Culture

Fukuoka, Japan - Compared with our own planet Earth, Mars might seem like a "dead" planet, but even there, the wind blows and the ground moves. On Earth, we study the ambient seismic noise rippling mainly due to ocean activity to peek underground at the structure of the Earth's interior. Can we do the same on Mars without ocean?

According to a new study by researchers at Kyushu University's International Institute for Carbon-Neutral Energy Research, we're closer than ever to achieving this goal.

The study, published in Geophysical Research Letters, is based on data collected by NASA's InSight ("Interior Exploration using Seismic Investigations, Geodesy and Heat Transport") Martian lander, which landed on Mars on November 26, 2018. The InSight lander placed a seismometer on the surface of Mars and its readings are transmitted back to Earth. Continuous seismic records collected between February and June 2019 revealed the existence of several hundred "marsquakes." Most were much weaker than the quakes typically felt on Earth, although some reached a magnitude of almost 4.

The data from these "microtremors" were analyzed to determine their directions of propagation and directional intensity. Study co-author Tatsunori Ikeda explains, "Our polarization analysis revealed that seismic waves of different frequencies and types showed different patterns of variation over the course of the Martian day. The temporal variations in low-frequency P-waves were related to distant changes in wind and solar irradiation, and the low-frequency Rayleigh waves were related to the wind direction in the region near the lander. Higher-frequency ambient noises were dominated by vibration of the lander itself. Thus, microtremors of different types and frequencies likely have different sources, and some are probably influenced by geological structures."

These important differences between the dominant sources of different types of Martian microtremors may help in efforts to identify geological structures in Mars's interior, as we inferred the lithological boundary beneath the seismometer from high frequency ambient noise.

A single seismometer is not yet enough to reconstruct images of the planet's interior, however. On Earth, data from networks of multiple seismometers must be used together for that purpose. But this analysis of the InSight lander's seismic data is an important step toward achieving that goal on Mars. According to senior author Takeshi Tsuji, "These results demonstrate the feasibility of ambient noise methods on Mars. Future seismic network projects will enable us to model and monitor the planet's interior geological structure, and may even contribute to resource exploration on Mars, such as for buried ice."

Hunger-Blocking Hormone Reverses Opioid Overdose In Mice

Media Contact: Vanessa McMains, vmcmain1@jhmi.edu

In 2018, researchers at Johns Hopkins Medicine showed that delivering the hunger-suppressing hormone leptin into the nose could ease breathing problems in sleeping obese mice. In addition to its role in metabolism, leptin stimulates breathing and combats obstructive sleep apnea -- a condition in which a person's airway collapses and blocks oxygen intake while sleeping. Apnea is more common in people who are obese.

In a new study published in the July 1, 2020, issue of the American Journal of Respiratory Cell and Molecular Biology, the researchers report that the same nasal delivery method for leptin also can stimulate respiration in obese mice that stop breathing when on morphine.

When on opioids, people with sleep apnea are likely to have more breathing pauses than those who are not medicated. This can lead to overdose and potentially, death. If someone who has sleep apnea is admitted to a hospital for trauma, the patient may be given high doses of opioids to relieve pain. This puts them at increased risk of an overdose and its complications. If this happens and the patient stops breathing, physicians can administer naloxone to negate the opioids and trigger the person to breathe again. However, the opioid's pain-relieving benefit is removed.

"We believe that if we can confirm our mouse study findings in human trials, applying leptin nasally would be highly useful in hospital trauma settings to keep patients safe while at the same time still treating their pain," says Vsevolod Polotsky, M.D., Ph.D., professor of medicine at the Johns Hopkins University School of Medicine.

In their experiments, the researchers showed that obese mice on morphine given leptin nasally had more airflow and their airways opened wider than control mice not given the hormone. When a mouse was given enough morphine to stop breathing, a single injection of leptin to the nose restarted the animal's respiration. Additionally, the mice given leptin retained morphine's pain-suppressing effects as measured by a flick to the tail.

Scientists Develop Method to Reveal the Cell Types Most Affected By Genetic Variation

Media Contact: Vanessa Wasta, wasta@jhmi.edu

Scientists at Johns Hopkins Medicine have found types of cells in the brain that are most susceptible to inherited genetic variants linked to schizophrenia. As a result, their work reveals a shortlist of the variants that most likely impact disease risk.

Details of the scientists' analysis, published April 17, 2020, in Genome Research, compared human genetic studies with data on how DNA is folded in mouse cells, including a diversity of brain cells.

"Every common disease has a major genetic component at its root," says Andrew McCallion, Ph.D., professor of genetic medicine at the Johns Hopkins University School of Medicine. "Studying genomes across human populations helps us find the genetic landmarks that are linked to disease, but these often don't give us the biological insight that pinpoints the cells in which that variation acts to impact disease risk."

For example, says McCallion, the functional region of a gene variant may act differently in the liver than in a brain cell.

For the study, McCallion and doctoral candidate Paul Hook aimed to find the specific cell types in the brain that show the most evidence of being affected by heritable variations in the genome linked with schizophrenia. To find genetic variants among human populations, scientists traditionally use data on the genetic sequence of DNA, or the chemical code that forms our DNA. However, other information about our DNA, such as which genes are turned on or off and how the DNA is folded in different cells reveals patterns that can shed light on what cell types are more likely to be affected by genetic variations in diseases. These variations could make the difference between inheriting risk for a condition such as schizophrenia or not.

One major challenge of human genetic studies is that even when scientists link a region of the genome to disease risk, there may be tens or even hundreds of variants in that location. McCallion and his lab search for ways to systematically use biological data to refine those long lists.

Information on how DNA, packaged with proteins as chromatin, is folded can tell scientists which regions of the genome may be activating genes in different cells at any point in time. Opening the tight constraints of chromatin allows critical proteins access to the DNA-encoded gene switches to start the process of making proteins. Yet, most of the data about chromatin folding in humans has come from cell samples among areas of the body that are easy to access.

For studying neurological disorders, those purified cell samples -- embedded deep in the brain -- are hard to come by, making it difficult for scientists to make progress on understanding disease origins. McCallion says scientists recently showed that cells from mouse brains often use the same gene "on-off" switches as in humans.

As a proof of principle, McCallion and Hook compared patterns among 25 sets of data on chromatin folding in a diverse range of mouse brain cells with 64 studies of human traits and their associated genetic variation. Their study of chromatin folding patterns in mice revealed a subset of cell types in which more than 170 regions of the human genome have been linked to increased risk for schizophrenia.

Then, the researchers drilled down into the 25 mouse cell datasets to find chromatin folding patterns among six types of brain cells that appear highly important to the origins of schizophrenia.

Looking layer by layer among cells in the cerebral cortex, they found the most similarities between genetic variants and chromatin folding in layers four and five.

McCallion and Hook also identified a short list of 281 variants (reduced from 62,000) that are most likely to increase schizophrenia risk and should be studied further.

The data confirm other genomic studies identifying the cerebral cortex as important for the biologic underpinnings of schizophrenia, McCallion notes, but their work goes further by implicating precise cell layers affected and predicting which variants impact risk.

"Using chromatin data from mice along with studies of human genomic variations can be an important model in identifying cell populations most impacted by genetic variation," he says.

Eventually, the findings can help scientists map precise locations for disease impact, says McCallion, and develop therapies that are targeted more specifically to cells in those locations.

Study Suggests Women Plastic Surgery Residents Rate Their Performance Harsher Than Do Men

Media Contact: Michael E. Newman, mnewma25@jhmi.edu

Recent news headlines, such as "Gender gap in self-promotion penalizes women," "Women less inclined to self-promote than men" and "Men exaggerate their importance at work while women do the exact opposite," vividly portray a long-standing problem in the working world: Women often do not evaluate their on-the-job performance accurately. This can create an undeserved gender bias that may result in severe disparities between the sexes in opportunities for leadership roles, career advancement and pay increases.

The medical community is not immune to these disparities. Research suggests that women in medical professions tend to follow the disturbing trend of not assessing their performance properly. Now, investigators at three medical institutions led by Johns Hopkins Medicine have added another group to the list: plastic surgery residents. The researchers showed in a recent study that by the second year of a residency program, self-assessment performance ratings by residents differed significantly from the evaluations by their attending physicians, but not surprisingly, in opposite directions according to gender. Male residents scored themselves much higher than did their advisers, while female residents rated themselves much lower.

"It appears based on our findings that for plastic surgery residents, it takes a year before the gender bias in performance evaluation develops," says Carisa Cooney, M.P.H., assistant professor of plastic and reconstructive surgery at the Johns Hopkins University School of Medicine and lead author of the study published online on April 23, 2020, in The American Journal of Surgery.

"During the first year of the residency program, we found that both male and female residents significantly underrated their performance," she explains. "However, the men moved their evaluations upward in post graduate years 2 to 6, while the women continued to significantly underrate themselves over the same period."

The study team -- including researchers from Johns Hopkins Medicine, the University of North Carolina School of Medicine and Baylor Scott & White Medical Center in Texas -- examined more than 8,100 evaluations made by 64 residents (25% women) and 51 attending surgeons (29% women) during training programs at the three institutions.

Based on their findings, the researchers recommend more studies to determine the reasons for the gender differences in self-assessments and to provide guidance for developing measures to reduce or eliminate bias.

A new study published in the Journal of Physiology has shown that misfolded protein build-up in the gut could contribute to the development of Alzheimer's-like symptoms in mice. This could suggest a new treatment approach for Alzheimer's disease that would target the gut before symptoms of cognitive deficits appear in patients.

As these proteins were found in the gut, which is a window to the world, this suggests environmental factors might be contributing to cognitive deficits seen in Alzheimer's disease and other conditions.

The misfolded protein, known to be involved in Alzheimer's disease, called beta amyloid, was injected into the guts of mice and travelled to the "gut-brain" (the nervous system in our gut), and also to the brain.

If some of the beta amyloid build up in the central nervous system (brain and spinal cord) is originating from the outside the brain (peripheral nervous system), reducing the amount that makes it to the brain, or trapping the protein in the periphery may delay the onset of Alzheimer's disease. This treatment would begin before any signs of dementia appear in the patient.

The researchers at The Chinese University of Hong Kong injected fluorescently-tagged beta-amyloid into the gut of mice. The proteins moved to the nervous system in our gut. The misfolded proteins were seen a year later in parts of the brain involved in cognitive deficits of Alzheimer's disease including the hippocampus, the part of our brain that affects our memory. These animals experienced cognitive impairments.

As this study was conducted in mice, it needs verification by looking for post-mortem changes in inflammation in the gut and brain of patients with Alzheimer's disease.

Development of drug treatments for Alzheimer's disease has been unsuccessful so we instead need new approaches for preventing AD development. This could be a potential route for preventing the disease by targeting these misfolded proteins in the gut.

Commenting on the study, senior author John A Rudd said:

"This concept is similar to the transport of misfolded proteins from the gut such as those responsible for mad cow disease. If this is the case, a similar process may start in humans many years ahead of the manifestations of the classical hallmarks of AD including memory loss, and so prevention strategies would need to start earlier as well."

Studies have shown the Arctic is warming roughly twice as fast as the rest of the world, and its soil holds twice the amount of carbon dioxide as the atmosphere. New research from San Diego State University finds that water from spring snowmelt infiltrates the soil and triggers fresh carbon dioxide production at higher rates than previously assumed.

This is in addition to trapped carbon escaping from the soil, which means an acceleration in warming that is not quite accounted for in current measurement techniques.

SDSU post-doctoral fellow Kyle Arndt and ecosystem ecologist Donatella Zona spent several years assessing the situation on the ground in Utqiagvik (formerly Barrow), Alaska and analyzing their findings once they returned to San Diego.

The cold season is an essential component of the annual carbon balance, and it was assumed to have a negligible impact on carbon production.

By analyzing soil core samples, what they found was that it wasn't just trapped greenhouse gases that were escaping but also likely increasing fresh production of carbon during the spring thaw.

Published June 30 in Global Change Biology, their study discovered that cold thaw accounts for nearly half of carbon emissions which can offset the summer uptake or absorption of carbon dioxide by vegetation. Their findings fill a gap in data that has long existed because harsh winters and springs made the Arctic difficult to access to conduct studies.

"Earlier we didn't have this data, but now that we do, we are seeing that these ecosystems are rapidly warming," Arndt said. "Many models already predict the Arctic will turn into a CO2 source, but they may be underestimating the size of the source if this spring process is not taken into account."

Arndt, first author of the paper, began visiting Utqiagvik in summer 2016 to maintain equipment set up by SDSU ecologist Walter Oechel, who has been working for nearly 40 years in these Arctic sites.

Using eddy covariance, a technique to measure carbon dioxide movement between the soil and atmosphere as well as ground and air temperatures, ground heat flux and snow depth, Arndt measured fluxes.

Heat flux is the energy transferred per unit of surface area for a given period of time, and it's challenging to collect it during the freeze. Arndt "came up with the idea of measuring it during spring snow melt, building on the need to fill a gap in data on the cold season Arctic heat fluxes," Zona said.

Arndt also worked with SDSU microbiologist David Lipson who collected soil core samples, which helped him and Zona understand the physical properties of the soil during the spring and fall season.

Arndt ascertained that fresh CO2 production was happening when "we found air pockets in the middle of the soil core that allowed for the melted snow to rush in. The snowmelt is rich in oxygen which helps with the production of carbon dioxide."

Iron is one of the many minerals soil contains. Their analysis showed the iron was completely oxidized, which can only happen if fresh oxygen in the soil bonds with and oxidizes the iron. The researchers found a steady rise in CO? emissions during this thawing period further suggesting the occurrence of production at this time.

Simpler models of data analysis may miss the rapid warming that happens due to snowmelt, when there's a rapid introduction of oxygen leading to the warming.

"There's a lot more going on in the soil than we previously thought," Arndt said. "Nature is efficient in that it breaks down lighter compounds preferentially to heavier ones, creating unique isotope signatures, kind of like fingerprints. By looking at isotopes, we can tell how long the compounds have been there and the source of the carbon emitted."

Arndt and Zona are planning to focus on isotopic analysis next, to reconstruct the age of the compounds in the samples, and the longer scale implications of these results.

"We will look for long-term trends in carbon dioxide release and how the heat fluxes have been changing over the last decade," Zona said.

Infecting some volunteers with COVID-19 may provide valuable insights for future rounds of vaccine testing, but would require very strict controls, argues a group of infectious disease experts in the New England Journal of Medicine.

Writing in a commentary on behalf of Accelerating COVID-19 Therapeutic Interventions and Vaccines's Vaccines Working Group, authors from the Walter Reed Army Institute of Research, University of Maryland School of Medicine, University of North Carolina School of Medicine and Henry M. Jackson Foundation for the Advancement of Military Medicine, detailed a series of scientific and ethical concerns and considerations required for robust controlled human infection models development. While CHIMs are unlikely to advance the timelines of current SARS-CoV-2 vaccines in advanced development, the authors argue, such tests may be able to accelerate later rounds of vaccine candidates.

Traditional vaccine development is typically linear, where animal then human testing informs a regulatory decision on vaccine licensure, finally allowing for mass production. In the face of the significant public health burden of COVID-19, the disease caused by SARS-CoV-2, vaccine developers have made unprecedented efforts to shorten timelines by compressing and overlapping these steps.

A component of this process is late stage efficacy trials, where large, randomized groups of study participants are vaccinated then exposed to the virus through natural transmission in their community. However, CHIMs, where healthy individuals are infected by a well-characterized virus in extremely controlled settings, have been advanced as an alternative to these trials. Several CHIMs are currently in use for other diseases, including malaria and influenza.

"CHIMs provide distinct advantages over traditional field efficacy trials, allowing researchers to answer a broader range of questions about the virus, vaccine and the body's immune response," said Dr. Nelson Michael, director of WRAIR's Center for Infectious Disease Research and an author on the commentary. "However, given that large efficacy studies are imminent and that developing a robust CHIM model will require at least one year, it is unlikely that they will significantly advance the current slate of vaccines in advanced development."

Building on the World Health Organization's essential criteria for conducting SARS-CoV-2 challenge studies, the commentary details several key considerations to address before SARS-CoV-2 CHIM studies can be implemented, including the lack of reliable treatments in case of vaccine inefficacy, risks of community transmission, access to the requisite infrastructure and understanding of the virus's progression within the body. Addressing these concerns in parallel could result in long-term discoveries to help mitigate the current and future pandemics.

Though CHIM development would be laborious, it could ultimately be advantageous, allowing researchers to answer a much broader range of questions about both the virus and vaccines designed to prevent it. Additionally, the development of CHIMs for other, less severe coronaviruses could provide meaningful insights to SARS-CoV-2 with less risk.

DALLAS - July 2, 2020 - Two new studies led by UT Southwestern scientists outline how individual cells maintain their internal clocks, driven both through heritable and random means. These findings, published online May 1 in PNAS and May 27 in eLife, help explain how organisms' circadian clocks maintain flexibility and could offer insights into aging and cancer.

Scientists have long known that organisms across the spectrum of life have internal clocks - with cycles about as long as a day - that govern behaviors including sleeping, eating, and immune response. However, individual cells also have their own clocks when removed from the organism, with periods that can vary substantially, stretching up to several hours longer or shorter. How cells maintain these different lengths of internal rhythms has been unknown given that these cells should be the same at the genetic level, explains Joseph S. Takahashi, Ph.D., chair of the department of neuroscience at UT Southwestern Medical Center, a member of UT Southwestern's Peter O'Donnell Jr. Brain Institute, and an investigator with the Howard Hughes Medical Institute.

To investigate this question, he and his colleagues worked with mouse cells that were genetically altered so that they glowed whenever a prominent circadian clock gene called Per2 turned on. Using this tool, they could see how long the cell's natural oscillations were - ranging from a shorter period of 21.5 hours up to a longer period of nearly 28 hours.

When they isolated cells at the extremes of this range and grew them as clones in petri dishes, the researchers found that these cells maintained their periods. The short and long period cells stayed at their extreme cycle lengths even after many cell divisions over months, suggesting that period length has a heritable component.

When the researchers compared gene expression between the two groups of cells, they found thousands of genes that were either more or less active. Many of these genes appeared to work together in large-scale networks and were associated with stress response signaling pathways and metabolic pathways, underlining the importance of these processes in the circadian cycle. Most of these genes have never been linked with circadian rhythms, says UT Southwestern's Yan Li, Ph.D., the lead author of the studies, suggesting a new pool of candidate genes that might be important in maintaining cellular periodicity.

Looking closer at what caused this differing gene expression between the short- and long-period cells, Takahashi and his colleagues traced it to epigenetic - or "above the genome" - control. Rather than differences in the DNA sequence of genes themselves that caused them to be more or less active, the researchers found that their activity hinged on chemical modifications to the DNA of the genes known as DNA methylation. When they shut down genes that placed or maintained these chemical tags, the cells' circadian cycle length changed.

Although this heritable mechanism accounts for some of the variation between cell period length, it's not responsible for all of it, Takahashi explains. Searching for other sources for cell periodicity, the researchers examined the exact length of circadian cycles in the short- and long-period groups. They found that those with longer periods had the most variability in their cycle lengths. Further tests suggest that this variance is caused by random fluctuations in gene activity. The more of this nonheritable fluctuation that cells exhibited, the longer their cycles were on average. When the researchers dosed cells with a drug that increased this fluctuation in gene activity, it increased their circadian cycles by about 1.5 hours on average.

Together, Takahashi says, these results suggest that the circadian rhythms of cells are controlled both by heritable and nonheritable components. Gaining a better understanding of these mechanisms could provide some insight on natural processes and health problems that are associated with a decline in circadian clock function, such as aging and cancer. It could also help researchers better understand how organisms maintain flexibility in situations that strain the circadian clock, such as jet lag.

"If every cell in our bodies oscillated in the same way, our bodies would act like one giant clock, inflexible and unable to adapt to a changing environment," Takahashi explains. "Having variability in the cell population makes it more flexible and increases the resilience of an organism."

Allogeneic stem cell transplantation can cause a loss of protective goblet cells from the colon's inner lining, which can be fatal. But boosting those cells beforehand could improve the outcome.

A significant loss of the colon cells following a stem cell transplantation leads to bacterial invasion of the intestinal mucosa, affecting recipient prognosis. An injection with a growth factor of goblet cells prior to the transplantation could improve the outcome. This finding, by Hokkaido University researchers and colleagues, was published in the journal Science Translational Medicine.

Allogeneic hematopoietic stem cell transplantation involves transferring immune and haematopoietic system from a healthy donor to the recipient to treat haematological disorders such as leukaemia and lymphoma. However, some patients develop a donor immunity-mediated disease known as graft-versus-host-disease following the transplantation. The disease can be fatal in some cases, limiting widespread use of the treatment.

Hokkaido University haematologists Daigo Hashimoto, Takanori Teshima, and colleagues wanted to further understand what happens in the intestine during graft-versus-host-disease at the cellular level.

Through studies on mice, they found allogeneic haematopoietic stem cell transplantation can lead to a significant reduction in a type of epithelial cell in the colon's inner lining called a goblet cell. These cells produce the protective mucus layer that prevents intestinal bacteria from crossing into the intestinal tissue and blood stream. The scientists found the reduction in mature goblet cells following transplantation disrupted the mucus layer they formed, leading to bacterial invasion of the intestinal tissue.

However, the number of goblet cells significantly increased in the colon after the scientists had injected mice with interleukin-25 (IL-25), a growth factor for goblet cells, for six days prior to transplantation. In the mice with IL-25 injection, significantly fewer bacteria were able to invade the intestinal mucosa after the allogeneic stem cell transplantation.

Further investigation revealed that an anti-microbial molecule called Lypd8, which is secreted by another type of colon cell and resides in the mucus, is lost in mice with disrupted inner mucus layer in graft-versus-host-disease. They also found that Lypd8 is necessary for IL-25 to have its protective effect. "These together show that the goblet cells inhibit bacterial invasion by maintaining the mucus layer where the anti-microbial molecule resides."

The researchers then studied colonic biopsies taken from human patients who had received this type of transplantation. Goblet cells were specifically damaged in patients who developed graft-versus-host-disease, and severe goblet cell loss was associated with a poor survival following the transplantation.

"We found that the intestinal goblet cells maintain the mucus layer that contains antimicrobial molecules, therefore preventing invasion by intestinal bacteria. So, administration of IL-25 to protect patients' goblet cells could turn out to be a successful strategy against graft-versus-host-disease after allogeneic hematopoietic stem cell transplantation," said Daigo Hashimoto. "Counting goblet cells using non-invasive methods, like confocal laser endomicroscopy, could also be used for diagnosing and monitoring graft-versus-host-disease," Takanori Teshima added.

Zinc (Zn) batteries have attracted more and more attention due to large volumetric capacity, abundance of Zn, and environmental friendliness. When the aqueous electrolytes are considered, Zn batteries provide a promising solution to safety hazards and economic challenges facing prevailing Li-ion batteries.

However, the currently available aqueous Zn electrolytes are far from ideal. Aqueous Zn batteries have been struggling with the rapid performance degradation arising from the poor reversibility of Zn anodes and the dissolution of cathodes.

A research team led by Prof. CUI Guanglei from the Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT) of the Chinese Academy of Sciences has proposed a new class of aqueous electrolytes, called hydrated eutectic electrolytes, to ensure better performance of aqueous Zn batteries. The study was published in Joule on July 1.

The new aqueous electrolyte was fabricated by coupling a hydrated Zn salt (Zn(ClO4)2·6H2O) exclusively with a neutral ligand (succinonitrile, SN).

"The aqua cationic Zn species and corresponding water molecules' coordination states are reorganized. SN enters the primary solvation shell of Zn2+, while all water molecules contribute to the formation of the eutectic structure and remain bound in the metal coordination sphere," said Dr. ZHAO Jingwen from QIBEBT, co-corresponding author of the study.

That's why the electrochemical behaviors of the hydrated eutectic electrolytes were different from those of traditional aqueous electrolytes. Hydrated eutectic electrolytes were highly suitable for the Zn-organic batteries from both anode and cathode aspects.

"It is known that the perchlorate anions are reactive and susceptible to decomposition in aqueous solutions," CUI said. "However, due to the suppressed Zn2+-H2O interplay, the commonly accepted nonideal perchlorate anion can be stabilized in the eutectic network."

Owning to the rich intermolecular interactions in the hydrated eutectic electrolytes, stable low-temperature operation even at -20°C was also obtained.

The study offers a simple and promising way to tame the multivalent electrolyte structure toward creating long-life rechargeable aqueous batteries.

The surviving core of a gas giant has been discovered orbiting a distant star by University of Warwick astronomers, offering an unprecedented glimpse into the interior of a planet.

The core, which is the same size as Neptune in our own solar system, is believed to be a gas giant that was either stripped of its gaseous atmosphere or that failed to form one in its early life.

The team from the University of Warwick's Department of Physics reports the discovery today (1 July) in the journal Nature, and is thought to be the first time the exposed core of a planet has been observed.

It offers the unique opportunity to peer inside the interior of a planet and learn about its composition.

Located around a star much like our own approximately 730 light years away, the core, named TOI 849 b orbits so close to its host star that a year is a mere 18 hours and its surface temperature is around 1800K.

TOI 849 b was found in a survey of stars by NASA's Transiting Exoplanet Survey Satellite (TESS), using the transit method: observing stars for the tell-tale dip in brightness that indicates that a planet has passed in front of them. It was located in the 'Neptunian desert' - a term used by astronomers for a region close to stars where we rarely see planets of Neptune's mass or larger.

The object was then analysed using the HARPS instrument, on a program led by the University of Warwick, at the European Southern Observatory's La Silla Observatory in Chile. This utilises the Doppler effect to measure the mass of exoplanets by measuring their 'wobble' - small movements towards and away from us that register as tiny shifts in the star's spectrum of light.

The team determined that the object's mass is 2-3 times higher than Neptune but it is also incredibly dense, with all the material that makes up that mass squashed into an object the same size.

Lead author Dr David Armstrong from the University of Warwick Department of Physics said: "While this is an unusually massive planet, it's a long way from the most massive we know. But it is the most massive we know for its size, and extremely dense for something the size of Neptune, which tells us this planet has a very unusual history. The fact that it's in a strange location for its mass also helps - we don't see planets with this mass at these short orbital periods.

"TOI 849 b is the most massive terrestrial planet - that has an earth like density - discovered. We would expect a planet this massive to have accreted large quantities of hydrogen and helium when it formed, growing into something similar to Jupiter. The fact that we don't see those gases lets us know this is an exposed planetary core.

"This is the first time that we've discovered an intact exposed core of a gas giant around a star."

There are two theories as to why we are seeing the planet's core, rather than a typical gas giant. The first is that it was once similar to Jupiter but lost nearly all of its outer gas through a variety of methods. These could include tidal disruption, where the planet is ripped apart from orbiting too close to its star, or even a collision with another planet. Large-scale photoevaporation of the atmosphere could also play a role, but can't account for all the gas that has been lost.

Alternatively, it could be a 'failed' gas giant. The scientists believe that once the core of the gas giant formed then something could have gone wrong and it never formed an atmosphere. This could have occurred if there was a gap in the disc of dust that the planet formed from, or if it formed late and the disc ran out of material.

Dr Armstrong adds: "One way or another, TOI 849 b either used to be a gas giant or is a 'failed' gas giant.

"It's a first, telling us that planets like this exist and can be found. We have the opportunity to look at the core of a planet in a way that we can't do in our own solar system. There are still big open questions about the nature of Jupiter's core, for example, so strange and unusual exoplanets like this give us a window into planet formation that we have no other way to explore.

"Although we don't have any information on its chemical composition yet, we can follow it up with other telescopes. Because TOI 849 b is so close to the star, any remaining atmosphere around the planet has to be constantly replenished from the core. So if we can measure that atmosphere then we can get an insight into the composition of the core itself."

Northwestern University researchers have cracked one of the secrets of tooth decay. In a new study of human enamel, the materials scientists are the first to identify a small number of impurity atoms that may contribute to the enamel's strength but also make the material more soluble. They also are the first to determine the spatial distribution of the impurities with atomic-scale resolution.

Dental caries -- better known as tooth decay -- is the breakdown of teeth due to bacteria. ("Caries" is Latin for "rottenness.") It is one of the most common chronic diseases and a major public health problem, especially as the average life expectancy of humans increases.

The Northwestern discovery in the building blocks of enamel -- with detail down to the nanoscale -- could lead to a better understanding of human tooth decay as well as genetic conditions that affect enamel formation, which can lead to highly compromised or completely absent enamel.

Enamel, the human tooth's protective outer layer, covers the entire crown. Its hardness comes from its high mineral content.

"Enamel has evolved to be hard and wear-resistant enough to withstand the forces associated with chewing for decades," said Derk Joester, who led the research. "However, enamel has very limited potential to regenerate. Our fundamental research helps us understand how enamel may form, which should aid in the development of new interventions and materials to prevent and treat caries. The knowledge also might help prevent or ameliorate the suffering of patients with congenital enamel defects."

The study will be published on July 1 by the journal Nature.

Joester, the corresponding author, is an associate professor of materials science and engineering in the McCormick School of Engineering. Karen A. DeRocher and Paul J.M. Smeets, a Ph.D. student and a postdoctoral fellow, respectively, in Joester's lab, are co-first authors.

One major obstacle hindering enamel research is its complex structure, with features across multiple length scales. Enamel, which can reach a thickness of several millimeters, is a three-dimensional weave of rods. Each rod, approximately 5 microns wide, is made up of thousands of individual hydroxylapatite crystallites that are very long and thin. The width of a crystallite is on the order of tens of nanometers. These nanoscale crystallites are the fundamental building blocks of enamel.

Perhaps unique to human enamel, the center of the crystallite seems to be more soluble, Joester said, and his team wanted to understand why. The researchers set out to test if the composition of minor enamel constitutents varies in single crystallites.

Using cutting-edge quantitative atomic-scale techniques, the team discovered that human enamel crystallites have a core-shell structure. Each crystallite has a continuous crystal structure with calcium, phosphate and hydroxyl ions arranged periodically (the shell). However, at the crystallite's center, a greater number of these ions is replaced with magnesium, sodium, carbonate and fluoride (the core). Within the core, two magnesium-rich layers flank a mix of sodium, fluoride and carbonate ions.

"Surprisingly, the magnesium ions form two layers on either side of the core, like the world's tiniest sandwich, just 6 billionths of a meter across," DeRocher said.

Detecting and visualizing the sandwich structure required scanning transmission electron microscopy at cryogenic temperatures (cryo-STEM) and atom probe tomography (APT). Cryo-STEM analysis revealed the regular arrangement of atoms in the crystals. APT allowed the researchers to determine the chemical nature and position of small numbers of impurity atoms with sub-nanometer resolution.

The researchers found strong evidence that the core-shell architecture and resulting residual stresses impact the dissolution behavior of human enamel crystallites while also providing a plausible avenue for extrinsic toughening of enamel.

"The ability to visualize chemical gradients down to the nanoscale enhances our understanding of how enamel may form and could lead to new methods to improve the health of enamel," Smeets said.

This study builds on an earlier work, published in 2015, in which the researchers discovered that crystallites are glued together by an extremely thin amorphous film that differs in composition from the crystallites.

The opioid and addiction epidemic didn't go away when the coronavirus pandemic began. But rapid changes in regulations and guidance made during COVID-19 response could also help many more people get care for opioid use disorder and other addiction problems.

That's according to experts from the University of Michigan Addiction Center and VA Ann Arbor Healthcare System, writing in this week's issue of JAMA Psychiatry.

They document the recent policy changes that have made it possible for more addiction care to take place through telemedicine, specifically video chats and even telephone calls. They also note the requirements for in-person visits for key addiction treatments that have been waived - though only temporarily -- during COVID-19.

Yet despite the recent rapid progress, they say, it will take more changes to truly lower barriers that stand in the way of delivering evidence-based addiction care to more people via telemedicine.

If that happens, more people with substance use disorders could have access to care such as medications, psychotherapy and peer group support, they say -- even in rural areas and other places where addiction specialists are scarce.

Some of the authors already used telehealth as part of their work at the VA even before the COVID-19 pandemic began. Based on that experience, and on the intense shifts to virtual care in the past three months, they give specific recommendations for how to make telehealth for addiction a sustainable option for more providers and patients.

"Before COVID, treatment of substance use disorders was one of the least-used forms of telemedicine, because of a combination of regulatory issues, clinician comfort and patient comfort," says Allison Lewei Lin, M.D., M.Sc., the lead author and an addiction psychiatrist at the U-M and VA.

"Now, many addiction providers haven't seen their patients in the office, or have substantially decreased in-person visits, by using telemedicine in the past three months," she says. "And where we once relied on referring patients to inpatient and residential programs, many of those have not been available during this time, so outpatient clinicians have been trying to take care of sicker patients as well."

Policy shifts

Relaxation of rules such as the Ryan Haight Act, which previously didn't allow prescribers to prescribe buprenorphine and other controlled addiction treatment medications to patients they had only seen virtually, have made a big difference, says Lin.

So have changes in rules and guidance from the Substance Abuse and Mental Health Services Administration to make it easier for clinicians to communicate and care for patients with addiction via telemedicine.

Plus, the same changes to Medicare and Medicaid telemedicine reimbursement rules that have helped move non-addiction care online this spring are helping addiction providers, too.

More research needed

As the coronavirus pandemic continues, she says, many in the addiction field have a lot of questions - ones that researchers are now scrambling to study. For instance, how are patients doing, and are they improving with telemedicine-delivered treatment? Also of intense interest: Can telemedicine potentially help patients start and stay engaged in treatment longer than they would have with traditional care?

The rapid move to virtual care has been a big switch for a field that has focused for so long on building interpersonal rapport between patient and provider - and also on in-person checks such as urine tests to make sure patients are adhering to their treatment and spot relapses early.

"Patients are now used to telemedicine and some really like it, so we shouldn't take it away even when coronavirus wanes," Lin says. "But we have to evaluate the impacts, including if the treatments are actually effective, as we go on."

Last year, Lin led a team that published a review of the existing evidence surrounding telemedicine for substance use disorders. They concluded that much more research was needed - but that early evidence showed efficacy and high patient satisfaction.

Key recommendations

In the new piece, she and colleagues Anne Fernandez, Ph.D., M.A. and Erin Bonar, Ph.D. recommend three key changes going forward:

Development of treatment guidelines that include both in-person and telemedicine-based care for substance use disorders, and that provide guidance on urine toxicology practices and use of new ways to monitor treatment progress including self-monitoring apps and other practices.

More work to increase the availability of buprenorphine via telemedicine, including by increasing the number of physicians who are trained to prescribe it and monitor patients taking it. This could especially help rural areas hit hard by the opioid epidemic. Lin and her colleagues currently lead regular training sessions to get new providers started with such prescribing, and offer ongoing support for prescribers.

More help for people with substance use disorders who are also coping with other mental health conditions, and with the psychological and financial stress brought on by the COVID-19 pandemic. Online resources including group therapy online will be key, they say.

"In this moment when clinical care has been transformed because of real-world necessity, rather than evidence produced by research, it makes research on the effects of that transformation all the more urgent," says Lin. "We need to understand to what extent we should be offering telemedicine even after COVID-19 has subsided."

Another urgent issue: making sure that patients in rural areas without broadband Internet access aren't left behind.

Lin has been seeing addiction patients for years using telehealth, but they had to travel to a clinic in a nearby city in order to connect with her. Now she is having visits with those patients in their homes instead.

"These past few months have been a natural experiment for substance use disorder treatment, much of which has traditionally been largely outside the realm of other types of medicine," she says. "It will be important to see how things change, for better or worse. When we have the option for in-person care again, we will also need to determine which is better - telemedicine or the traditional approach - and for which patients to keep them engaged and make care more accessible, especially for vulnerable populations."

CLEVELAND--A team led by Case Western Reserve University medical researchers has developed a potential treatment method for Pelizaeus-Merzbacher disease (PMD), a fatal neurological disorder that produces severe movement, motor and cognitive dysfunction in children. It results from genetic mutations that prevent the body from properly making myelin, the protective insulation around nerve cells.

Using mouse models, the researchers identified and validated a new treatment target--a toxic protein resulting from the genetic mutation. Next, they successfully used a family of drugs known as ASOs (antisense oligonucleotides) to target the ribonucleic acid (RNA) strands that created the abnormal protein to stop its production. This treatment reduced PMD's hallmark symptoms and extended lifespan, establishing the clinical potential of this approach.

By demonstrating effective delivery of the ASOs to myelin-producing cells in the nervous system, researchers raised the prospect for using this method to treat other myelin disorders that result from dysfunction within these cells, including multiple sclerosis (MS).

Their research was published online July 1 in the journal Nature.

"The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment," said Paul Tesar, principal investigator on the research, a professor in the Department of Genetics and Genome Sciences at the School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics. "Our results open the door for the development of the first treatment for PMD as well as a new therapeutic approach for other myelin disorders."

Study co-authors include an interdisciplinary team of researchers from the medical school, Ionis Pharmaceuticals Inc., a Carlsbad, California-based pioneer developer of RNA-targeted therapies, and Cleveland Clinic. First author Matthew Elitt worked in Tesar's lab as a Case Western Reserve medical and graduate student.

PMD attacks the young

PMD is a rare, genetic condition involving the brain and spinal cord that primarily affects boys. Symptoms can appear in early infancy and begin with jerky eye movements and abnormal head movements. Over time, children develop severe muscle weakness and stiffness, cognitive dysfunction, difficulty walking and fail to reach developmental milestones such as speaking. The disease cuts short life-expectancy, and people with the most severe cases die in childhood.

The disease results from errors in a gene called proteolipid protein 1 (PLP1). Normally, this gene produces proteolipid protein (PLP) a major component of myelin, which wraps and insulates nerve fibers to allow proper transmission of electrical signals in the nervous system. But a faulty PLP1 gene produces toxic proteins that kill myelin producing cells and prevent myelin from developing and functioning properly--resulting in the severe neurological dysfunction in PMD patients.

PMD impacts a few thousand people around the world. So far, no therapy has lessened symptoms or extended lifespans.

For nearly a decade, Tesar and his team have worked to better understand and develop new therapies for myelin disorders. They have had a series of successes, and their myelin-regenerating drugs for MS are now in commercial development.

Latest research

In the current laboratory work, the researchers found that suppressing mutant PLP1 and its toxic protein restored myelin-producing cells, produced functioning myelin, reduced disease symptoms and extended lifespans.

After validating that PLP1 was their therapeutic target, the researchers pursued pre-clinical treatment options. They knew mutations in the PLP1 gene produced faulty RNA strands that, in turn, created the toxic PLP protein.

So they teamed with Ionis Pharmaceuticals, a leader in RNA-targeted therapeutics and pioneer of ASOs. These short strings of chemically modified DNA can be designed to bind to a specific RNA target and block production of its protein product.

And that's exactly what happened in their studies. The result was improved myelin and locomotion, and substantial extension of lifespan. "ASOs provided an opportunity to cut the disease-causing protein off at its source," Elitt said.

The successful clinical use of ASOs is relatively new, yet recent developments seem promising. In 2016, the U.S. Food and Drug Administration approved the first ASO drug for a neurological disorder, spinal muscular atrophy. The drug, Spinraza, was developed by Ionis and commercialized by Biogen Inc. More ASO therapies are in development, and clinical trials and hold promise for addressing many neurological diseases that as of now have no effective treatment options.

Tesar said that ongoing and planned experiments in his laboratory will help guide future clinical development of ASO therapy for PMD. For example, researchers want to understand more about how well the treatment works after the onset of symptoms, how long it lasts, how often treatment needs to be given and whether it might be effective for all PMD patients, regardless of their specific form of the disease.

"While important research questions remain, I'm cautiously optimistic about the prospect for this method to move into clinical development and trials for PMD patients," Tesar said. "I truly hope our work can make a difference for PMD patients and families."

A new, ultra-rapid formulation of insulin reached peak activity in pigs with diabetes about twice as fast as a commercially available option, according to new research. The formulation, which peaked in as little as 9 minutes, could improve quality-of-life for patients with diabetes by allowing them to more quickly manage their blood sugar levels during mealtimes. Type 1 diabetes is one of the most common chronic conditions, affecting about 40 million people around the world. Patients with diabetes usually receive routine injections of insulin to control their blood sugar levels, but current insulin formulations suffer from various drawbacks. For example, even fast-acting insulin treatments can take as long as 90 minutes to peak in activity, making them less than ideal for patients who need quick and effective blood sugar control during mealtimes. Here, Joseph Mann and colleagues designed a faster-acting insulin formulation based on polymer excipients, compounds that maintain the insulin in a less aggregated form that more closely mimics how the hormone is naturally released in the body. The scientists used a high-throughput screen to evaluate various excipients, and integrated the top-performing candidate into an insulin formulation named UFAL. When injected into pigs with diabetes, the new formulation reached peak activity in 9 minutes - twice as fast as the commercially available insulin formulation Humalog, which peaked in 25 minutes. Furthermore, UFAL was safe in rats and outperformed Humalog and similar rapid-acting insulin analogs in a model that simulates drug activity in humans. The authors caution that more work is needed to pin down their formulation's activity and safety in people, as pigs show different insulin dynamics compared with humans.

What The Study Did: The clinical findings of four children who experienced neurological symptoms associated with COVID-19 are presented in this case series.

Authors: Yael Hacohen, M.D., Ph.D., of University College London, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamaneurol.2020.2687)

Editor's Note: The article includes conflicts of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

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Media advisory: The full study is linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2020.2687?guestAccessKey=814c2fa0-6c23-4d4e-85df-928b66ab0034&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=070120

What The Viewpoint Says: The need for and implementation of telemedicine for patients with substance use disorder in the era of COVID-19 is discussed in this Viewpoint.

Authors: Lewei (Allison) Lin, M.D., M.S., of the University of Michigan in Ann Arbor, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapsychiatry.2020.1698)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

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Media advisory: The full article is linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time https://jamanetwork.com/journals/jamapsychiatry/fullarticle/10.1001/jamapsychiatry.2020.1698?guestAccessKey=2ee5e96a-66ee-4445-b892-16005d7ca2b9&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=070120