Tech

Piezoelectric materials can convert electrical voltage to mechanical displacement and vice versa. They are ubiquitous in modern wireless communication networks such as in cellphones. Today, piezoelectric devices, including filters, transducers and oscillators, are used in billions of devices for wireless communications, global positioning, navigations, and space applications.

In an article published in Nature, a collaboration lead by Professor Tobias J. Kippenberg at EPFL and Professor Sunil A. Bhave at Purdue University has combined piezoelectric aluminium nitride (AlN) technology - used in modern cellphones' radio frequency filters - with ultralow-loss silicon nitride (Si3N4) integrated photonics, demonstrating a new scheme for on-chip acousto-optic modulation.

The hybrid circuit allows wideband actuation on photonic waveguides with ultralow electrical power - a feat that has been so far challenging. The circuit itself was manufactured using CMOS-compatible foundry processes, which are widely used to construct microprocessors, microcontrollers, memory chips, and other digital logic circuits.

Light and sound

To build the circuit, the scientists used Si3N4, which has emerged as a leading material for chip-scale, microresonator-based optical frequency combs ("microcombs"). Microcombs are used in a range of precision-demanding applications, including coherent communications, astronomical spectrometer calibration, ultrafast ranging, low-noise microwave synthesis, optical atomic clocks, and most recently, parallel coherent LiDAR.

The researchers fabricated piezoelectric AlN actuators on top of the ultralow-loss Si3N4 photonic circuits, and applied a voltage signal on them. The signal induced bulk acoustic waves electromechanically, which can modulate the generated microcomb in the Si3N4 circuits. In short, sound shakes light.

A key feature of this scheme is that it maintains the ultralow loss of Si3N4 circuits. "This achievement represents a new milestone for the microcomb technology, bridging integrated photonics, microelectromechanical systems engineering and nonlinear optics," says Junqiu Liu, who leads the fabrication of Si3N4 photonics chips at EPFL's Center of MicroNanoTechnology (CMi). "By harnessing piezoelectric and bulk acousto-optic interactions, it enables on-chip optical modulation with unprecedented speed and ultralow power consumption."

Two new applications

Using the new hybrid system, the researchers demonstrated two independent applications: First, the optimization of a microcomb-based massively parallel coherent LiDAR, based on their previous work also published in Nature recently. This approach could provide a route to chip-based LiDAR engines driven by CMOS microelectronic circuits.

Second, they built magnet-free optical isolators by spatio-temporal modulation of a Si3N4 microresonator, which was published recently in Nature Communications. "The tight vertical confinement of the bulk acoustic waves prevents cross-talk and allows for close placement of the actuators, which is challenging to achieve in p-i-n silicon modulators," says Hao Tian, who fabricated the piezoelectric actuators at the Scifres cleanroom in Purdue's Birck Nanotechnology Center.

The new technology could provide impetus to microcomb applications in power-critical systems, e.g. in space, datacenters and portable atomic clocks, or in extreme environments such as cryogenic temperatures. "As yet unforeseen applications will follow up across multiple communities," says Professor Kippenberg. "It's been shown time and again that hybrid systems can obtain advantages and functionality beyond those attained with individual constituents."

"I recently read a Scientific American article that really resonated with me," adds Professor Bhave. "It is called - Why Science is Better When its Multinational. Our results would not be possible without this multidisciplinary and inter-continental collaboration."

Warmblood fragile foal syndrome is a severe, usually fatal, genetic disease that manifests itself after birth in affected horses. Due to the defect, the connective tissue is unstable. Under force, for instance, the skin tears from the tissue underneath and the joints can suffer dislocation. A research team from the Universities of Göttingen and Halle has now been able to prove that the disease did not stem from the English thoroughbred stallion Dark Ronald XX, which had been the assumption until now. The results have been published in the journal Animal Genetics.

The mystery of the genetic defect could have been solved in 2012: this is when gene responsible was identified. It is called PLOD1 and normally ensures that collagen molecules in the skin and connective tissue can bind to form a stable network. The mutation in the PLOD1 gene prevents "cross-linking" which is needed for stable collagen. The exact origin of the mutation was previously unclear. Since the spread of the genetic defect is also a problem in horse-breeding in Germany, the Vereinigte Informationssysteme Tierhaltung (IT-Solutions for Animal Production) in Verden 2019 determined the possible origin of the genetic defect from the test results of around 2,000 horses and their pedigree records. The investigation concluded that the genetic defect was probably due to the English thoroughbred stallion Dark Ronald XX (1905-1928) or his father, Bay Ronald XX, and the defect was then spread through their offspring. The current research, led by the University of Göttingen, calls this theory into question. "We have now succeeded in proving that Dark Ronald XX was not a carrier of the PLOD1 mutation and can therefore be excluded as the original source of this genetic defect," says Professor Bertram Brenig, Director of the Institute of Veterinary Medicine at the University of Göttingen and lead author of the study. Doubts about whether the mutation descended from Dark Ronald XX were already expressed in 2019, and further investigation reveals a Hanoverian stallion born in 1861.

Dark Ronald XX was an important thoroughbred stallion who had a great influence on German horse-breeding. He was sold to Germany in 1913 and was used as a stud - a stallion with highly prized heritable characteristics - first in Graditz and later in Altefeld. In 1928, he was brought to the veterinary clinic of the University of Halle for treatment due to intestinal colic and this is where he died. Since then his remains - such as skeleton, heart and skin - have been kept in one of the natural science collections of the Martin Luther University Halle-Wittenberg. "This is most fortunate, as it has allowed us to examine Dark Ronald XX directly for the presence of the PLOD1 mutation," says Brenig. The scientists were thus able to examine small pieces of Dark Ronald XX's skin. "Examining the DNA from the nearly 100-year-old skin of Dark Ronald XX was not easy," says co-author Dr Renate Schafberg from the University of Halle, "because we knew nothing about the tanning or other preservation treatments of the skin."

The disease itself is not new and probably originated in the middle of the 18th century. Since then, all breeding animals have been consistently tested for the genetic defect. There is a comparable genetic disease in humans, known as Ehlers-Danlos syndrome, which shows similar symptoms.

Pharmacists at Martin Luther University Halle-Wittenberg (MLU) have succeeded in detecting small amounts of coronavirus SARS-CoV-2 using mass spectrometry. For their investigation, they used gargle solutions of COVID-19 patients. The novel method might supplement conventional tests. It is currently undergoing improvements and might be available as standard diagnostic tool for COVID-19 in the future. Initial results have been published in the Journal of Proteome Research.

The most prominent test method being used to detect whether someone suffers from an acute COVID-19 infection is the polymerase chain reaction, or briefly, PCR. The PCR technique is highly specific as it detects the viral genome. Alternative tests detect antibodies against the disease. As antibodies are generated in the body during the course of the infection, they can only be used to detect a past infection or an advanced stage of the disease. Antibody tests are often non-specific and sometimes unable to distinguish between the different corona viruses that can affect humans. Testing labs worldwide are therefore reaching the limits of their capabilities.

Professor Andrea Sinz, a mass spectrometry expert at the Institute of Pharmacy at MLU, had the idea of developing a new mass spectrometry-based test to complement PCR. Mass spectrometry allows molecules to be precisely identified based on their mass and charge. Sinz and her colleagues developed a method to look for components of SARS-CoV-2 viruses. "We directly measure the proteins of the virus, not the genetic material," Sinz explains.

For the experiments, University Medicine Halle provided gargle solutions of three COVID-19 patients. Sinz's research group developed a method to detect virus components in these highly diluted samples. "Although we received only a small amount of gargle solution, we were able to detect components of viral proteins," says Dr Christian Ihling, who carried out the tests. "This was quite surprising, and I hadn't expected it to work myself," Sinz adds. The test is highly specific for the virus since the corresponding proteins are only present in SARS-CoV-2. In addition, the test can be used in the early stages of the disease when many viruses are present in the mouth and throat.

According to Sinz, the test currently takes about 15 minutes. The research group is now trying to further reduce the analysis time using artificially produced virus components. Sinz is also looking for further collaborations, including companies. "Together with a company from Hesse, we are planning to use another mass spectrometric method that would enable us to perform measurements within seconds". This method would then be comparable to so-called "biotyping", which is an established method used by hospitals to diagnose bacterial or fungal infections. However, it remains to be seen whether this approach will also be suitable for detecting SARS-CoV-2. Sample preparation would no longer be time-consuming and the measurements could also be carried out by non-specialized personnel.

The novel diagnostic method relying on mass spectrometry will however not be available immediately. Sinz hopes that it will be up and ready in a few months. "I am in close contact with colleagues worldwide, some of whom have had a far worse experience of the pandemic than we have." She is also a founding member of the "COVID-19 Mass Spectrometry Coalition", a research association that relies on mass spectrometry for a better understanding of the disease.

In the pandemic age of telehealth and new technologies, remote site lab or point-of-care (POC) testing of biofluids is a potentially rapid and non-invasive way to test for most diseases - including COVID-19.

Now scientists at Flinders University have run tests on the bioprobe industry, recommending the potential of a novel group of bioprobes with aggregation-induced emission (AIE) properties, so-called AIEgens, as being the best way forward to deliver accurate clinical biomarkers.

Every drop of bodily fluid, or biofluid, holds valuable clues to a person's health. The bioprobe industry is rapidly responding to the rising need for fast screening and early detection of diseases via biomarkers in saliva, blood, urine or sweat samples.

In a new journal article, the researchers recommend rapid and widespread rollout of low-cost, accurate AIE bioprobe applications which can pick up disease biomarkers in very low concentrations.

"AIE bioprobes with portable device are an exciting new method for detecting biomarkers in bodily fluids," says Flinders University Professor Youhong Tang, from the Australia-China Centre for Personal Health Technologies.

"Increasingly, these low cost and convenient technologies will help raise health servies in rural areas and developing countries.

"This technique can be easily enhanced by commonly available wearable devices such as smartphone data capture and analysis, and data cloud storage," he says.

Several applications of AIE bioprobes, such as paper-based strips and POC devices, are currently under development, and offer potential to be realized simply by use with smartphone data capture and analysis and data cloud storage.

These low-cost and highly reliable AIE bioprobe applications are beneficial for both early detection of disease and chronic disease management, and may facilitate greater involvement of health care consumers in managing their own care.

"We need to accelerate AIEgen sensor development for bodily fluids and the development of corresponding analytical and portable devices," says Xinyi Zhang, lead author on the new Materials Chemistry Frontiers article.

"As well as rapid diagnostics, it can also facilitate greater involvement of health care consumers in managing their own care, leading to greater benefits to more people at lower cost to the system."

The Medical Device Research Institute at Flinders University is at the forefront of developing point of care devices using this technology, says Carolyn Ramsey, director of the Australia-China Centre for Personal Health Technologies.

"As well, our partners at Nankai University in China are developing an AIEgen technology to diagnose COVID-19," she adds.

The Australia-China Centre for Personal Health Technologies is a multidisciplinary initiative in medicine, chemistry, biotechnology, engineering and digital health research led by the Flinders University Medical Device Research Institute. La Trobe University, Motherson, Nankai University, South China University of Technology and Shandong Computer Science Centre are partners in the centre.

AIEgen Luminogens for specific biomarkers - e.g. albumin, a protein produced in chronic kidney disease - works by lighting up (or fluorescing) in response to the amount of biomarker present in a person's bodily fluid.

Animals have an innate preference for certain scents and tastes. Attractive scents are linked to things like good food. Less attractive scents - that of spoiled food, for example - instinctively give the animal a signal which says: "There could be danger here!" When it comes to taste, all animals have similar preferences: Sugars and fats are perceived positively, whereas a bitter taste is perceived rather negatively.

In order to be able to make such evaluations, we need signals in the brain that tell us "This is good" or "This is bad". The dopaminergic system in the brain, better known as the reward system, plays an important role in these evaluations.

Understanding what happens in the brain

Neurons that produce dopamine, known as dopaminergic neurons, play a role in a range of diseases, from addictive behavior and obesity to Parkinson's disease. In addiction or obesity, the reward system signals can be too strong or also too weak. In Parkinson's disease, dopaminergic neurons degenerate, and this affects the control of motor functions.

To learn more about the processes in the brain, basic research is essential. Ilona Grunwald Kadow, Professor of Neural Control of Metabolism at the TUM School of Life Sciences in Weihenstephan, and her team are conducting research on the fly Drosophila melanogaster.

Neuroscientists often use this fly as a model because its neuronal networks are much simpler than those of humans. Using genetic tricks, scientists can turn individual network components on and off or change them. This enables the researchers to understand the principles of neuronal circuits that underlie the functions of more complex brains. "Dopamine plays a very similar role in the brain of humans and insects," explains the scientist.

Further clarifying the effect of dopamine

Dopamine is one of the most intensively studied signals in the brain. It is involved in both cognitive (e.g. motivation, reinforcement, goal-oriented behavior, motor control and movement, decision-making and learning) and more basic functions (e.g. reproduction and nausea).

How dopamine contributes to the various aspects of neural circuit functionality and behavior is an open question, but it is believed that dopaminergic neurons use different activity patterns to send a signal to the brain about what the body needs and senses. "We have now investigated the activity of the dopaminergic neurons in greater detail," said Ilona Grunwald Kadow. The team developed a custom 3D-imaging method based on in-vivo calcium imaging, as calcium is a good indicator of neuronal activity.

Neurons react flexibly and individually

Using this method, the research team was able to show that the activity of a network of dopaminergic neurons reflects both the innate preferences for smell and taste as well as the physiological state of the organism.

In addition to sensory stimuli such as smell or taste, dopaminergic neurons also record information as to whether an organism is moving or not. The neurons can respond to both internal behavioral states and external signals, bring them together, and use this to support both cognitive and motor processes.

"By doing that, the neurons can react flexibly and individually to the most important information - such as smell, taste, but also hunger or one's own movement. This is important to reach a balanced decision, because an external sensory signal can sometimes mean something good or bad, depending on an organism's condition," says Prof. Grunwald Kadow.

Surprising results

The researchers were surprised that dopaminergic neurones behave quite differently in different animals. The scientists speculate that this might explain individual preferences and behavioral differences between individuals.

In addition, the researchers found that the movement of the animal not only activates these dopaminergic neurones, but also other areas of the brain that actually have nothing per se to do with movement. This provides starting points for further research, for example what role movement plays in general when reacting to an environmental stimulus.

In the 1600s, two private chapels were erected as family burial sites for two noble families. One in the town Svendborg in Denmark, the other in Montella, Italy. They were both attached to a Franciscan Friary, and only a few meters from the chapels, more common townspeople and friars were buried in the cloister walks.

Now scientists have had access to the earthly remains of both the noble families and the less fortunate in Svendborg and Montella, and this gives an intriguing insight into what these people consumed while they were alive.

- We expected to find common features for the two different social classes, and we did so - in part. But we also found similarities and differences that are not linked to social status, says professor of archaeometry, Kaare Lund Rasmussen, University of Southern Denmark.

The researchers looked for a number of specific trace elements and heavy metals in the bone samples: Strontium, barium, lead, copper and mercury.

Common to these elements is that their presence in bones reveal information about a person's diet and what that person's mouth has been in touch with during his or her life.

Less strontium and barium were found in the bones from the noble chapels compared to the bones from the cloister walks.

These two trace elements are most often ingested through food, and the low levels in the nobles indicate that they ate more animal meat. This makes good sense, because meat in both Italy and Denmark was a more expensive than for example cereals and porridge.

The copper content in the Danish bones is significantly lower than in the Italian - both in those from the chapels and the cloister walks.

- This can be explained by the fact that the Danes did not prepare food in copper pots and vessels - and conversely, that the Italians did it diligently, regardless of their social status, Kaare Lund Rasmussen comments.

When cooking or storing food in copper pots, knives and spoons may scrape off small amounts of copper, which are then consumed with the food, and thus the body can accumulate copper over time. The copper level was 21 times higher in the Italians than in the Danes.

Both the Danish and Italian noble families had more lead in the bones than the less wealthy - the Danes slightly more than the Italians.

- High lead concentrations indicate high social status. We have also seen that from other studies, says Kaare Lund Rasmussen.

Lead had many uses in the Middle Ages, and especially the wealthy could afford it: It was used to glaze earthenware: kitchen utensils could consist of pure lead; lead salts were added to wine to inhibit fermentation, and lead sheets were used as roofing with the result that collected rainwater came to contain some lead.

Kaare Lund Rasmussen has previously shown that the ancient Romans and wealthy Germans and Danes in the Middle Ages could be more or less permanently sick with lead poisoning from consuming too much food and drink that had been in contact with lead.

Mercury was a widespread remedy for diseases such as leprosy and syphilis in the Middle Ages. The analyzes show that at least a handful of the noble Italian Iannelli family members ingested mercury in their lifetime. None of the skeletons from the Italian cloister walk contained mercury.

In Denmark, the distribution of mercury was more equal.

- It seems that both social groups in Denmark had equal access to mercury containing medicine. However, none of them exhibited particularly high levels.

Researchers have proved that a microvesicle-based instrument can be effective in reducing inflammation and immune response.

Group leader, Senior Research Associate Marina Gomzikova explains how microvesicles - bubbles surrounded by a natural cell membrane - can be biocompatible therapeutic instruments.

"We created a technology to obtain microvesicles from human stem cells and showed that they have significant biological activity and therapeutic potential. Microvesicles are basically miniature copies of cells. But, unlike stem cells, they are not oncogenic and can be a safe treatment medium," she says.

The authors compared the activity of induced microvesicles with natural microvesicles and stem cells. The results show that induced microvesicles indeed can reduce the intensity of immune response.

"The uniqueness of induced microvesicles is that their technology is scalable and can be implemented at an industrial level. A new class of biomedical compounds can be based on microvesicles. The immunomodulating activity may be used to treat inflammations and autoimmune syndromes," adds Albert Rizvanov, Director of Kazan Federal University's Center for Precision and Regenerative Medicine.

Induced microvesicles can further down the road serve as vehicles to deliver medications against nervous system injuries, locomotor damage, ischemia, and many other illnesses. In contrast to stem cells, microvesicles can be prepared in large quantities, are easily stored and utilized even in facilities not equipped with biobanks or cell labs.

In the summer, many people enjoy walks along the beach looking for seashells. Among the most prized are those that contain iridescent mother of pearl (also known as nacre) inside. But many beachcombers would be surprised to learn that shimmery nacre is one of nature's strongest, most resilient materials. Now, researchers reporting in ACS Nano have made a material with interlocked mineral layers that resembles nacre and is stronger and tougher than previous mimics.

Some mollusks, such as abalone and pearl oysters, have shells lined with nacre. This material consists of layers of microscopic mineral "bricks" called aragonite stacked upon alternating layers of soft organic compounds. Scientists have tried to replicate this structure to make materials for engineering or medical applications, but so far artificial nacre has not been as strong as its natural counterpart. Hemant Raut, Caroline Ross, Javier Fernandez and colleagues noticed that prior nacre mimics used flat mineral bricks, whereas the natural material has wavy bricks that interlock in intricate herringbone patterns. They wanted to see if reproducing this structure would create a stronger, tougher nacre mimic for sustainable medical materials.

Using the components of natural nacre, the team made their composite material by forming wavy sheets of the mineral aragonite on a patterned chitosan film. Then, they interlocked two of the sheets together, filling the space between the wavy surfaces with silk fibroin. They stacked 150 interlocked layers together to form a composite that was about the thickness of a penny. The material was almost twice as strong and four times as tough as previous nacre mimics -- close to the strength and toughness reported for natural nacre. The artificial nacre was also biocompatible, which the researchers demonstrated by culturing human embryonic stem cells on its surface for one week. These features suggest that the material could be suitable for sustainable, low-cost medical uses, the researchers say.

Planting huge numbers of trees to mitigate climate change is "not always the best strategy" - with some experimental sites in Scotland failing to increase carbon stocks, a new study has found.

Experts at the University of Stirling and the James Hutton Institute analysed four locations in Scotland where birch trees were planted onto heather moorland - and found that, over decades, there was no net increase in ecosystem carbon storage.

The team - led by Dr Nina Friggens, of the Faculty of Natural Sciences at Stirling - found that any increase to carbon storage in tree biomass was offset by a loss of carbon stored in the soil.

Dr Friggens said: "Both national and international governments have committed to plant huge numbers of trees to mitigate climate change, based on the simple logic that trees - when they photosynthesise and grow - remove carbon from the atmosphere and lock it into their biomass. However, trees also interact with carbon in soil, where much more carbon is found than in plants.

"Our study considered whether planting native trees on heather moorlands, with large soil carbon stores, would result in net carbon sequestration - and, significantly, we found that over a period of 39 years, it did not."

The tree-planting experiments - in the Grampians, Cairngorms and Glen Affric - were set up by the late Dr John Miles, of the then Institute of Terrestrial Ecology (a forerunner to the UK Centre for Ecology and Hydrology), in 1980, and the Hutton Institute in 2005. The research sites enabled the team to assess the impact of tree planting on vegetation and soil carbon stocks, by comparing these experimental plots to adjacent control plots consisting of original heath vegetation.

Working with Dr Ruth Mitchell and Professor Alison Hester, both of the James Hutton Institute, Dr Friggens measured soil respiration - the amount of carbon dioxide released from the soil to the atmosphere - at regular intervals during 2017 and 2018. Along with soil cores taken by Dr Friggens and Dr Thomas Parker to record soil carbon stocks and calculated tree carbon stocks by using non-destructive metrics, including tree height and girth.

The study recorded a 58 percent reduction in soil organic carbon stocks 12 years after the birch trees had been planted on the heather moorland - and, significantly, this decline was not compensated for by the gains in carbon contained in the growing trees.

It also found that, 39 years after planting, the carbon sequestered into tree biomass offset the carbon lost from the soil - but, crucially, there was no overall increase in ecosystem carbon stocks.

Dr Friggens said: "When considering the carbon stocks both above and below ground together, planting trees onto heather moorlands did not lead to an increase in net ecosystem carbon stocks 12 or 39 years after planting. This is because planting trees also accelerated the rate at which soil organisms work to decompose organic matter in the soil - in turn, releasing carbon dioxide back into the atmosphere.

"This work provides evidence that planting trees in some areas of Scotland will not lead to carbon sequestration for at least 40 years - and, if we are to successfully manage our landscapes for carbon sequestration, planting trees is not always the best strategy.

"Tree planting can lead to carbon sequestration; however, our study highlights the need to understand where, in the landscape, this approach is best deployed in order to achieve maximum climate mitigation gains."

Dr Ruth Mitchell, a researcher within the James Hutton Institute's Ecological Sciences department and co-author of the study, said: "Our work shows that tree planting locations need to be carefully sited, taking into account soil conditions, otherwise the tree planting will not result in the desired increase in carbon storage and climate change mitigation."

Although conducted in Scotland, the study's results are relevant in vast areas around the northern fringes of the boreal forests and the southern Arctic tundra, of North America and Eurasia.

Dr Friggens added: "The climate emergency affects us all - and it is important that strategies implemented to mitigate climate change - such as large-scale tree planting - are robust and achieve the intended outcomes.

"Changes to carbon storage - both above and below ground - must be better quantified and understood before we can be assured that large-scale tree planting will have the intended policy and climate outcomes."

For the past century, the world has relied on combustion engines powered by fossil fuels for transportation, but now lithium-ion battery-powered vehicles are emerging as sustainable successors. As major vehicle producers, European manufacturers are looking to establish their own lithium-ion battery market to compete with firms in Asia and the U.S. A new report in Chemical & Engineering News, the weekly newsmagazine of the American Chemical Society, explores the challenges and opportunities powering Europe's mission.

Manufacturers in China, Japan and the U.S. make up 85% of the global lithium-ion battery market, with Europe holding only a 3% market share despite its large automotive industry. With global demand for electric vehicles increasing steadily, European manufacturers have yet to catch up with companies like Tesla, and the high value of lithium-ion batteries for electric vehicles emphasizes Europe's potential to meet demand while also creating hundreds of thousands of jobs, writes Senior Editor Alex Scott. The European Commission, in partnership with global corporations, has invested heavily in initiatives that would see new factories and mining operations established across the region, but the challenges of obtaining raw materials and playing catch-up to other markets persist. 

In Germany, home to major car brands like BMW and Volkswagen, the government has invested nearly $3 billion in support of battery cell production. Elsewhere in Europe, companies are looking to tap into reserves of cobalt and other raw materials that make up lithium-ion batteries, with the goals of reducing the carbon footprint of production and avoiding human rights violations associated with cobalt mining in the Democratic Republic of Congo. Beyond competing for a share in the current technologies, European firms are also hoping to capitalize on the next generation of batteries, including lithium-sulfur batteries, which experts say are lighter, safer and more energy dense. Battery recycling is also a key element in this regional shift, given the limited local availability of materials and high cost of international shipping. Stakeholders across Europe hope that the combination of local mining, clean energy-powered manufacturing and recycling batteries will help them stand out as the world's most environmentally sustainable battery producer.

A new and promising approach for treatment of lung cancer has been developed by researchers at Lund University. The treatment combines a novel surgical approach with smart nanoparticles to specifically target lung tumors. The new study has been published in the July issue of Advanced Therapeutics.

Lung tumors are often difficult to remove using current surgical techniques due to their location in the lung or the fact that there are multiple tumors which are too small to observe. Tumors also develop natural barriers to prevent drugs and immune cells from reaching the tumor cells.

"Therefore, patients often receive high doses of chemotherapeutics which are circulated through the entire body and lead to major side effects in other organs. While a number of new experimental therapies have been developed for lung cancer and have shown promise in the lab, a major remaining challenge has been how to deliver the right drug specifically to these difficult to reach tumors", explains Darcy Wagner, Associate Professor and Head of the research group.

In order to overcome this challenge, the researchers behind the new study: Deniz Bölükbas and Darcy Wagner, researchers of the Lung Bioengineering and regeneration group, and colleagues developed a novel surgical technique which introduces the nanoparticles only into the blood vessels of the lung. The blood vessels around and in tumors are different than those in normal organs. The researchers used this difference to their benefit to direct nanoparticles to the interior of large and dense solid lung tumors.

Bölükbas and colleagues also used animal models which have a full immune system and closely resemble the types of lung tumors that patients have.

"Using this technique, which we call 'organ restricted vascular delivery' (ORVD), we were able to see lung cancer cells with the delivered nanoparticles inside of them - something which has not been achieved previously in these types of lung cancer animal models, which closely resemble the clinical scenario", explains Deniz Bölükbas, post-doctoral fellow and leading author of the article.

As an extra level of specificity, the nanoparticles were engineered to only release their drug content upon a specific cue which is present in the tumor area. This reduces the risk that the drugs contained within the nanoparticle will cause damage in healthy lung cells and could allow for higher amounts of toxic drugs to be used to increase the number of tumor cells killed, without causing unwanted side effects.

"While smart nanoparticles with unique features can be engineered in various ways, systemic administration of these agents into the bloodstream often results in uncontrolled spread of the particles with only a few of them reaching the interior of solid tumors. This has been a global challenge hampering more wide-spread use of nanoparticle systems in the clinics", explains Darcy Wagner.

The study was led by first author Dr. Deniz Bölükbas, a postdoctoral fellow working in Wallenberg Molecular Medicine Fellow at Lund University and Associate Professor Darcy Wagner's research group. Wagner and her team focus on designing new therapies for patients with lung disease by combining concepts from engineering, medicine, and cell biology.

"Direct administration of these nanoparticles into the blood vessels of the lungs allowed us to restrict the accumulation of these particles only in the lungs which eventually led to successful and selective tumor targeting", says Bölükbas.

ORVD of nanoparticles puts a new twist on a decades-old technique called "isolated lung perfusion" which involves direct administration of chemotherapeutic drugs into the blood vessels of the lungs. It has been demonstrated to be surgically safe in patients with lung tumors by various centers around the world, but chemotherapeutics had negative side effect on the healthy tissue neighboring the lung tumor. According to Wagner and Bölükbas, this surgical approach combined with the features of smart nanoparticles holds promise to overcome this previous limitation and has potential as a new treatment.

"The development of this new approach is a significant step forward"in the field of lung cancer treatment, say Bölükbas and his coauthors, but "it is important to validate the therapeutic potential of this approach to deliver specific chemotherapeutics and to explore the feasibility of this approach in large animal models".

Scientists at the Department of Energy's Oak Ridge National Laboratory used neutron scattering and supercomputing to better understand how an organic solvent and water work together to break down plant biomass, creating a pathway to significantly improve the production of renewable biofuels and bioproducts.

The discovery, published in the Proceedings of the National Academy of Sciences, sheds light on a previously unknown nanoscale mechanism that occurs during biomass deconstruction and identifies optimal temperatures for the process.

"Understanding this fundamental mechanism can aid in the rational design of even more efficient technologies for processing biomass," said Brian Davison, ORNL chief scientist for systems biology and biotechnology.

Producing biofuels from plant material requires breaking its polymeric cellulose and hemicellulose components into fermentable sugars while removing the intact lignin -- a structural polymer also found in plant cell walls -- for use in value-added bioproducts such as plastics. Liquid chemicals known as solvents are often employed in this process to dissolve the biomass into its molecular components.

Paired with water, a solvent called tetrahydrofuran, or THF, is particularly effective at breaking down biomass. Discovered by Charles Wyman and Charles Cai of the University of California, Riverside, during a study supported by DOE's BioEnergy Science Center at ORNL, the THF-water mixture produces high yields of sugars while preserving the structural integrity of lignin for use in bioproducts. The success of these cosolvents intrigued ORNL scientists.

"Using THF and water to pretreat biomass was a very important technological advance," said ORNL's Loukas Petridis of the University of Tennessee/ORNL Center for Molecular Biophysics. "But the science behind it was not known."

Petridis and his colleagues first ran a series of molecular dynamics simulations on the Titan and Summit supercomputers at the Oak Ridge Leadership Computing Facility, a DOE Office of Science user facility at ORNL. Their simulations showed that THF and water, which stay mixed in bulk, separate at the nanoscale to form clusters on biomass.

THF selectively forms nanoclusters around the hydrophobic, or water-repelling, portions of lignin and cellulose while complementary water-rich nanoclusters form on the hydrophilic, or water-loving, portions. This dual action drives the deconstruction of biomass as each of the solvents dissolves portions of the cellulose while preventing lignin from forming clumps that would limit access to the cellulosic sugars -- a common occurrence when biomass is mixed in water alone.

"This was an interesting finding," Petridis said. "But it is always important to validate simulations with experiments to make sure that what the simulations report corresponds to reality."

This phenomenon occurs at the tiny scale of three to four nanometers. For comparison, a human hair is typically 80,000 to 100,000 nanometers wide. These reactions presented a significant challenge to demonstrate in a physical experiment.

Scientists at the High Flux Isotope Reactor, a DOE Office of Science user facility at ORNL, overcame this challenge using neutron scattering and a technique called contrast matching. This technique selectively replaces hydrogen atoms with deuterium, a form of hydrogen with an added neutron, to make certain components of the complex mixture in the experiment more visible to neutrons than others.

"Neutrons see a hydrogen atom and a deuterium atom very differently," said ORNL's Sai Venkatesh Pingali, a Bio-SANS instrument scientist who performed the neutron scattering experiments. "We use this approach to selectively highlight parts of the whole system, which otherwise would not be visible, especially when they're really small."

The use of deuterium rendered the cellulose invisible to neutrons and made the THF nanoclusters visually pop out against the cellulose like the proverbial needle in a haystack.

To mimic biorefinery processing, researchers developed an experimental setup to heat the mixture of biomass and solvents and observe the changes in real time. The team found the action of the THF-water mix on biomass effectively kept lignin from clumping at all temperatures, enabling easier deconstruction of the cellulose. Increasing the temperature to 150 degrees Celsius triggered cellulose microfibril breakdown. These data provide new insights into the ideal processing temperature for these cosolvents to deconstruct biomass.

"This was a collaborative effort with biologists, computational experts and neutron scientists working in tandem to answer the scientific challenge and provide industry-relevant knowledge," Davison said. "The method could fuel further discoveries about other solvents and help grow the bioeconomy."

In a groundbreaking new study, researchers at the University of Minnesota have 3D printed a functioning centimeter-scale human heart pump in the lab. The discovery could have major implications for studying heart disease, the leading cause of death in the United States killing more than 600,000 people a year.

The study is published and appears on the cover of Circulation Research, a publication of the American Heart Association.

In the past, researchers have tried to 3D print cardiomyocytes, or heart muscle cells, that were derived from what are called pluripotent human stem cells. Pluripotent stem cells are cells with the potential to develop into any type of cell in the body. Researchers would reprogram these stem cells to heart muscle cells and then use specialized 3D printers to print them within a three-dimensional structure, called an extracellular matrix. The problem was that scientists could never reach critical cell density for the heart muscle cells to actually function.

In this new study, University of Minnesota researchers flipped the process, and it worked.

“At first, we tried 3D printing cardiomyocytes, and we failed, too,” said Brenda Ogle, the lead researcher on the study and head of the Department of Biomedical Engineering in the University of Minnesota College of Science and Engineering. “So with our team’s expertise in stem cell research and 3D printing, we decided to try a new approach. We optimized the specialized ink made from extracellular matrix proteins, combined the ink with human stem cells and used the ink-plus-cells to 3D print the chambered structure. The stem cells were expanded to high cell densities in the structure first, and then we differentiated them to the heart muscle cells.”

What the team found was that for the first time ever they could achieve the goal of high cell density within less than a month to allow the cells to beat together, just like a human heart.

“After years of research, we were ready to give up and then two of my biomedical engineering Ph.D. students, Molly Kupfer and Wei-Han Lin, suggested we try printing the stem cells first,” said Ogle, who also serves as director of the University of Minnesota’s Stem Cell Institute. “We decided to give it one last try. I couldn’t believe it when we looked at the dish in the lab and saw the whole thing contracting spontaneously and synchronously and able to move fluid.”

Ogle said this is also a critical advance in heart research because this new study shows how they were able to 3D print heart muscle cells in a way that the cells could organize and work together. Because the cells were differentiating right next to each other it’s more similar to how the stem cells would grow in the body and then undergo specification to heart muscle cells.

Compared to other high-profile research in the past, Ogle said this discovery creates a structure that is like a closed sac with a fluid inlet and fluid outlet, where they can measure how a heart moves blood within the body. This makes it an invaluable tool for studying heart function.

“We now have a model to track and trace what is happening at the cell and molecular level in pump structure that begins to approximate the human heart,” Ogle said. “We can introduce disease and damage into the model and then study the effects of medicines and other therapeutics.”

The heart muscle model is about 1.5 centimeters long and was specifically designed to fit into the abdominal cavity of a mouse for further study.

“All of this seems like a simple concept, but how you achieve this is quite complex. We see the potential and think that our new discovery could have a transformative effect on heart research,“ Ogle said.

In addition to Ogle, Kupfer and Lin, other University of Minnesota researchers involved include University of Minnesota College of Science and Engineering faculty Professor Alena G. Tolkacheva (biomedical engineering) and Professor Michael McAlpine (mechanical engineering); University of Minnesota Medical School Associate Professor DeWayne Townsend (integrative biology and physiology); current and former University of Minnesota master’s, Ph.D. students and postdocs Vasanth Ravikumar (electrical engineering), Kaiyan Qiu (Ph.D., mechanical engineering), and Didarul B. Bhuiyan (Ph.D.), Megan Lenz (M.S.), and Ryan R. Mahutga (biomedical engineering); and undergraduate student Jeffrey Ai (biomedical engineering). The team also included University of Alabama Department of Biomedical Engineering Professor and Chair Jianyi Zhang and University of Alabama biomedical engineering Ph.D. student Lu Wang and research associate Ling Gao (Ph.D.).

This research was primarily funded by the National Institutes of Health (National Heart Lung and Blood Institute, National Institute of Biomedical Imaging and Bioengineering, and National Institute of General Medical Science) with additional funding from the National Science Foundation Graduate Research Fellowship Project and the University of Minnesota Doctoral Dissertation Fellowship.

To read the full research paper entitled “In Situ Expansion, Differentiation and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid,” visit the Circulation Research website.

Journal

Circulation Research

DOI

10.1161/CIRCRESAHA.119.316155

NEW YORK, NY (July 15, 2020) - A study supported by the Alzheimer's Drug Discovery Foundation and published today in JAMA Network Open provides the first evidence that rotigotine, a drug that acts on dopamine transmission in the brain, improves cognitive function in patients with mild-to-moderate Alzheimer's disease.

While rotigotine did not show a significant effect on memory functions, the drug improved frontal lobe executive function and patients' ability to perform activities of daily living. The randomized clinical trial, Effects of Dopaminergic Therapy in Patients with Alzheimer's Disease (DOPAD), was led by Giacomo Koch, M.D., Ph.D., a neurologist at the Santa Lucia Foundation in Rome, in collaboration with Alessandro Martorana, M.D. of the University of Tor Vergata in Rome.

"Patients treated with rotigotine in this study had some practical improvements that are very important for people with Alzheimer's," said Howard Fillit, M.D., the ADDF's Founding Executive Director and Chief Science Officer. "Rotigotine improved executive function, which helps patients with key cognitive tasks, such as reasoning, judgment, working memory, and orientation. It also improved their ability to complete routine daily activities like shopping, planning, and even bathing, toileting and feeding themselves, which means preserving their independence longer and reducing the burden on caregivers."

Current treatments for Alzheimer's act on the neurotransmitter acetylcholine, but research has suggested that dopamine also plays a key role in the disease. Investigators focused on changes in the frontal lobe because dopamine modulates activity in this section of the brain. The improvements patients experienced in frontal-lobe controlled cognitive functions corresponded with a lab test showing that rotigotine enhanced dopaminergic pathways reaching this section of the brain. Investigators used novel biomarker tests--a combination of transcranial magnetic stimulation and electroencephalography recordings--to understand how rotigotine affects brain connectivity and function.

"This study is an important step forward in showing that Alzheimer's disease patients may benefit from the combinations of drugs that enhance brain functions by interacting with different neurotransmitter systems," said lead investigator Dr. Koch. "Moreover, it could open novel therapeutic options focused on dopaminergic transmission to treat patients early, when the cognitive functions related to frontal lobe activity and daily life abilities are only mildly impaired, to delay the onset of full-blown Alzheimer's disease dementia." Dr. Koch and his co-authors say further studies are needed to determine the potential role of rotigotine in treating Alzheimer's.

"The ADDF has a long history of supporting trials like this that repurpose existing drugs because it can speed up our ability to find new treatments for Alzheimer's," said Dr. Fillit. He explained that this
is because the safety and toxicity of existing drugs (rotigotine is used to treat Parkinson's disease and restless leg syndrome) are already well studied, leading to quicker approval times. "At the ADDF we focus on funding trials that target novel pathways implicated in Alzheimer's disease, beyond beta-amyloid and tau, because Alzheimer's is a complex disease caused by multiple factors. Among these, addressing abnormalities in dopaminergic pathways holds great promise."

Door knobs, light switches, shopping carts. Fear runs rampant nowadays when it comes to touching common surfaces because of the rapid spread of the coronavirus.

A Virginia Tech professor has found a solution.

Since mid-March, William Ducker, a chemical engineering professor, has developed a surface coating that when painted on common objects, inactivates SARS-CoV-2, the virus that causes COVID-19.

"The idea is when the droplets land on a solid object, the virus within the droplets will be inactivated," Ducker said.

Since mid-April, Ducker has been working with Leo Poon, a professor and researcher at the University of Hong Kong's School of Public Health, to test the film's success at inactivating the virus. Their research was published July 13 in ACS Applied Materials & Interfaces, a scientific journal for chemists, engineers, biologists, and physicists.

The results of the tests have been outstanding, Ducker said. When the coating is painted on glass or stainless steel, the amount of virus is reduced by 99.9 percent in one hour, compared to the uncoated sample.

"One hour is the shortest period that we have tested so far, and tests at shorter periods are ongoing," Ducker said.

His expectation is that his team can inactivate the virus in minutes. Results have shown that the coating is robust. It does not peel off after being slashed with a razor blade. It also retains its ability to inactivate the virus after multiple rounds of being exposed to the SARS-CoV-2 virus and then disinfection or after being submerged in water for a week, based on the tests.

If the project's success continues, it is a significant discovery in fighting the virus' spread.

"Everybody is worried about touching objects that may have the coronavirus," said Ducker, who recalled that his wife, in March, questioned whether she should sit on a park bench during the pandemic. "It would help people to relax a little bit."

Already, Ducker's research was focused on making films that kill bacteria. As the COVID-19 virus began to spread to the United States a few months ago, Ducker asked himself "Why not make a coating that can eradicate a virus, rather than bacteria?"

"We have to use our chemical knowledge and experience of other viruses to guess what would kill it [SARS-CoV-2]," Ducker said.

Virginia Tech granted essential personnel status to Ducker, his two PhD. chemical engineering graduate students -- Saeed Behzadinasab and Mohsen Hossein -- and Xu Feng from the university's Department of Chemistry so that they could enter campus labs to make the film and test its properties.

"It was an interesting experience," Ducker said. "Almost the entire campus was shut down, and we were like ghosts wandering the empty halls of Goodwin Hall. But it was very exciting to have such a clear goal. I know that it was a difficult time for many people who were bored, unhappy, or scared. We were just focused on making a coating."

Next, he needed to find someone who could test the coating's effectiveness. Through an internet search, Ducker found Poon, who is known for his work studying SARs-CoV-1, which was the virus that caused the SARS outbreak in 2003 and 2004. Poon has been active in the fight against SARS-CoV-2.

For Poon's tests, Ducker and the graduate students spread three different kinds of coatings on glass and stainless steel. Then, they shipped the samples to Poon.

Now, Ducker said he hopes to attract funding in order to mass produce the film.

To be sure, the film doesn't replace other safety measures that people should take to stop the spread of the coronavirus, such as handwashing, physical distancing, and wearing a mask.

Even so, "people won't have to worry as much about touching objects," Ducker said. "It will be both practical and reducing fear."