Earth

PHILADELPHIA - Patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, lose muscle control as nerve cells or neurons in the brain and spinal cord degenerate and can no longer send signals to muscles. Previous studies have identified that problems at the synapse, the point where signals jump from one neuron to another neuron or to a muscle, could contribute to that disconnect. But it's unclear what causes these problems. New research from the Jefferson Weinberg ALS Center has identified a new mechanism by which the buildup of toxic proteins - a common hallmark of ALS - disrupts neuronal transmission. The findings provide a groundwork for understanding how to maintain the nerve-muscle connection in ALS, and could lead the search for new therapies. The study was published in EMBO Molecular Medicine on April 29th, 2020.

The culprit behind inherited cases of ALS is frequently an error in the C9orf72 gene, which incorrectly instructs the cell to over-produce a repetitive sequence of proteins, called dipeptide repeats (DPRs). One of the most abundant of these DPRs is the GA protein, which forms aggregates and gradually causes toxicity that can kill the neuron.

"Our collaborators in Germany had found in a previous mouse model where GA is over-produced that there are deficits in motor function," explains Davide Trotti, PhD, professor of neuroscience, Research Director of the Weinberg ALS Center and co-senior author of the study. "But we did not know what GA was doing in the neuron itself."

The researchers cultured motor neurons, the neurons that connect to muscle, from rats to take a closer look at the GA aggregates. They found that the GA aggregates are in fact mobile, traveling within the neuron and accumulating along dendrites and axons, where synapses are found. The researchers also found that the presence of GA aggregates led to an influx of calcium ions, disrupting the electrical balance of the neuron. This imbalance can impair the neuron's ability to detect and send signals.

Indeed, when the researchers examined the synaptic machinery responsible for sending signals from the neuron to muscle, they found a reduction in a key protein called synaptic vesicle-associated protein 2 (SV2) in motor neurons grown or cultured in a petri dish. SV2 regulates the release of neurotransmitters, which are the signaling molecules that neurons use to communicate with each other and muscles.

This decrease in SV2 results in diminished release of neurotransmitters, preventing the neuron from properly communicating with the muscle. Importantly, this reduction in SV2 was also found in vivo at the neuron-muscle connections in a mouse model of GA aggregation, as well as in motor neurons derived from induced pluripotent stem cells (iPSCs) of patients with the C9orf72 form of ALS.

"The results suggest that these impairments in neuronal transmission also occur in patients' cells," says Piera Pasinelli, PhD, professor of neuroscience, Director of the Weinberg ALS Center and co-senior author of the study.

"This helps us to understand the basis for symptoms ultimately observed in patients. Importantly, it helps identify targets and mechanisms in disease-relevant systems where GA is not artificially made or over-expressed."

Using genetic tools, the researchers then replenished the SV2 protein in the cultured motor neurons with GA aggregates, and found that synaptic function was restored to normal levels. Restoring SV2 also reduced toxicity normally caused by the GA aggregates, and even prevented cells from dying and prolonged their survival. Notably, the deficits in SV2 and synaptic transmission occur before toxicity and cell death, so intervening in that time window could be significantly beneficial in slowing disease progression.

"We've shown that even though the GA aggregates are still present, replenishing the SV2 protein can combat the most detrimental effects of this protein buildup," says Brigid Jensen, PhD, a postdoctoral fellow at the Weinberg Center and first author of the study. "This points to SV2 as a promising therapeutic target for this genetic form of ALS."

"We now have a better understanding of what contributes to the degradation of the nerve-muscle connectivity in this devastating disease" says Dr. Pasinelli.

"Future studies will help determine if SV2 can prolong muscle strength and slow disease progression in C9orf72?ALS patients," adds Dr. Trotti.

DURHAM, N.H.— Climate change has contributed to the increase in the number of wildfires across the globe especially in the Arctic where forest fires, along with increased permafrost thaw, can dramatically shift stream chemistry and potentially harm both ecosystems and humans. Researchers at the University of New Hampshire have found that some of the aftereffects of a burn, like decreased carbon and increased nitrogen, can last up to five decades and could have major implications on nearby vital waterways like the Yenisei River that drains into the Arctic Ocean, and other similar waterways around the world.

“Forest fires in this region of the Arctic used to happen about every hundred years and now we’re seeing them every summer,” said Bianca Rodríguez-Cardona ’20G, who just received a Ph.D. in UNH’s natural resources and Earth system sciences program. “This increase in fires leads to more input of inorganic solutes into local streams which can alter the chemistry and trigger issues like increased algae blooms and bacteria that can be harmful to humans who depend on these waterways for drinking water, fishing and their livelihood.”

In the study, recently published in the journal Nature’s Scientific Reports, UNH researchers collected stream water samples in the Central Siberian Plateau in Russia during the summer months of June and July from 2016 to 2018. They compared the concentration of nutrients and dissolved organic matter in the streams and found that inorganic nitrogen, or nitrate which is a nutrient important for cell development and growth in aquatic plants, remained elevated for 10 years after a burn. And, levels of dissolved organic carbon (DOC) and dissolved organic nitrogen (DON), major sources of energy, were substantially decreased and took 50 years to return to pre-burn levels.

Boreal forests, forests that grow in high latitudes at low temperatures, have been burning with greater frequency due to longer growing seasons, warmer temperatures and changing weather patterns adding additional uncertainty to how these ecosystems will be affected. While other studies have documented the effects of wildfires on stream chemistry, few have evaluated how these changes will impact the processing and export of nutrients from Arctic watersheds.

“Arctic rivers transfer large quantities of nutrients to the Arctic Ocean, and river water chemistry could be dramatically changed in the coming decades as permafrost thaws and wildfires become more frequent,” said William McDowell, professor of environmental science and a co-author on the study. The researchers say even though responses of arctic watersheds can vary from region to region, this offers further understanding of what could happen in other areas of the Arctic, like Alaska, Canada, Norway or Sweden.

The University of New Hampshire inspires innovation and transforms lives in our state, nation and world. More than 16,000 students from all 50 states and 71 countries engage with an award-winning faculty in top-ranked programs in business, engineering, law, health and human services, liberal arts and the sciences across more than 200 programs of study. As one of the nation’s highest-performing research universities, UNH partners with NASA, NOAA, NSF and NIH, and receives more than $110 million in competitive external funding every year to further explore and define the frontiers of land, sea and space.

PHOTOS FOR DOWNLOADImage: https://www.unh.edu/unhtoday/sites/default/files/media/watershed_n9.jpgCaption: One of the smaller streams in the Central Siberian Plateau where the UNH team took samples.Credit: Bianca Rodriguez-Cardona/UNH

Image: https://www.unh.edu/unhtoday/sites/default/files/media/kochechum_river.jpgCaption: Kochechum River in the Central Siberian Plateau, a typical river view of landscape and sky without any smoke.Credit: Bianca Rodriguez-Cardona/UNH

Image: https://www.unh.edu/unhtoday/sites/default/files/media/firesun.jpgCaption: View of Siberian waterway after a forest fire – smoke and soot linger in the air for several days even after rainfall. UNH researchers find aftereffects of a burn can last up to five decades and could have major implications on vital waterways.Credit: Bianca Rodriguez-Cardona/UNH

Image: https://www.unh.edu/unhtoday/sites/default/files/media/boreal_forest_n20.jpgCaption: A boreal forest near one of the UNH control watersheds that burned over 100 years ago.Credit: Bianca Rodriguez-Cardona/UNH

Journal

Scientific Reports

NEWPORT, Ore. - Oregon State University researchers who recently discovered a population of blue whales in New Zealand are learning more about the links between the whales, their prey and ocean conditions that are changing as the planet warms.

Understanding how changes in climate affect the ability of blue whales to feed gives researchers more insight into the whales' overall health and provides critical information for conservation and management, said Leigh Torres, an assistant professor and director of the Geospatial Ecology of Marine Megafauna Laboratory at OSU's Marine Mammal Institute.

"These whales don't move around at random. We found that the same ocean patterns that determine where whales are also determine where their prey are, under both typical and warm ocean conditions," Torres said. "The more we learn about what drives these whales' movement, the more we can help protect them from whatever threats they face."

The researchers' findings were published today in the journal Marine Ecology Progress Series. The study's lead author is Dawn Barlow, a doctoral student in Torres' lab; additional co-authors are Kim Bernard of OSU's College of Earth, Ocean, and Atmospheric Sciences; Daniel Palacios of OSU's Marine Mammal Institute; and Pablo Escobar-Flores of the National Institute of Water and Atmospheric Sciences in New Zealand.

Torres, Barlow and colleagues recently documented this new population of New Zealand blue whales, which is genetically distinct from other blue whale populations and spends much of its time in the South Taranaki Bight between New Zealand's North and South Islands.

"The goal of our study is to understand the habitat use patterns of this population of blue whales - why they are where they are and how they respond to changing ocean conditions," Barlow said. "We know this area is important to this population of whales, and we want to understand what it is about this spot that is desirable to them."

The region is often rich in prey - blue whales feast on patches of krill - but the prey is patchy and influenced by changing ocean conditions, including warmer temperatures and changes in ocean properties. The South Taranaki Bight also sees frequent shipping traffic and activity from oil and gas exploration and production, Torres said.

Using data collected during typical summer conditions in 2014 and 2017 and warmer than average conditions in 2016, the researchers analyzed how changing ocean conditions affect the blue whales' distribution in the region's waters and the availability and location of their prey within the water column.

They found that during a regional marine heat wave in 2016, there were fewer aggregations of krill for the whales to dine on. With fewer options, the whales pursued the densest aggregations of krill they could find, Barlow said.

The researchers also found that during both warm and more typical ocean conditions the whales were more likely to feed in areas where the water was cooler. During the marine heat wave, when even the coolest water temperatures were higher than normal conditions, the whales still sought the coolest waters available for feeding.

In this region, cooler water temperatures represent deeper water that was pushed toward the surface in a process called upwelling and tends to be nutrient-rich, Torres said.

The nutrient-rich water supports aggregations of krill, which in turn provide sustenance for the blue whales. In their study, the researchers were able to bring all of the pieces of this trophic pathway together to describe the relationships between oceanography, krill and whales.

As warmer ocean conditions become more frequent, this new knowledge can be used to inform and adjust spatial management of human activities in the region in an effort to reduce impacts on New Zealand blue whales, Torres said.

"Documenting information like this can really help us understand how to reduce threats to these animals," Torres said. "We need continued monitoring to understand how these whales will respond to both the changing climate and human impacts."

A Ludwig Cancer Research study has profiled, in a sweeping comparative analysis, the distinct immune landscapes of tumors that arise in the brain, or gliomas, and those that metastasize to the organ from the lungs, breast and skin. Led by Ludwig Lausanne Member Johanna Joyce and published in the current issue of Cell, the study captures in granular detail how the functions, locations and characteristics of various immune cells sculpt the tumor microenvironment (TME) to thwart immune attack, support cancer cell survival and drive tumor progression.

"Looking at these tumors side by side, we could very clearly see the differences not just between primary and metastatic brain cancers but also high-grade versus low-grade gliomas, and then among metastases originating from different primary sites," says Joyce. "Without juxtaposing those different disease entities, we wouldn't have been able to discover how profoundly different their immune landscapes are."

Cancers selectively harness a variety of immune cells and even manipulate their gene expression programs to get them to suppress anti-tumor immune responses, aid metastasis, establish a blood supply and provide other critical support. Targeting such turncoat immune cells, or "reeducating" them to attack their host tumors, is now a major focus of cancer immunology.

"Our findings underscore that we can't take a one-size-fits-all approach to targeting brain cancers," says Joyce.

In their study, Joyce and her colleagues surveyed the numbers and preferential locations of 14 subtypes of immune cells in 100 brain tumor samples obtained from patients. They also profiled the full spectrum of proteins in the samples and the global gene expression patterns of individual immune cells. They then integrated these richly detailed, large-scale analyses to comprehensively map the immune landscape of each tumor type and capture differences in the functional states of their resident immune cells.

This comparative analysis revealed that five types of immune cells predominantly sculpt the brain TME. These include monocyte-derived macrophages that enter the brain from elsewhere in the body; microglia, the brain's resident version of those cells; related myeloid cells called neutrophils; CD4+ T cells, which orchestrate and regulate immune responses; and the CD8+ (killer) T cells that destroy cancer cells and can be activated by checkpoint blockade immunotherapies. The specific composition of the immune landscapes and the functional states of their constituent cells are shaped by the interplay of the brain's unique biology and the innate characteristics of each type of tumor.

"We have to think very differently about these brain malignancies," in targeting the TME, says Joyce. "We can't just bin them all together and hope that therapy X is going to work for all these disease entities."

The study shows, for example, that brain metastases of melanoma--one of the few brain tumors that have responded to checkpoint blockade--have an abundance of T cells. Gliomas, which are rich in macrophages and microglia, hardly have any. "You can imagine," says Joyce, "that for gliomas, you would want to develop therapies that increase the infiltration of T cells into the microenvironment." For melanoma brain metastases, on the other hand, the primary aim would be to activate the existing T cells in the TME to attack cancer cells.

Differences abound even within gliomas. The researchers show that microglia predominate in low-grade gliomas that are characterized by a mutation in an enzyme known as IDH. High-grade gliomas or glioblastomas (GBMs) associated with a normal IDH gene have a greater abundance of macrophages that migrate into the brain from the blood circulation.

"Therapies to block macrophage infiltration into the brain might be more beneficial for the treatment of high-grade gliomas than the depletion of microglia," says Joyce. In addition, therapies that "reeducate" macrophages to attack rather than nurture cancer cells could prove effective against gliomas in general--a possibility the Joyce lab is exploring.

The findings also open exciting new areas for research. Brain metastases of breast cancer, for instance, were found to be teeming with neutrophils. The Joyce lab's previous studies found that these cells play an important role in establishing a niche in the lungs for breast cancer metastases. Joyce and her team are now exploring how neutrophils might influence their growth in the brain as well.

"I think, and I hope, that these data will be a very important resource not only for my lab, but for the whole brain tumor community to help advance the development of immune-targeted therapies," says Joyce.

A noticeable impact on the waistline of many people is a side-effect of the quarantine due to the global COVID19 outbreak. Reduced activity and lack of sports while consuming the same, or even elevated amounts of calories can quickly cause a substantial weight gain. Strikingly, some individuals can make it through this period without gaining any weight - we all know these people who can eat what they want but do not appear to gain weight. A consortium of international researchers including scientists from IMBA, the University of British Columbia, Medical University of Vienna, and the Estonian Biobank have now taken a unique approach: thus far, the regulation of fat metabolism has mainly focused on finding genes linked to obesity. The team, however, went on a quest to discover genes linked to thinness, or the resistance to weight gain.

In order to identify candidate thinness genes, the research team conducted genome-wide association studies in an Estonian population cohort, profiling over 47000 people. They compared thin to control individuals and were thereby able to pinpoint ALK, which codes for Anaplastic Lymphoma Kinase, as a candidate gene for thinness. ALK was mainly known due to its involvement in cancer, as it is frequently mutated in multiple cancers. However, its physiological function was largely elusive.

To test the hypothesis of ALK being involved in thinness, the researchers inactivated the Alk gene in mice. Strikingly, despite normal food intake and activity, Alk deficient mice were skinnier because of a much-reduced fat mass and strikingly protected against diet-induced obesity as opposed to littermate controls. Interestingly, when knocking down the ALK orthologues in the fruit fly Drosophila melanogaster, they also found significantly lower triglyceride fat accumulation, even when flies were fed a high-sucrose diet.

First author Michael Orthofer from the Penninger lab explains: "By using a technique called indirect calorimetry, we could show that Alk deficient mice exhibit increased energy expenditure. This means that they burn more calories than normal mice and explains why they remain thin even if they eat the same amount of food. In addition to that, these animals also show improved glucose tolerance."

ALK is highest expressed in a very specific brain region called the paraventricular nucleus (PVN) of the hypothalamus. When the scientists depleted Alk in this brain area, a similar body weight reduction was observed compared to full-body Alk knockout models. The PVN is known to be involved in the regulation of energy homeostasis, both via hormonal pathways and the sympathetic nervous system, which uses norepinephrine as neurotransmitter. Indeed, levels of the neurotransmitter norepinephrine were elevated in both white and brown fat of the mutant mice, indicating that ALK deficiency increases sympathetic tone to adipose tissues. Consequently, Alk knockout mice showed increased breakdown of fat, which explains their low body adiposity and resistance to weight gain.

"This strengthens the notion that ALK is indeed part of a larger brain circuit involved in energy expenditure. We are very excited about these results on the genetics of thinness and will further investigate the mechanisms of how ALK-expressing neurons are able to control weight. Our results also highlight the important therapeutic potential of ALK inhibition," says Josef Penninger, IMBA group leader and founding director, who is now director of the Life Sciences Institute of the University of British Columbia.

Astronomers have used mysterious fast radio bursts to solve a decades-old mystery of 'missing matter', long predicted to exist in the Universe but never detected--until now.

The researchers have now found all of the missing 'normal' matter in the vast space between stars and galaxies, as detailed today in the journal Nature.

Lead author Associate Professor Jean-Pierre Macquart, from the Curtin University node of the International Centre for Radio Astronomy Research (ICRAR), said astronomers have been searching for the missing matter for almost thirty years.

"We know from measurements of the Big Bang how much matter there was in the beginning of the Universe," he said.

"But when we looked out into the present Universe, we couldn't find half of what should be there. It was a bit of an embarrassment."

"Intergalactic space is very sparse," he said. "The missing matter was equivalent to only one or two atoms in a room the size of an average office."

"So it was very hard to detect this matter using traditional techniques and telescopes."

The researchers were able to directly detect the missing matter using the phenomenon known as fast radio bursts--brief flashes of energy that appear to come from random directions in the sky and last for just milliseconds.

Scientists don't yet know what causes them but it must involve incredible energy, equivalent to the amount released by the Sun in 80 years. They have been difficult to detect as astronomers don't know when and where to look for them.

Associate Professor Macquart said the team detected the missing matter by using fast radio bursts as "cosmic weigh stations".

"The radiation from fast radio bursts gets spread out by the missing matter in the same way that you see the colours of sunlight being separated in a prism," he said.

"We've now been able to measure the distances to enough fast radio bursts to determine the density of the Universe," he said. "We only needed six to find this missing matter."

The missing matter in this case is baryonic or 'normal' matter--like the protons and neutrons that make up stars, planets and you and me.

It's different from dark matter, which remains elusive and accounts for about 85 per cent of the total matter in the Universe.

Co-author Professor J. Xavier Prochaska, from UC Santa Cruz, said we have unsuccessfully searched for this missing matter with our largest telescopes for more than 20 years.

"The discovery of fast radio bursts and their localisation to distant galaxies were the key breakthroughs needed to solve this mystery," he said.

Associate Professor Ryan Shannon, another co-author from Swinburne University of Technology, said the key was the telescope used, CSIRO's Australian Square Kilometre Array Pathfinder (ASKAP) radio telescope.

"ASKAP both has a wide field of view, about 60 times the size of the full Moon, and can image in high resolution," he said. "This means that we can catch the bursts with relative ease and then pinpoint locations to their host galaxies with incredible precision.

"When the burst arrives at the telescope, it records a live action replay within a fraction of a second," said Dr Keith Bannister from Australia's national science agency, CSIRO, who designed the pulse capture system used in this research.

"This enables the precision to determine the location of the fast radio burst to the width of a human hair held 200m away," he said.

Associate Professor Macquart said the research team had also pinned down the relationship between how far away a fast radio burst is and how the burst spreads out as it travels through the Universe.

"We've discovered the equivalent of the Hubble-Lemaitre Law for galaxies, only for fast radio bursts," he said.

"The Hubble-Lemaitre Law, which says the more distant a galaxy from us, the faster it is moving away from us, underpins all measurements of galaxies at cosmological distances."

The fast radio bursts used in the study were discovered using ASKAP, which is located at the Murchison Radio-astronomy Observatory in outback Western Australia. The international team involved in the discovery included astronomers from Australia, the United States and Chile.

ASKAP is a precursor for the future Square Kilometre Array (SKA) telescope.

The SKA could observe large numbers of fast radio bursts, giving astronomers greater capability to study the previously invisible structure in the Universe.

Researchers at the University of Southampton have shown that an extinction event 360 million years ago, that killed much of the Earth's plant and freshwater aquatic life, was caused by a brief breakdown of the ozone layer that shields the Earth from damaging ultraviolet (UV) radiation. This is a newly discovered extinction mechanism with profound implications for our warming world today.

There have been a number of mass extinction in the geological past. Only one was caused by an asteroid hitting the Earth, which was 66 million years ago when the dinosaurs became extinct. Three of the others, including the end Permian Great Dying, 252 million years ago, were caused by huge continental scale volcanic eruptions that destabilised the Earth's atmospheres and oceans.

Now, scientists have found evidence showing it was high levels of UV radiation which collapsed forest ecosystems and killed off many species of fish and tetrapods (our four limbed ancestors) at the end of the Devonian geological period, 359 million years ago. This damaging burst of UV radiation occurred as part of one of the Earth's climate cycles, rather than being caused by a huge volcanic eruption.

The ozone collapse occurred as the climate rapidly warmed following an intense ice age and the researchers suggest that the Earth today could reach comparable temperatures, possibly triggering a similar event. Their findings are published in the journal Science Advances.

The team collected rock samples during expeditions to mountainous polar-regions in East Greenland, which once formed a huge ancient lake bed in the arid interior of the Old Red Sandstone Continent, made up of Europe and North America. This lake was situated in the Earth's southern hemisphere and would have been similar in nature to modern day Lake Chad on the edge of the Sahara Desert.

Other rocks were collected from the Andean Mountains above Lake Titicaca in Bolivia. These South American samples were from the southern continent of Gondwana, which was closer to the Devonian South Pole. They held clues as to what was happening at the edge of the melting Devonian ice sheet, allowing a comparison between the extinction event close to the pole and close to the equator.

Back in the lab, the rocks were dissolved in hydrofluoric acid, releasing microscopic plant spores (like pollen, but from fern like plants that didn't have seeds or flowers) which had lain preserved for hundreds of millions of years. On microscopic examination, the scientists found many of the spores had bizarrely formed spines on their surface - a response to UV radiation damaging their DNA. Also, many spores had dark pigmented walls, thought to be a kind of protective 'tan', due to increased and damaging UV levels.

The scientists concluded that, during a time of rapid global warming, the ozone layer collapsed for a short period, exposing life on Earth to harmful levels of UV radiation and triggering a mass extinction event on land and in shallow water at the Devonian-Carboniferous boundary.

Following melting of the ice sheets, the climate was very warm, with the increased heat above continents pushing more naturally generated ozone destroying chemicals into the upper atmosphere. This let in high levels of UV-B radiation for several thousand years.

Lead researcher Professor John Marshall, of the University of Southampton's School of Ocean and Earth Science, who is a National Geographic Explorer, comments: "Our ozone shield vanished for a short time in this ancient period, coinciding with a brief and quick warming of the Earth. Our ozone layer is naturally in a state of flux - constantly being created and lost - and we have shown this happened in the past too, without a catalyst such as a continental scale volcanic eruption."

During the extinction, plants selectively survived, but were enormously disrupted as the forest ecosystem collapsed. The dominant group of armoured fish became extinct. Those that survived - sharks and bony fish - remain to this day the dominant fish in our ecosystems.

These extinctions came at a key time for the evolution of our own ancestors, the tetrapods. These early tetrapods are fish that evolved to have limbs rather than fins, but still mostly lived in water. Their limbs possessed many fingers and toes. The extinction reset the direction of their evolution with the post-extinction survivors being terrestrial and with the number of fingers and toes reduced to five.

Professor Marshall says his team's findings have startling implications for life on Earth today: "Current estimates suggest we will reach similar global temperatures to those of 360 million years ago, with the possibility that a similar collapse of the ozone layer could occur again, exposing surface and shallow sea life to deadly radiation. This would move us from the current state of climate change, to a climate emergency."

The remote locations visited in East Greenland are very difficult to access, with travel involving light aircraft capable of landing directly on the tundra. Transport within the vast field area was by inflatable boats equipped with outboard motors, all of which had to fit in the small aircraft.

All field logistics was organised by CASP, an independent charitable trust based in Cambridge specialising in remote geological fieldwork. Mike Curtis, Managing Director of CASP says: "We have a history of assisting research geologists such as John Marshall and colleagues to access remote field areas and we are particularly pleased that their research has proved to have such potentially profound implications."

Despite the fact that the Nordic countries are often seen as ideal in practically every global ranking of quality of life and social equality, the number of drug-related deaths in these countries are among the highest in Europe.

The Nordic countries are, however, far behind the United States in the number of fatal drug overdoses. Various measures to reduce drug-related harms have been introduced. Still hundreds of people die every year of fatal drug overdose.

"Despite the geographic vicinity and similarity of the social security and health care systems, there are differences in the drugs that cause overdose deaths in the Nordic countries", says Kirsten Wiese Simonsen who leads the group of Nordic researchers.

In Norway and Denmark, the number of deaths caused by a drug overdose decreased, whereas in Finland, Sweden and Iceland it increased, compared to a previous study from 2012.

This is shown in a recent scientific paper in which all overdose deaths among users of illegal drugs in the Nordic countries in 2017 were investigated by a group of forensic toxicologists and pathologists from all five countries.

The same study has been conducted seven times over a period of nearly 30 years, which gives excellent insight into changes in time as well as into differences and similarities between the countries.

Opioids were responsible for most of the overdose deaths

Heroin still causes a big portion of deaths in all Nordic countries except in Finland where buprenorphine continues to be the main drug causing overdose deaths. Heroin was the most common intoxicant in Sweden and Norway. In Denmark, heroin was the second most common drug, after methadone.

"All in all, opioids such as heroin, methadone and buprenorphine were responsible for the majority of all overdose deaths in the Nordic countries", Wiese Simonsen says.

Overall, deaths caused by an overdose by cocaine and MDMA increased, when compared to the previous study from 2012.

Sweden faced an epidemic of fentanyl derivatives in 2017, which caused an overall increase in the country's overdose mortality rate. The epidemic inflicted some legislative changes in the country, which have later reduced the number of deaths related to fentanyl derivatives to a markedly lower level.

In addition to the extremely dangerous fentanyl derivatives, many other new psychoactive substances (NPS) were seen in the Nordic countries, especially stimulant drugs. Most of the deaths were poly-drug poisonings with 4-6 different substances contributing to the overdose.

Twice the European average

The overdose mortality rate in the Nordic countries has levelled off over the years, with Sweden and Iceland being the top countries, and Denmark having the lowest rate. In all countries, however, the rate is more than twice the European average (2.26) published by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

The Nordic countries are still well behind the United States, where, according to the Center for Disease Control and Prevention (CDC), there occurred 20.7 drug overdose deaths per 100 000 inhabitants in 2018.

The age of the individuals in this study ranged between 14 and 70. The mean age at death in drug overdoses varied between the countries. In Denmark and Norway, a typical victim of an overdose death was 41 years, whereas the mean age was between 33 and 35 in the other countries.

[Background]

Alkyl radicals are carbon radicals of normal chain and branched chain alkanes, available as reaction intermediates even at late stages of synthesis. Recently, it has become possible to generate alkyl radicals under mild conditions by using a photoredox catalyst with organic chemicals (radical precursors) under visible-light irradiation (Figure 1A). However, since many photoredox catalysts are expensive and since it is necessary to consider the redox process of the catalysts themselves, chemical transformations may become complicated. Thus, a new method was reported on the generation of alkyl radicals by direct visible-light excitation, taking into account the photophysical properties of the organic chemicals themselves (Figure 1B). This is an excellent method in which the use of photoredox catalysts is unnecessary. Nonetheless, there are limitations in terms of the carbon radical species that can be generated. For example, it was difficult to generate bulky tertiary alkyl radicals and unstable methyl radicals, which are useful carbon sources for chemical reactions. In addition, it is problematic that the generation of carbon radicals is accompanied by the generation of waste chemicals of large molecular mass.

[Research results]

The research group at Kanazawa University led by Prof. Ohmiya including graduate students, in collaboration with scientists from RIKEN/Tokyo Medical and Dental University, has succeeded in generating carbon radicals with high chemical reactivity. By using the latest measurement technologies, they made a rational and precise design of an organoborate complex*1) prepared from "boracene," which has a boron atom in the tetracene-like skeleton, through making full use of various latest measurement technologies. The organoborate complex thus designed and synthesized was able to absorb visible-light, giving rise to alkyl radicals under blue LED irradiation in the absence of photoredox catalysts (Figure 2).

The key to the success of the present study was that the organoborate complex prepared by the reaction of an alkyl nucleophile with "boracene," in which three carbon atoms of a benzo[fg]tetracene*2) skeleton were replaced with a boron atom and two oxygen atoms, gave rise to homolytic cleavage*3) of a carbon-boron bond upon absorbing visible-light (Figure 2C). The organoborate complex excited by visible-light transfers a single electron to the other reactant or directly induces homolytic cleavage to give an alkyl radical. This process is highly efficient and enables generation of bulky tertiary alkyl radical and unstable methyl radicals, but production of these radicals was difficult to control. The alkyl radical generated by the present method could be used as a carbon source for chemical reactions. It was applied to, for example, decyanoalkylation, radical addition such as Giese addition, and nickel-catalyzed cross-coupling for the synthesis of compounds having complicated structures (Figure 3). It should be especially mentioned that the organoborate complex used in the present method can be reused by reacting an alkyl nucleophile with the boracene recovered after the chemical reaction.

[Future prospects]

The present study has enabled direct visible-light excitation of organoboron compounds*4) prepared from "boracene," which has successfully generated a variety of alkyl radicals. The alkyl radicals generated by the present method can be used as carbon sources for chemical reactions and employed for the synthesis of complicated and/or bulky organic compounds, which were so far difficult to achieve. The present research outcome represents a novel organic synthesis protocol enabled by the combination of organoboron compounds and light energy and is expected to accelerate synthesis, for example, in drug discovery research. From an academic viewpoint, the reaction process of homolytic cleavage of the carbon-boron bond triggered by visible-light irradiation provides a framework for new molecular transformation technology.

Researchers from the Skoltech Center for Energy Science and Technology (CEST) visualized the formation of a solid electrolyte interphase on battery-grade carbonaceous electrode materials using in situ atomic force microscopy (AFM). This will help researchers design and build batteries with higher performance and durability.

A solid electrolyte interphase (SEI) is a thin layer of electrolyte reduction products formed on the surface of a lithium-ion battery anode during several initial cycles. It prevents further electrolyte decomposition, stabilizing the electrode/electrolyte interface, and ensures a long battery life. Forming a SEI film takes time and energy, and its quality largely governs battery performance and durability: a poorly formed SEI results in rapid degradation of battery performance.

Still, the formation of SEI remains poorly understood, and scientists use in situ atomic force microscopy that allows direct observation of this process. Until now, most of these measurements were carried out on Highly Oriented Pyrolytic Graphite (HOPG), a very pure and ordered form of graphite which has a clean and atomically flat basal plane surface. However, HOPG is a poor replacement for actual battery-grade electrode materials, so the process is significantly different from what happens inside a commercial battery.

A Skoltech team led by research scientist Sergey Luchkin and professor Keith Stevenson succeeded in visualization of SEI formation on battery-grade materials. For this, they had to design an electrochemical cell that allowed the measurements necessary for this direct observation of SEI formation.

"Battery-grade materials are powders, and visualizing dynamic processes on their surface by AFM, especially in liquid environment, is challenging. A standard battery electrode is too rough for such measurements, and isolated particles tend to detach from substrate during scanning. To overcome this issue, we embedded the particles into epoxy resin and made a cross section, so the particles were firmly fixed in the substrate," says Luchkin.

The researchers found that the SEI on battery-grade materials nucleated at different potential than that on HOPG. It was also more than two times thicker and mechanically stronger. Finally, they were able to demonstrate that SEI was better bound with the rough surface of battery-grade graphite than with the flat surface of HOPG.

"Spatially-resolved investigations of battery interfaces and interphases detailed in this work provide significant new insights into the structure and evolution of the anode SEI. Therefore, they provide firm guidelines for rational electrolyte design to enable high performance batteries with improved safety," adds Stevenson.

Every year there are ten million new cases of cancer in the world and the World Health Organisation estimates that number of annual deaths associated with this disease will reach 13 million by the year 2030. There are various treatments for cancer but in many cases they cause toxicity in some patients or lead to the development of resistance in others. This has led in recent years to an increase in the use of bioactive compounds (BAC) such as polyphenols and flavonoids in these medical treatments because of their proven anti-carcinogenic properties based on their antioxidant, anti-inflammatory and immune-modulating components. Until now, these components have primarily been used as dietary supplements and their introduction into cancer treatment is highly challenging because they need to be sterilized first, and that process can cause them to lose their beneficial properties. However, research led by the Universitat Rovira i Virgili has led to a method that can preserve these properties in 90% of cases. These results are a big step forward in the use of these more natural components in cancer treatments and they have been published in the journal Scientific Reports.

The research team, led by Marta Giamberini, from the Department of Chemical Engineering at the URV, and Bartosz Tylkowski, from Eurecat, studied how BAC were affected by different sterilization processes. To do so, "we made a solid-liquid extraction of the flavonoid and polyphenol content of the Cistus shrub and we mixed it with biodegradable polymers that are used in medicine and are more environmentally friendly. We then subjected these mixtures to three different sterilization methods: steam sterilization, gamma ray sterilization and membrane filtration", explained Marta Giamberini.

The researchers found that the best method for sterilizing the biological compounds was steam sterilization because it left 90% of their properties intact. The next step was to make capsules of the compounds with the same biodegradable polymer. Capsules are increasingly being used to store and administer substances and medicines because they protect them from environmental factors that can alter them, such as light, humidity or oxygen, and because they release their content in a more controlled manner.

During in vitro experiments, the researchers observed how polyphenols and flavonoids administered in capsules impacted glioblastoma, an aggressive type of cancer affecting the brain or the spinal cord. The BACs were found to be highly effective in treating glioblastoma whilst showing low levels of toxicity towards non-cancerous cells.

"These results open up the possibility of using more natural cancer treatments, both in terms of the material used for the capsules and the medicines themselves", explained Giamberini. "Furthermore, it shows that the manufacturing drugs in capsules is efficient and has significant growth potential in pharmaceutical terms", Bartosz Tylkowsky added.

Research from Karolinska Institutet published today in Nature shows that an RNA molecule involved in preventing tumour formation can change its structure and thereby control protein production in the cell. The finding can have important clinical implications as it opens for new strategies to treat different types of cancer.

Short RNA molecules in our cells, called microRNAs, are important regulators of messenger RNAs (mRNA) - the molecule that codes for the building blocks of our body, the proteins. The exact mechanism of this regulation remains elusive, but it is known that microRNAs can silence mRNA molecules and thereby prevent protein production. Therefore, they have the potential to be used as tools or targets for drugs.

"It's important to increase our understanding of how microRNA regulates protein production because this process is disturbed in many different types of diseases, including cancer," says Katja Petzold, Associate Professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet in Sweden who led the study. "We show for the first time that a microRNA-mRNA complex has a structure that changes and that this movement has an effect on the biological outcome, i.e. the amount of protein produced in the cell."

The researchers studied a microRNA known as miR-34a, which plays an important role in cancer by indirectly regulating the activity of the p53 protein, known as the guardian of the genome for its ability to prevent cancer formation. Changes in the function of p53 are very common in human cancers. miR-34a downregulates the mRNA that codes for Sirt1, a protein that deactivates p53.

Using Nuclear Magnetic Resonance (NMR) and other biophysical methods, the researchers solved the structure and dynamics of miR-34a binding the mRNA molecule. When they measured these dynamics, they found that the complex exists in two structurally different states, one moderately active with a population of 99 per cent and one with enhanced activity, a population of 1 per cent. These states can interconvert, as they are in equilibrium, and the population of each state can be modified by external factors.

"Once we find out how to turn the switch, we can use this in the clinic as a drug to control the production of specific proteins," explains Katja Petzold.

The researchers were then able to show that miR-34a uses the same strategy to downregulate the production of other proteins, not just Sirt1.

"We reveal the first understanding of how regulation of protein output is steered by small microRNAs based on structure and dynamics," says Lorenzo Baronti, PhD student in Katja Petzold's research group and first author of the study. "This is important because it opens for the development of drugs with a completely new mechanism of action."

A study performed by researchers at the Institute for Advanced Chemistry of Catalonia (IQAC) from the Spanish National Research Council (CSIC) pioneers the use of whole living cells (human lung adenocarcinoma) in dynamic combinatorial chemistry systems. This research, published in the journal Angewandte Chemie International Edition, proposes a new methodology to discover new bioactive molecules in a realistic biological medium. This methodology could help in the future to develop methods to differentiate healthy versus cancer cells, or to protect the extracellular matrix against pathogens.

This new methodology is based on Dynamic Combinatorial Chemistry (DCC), which combines in a single process the selection, identification and preparation of molecules for a given application, accelerating the development of new functional compounds. Therefore, this methodology has a great potential in the rapid identification of new molecules with potential biological activity. In the present work, the group led by Ignacio Alfonso, from the Institute of Advanced Chemistry of Catalonia, pioneers the use of 'live templates' for the identification and optimization of new ligands (simple synthetic molecules) for biological targets.

"In our study we have worked with cancer cells used as a 'templates', so the molecule able to interact with the outside of these cells (templates), will increase its concentration over the mixture of molecules that integrate the dynamic combinatorial library. The extracellular matrix is closely related to cellular communication and signaling, and it is essential in processes such as cancer metastasis or cellular infection by pathogens. Besides, it is the first barrier that a drug has to cross to enter our cells", explains the researcher. "Another hurdle is the difficulty to design molecules able to interact with the extracellular matrix due to its complex structure. But the results of our study allow us to identify and quantify the ligands for the extracellular matrix directly using living cells, which opens up multiple development possibilities in this field of research".

The next step was to synthesize the amplified molecule. Later, the interaction between these molecules and the extracellular matrix of the living cells was confirmed by means of Nuclear Magnetic Resonance. Finally, after these studies with cells, assays between the identified molecules and chondroitin sulfate, the major component of the glycosaminoglycans in the extracellular matrix of this type of cells, were carried out. "We also used molecular dynamics simulations to understand the molecular recognition process that explains our results from a chemical point of view", explains Alfonso.

The methodology used in this study is an excellent research tool with potential applications in disease characterization and diagnosis. "It could lead to the faster discovery of bioactive molecules, since the selection is made in a medium that is more similar to the biological medium in which these biomolecules will act", concludes the researcher.

The vertebrate ear is a remarkable structure. Tightly encapsulated within the densest bone of the skeleton, it comprises the smallest elements of the vertebrate skeleton (auditory ossicles) and gives rise to several different senses: balance, posture control, gaze stabilization, and hearing. Nowhere else in the vertebrate skeleton are different functional units packed so close together and jointly embedded in its skeletal environment, which also hampers the independent evolution of the ear components.

Even the growth pattern of the ear deviates from that of the remaining skeleton: In humans and other mammals, the inner and middle ears achieve their final size already before or early after birth, which further challenges evolutionary change because postnatal development substantially contributes to anatomical differences between many mammals otherwise.

All this makes it puzzling how mammals, as a predominantly nocturnal group reliant on hearing, were able to occupy such a vast diversity of environments in the aquatic, terrestrial, subterranean, and aerial realms that require an amazing disparity not only in hearing abilities, but also in locomotion and posture. How could the different, tightly connected parts of the ear adapt independently to these diverse functional and environmental regimes?

A group of researchers around Philipp Mitteroecker from the University of Vienna proposed a new explanation for this evolutionary puzzle. Despite its similar function, the ear is composed of different bones in mammals, birds, and reptiles. In birds and reptiles, the lower jaw and its joint are composed of multiple bones, and they have a single auditory ossicle that transmits the sound. Extant mammals, by contrast, have three ossicles (malleus, incus, stapes) and one ectotympanic bone, supporting the tympanic membrane, all of which are separate from the jaw. This evolutionary transformation of the primary jaw joint into the mammalian ear ossicles is one of the most iconic transitions in vertebrate evolution, but it is not clear why this complex transition has happened.

The Austrian research team proposed that this substantial evolutionary change of mammalian ear anatomy has - in addition to any direct enhancements of mastication and hearing - also increased the "evolvability" (capacity for adaptive evolution) of the ear and its associated sensory functions. The incorporation of the bones of the primary jaw joint into the ear has considerably increased the genetic, regulatory, and developmental complexity of the mammalian ear. This increase in the number of genetic and developmental factors, in turn, has increased the evolutionary degrees of freedom for an independent adaptation of the different functional units of the ear: the number of genetic and developmental "knobs" for natural selection to turn.

They suggest that despite the tight spatial entanglement of functional ear components, the increased evolvability of the mammalian ear may have contributed to the evolutionary success and adaptive diversification of mammals in the vast diversity of ecological and behavioral niches observable today. In their article, they show that mammals, as compared to birds, were indeed able to evolve a much wider morphological and functional diversity, including numerous evolutionary "novelties", even though birds are more diverse in species number than mammals.

Yale researchers have found a neural home of the feeling of stress people experience, an insight that may help people deal with the debilitating sense of fear and anxiety that stress can evoke, Yale researchers report May 27 in the journal Nature Communications.

Brain scans of people exposed to highly stressful and troubling images -- such as a snarling dog, mutilated faces or filthy toilets -- reveal a network of neural connections emanating throughout the brain from the hippocampus, an area of the brain that helps regulate motivation, emotion and memory.

The brain networks that support the physiological response to stress have been well studied in animals. Activation of brain areas such as the hypothalamus triggers production of steroid hormones called glucocorticoids in the face of stress and threats. But the source of the subjective experience of stress experienced by people during the COVID-19 pandemic, for instance, has been more difficult to pinpoint.

"We can't ask rats how they are feeling," said Elizabeth Goldfarb, associate research scientist at the Yale Stress Center and lead author of the study.

Goldfarb and co-authors, including senior author Rajita Sinha, the Foundations Fund Professor of Psychiatry, conducted a series of fMRI scans of subjects who were asked to quantify their stress levels when presented with troubling images.

The study reveals that neural connections emanating from the hippocampus when viewing these images reached not only areas of the brain associated with physiological stress responses, but also the dorsal lateral frontal cortex, an area of the brain involved in higher cognitive functions and regulation of emotions. The Yale team found that when neural connections between the hippocampus and frontal cortex were stronger, subjects reported feeling less stressed by the troublesome images.

Conversely, subjects reported feeling more stressed when the neural network between the hippocampus and hypothalamus was more active.

The authors note there is also evidence from other studies that those suffering from mental health disorders such as anxiety may have difficulty receiving calming feedback from the frontal cortex in times of stress.

"These findings may help us tailor therapeutic intervention to multiple targets, such as increasing the strength of the connections from the hippocampus to the frontal cortex or decreasing the signaling to the physiological stress centers," said Sinha, who is also a professor in Yale's Child Study Center and neuroscience department.

All study subjects were healthy, she said, and in some cases their responses during the experiment seemed to be adaptive -- in other words, the network connections with the frontal cortex became stronger as the subjects were exposed to the stressful images. Sinha and Goldfarb speculated that these subjects might be accessing memories that help moderate their response to stressful images.

"Similar to recent findings that remembering positive experiences can lower the body's stress response, our work suggests that memory-related brain networks can be harnessed to create a more resilient emotional response to stress," Goldfarb said.