Tech

In the summer of 2019, larotrectinib was approved as the first drug in Europe to be used in numerous different solid tumours if the tumour tissue displays a so-called NTRK gene fusion. Since such a fusion of a Neurotrophic Tyrosine Receptor Kinase gene with another gene leads to increased proliferation of the tumour cells, the aim is to selectively block the corresponding signal pathway. The new inhibitor was approved for cases in which the disease is locally advanced or metastatic and there are no other satisfactory treatment options.

These cases are so rare that the approval studies - including a study in the so-called basket design, i.e. the testing of one substance in patients with different types of cancer - are rather small. In addition, none of the three phase 1 and phase 2 studies has a comparator arm, which makes it very difficult to conduct an early benefit assessment, as, by definition, an added benefit can only be proven in comparison with another treatment. Nonetheless, the German Institute for Quality and Efficiency in Health Care (IQWiG) has now investigated on behalf of the Federal Joint Committee (G-BA) whether the drug offers the affected children and adults an added benefit in comparison with the appropriate comparator therapy (best supportive care) - or, alternatively, in comparison with other therapies. The result: No conclusions on an added benefit can be derived from the study data and analyses presented by the company. An added benefit is therefore not proven.

Drug manufacturer uses "dramatic effects" as an argument

Although its dossier did not contain any comparator data of patients treated with best supportive care, the manufacturer derived a hint of a non-quantifiable added benefit across all tumour types from the studies. The manufacturer based this conclusion on several effects that it classified as being so large ("dramatic") that they can be used to derive a conclusion despite the lack of comparisons: The median overall survival of the severely ill patients was 44.4 months under larotrectinib at the last data cut-off; the time to progression in about one third of them was at least 5 times as long as under their previous systemic therapy; about one sixth of the patients achieved complete remission; and amputation of the affected limbs was avoided in numerous children. According to the manufacturer, symptoms and health-related quality of life also improved significantly in many patients, and the drugs hardly had any severe side effects.

Lack of comparisons and deficiencies in analysis of data

In exceptional cases, studies without comparator data may be sufficient for an approval if the aim is to show that the substance has an effect on the tumour. Explicit comparator data are needed, however, if the question is whether such an effect is associated with a patient-relevant benefit. IQWiG therefore tried to analyse also study data on other drugs for the 15 types of cancer treated in the studies - data, which the manufacturer itself partly presented in the dossier, but did not use. The Institute conducted these additional analyses separately for each disease, as both best supportive care and other treatments are tailored to the respective type of cancer and its stage: They are different for soft tissue sarcoma than for tumours in the brain or cancer in the lungs, chest or bowel.

Regarding the outcome "overall survival", the differences between larotrectinib and other treatments observed so far were not so large in any of the cancer diseases that they could not be caused by systematic bias alone. Regarding patient-relevant outcomes from the categories of morbidity, health-related quality of life and side effects, there were no suitable data or no data differentiated by tumour type either for the new drug or for the comparator therapies, so that it was also not possible to derive an added benefit.

Basket studies principally allow comparisons

In addition, there are deficiencies in the histology-independent analyses presented by the company. Analyses were not prespecified and results were reported selectively. Thus, it was unfortunately also not possible to check the information provided on the avoidance of amputations in children.

"There are many signs that the drug may have great potential. But even for an 'early benefit assessment' it can sometimes be too early - this is the case when the data presented do not allow conducting meaningful comparisons," says Stefan Lange, Deputy Director of IQWiG. "In future we will need robust comparator data for benefit assessments of histology-independent treatments. Basket studies can also be conducted with control groups that were treated with the best current treatment - which may well be best supportive care. Like the Canadians, who have recently denied regular reimbursement of larotrectinib, or our English colleagues, who are currently discussing the multiple challenges in the benefit assessments of these types of drugs in the British Medical Journal, we see the lack of suitable data as the main obstacle to making adequate assessments."

G BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

More English-language information will be available soon (Sections 2.1 to 2.6 of the dossier assessment as well as easily understandable information on informedhealth.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.

Superconductors allow electrical current to flow without any resistance - but only below a certain critical temperature. Many materials have to be cooled down to almost absolute zero, while some materials keep their superconducting properties up to much higher temperatures. How this "high-temperature superconductivity" works and how it is possible to develop new materials that are superconductors even at normal room temperature is still one of the great mysteries of modern physics.

The key to success could be research on "strange metals". These are special materials whose electrical resistance shows a very unusual temperature behaviour. This phenomenon is closely related to superconductivity: many classes of high-temperature superconductors exhibit this "strange metal" behavior. Now there has been a major breakthrough: a research team from the TU Wien (Vienna, Austria) and Rice University (Houston, Texas) has developed a new process that allows extremely thin layers of such materials to be produced and then optically analyzed. In this way, important data about these materials are obtained that cannot be measured otherwise, which may lead to the development of better materials and new theories of high-temperature superconductivity. The results have now been published in Science.

Strange Metals as the Key to Superconductivity

"Already in 1987, the Nobel Prize in Physics was awarded for the discovery of high-temperature superconductivity, but even today our understanding of this phenomenon is still poor", says Prof. Silke Bühler-Paschen from the Institute of Solid State Physics at Vienna University of Technology. "However, we know that strange metals are closely related to this technologically important class of superconductors." Above their critical temperature, high-temperature superconductors show a relationship between temperature and resistance that is completely different from that of ordinary metals. "In contrast to simple metals such as copper or gold, the electrical resistance in strange metals does not appear to be caused by the thermal motion of the atoms, but by certain quantum fluctuations," says Bühler-Paschen.

To confirm this assumption and to find out more about the nature of quantum fluctuations, not only the temperature dependence of the resistance, but also its frequency dependence must be investigated. The best way to do this is irradiating the material with light in the appropriate frequency range.

A material made of ytterbium, rhodium and silicon (YbRh2Si2), which is known for its particularly pronounced "strange metal" behaviour, was selected for the investigations. To study this material, radiation in the terahertz range is required.

"At this point, things became technologically challenging," says Silke Bühler-Paschen. "High-precision measurements are only possible in transmission, that is, when the material is penetrated by the terahertz radiation. While electrically insulating materials usually allow terahertz radiation to pass, metals strongly reflect and absorb this type of radiation. Only if an extremely thin layer of the material is available, sufficient terahertz radiation will pass and thus enable precise measurements."

Developing a New Manufacturing Process

In the clean room laboratories at TU Wien, a new complex molecular beam epitaxy process was developed to produce thin layers of this material: "Ytterbium, rhodium and silicon are evaporated in precisely the right ratio. Atom by atom, these materials impinge on a substrate," says Maxwell Andrews (Institute for Solid State Electronics, TU Vienna). "If all parameters are set correctly, YbRh2Si2 grows in atomic layers. By choosing the right duration of the growth process, you can achieve exactly the desired layer thickness."

"The decisive breakthrough was finding a perfectly fitting substrate on which to apply these layers - namely germanium," says Lukas Prochaska, one of the three leading doctoral students in the team. "The crystal structure of germanium fits geometrically perfectly the arrangement of the Ytterbium atoms. This allowed us to grow thin films of excellent quality."

Understanding the Movement of Charge Carriers

PhD student Xinwei Li in the Kono group at Rice University then performed challenging high-precision tetahertz measurements on the thin films. The analysis of the data, in which Rice theorist Qimiao Si also played a major role, yielded decisive new evidence: "Our assumption that quantum-critical charge fluctuations play an important role has now been confirmed," says Silke Bühler-Paschen. "We have come full circle here: In 2004, we were able to show that the "strange metal" behavior in this material is accompanied by a sudden change in the charge carrier concentration. At that time, Qimiao Si and I had already recognized the need for dynamical measurements, but the technology to realize them was not available. Now we were finally able to scrutinize and understand this process."

The new results indicate how to describe these unusual material effects. "Our new ideas can also be transferred to other classes of high-temperature superconductors," explains Bühler-Paschen. "We hope that this will lead to a new theory of high-temperature superconductivity, and to the design of better superconductors with even higher critical temperatures; this would be a tremendous technological success."

Nanoscience can arrange minute molecular entities into nanometric patterns in an orderly manner using self-assembly protocols. Scientists at the Technical University of Munich (TUM) have functionalized a simple rod-like building block with hydroxamic acids at both ends. They form molecular networks that not only display the complexity and beauty of mono-component self-assembly on surfaces; they also exhibit exceptional properties.

Designing components for molecular self-assembly calls for functionalities that 'interlock'. For example, our genetic information is encoded in two DNA strands, zipped together in a 'spiral staircase' double helix structure in a self-assembly process that is stabilized by hydrogen bonding.

Inspired by nature's 'zippers' researchers at the Technical University of Munich aim to construct functional nanostructures to push the boundaries of man-made structures.

Building blocks for complex nanostructures

Scientists at the Technical University of Munich, diverse in discipline, nationality and gender, joined forces to explore a new feature in two-dimensional architectures: a chemical group named hydroxamic acid.

A conceptually simple building block was prepared at the Chair of Proteomics and Bioanalytics: a rod-like molecule with a hydroxamic acid group at each end. This building block was then transferred to the Chair of Surface and Interface Physics, where its assembly was inspected on atomically planar silver and gold surfaces.

A nano-porous network

A combination of advanced microscopy tools, spectroscopy and density functional theory investigations found that the molecular building block adapts its shape somewhat in the environment of the supporting surface and its neighboring molecules. This affords an unusual manifold of supramolecular surface motifs: two to six molecules held together by intermolecular interactions.

Only a handful of these motifs self-organized into 2-D crystals. Among them, an unparalleled network emerged, whose patterns evoke images of sliced lemons, snowflakes or rosettes. They feature three differently sized pores able to snuggly hold individual small molecules of gas such as carbon monoxide in the smallest, or small proteins like insulin in the largest.

"In this regard, it is a milestone in the tessellations achieved by molecular nanostructures and the number of different pores expressed in crystalline 2-D networks," says Dr. Anthoula Papageorgiou, last author of the publication. "It thus offers unique opportunities in bottom-up nano-templating, which we will explore further."

Nanocages with a twist

Like our left and right hands, the shape of two mirrored cage structures cannot be superimposed. Since the 19th century, academics have characterized this type of object symmetry as 'chiral', from the ancient Greek χε?ρ (hand). These kinds of molecules are frequently found in natural compounds. Chirality influences interactions of polarized light and magnetic properties and plays a vital role in life.

For example, our olfactory receptors react very differently to the two mirror images of the limonene molecule: one smells like lemon, the other like pine. This so-called chiral recognition is a process that can determine whether a molecule acts as medicine or poison.

The inner walls of the obtained nanostructure cages offer sites that can direct guest molecules. The researchers observed such a process in some of the larger pores, where three of the same molecules assembled as a chiral object. At room temperature, this object is in motion, like a music box ballerina, leading to a blurred image.

In their future work, the team hopes to steer these kinds of phenomena for chiral recognition and artificial nano-machinery.

UNIVERSITY PARK, Pa. -- Walnuts may not just be a tasty snack, they may also promote good-for-your-gut bacteria. New research suggests that these "good" bacteria could be contributing to the heart-health benefits of walnuts.

In a randomized, controlled trial, researchers found that eating walnuts daily as part of a healthy diet was associated with increases in certain bacteria that can help promote health. Additionally, those changes in gut bacteria were associated with improvements in some risk factors for heart disease.

Kristina Petersen, assistant research professor at Penn State, said the study -- recently published in the Journal of Nutrition -- suggests walnuts may be a heart- and gut-healthy snack.

"Replacing your usual snack -- especially if it's an unhealthy snack -- with walnuts is a small change you can make to improve your diet," Petersen said. "Substantial evidence shows that small improvements in diet greatly benefit health. Eating two to three ounces of walnuts a day as part of a healthy diet could be a good way to improve gut health and reduce the risk of heart disease."

Previous research has shown that walnuts, when combined with a diet low in saturated fats, may have heart-healthy benefits. For example, previous work demonstrated that eating whole walnuts daily lowers cholesterol levels and blood pressure.

According to the researchers, other research has found that changes to the bacteria in the gastrointestinal tract -- also known as the gut microbiome -- may help explain the cardiovascular benefits of walnuts.

"There's a lot of work being done on gut health and how it affects overall health," said Penny Kris-Etherton, distinguished professor of nutrition at Penn State. "So, in addition to looking at factors like lipids and lipoproteins, we wanted to look at gut health. We also wanted to see if changes in gut health with walnut consumption were related to improvements in risk factors for heart disease."

For the study, the researchers recruited 42 participants with overweight or obesity who were between the ages of 30 and 65. Before the study began, participants were placed on an average American diet for two weeks.

After this "run-in" diet, the participants were randomly assigned to one of three study diets, all of which included less saturated fat than the run-in diet. The diets included one that incorporated whole walnuts, one that included the same amount of alpha-linolenic acid (ALA) and polyunsaturated fatty acids without walnuts, and one that partially substituted oleic acid (another fatty acid) for the same amount of ALA found in walnuts, without any walnuts.

In all three diets, walnuts or vegetable oils replaced saturated fat, and all participants followed each diet for six weeks with a break between diet periods.

To analyze the bacteria in the gastrointestinal tract, the researchers collected fecal samples 72 hours before the participants finished the run-in diet and each of the three study diet periods.

"The walnut diet enriched a number of gut bacteria that have been associated with health benefits in the past," Petersen said. "One of those is Roseburia, which has been associated with protection of the gut lining. We also saw enrichment in Eubacteria eligens and Butyricicoccus."

The researchers also found that after the walnut diet, there were significant associations between changes in gut bacteria and risk factors for heart disease. Eubacterium eligens was inversely associated with changes in several different measures of blood pressure, suggesting that greater numbers of Eubacterium eligens was associated with greater reductions in those risk factors.

Additionally, greater numbers of Lachnospiraceae were associated with greater reductions in blood pressure, total cholesterol, and non-HDL cholesterol. There were no significant correlations between enriched bacteria and heart-disease risk factors after the other two diets.

Regina Lamendella, associate professor of biology at Juniata College, said the findings are an example of how people can feed the gut microbiome in a positive way.

"Foods like whole walnuts provide a diverse array of substrates -- like fatty acids, fiber and bioactive compounds -- for our gut microbiomes to feed on," Lamendella said. "In turn, this can help generate beneficial metabolites and other products for our bodies."

Kris-Etherton added that future research can continue to investigate how walnuts affect the microbiome and other elements of health.

"The findings add to what we know about the health benefits of walnuts, this time moving toward their effects on gut health," Kris-Etherton said. "The study gives us clues that nuts may change gut health, and now we're interested in expanding that and looking into how it may affect blood sugar levels."

While studies of the microbiomes (which comprises all the microorganisms, mainly bacteria and fungi) of the phyllosphere and the rhizosphere of plants are important, scientists at INRA believe more attention should be given to the microbiomes of crop residues.

Crop residues are important as a key microbial ecosystem with the power to contribute both negatively and positively to crop health and productivity. Crop residues are a breeding ground for plant disease but also contribute significantly to the stability of agrosystems.

"Residues deserve special attention in the context of crop protection," plant pathologist Frédéric Suffert explains. "First, because residues are 'the problem' as the main support of pathogens that cause disease. Second because residues can be also part of the solution to control these diseases."

Focusing on cereal crops, the INRA scientists explored how dynamic interactions between microbial communities of residues can contribute to innovative disease management strategies such as next-generation microbiome-based biocontrol.

"We connected residue microbiome with the survival of residue-borne fungal plant pathogens by combining knowledge in microbial ecology and epidemiology," explained Frédéric Suffert. "This is the first time this connection has been made."

Experimental physicists have combined several measurements of quantum materials into one in their ongoing quest to learn more about manipulating and controlling the behavior of them for possible applications. They even coined a term for it-- Magneto-elastoresistance, or MER.

Scientists in condensed matter physics at the U.S. Department of Energy's Ames Laboratory have a long history of investigating "weird" materials, according to Paul Canfield, Ames Lab physicist, Distinguished Professor and the Robert Allen Wright Professor of Physics and Astronomy at Iowa State University.

"Weird" in this case means metallic and semi-metallic compounds that have magnetic, superconducting, or other properties that might be useful in tech applications such as quantum computing. To force those compounds to reveal their secrets, however, experimentalists must poke, prod, and measure the materials to see how and how much they react.

Canfield and his fellow researchers systematically studied WTe2, a semi-metal, by exposing it to electric current, magnetic field, and strain from pushing and pulling. The measurements of resistance under a combination of external magnetic field and strain-- was something that had not been studied in any systematic matter before.

They found that the material reacted with large changes in elastoresistance and that it was further controllable by magnetic field, especially at low temperatures.

By pairing experimental findings with density functional theory and modeling, "we were able to demonstrate that MER is tied to the redistribution of carriers from different bands (i.e. heavy hole band, light hole and electron band)" said Na Hyun Jo, a postdoctoral research associate at Ames Laboratory. "This means engineering WTe2 and others like it is possible for future applications."

Scientist Sergey Bud'ko was gratified by the outcome of the experiment, showing a large effect in MER, proving to the larger scientific community that it's a worthy way of looking for similar effects in similar materials and learning how or when they will occur. "While we have investigated a number of these materials with large magnetoresistance over the decades, we are only just beginning to get a sense of why some materials demonstrate it and not others; here we open the door to a clearer theoretical explanation of their properties."

The research is further discussed in the paper, "Magneto-elastoresistance in WTe2: exploring electronic structure and extremely large magnetoresistance under strain," authored by Na Hyun Jo, Lin-Lin Wang, Peter P. Orth, Sergey L. Bud'ko and Paul C. Canfield; and published in the Proceedings of the National Academy of Sciences.

Tropical Cyclone Claudia was dissipating in the Southern Indian Ocean when NASA's Terra satellite captured a visible image of storm as it flew overhead in its orbit around the Earth.

On Jan. 15 at 4 p.m. EST (2100 UTC) the Joint Typhoon Warning Center (JTWC) noted in their final warning that Tropical Cyclone Claudia's maximum sustained winds were down to 35 knots (40 mph/65 kph). Claudia was far from land, near latitude 21.4 degrees south and longitude 104.8 degrees east, about 521 nautical miles west of Learmonth, Australia.

On Jan. 16, 2020, the Moderate Resolution Imaging Spectroradiometer or MODIS instrument that flies aboard NASA's Terra satellite provided a visible image of Claudia that showed the storm was dissipating. Strong northeasterly wind shear had pushed the bulk of clouds to the southwest of the center of circulation. The center appeared exposed and surrounded by a wispy circle of clouds in the Terra satellite image.

The JTWC forecast said Claudia remnants are expected to continue moving in a southwest direction and dissipate later today, Jan. 16.

Fish sticks may be a tasty option for dinner, but are they good for the planet?

A new study of the climate impacts of seafood products reveals that the processing of Alaskan pollock into fish sticks, imitation crab, and fish fillets generates significant greenhouse gas emissions.

Post-catch processing generates nearly twice the emissions produced by fishing itself, which is typically where the analysis of the climate impact of seafood ends, according to the findings by researchers at the University of California, Santa Cruz.

"The food system is a significant source of global greenhouse gas emissions, and Alaskan pollock is one of the biggest fisheries in the world," said Brandi McKuin, a postdoctoral researcher in environmental studies at UCSC. "These findings highlight the need to take a comprehensive approach to analyzing the climate impacts of the food sector."

McKuin is the lead author on a new paper that appears online in the journal Elementa: Science of the Anthropocene. Titled "Climate Forcing by Battered-and-breaded Fillets and Crab-flavored sticks from Alaska Pollock," the paper takes a detailed, comprehensive look at the climate impact of the seafood supply chain.

Alaskan pollock is sold as fillets and trim pieces that are used to make products like fish sticks and imitation crab, said McKuin. "It's a huge market," she said.

Unlike previous studies that have largely overlooked the downstream processing activities associated with Alaskan pollock, this study examined all the components of the supply chain, from fishing through the retail display case. The results identify "hot spots" where the seafood industry could concentrate its efforts to reduce its climate impacts, said McKuin.

The authors analyzed the climate impacts of transoceanic shipping of exported seafood products, and their study is the first to consider the climate effects of so-called "short-lived" pollutants in the carbon footprint of seafood.

They found that Alaskan pollock is a relatively fuel-efficient fishery: Pollock are caught in large nets called midwater trawls that are towed behind boats, hauling in a lot of fish in each landing, and reducing the climate impact of the fishing process. After the catch, Alaskan pollock are shipped for processing, and in some cases, transported on large container ships that burn copious amounts of fuel, including cheaper, poor-quality bunker fuel that produces high levels of sulfur particles.

McKuin noted that sulfur oxides from ship fuels have a climate-cooling effect. "Seafood products that are exported have a lower climate impact than domestic seafood products," she said, adding that the climate impacts of shipping will change this year as new regulations for cleaner marine fuels take effect. "Shipping has a massive influence on climate and a shift to cleaner fuels will diminish the cooling effect from sulfur oxides and increase the climate impact of products that undergo transoceanic shipping, including seafood," said McKuin.

Coauthor Elliot Campbell, a professor of environmental studies at UCSC, is a pioneer of data-driven methods of assessing the climate impact of food production.

"This study highlights the need to expand our view to encompass the entire supply chain," he said. "It's not enough to look just at fishing. The picture is much bigger, and it's much more complicated."

Organizations like Seafood Watch have developed tools to calculate the carbon footprint of seafood but haven't included processing yet, noted McKuin, adding, "This study adds more data, so they can create a better tool."

Common medical imaging procedures use low doses of radiation that are believed to be safe. A new study, however, finds that in human cell cultures, these doses create breaks that allow extra bits of DNA to integrate into the chromosome. Roland Kanaar and Alex Zelensky of Erasmus University Medical Center and Oncode Institute and colleagues report these new findings in a study published 16th January in PLOS Genetics.

Scientists have long known that exposing cells to high doses of ionizing radiation generates mutations by creating double-strand breaks that let in external segments of DNA. These extraneous fragments of DNA can occur in the nucleus, left over from natural processes, such as genomic DNA repair and viral infections. In the new study, researchers investigated whether low doses of ionizing radiation have damaging side effects by irradiating human and mouse cells grown in the lab. When they counted the cells that had taken up foreign DNA, they found that low doses of radiation, in the upper range of common diagnostic procedures, create mutations through inserted DNA even more efficiently than the much larger doses studied previously.

While the new results in cell cultures are potentially concerning, the study's authors stress that translating radiation's effects on lab-grown cell cultures to effects in the body is premature. Future experiments using animal models will be necessary to determine the full effects of low-dose radiation, and whether its use in medical imaging has an impact on patient health. If the same phenomenon does occur inside the body, then doctors may need to take into account levels of extraneous DNA, such those resulting from a long-term viral infection, when assessing a patient's risk from a procedure that requires radiation.

"Most molecular radiobiological research is focused on high doses of ionizing radiation relevant to cancer treatment, while effects of physiologically relevant doses of radiation on the cell are notoriously difficult to study at the molecular level," said author Roland Kanaar. "Our discovery that mutagenic insertion of foreign DNA into cell's genome is remarkably responsive to doses encountered during diagnostic, rather than therapeutic, procedures provides a new simple and sensitive tool to study their consequences and revealed surprising molecular genetic details of how cells cope with natural amounts of DNA damage."

Characterized by alligators, airboats and catfish, the Everglades is a region of swampy wetlands in southern Florida. In addition to the area's role in Florida's tourism industry, the Everglades play a significant part in protecting our environment - through carbon sequestration.

Over a quarter of the Everglades are encompassed in the Everglades Agricultural Area. The Everglades Agricultural Area includes 700,000 acres of farmland where sugar cane, winter vegetables and other crops are grown.

The farmland was created by draining the Everglades, starting over 100 years ago. There are four main canals that drain the area. Farmers also have systems of ditches to manage the water levels in their fields and to provide irrigation to crops.

Since the 1950s, scientists have been studying an environmental change in the Everglades, called soil subsidence. Soil subsidence is the sinking or settling of the earth's surface. Researchers estimate a subsidence rate of about 1 inch per year.

Soil subsidence is a growing problem. In recent years, soils around the Everglades are so shallow that farmers are struggling to manage water and grow crops.

Previously, it was not clear if carbon quality played a role in soil subsidence. So, Andres Rodriguez, a researcher at University of Florida, was ready to find out. Ultimately, Rodriguez and his team want to improve soil conservation and explore different water management strategies. This research is important to protect the Everglades Agricultural Area, which plays a large role in Florida's agriculture economy.

Carbon sequestration is a process where carbon from the atmosphere is stored in the soil, which helps lessen global warming. Plants, ocean, and the soil all capture and store carbon.

The soil of the Everglades, called peat, is largely made up of waterlogged, decomposing plant and animal materials. The peat soil stores a large amount of carbon compared to other soils across the globe.

When the Everglades Agricultural Area was drained, the soil was exposed to higher levels of oxygen. Decomposition of the plant and animal materials happens much faster with more oxygen. When the carbon in the soil decomposes, it becomes carbon dioxide gas. The mass of the soil decreases, and gas goes into the atmosphere. It's a big chemistry equation.

"It's not easy to picture a soil that disappears," says Rodriguez. "The most challenging process I have to explain - and the most striking - is how carbon in the soil goes from the soil to the atmosphere."

The process of soil subsidence can release significant amounts of greenhouse gasses. This can have connections with climate change.

"To improve soil conservation, I recommend farmers avoid using short flood cycles," says Rodriguez. "I also suggest they use a crop rotation with rice during the summer." These practices decrease the amount of oxygen reaching the soil, which minimizes decomposition.

He also encourages increasing soil carbon by adding plant material back into the soil. Farmers can do this by incorporating residue from sugarcane harvest into the soil. "I am aware that the practices I recommend present challenges from the agronomic point of view, but I am confident they can be sorted." Says Rodriguez.

Rodriguez presented his research at the November International Annual Meeting of the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America in San Antonio. This research was funded by the Soil and Water Sciences Department and the Everglades Research and Education Center at the University of Florida.

Use of an AC rather than a DC electric field can improve the piezoelectric response of a crystal. Now, an international team of researchers say that cycles of AC fields also make the internal crystal domains in some materials bigger and the crystal transparent.

"There have been reports that the use of AC fields could significantly improve the piezoelectric responses -- for example by 20% to 40% -- over DC fields and the improvements have always been attributed to the smaller internal ferroelectric domain sizes that resulted from the cycles of AC fields," said Long-Qing Chen, Hamer Professor of Materials Science and Engineering, professor of engineering science and mechanics, and professor of mathematics at Penn State. "About three years ago, Dr. Fei Li, then a research associate at the Materials Research Institute at Penn State, largely confirmed the improvement of piezoelectric performances from application of AC fields. However, it was not clear at all how the internal ferroelectric domains evolved during AC cycles.

"Our group does mostly computer modeling, and more than a year ago we started looking into what happens to the internal domain structures if we apply AC fields to a ferroelectric piezoelectric crystal. We are very curious about how the domain structures evolve during AC cycles. Our computer simulations and theoretical calculations did show an improved piezoelectric response, but our simulations also demonstrated that the ferroelectric domain sizes actually got bigger during AC cycles rather than smaller as reported in the literature."

Piezoelectric materials generate electric charges when a mechanical force is applied and deform or change shape when an electric field is applied. The researchers investigated lead magnesium niobate-lead titanate -- PMN-PT -- a commercially available piezoelectric material. The computational results were unexpected because most people in the piezoelectric community believe that the smaller the domains are, the higher the piezoelectric response.

Domains within a crystal are areas within which the electric dipoles or electric polarization arrange themselves along the same direction. Before the alignment of dipoles or polarization of a PMN-PT crystal using an electric field, there are many tiny domains with polarization along different directions. As cycles of AC electric fields are applied to the crystal, the domains realign, becoming fewer and larger. After several AC cycles, the domains are large and in layers.

"The simulation results were in contradiction to reports in the literature," said Chen. "We needed to dig deeper to see if reality agrees with our simulation results."

Researchers at Xi'an Jiaotong University in China then grew their own PMN-PT crystals and carefully examined the domain configurations within their samples using various experimental characterization techniques under different AC cycling conditions. They confirmed the computational predictions from Penn State that domains actually become larger during AC cycles.

The larger domain size and the particular layer domain structures also suggest that a ray of light shown onto the crystal would be unimpeded and shine right through -- the crystal would be transparent. The crystals not only possess ultrahigh piezoelectricity, but also are highly transparent after their surfaces are carefully polished. In the past, crystals like this have always been opaque.

The researchers report today (Jan. 15) in Nature that "the work presents a paradigm to achieve an unprecedented combination of properties and functionalities through ferroelectric domain engineering, and the new transparent ferroelectric crystals reported here are expected to open up a wide range of hybrid device applications, such as medical imaging, self-energy-harvesting touch screens and invisible robotic devices."

CHAMPAIGN, Ill. -- Composites made from self-assembling inorganic materials are valued for their unique strength and thermal, optical and magnetic properties. However, because self-assembly can be difficult to control, the structures formed can be highly disordered, leading to defects during large-scale production. Researchers at the University of Illinois and the University of Michigan have developed a templating technique that instills greater order and gives rise to new 3D structures in a special class of materials, called eutectics, to form new, high-performance materials.

The findings of the collaborative study are published in the journal Nature.

Eutectic materials contain elements and compounds that have different melting and solidification temperatures. When combined, however, the composite formed has single melting and freezing temperatures - like when salt and water combined to form brine, which freezes at a lower temperature than water or salt alone, the researchers said. When a eutectic liquid solidifies, the individual components separate, forming a cohesive structure - most commonly in a layered form. The fact that eutectic materials self-assemble into composites makes them highly desirable to many modern technologies, ranging from high-performance turbine blades to solder alloys.

"Having a single melting point has advantages in composite materials processing," said Paul Braun, a professor of materials science and engineering and director of the Materials Research Lab at the U. of I., who led the project. "Instead of depositing layers of material individually, we start with a liquid that self-assembles as it solidifies. This can speed up production and allows us to make larger volumes at one time."

However, self-assembly can lead to problems, he said, as its uncontrolled nature can form defects.

"Templating is a common practice used in organic polymers processing," said Ashish Kulkarni, an Illinois graduate student and the first author of the study. "However, it is not something that has been explored in inorganic materials processing because inorganic microstructures are more rigid and harder to control."

To demonstrate this process in the lab, the team built templates with tiny posts arranged in hexagonal shapes to control the resolidification of a melt containing silver chloride and potassium chloride - a eutectic material that naturally forms layers as it cools.

"If not controlled, the only microstructures this system will form are layers," said Katsuyo Thornton, a professor of materials science and engineering at Michigan, who conducted computer simulations with graduate student Erik Hanson, both of whom are study co-authors. "We can vary the cooling rate to make the layers thicker or thinner, but the pattern stays the same. By adding a template that the liquid solidifies around, we hoped new patterns would emerge."

The team found that as the silver and potassium chloride melt to solidify around the hexagonal-shaped templates, the posts get in the way of the layer formation and produce a composite with an array of different square, triangular and honeycomb-shaped microstructures instead - the specifics of structure depending on the distance between the posts on the template.

"The repeating nature of these templates and newly formed structures reduces the chances for defects to form," Braun said. "So, not only did we form exciting new microstructures, but we also reduced the number of defects in the resulting composite material."

The researchers will explore how the new microstructures influence the physical properties of a wide range of eutectic materials.

"The materials we used in our experiments are transparent, so the first direction to head in might be to explore optical materials, and there is a lot of potential in the area of photonic crystals," Braun said. "We're still a long way from real application, but the possibilities are abundant."

Researchers at the University of Maryland School of Medicine (UMSOM) developed a new nanoparticle drug formulation that targets a specific receptor on cancer cells, and appears to be more effective than a standard nanoparticle therapy currently on the market to treat metastatic breast cancer. The study, published today in the journal Science Advances, found that the new 'DART' nanoparticles bypass healthy cells and tissues and bind to tumor cells, dispersing evenly throughout the tumor while releasing the chemotherapy drug paclitaxel.

"The marketed drug Abraxane, a nanoformulation containing paclitaxel that is currently used to treat women with aggressive breast cancer, is an effective agent, but it was not designed to selectively deliver paclitaxel to only the cancerous cells within the body," said study corresponding co-author Jeffrey Winkles, PhD, Professor of Surgery at UMSOM. "Our DART nanoparticle specifically targets the Fn14 receptor found abundantly on breast cancer cells; it uses this receptor to gain entry through the plasma membrane and deliver the drug to destroy the cancer." Dr. Winkles' group discovered the Fn14 receptor and described its potential as a target for new therapeutics more than a decade ago.

For this study, UMSOM researchers engineered and tested a new therapeutic nanoparticle platform to deliver the drug paclitaxel to treat triple-negative breast cancer. About one in five women with breast cancer have this type of aggressive tumor, which is particularly difficult to treat; these cancers lack receptors commonly expressed by most breast cancer cells, like hormone receptors, for which effective drugs have been designed. But many triple-negative breast cancers express high levels of Fn14; indeed, most solid tumor types, including lung, prostate and colorectal cancer, overexpress this cell surface receptor.

"After much initial anticipation and some disappointments in the field, nanoparticle delivery systems for cancer treatment are starting to show real promise for patients," said study co-author Graeme Woodworth, MD, Professor and Interim Chair in the Department of Neurosurgery at UMSOM. "We established a proof-of-concept with this study, outlining the design of an optimized nanoparticle delivery system that balances the specific binding to cancer cells while minimizing non-specific, off-target binding to other cells in a very fine-tuned way."

To accomplish this, the research team attached a monoclonal antibody called ITEM 4 to the surface of the nanoparticle because it specifically binds to Fn14, providing a key to unlock entry into the cancer cell. The surface of the nanoparticles was also coated with polyethylene glycol to keep them circulating through the bloodstream and lymph system until they reached the tumor and to prevent them from being quickly flushed out of the body.

"Many drug delivery carriers exhibit nonspecific binding to healthy cells and tissues in addition to the diseased cells they are targeting, which often leads to unintended side effects or toxicities," said study corresponding co-author Anthony Kim, PhD, Associate Professor of Neurosurgery and Pharmacology at UMSOM. "This DART nanoparticle platform has unique capabilities to improve therapeutic delivery to difficult-to-treat locations within the body, while also allowing us to potentially increase the maximum tolerated dose of the encapsulated drug without increasing side effects to patients."

The researchers then filled their optimized DART nanoparticle formulation with paclitaxel and tested it against Abraxane (the marketed nanoparticle which also contains paclitaxel) in animals with triple-negative breast cancer tumors. In one set of experiments, the nanoparticles were delivered to mice harboring breast tumors grown above the natural breast region. They found the DART formulation led to a significantly increased median overall survival (68 days) compared to Abraxane treatment (45 days). They saw a clear benefit to using the DART nanoparticles when they compared the treatments again in animals that harbored breast tumors implanted in the brain (akin to a metastatic brain tumor).

"This is a compelling finding and significant step forward in the use of nanoparticles to treat cancer," said UMSOM Dean E. Albert Reece, MD, PhD, MBA, University Executive Vice President for Medical Affairs and the John Z. and Akiko K. Bowers Distinguished Professor. "Our faculty continue to lead in making breakthrough discoveries that help patients with the most difficult to treat cancers."

The UMSOM researchers are members of the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. A former Ph.D. student, Jimena Dancy, PhD, and a former Postdoctoral Fellow, Aniket Wadajkar, PhD, are listed as co-first authors on the publication. Researchers from the Translational Genomics Research Institute in Phoenix, Arizona and the Mayo Clinic Arizona in Scottsdale also contributed to the work.

This study was primarily funded by the National Institutes of Health.

Future research includes testing the DART therapy in other cancer types, including an aggressive form of brain cancer called glioblastoma and developing a similar version of the nanoparticle designed to work specifically in humans. This would involve using a humanized antibody on the surface of the nanoparticle and scaling up the formulation. The researchers recently received a grant from the TEDCO Maryland Innovation Initiative Commercialization Program to move forward with efforts to adapt their nanoparticle system and eventually test the treatment in cancer patients.

A young boy with a rare genetic disease that typically kills within weeks of birth is now 3 years old and in remission thanks to a collaborative effort that included physicians at King Saud University Department of Pediatrics in Riyadh, Saudi Arabia, and immunologists at the Icahn School of Medicine at Mount Sinai in New York.

A report published in the New England Journal of Medicine today describes how the global team combined exceptional supportive clinical therapy, genetic diagnosis and a novel immunotherapeutic drug known as a protein kinase inhibitor to bring the Saudi Arabian boy into full remission from his deadly disease, known as "USP18 deficiency" because it is caused by a mutation of the USP18 gene.

"The teamwork between our two institutions and others around the world is a textbook case of science without borders," says Dusan Bogunovic, PhD, Associate Professor of Microbiology, and Pediatrics, at the Icahn School of Medicine at Mount Sinai and co-corresponding author of the study. "We showed that even with a disease like USP18 deficiency, sound clinical care and timely drug administration can rescue patients from what was previously considered a death sentence."

USP18 (ubiquitin-specific peptidase 18) is a protein coding gene involved in immune system. It is important to regulate inflammation driven by a substance that our body normally secretes to fight off viruses, type 1 interferons. Mutations of USP18 result in an uncontrolled response to type 1 interferons, triggering IFN-I-mediated inflammation that's lethal in utero or shortly after birth. JAK1 inhibitor drugs, like ruxolitinib, the protein kinase inhibitor given to the Saudi Arabian boy, take over the intended role of USP18, and thus have the potential for a prompt and sustained recovery by patients.

Dr. Bogunovic and his lab, widely known for their work in the field of rare inflammatory diseases in children, first described USP18 deficiency in 2016. The following year, physicians at King Saud University reached out to Mount Sinai via Paris Descartes University in France about a gravely ill young patient in their intensive care unit who appeared to have a variant of the USP18 gene. Thus began a clinical/research collaboration--which included Paris Descartes University as well as Rockefeller University in New York--in which scientists characterized in detail the molecular basis of the disease through a battery of whole exome sequencing, expression assays, protein analysis, and antibody detection. "After seeing a potential variation in the USP18 gene, we conducted a complete set of tests to determine what it meant in terms of protein function," explains Marta Martin-Fernandez, PhD, a postdoctoral fellow at the Icahn School of Medicine and a first author of the published study, who performed many of its biochemical and genetic analyses. "Those findings confirmed for us that ruxolitinib was the appropriate treatment."

The young patient, who had been kept alive for months through the extraordinary care of physicians led by Fahad Alsohime, MD, Assistant Professor at the College of Medicine, King Saud University, was promptly put on oral, twice-daily doses of ruxolitinib. The dosage was increased after insufficient changes were seen, and within two weeks his symptoms began to rapidly improve, allowing doctors to wean him from respiratory support. Subsequent CT and MRI imaging showed a resolution of hemorrhaging, ischemia, cellulitis of the right forearm, and hydrocephalus, a condition in which cerebrospinal fluid accumulates in the brain. After two years of follow-up in an outpatient clinic in Riyadh, and continued administration of the JAK1 inhibitor, the child remains free of clinical problems and has been given an encouraging prognosis by his physicians. He will likely have to take ruxolitinib for the rest of his life.

The success of this case has provided a further springboard for Mount Sinai scientists to investigate the genomics and molecular/cellular biology behind conditions less severe than the boy's. This ongoing work links to other studies that have shown that JAK inhibitors--which were initially developed as anti-cancer drugs but proved to be largely ineffective--can improve symptoms and control disease activity in patients with other type 1 interferon abnormalities.

"We were able to demonstrate the benefits of rapid genetic diagnosis of an inherited disorder for which an immunosuppressant drug like ruxolitinib can provide effective and sustained treatment," says Dr. Bogunovic of Mount Sinai, a senior author on the publication. "That kind of discovery and drug repurposing must continue to be pursued by the scientific community without interruption."

As the drug epidemic began to unfold in the United States, deaths classified as drug-related for 15- to 64-year-olds hit 9% in 2016, up from about 4% less than two decades earlier. But new research published in PLOS ONE from the University of Pennsylvania and Georgetown University suggests that drug-associated mortality in this country is actually more than double that.

"It's obvious that the drug epidemic is a major American disaster," says Penn demographer Samuel Preston, who conducted this work with Georgetown demographer Dana Glei. "The basic records being kept are annual reports on the number of deaths from drug overdose. But that's only part of the picture."

Among this group of Americans in 2016, 63,000 deaths were attributed to drug-related causes--mostly poisonings--but Glei and Preston estimate that the overall number of drug-associated deaths is far higher: around 142,000. They also found that, on average, drug use decreased life expectancy after age 15 by 1.4 years for men and by 0.7 years for women--figures that more than doubled for the hardest-hit state, West Virginia.

"The drug epidemic is probably killing a lot more Americans than we think," says Glei, a senior research investigator in Georgetown's Center for Population and Health. "That's the main point we're trying to make."

Beyond overdoses

To draw these conclusions, the researchers turned to a dataset from the National Center for Health Statistics, part of the Centers for Disease Control and Prevention. They built models to assess the mortality rates for males and females in all 50 states from 15 age groups and for 18 calendar years. The dataset represented more than 44 million deaths, 667,196 of which were coded as related to drugs. Their models eventually showed that drug-coded deaths, which include drug overdoses and mental and behavioral disorders related to drugs, represent only about half of all drug-associated deaths.

"Drugs can kill in other ways," says Preston, a professor of sociology and member of Penn's Population Studies Center. "Infectious disease like HIV/AIDS and hepatitis, impaired judgement, suicide, circulatory disease--these are all affected by drug use. People who are perpetual drug users have much higher mortality in general."

The statistical associations between drug-coded deaths and other deaths suggest that drug use likely cost something in the neighborhood of 142,000 deaths in 2016, or 2.2 times the number of death certificates that coded "drugs" as the underlying cause of death.

Decreased life expectancy

Glei and Preston then looked at life expectancy. They found that drug use shaved off nearly a year-and-a-half of life for men and three-quarters of a year for women. "That may not sound like a lot," says Glei, "but it's a big effect. It's big enough to account for the recent reversal of life-expectancy trends in the United States."

West Virginia--known to be the opioid crisis epicenter, with high drug-overdose rates--fared the worst, with drug-associated deaths for 15- to 64-year-olds hitting 39% for males and 27% for females. Other states with high rates included Massachusetts, Maryland, Pennsylvania, and Ohio. "Pennsylvania is one of the hardest hit," Preston says. "We estimate that for 15- to 64-year-olds, 34% of male deaths and 23% of female deaths in 2016 were attributable to drugs."

Nebraska, on the other end of the spectrum, fared best for both sexes, with Iowa, Montana, North Dakota, and South Dakota rounding out the five states with the lowest numbers among men.

Variation in regional patterns helped the researchers see pockets of drug-related mortality that could easily have been missed, Preston adds. "The rates are high in the Southwest, in Appalachia, and in New England. They're low in the Great Plains. The fact that this imprint is so distinctive helped us identify statistically significant associations."

No root causes

Though this work does recalculate the magnitude of the drug problem in the U.S., the researchers say it doesn't get at root causes.

Currently two theories prevail: The first has to do with drug supply, fueled initially by a wave of addiction to prescription drugs like oxycontin, then again with street drugs like heroin, and finally by opioids like fentanyl.

The second has to do with what are called "deaths of despair" that stem from abuse of alcohol and other drugs and also suicide, all of which are spurred by a deeper underlying cause. In this theory, "it's not just about the supply of drugs but that there's something else behind all of it that causes people to either use drugs or alcohol or commit suicide because they've lost interest in their life," Glei explains.

"We're not differentiating between these two approaches or identifying any other explanations of what's going on," Preston adds. That could potentially come in future work. For now, this research aims to paint a broad picture and get at the true extent of the drug epidemic in the United States.