Inability to get a dentist appointment during the pandemic was three times as common for children with Medicaid versus those with private dental coverage, according to the C.S. Mott Children's Hospital National Poll on Children's Health at Michigan Medicine.

"Regular preventive dental care helps keep children's teeth healthy and allows providers to address any tooth decay or dental problems before they become more serious," says Mott Poll co-director Sarah Clark, M.P.H.

"Our findings highlight how the pandemic may have disrupted families' dental care and exasperated potential disparities among those with insurance barriers."

Some parents attempted to continue their child's regular dental check-ups, only to find a lengthy wait time for an appointment, Clark says. Others found that the dental office had closed or reduced patient visits to urgent cases.

But the Mott Poll report revealed a silver lining too: One in four parents described improvements in how their children are taking care of their teeth and gums at home during the pandemic.

The nationally representative report is based on responses from 1,882 parents with at least one child ages 3-18.

Clark speaks more about the Mott Poll findings and dental care recommendations for families below:

1 in 3 Parents Cite Challenges Getting Preventive Dental Care

The American Association of Pediatric Dentists recommends that children receive regular teeth cleaning and exams every six months, starting when their first tooth comes in. Check-ups provide a consistent opportunity to identify and treat tooth decay, to apply protective treatments like sealants and fluoride varnish, and to educate parents and children about good dental hygiene.

But to protect patients and staff, some dental offices have changed or limited their operations to limit the spread of COVID-19.

Sixty percent of parents in the poll have tried to get preventive dental care for their child since the pandemic started. While most got an appointment in the usual time frame, 24% experienced a delay, and 7% could not get an appointment at all.

Overall, one in three parents (32%) feel COVID-19 has made it harder to get preventive dental care for their child.

Clark says a challenge for parents during the pandemic has been keeping up to date on the many changes in schedules and operations, from schools to stores to health care providers.

"Parents who were unable to get a dental appointment for their child should check back with their regular dentist, as lengthy wait times or patient restrictions may have changed," she says.

COVID-19 Safety Concerns May Delay Care

This Mott Poll suggests that some parents are worried about the risk of COVID-19 exposure during a dental visit and are delaying making a dental appointment for their child.

The majority of parents who didn't attempt to schedule preventive dental care for their child during the pandemic cited COVID-related reasons. Some 40% don't want to risk getting exposed, while 23% say the dentist office was closed or only seeing urgent patients.

Other parents say they did not call for an appointment because their child wasn't due for dental care or wasn't having any dental problems.

Most parents (67%) believe it's safe for their child to get dental care at this point in the pandemic, while 14% feel it's unsafe and 19% are unsure.

Clark recommends parents who are concerned about COVID exposure to contact their child's dentist to learn about what types of precautions have been put in place. These may include patient and staff screenings and temperature checks, and having patients wait in their cars rather than the waiting room.

"It may be helpful for dental providers to be proactive in reminding parents about the importance of regular dental check-ups for children," she says. "Reminder notices and website updates outlining changes to practice operations may also help more parents feel safe bringing children in for their visit."

Insurance Barriers Contribute to Dental Health Accessibility

Barriers to dental appointments occurred more frequently for children with Medicaid dental coverage compared to those with private dental insurance.

Among parents who tried to get their child in for preventive dental care, 15% of parents of children with Medicaid dental coverage reported not being able to get an appointment, compared to 4% of those with private dental insurance and 5% who had no coverage.

Clark notes that even outside the pandemic, these children often have difficulty finding a dentist, as many providers don't accept Medicaid payment. Some children receive preventive dental services through school or public dental clinics, but those services have decreased during the pandemic.

Among parents who didn't try to schedule a preventive dental appointment, cost was the reason for 23% of parents who lacked dental insurance, compared to very few of those with private or Medicaid coverage.

"Insurance barriers may lead to unequal opportunities for families to receive dental care critical to keeping their children's teeth healthy," Clark says.

1 in 4 Parents See Improvements in Child's Oral Health Habits

An unexpected finding from the Mott Poll report was that a fourth of parents reported improvements in their child's oral health habits during the pandemic.

This included more frequent brushing (16%), flossing (11%) and use of fluoride rinse (9%), and less drinking of sugary beverages (15%).

Overall, 28% of parents say their child has made at least one positive change, including more parents of children with Medicaid (37%) or no dental coverage (32%) compared to private dental insurance (24%).

"We were pleased to find parents describing positive changes in how their children are taking care of their teeth at home," Clark says. "Daily brushing and flossing and avoiding sugary drinks are important ways to prevent tooth decay.

"Parents whose child is not getting regular dental check-ups should take extra steps to improve daily oral health habits, particularly if regular dental care has been delayed or disrupted," she adds.

A new type of drug that helps target chemotherapy directly to cancer cells has been found to significantly increase survival of patients with the most common form of bladder cancer, according to results from a phase III clinical trial led in the UK by Queen Mary University of London and Barts Health NHS Trust.

The results are published in the New England Journal of Medicine and were presented at the 2021 American Society of Clinical Oncology's Genitourinary Cancers Symposium.

Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra. Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.

One of the most widely used treatments for this type of cancer is chemotherapy which works by targeting all the cells in the body, successfully acting upon cancer cells, but also affecting non-cancer cells, causing side effects.

A new class of drugs known as 'antibody-drug conjugates' (ADC) work by having an antibody attached to a chemotherapy-like drug. The antibody specifically targets and attaches to the cancer cells, bringing with it the chemotherapy-like drug, allowing it to only act upon those cancer cells and ignore normal cells in the body.

The trial involved 608 patients in 19 countries and tested a new ADC drug enfortumab vedotin, developed by Astellas Pharma Inc. and Seagen Inc., in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and an immunotherapy drug called a PD-1/L1 inhibitor. It found that:

The risk of death was 30 per cent lower with the new drug than with chemotherapy, with a median survival of approximately 13 months for the new drug.

Median progression-free survival, which is the time without progression of cancer, was 5.6 months for the new drug vs. 3.7 months for chemotherapy

Overall response rate, the percentage of patients with either complete or partial response, was 40.6 percent vs. 17.9 percent of patients in the chemotherapy arm

The side effects of the drug were manageable and overall similar to chemotherapy.

Lead UK researcher, Tom Powles, Professor of Genitourinary Oncology at Queen Mary University of London, and Director of Barts Cancer Centre, Barts Health NHS Trust, said: "This new type of drug has led to a survival advantage in bladder cancer which has been difficult to achieve in this difficult disease. It reduced the death rate by 30 per cent and beat chemotherapy in every setting, so this really is a big deal."