Culture

CINCINNATI - Physicians and scientists at Cincinnati Children's Hospital Medical Center used new stem cell technology to regenerate and study living patient-specific skin in the lab, giving them a precise close up view of how inherited DNA defects cause skin damage and deadly squamous cell carcinoma in children and young adults with Fanconi anemia (FA).

Reporting their findings in the journal Cell Stem Cell, the researchers are now using the complex 3D laboratory models of FA patient epidermis - and the enhanced biological detail they provide - to screen for drugs that could slow or stop the disease progression. Study authors explain that new human stem cell-derived tissue models overcome inherent limitations when studying human disease in mice, giving researchers an innovative tool to finally solve what has been a long-standing and dangerous molecular mystery.

"Squamous cell carcinoma is a global health problem, and DNA instability in children with Fanconi anemia makes them extremely susceptible," said Susanne Wells, PhD, the study's principal investigator and a cancer biologist at the Cincinnati Children's Cancer and Blood Diseases Institute. "Unlike the general population, squamous cell carcinomas that arise in the head, neck, anogenital regions, and skin of children and young adults with FA tend to be unusually aggressive and deadly."

Treatments are available for FA, but Wells explained that they come with side effects because of how the disease works.

"We need effective treatments, but identifying the molecular and cellular consequences of FA gene mutations has been difficult because mouse models don't fully recapitulate human disease. Fortunately, our bioengineered models of 3D human epidermis are helping us overcome this," said Wells, who is also director of the Epithelial Carcinogenesis and Stem Cell Program.

A Pathway to DNA Instability

FA is an inherited disorder caused by loss of function mutations in over 20 genes in human reproductive (germline) cells. Usually, the FA pathway plays an important role in normal skin structure and function. And although all cells contain crosslinked DNA, defective DNA repair machinery in people with FA causes the accumulation of defective crosslinks. This makes kids with FA prone to DNA instability, bone marrow failure, and cancer.

Researchers on the current study demonstrate this important role in their most recent data. They conducted a small controlled clinical test to demonstrate that patients with FA mutations are more prone to skin damage and blistering from environmental stress. The test, approved by the Cincinnati Children's Institutional Review Board, involved applying moderate pressure to the arms of children and young adults with FA and to a control group without FA.

Individuals with FA developed skin blisters much faster when compared to individuals in the non-FA control group, suggesting intrinsic skin fragility in this population.

Mimicking Nature's Developmental Process

To track the biological development of epidermal vulnerabilities in children with FA, donated skin tissue was used to generate patient-derived pluripotent stem cells (PSCs). The PSCs take on embryonic-like traits and can form any kind of tissue in the body. The patient-specific stem cells in this study harbored FA gene mutations, which for the purpose of direct comparison could be corrected by researchers using an inducible system.

The PSCs were then biochemically converted into epidermal stem and progenitor cells, the developmental stage at which FA mutations usually begin to disrupt skin function. Epidermal stem and progenitor cells were then used to generate complex 3D epidermal models called organotypic skin rafts, which also harbored FA mutations when left uncorrected.

The FA patient-specific tissues had diminished cell-to-cell junctions, key biological connections important to skin formation and function, together with other molecular and structural defects. These defects translated into accelerated blistering of skin after mechanically induced stress, which sets off disease processes that can progress into cancer. Skin fragility in FA might also promote cancer via elevated exposure of the body to carcinogens in the external environment.

According to the study's first author, Sonya Ruiz-Torres, PhD, a fellow in the Wells laboratory, the researchers are continuing their project. Because the study was limited by a small number of patients, the researchers are generating 3D human organotypic skin rafts to study a broader range of people with FA mutations. This should give scientists a more comprehensive look at different FA gene mutation disease processes, understand how these promote squamous cell carcinoma, and help advance the potential clinical impact of their work.

Special activity trackers can be used to fairly accurately determine the respiratory rate of people while they sleep. This is the result of a new study conducted by researchers at Martin Luther University Halle-Wittenberg (MLU) together with Charité - Universitätsmedizin Berlin and published in the journal Scientific Reports. In the future, activity trackers could be used to detect the early stages of a disease, as a person's respiratory rate can indicate signs of an undetected medical problem.

Breathing tells a lot about a patient's health. Several studies have shown that deviations from a normal respiratory rate, which is about 12 to 18 times a minute, can be an indication of a serious illness. Breathing less than six times a minute is a stronger indication of a life-threatening issue than an abnormal heartbeat. Conversely, very rapid breathing can be an early sign of heart problems. "Nevertheless, the relevance of respiratory rates in the early detection of medical risks has garnered little attention," says Dr Jan Kantelhardt, a physicist at MLU. For several years now, his research group has been investigating how physical data from measuring devices can improve patient diagnostics.

To date, a reliable measurement of respiratory rates over longer periods of time is only possible in clinics that have the right equipment. However, health studies with several hundred thousand participants, for example, require simpler devices. Up to now, a standard electrocardiogram (ECG) has often been used to measure heart rates and rhythms, thus allowing conclusions to be drawn about breathing. "We were looking for a new, inexpensive way to measure respiration," says Kantelhardt.

Together with the research group led by Professor Thomas Penzel from the Interdisciplinary Center of Sleep Medicine at the Charité, the team from Halle wanted to examine whether special activity trackers could provide a reliable alternative to ECGs. Staff members in the sleep laboratory at the Charité placed a wristband, in addition to the usual equipment, on around 400 patients. The wristbands registered movement and also took a simple ECG measurement via an electrode attached to the skin. "They are like fitness trackers but much more precise. We can use our own software to analyse the raw data," says Kantelhardt. This enables the researchers to detect the slightest bit of movement - even if the patient's arm turns slightly when breathing while asleep.

A comparison of the data from the sleep laboratory showed that these minimal movements allow more precise conclusions to be drawn about the respiratory rate than the ECG recorded at the same time. "If there is too much movement, breathing can no longer be measured with the armbands. But there are always periods at night where we can very reliably observe breathing," says Kantelhardt. According to the researcher, the armbands could be used, for example, as a diagnostic tool before a patient is sent to a sleep laboratory.

The new method will initially be used to evaluate some of the data from the so-called GNC Health Study, which began in 2014. As part of the long-term nationwide study, approximately 200,000 people regularly undergo medical examinations and interviews about their living conditions and medical histories. Some of the participants also received the same activity trackers as those in the current study. The overall aim of the project is to better understand the development of common diseases such as cancer, diabetes or cardiac arrhythmia in order to improve preventative measures, early diagnosis, and treatment in Germany.

Researchers from King's College London have identified the brain activity for the first time in a newborn baby when they are learning an association between different types of sensory experiences. Using advanced MRI scanning techniques and robotics, the researchers found that a baby's brain activity can be changed through these associations, shedding new light on the possibility of rehabilitating babies with injured brains and promoting the development of life-long skills such as speech, language and movement.

Published recently in Cerebral Cortex, the researcher builds on the fact that learning associations is a very important part of babies' development but the activity inside the brain that was responsible for learning these associations was unknown and unstudied.

Lead researcher, Dr Tomoki Arichi said it is the first time it has been shown that babies' brain activity can be altered through associative learning - and in particular, brain responses become associated with particular stimuli, in this case, sound.

"We also found that when a baby is learning, it actually is activating lots of different parts of the brain, so it is starting to incorporate the 'wider network' inside the brain which is important for processing activity," he said.

A total of 24 infants were studied by playing them a sound of a jingling bell for six seconds, coupled with a gentle movement induced by a custom-made 3D printed robot strapped to their right hand.

During this time, the resulting brain activity was measured using functional MRI (fMRI). After 20 minutes of learning an association between the two types of stimuli, the babies then just heard the sound on its own and the resulting brain activity was compared to that seen before the period of learning.

Dr Arichi said not only do the results provide new information about what is happening inside the normal baby brain when it is learning, but also have implications for the injured brain.

If a baby was not capable of processing movement, or movement is not associated with normal activity inside the brain (such might be the case in a baby with cerebral palsy), clinicians could then be able to induce that activity by learning an association with sound, and using the sound simulation to try and amplify and rehabilitate their movement.

"With our findings it raises the possibility of trying to do something to help with that through targeted stimulation and learning associations," Dr Arichi said.

"It is possible to induce activity inside the part of the brain that normally processes movement, for instance, just by using a single sound. This could be used in conjunction with rehabilitation or to try and help guide brain development early in life."

When babies are born, they have a new sensory experience around them that is completely different to what they would have been experiencing inside the womb.

They must then start to quickly understand their environment and the relationships between different things happening, which is even more important in babies that have injuries to their brain.

The researchers sought to understand how babies start to learn these key relationships between different kinds of sensory experiences and how this then contributes to the early stages of overall brain development.

"A baby's brain is constantly learning associations and changing its activity all the time so that it can respond to the new experiences that are around it," Dr Arichi said.

"In terms of influencing patients and interpreting it in a wider context, what it means is that we should be thinking about how we could help with disorders of brain development from a very early stage in life because we know that experience is constantly shaping the newborn brain's activity."

Two teams of scientists have resolved a longstanding controversy surrounding the origins of complex life on Earth.

The joint studies found molecular fossils extracted from 635-million-year-old rocks aren't the earliest evidence of animals, but instead common algae.

The researchers from The Australian National University (ANU), Max Planck Institute and Caltech say the finding has big implications for our understanding of evolution.

"It brings the oldest evidence for animals nearly 100 million years closer to the present day," Dr Lennart van Maldegem from ANU, co-author author of one study, said.

"We were able to demonstrate that certain molecules from common algae can be altered by geological processes - leading to molecules which are indistinguishable from those produced by sponge-like animals.

Professor Jochen Brocks, also based at ANU, said the mystery of when our very earliest animal ancestors emerged and became abundant in the oceans has puzzled palaeontologists for more than a century.

"Ten years ago, scientists discovered the molecular fossils of an animal steroid in rocks that were once at the bottom of an ancient sea in the Middle East," Professor Brocks said.

"The big question was, how could these sponges have been so abundant, covering much of the seafloor across the world, but leave no body fossils?"

Dr Ilya Bobrovskiy, lead author of the other study, said the researchers have been able to "solve this mystery".

"While it holds true sponges are the only living organism which can produce these steroids, chemical processes can mimic biology and transform common and abundant algae sterols into 'animal' sterols," he said.

"These molecules can be generated in the lab when simulating geological time and temperatures, but we also showed such processes did happen in ancient rocks."

Researchers have developed a new theory for observing a quantum vacuum that could lead to new insights into the behaviour of black holes.

The Unruh effect combines quantum physics and the theory of relativity. So far it has not been possible to measure or observe it, but now new research from a team led by the University of Nottingham has shed light on how this could be achieved using sound particles. The team's research has been published today in the journal Physical Review Letters.

The Unruh effect suggests that if you fly through a quantum vacuum with extreme acceleration, the vacuum no longer looks like a vacuum: rather, it looks like a warm bath full of particles. This phenomenon is closely related to the Hawking radiation from black holes.

A research team from the University of Nottingham's Black Hole Laboratory in collaboration with University of British Columbia and Vienna University of Technology has shown that instead of studying the empty space in which particles suddenly become visible when accelerating, you can create a two-dimensional cloud of ultra-cold atoms (Bose-Einstein condensate) in which sound particles, phonons, become audible to an accelerated observer in the silent phonon vacuum. The sound is not created by the detector, rather it is hearing what is there just because of the acceleration (a non-accelerated detector would still hear nothing).

The vacuum is full of particles

One of the basic ideas of Albert Einstein's theory of relativity is: Measurement results can depend on the state of motion of the observer. How fast does a clock tick? How long is an object? What is the wavelength of a ray of light? There is no universal answer to this, the result is relative - it depends on how fast the observer is moving. But what about the question of whether a certain area of space is empty or not? Shouldn't two observers at least agree on that?

No - because what looks like a perfect vacuum to one observer can be a turbulent swarm of particles and radiation to the other. The Unruh effect, discovered in 1976 by William Unruh, says that for a strongly accelerated observer the vacuum has a temperature. This is due to so-called virtual particles, which are also responsible for other important effects, such as Hawking radiation, which causes black holes to evaporate.

"To observe the Unruh effect directly, as William Unruh described it, is completely impossible for us today," explains Dr. Sebastian Erne who came from the University of Nottingham to the Atomic Institute of the Vienna University of Technology as an ESQ Fellow a few months ago. "You would need a measuring device accelerated to almost the speed of light within a microsecond to see even a tiny Unruh-effect -we can't do that." However, there is another way to learn about this strange effect: using so-called quantum simulators.

Quantum simulators

"Many laws of quantum physics are universal. They can be shown to occur in very different systems. One can use the same formulas to explain completely different quantum systems," says Jörg Schmiedmayer from the Vienna University of Technology. "This means that you can often learn something important about a particular quantum system by studying a different quantum system."

"Simulating one system with another has been especially useful for understanding black holes, since real black holes are effectively inaccessible," Dr. Cisco Gooding from the Black Hole laboratory emphasizes. "In contrast, analogue black holes can be readily produced right here in the lab."

This is also true for the Unruh effect: If the original version cannot be demonstrated for practical rea-sons, then another quantum system can be created and examined in order to see the effect there.

Atomic clouds and laser beams

Just as a particle is a "disturbance" in empty space, there are disturbances in the cold Bose-Einstein condensate - small irregularities (sound waves) that spread out in waves. As has now been shown, such irregularities should be detectable with special laser beams. Using special tricks, the Bose-Einstein condensate is minimally disturbed by the measurement, despite the interaction with the laser light.

Jörg Schmiedmayer explains: "If you move the laser beam, so that the point of illumination moves over the Bose-Einstein condensate, that corresponds to the observer moving through the empty space. If you guide the laser beam in accelerated motion over the atomic cloud, then you should be able to detect disturbances that are not seen in the stationary case - just like an accelerated observer in a vacuum would perceive a heat bath that is not there for the stationary observer."

"Until now, the Unruh effect was an abstract idea," says Professor Silke Weinfurtner who leads the Black Hole laboratory at the University of Nottingham, "Many had given up hope of experimental verification. The possibility of incorporating a particle detector in a quantum simulation will give us new insights into theoretical models that are otherwise not experimentally accessible. "?

Preliminary planning is already underway to carry out a version of the experiment using superfluid helium at the University of Nottingham. "It is possible, but very time-consuming and there are technical hurdles for us to overcome," explains Jörg Schmiedmayer. "But it would be a wonderful way to learn about an important effect that was previously thought to be practically unobservable."

The condition trimethylaminuria, is more commonly known as fish odour syndrome, it currently has no cure.

The syndrome occurs when an unpleasant smelling chemical trimethylamine (TMA) can't be broken down by the liver into a different chemical that doesn't smell.

Researchers at the University of Warwick have been able to stabilise and inhibit the enzyme that produces TMA, which means once a drug has been discovered they can test how it to stop TMA production.

Fish odour syndrome (trimethylaminuria) is a debilitating disease, in which the liver cannot break down the smelly chemical trimethylamine which is produced by enzymes from bacteria residing in the gut leaving people with a fish like odour. Researchers from the University of Warwick are paving the way to prevent the syndrome after a breakthrough in studying the enzyme in the gut which produces trimethylamine.

Currently there is no cure for fish odour syndrome, a condition which causes an unpleasant fishy smell that can affect breath, sweat, pee and vaginal fluids.

The cause of fish odour syndrome is when an enzyme pathway in the gut called CntA/B, produces TMA, this happens when the enzyme breaks down a TMA precursor called L-Carnitine which is found in dairy, fish and meat. If an individual lacks a functional liver enzyme called FMO3, they cannot degrade TMA into a non-smelly chemical form, TMAO (trimethylamine oxide). The TMA then builds up in the body and ends up in bodily fluids.

In the paper, 'Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition and inter-subunit electron transfer' published in the Journal of Biological Chemistry, researchers from the School of Life Sciences at the University of Warwick have specifically focused on the CntA protein of the CntA/B enzyme, to stabilise and study it.

CntA/B is a notoriously hard enzyme to study, but once it was stabilised the research group of Prof. Yin Chen were able to gain insight into how CntA perceives its L-Carnitine substrate, with a 3D crystal structure model and by studying the complete electron transfer pathway they could see how the protein is able to turnover TMA.

Now that it is understood how exactly TMA is produced in the gut and that the enzyme can be inhibited, there are grounds for further research into future discovery of drugs targeting the TMA-producing enzyme in the human gut.

The lead researcher, Dr Mussa Quareshy, from the School of Life Sciences at the University of Warwick comments: "We have identified novel, drug-like inhibitors which can inhibit CntA function and thus TMA formation with the potential to attenuate TMA formation in the gut microbiome. This is vital not only for people who have fish odour syndrome, but also because TMA can accelerate atherosclerosis and heart disease, therefore it's urgency to be targeted by drugs is rather significant."

Using modern nanotechnology, it is possible nowadays to produce structures which have a feature sizes of just a few nanometres. This world of the most minute particles - also known as quantum systems - makes possible a wide range of technological applications, in fields which include magnetic field sensing, information processing, secure communication or ultra-precise time keeping. The production of these microscopically small structures has progressed so far that they reach dimensions below the wavelength of light. In this way, it is possible to break down hitherto existent boundaries in optics and utilize the quantum properties of light. In other words, nanophotonics represent a novel approach to quantum technologies.

As individual photons move in the quantum regime, scientists describe the relevant light sources as quantum emitters that can be embedded in nanodiamonds, among others. These special diamonds are characterized by their very small particle size, which can range from just a few to several hundred nanometres. Researchers at the University of Münster have now succeeded for the first time in fully integrating nanodiamonds into nanophotonic circuits and at the same time addressing several of these nanodiamonds optically. In the process, green laser light is directed onto colour centres in the nanodiamonds, and the individual red photons generated there are emitted into a network of nano-scale optical components. As a result, the researchers can now control these quantum systems in a fully integrated state. The results have been published in the journal Nano Letters.

Background and methodology

Previously, it was necessary to set up bulky microscopes in order to control such quantum systems. With fabrication technologies similar to those for producing chips for computer processors, light can be directed in a comparable way using waveguides (nanofibres) on a silicon chip. These optical waveguides, measuring less than a micrometre, were produced with the electron-beam lithography and reactive ion etching equipment at the Münster Nanofabrication Facility (MNF). "Here, the size of a typical experimental set-up was shrunk to a few hundred square micrometres," explains Assistant Professor Carsten Schuck from the Institute of Physics at the University of Münster, who led the study in collaboration with Assistant Professor Doris Reiter from the Institute of Solid State Theory. "This downsizing not only means that we can save space with a view to future applications involving quantum systems in large numbers," he adds, "but it also enables us, for the first time, to control several such quantum systems simultaneously." In preliminary work prior to the current study, the Münster scientists developed suitable interfaces between the nanodiamonds and nanophotonic circuits. These interfaces were used in the new experiments, implementing the coupling of quantum emitters with waveguides in an especially effective way. In their experiments, the physicists utilized the so-called Purcell effect, which causes the nanodiamond to emit the individual photons with a higher probability into the waveguide, instead of in some random direction.

The researchers also succeeded in running two magnetic field sensors, based on the integrated nanodiamonds, in parallel on one chip. Previously, this had only been possible individually or successively. To make this possible, the researchers exposed the integrated nanodiamonds to microwaves, thus inducing changes of the quantum (spin) state of the colour centres. The orientation of the spin influences the brightness of the nanodiamonds, which was subsequently read out using the on-chip optical access. The frequency of the microwave field and therewith the observable brightness variations depend on the magnetic field at the location of the nanodiamond. "The high sensitivity to a local magnetic field makes it possible to construct sensors with which individual bacteria and even individual atoms can be detected," explains Philip Schrinner, lead author of the study.

First of all, the researchers calculated the nanophotonic interface designs using elaborate 3D simulations, thus determining optimal geometries. They then assembled and fabricated these components into a nanophotonic circuit. After the nanodiamonds were integrated and characterized using adapted technology, the team of physicists carried out the quantum mechanical measurements by means of a set-up customized for the purpose.

"Working with diamond-based quantum systems in nanophotonic circuits allows a new kind of accessibility, as we are no longer restricted by microscope set-ups," says Doris Reiter. "Using the method we have presented, it will be possible in the future to simultaneously monitor and read out a large number of these quantum systems on one chip," she adds. The researchers' work creates the conditions for enabling further studies to be carried out in the field of quantum optics - studies in which nanophotonics can be used to change the photo-physical properties of the diamond emitters. In addition to this there are new application possibilities in the field of quantum technologies, which will benefit from the properties of integrated nanodiamonds - in the field of quantum sensing or quantum information processing, for example.

The next steps will include implementing quantum sensors in the field of magnetometry, as used for example in materials analysis for semi-conductor components or brain scans. "To this end", say Carsten Schuck, "we want to integrate a large number of sensors on one chip which can then all be read out simultaneously, and thus not only register the magnetic field at one place, but also visualize magnetic field gradients in space."

(Jena, Germany) Everything that lives has metabolites, produces metabolites and consumes metabolites. These molecules arise as intermediate and end products from chemical processes in an organism's metabolism. Therefore, they not only have huge significance for our lives, but they also provide valuable information about the condition of a living being or an environment. For example, metabolites can be used to detect diseases or, in the field of environmental technology, to examine drinking water samples. However, the diversity of these chemical compounds causes difficulties in scientific research. To date, only few molecules and their properties are known. If a sample is analysed in the laboratory, only a relatively small proportion of it can be identified, while the majority of molecules remain unknown.

Bioinformaticians at Friedrich Schiller University Jena, Germany together with colleagues from Finland and the USA, have now developed a unique method with which all metabolites in a sample can be taken into account, thus considerably increasing the knowledge gained from examining such molecules. The team reports on its successful research in the renowned scientific journal Nature Biotechnology.

Learning, recognising and assigning structural properties

"Mass spectrometry, one of the most widely used experimental methods for analysing metabolites, identifies only those molecules that can be uniquely assigned by matching them against a database. All other, previously unknown, molecules contained in the sample do not provide much information," explains Prof. Sebastian Böcker from the University of Jena. "With our newly developed method, called CANOPUS, however, we also obtain valuable insight from the unidentified metabolites in a sample, as we can assign them to existing compound classes."

CANOPUS works in two phases: first, the method generates a 'molecular fingerprint' from the fragmentation spectrum measured by means of mass spectrometry. This contains information about the structural properties of the measured molecule. In the second phase, the method uses the molecular fingerprint to assign the metabolite to a specific compound class without having to identify it.

Learning from the data

"Machine learning methods usually require large amounts of data in order to be trained. In contrast, our two-stage process makes it possible in the first step to train on a comparatively small amount of data of tens of thousands of fragmentation mass spectra. Then, in the second step, the characteristic structural properties that are significant for a compound class can be determined from millions of structures," explains Dr Kai Dührkop from the University of Jena.

The system therefore identifies these structural properties in an unknown molecule within a sample and then assigns it to a specific compound class. "This information alone is sufficient to answer many important questions," Böcker emphasises. "The precise identification of a metabolite would be far more complex and is often not necessary at all." The CANOPUS method uses a deep neural network predicting around 2,500 compound classes.

With their method, the Jena bioinformaticians have compared, for example, the intestinal flora of mice in which one experimental group had been treated with antibiotics. The examinations show which metabolites the mouse and its intestinal flora produce. Such research results can provide important information about the human digestive and metabolic system. Through two further application examples, which they present in their study, the Jena scientists demonstrate the functionality and power of the CANOPUS method.

Jena molecule search engine used millions of times

With the new method, the bioinformaticians from Jena are expanding the possibilities of the search engine for molecular structures "CSI:FingerID", which they have been making available to the international research community for around five years. Researchers around the world now use this service thousands of times a day to compare a mass spectrum from a sample with various online databases, in order to identify a metabolite more precisely. "We are approaching the one hundred millionth request and we are sure that CANOPUS will further increase the number of users," says Sebastian Böcker.

The new process strengthens the field of metabolomics - that is, research on these omnipresent small molecules - and increases its potential in many research areas, such as pharmaceuticals. Many active pharmaceutical substances in use for decades, such as penicillin, are metabolites; others could be developed with their help.

Ordinary solid-state lasers, as used in laser pointers, generate light in the visible range. For many applications, however, such as the detection of molecules, radiation in the mid-infrared range is needed. Such infrared lasers are much more difficult to manufacture, especially if the laser radiation is required in the form of extremely short, intense pulses.

For a long time, scientists have been looking for simple methods to produce such infrared laser pulses - at the TU Wien this has now been achieved, in cooperation with Harvard University. The new technology does not require large experimental setups; it can be easily miniaturized and is therefore particularly interesting for practical applications. The new results have now been presented in the journal "Nature Communications".

The frequency comb

"We generate laser light in the mid-infrared range with tailor-made quantum cascade lasers manufactured in the ultra-modern Nano-Center of TU Wien", says Johannes Hillbrand from the Institute of Solid State Electronics at the TU Vienna, first author of the study. While in ordinary solid-state lasers the type of light emitted depends on the atoms in the material, in quantum cascade lasers tiny structures in the nanometer range are crucial. By designing these structures appropriately, the wavelength of the light can be precisely adjusted.

"Our quantum cascade lasers do not just deliver a single color of light, but a whole range of different frequencies," says Ass.Prof. Benedikt Schwarz, who led the research work in his ERC grant funded project. "These frequencies are arranged very regularly, always with the same distance in between, like the teeth of a comb. Therefore, such a spectrum is called a frequency comb".

Light is like a pendulum

However, it is not only the frequencies emitted by such a quantum cascade laser that are decisive, but also the phase with which the respective light waves oscillate. "You can compare this to two pendulums connected by a rubber band," explains Johannes Hillbrand. "They can either swing back and forth, exactly in parallel, or opposite to each other, so that they either swing towards each other or away from each other. And these two vibration modes have slightly different frequencies."

It is quite similar with laser light, which is composed of different wavelengths: The individual light waves of the frequency comb can oscillate exactly in sync - then they superimpose each other in an optimal way and can generate short, intense laser pulses. Or there can be shift between their oscillations, in which case no pulses are created, but laser light with an almost continuous intensity.

The light modulator

"In quantum cascade lasers, it has previously been difficult to switch back and forth between these two variants," says Johannes Hillbrand. "However, we have built a tiny modulator into our quantum cascade laser, which the light waves pass by again and again." An alternating electrical voltage is applied to this modulator. Depending on the frequency and strength of the voltage, different light oscillations can be excited in the laser.

"If you drive this modulator at exactly the right frequency, you can achieve that the different frequencies of our frequency comb all oscillate at exactly in sync," says Benedikt Schwarz. "This makes it possible to combine these frequencies into short, intense laser pulses - more than 12 billion times per second".

This level of control over short infrared laser pulses was previously not possible with semiconductor lasers. Similar types of light could at best only be generated using very expensive and lossy methods. "Our technology has the decisive advantage that it can be miniaturized," emphasizes Benedikt Schwarz. "One could use it to build compact measuring instruments that use these special laser beams to search for very specific molecules in a gas sample, for example. Thanks to the high light intensity of the laser pulses, measurements that require two photons at the same time are also possible.

Resistive switching memory devices offer several advantages over the currently used computer memory technology. Researchers from the MIPT Atomic Layer Deposition Lab have joined forces with colleagues from Korea to study the impact of electrode surface morphology on the properties of a resistive switching memory cell. It turned out that thicker electrodes have greater surface roughness and are associated with markedly better memory cell characteristics. The research findings were published in ACS Applied Materials & Interfaces.

Some materials, such as transition metal oxides, can switch from a dielectric to a conductive state and back under applied voltage. This effect underlies resistive random-access memory, a highly promising technology for nonvolatile storage. RRAM devices based on transition metal oxides are characterized by low energy consumption, great endurance, ease of extension, and rapid operation, prompting many companies to invest in the technology.

A resistive memory cell is a layered structure with an insulating layer positioned between two electrodes, to which the switching voltage is applied. The properties of the cell depend on the material between the electrodes, as well as on the composition and shape of the electrodes themselves. It is common for one electrode to be made of titanium nitride and the other of platinum. However, platinum is incompatible with modern semiconductor technology due to the absence of dry etching capability. This is not the case with ruthenium, which has a further advantage of being suitable for atomic layer deposition (ALD), enabling the manufacture of 3D vertical memory structures.

Study co-author and MIPT PhD student Aleksandra Koroleva from the University's School of Electronics, Photonics and Molecular Physics commented: "To investigate how electrode thickness affects memory cell parameters, we grew ruthenium electrodes with a varying number of atomic layer deposition cycles. We then examined the surface of the electrodes using atomic force microscopy." The team found that as the number of ALD layers grew, the grain size on the electrode surface increased from 5 to 70 nanometers.

The researchers tested the performance of their ruthenium films with different thicknesses as the bottom electrode in tantalum oxide-based RRAM, showing that thicker -- and therefore rougher -- electrodes actually improved the key performance characteristics of the memory device: its stability and endurance. Increasing ruthenium film thickness resulted in a lower memory cell resistance in both states and a higher resistance ratio between the low- and high-resistance states. Enhancing electrode roughness also decreased the forming and switching voltages, and increased the device's endurance to an impressive 50 million switching cycles.

To explain their findings, the team proposed a simplified model that reflects the electric field distribution on large grains on the ruthenium electrode surface. The explanation was confirmed with conductive atomic force microscopy.

"Our findings offer insights into how memory cells of the new type could be greatly improved. Thicker ruthenium films used as electrodes have rougher surfaces. This in turn gives rise to areas of locally enhanced electric field on the slopes of the grains that boost the key performance characteristics of the device. We believe that our investigation will help to create more efficient and reliable memory devices in the future," adds study co-author Andrey Markeev, who leads the ALD group at MIPT.

FRANKFURT. The surface of the SARS-CoV-2 virus is studded with spike proteins. The virus needs these in order to dock onto proteins (ACE2 receptors) on the surface of the host cell. Before this docking is possible, parts of the spike protein have to be cleaved by the host cell's enzymes - proteases.

In cell culture experiments with various cell types, the international scientific team led by Professor Jindrich Cinatl, Institute for Medical Virology at the University Hospital Frankfurt, Professor Martin Michaelis, and Dr Mark Wass (both University of Kent) demonstrated that the protease inhibitor aprotinin can inhibit virus replication by preventing SARS-CoV2 entry into host cells. Moreover, aprotinin appears to compensate for a SARS-CoV2-induced reduction of endogenous protease inhibitors in virus-infected cells.

Influenza viruses require host cell proteases for cell entry in a similar way as coronaviruses. Hence, an aprotinin aerosol is already approved in Russia for the treatment of influenza.

Professor Jindrich Cinatl said: "Our findings show that aprotinin is effective against SARS-CoV2 in concentrations that can be achieved in patients. In aprotinin we have a drug candidate for the treatment of COVID-19 that is already approved for other indications and could readily be tested in patients."

Galaxies like the Milky Way formed by the merging of smaller progenitor galaxies. An international team of astrophysicists led by Dr Diederik Kruijssen from the Centre for Astronomy at Heidelberg University has succeeded in reconstructing the merger history of our home galaxy, creating a complete family tree. To achieve this, the researchers analysed the properties of globular clusters orbiting the Milky Way with artificial intelligence. Their investigations revealed a previously unknown galaxy collision that must have permanently altered the appearance of the Milky Way.

Globular clusters are dense groups of up to a million stars that are almost as old as the universe itself. The Milky Way hosts over 150 of such clusters. "Many of them came from smaller galaxies that later merged to form the Milky Way that we live in today," explains Dr Kruijssen. To study the merger history, the Heidelberg researcher and his colleague Dr Joel Pfeffer of Liverpool John Moores University (United Kingdom) and their research groups developed a suite of advanced computer simulations, called E-MOSAICS. These simulations include a complete model for the formation, evolution, and destruction of globular clusters.

The German-British team used these simulations to relate the ages, chemical compositions, and orbital motions of the globular clusters to the properties of the progenitor galaxies in which they formed, more than ten billion years ago. By applying these insights to groups of globular clusters in the Milky Way, they not only determined how massive these progenitor galaxies were, but also when they merged with our home galaxy.

"The main challenge was that the merger process is extremely messy, because the orbits of the globular clusters are completely reshuffled," explains Dr Kruijssen. "To overcome this complexity, we developed an artificial neural network and trained it on the E-MOSAICS simulations. We were astonished at how precisely the artificial intelligence allowed us to reconstruct the merger histories of the simulated galaxies, using only their globular clusters." The researchers then applied the neural network to groups of globular clusters in the Milky Way and precisely determined the stellar masses and merger times of the progenitor galaxies. They also discovered a previously unknown collision between the Milky Way and an unknown galaxy, which the researchers named "Kraken".

"The collision with Kraken must have been the most significant merger the Milky Way ever experienced," Dr Kruijssen adds. Before, it was thought that a collision with the Gaia-Enceladus galaxy some nine billion years ago was the biggest collision event. However, the merger with Kraken took place eleven billion years ago, when the Milky Way was four times less massive than today. "As a result, the collision with Kraken must have truly transformed what the Milky Way looked like at the time," explains the Heidelberg scientist.

Taken together, these findings allowed the team of researchers to reconstruct the first complete family tree of our home galaxy. Over the course of its history, the Milky Way cannibalised about five galaxies with more than 100 million stars, and about ten more with at least ten million stars. The most massive progenitor galaxies collided with the Milky Way between six and eleven billion years ago. Dr Kruijssen expects that these predictions will aid the future search for the remains of the progenitor galaxies. "The debris of more than five progenitor galaxies has now been identified. With current and upcoming telescopes, it should be possible to find them all," the Heidelberg researcher concludes.

The research results were published in Monthly Notices of the Royal Astronomical Society.

ATHENS, Ohio (Nov. 23, 2020) - Dr. Jeff Russell, associate professor of athletic training within the College of Health Sciences and Professions at Ohio University, is shining a light on a segment of concussion patients who often go unnoticed in comparison to athletes: performing artists.

Russell's new paper highlights the risk of concussion for dance, circus, theater and film and television stunt performers, along with guidelines for treatment. It is the first-time concussion risk for film and television stunt performers that is being highlighted in scientific literature.

"When you stop and think about how influential a field is, pretty much everybody in the world watches movies and television. This type of medium is an art form with a huge influence, but people don't know what goes on behind the scenes to make it look so cool on television or on the movie screen," Russell said. "That's where my role as a healthcare worker in performing arts comes into play. I understand what artists go through - I look at what they do with different eyes, and I look at it in terms of risk and what potential injuries could happen or what might be an unsafe condition."

The article was released by Physical Medicine and Rehabilitation Clinics of North America on Oct. 29, 2020. The key findings include that dance and performing arts are highly physical activities and performers could experience a head impact from many sources, yet the scientific literature devoted to concussions in performing arts is very low in comparison to that in sports.

Russell noted that this may be due to the fact that, while everyone watches sports and can see injuries occur, injuries to stunt actors and performing artists often occur behind the scenes and away from the public view.

"When football players are running into each other, when hockey players are skating into each other, when soccer players are heading the ball, it's obvious to us that concussions can happen, but that is not obvious in the arts," Russell said. "The injuries aren't necessarily happening only during the performances because that's just one small piece of artistic effort. Injuries happen a lot in the rehearsals or backstage behind the scenes where you can't see them."

Those with sport concussions also receive better care because their injuries are more well known. In fact, many athletes have athletic trainers on hand who are equipped to recognize concussion symptoms; however, performing artists, including stunt performers, do not always have the same healthcare resources.

"It's quite unfortunate," Russell said, noting the lack of adequate concussion care for performing artists. "We've got to change the way things are done, with the goal of protecting the performers while not impeding the production of the film or television program and not negatively affecting the profitability of the production companies."

Stunt performers may also be more prone to remain quiet about an injury in fear of losing their job. Russell compared it to the NFL, where athletes won't receive a pay cut if they have to sit out of games while on concussion protocol. However, for the stunt performers, if they cannot perform their stunts, they are out of a job. This means that their symptoms can go undiagnosed and untreated, which can be dangerous.

"Concussions are important primarily because they're an injury to your brain. If you're not taking care of your brain, that means the rest of your body won't work right," Russell said. "If you have a concussion and you don't tell anybody, and keep doing what you're doing then you have another concussion on top of it, that can be a very, very dangerous situation. One of the side effects of doubling concussions can even be death - the brain just can't handle it and shuts down."

Director of OHIO's School of Theater Merri Biechler said that Russell's research is changing the way that the performing arts industry views and addresses injuries.

"Many theater professionals push through injury because there's a false sense that 'the show must go on.' Dr. Russell's work requires us to slow down, to focus on self care," Biechler said.

Russell has been working with concussions in performing artists since the early 2000s after a student came to him and requested help. Since then, he has led research into the causes and risks of the injury in performers. He is also the director of OHIO's Science and Health in Artistic Performance (SHAPe) Clinic, a facility that provides injured performing artists care from licensed athletic trainers.

"This is why I changed my career from sports medicine to performing arts medicine. I saw dancers and some other artists that were suffering injuries, but there was nobody to take care of them. It didn't sit right with me," Russell said. "I can't solve all the world's problems, but I can work right here and take care of these people. So that's what we're doing now at OHIO with the SHAPe Clinic. We can't do it for everyone, but we're going to do it for these ones here at our University. We're going to set an example, and we're going to move forward and be ones that are on the cutting edge of this. Both the clinical care and the research are fundamental to this mission."

OHIO's SHAPe Clinic is a partnership between College of Fine Arts and the College of Health Sciences and Professions, and provides care to many students in the performing arts, including dance, music, theater and the Ohio University Marching 110.

"The work being done by the SHAPe Clinic to not only support the physical needs of our performance students in theater, dance and music, but also to bring attention to the importance of access to this type of expert care and oversight in the field is extraordinary," College of Fine Arts Dean Dr. Matthew Shaftel said. "This early socialization of often overlooked specialized care for performing artists makes a world of difference when these students transition to the professional stage and screen."

This interdisciplinary collaboration has already made great strides in increasing the safety of OHIO's theater performers.

"A few years back, an actor experienced a concussion during a performance. We allowed the actor to perform future shows within the concussion protocol and informed the audience that they would see a slightly different physical performance. The production experienced a heightened attention that literally generated something new on the stage," Biechler said. "It was a great lesson that when we take care of our health, unique experiences are created."

Russell hopes that his research work will continue to shine a light on the subpar care many performing artists--not just stunt performers--receive for concussions, and that eventually this will lead to changes in the industry and the care artists receive.

"Ultimately, this work is about helping people," Russell said. "It's about serving them, lifting them up, adding value to them and helping them, and if that is what your research is about, I don't think you can do any better than that."

Cambridge, MA (November 23, 2020)--An international team of scientists led by the Center for Astrophysics | Harvard & Smithsonian, has identified a problem with the growing interest in extractable resources on the moon: there aren't enough of them to go around. With no international policies or agreements to decide "who gets what from where," scientists believe tensions, overcrowding, and quick exhaustion of resources to be one possible future for moon mining projects. The paper published today in the Philosophical Transactions of the Royal Society A.

"A lot of people think of space as a place of peace and harmony between nations. The problem is there's no law to regulate who gets to use the resources, and there are a significant number of space agencies and others in the private sector that aim to land on the moon within the next five years," said Martin Elvis, astronomer at the Center for Astrophysics | Harvard & Smithsonian and the lead author on the paper. "We looked at all the maps of the Moon we could find and found that not very many places had resources of interest, and those that did were very small. That creates a lot of room for conflict over certain resources."

Resources like water and iron are important because they will enable future research to be conducted on, and launched from, the moon. "You don't want to bring resources for mission support from Earth, you'd much rather get them from the Moon. Iron is important if you want to build anything on the moon; it would be absurdly expensive to transport iron to the moon," said Elvis. "You need water to survive; you need it to grow food--you don't bring your salad with you from Earth--and to split into oxygen to breathe and hydrogen for fuel."

Interest in the moon as a location for extracting resources isn't new. An extensive body of research dating back to the Apollo program has explored the availability of resources such as helium, water, and iron, with more recent research focusing on continuous access to solar power, cold traps and frozen water deposits, and even volatiles that may exist in shaded areas on the surface of the moon. Tony Milligan, a Senior Researcher with the Cosmological Visionaries project at King's College London, and a co-author on the paper said, "Since lunar rock samples returned by the Apollo program indicated the presence of Helium-3, the moon has been one of several strategic resources which have been targeted."

Although some treaties do exist, like the 1967 Outer Space Treaty--prohibiting national appropriation--and the 2020 Artemis Accords--reaffirming the duty to coordinate and notify--neither is meant for robust protection. Much of the discussion surrounding the moon, and including current and potential policy for governing missions to the satellite, have centered on scientific versus commercial activity, and who should be allowed to tap into the resources locked away in, and on, the moon. According to Milligan, it's a very 20th century debate, and doesn't tackle the actual problem. "The biggest problem is that everyone is targeting the same sites and resources: states, private companies, everyone. But they are limited sites and resources. We don't have a second moon to move on to. This is all we have to work with." Alanna Krolikowski, assistant professor of science and technology policy at Missouri University of Science and Technology (Missouri S&T) and a co-author on the paper, added that a framework for success already exists and, paired with good old-fashioned business sense, may set policy on the right path. "While a comprehensive international legal regime to manage space resources remains a distant prospect, important conceptual foundations already exist and we can start implementing, or at least deliberating, concrete, local measures to address anticipated problems at specific sites today," said Krolikowski. "The likely first step will be convening a community of prospective users, made up of those who will be active at a given site within the next decade or so. Their first order of business should be identifying worst-case outcomes, the most pernicious forms of crowding and interference, that they seek to avoid at each site. Loss aversion tends to motivate actors."

There is still a risk that resource locations will turn out to be more scant than currently believed, and scientists want to go back and get a clearer picture of resource availability before anyone starts digging, drilling, or collecting. "We need to go back and map resource hot spots in better resolution. Right now, we only have a few miles at best. If the resources are all contained in a smaller area, the problem will only get worse," said Elvis. "If we can map the smallest spaces, that will inform policymaking, allow for info-sharing and help everyone to play nice together so we can avoid conflict."

While more research on these lunar hot spots is needed to inform policy, the framework for possible solutions to potential crowding are already in view. "Examples of analogs on Earth point to mechanisms for managing these challenges. Common-pool resources on Earth, resources over which no single actor can claim jurisdiction or ownership, offer insights to glean. Some of these are global in scale, like the high seas, while other are local like fish stocks or lakes to which several small communities share access," said Krolikowski, adding that one of the first challenges for policymakers will be to characterize the resources at stake at each individual site. "Are these resources, say, areas of real estate at the high-value Peaks of Eternal Light, where the sun shines almost continuously, or are they units of energy to be generated from solar panels installed there? At what level can they can realistically be exploited? How should the benefits from those activities be distributed? Developing agreement on those questions is a likely precondition to the successful coordination of activities at these uniquely attractive lunar sites."

Oversized, hairy tarantulas may be unsightly and venomous, but surprisingly their hunter toxin may hold answers to better control of chronic pain.

A bird-catching Chinese tarantula bite contains a stinger-like poison that plunges into a molecular target in the electrical signaling system of their prey's nerve cells.

A new high-resolution cryo-electron microscopy study shows how the stinger quickly locks the voltage sensors on sodium channels, the tiny pores on cell membranes that create electrical currents and generate signals to operate nerves and muscles. Trapped in their resting position, the voltage sensors are unable to activate.

The findings are published Nov. 23 in Molecular Cell, a journal of Cell Press.

"The action of the toxin has to be immediate because the tarantula has to immobilize its prey before it takes off," said William Catterall, professor of pharmacology at the University of Washington School of Medicine. He was the senior researcher, along with pharmacology professor and Howard Hughes Medical Institute investigator, Ning Zheng, on the study of the molecular damage inflicted by tarantula venom.

While some might dismiss those tarantulas as ugly, tough and mean, medical scientists are actually interested in their venom's ability to trap the resting state of the voltage sensor on voltage-gated sodium channels and shut them down. Such studies of toxins from these "big, nasty dudes," as Catterall describes them, could point to new approaches to structurally designing drugs that might treat chronic pain by blocking sensory nerve signals.

Catterall explained that chronic pain is a difficult-to-treat disorder. Efforts to seek relief can sometimes be a gateway to opiate overdose, addiction, prolonged withdrawal, and even death. The development of safer, more effective, non-addictive drugs for pain management is a vital need.

However, because it has been hard to capture the functional form of the tarantula toxin-ion channel chemical complex, reconstructing the toxin's blocking method in a small molecule has so far eluded molecular biologists and pharmacologists seeking new ideas for better pain drug designs.

Researchers overcame this obstacle by engineering a chimeric model sodium channel. Like mythical centaurs, chimeras are composed of parts of two or more species. The researchers took the toxin-binding region from a specific type of human sodium channel that is crucial for pain transmission and imported it into their model ancestral sodium channel from a bacterium. They were then able to obtain a clear molecular view of configuration of the potent toxin from tarantula venom as it binds tightly to its receptor site on the sodium channel.

This achievement revealed the structural basis for voltage sensor trapping of the resting state of the sodium channel by this toxin.

"Remarkably, the toxin plunges a 'stinger' lysine residue into a cluster of negative charges in the voltage sensor to lock it in place and prevent its function," Catterall said. "Related toxins from a wide range of spiders and other arthropod species use this molecular mechanism to immobilize and kill their prey."

Catterall explained the medical research importance of this discovery. The human sodium channel placed into the chimeric model is called the Nav1.7 channel. It plays an essential role, he noted, in transmission of pain information from the peripheral nervous system to the spinal cord and brain and is therefore a prime target for pain therapeutics.

"Our structure of this potent tarantula toxin trapping the voltage sensor of Nav1.7 in the resting state," Catterall noted, "provides a molecular template for future structure-based drug design of next-generation pain therapeutics that would block function of Nav1.7 sodium channels."