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ROCHESTER, Minn. -- Chronic pain affects a large proportion of older adults and most long-term care residents. Managing chronic pain effectively is essential but challenging, and it has been complicated by concerns about opioid abuse.

Pain management can be safely optimized with a plan that balances the risks and benefits of treatments, according to a commentary in Mayo Clinic Proceedings. Treating chronic pain is best achieved when pharmacologic strategies and nondrug therapies are used at the same time.

"Chronic pain is very common in older adults, and is often associated with other issues, such as depression, insomnia, social isolation and poor quality of life," says Brandon Verdoorn, M.D., a geriatrician and internist at Mayo Clinic. "While it's generally not curable, it can be managed with a systematic approach that begins with a thorough, function-based pain assessment followed by recognition and treatment of contributing conditions."

Then the emphasis should be on initial low-risk strategies to address pain, which typically include noninvasive, nonpharmacological options, says Dr. Verdoorn, who co-authored the commentary with Christina Y. Chen, M.D., also a Mayo Clinic geriatrician and internist. "Virtually every patient can benefit from these low-risk options," he says.

"Some may wonder if pain medications can be safely used in older adults," says Dr. Chen. "This is a timely question, given the opioid crisis. Though many medications used for managing chronic pain can have substantial adverse impacts, it's important to keep in mind that older adults also are affected by a pain epidemic. With judicious use, these medications, including opioids, are important tools for addressing chronic pain, which ultimately affects one's function and independence."

The article in Mayo Clinic Proceedings offers a practical, step-by-step framework that can assist providers who are treating older adult patients with chronic pain:

Begin with a thorough assessment of pain, focusing on pain-related function.

Address associated conditions, such as depression and insomnia, at the same time.

Start with low-risk pain management strategies, including nondrug methods that get the patient actively involved in her or his own improvement.

Use higher-risk - often pharmacologic - strategies cautiously, when needed.

Frequently reassess and discontinue ineffective treatments.

Drs. Chen and Verdoorn also dispel some commonly held -- and inaccurate or misleading -- beliefs about the effects of pain medications on older adults, such as that opioid medications cause delirium and falls. "Despite conventional wisdom, the idea that opioids cause falls is not supported by current evidence," says Dr. Verdoorn, though opioids appear to increase the risk of fracture when a fall occurs. This may affect the pain management strategy for patients who have had falls or are at risk for falling.

"Though the elements of our framework are not new, they have not previously been conceptualized in this fashion as far as we are aware," says Dr. Chen. "The intent is to provide a useful in-office tool to help guide management of chronic pain. With a careful and systematic approach, pain management can be safely optimized for older adults."

In systems from batteries to semiconductors, edges and interfaces play a crucial role in determining the properties of a material. Scientists are driven to study places in a sample where two or more different components meet in order to create materials that are stronger, more energy-efficient or longer lasting.

In a new study from the U.S. Department of Energy’s (DOE) Argonne National Laboratory, researchers have put a new technique based on machine learning to work uncovering the secrets of buried interfaces and edges in a material. By using machine learning as an image processing technique, scientists can dramatically accelerate the heretofore laborious manual process of quantitatively looking at interfaces without having to sacrifice accuracy.

The experimental technique used to generate data that were analyzed using machine learning is called atom probe tomography, in which researchers select out small needle-like, three-dimensional samples. Individual atoms are then ripped off from the sample. Time-of-flight measurements and mass spectrometry are then performed to identify where in a material a particular atom originated.

“Our method is scalable, you can put it on high performance computing and fully automate it, rather than going through manually and looking at different concentrations. Here you send your code and push a button.” — Argonne materials scientist Olle Heinonen

This process generates a very large dataset of positions of atoms in the sample. To analyze this data set, the researchers segmented it into two-dimensional slices. Each slice was then represented as an image on which the machine learning algorithm could determine the edges and interfaces.

In training the algorithm to recognize interfaces, the team led by Argonne materials scientist and study author Olle Heinonen used an unconventional approach. Rather than using images from a library of materials that might have had poorly defined boundaries, Heinonen and his colleagues began with pictures of cats and dogs to help the machine learning algorithm to learn about edges in an image.

“When it comes to training an algorithm, these shapes that are simple for us but complex to a computer provide a useful proving ground,” Heinonen said.

Then, Heinonen and his colleagues were able to prove the accuracy of the machine learning algorithm by compiling a set of molecular dynamics simulations. These they used to make synthetic datasets in which the composition of the simulated sample was completely known. By going back to the machine learning method, they were able to extract composition profiles and compare them to the actual ground truth.

Previously, attempts to create these types of concentration profiles from atom probe tomography data involved a labor intensive, manual process. By pairing the machine learning algorithm with newly developed quantitative analysis software, Heinonen said that he could dramatically speed the analysis of a wide range of material interfaces.

“Our method is scalable, you can put it on high performance computing and fully automate it, rather than going through manually and looking at different concentrations,” he said. “Here you send your code and push a button.”

Although the technique was developed for atom probe tomography, Heinonen explained that it could be adapted for any kind of tomography — even techniques like X-ray tomography that do not necessarily reveal atomic positions. “Wherever you have 3D datasets with some structural information and interfaces, this technique could be useful,” he said.

The collaboration that spawned the study was notable for including experts from a wide variety of different domains, including mathematics, artificial intelligence, nanoscience, materials science and computer science. “We pulled together a wide variety of expertise to solve a challenging issue in materials characterization,” Heinonen said.

“From the machine learning perspective, a key challenge that we have to overcome is data paucity,” said Argonne computer scientist Prasanna Balaprakash, another study author. “In a typical machine learning setting, the labeled data required for training and learning is abundant, but in atom probe tomography, significant time and effort are required to conduct each experiment and to manually identify the iso-concentration surfaces as labeled data. This prevents us from applying deep learning approaches directly.”

According to Argonne computational scientist Sandeep Madireddy, the researchers leveraged transfer learning techniques, including the use of deep learning models trained on natural images, to automatically identify the edges in the atom probe tomography data.

James Cook University researcher Associate Professor Richard Franklin says drownings globally have dropped by half over the last 30 years, with rates reducing in all regions except Oceania.

Dr Franklin was the lead author of a world first study in partnership with the Institute of Health Metric and Evaluation and published in the journal BMJ Injury Prevention which found that age standardised mortality rates from unintentional drowning have decreased by 57% between 1990 and 2017.

Dr Franklin said the decrease was not uniform across countries and the revised global estimate is now approximately 300,000 drowning deaths per year. He said China, India, Pakistan and Bangladesh accounted for half of the drowning deaths and with children bearing the highest burden and overrepresented in the figures.

"Approximately 90 per cent of drowning deaths occur in low and middle income countries and are often due to everyday activities such as collecting water, bathing or walking to school.

"There is a particular need for us to work with our neighbours in Oceania where there was an 80% increase in drowning, with Papua New Guinea seeing a 93% increase," he said.

Dr Franklin has been working with the Institute for Health Metrics and Evaluation in the US to publish what is the first Global Burden of Disease Report on unintentional drowning.

"Drowning is a significant global challenge, described by the World Health Organization as a hidden public health threat, with Australian organisations such as Royal Life Saving leading efforts to build capacity to reduce drowning in low and middle income countries such as Bangladesh and Vietnam," he said.

Justin Scarr, CEO Royal Life Saving said "Associate Professor Franklin's study is globally significant, brings new focus and energy to an under-resourced health and development issue."

Dr Franklin said high rates of drowning in children will shock most Australians, and much more needs to be done by UN bodies WHO, UNICEF, development agencies and donors to support nations in the Indo-Pacific region.

Dr Franklin said in Australia there are on average 288 unintentional drowning deaths per annum (Royal Life Saving National Drowning Report). While the good news is the numbers have been reducing, there is a need for more work.

Monday 02 March 2020 - Results from a study looking at an experimental drug to tackle the debilitating side effect of dyskinesia, have offered hope that it may have potential as a future treatment for people with Parkinson's.

Research carried out by US biotech company Neurolixis with funding from Parkinson's UK, investigated the effect of the drug NLX-112 on dyskinesia, a common side effect experienced by people with Parkinson's who have been taking levodopa-based medications for several years. It causes involuntary movements that can affect various parts of the body, making everyday tasks impossible. The main medication available to manage dyskinesia is amantadine, which can have side effects and does not work for everyone.

Around half (40 to 50 per cent) of all people with Parkinson's will experience dyskinesia after just five years of taking levodopa, and up to 80 per cent of people will experience it after ten years of taking the medication.

NLX-112 works by targeting serotonin cells inside the brain which are believed to contribute to the development of dyskinesia, by releasing dopamine in an erratic manner. It aims to reduce dyskinesia by decreasing the amount of dopamine the cells release.

In this study, NLX-112 was tested in marmosets with Parkinson's-like symptoms. The marmosets had developed the side effect of dyskinesia in response to levodopa treatment in a similar way to many people with Parkinson's.

The study looked at the effect of NLX-112 both on its own and in combination with levodopa, to understand how it impacted both dyskinesia and Parkinson's symptoms. The results showed that NLX-112 successfully reduced dyskinesia and crucially, did not significantly reduce the effectiveness of levodopa, which many other similar drugs do. When NLX-112 was used on its own (without levodopa), it again improved movement problems.

These promising results published online in Neuropharmacology, suggest that NLX-112 has potential as a future treatment for not only reducing dyskinesia, but also for improving the movement symptoms of Parkinson's.

The one-year project was funded through the Parkinson's Virtual Biotech, led by charity Parkinson's UK, which is plugging the funding gap in drug development and fast-tracking the projects with the greatest scientific potential, to transform the lives of people with Parkinson's.

Dr Arthur Roach, Director of Research at Parkinson's UK, said:

"This promising research on NLX-112 offers hope that we can find a treatment that can tackle dyskinesia, which can make everyday tasks, such as eating, writing and walking, extremely difficult. People with Parkinson's tell us it is one of the most critical issues that impacts quality of life so we're delighted that this project is progressing so positively.

"With 145,000 people living with Parkinson's in the UK, we are desperately in need of a breakthrough treatment and we're committed to delivering one by 2024. It is vital we continue to work with biotech companies like Neurolixis to drive forward new treatments that may slow, stop or reverse Parkinson's and also those, like NLX-112, that could bring relief from symptoms or side effects."

Adrian Newman-Tancredi, PhD, co-founder and Chief Executive Officer at Neurolixis, said:

"We are excited that NLX-112 has shown such positive results in reducing dyskinesia in marmosets. If the striking preclinical data are reproduced in clinical trials, NLX-112 could significantly alleviate the troubling dyskinesia that prevent many Parkinson's patients from performing routine daily tasks, thereby improving their quality of life.

"We are currently making plans and seeking funding to take NLX-112 into clinical trials and hope to be able to initiate these before the end of 2020.

"We're hugely grateful for the funding from the Parkinson's Virtual Biotech which has helped us complete the essential final experiments and preparations to get us to this crucial point."

NLX-112 has been previously tested in people with diabetes to treat pain. As it has been found to be safe and well-tolerated in humans, it is hoped the drug will now be moved into phase 2 clinical trials in people with Parkinson's.

39-year-old TV director Michael Gibson lives in Preston and was diagnosed with young onset Parkinson's at the age of 18. He lives with his wife and two children. Michael experiences the symptoms of stiffness, rigidity and slow speech. His medication has resulted in him experiencing the side effect of dyskinesia which has worsened over time and impacts his life the most.

"The side effect developed five years ago but it has ramped up recently and I am struggling with my mental health as a result. I can cope with the stiffness but it's the twitching movements that I am most embarrassed about.

"Sometimes I go to work in the morning and my body is nervous, my legs are bouncing around and I get stressed at my desk. I get conscious that my colleagues are looking at me. When I order a drink from a bar, I'm terrified that the dyskinesia will make me spill my drink, affect my walking and make people stare! It does and it really gets me down; that's why I never offer to make brews at work.

"I have two children and their friends often ask, 'why does your Dad keep dancing?' It makes me feel awful because I don't want to continue explaining things.

"When I found out about this drug, it gave me hope. Dyskinesia affects me every day by making me stand out. I just want to be normal and not jig about. I would want nothing more than to find something that could reduce it."

Biomedical researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich have isolated immune cells from human tonsils obtained following routine surgery, and used them to analyze aspects of the immune response and test the effects of anti-inflammatory agents at the cellular level. 

Human tissues that have been surgically removed from patients are normally treated as waste, especially when they are derived from a 'dispensable' organ like the tonsils. But LMU immunologist Dirk Baumjohann and his team have a special interest in the pharyngeal tonsil tissue excised during a routine adenoidectomy. The reason for this is that tonsils are part of the lymphatic system. As lymphoid organs, freshly isolated, intact tonsils are a useful source of immune cells, and can serve as a platform for investigating the cell biology of the immune response. The primary immunological role of the tonsils is to provide protection against airborne and ingested infectious agents. As they are directly exposed to such pathogens, they contain much higher frequencies of activated immune cells than are found in the bloodstream.  

Dirk Baumjohann, an Emmy Noether Research Group Leader at the LMU Biomedical Center who recently obtained a faculty position at the University of Bonn, is interested in the functional interactions between two major classes of lymphoid cells, called T helper cells and B cells. Among T helper cells, so-called T follicular helper cells play an essential activating role in enabling B cells to produce and secrete antibodies that specifically recognize foreign proteins ('antigens') introduced by either infection or vaccination. Conversely, misdirected immune reactions mediated by these cells can cause allergies and autoimmune diseases. B cell activation by T follicular helper cells takes place in what are called germinal centers, which are located in lymphatic tissues such as the lymph nodes, the spleen - and the tonsils.

In the context of a strategic partnership between LMU, the LMU Medical Center, and Sanofi (which also provided funding for the project), the authors of the new study have established a system which allows them to maintain cells isolated from tonsil tissue in culture. The system not only allows researchers to study the processes that underlie the immune response at the cellular level, but it can also be used as a testbed to analyze the impact of drug candidates on the body's immune defenses. Their findings appear in EBioMedicine, an open-access title issued by the publishers of The Lancet, a leading medical journal. In addition to Baumjohann and members of his group, the authors include specialists based at Sanofi-Aventis Germany, as well as colleagues in the Max von Pettenkofer Institute and the Walter Brendel Center for Experimental Medicine at LMU Munich.

In the study, the researchers tested their system with several drugs that have been approved for the treatment of various inflammatory autoimmune diseases, including rheumatoid arthritis, psoriasis, Crohn's disease and ulcerative colitis. They showed that these agents suppressed the activity of T follicular helper cells and B cells, thereby confirming the drugs' anti-inflammatory effect. Inflammatory reactions are mediated by the binding of signal proteins known as cytokines to specific receptors on immune cells. Binding activates various intracellular signaling pathways, which in turn lead to changes in gene expression by altering the set of transcription factors (which control gene expression) available. When the team inhibited pathways triggered by specific cytokines using these drugs, they noted significant changes in the responses of the cells. For example, one particular transcription factor that is critical for T follicular helper cells and B cells in germinal centers was inhibited by several of the agents tested. These results provide new insights into the regulation of human follicular helper cells.

In these experiments, the immunologists made use of small blocks of tonsil tissue, as well as highly concentrated suspensions of dissociated tonsil cells. "Suspensions are easier to handle and we were able to reproduce the results using cell material that had been stored in the freezer," says Angelika Schmidt, a post-doc in Baumjohann's group and lead author of the study.

According to the authors, the new culture system will enable researchers to study human lymphoid tissue under physiologically relevant conditions. It thus provides a new and valuable experimental model for the study of human immune cells, which is not restricted to cells isolated from the blood. "The availability of this material, derived from human tissue, gives us the opportunity to analyze immune defense mechanisms directly in human cells, and to test the anti-inflammatory effects of drug candidates in a system that is appropriate for this purpose," says Schmidt." Although animal models will remain indispensable in immunological research, they could soon be complemented by the new human-tissue-based test system.

Metal-organic frameworks (MOFs) are porous, crystalline materials that can trap compounds within their molecular cavities, giving them a wide range of applications in gas storage and separation, carbon capture, and in the catalysis of chemical reactions, to name a few. A new range of applications are now being investigated by converting crystalline MOFs into liquid and/or glassy states.

"MOFs are a relatively new class of material, and most of those developed in the last 20 years are in the crystalline state," says Satoshi Horike, a materials scientist of Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS). "Recently, we have found non-crystalline glass or liquid states in MOFs and propose they have great potential as future materials."

Horike reviewed the latest advancements and perspectives in the field, together with material chemist Susumu Kitagawa and colleagues for the journal Angewandte Chemie International Edition.

Tens of thousands of MOFs have been synthesized since they were first discovered in the late 1990s. Technology advances are now allowing researchers to uncover what happens at the molecular level when some MOFs are heated to a melting point and then cooled to produce a glass-like state. So far, researchers have reported about ten MOFs that can be melted into a liquid and/or turned into a glass state. Their melting temperatures range from 184°C to 593°C, depending on their crystal structures.

When this type of MOF is heated, its metal ions and organic ligands start to wobble within the crystals as the material melts. The bond distances in its polymer chains also lengthen as temperatures continue to rise. The structure of a MOF's crystalline state is very ordered. The glass state has a 'middle-range order', where the connections break but portions of the extended structure remain generally in place. Much more molecular fragmentation occurs when a MOF reaches the liquid state, but some of its internal structure retains an element of connectivity.

Not all of these MOFs can be transformed into glass by cooling their liquid state. Some require a mechanical grinding-like treatment for glass to form. During this process, adding certain chemicals to the material could modulate some of its physical properties, such as enhancement of proton conductivity.

Liquid and glass MOFs could provide a new state of material that demonstrates porosity, ion conductivity, and optical properties such as luminescence. They also show promise for heat storage, in energy devices, and for gas permeation. Hybrid materials incorporating glass or liquid MOFs with other materials, such as organic polymers, metal particles, or metal ions, could be used as strong adhesives in energy devices or in catalytic reactions.

The researchers suggest that scientists should revisit the huge library available for crystalline MOFs from the viewpoint of phase change to liquid and/or glass. Doing so could lead to the design of new functional materials.

For the first time, scientists from the VIB Center for Inflammation Research, Ghent University, The Wellcome Sanger Institute (UK), and Newcastle University (UK) have composed a complete map of the cells in the developing human thymus. This novel approach with single cell resolution allowed them to identify more than 50 different cell states in the human thymus which dynamically change in abundance during life.

A collaboration to map the vital thymus

The thymus is a vital organ for the establishment of the immune system. Its main function is to support the maturation of T cells, which are essential white blood cells and part of the adaptive immune system that protects us from infections and tumor cells. Up to now, it was not precisely clear how these T cells develop from early immune precursor cells in the thymus over the course of a human life.

Researchers from the labs of Tom Taghon (Ghent University) and Yvan Saeys (VIB Center for Inflammation Research) played a crucial role in the story of mapping all the cells in the thymus. This single-cell transcriptomic atlas comprises more than 250,000 cells.

Yvan Saeys explains: "A few years ago, we kicked off the first project on single-cell technologies at Ghent University. This collaboration has proven very fruitful, and through the team of Tom Taghon, which has a longstanding expertise in T cell development, we got involved in the human Thymus Cell Atlas project of the Chan Zuckerberg initiative. The current publication is the first result of that collaboration."

The value of single cell research

Niels Vandamme, who coordinates the single-cell platform at Saeys' lab, adds: "The thymus atlas project provided essential data to set up our single-cell infrastructure, the Singularity platform, which allows researchers to perform single-cell analysis from wet lab experiments up to analysis and visualization within one workflow."

"The thymus atlas project will provide a great resource for the community," says Tom Taghon, a co-senior author on the study. "We now have a very detailed understanding of how T cells are generated in healthy tissue and this helps us understand how immunity develops. Since we now know which genes need to be activated to generate T cells, we can exploit this information to engineer T cells with, for instance, a desired specificity to target tumor cells."

An atlas to discover new therapies

The thymus cell atlas project establishes a firm foundation for new clinical applications and therapies. It also helps scientists better understand diseases that affect T cell development, such as severe combined immunodeficiency (SCID) and T cell leukemia. In addition, the knowledge of all thymus cell types will help researchers to possibly generate an artificial thymus for regenerative medicine.

A 475-km-long dam between the north of Scotland and the west of Norway and another one of 160 km between the west point of France and the southwest of England could protect more than 25 million Europeans against the consequences of an expected sea level rise of several metres over the next few centuries. The costs, 250-500 billion euros, are "merely" 0.1% of the gross national product, annualy over 20 years, of all the countries that would be protected by such a dam. That's what Dr Sjoerd Groeskamp, oceanographer at the Royal Netherlands Institute for Sea Research, calculated together with his Swedish colleague Joakim Kjellson at GEOMAR in Kiel, Germany, published this month in the scientific journal the Bulletin of the American Meterological Society. 'Besides being a possible solution, the design of such an extreme dam is mainly a warning', says Groeskamp. 'It reveals the immensity of the problem hanging over our heads.'

Technically feasible

'The construction of such a "North-European Enclosure Dam" seems to be technically feasible', Groeskamp emphasises. 'The maximum depth of the North Sea between France and England is scarcely one hundred metres. The average depth between Scotland and Norway is 127 metres, with a maximum of 321 metres just off the coast of Norway. We are currently able to build fixed platforms in depths exceeding 500 metres, so such a dam seems feasible too.'

Economy and wildlife

The authors acknowledge that the consequences of this dam for North Sea wildlife would be considerable. 'The tide would disappear in a large part of the North Sea, and with it the transport of silt and nutrients. The sea would eventually even become a freshwater lake. That will drastically change the ecosystem and therefore have an impact on the fishing industry as well', Groeskamp elaborates.

'We estimated the financial costs for the construction of the dam by extrapolating the costs for large dams in South Korea, for example. In the final calculation, we must also take into account factors such as the loss of income from North Sea fishing, the increased costs for shipping across the North Sea and the costs of gigantic pumps to transport all of the river water that currently flows into the North Sea to the other side of the dam.'

Warning

Ultimately, the description of this extreme dam is more of a warning than a solution, Groeskamp states. 'The costs and the consequences of such a dam are huge indeed. However, we have calculated that the cost of doing nothing against sea level rise will ultimately be many times higher. This dam makes it almost tangible what the consequences of the sea level rise will be; a sea level rise of 10 metres by the year 2500 according to the bleakest scenarios. This dam is therefore mainly a call to do something about climate change now. If we do nothing, then this extreme dam might just be the only solution.'

A study that set out to measure how much wildlife domestic cats eat to supplement the food they are given by their owners was unsuccessful due to an unexpectedly high variability in cat food ingredients. This accidental discovery suggests that some cat food manufacturers regularly change ingredient composition, even within the same flavors of cat food.

Feral cats are responsible for several native wildlife declines, like the Key Largo woodrat, but the impact of pet cats on urban wildlife isn't well understood. This inspired a collaborative study led by researchers at North Carolina State University to directly measure how often pet cats eat outside of their food bowls.

A common way to understand the composition of animal diets is to collect samples of fur, nails, or blood from an animal and analyze its carbon and nitrogen isotopes. All organic materials contain isotopes of elements that get locked into body tissues, following the basic principle that you are what you eat. For example, the ratios of nitrogen isotopes present in carnivores are dependably distinct from those of plant eaters. Similarly, researchers can distinguish the types of plants that an animal eats by measuring the ratio of carbon isotopes.

For this study, researchers collected isotopes from things a cat might eat, including different brands and flavors of cat foods. They predicted cats that only ate from their food bowls would have an identical isotopic match to the food, while differences between cat and pet food would indicate a cat supplementing its diet with wild prey.

"We really thought this was going to be an ideal application of the isotope methodology," says Roland Kays, a co-author of the study and scientist at NC State and the NC Museum of Natural Sciences. "Usually these studies are complicated by the variety of food a wild animal eats, but here we had the exact pet food people were giving their cats."

This assumes that cat food producers use consistent types and amounts of ingredients. As it turns out, that is not the case.

The carbon and nitrogen isotopes in cat foods varied widely - even between foods that were the same flavor and from the same brand. The only clear relationship found was that the least expensive cat foods had higher carbon values, indicating a strong presence of corn product in inexpensive cat food. In addition, pet foods sampled from the United Kingdom had lower carbon values, suggesting less input from corn products.

"This isn't what we aimed to study, but it is important in as much as there are hundreds of millions of cats (perhaps more) on Earth," says Rob Dunn, co-author of the study and a professor in NC State's Department of Applied Ecology. "The diets of cats, dogs and domestic animals have enormous consequences for global sustainability, cat health and much else. But they are very non-transparent. In short, at the end of this study we are still ignorant about why some cats kill more wildlife than others, and we have also found we are ignorant about something else, the shifting dynamics of 'Big Pet Food.'"

The paper, "High variability within pet foods prevents the identification of native species in pet cats' diets using isotopic evaluation," is published in the journal PeerJ. The paper was authored by Brandon McDonald, Troi Perkins, and Roland Kays from NC State's Department of Forestry and Environmental Resources and the North Carolina Museum of Natural Sciences; Rob Dunn from NC State's Department of Applied Ecology; Jennifer McDonald and Holly Cole from the University of Exeter's Center for Ecology and Conservation; and Robert Feranec from New York State Museum.

Itokawa would normally be a fairly average near-Earth asteroid - a rocky mass measuring only a few hundred metres in diameter, which orbits the sun amid countless other celestial bodies and repeatedly crosses the orbit of the Earth. But there is one fact that sets Itokawa apart: in 2005 it became a visit from Earth. The Japanese space agency JAXA sent the Hayabusa probe to Itokawa, which collected soil samples and brought them safely back to Earth - for the first time in the history of space travel. This valuable cargo arrived in 2010 and since then, the samples have been the subject of intensive research.

A team from Japan and Jena has now succeeded in coaxing a previously undiscovered secret from some of these tiny sample particles: the surface of the dust grains is covered with tiny wafer-thin crystals of iron. This observation surprised Prof. Falko Langenhorst and Dr Dennis Harries of Friedrich Schiller University in Jena. After all, over the last 10 years, research teams all over the world have exhaustively studied the structure and chemical composition of the dust particles from Itokawa, and no one had noticed the iron 'whiskers'. It was only when Japanese researcher Dr Toru Matsumoto, who is spending a year as a visiting scientist with the Analytical Mineralogy group at the Institute of Geosciences in Jena, examined the particles with a transmission electron microscope that he was able to locate the crystals using high-resolution images.

Solar wind weathers celestial bodies

This discovery is exciting not only because the tiny iron 'whiskers' - which have since been shown on other particles from the asteroid as well - had previously been missed. Of particular interest is how they were formed. "These structures are the consequence of cosmic influences on the surface of the asteroid," explains Falko Langenhorst. In addition to rocks, high-energy particles from the solar wind also strike the asteroid's surface, thus weathering it. An important constituent of the asteroid is the mineral troilite, in which iron and sulphur are bound. "As a result of space weathering, the iron is released from the troilite and deposited on the surface in the form of the needles that have now been discovered," says the mineralogist Langenhorst. The sulphur from the iron sulphide then evaporates into the surrounding vacuum in the form of gaseous sulphur compounds.

From the size and number of the ice crystals detected, the researchers can also estimate how quickly the asteroid loses sulphur. "The process is incredibly fast from a cosmic perspective," explains Toru Matsumoto. The crystals he analysed are up to two-and-a-half micrometres long, which is around one-fiftieth of the thickness of a human hair. "The tiny whiskers have already reached these sizes after around 1,000 years," adds the researcher from Kyushu University in Fukuoka. Over the long term, the analysis of the ice crystals can be used to gain a better understanding of weathering processes on other celestial bodies as well, and to determine their age.

To this end, the researchers already have specific asteroids in their sights. NASA's OSIRIS-REx probe is currently preparing to take samples from asteroid Bennu, while JAXA's Hayabusa2 is already on its way back to Earth. The Japanese probe visited the Ryugu asteroid last year and, as with Itokawa, it collected dust particles. The samples should land on Earth at the end of 2020 and the international team of Jena mineralogists and Toru Matsumoto are awaiting them with anticipation.

Cells can both survive and multiply under more stress than previously thought, shows research from the Faculty of Health and Medical Sciences.

This was found by inhibiting the essential gene DNA polymerase alpha, or POLA1, which initiates DNA replication during cell division.

The discovery gives researchers new insights into DNA replication and may potentially be used for a new type of cancer treatment. Research Leader and Associate Professor Luis Toledo of the Center for Chromosome Stability at the Department of Cellular and Molecular Medicine states as follows:

'If we are visionaries, I would say that we might be at the birth of a whole new set of molecules that could be used in fighting cancer', adding:

'Basically, if we turn the finding on its head, this novel strategy aims at exploiting an in-built weakness in cancer cells and make them crash while they divide.'

Loose zippers

When a cell divides, the double DNA strand is opened lengthwise like a zipper that is unzipped. The new double strands are built at each of the separated strands, so that you gradually end up with two new "zippers".

Before the new halfs of the zipper are made, a bit of DNA is temporally exposed in single stranded form. This process is required for the new zippers to form. Nevertheless, large amounts of single-stranded DNA have traditionally been considered by researchers to be a sign of pathological stress during cell proliferation.

However, the researchers behind the new study discovered that DNA unzippers act more loosely than expected. This can generate large amounts of single-stranded DNA, which the researchers now show is no more than a form of natural stress that cells can actually tolerate in high quantities.

Still, for this tolerance to exist, cells require a sufficient amount of the protective protein RPA to cover the single-stranded DNA parts.

'We have seen that cells can duplicate their genome, even with large amounts of single stranded DNA. They can divide and go on living healthily because they have a large excess of RPA molecules that acts as a protective umbrella.' says the study's first author and former postdoc at the University of Copenhagen Amaia Ercilla, adding:

'But there is a flip side of the coin. When we make the cells generate single strand DNA faster than what they can protect, chromosomes literally shatter in hundreds of pieces, a phenomenon we call replication catastrophe. We always thought that we could use this for instance to kill cancer cells,' she adds.

Weapon against cancer

Both Amaia Ercilla and Luis Toledo explain that under normal circumstances it is extremely difficult to deplete a cell's reserve of RPA.

The same was true in the new study, when researchers used different types of chemotherapy to increase the amount of single-stranded DNA. Even when using the best compounds available so far it took around one hour to deplete the RPA reserve in a cell, provoking a replication catastrophe and the associated cell death.

However, the researchers behind the new study believe to have found what Luis Toledo calls 'the ultimate single-stranded DNA generator': When the researchers used a so-called POLA1 inhibitor, the cells met their final destiny after just five minutes.

'Although no new DNA can be made when we inhibit POLA1, the DNA unzippers keep advancing and generate single-stranded DNA at very high speed,' says the Associate Professor, adding:

'All cells can be sensitive to POLA1 inhibitors, including cancer cells, and we might speculate that the strategy could be especially useful against very aggressive forms of cancer that proliferate at a high pace'.

The next step of the research group is to find more molecules that biologically inhibits the POLA1 gene and which, in combination with other substances, may be used in the treatment of cancer patients.

Researchers have discovered how a notorious pathogen may have hijacked one of nature's most enduring mutual relationships.

The work sheds new light on a long-standing enigma about why plants possess genes that appear to be detrimental to their well-being.

It's long been known that the Mildew Locus O (MLO) gene causes the majority of major crops to be susceptible to the fungal leaf pathogen powdery mildew. Loss of the gene causes durable and robust resistance to the pathogen.

But if this gene is disadvantageous to the host, why has it been conserved throughout evolutionary history? Does this susceptibility factor also fulfil some other beneficial role?

In a joint project between the John Innes Centre and the Shanghai Institute of Plant Physiology and Ecology, scientists found that the MLO gene needed by the powdery mildew pathogens is also used by symbiotic mycorrhizal fungi that help plants obtain nutrients from the soil.

Mycorrhizal fungi are beneficial soil microorganisms that establish symbiotic interactions in plant roots and contribute to nutrient uptake. Powdery mildews are serious leaf fungal pathogens that infect many different plant genera and cause significant crop losses in agriculture.

Importantly, the MLO gene and mycorrhizal symbiosis appeared very early in the evolution of land plants, millions of years before the occurrence of powdery mildew fungi.

In this study, experiments showed that mycorrhizal colonisation was reduced in mutant plants of barley, wheat and Medicago truncatula which did not express the MLO gene. This was accompanied by a pronounced decrease in the expression of many key genes required for accommodation of arbuscular mycorrhizal fungi inside plant cells. The findings suggest the primary role for MLO in flowering plants is in colonisation by the arbuscular mycorrhizal fungi, and that this role has been appropriated by powdery mildew.

The MLO gene is present in a wide variety of plants including important crops such as rice, wheat and legumes. The results have important implications for crop improvement and for sustainable agriculture to enhance beneficial mycorrhizal interactions while reducing losses from disease.

"The MLO gene has been widely studied for its role in powdery mildew resistance, although its ancestral role has remained elusive," explains first author Dr Catherine Jacott.

"Since mycorrhizal fungi and powdery mildew respectively infect root and shoot, it may be possible to generate cereals that could fully support mycorrhiza while remaining non-hosts for powdery mildew."

The study: Mildew Locus O facilitates colonization by arbuscular mycorrhiza in angiosperms, appears in New Phytologist journal.

A new study from North Carolina State University shows that lung stem cell secretions - specifically exosomes and secretomes - delivered via nebulizer, can help repair lung injuries due to multiple types of pulmonary fibrosis in mice and rats. The work could lead to more effective, less invasive treatment for human pulmonary fibrosis sufferers.

Pulmonary fibrosis is a fatal disease that thickens and scars healthy lung tissue, creating inflammation and replacing the lining of the lung cells with fibrotic tissue. In the last five years, Ke Cheng and his lab developed spheroid-produced lung stem cells (LSCs) as a potential therapeutic for pulmonary fibrosis. Cheng is the Randall B. Terry Jr. Distinguished Professor in Regenerative Medicine at NC State, a professor in the NC State/UNC-Chapel Hill Joint Department of Biomedical Engineering, and corresponding author of the research.

"The mixture of cells in LSCs recreates the stem cells' natural microenvironment - known as the stem cell niche - where cells secrete exosomes to communicate with each other just as they would inside your body," Cheng says. "LSCs secrete many beneficial proteins and growth factors known collectively as 'secretome' - exosomes and soluble proteins which can reproduce the regenerative microenvironment of the cells themselves. In this work we took it one step further and tested the secretome and exosomes from our spheroid-produced stem cells against two models of pulmonary fibrosis."

Cheng and his colleagues tested lung spheroid cell secretome (LSC-Sec) and lung spheroid cell exosomes (LSC-Exo) against commonly used mesenchymal stem cells (MSCs) in mouse and rat models of chemically induced and silica- or particle-induced pulmonary fibrosis. The stem cell-derived therapeutics were delivered through a "stem cell sauna," a nebulizer that allowed the therapeutic proteins, small molecules and exosomes to be inhaled directly into the lungs.

In the mouse model of chemically induced fibrosis, the researchers found that although inhalation treatment with either LSC-Sec or MSC-Sec led to improvements compared to the saline-treated control, LSC-Sec treatment resulted in nearly 50% reduction of fibrosis compared to 32.4% reduction with MSC-Sec treatment.

In the mouse model of silica-induced pulmonary fibrosis, LSC-Sec treatment resulted in 26% reduction of fibrosis compared to 16.9% reduction with MSC-Sec treatment.

The researchers also looked at rat models of both types of pulmonary fibrosis, and tested both LSC-exosome and LSC-Sec treatments against MSC-Exo with similar results. Additionally, they found that while LSC-exosome inhalation treatment alone can elicit a therapeutic effect similar to LSC-Sec treatment, the full secretome was still the most therapeutic.

"This work shows that lung spheroid cell secretome and exosomes are more effective than their mesenchymal stem cells counterparts in decreasing fibrotic tissue and inflammation in damaged lung tissue," Cheng says. "Hopefully we are taking our first steps toward an efficient, non-invasive and cost-effective way to repair damaged lungs.

"Given the therapy's effectiveness in multiple models of lung fibrosis and inflammation, we are planning to expand the test into more pulmonary diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and pulmonary hypertension (PH)."

"The finding that products released by lung stem cells can be just as efficacious, if not more so, than the stem cells themselves in treating pulmonary fibrosis can be a major finding that can have implications in many other diseases where stem cell therapy is being developed," says Kenneth Adler, Alumni Distinguished Graduate Professor at NC State and a co-author of the paper.

Synthetic biology researchers at Northwestern University have developed a system that can rapidly create cell-free ribosomes in a test tube, then select the ribosome that can perform a certain function.

The system, called ribosome synthesis and evolution (RISE), is an important step toward using ribosomes beyond their natural capabilities. The key feature of RISE is the ability to evolve ribosomes without cell viability constraints. The result could be new ways to synthesize materials, like nylon, or therapies, like new antibiotics that could address rising antibiotic resistance.

"Ribosomes have an extraordinary capability as the protein synthesis machinery of the cell," said Michael Jewett, Walter P. Murphy Professor of Chemical and Biological Engineering and director of the Center for Synthetic Biology at Northwestern's McCormick School of Engineering, who led the research. "But to synthesize proteins beyond those found in nature, we have to design and modify the ribosome to work with non-natural substrates. Developing ribosomes in vitro is an important part of that system, and we are very excited to have this new capability."

The results will be published February 28 in the journal Nature Communications.

The ribosome is like the chef of translation, cooking up the synthesis of a diverse array of biopolymers, or proteins, that enable life. Researchers have already used the ribosome's ability to build proteins to develop new biopharmaceuticals, like insulin. But teaching ribosomes to cook "new cuisines," or make biopolymers that are new to nature, is difficult. Since the ribosome is required for the life of the cell, there are big constraints on how it can be altered.

Jewett and his group developed the new RISE system to overcome those cell viability constraints and ultimately repurpose the ribosome in ways that have never been possible before. By building DNA that encodes for ribosome mutants, the system can make hundreds of thousands of mutant ribosomes within hours. Using magnetic beads, researchers can then select ribosomes with functions that they want. This platform sets the stage to understand the fundamental constraints of the ribosome's active site and create new biopolymers that could transform society. Additionally, the method could potentially be used to manufacture new materials to improve soldier and police protection.

"We validated the RISE method by selecting highly active ribosomes that are resistant to the antibiotic clindamycin from a library of variants," Jewett said. "Our hope is that others will be able to use this platform to select for ribosomes that can carry out a new function."

With the ability to evolve ribosomes at hand, Jewett's team has separately been trying to understand which parts of the ribosome are amenable to change. In a related paper recently published in the journal Nucleic Acids Research, the team also mapped out the nucleotides of the active site of the ribosome to find out which nucleotides could be changed without breaking the ribosome. By building and testing every possible single nucleotide mutation in the active site, 180 in total, the researchers were surprised to find that 85 percent of these nucleotides possessed some flexibility and could be altered. Additionally, the method could potentially be used to manufacture new materials to improve soldier and police protection.

"It proves to us that you can change almost every nucleotide in the active site and still get a functional ribosome. This is so exciting for synthetic biology," Jewett said.

Last year, the researchers also published a paper in which they developed a set of design rules that guide how ribosomes can incorporate new kinds of monomers not found in nature.

Together, this collection of papers provides a comprehensive platform for transforming the ribosome into a machine that can create new kinds of therapeutics and materials.

"Right now, the ribosome is a chef that can only make certain meals," Jewett said. "We want to create many chefs that can make many different cuisines. This is a huge step forward toward that vision."

The research is part of the Defense Department's Multidisciplinary University Research Initiative program, which is supported by the Army Research Office.

"This collection of results represents a truly exciting step towards harnessing and adapting the biological cellular machinery to produce non-biological polymers," said Dawanne Poree, polymer chemistry program manager, Army Research Office, an element of US Army Combat Capabilities Development Command's Army Research Office. "If successful, this work will, in essence, bring synthetic materials into the realm of biological functions, and potentially rendering advanced, high-performance materials capable of catalysis, molecular encoding and data storage, nanoelectronics, self-healing, among many other functions."

Metals and their alloys are the main structural materials of modern civilization. The properties of metal melts are well studied. However, according to Anatoly Mokshin, one of the co-authors of the publication, Chair of the Department of Computational Physics at Kazan Federal University, for more than 25 years, scientists from all over the world have been trying to explain experimentally observed structural features of the melts of such metals as gallium, germanium and bismuth. These features are called "structural anomalies."

"One of the most popular hypotheses explaining structural anomalies in liquid gallium is that there must be covalently bound pairs of atoms, which are also called Ga2 dimers. But is this really so? Until now, this was unknown. Experimental physicists from Obninsk, from the Leypunsky Institute of Physics and Power Engineering, approached us with a proposal to tackle this problem. They had obtained a large array of experimental data on neutron diffraction in metal melts, containing information on the internal structure of these melts. However, they could not explain many of the observed features. As a result of this joint work, it was possible to prove the absence of any stable crystalline domains, as well as of molecule-like Ga2 dimers, in the gallium melt. It is noteworthy that these results allow us to take a fresh look at the processes associated with the formation of these melts," Mokshin explained.

The paper was co-authored by Kazan Federal University and RAS Institute of High Pressure Physics and supported by the Russian Science Foundation (project title "Theoretical, simulation and experimental studies of physico-mechanical features of amorphous systems with inhomogeneous local viscoelastic properties").