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Yale researchers have discovered a "jamming signal" that blocks a powerful immune system stimulant called interleukin-18 (IL-18) from reaching tumors, including in cancers that are resistant to conventional immunotherapy treatments, they report June 24 in the journal Nature.

The research team created a version of IL-18 that could not be jammed and significantly reduced tumors in mice that are resistant to current immunotherapy.

Interleukin-18 is part of a vast immune system arsenal called cytokines and has the specific role of mobilizing T cells and "natural killer" cells to combat infections. Because of this activity, pharmaceutical companies had previously tried to use IL-18 as a cancer treatment. However, the approach failed to show any benefit in clinical trials.

"This was a major paradox to us because IL-18 sends an incredibly powerful inflammatory message to the 'right' immune cells that attack tumors," said Yale's Aaron Ring, assistant professor of immunobiology and pharmacology and senior author of the research. "The fact that there was no response to natural IL-18 in previous clinical trials made us think that tumors were employing immunological countermeasures"

The Yale team set out to find out how tumors shut down IL-18. They discovered that within many forms of cancer, there are high levels of a protein called interleukin-18 binding protein (IL-18BP), which acts as "decoy receptor," blocking the ability of IL-18 to bind to its receptor on immune system cells and activate an immune response.

"We figured that IL-18 was the right pathway to engage, but that IL-18BP was acting as a barrier to its activity," Ring said. "So we wondered if we could make a synthetic version of IL-18 that could overcome this problem."

Using a process called directed evolution, Ring's team searched through approximately 300 million different mutant forms of IL-18 to find rare variants that only bound the true IL-18 receptor and not the decoy.

"We just changed IL-18's frequency in order to eliminate the jamming signal," Ring said.

Working with the laboratory of co-author Marcus Bosenberg, interim director of the Yale Center for Immuno-oncology and professor of dermatology, pathology, and immunobiology, the team administered the modified IL-18 to mice with a variety of tumor types, including those resistant to conventional immunotherapy. They found that the synthetic IL-18 greatly reduced the growth of the tumors and was able to completely eradicate cancer in many of the mice. When they looked within the tumors, the team discovered that the IL-18 drug worked to increase the numbers of an important population of "stem-like" T cells that sustain effective anti-tumor responses.

Existing cancer immunotherapies have proved highly successful in attacking so-called "hot tumors" or those characterized by the presence of inflammation. However, "cold" tumors or those lacking immune system activity, have been resistant to forms of immunotherapy currently in use.

"Because IL-18 can act on cells of the 'innate' immune system such as natural killer cells, it has potential to be effective against 'cold tumors' that have become resistant to conventional immunotherapies," said Bosenberg. "This is a major unmet need and one that the IL-18 pathway is poised to address."

Ring has formed a company called Simcha Therapeutics and hopes to begin clinical trials of the drug in cancer patients next year.

Targeted cancer drugs work by striking a tight bond between cancer cell and specific molecular targets that are involved in the growth and spread of cancer. Detailed images of such chemical bonding sites or pathways can provide key information necessary for maximizing the efficacy of oncogene treatments. However, atomic movements in a molecule have never been captured in the middle of the action, not even for an extremely simple molecule such as a triatomic molecule, made of only three atoms.

A research team led by IHEE Hyotcherl of the Institute for Basic Science (IBS, South Korea) (Professor, Department of Chemistry, KAIST), in collaboration with scientists at the Institute of Materials Structure Science of KEK (KEK IMSS, Japan), RIKEN (Japan) and Pohang Accelerator Laboratory (PAL, South Korea), reported the direct observation of the birthing moment of chemical bonds by tracking real-time atomic positions in the molecule. "We finally succeeded in capturing the ongoing reaction process of the chemical bond formation in the gold trimer. The femtosecond-resolution images revealed that such molecular events took place in two separate stages, not simultaneously as previously assumed," says Associate Director IHEE Hyotcherl, the corresponding author of the study. "The atoms in the gold trimer complex atoms remain in motion even after the chemical bonding is complete. The distance between the atoms increased and decreased periodically, exhibiting the molecular vibration. These visualized molecular vibrations allowed us to name the characteristic motion of each observed vibrational mode." adds Ihee.

Atoms move extremely fast at a scale of femtosecond (fs) -- quadrillionths (or millionths of a billionth) of a second. Its movement is minute in the level of angstrom equal to one ten-billionth of a meter. They are especially elusive during the transition state where reaction intermediates are transitioning from reactants to products in a flash. The research team made this experimentally challenging task possible by using femtosecond x-ray liquidography (solution scattering). This experimental technique combines laser photolysis and x-ray scattering techniques. When a laser pulse strikes the sample, X-rays scatter and initiate the chemical bond formation reaction in the gold trimer complex. Femtosecond x-ray pulses obtained from a special light source called an x-ray free-electron laser (XFEL) were used to interrogate the bond-forming process. (Figure 1) The experiments were performed at two XFEL facilities (4th generation linear accelerator), PAL-XFEL in South Korea and SACLA in Japan, and this study was conducted in collaboration with researchers from KEK IMSS, Pohang Accelerator Laboratory (PAL), RIKEN, and the Japan Synchrotron Radiation Research Institute (JASRI).

Scattered waves from each atom interfere with each other and thus their x-ray scattering images are characterized by specific travel directions. The IBS research team traced real-time positions of the three gold atoms over time by analyzing x-ray scattering images, which are determined by a three-dimensional structure of a molecule. Structural changes in the molecule complex resulted in multiple characteristic scattering images over time. When a molecule is excited by a laser pulse, multiple vibrational quantum states are simultaneously excited. The superposition of several excited vibrational quantum states is called a wave packet. The researchers tracked the wave packet in three-dimensional nuclear coordinates and found that the first half round of chemical bonding was formed within 35 fs after photoexcitation. The second half of the reaction followed within 360 fs to complete the entire reaction dynamics. (Figure 2)

They also accurately illustrated molecular vibration motions in both temporal- and spatial-wise. This is quite a remarkable feat considering that such an ultrafast speed and a minute length of motion are quite challenging conditions for acquiring precise experimental data.

In this study, the IBS research team improved upon their 2015 study published by Nature. In the previous study in 2015, the speed of the x-ray camera (time resolution) was limited to 500 fs, and the molecular structure had already changed to be linear with two chemical bonds within 500 fs. (Figure 2, upper right) In this study, the progress of the bond formation and bent-to-linear structural transformation could be observed in real time, thanks to the improvement time resolution down to 100 fs. Thereby, the asynchronous bond formation mechanism in which two chemical bonds are formed in 35 fs and 360 fs, respectively, and the bent-to-linear transformation completed in 335 fs were visualized. (Figure 2, lower right) In short, in addition to observing the beginning and end of chemical reactions, they reported every moment of the intermediate, ongoing rearrangement of nuclear configurations with dramatically improved experimental and analytical methods.

They will push this method of 'real-time tracking of atomic positions in a molecule and molecular vibration using femtosecond x-ray scattering' to reveal the mechanisms of organic and inorganic catalytic reactions and reactions involving proteins in the human body. "By directly tracking the molecular vibrations and real-time positions of all atoms in a molecule in the middle of reaction, we will be able to uncover mechanisms of various unknown organic and inorganic catalytic reactions and biochemical reactions," notes Dr. KIM Jong Goo, the first author of the study.

Fresh insights into why some harmful substances are so efficient at causing cancer could aid the quest for better treatments.

New research reveals how chemicals can cause changes in cells to help them dodge the body's immune system and build resistance to cancer drugs.

Scientists tracked the impact of a toxic substance - similar to compounds found in tobacco, exhaust and some plants - to better understand how chemicals cause mutations in our cells' DNA.

The team found that damage caused by the substance lingered long enough to be inherited when a cell divides. The damage stops cells' replication machinery reading DNA sequences correctly giving a high chance of a new mutation each time a new copy is made.

Each cell division with the damage produces a new combination of mutations. Because only certain combinations of mutations will turn healthy cells cancerous, the more combinations produced, the greater the chances of disease.

This rapid increase in new combinations of mutations means more throws of the genetic dice that are capable of producing cancer cells.

The greater genetic diversity introduced into cells as a result of these extra throws provides more opportunities for tumours to evade the body's immune system and develop resistance to treatment.

The unique mutation patterns recognised by the team allowed them to trace back to the point where a turmour develops. This new found clarity will aid future research understand the mechanisms behind cancer development and DNA repair processes.

A group led by the Universities of Edinburgh and Cambridge and the German Cancer Research Center identified the specific combinations of mutations that will create cancer cells. The findings could help doctors prescribe the most appropriate course, and dosage, of chemotherapy for patients.

The team studied how cancer cells evolved in the livers of mice given the tumour-causing chemical, diethylynitrosamine. It causes lingering DNA damage like that triggered by a chemical called aristolochic acid, which is found in some plants and herbal medicine and linked to liver cancer.

The DNA damage is also similar to that caused by UV light and a wide a range of polycyclic aromatic hydrocarbons present in tobacco smoke, vehicle exhaust and some burnt food. Temozolomide and other drugs used in chemotherapy were also found to produce lingering DNA damage.

All of the mutations had a clear pattern that suggested damage took place on just one of the two DNA helix strands. This process, where most mutations stem from damage to a single strand, is now known as lesion segregation. Knowing segregation had occurred, helped the team pinpoint the cancer causing mutations.

Having identified mutation patterns in mice, the team used published data from human cells, to find evidence of lesion segregation in cancer patients that had been caused by chemicals and ultraviolet radiation.

The research is the result of collaboration between researchers from EMBL European Bioinformatics Institute near Cambridge and the Institute for Research in Biomedicine, Barcelona.

The study is published in Nature. It was funded by Cancer Research UK with support from the European Research Council, the Wellcome, the Helmholtz Society and the Medical Research Council.

Professor Martin Taylor, University of Edinburgh's MRC Human Genetic Unit, said: "DNA lesions caused by cancer-causing agents are individual to each strand and can trigger several generations of mutations. It is important to be aware of this when tumours are being treated and new drugs are being developed."

Dr Duncan Odom, a director of research at the University of Cambridge's Cancer Research UK Cambridge Institute, said: "The concept of lesion segregation helps us better understand how the surprising complexity of mutations in cancer cells can arise. It may help explain how cancer cells can react so flexibly and, in turn, shape cancer genome evolution."

Dr Sarah Aitken, University of Cambridge, said: "In the end, those cancer cells that carry the most favourable pattern of mutations will prevail. They can grow the fastest, escape the immune system, and possibly survive therapies better."

Two new genera and four new species of giant, single-celled xenophyophores (protozoans belonging to a group called the foraminifera) were discovered in the deep Pacific Ocean during a joint project between scientists at the National Oceanography Centre, UK (NOC), the University of Hawai'i, and the University of Geneva. 'Moana' has inspired the name Moanammina for one of the new genera, while the second has been named Abyssalia in recognition of its abyssal habitat.

The species were described, based on morphology and genetic data, from specimens collected with the University of Hawai'i's Remotely Operated Vehicle Lu'ukai on an expedition to the western Clarion Clipperton Zone (CCZ) aboard the RV Kilo Moana in 2018. The seabed in this area is over three miles deep. The CCZ occupies a vast swathe of the Pacific Ocean with extensive seafloor polymetallic nodule deposits, and is targeted for deep-sea mining.

"We were excited to find these beautiful new xenophyophores," said Andrew Gooday, professor at NOC and lead author of the recently published findings. "It seemed appropriate to name one after 'Moana', a Hawaiian word meaning ocean. Xenophyophores are one of the most common types of large organism found on the CCZ abyssal plains, so the name of the second genus was chosen to reflect this."

Like some other types of foraminifera, xenophyophores construct shells, called tests, composed of particles that they obtain from the surrounding environment. These are often elaborate structures that can reach sizes of four inches or more.

Moanammina semicircularis sp. nov., the new species of the new genus, has a stalked, fan-shaped test, around three inches tall and three and one-half inches wide. Two other new species, Abyssalia foliformis sp. nov. and Abyssalia sphaerica sp. nov., have tests that resemble a flat leaf and an almost perfect sphere, respectively. They are remarkable for being constructed entirely of glass sponge spicules. The fourth new species is Psammina tenuis sp. nov., which has a delicate, thin, plate-like test.

"These four new species and two new genera have increased the number of described xenophyophores in the CCZ abyss to 17 (22% of the global total for this group), with many more known but still undescribed," said Gooday. "This part of the Pacific Ocean is clearly a hotspot of xenophyophore diversity."

"The abundance and diversity of these giant single-celled organisms is truly amazing!" said oceanographer Craig Smith from the UH Mānoa School of Ocean and Earth Science and Technology (SOEST), co-author and Chief Scientist of the RV Kilo Moana cruise on which the xenophyophores were discovered.

"We see them everywhere on the seafloor in many different shapes and sizes. They clearly are very important members of the rich biological communities living in the CCZ. Among other things they provide microhabitats and potential food sources for other organisms. We need to learn much more about the ecology these weird protozoans if we wish to fully understand how seafloor mining might impact these seafloor communities."

Moanammina semicircularis is genetically identical to another specimen found in 2017 in the eastern CCZ. Thus, this study provided the first genetic confirmation of wide geographic ranges (at least ~2,300 miles) for an abyssal xenophyophore species.

DNA, or deoxyribonucleic acid, carries genetic information in the chromosomes of cell nuclei and in mitochondria. DNA is a double helix composed of two long, coiled strands of polynucleotide chains. The chains are composed of four different deoxyribonucleosides attached to each other through phosphate bonds: deoxyadenosine (dA), deoxythymidine (dT), deoxycytidine (dC) and deoxyguanosine (dG).

When DNA is replicated during cell division or when it requires repair, DNA polymerase enzymes produce a new strand of DNA, using deoxyribonucleoside triphosphates (dNTP) as its building blocks. The energy needed for this synthesis comes from the chemical energy charged in the phosphate bonds of the dNTPs.

With previously available techniques, measuring dNTP concentration has been a challenge particularly in the case of samples with little DNA synthesis and, thus, a low dNTP concentration. Now, researchers have developed a technique which allows measurement of dNTP concentrations with much improved sensitivity, for example, from small tissue samples collected from mice.

The study was published in the Nucleic Acids Research journal.

"Our assay is based on DNA polymerase and other materials commonly used in molecular biology laboratories. The assay requires no special equipment or radioactive substances," Docent Jukka Kallijärvi says.

A sensitive method needed for investigating mitochondrial diseases

Mitochondria are organelles that are responsible for cellular respiration, but they also have many other functions. The synthesis of pyrimidine nucleosides, such as thymidine and cytidine, is directly dependent on the mitochondrial respiratory chain. In mitochondrial diseases, deficiency in the respiratory chain function can cause disturbances in the biosynthesis of nucleosides and their phosphorylated counterparts nucleotides.

In rapidly dividing cells, such as those in the bone marrow and cancerous tissue, dNTP concentrations are high, while in cells that divide slowly or not at all, such as liver and muscle cells, the concentrations are very low. However, all cells need some dNTPs for repairing DNA damage and maintaining mitochondrial DNA.

In patients suffering from a mitochondrial disease known as GRACILE syndrome and in its mouse model, the main symptoms appear in the liver and kidneys. These tissues have few dividing cells and, therefore, also a low dNTP concentration.

"I started measuring the amount of dNTPs in mouse tissue and quickly realized that the previous method was not suitable for tissue samples," says doctoral student Janne Purhonen.

A novel robust and sensitive assay solved the problem

In the new dNTP assay developed by the researchers, significant innovations included the use of a DNA polymerase, which tolerates impurities in the sample, as well as the utilisation of a sensitive fluorescent dye that separated double-stranded from single-stranded DNA.

One of the technical challenges was the disturbance potentially caused by ribonucleotides, the building blocks of RNA that may be thousands of times more abundant than dNTPs in tissues.

Developing the technique, Purhonen realized that the addition of another enzyme that cuts the DNA strand at an erroneously added ribonucleotide allows differentiation of the correct and false reaction products based on their melting temperature. This way, the signal due to erroneously incorporated ribonucleotides could be removed.

The study was carried out by the GRACILE research group headed by Docent Jukka Kallijärvi and Professor Emerita Vineta Fellman at the Folkhälsan Research Center.

"We hope the assay will turn out useful to researchers of mitochondrial diseases as well as elsewhere in biological and medical research," Kallijärvi sums up.

The global redistribution of marine and terrestrial species due to climate change is a major concern for conservation planners and resource managers. Now, new research using data from long term surveys of tropical fishes indicates that traditional studies of this range shift phenomenon largely ignore the sequential nature of species movement.

The study, published in Global Change Biology shows that what makes a species a successful "arriver" doesn't necessarily make you a successful "stayer".

The paper is part of an Australian Research Council-funded study, led by Prof Ivan Nagelkerken from the University of Adelaide.

"Typically ecologists use life-history traits to predict which species have the highest probability of moving due to new environmental conditions. This can include traits such as large body size, broad latitudinal range, long dispersal duration," Professor Nagelkerken said.

"However our analyses of tropical fishes at the poleward edge of their distribution in Australia, shows that these traits predisposing larval fishes to extend their range southwards did not drive the early stages of redistribution.

"Instead, a broad diet was the main contributor to the establishment success during early stages," he said

Professor Nagelkerken said that generalist species generally fare better than specialists when "their environment is suffering from human impacts".

"We now show that being a generalist with a broad diet is also favourable when species escape warming environments and relocate to cooler areas".

Professor of Marine Biology, and Chief Investigator on the project, David Booth, from The University of Technology Sydney, said "The study makes great use of the 18 year survey dataset we have on invading tropical fishes, and involved an ongoing collaboration with four academic institutions and a number of graduate students, both local and International."

"If we don't also consider the traits that make these same species capable of establishing and persisting, we're more likely to make erroneous predictions and be surprised by what future fish communities might look like," Professor Booth said.

The authors conclude the results highlight that generalist species best able to adapt to novel food sources might be most successful in a future ocean.

Childhood obesity is a health threat that is becoming more and more common worldwide. It increases risk later on for a variety of life-threatening challenges, including type 2 diabetes, cancer, heart disease and even mental health problems.

A new study led by scientists at the Barcelona Institute for Global Health (ISGlobal) and USC is the first to comprehensively profile environmental factors linked to childhood obesity. The research showed that a higher body mass index (BMI), an estimate of body fat, during childhood is associated with exposure to smoking -- both in the womb and while growing up -- as well as air pollution and certain characteristics seen in some urban areas. Differences in socioeconomic status did not explain these results.

The findings were just published in the journal Environmental Health Perspectives.

"People are not exposed to only one chemical during their lives," said Dr. Lida Chatzi, professor of preventive medicine at the Keck School of Medicine of USC and the senior author of the study. "They are exposed to multiple chemicals. With that in mind, we try to understand the totality of environmental exposures."

Dr. Chatzi and her colleagues are exploring the exposome, an endeavor meant to complement investigations into the genome. Just as many studies of the genome attempt to clarify how the content of genes affect health, studies such as this one attempt to clarify how health is affected by every environmental influence from conception onward. This new approach contrasts with a traditional method for probing population health, zeroing in on one or two environmental factors in a given investigation.

All told, the paper examined 173 factors -- 77 during pregnancy and 96 during childhood. These included air pollutants, families' human-made surroundings and access to green space, tobacco smoke and chemical pollutants such as heavy metals and pesticides.

The researchers studied a group of about 1,300 children aged 6 to 11 years from six European countries: France, Greece, Lithuania, Norway, Spain and the United Kingdom. Data about the women and their children have been gathered, starting at pregnancy, through a collaborative longitudinal research project known as the Human Early Life Exposome (HELIX) study.

Smoking exposure, air pollution and lack of exercise

Mothers' smoking during pregnancy was the most prominent association with high BMI among children, and the only prenatal factor with a significant association. Additionally, high BMI was associated with exposure to secondhand smoke, as measured through levels of a certain chemical in childrens' urine samples. Taken together, these findings suggest that kicking the habit -- or never picking it up -- is one way that parents can safeguard the long-term health of their offspring.

"This is quite an important message," Dr. Chatzi said. "Maternal smoking during pregnancy and exposures to secondhand smoke are quite prevalent worldwide."

Exposure to air pollution, both indoors and out, was another factor linked to higher BMI. Specific pollutants were nitrogen dioxide -- a component of automobile exhaust and other gases released when fossil fuels burn -- as well as particles in the atmosphere.

Certain attributes of the areas where children live also showed a strong correlation with BMI. BMI was higher for children who live in densely populated areas. But BMI was lower for those who went to school in areas that are denser in facilities such as businesses, community services, educational institutions, restaurants and shopping -- a proxy for a neighborhood's walkability.

"With more facilities, children can walk, ride their bikes, go play sports," Dr. Chatzi said. "You can contrast this with what are described as food deserts, or areas with fewer facilities."

The researchers note that better understanding of the impact of environmental exposure could create opportunities to take action that reverses the trend of increasing childhood obesity, ultimately mitigating its long-term dangers.

"These findings provide further evidence that modifying environmental exposures early in life can limit the risk of obesity and associated complications," said first author Martine Vrijheid, research professor at ISGlobal and principal investigator of the HELIX project. "The implications for public health are important since these results may help to identify obesity-related exposures that could be targeted for prevention and intervention early in life."

Migraine is one of the most disabling disorders, affecting one in seven people and causing a tremendous social and economic burden. Several findings suggest that migraine is a disease affecting a large part of the central nervous system and characterized by a global dysfunction in sensory information processing and integration, which also occurs between migraine episodes (interictal period). For example, patients with migraine exhibit increased cortical responses to sensory stimuli during the interictal period. At present, the cellular mechanisms responsible for these alterations are largely unknown.

Malfunction of astrocytes in the cingulate cortex

A team of neuroscientists led by Mirko Santello at the Institute of Pharmacology and Toxicology of the University of Zurich, in collaboration with the University of Padua, has identified a new mechanism implicated in a special form of migraine caused by genetic mutation. They report that this familial hemiplegic migraine type 2 (FHM2) causes a malfunction of astrocytes in the cingulate cortex, a brain region that is involved in the feeling of pain. Astrocytes, specific star-shaped brain cells, are essential contributors to neuronal function and have a strong impact on brain circuits and behavior.

"Despite their abundance, astrocytes have been relatively overlooked by neuroscientists," says Mirko Santello, last author of the study. Yet these cells are extremely important to clear transmitters released by neurons. In their study the researchers were able to show that in familial migraine the astrocytes cannot remove excessive transmitters released by neurons. "The impairment in astrocytic glutamate uptake in the cingulate cortex strongly enhances cortical dendritic excitability and thus enhances firing of the neurons," Santello says.

Less migraine occurrence due to genetic manipulations

Furthermore, the study reported that the malfunction of the cingulate cortex also influences migraine occurrence. In a mouse model the researchers showed that the mice displayed increased sensitivity to head pain triggers. "By manipulating astrocytes in the cingulate cortex, we were able to reverse their dysfunction. This prevented an increase in head pain in mice carrying the genetic defect," says Jennifer Romanos, first author of the study.

Migraine is a complicated disorder that affects part of the nervous system. "Our results provide a clear example of how astrocyte dysfunction produced by a genetic defect affects neuronal activity and sensitivity to head pain triggers," explains Mirko Santello. The findings help to better understand migraine pathophysiology and suggest that the cingulate cortex may represent a critical hub in the disease. The demonstration of the link between dysfunction of astrocytes in the cingulate cortex and familial migraine could help in devising new migraine treatment strategies.

Recreating extreme conditions in the lab, like those in the interior of planets and stars, is very complex and can only be achieved for fractions of a second. An international research team led by the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) has now presented a new, very precise method of evaluating the behavior of mixtures of different elements under high pressure with the help of X-ray scattering. The results hone previous measurements and reinforce the premise that the matter in planets like Neptune and Uranus can alter dramatically: the hot hydrocarbon mixture in the interior of the ice giants can produce a kind of diamond rain, as the researchers report in Nature Communications (DOI: 10.1038/s41467-020-16426-y).

Neither solid, nor fluid, neither gaseous, nor a plasma: the matter inside planets and stars can take on a particular intermediate state, at a temperature of thousands of degrees, and compressed a thousand times more than our Earth's atmosphere - experts call it warm dense matter. There is a lot we still don't know about it. Lab experiments are set to change all that but are technically highly complex because this exotic state does not occur naturally on Earth. Which all means that both the crafting and study of artificial warm dense matter is a challenge for investigators and theoreticians alike. "But in the last resort, we have to understand the processes in warm dense matter if we want to model planets," explains Dr. Dominik Kraus, lead author of the study and the mastermind behind the measuring method. "We now have a very promising new approach based on X-ray scattering. Our experiments are delivering important model parameters where, before, we only had massive uncertainty. This will become ever more relevant the more exoplanets we discover."

Diamond showers - a planetary energy source

At SLAC National Accelerator Laboratory at Stanford University, the researchers studied the structure of the matter in mixtures that are typical for planets, in the case of ice giants, hydrocarbon, employing intense laser light. Standard plastic film served as a substitute for planetary hydrocarbon. An optical high-energy laser converts the plastic into warm dense matter: short, strong laser pulses generate shock waves in the film and compress the plastic to the extreme. "We produce about 1.5 million bars, that is equivalent to the pressure exerted by the weight of some 250 African elephants on the surface of a thumbnail," says Kraus, illustrating the dimensions. What happens is that the laser shock waves also heat up the matter to approximately 5,000 degrees. To evaluate the effect, researchers shoot an extremely powerful X-ray laser at the sample. Depending on how the light is scattered as it passes through the sample, they can draw inferences about the structure of the matter.

The researchers observed that in a state of warm dense matter, what was formerly plastic produces diamonds. The high pressure can split the hydrocarbon into carbon and hydrogen. The carbon atoms that are released compact into diamond structures. In the case of planets like Neptune and Uranus this means that the formation of diamonds in their interior can trigger an additional energy source. The diamonds are heavier than the matter surrounding them and slowly sink to the core of the planet in a kind of diamond rain. In the process, they rub against their surroundings and generate heat - an important factor for planet models.

X-ray scattering enhances measuring precision

In an earlier experiment, Kraus and his team were the first to prove the possible formation of diamonds in planets using X-ray diffraction in an experimental setting (DOI: 10.1038/s41550-017-0219-9). But the diffraction patterns of X-ray light can only reveal crystalline structures. Using additional detectors, the researchers now also analyzed how the light was scattered by the electrons in the matter. They compared the various scattering components with one another as well as with theoretical simulations. This process enables precise scrutiny of the entire structure of matter. "In the case of the ice giants we now know that the carbon almost exclusively forms diamonds when it separates and does not take on a fluid transitional form," explains Kraus.

The method is not only more sensitive than X-ray diffraction, it can also be used more extensively because it makes fewer technical demands on the light source for the analysis. The international research team is now planning to apply it to hydrogen mixtures similar to those that occur in gaseous planets and to compressed pure hydrogen as found in the interior of small stars. These experiments, which are planned to be conducted, among others, at the Helmholtz International Beamline for Extreme Fields (HIBEF) at the European XFEL, could help researchers to understand the many planets we already know about outside our solar system to ascertain whether life might even be possible on any of them.

Fusion experiments could benefit practically from the new measuring method, as well. Fusion research also tries to recreate on Earth processes that occur under great pressure in stars. During inertial confinement fusion, deuterium and tritium fuels are heated to extremes and compressed - warm dense matter is an intermediate state. With the help of X-ray scattering, this process could be monitored precisely.

Graduate student Ubadah Sabbagh placed a cold glass slide on the microscope. It was getting late and the lab was quiet. He adjusted a few settings, and traced along the optic tract before zooming in on the brain's thalamus. What he saw surprised him: two adjacent stripes of glowing spots, each dot denoting a cell body.

At that point, two decades had passed since scientists reported that a small area in the brain's visual thalamus had unique characteristics that set it apart from nearby regions.
Previous studies led by other researchers showed that the region, called the ventral lateral geniculate nucleus, connects to neural circuits involved in regulating circadian rhythm and mood.

But little was known about the region's cellular architecture - until now.

In a new study published online this week in the Journal of Neurochemistry, Virginia Tech scientists identified more than 40 genes expressed in the vLGN and discovered more than half a dozen brand new neuron subtypes, each expressing unique molecules and clustered in tightly packed striped layers.

"The 'wow' moment for me was when Ubadah showed me the image of the two cell subtypes aligning in adjacent layers," said Michael Fox, the study's senior author and a professor at the Fralin Biomedical Research Institute at VTC. "It struck us because when we see layered groups of neurons, it usually means that brain area is segregating different types of information. Now we have a more precise tool kit to help us understand what specific cell types in the vLGN do."

The vLGN spans just a few hundred micrometers in mice and receives signals from the eye via the optic nerve. But unlike some other visual brain regions, it is not associated with classical image-forming.

Neuroscientists initially studied this brain region by destroying its cells and documenting the effects. In the process, however, they also interrupted collateral brain circuits. This led to significant behavioral changes and made it harder to discern which effects were linked to the vLGN. Researchers have since developed more precise, less invasive genetic tools that let them see what happens when a specific cell type's activity is turned on or off.

Fox wanted to apply these modern techniques to understand the vLGN's function and downstream connections, but first he needed to determine which cell types to target. Sabbagh, then a second-year graduate student in Virginia Tech's Translational Biology, Medicine, and Health graduate program, set out to develop an atlas describing the vLGN's cellular structure as part of his doctoral thesis.

It wasn't long before they found the first clue that the vLGN might be organized by cell type in segregated layers, which the researchers described in a 2018 study.

In that study, Fox's team revealed two types of specialized lattice-like structures, called perineuronal nets, that wrapped around distinct types of inhibitory neurons. When the scientists stained these perineuronal nets, they discovered that different populations of neurons covered by these nets were distributed in distinct stripes across the vLGN.

"That was our first hint that there could be layers, but we still needed to identify more cell types to see if they also aligned in non-overlapping domains," Fox said.

Over the next year, Sabbagh tested roughly 70 different riboprobes to map out the vLGN's cellular landscape. Riboprobes are segments of ribonucleic acids (RNA) that bind to complementary segments of RNA.

Scientists add fluorescence genes borrowed from other organisms and viruses to the probe, so when a segment of RNA meets its matching sequence, the targeted molecules light up. The researchers combined these tools to visualize cells producing specific genetic molecules in the vLGN, with each molecule glowing in a different color under the microscope.

This method revealed distinct layers on the scans, but the scientists wanted to be sure. Sabbagh coded a computer program to scan pictures of the vLGN and measure probe signals, which verified their findings and showed distinct layers.

But a question lingered: Where were these cells getting their information from?

The researchers used a nonhazardous viral tracing tool to determine which neurons in the vLGN communicated with the neurons lining the eye's retina. It took a month for the virus to travel a few millimeters between the retina and the thalamus, but it was worth the wait.

The virus revealed that cells in each of the vLGN's main layers received direct visual signals from retinal neurons in the eye. Next, collaborators at the University of Louisville analyzed the communications properties of those connections. Together, these insights help describe how visual information is processed in the vLGN.

"This is an exciting find. We still have more work to do to fill in gaps, but I expect we'll find more cell types, and maybe even more layers as we continue to find more biomarkers," said Fox, who is also a professor in Virginia Tech's College of Science and was recently named director of the College's School of Neuroscience.

His team has started analyzing gene expression in individual cells, using a process called single cell RNA sequencing. Fox says that once they know more about specific cell types, they can trace the circuits and begin revealing how the vLGN's neurons engage with other brain regions.

"We suspect the vLGN has numerous functions, including regulating mood, but now we'll be able to analyze how specific cell types contribute to those functions with greater precision," said Sabbagh, who was recently awarded a six-year $390,000 National Institutes of Health award to support his research.

This research also raises questions about brain evolution and comparative biology. As mammals evolved into larger species, their vLGNs shrank relative to the rest of the visual thalamus. By revealing the vLGN's complicated architecture in mice, Fox hopes to shed light on how these genetic instructions might cross over in other species.

Researchers from Swansea University have developed a new environmentally friendly method for removing toxic chemicals from water.

A newly invented machine, called the Matrix Assembly Cluster Source (MACS), has been used to design a breakthrough water treatment method using a solvent-free approach.

The research, from The Institute for Innovative Materials, Processing and Numerical Technologies (IMPACT) within the College of Engineering at Swansea University, was funded by the EPSRC and led by Professor Richard Palmer.

Professor Richard Palmer explains:

"The harmful organic molecules are destroyed by a powerful oxidising agent, ozone, which is boosted by a catalyst. Usually such catalysts are manufactured by chemical methods using solvents, which creates another problem - how to deal with the effluents from the manufacturing process?

The Swansea innovation is a newly invented machine that manufactures the catalyst by physical methods, involving no solvent, and therefore no effluent. The new technique is a step change in the approach to water treatment and other catalytic processes."

Professor Palmer continues:

"Our new approach to making catalysts for water treatments uses a physical process which is vacuum-based and solvent free method. The catalyst particles are clusters of silver atoms, made with the newly invented MACS machine.

It solves the long-standing problem of low cluster production rate - meaning, for the first time, it is now possible to produce enough clusters for study at the test-tube level, with the potential to then scale-up further to the level of small batch manufacturing and beyond."

The clusters are approximately 10,000 times smaller than the width of a human hair and have been of significant interest to researchers because of their unique properties. However, due to the inadequate rate of cluster production, research in this area has been limited.

The new MACS method has changed this - it scales up the intensity of the cluster beam to produce enough grams of cluster powder for practical testing. The addition of ozone to the powder then destroys pollutant chemicals from water, in this case nitrophenol.

On the future potential of this breakthrough technology, Professor Palmer summarises:

"The MACS approach to the nanoscale design of functional materials opens up completely new horizons across a wide range of disciplines - from physics and chemistry to biology and engineering. Thus, it has the power to enable radical advances in advanced technology - catalysts, biosensors, materials for renewable energy generation and storage.

It seems highly appropriate that the first practical demonstration of Swansea's environmentally friendly manufacturing process concerns something we are all concerned about - clean water!"

Cardiovascular disease (also called heart disease) is one of the most common medical conditions older adults face. In nursing homes, almost half of all older adult residents have been diagnosed with problems affecting the heart and/or blood vessels.

In spite of this, we know very little about how effective a class of popular heart disease medications may be for those 75 and older. Known as statins, these medications are prescribed to reduce the amount of cholesterol in your blood. High blood levels of cholesterol can damage your heart’s blood vessels and lead to the formation of blood clots, which can cause stroke and heart attacks.

The reason we have a knowledge gap as to how well statins work in older adults is because early medical studies that examined statin therapy for heart disease prevention included few adults age 75 and older. More recent trials that did include older adults often found that statin therapy did not help prevent these individuals from developing heart disease.

Why? It’s possible that, as we age, our sensitivity to medications may change. For instance, myopathy (muscle pain and weakness) is a commonly reported side effect of statins. This side effect may have a heightened effect on older adults who are already frail, which could speed up physical decline.

A team of researchers conducted a study to learn more about statin use among older adults, especially those nearing the end of their lives. Their study stemmed from concern about unclear statin prescribing guidelines for people over age 75, and a lack of information on the medications’ uses in nursing homes. The study, published in the Journal of the American Geriatrics Society, evaluated statin use by people with life-limiting conditions across nearly all U.S. nursing homes. The researchers hoped to identify statin use among nursing home residents who were unlikely to benefit from treatment.

This appears to be the first nationwide study to report statin use across U.S. nursing homes among older adults not likely to benefit from continued use.

The researchers noted the following facts as background for their research:

As of 2016, the U.S. Preventive Services Task Force declined to offer statin recommendations for adults older than 75, due to a cited lack of evidence to support any recommendation in this age group. Despite this, statin use has been on the rise in older age groups. In the U.S., approximately half of the 75-and-older population were prescribed statins from 2012 to 2013, a nearly 20 percent increase over the past decade.
Little is known about statin prescribing patterns in nursing homes, where most residents have multiple chronic conditions including Alzheimer’s disease/dementia and physical frailty. A few previous studies had suggested that statin use in nursing homes is common and occurs even when people have life-limiting illnesses.
What’s more, recent evidence suggests that stopping (deprescribing) statins for people with a limited life expectancy could potentially improve quality of life. In fact, the American Medical Directors Association does not recommend prescribing statins to people with a limited life expectancy, due in part to potential harm in older adults.

In their study, researchers examined information from long-stay nursing home residents near the end of life who resided in Medicare- and Medicaid-certified nursing home facilities. Participants were age 65 and older with life-limiting illness diagnoses or limited life expectancy.

The key findings were:

Even with life-limiting illness, over a third of these U.S nursing home residents were on some form of oral statin medication as of September 2016.
While statin use varied by life-limiting illness classification, other medical diagnoses were not strongly associated with the use of statins. This included assessments of people with a documented prognosis less than six months.
Polypharmacy (taking several different medications) appears to remain an issue in U.S. nursing homes. More than 50 percent of the study’s participants were on six or more non-statin prescription medications. And 10 to 20 percent were on 11 or more non-statin medications, depending on age. It appeared that the more non-statin medications residents were on, the more likely they were to be on statins.

Take-aways:

Because statins do not appear to promote longevity and comfort in older patients near the end of life, their use in these older adults should be carefully reviewed.
Since statins are used so widely in older adults, including those over age 75, major medical societies and organizations should have guidelines that specifically address these patients’ needs, especially the needs of those who are frail and have multiple chronic conditions.

This summary is from “Prevalent Statin Use in Long-Stay Nursing Home Residents with Life-Limiting Illness.” It appears online ahead of print in the Journal of the American Geriatrics Society. The study authors are Deborah S. Mack, MPH; Jennifer Tjia, MD, MSCE; Anne L. Hume, PharmD; and Kate L. Lapane, PhD, MS.

Journal

Journal of the American Geriatrics Society

DOI

10.1111/jgs.16336

ITHACA, N.Y. - When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

In this process, called organ sparing, resources are preferentially delegated to the nervous system at the cost of less important organs or tissues.

New research now shows that developing nervous systems demonstrate this preferential growth even at the level of individual neurons. In a paper published in eLife June 22, "Low FoxO expression in Drosophila somatosensory neurons protects dendrite growth under nutrient restriction," a team of Cornell researchers discovered the molecular mechanism that helps facilitate organ sparing on this cell-by-cell basis.

"The phenomena we found is similar to the phenomena of the sparing of the brain, but there are very important differences," said Chun Han, senior author and a Nancy M. and Samuel C. Fleming Associate Professor in the Department of Molecular Biology and Genetics in the College of Agriculture and Life Sciences and in the Weill Institute for Cell and Molecular Biology. "The neurons are protected at the growth level of individual neurons, and they become bigger and bigger by extending their branches."

Those branches are called dendrites. They form a system of elaborate arms that extend from neurons' cellular bodies, and they can receive stimuli from the external environment.

Han and his team wanted to look at how nutrient deficiency affects the dendrite growth of individual neurons, and then examine what cellular sacrifices bodies make so that vital organs, including the brain, continue to develop.

They divided Drosophila (fruit fly) larva into groups receiving either a high- or low-yeast diet, simulating nutrient-rich and nutrient-poor environments. Then they observed how neural cells developed compared to neighboring skin cells on the body wall. They monitored the progress every 24 hours using confocal microscopy that uses lasers to light up fluorescent markers that label individual cells.

"We have very beautiful markers that specifically label these populations of neurons," Han said. "Every neuron is very clear to us - down to every single branch."

The researchers observed that the neurons grew at a much higher rate than skin cells in the low-yeast environment. Skin cells grew faster when there was less competition for nutrients. Han and his team learned that this difference is due to a critical gene called FoxO - an important regulator of cellular stress response.

"FoxO is a gene that's expressed in pretty much most cells of the body," Han said. "When the cells face low nutrients, FoxO puts a brake on the system and slows cell growth."

What's particularly interesting about FoxO is that just because most cells have it, doesn't mean they all use it at the same time or under the same conditions. Han's team discovered that even during malnutrition, the Drosophila neurons expressed very little FoxO, whereas the epidermal cells expressed FoxO at much higher levels.

When there are fewer nutrients available, FoxO triggers a response in epidermal cells called autophagy, which tells the cell to self-destruct by consuming itself. However, the limited FoxO expression in neurons preserves individual neural cells and their dendrite growth.

And while humans have more complex systems than Drosophila, Han said that this research helps pave the way for investigating similar phenomenon in humans.

"Our study reveals another layer of nervous system sparing under nutrient deficiency and discovers a novel mechanism by which neurons are protected." Han said. "These findings may facilitate the development of better approaches to treat problems caused by malnutrition during early development.

A recent paper published in Frontiers in Neuroscience, outlines a pulse-pressure-induced pathway of cognitive decline that sheds light on why previous treatments for dementia may have failed and proposes promising new directions for the prevention and treatment of dementia.

"Over the last couple years, a sea change in dementia and Alzheimer's disease research has occurred. Focus has shifted from solely targeting amyloid-beta in the brain to the opinion that more fruitful progress could be made by addressing factors that compromise the blood brain barrier," explains co-author Mark Carnegie, of The Brain Protection Company based in Australia. "Elements of the constellation include chronic age-related inflammation, genetic predisposition, and cardiovascular abnormalities, notably high blood pulse pressure."

Connecting a large and rapidly growing body of evidence, the researchers elucidate how elevated pulse pressure may cause dementia. Pulse pressure is the difference between systolic and diastolic blood pressure and commonly increases with age.

The researchers propose that elevated pulse pressure in blood travelling to the brain can cause inflammation, oxidative stress, mechanical stress, cellular dysfunction, and cell death in the blood brain barrier that leads to brain damage.

The link between blood brain barrier breakdown and dementia is intuitive, as the blood brain barrier has specifically evolved to support and protect delicate brain tissue by keeping circulating cells, pathogens, and other unhealthy substances in blood from infiltrating the brain. There is significant evidence supporting that disruption of the blood brain barrier is a key driver of cognitive decline and dementia.

Senior author of the paper, Prof. David Celermajer of The Brain Protection Company, says that "this is an important paradigm shift in our understanding of the pathogenesis of dementia."

He further adds that "although there are likely several causes of blood brain barrier disruption, recent human cell culture experiments, animal models, and epidemiological evidence have pointed to high blood pulse pressure as one potential key cause."

Pulse pressure may therefore be a promising new therapeutic target for preventing or slowing cognitive impairment, which gives new hope in the fight against dementia.

Moreover, the authors discuss how elevated pulse pressure may have also prevented previous treatment strategies from working optimally against dementia.

For the past two decades, a primary focus of drug development for Alzheimer's disease, the most prevalent form of dementia, has been to target the molecule amyloid-beta. However, despite billions of dollars spent on R&D, that approach has yet to be successful.

The researchers suggest that targeting amyloid-beta alone to treat dementia may be an uphill battle since concurrent elevated pulse pressure will continue to activate secretion of various inflammatory and oxidative molecules and amyloid-beta from the blood brain barrier into brain tissue.

Also, stem and progenitor cell therapies have gained significant attention as potential strategies to repair blood brain barrier damage and treat dementia, but chronic inflammatory and oxidative stress due to elevated pulse pressure can impact the health of stem and progenitor cells.

Dr. Rachel Levin, lead author of the paper, says that "combination therapy has been paramount in the treatment of other challenging diseases, in particular cancer. Therefore, in dementia, reducing elevated pulse pressure could prove to be synergistic with other therapeutic approaches such as anti-amyloid-beta drugs or stem cell therapy."

The authors issue a call to action for academic and industry leaders to develop novel drug candidates or devices that reduce elevated pulse pressure and progress them to clinical trials. Celermajer states that "strong animal model data already supports the role of high pulse pressure in blood brain barrier disruption and dementia pathology; now more human studies are needed."

A flame-retardant carbon-fiber-reinforced composite material has been developed. Korea Institute of Science and Technology (KIST) announced that a research team from its Institute of Advanced Composite Materials, headed by Dr. Yong chae Jung used plant-originated *tannic acid to develop a flame-retardant **carbon fiber-reinforced plastic (CFRP), and also presented a method for its eco-friendly recycling.

*Tannic acid: A substance that is abundant in nature, tannic acid is a type of polyphenol that is usually synthesized by plants.

**Carbon fiber-reinforced plastic: An advanced lightweight composite material reinforced by carbon fiber, with high rigidity and high elasticity that is suitable for a wide range of applications.

CFRP, a composite material that contains carbon fiber, which is about four times lighter than steel yet 10 times stronger, is widely used in the aerospace, automotive, shipbuilding, and sports equipment industries. Structurally, CFRP is made up of carbon fiber and epoxy resin, which serve functions in this composite material similar to the respective roles that reinforcing rods and cement play in concrete structures. To achieve mechanical rigidity, the binding of carbon fiber and epoxy resin in CFRP must be strong. Moreover, CFRP must be fire-safe as it is used for purposes closely related to everyday life, e.g. use as a construction material. To induce these traits in CFRP, sometimes it is synthesized with additives.

Due to its susceptibility to heat, CFRP had been made fire-safe by adding a ***halogen flame-retardant. However, the use of halogen in CFRP was banned worldwide, because it generates toxic substances when incinerated for recycling. As such, the task at hand was to make CFRP flame-retardant with the use of a non-toxic, safe material.

***Halogen: Elements that belong to Group 17 on the periodic table, including fluorine, chlorine, bromine, and iodine.

Jung Yong-chae, head researcher at KIST's Institute of Advanced Composite Materials, sought to improve the mechanical rigidity and flame-retardance of CFRP with tannic acid, an eco-friendly substance. Tannic acid characteristically bonds strongly with carbon fiber. It also turns into charcoal when burned. Charred tannic acid functions as a barrier that blocks the inflow of external oxygen. By manufacturing epoxy resin from tannic acid and mixing it into carbon fiber, the KIST research team successfully developed a CFRP that is strong and flame-retardant.

Unlike conventional epoxy resin that is vulnerable to heat, epoxy resin made from tannic acid is flame-retardant and needs no additives. This means that the toxic substances generated when incinerating CFRP for recycling would no longer be a problem. Also, because conventional CFRP when burned decreased the performance of its epoxy resin, precluding complete recycling, the research team came up with a new recycling method.

By dissolving CFRP in water in a ****supercritical Fluid state - i.e. temperature and pressure over a set level - over 99% of the CFRP could be recovered without reduced carbon fiber performance. It was also found that epoxy resin when dissolved produced a substance called "*****carbon dots," which can be used as an electronic material (Optronics, Sensing, Bioimaging etc.,). Unlike the method of recycling by incineration, which burns up epoxy resin leaving only the incomplete carbon fiber to be recycled, this new method of recycling enables the recycling of all components of a composite material.

****Supercritical fluid: A substance with a temperature and pressure above the critical level. Related to expandability of gas and dissolvability of liquid. Water and carbon dioxide are substances commonly used as supercritical fluids. Supercritical water can dissolve even gold.

*****Carbon dots: Carbon quantum dots, with carbon as their major element, have the characteristics of photoluminescence and a semiconductor, making them similar to inorganic quantum dots. Due to said characteristics, carbon quantum dots are being widely used in areas such as bio-imaging, sensors, light-emitting diode (LED) lighting, organic solar cells, and photocatalysts.

Head researcher Dr. Jung said, "We have created a composite material with an expanded range of application that is a dramatic improvement over conventional carbon fiber-reinforced plastic in terms of flame-retardancy, mechanical rigidity, and recyclability. These improved traits are significant in that they determine the range of application of said composite material." He added, "We will be reviewing the structure of this composite material to achieve even further improved properties and to further expand the range of its application."