Culture

A group of scientists from Osaka University, in cooperation with Kaneka Corporation, evaluated the interplanar bond strength of graphene by measuring the elastic constant of graphite, demonstrating that the elastic constant of monocrystalline graphite (Figure 1, top) was above 45 gigapascal (GPa), which was higher than conventionally believed. Their research results were published in Physical Review Materials.

Graphite consists of layers of graphene and the layers are bonded via weak van der Waals (vdW) forces, a ubiquitous attraction between all molecules. It was believed that the elastic constant of graphite crystal did not exceed 40 GPa.

This is because the elastic constants obtained from experiments using artificial highly oriented pyrolytic graphite (HOPG) were low due to structural defects in the graphite (as exemplified in Figure 1, bottom) and theoretical calculations also demonstrated that the elastic constant of graphite was less than 39 GPa.

Since a direct characteristic of an interplanar interaction is the elastic constant along the c axis of graphite, which reflects the interlayer bond strength, the elastic constant of graphite has been used to validate proposed theoretical approaches, and its accurate measurement is critical to thoroughly understanding vdW interactions.

In this study, Kaneka Corporation created a high-quality defect-free monocrystalline graphite by heating high orientation polyimide thin films at high temperatures; however, it was very difficult to measure the elastic constant of this crystal (10 μm in diameter, 1μm in thickness) along the thickness direction.

Thus, in order to experimentally obtain the elastic constant of graphite, using picosecond laser ultrasound spectroscopy, this group applied a laser of 1μm in diameter to the surface of a multilayered graphene for one 10 trillionth of a second to generate ultra-high frequency ultrasound. By accurately measuring the longitudinal wave sound velocity along the thickness direction, they obtained the elastic constant.

Although it had been thought that the interplanar bond strength of graphite was very weak, the results of this study showed that it had a strong bond strength: the elastic constant was nearly 50 GPa, which cannot be explained by conventional theories.

In this study, the short-range correlation effect selectively strengthened the potential energy surface (PES). This anharmonic PES enhanced the elastic constant of graphite. Using the ACFDT-RPA+U method, they demonstrated that the elastic constant reached 50 GPa due to the short-range correlation effect.

Lead author KUSAKABE Koichi says, "Our research group shows that graphite exhibits its superiority in a highly crystalline state. We have created high-quality, high-crystallinity graphite, which has stronger interplanar bond strength than previously believed. Applying ultrasonic measurement techniques to this defect-free monocrystalline graphite thin film will lead to the production of highly sensitive sensors for identifying biological matter such as proteins in non-destructive testing."

MEDIA ADVISORY

Bottom Line: Lower levels of ACE2 nasal gene expression in children may explain why children have a lower risk of Covid-19 infection and mortality. The SARS-CoV-2 virus uses ACE2 to enter the host. ACE2 nasal gene expression could potentially be used as a biomarker to evaluate Covid-19 susceptibility.

Results: ACE2 gene expression in nasal epithelium, the first point of contact for SARS-CoV-2 and the human body, was lowest in younger children and increased with age.

How: A retrospective analysis of 305 patients aged 4 to 60 years encountered within the Mount Sinai Health System in New York.

Study Conclusions: These findings could help explain why children appear to be less susceptible to Covid-19 infection. The results may point to a potential biomarker of Covid-19 susceptibility. Prospective studies are needed to assess the degree to which ACE2 expression can be used as a biomarker for COVID-19 susceptibility.

Publication

Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults

JAMA. Published online May 20, 2020. doi:10.1001/jama.2020.8707

"Why children get COVID-19 less than adults has been a puzzle. Researchers have hypothesized that lower expression of ACE2, which the SARS-Cov-2 virus uses to enter our bodies, might explain why children are less likely to get COVID-19. Our study shows that ACE2 expression in the nasal epithelium is lowest in younger children and increases with age into adulthood. Our results may help explain why children account for less than 2% of identified cases of Covid-19. A biomarker of COVID-19 susceptibility based on ACE2 expression might be possible," said Mount Sinai's Dr. Supinda Bunyavanich of the research

Scientists from the Antibody and Vaccine group at the University of Southampton have discovered a way to transform antibody drugs previously developed to treat autoimmunity into antibodies with powerful anti-cancer activity through a simple molecular "switch".

This work, published in the journal Cancer Cell, focuses on a molecule called CD40 which is present on the surface of immune cells and controls both autoimmunity and cancer. In autoimmunity, CD40 is thought to be over-stimulated, increasing the chance of the immune system attacking healthy tissues; whereas in cancer, CD40 is believed to be under-stimulated, enabling tumour cells to evade the immune system. Targeting of CD40 with antibody drugs is ongoing in therapeutic interventions for both diseases.

Accordingly, antibody drugs have been developed to either activate (agonists) or suppress (antagonists) the CD40 immune pathway. Researchers at the Centre for Cancer Immunology in Southampton, led by Professors Mark Cragg and Martin Glennie now reveal that an antagonist CD40 antibody can be transformed into an agonist by simply modifying the "constant" domain of the antibody. The antagonist-turned agonist "trick" was shown for three different antagonists, being driven by the hinge part of the constant domain that controls the flexibility of the antibody. One of these antibodies, was shown to be a "super"-agonist that could stimulate the immune system and cure cancer more effectively in preclinical models than the best CD40-targeting antibody currently in clinical trial.

"Being able to toggle between an autoimmune drug and a cancer medicine with a simple switch is really exciting." said Dr Xiaojie Yu, first author of the study. "We gained a deeper understanding of the mechanism through which CD40 becomes activated, and eagerly look forward to applying this technology to more drug candidates."

"Our findings build on a history of CD40 research here in Southampton and were surprising and exciting in equal measure," said Professor Mark Cragg, senior author of the study. "Taking an antibody that suppresses the immune system and turning it on its head, to activate the immune system for cancer through a relatively simple process is unprecedented. More than that, the same approach could be used for other immune targets and we look forward to seeing testing this in the near future".

May 20, 2020, Alexandria, Va.-- The June 2020 issue of Journal of Dental Research brings together a collection of the latest research on the oral microbiome. This issue includes reviews and reports of new tools for analyzing microbial communities and for cultivating microbial species.

"Through much of the 20th Century, bacteria and other microorganisms were considered to exist predominantly as single cells with independent lifestyles," said Wenyuan Shi, JDR Special Issue guest editor; CEO and Chief Scientific Officer of the Forsyth Institute. "However, we've learned that from environment to agriculture to energy to healthcare, these microbial communities have deep connections with everything that matters to us, including being the "special extra organ" that lives and grows with our bodies."

The papers in this issue highlight the rapid progress that has been made over the last decade in understanding the dynamics of the human oral microbiome. Topics include:

Reviews and reports of new tools for analyzing microbial communities and for cultivating microbial species, including new members of the Saccharibacteria and other difficult-to-culture taxa

The oral microbiome in animal models with a view to understanding the stability of the microbiome and responses to periodontitis

The structural and functional characteristics of the human oral microbiome in connection with dental caries, periodontitis or medication-related osteonecrosis of the jaw

Evidence that the oral microbiome is involved in oral cancer and diabetes mellitus

"This issue is a major contribution to the Oral Microbiome field," Shi continued. "The key goal of the next era of oral microbiome research will be to translate the detailed understanding of the system into practical solutions for predicting, preventing or treating oral microbial diseases."

Rice has always been the most important food in Asia and the world. About half of the population on earth use rice as their main food source. The origin, spread, evolution, and ecological adaptation of cultivated rice are still one of the most important issues which currently concerned by global archaeologists, biologists, and agricultural scientists.

In recent years, archaeobotany and molecular biology studies have shown the originally cultivated rice was domesticated into japonica rice (Oryza sativa japonica) in the lower Yangtze region, China, 10000 years ago, then spread to Japan, South and Southeast Asia. About 5000-4000 years ago, the cultivated japonica rice spread to South Asia, hybridized with the native wild rice, gradually form the indica rice (Oryza sativa indica) and become the main crop in South Asia today.

However, in recent years, research on the origin and spread of rice have mainly focused on East Asia, Southeast Asia, and South Asia. At present, we still know very little about when and how rice spread into West Asia, Europe, and Africa. The Central Asia region, as an important node in the ancient Silk Road cannot be ignored, because it is the "crossroad" of world civilization. Therefore, studying the time and location of rice emergence in Central Asia can help us restore the spread process about of rice agriculture and add an important part for the early crop globalization research.

Recently, Li Xiaoqiang research group in Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences (IVPP, CAS) and other researchers in College of Cultural Heritage, Northwest University, China, Institute of Archaeology, Uzbekistan Academy of Sciences reported their latest research about the agricultural remain in Khalchayan site, Uzbekistan, which published in the Science China: Earth Science. Researchers investigated 11 sites on the northern bank of the Amu Darya from Bronze Age to Arabian period and found carbonized rice remain at Kalchayan site. With archaeobotany, chronology method and other local archaeological records, researchers provide a new physical evidence for the spread of rice to western Asia and the exchange of eastern and western civilizations along the ancient Silk Road.

Khalchayan site is a city site in southeastern Uzbekistan. Researchers use flotation method obtain large amount of botanical materials at a cultural layer in southwest part of the site. The AMS 14C dating results showed that the age of the rice remains in the site are 1714-1756 cal. B.P., which in Kushan period. In addition to the rice remains, carbonized wheat, 2-row barley, pea, millet, grapes, flax and other crops were recovered at the site. These crops include both West Asian and East Asian origin, which illustrates a diverse and complex oasis farming system. Because rice cultivation requires a lot of heat and water then wheat and millet, make it difficult to cultivate in arid regions in early times. But combining the carbonized rice remains with the records of the irrigation system existing in other local oases agricultural archeological sites during Kushan period, researchers believe it has the possibility of cultivation rice locally during that time.

Morphological studies show that the carbonized rice remains are japonica rice, and their morphology is similar to the remains found in some sites in southern China and northwestern India during the same period. That indicating the possibility of rice in Central Asia was spread from South Asia. Meanwhile, when rice appeared in Central Asia, Kushan Empire has already established in northwest India and conquered most part of Central Asia and South Asia. The imperial expansion and political unrest may have further fueled the dispersal of crops across Inner Asia. The emergence of rice may also indicate the beginning of the rice-based diet culture gradual integration with the local wheat-based diet system in Central Asia and finally form Central Asia diet system today, like baked dough (Naan), pilaf and barbecue.

The rice remains in Khalchayan site is the first well reported rice remain in Central Asia. It is also one of the few ancient cultivated rice found without in East Asia, South Asia and Southeast Asia. It has a great value for further understanding the exchange process of the early agricultural activities in the Southern Himalayan route, and also provided a new evidence to explain how rice further spreads westward to Iran, Europe, and Africa, where rice cultivation activities exist today.

Hundreds of new links have been found between people's DNA and the heart's electrical activity, according to a study of almost 300,000 people led by researchers at Queen Mary University of London and the Broad Institute of MIT and Harvard.

The results could one day lead to advanced screening methods to discern who is at greatest risk of developing disease, and could help reveal new genetic targets for research and drug development.

Over the past 10 years, researchers have identified many genetic factors that contribute to--or protect against--the onset of specific heart diseases. However, it has been difficult to find genetic factors associated with arrhythmias - one of the most common forms of heart disease where the heart beats abnormally.

The team of scientists from more than 140 institutions looked at data from 293,051 people across the world, studying their individual genomes and their measurements on an electrocardiogram - one of the oldest and most widely used heart diagnostic tests.

The investigators specifically studied the length of time between two points on the electrocardiogram read-out known as the 'PR interval', which is associated with a number of common electrical disorders such as atrial fibrillation and other arrhythmias.

The findings, published in the journal Nature Communications, report 202 locations in the genome with links to this type of electrical activity in the heart--141 of which had not been previously identified. This more than triples the number of known genetic regions linked to this type of electrical activity and explains about 62 percent of its heritability.

Co-lead researcher Professor Patricia Munroe from Queen Mary's William Harvey Research Institute said: "This is the largest global study of its kind to investigate the genetic basis of the PR interval - a well-established electrocardiogram risk marker for heart disease and mortality. The insights provide new knowledge on biological processes relating to the heart's electrical activity and potential avenues of drug research for preventing and treating heart conditions."

Steven Lubitz from Massachusetts General Hospital and the Broad Institute added: "That's really a striking discovery that wouldn't have been possible a few years ago. But thanks to many studies, including the UK Biobank, we now have all this imaging and electrocardiogram data paired with genetic data, which has proven to be a really powerful combination."

The findings indicate that an individual's inherited predisposition to heart disease is not the result of single-gene mutations, but rather a cumulative effect of many variants across the genome.

DALLAS – May 21, 2020 – A new cooling insole developed by UT Southwestern scientists reduced the foot temperature of patients with diabetic neuropathy by several degrees, diminishing a significant risk factor for diabetic foot ulcers. This new device, detailed in an article published online ahead of print May 6 in The Journal of Foot & Ankle Surgery, could eventually prevent thousands of amputations that take place worldwide each year because of this condition.

Just in the U.S., more than 100,000 lower extremity amputations take place every year, many of them prompted by diabetic foot ulcers. These ulcers are associated with numerous quality-of-life and health consequences, including a mortality rate of 50 percent within five years for patients who develop them. Although the exact cause of this common diabetes complication is unclear, high foot pressure has long been considered a prevailing cause. Consequently, the most prescribed preventive treatment for diabetic foot ulcers is pressure-relieving insoles.

However, says Metin Yavuz, D.Eng., an associate professor in the School of Health Professions’ Division of Prosthetics and Orthotics at UT Southwestern Medical Center, this prophylactic intervention isn’t accomplishing its goal, since diabetic amputation rates have been on the rise despite widely available pressure-reliving insoles. “Even when patients receive therapeutic shoes and insoles, education, and close monitoring,” he says, “30 to 40 percent of patients who have had one diabetic foot ulcer will still develop another within a year.”

Hoping to decrease these numbers, Yavuz and his colleagues focused on another risk factor for these ulcers: foot temperature. Animal studies have shown that skin maintained between 25 and 30 degrees C is less likely to break down under pressure than skin at higher temperatures. The feet of diabetic patients already tend to be warmer due to inflammation associated with the disease, Yavuz explains, compounded by friction from walking and the stiff therapeutic shoes that patients wear, which are usually made of synthetic materials that act as heat insulators.

“We thought, why don’t we break that vicious cycle by cooling the foot?” he says.

To do that, Yavuz and his lab, aided by a pilot grant from UTSW’s Center for Translational Medicine, developed a system that circulates cool water into pressure-relieving insoles. The device, which the researchers named Temperature and Pressure Monitoring and Regulating Insoles (TAPMARI), consists of a small box strapped to the wearer’s calf that houses a cooling unit, a small water pump, a battery pack, and a thermostat. The cooling unit harnesses a type of thermoelectric cooling called the Peltier effect to chill water to a desired temperature that’s then pumped into insoles placed in the wearer’s shoes. Yavuz later teamed up with the engineering company Vivonics Inc. and obtained funding from the National Institutes of Health to improve the design.

The researchers tested the improved device in eight volunteers: one man and seven women of a median age of 45 years. Five of these volunteers were healthy and three had diabetic neuropathy.

Using an infrared thermal camera, the researchers took photos of the subjects’ feet at baseline before wearing the insoles, then placed a cooling insole in only their right shoes. They took more thermal photos after the subjects walked five minutes on a treadmill and again after they wore the insoles an additional two hours and walked five minutes on the treadmill again.

Results showed that the mean baseline foot temperature in the group was 28.1 degrees C. Mean foot temperatures at the end of the study were 31.7 degrees C for the left foot and 25.9 degrees C for the right, which was cooled by TAPMARI. Although the diabetics’ feet got warmer than those of the healthy volunteers during walking, they still maintained a mean temperature of 27.5 degrees C in the right foot, suggesting that the insoles could maintain temperature in a range that protects against skin breakdown.

Cool temperatures from the insoles didn’t cause vasoconstriction (narrowing of blood vessels) in the foot, which could have damaged tissue, Yavuz says. However, sole temperatures reached as high as 30.8 degrees C in some regions of the cooled feet, particularly in the midfoot, suggesting that the design of the insole needs to be improved. Other design elements could also be tweaked, he says, such as reducing the size of the unit worn on the calf.

Eventually, Yavuz says, these devices could change the course for patients with diabetes, preventing this common and often serious complication.

“Diabetic foot ulcers can be a major burden on patients, their families, caregivers, and the health system,” he says. “What we’re doing now to prevent these ulcers or simply maintain the status quo isn’t working. TAPMARI could be the start of a whole new approach.”

Other researchers who contributed to this study include Ali Ersen and Lawrence A. Lavery of UTSW; Aakshita Monga and Yasser Salem of the University of North Texas Health Science Center; Alan Garrett of the John Peter Smith Hospital; and Gordon B. Hirschman and Ryan Myers of Vivonics Inc.

We often think of asteroids and comets as distinct types of small bodies, but astronomers have discovered an increasing number of "crossovers." These objects initially appear to be asteroids, and later develop activity, such as tails, that are typical of comets.

Now, the University of Hawai'i Asteroid Terrestrial-impact Last Alert System (ATLAS) has discovered the first known Jupiter Trojan asteroid to have sprouted a comet-like tail. ATLAS is a NASA-funded project using wide-field telescopes to rapidly scan the sky for asteroids that might pose an impact threat to Earth. But by searching most of the sky every two nights, ATLAS often finds other kinds of objects - objects that aren't dangerous, but are very interesting.

Early in June 2019, ATLAS reported what seemed to be a faint asteroid near the orbit of Jupiter. The Minor Planet Center designated the new discovery as 2019 LD2. Inspection of ATLAS images taken on June 10 by collaborators Alan Fitzsimmons and David Young at Queen's University Belfast revealed its probable cometary nature. Follow-up observations by UH astronomer J.D. Armstrong and his student Sidney Moss on June 11 and 13 using the Las Cumbres Observatory (LCO) global telescope network confirmed the cometary nature of this body.

Later, in July 2019, new ATLAS images caught 2019 LD2 again - now truly looking like a comet, with a faint tail made of dust or gas. The asteroid passed behind the Sun and was not observable from the Earth in late 2019 and early 2020, but upon its reappearance in the night sky in April of 2020, routine ATLAS observations confirmed that it still looks like a comet. These observations showed that 2019 LD2 has probably been continuously active for almost a year.

While ATLAS has discovered more than 40 comets, what makes this object extraordinary is its orbit. The early indication that it was an asteroid near Jupiter's orbit have now been confirmed through precise measurements from many different observatories. In fact, 2019 LD2 is a special kind of asteroid called a Jupiter Trojan - and no object of this type has ever before been seen to spew out dust and gas like a comet.

Trojan asteroids follow the same orbit as a planet, but stay either around 60 degrees ahead or 60 degrees behind along the orbit. Earth has at least one Trojan asteroid, and Neptune has dozens. Jupiter has hundreds of thousands. The Jupiter Trojan asteroids orbit the Sun in two huge swarms, one swarm orbiting ahead of the planet (where 2019 LD2 was found) and one swarm orbiting behind it. The Trojan asteroids have been captured into these orbits by Jupiter's strong gravity. What makes 2019 LD2 so interesting is that we think most Jupiter Trojans were captured billions of years ago. Any surface ice that could vaporize to spew out gas and dust should have done so long ago, leaving the objects quietly orbiting as asteroids - not behaving like comets.

"We have believed for decades that Trojan asteroids should have large amounts of ice beneath their surfaces, but never had any evidence until now. ATLAS has shown that the predictions of their icy nature may well be correct" said Fitzsimmons.

What could have made 2019 LD2 suddenly show cometary behavior? Maybe Jupiter captured it only recently from a more distant orbit where surface ice could still survive. Maybe it recently suffered a landslide or an impact from another asteroid, exposing ice that used to be buried under layers of protective rock. New observations to find out are being acquired and evaluated. What's certain is that the Universe is full of surprises - and surveys to guard the Earth from dangerous asteroids often make unexpected discoveries of harmless but fascinating objects that can reveal more about our Solar System's history.

"Even though the ATLAS system is designed to search for dangerous asteroids, ATLAS sees other rare phenomena in our solar system and beyond while scanning the sky," said ATLAS project principal investigator Larry Denneau. "It's a real bonus for ATLAS to make these kinds of discoveries."

A Monash University study has uncovered the role DNA repair plays in preserving egg quality, offering hope for women whose eggs may be damaged through treatments such as radiation and chemotherapy.

The study, led by Monash Biomedicine Discovery Institute (BDI), found that when the cell death pathway is inhibited in oocytes (eggs) these eggs are capable of repairing severe DNA damage sufficiently to produce healthy offspring.

By exposing female mice deficient in TAp63, a key regulator of cell death in eggs, to various doses of gamma irradiation, it was observed that the oocytes will rapidly repair the DNA damage to maintain oocyte quality and female fertility.

Findings published in the medical journal PNAS, led by Associate Professor Karla Hutt and Dr Jessica Stringer, outline that among the many types of DNA damage, double-strand breaks (DSBs) are the most harmful and promote chromosome rearrangements and mutations and lead to genetic instability if the DSBs are repaired incorrectly.

"Women are born with their lifetime supply of eggs, which makes them one of the longest living cells in the human body. This means that eggs are exposed to years of external and internal stressors that may damage the DNA and contribute to the reduced oocyte quality in women over 35 years of age. We have identified the DNA repair pathway that oocytes use to repair DSBs and confirmed that repair is efficient and accurate to prevent mutations in offspring generated from these eggs," Associate Professor Hutt said.

Unlike other cells in the human body, oocytes have an extremely low tolerance for DNA damage and will activate cell death pathways when exposed to the stressors of things like radiation, chemotherapeutic drugs, and environmental toxins (e.g. pollution, pesticides). Blocking oocyte death is being actively investigated as one of the most promising methods to preserve future fertility and endocrine health in female cancer patients.

"Cancer treatments work by causing DNA damage, and a common side effect for female patients is ovarian damage which can lead to infertility and loss of endocrine function (such as early onset menopause). This study provides a fundamental step towards developing a truly effective fertility preservation strategy for female cancer patients and has important implications for prolonging women's fertile lifespan," Dr Stringer said.

With survival rates for many common cancers now exceeding 80 per cent, and an estimated population of 14 million female cancer survivors world-wide, there is a clear need to develop innovative approaches to protect the ovary from damage during anti-cancer treatment.

Moreover, in Australia, 20 per cent of women have their first child after 35 years of age, an age at which fertility plummets and rates of miscarriage and birth defects increase dramatically. This striking maternal age effect is due to loss of oocyte quality and possibly diminished DNA repair capacity.

Liver cancer is one of the deadliest cancers. It is insidious and does not present symptoms until it has progressed considerably, at which point, treatment options are limited and chances of survival are low. The most common type of liver cancer is hepatocellular carcinoma (HCC). HCC is most frequently seen in patients with chronic liver conditions such as hepatitis B or C and cirrhosis, and it takes the lion's share in mortality rates from liver cancer.

Over the past two decades or so, research on liver cancer and cancer in general has advanced with great strides. Scientists have found that all cancer cells for a particular type of cancer are not alike. Among a set of cancer cells, there is a rare subset of cells called cancer stem cells (CSCs) which function similarly to normal stem cells in that they are what cause cancer cells to form, renew, and proliferate. In a cancer patient, if you resected a tumor and removed all other cancer cells but left CSCs alive, the CSCs would cause the cancer to grow back. CSCs are what sustain the cancer.

But what causes CSCs to form? Research posits that normal stem cells mutate into CSCs under specific body environmental and/or genetic conditions. However, in the case of the liver, until recently, studies were yet to confirm the particular conditions and triggers for this conversion to CSCs, and whether these are environmental or genetic or both.

Now, for the first time, a group of scientists from Okayama University, led by Professor Masaharu Seno and Said Mohamed Abdelsabour Afify, has been able to develop CSCs from a type of normal stem cells by merely exposing them to what are believed to be favorable body environmental conditions, without introducing any mutations or foreign genes. "This is the world's first successful establishment of a liver CSC model from normal iPSCs without genetic manipulation," Prof. Seno remarks.

Normal iPSCs, or normal induced pluripotent stem cells, are a type of stem cell that can regenerate to develop into any type of human tissue, given the right conditions. In their laboratory, Prof. Seno and team placed iPSCs obtained from mice in a conditioned medium of HCC cell lines (comprising a type of liver-cancer derived cells called Huh7 cells). These Huh7 cells secreted chemicals that cause inflammation, creating an environment mimicking chronic inflammation in the liver. This was expected to trigger the conversion of the iPSCs to liver CSCs.

To find out whether this conversion occurred, the scientists had to evaluate in vivo whether the resultant cells formed malignant tumors. So, they injected the cells into the livers of immunodefficient mice. With high efficiency, after only 28 days of injection, the livers had developed malignant tumors. In contrast, untreated iPSCs gave rise to teratoma-like tumors with various germ layers, which were benign. Observation and chemical assays revealed that a considerable proportion of the cells of the malignant tumors had high nuclear-to-cytoplasmic ratios and high proliferation rates. Further, in these cells, liver cancer-associated markers such as alpha fetoprotein, glypican 3 and carcinoembryonic antigen, were expressed. Thus, the cells they had managed to develop from the iPSCs were not only confirmed CSCs, but also confirmed liver CSCs.

This work shows that liver CSCs could be born from normal stem cells in an environment of chronic inflammation without genetic mutation. It also provides a model for how liver cancer cells could be metastasizing. A model is a prerequisite for further scientific study. With the model that this study establishes, more targeted drugs could be developed and tested and perhaps, prevention techniques, such as tailored diets, can be discovered.

The scientists plan to test their model using human-tissue-derived iPSCs in future and adapt it to other human tissues in addition to liver tissue. Speaking of his vision, Prof. Seno says: "The results of further investigations will make liver cancer prevention, diagnosis, and treatment surer and surer. Finally, one day, the number of liver cancer patients in the world will reduce and the complete treatment of liver cancer will be possible." The journey to the future that Prof. Seno envisions, begins here.

Chinese researchers from The Trauma Center of Peking University People's Hospital and National Institute of Health Data Science at Peking University are using big data to help identify trauma patients who could experience potential adverse health events in the emergency department through the aid of a clinical decision support system. It was developed using a novel real-world evidence mining and evidence-based inference method, driven by improved information storage and electronic medical records.

The researchers published their results online on February 7 in IEEE Transactions on Systems, Man, and Cybernetics: Systems, a journal of the Institute of Electrical and Electronics Engineers. This is the first clinical decision support systems developed using evidential reasoning in an emergency department setting.

"Appropriate use of information technologies, particularly clinical decision support systems, may aid clinicians to make better clinical decisions and reduce the rate of medical errors," said the corresponding author Prof. Baoguo Jiang, Director of The Trauma Center of Peking University People's Hospital and China's National Center for Trauma Medicine. "By inputting clinical data of a patient, combined with available historical data, our proposed clinical decision support system outputs a predicted belief degree of severe trauma, including ICU admission and in-hospital death."

"The clinical variable signs and symptoms may be interrelated and lead to a clinical outcome. For example, a patient may have low level of consciousness because of the location of the injury, or it might be related to the high body temperature". In developing their clinical decision support system, the researchers used a trauma dataset from the emergency department at Kailuan Hospital in China, a hospital that has a close research collaboration with The Trauma Center of Peking University People's Hospital. Through the dataset, the researchers obtained the data of 1,299 trauma patients. The degree of interdependence between clinical signs and symptoms can be calculated from historical patient data. In the proposed clinical decision support system, the emergency room physician supplies information about the patient, including blood pressure, pulse rate, respiration rate, consciousness level, body temperature, age, comorbidities, mechanism and location of injury. These clinical signs and symptoms are then processed using an evidential reasoning rule, which compares each piece against the evidence mined from real-world data to predict the probability of adverse events and to optimally manage trauma patients and help them achieve ideal outcomes, trauma patients with a high probability of being admitted to the intensive care unit or dying in hospital need to be identified quickly and accurately upon their arrival at a hospital.

The team found that not only did their model prove especially useful in cases without prior expert knowledge or clinical experiences, but that the clinical decision support system also allowed for more accurate identification of trauma patients with adverse events compared to other systems with traditional machine learning models. Furthermore, the clinical decision support system works in a real-time fashion. From a physician's input of a patient's data to generating appropriate advices, the system works almost without any delay, which in turn helps buy trauma patients valuable time.

Next, the researchers plan to finetune their system and to generalize it for use in other clinical areas and non-emergent department settings.

Many insects' breathing pores open and close rapidly during respiration; oxygen diffusion analysis suggests that this spiracle fluttering enables high oxygen intake and low water loss, according to a study publishing May 20, 2020 in the open-access journal PLOS ONE by H. Frederik Nijhout and Michael C. Reed of Duke University, USA, and Sean D. Lawley of the University of Utah, USA.

For engineers developing new materials or protective coatings, there are billions of different possibilities to sort through. Lab tests or even detailed computer simulations to determine their exact properties, such as toughness, can take hours, days, or more for each variation. Now, a new artificial intelligence-based approach developed at MIT could reduce that to a matter of milliseconds, making it practical to screen vast arrays of candidate materials.

The system, which MIT researchers hope could be used to develop stronger protective coatings or structural materials -- for example, to protect aircraft or spacecraft from impacts -- is described in a paper in the journal Matter, by MIT postdoc Chi-Hua Yu, civil and environmental engineering professor and department head Markus J. Buehler, and Yu-Chuan Hsu at the National Taiwan University.

The focus of this work was on predicting the way a material would break or fracture, by analyzing the propagation of cracks through the material's molecular structure. Buehler and his colleagues have spent many years studying fractures and other failure modes in great detail, since understanding failure processes is key to developing robust, reliable materials. "One of the specialties of my lab is to use what we call molecular dynamics simulations, or basically atom-by-atom simulations" of such processes, Buehler says.

These simulations provide a chemically accurate description of how fracturing happens, he says. But it's slow, because it requires solving equations of motion for every single atom. "It takes a lot of time to simulate these processes," he says. The team decided to explore ways of streamlining that process, using a machine-learning system.

"We're kind of taking a detour," he says. "We've been asking, what if you had just the observation of how fracturing happens [in a given material], and let computers learn this relationship itself?" To do that, artificial intelligence (AI) systems need a variety of examples to use as a training set, to learn about the correlations between the material's characteristics and its performance.

In this case, they were looking at a variety of composite, layered coatings made of crystalline materials. The variables included the composition of the layers and the relative orientations of their orderly crystal structures, and the way those materials each responded to fracturing, based on the molecular dynamics simulations. "We basically simulate, atom by atom, how materials break, and we record that information," Buehler says.

They painstakingly generated hundreds of such simulations, with a wide variety of structures, and subjected each one to many different simulated fractures. Then they fed large amounts of data about all these simulations into their AI system, to see if it could discover the underlying physical principles and predict the performance of a new material that was not part of the training set.

And it did. "That's the really exciting thing," Buehler says, "because the computer simulation through AI can do what normally takes a very long time using molecular dynamics, or using finite element simulations, which are another way that engineers solve this problem, and it's very slow as well. So, this is a whole new way of simulating how materials fail."

How materials fail is crucial information for any engineering project, Buehler emphasizes. Materials failures such as fractures are "one of the biggest reasons for losses in any industry. For inspecting planes or trains or cars, or for roads or infrastructure, or concrete, or steel corrosion, or to understand the fracture of biological tissues such as bone, the ability to simulate fracturing with AI, and doing that quickly and very efficiently, is a real game changer."

The improvement in speed produced by using this method is remarkable. Hsu explains that "for single simulations in molecular dynamics, it has taken several hours to run the simulations, but in this artificial intelligence prediction, it only takes 10 milliseconds to go through all the predictions from the patterns, and show how a crack forms step by step."

The method they developed is quite generalizable, Buehler says. "Even though in our paper we only applied it to one material with different crystal orientations, you can apply this methodology to much more complex materials." And while they used data from atomistic simulations, the system could also be used to make predictions on the basis of experimental data such as images of a material undergoing fracturing.

"If we had a new material that we've never simulated before," he says, "if we have a lot of images of the fracturing process, we can feed that data into the machine-learning model as well." Whatever the input, simulated or experimental, the AI system essentially goes through the evolving process frame by frame, noting how each image differs from the one before in order to learn the underlying dynamics.

For example, as researchers make use of the new facilities in MIT.nano, the Institute's facility dedicated to fabricating and testing materials at the nanoscale, vast amounts of new data about a variety of synthesized materials will be generated.

"As we have more and more high-throughput experimental techniques that can produce a lot of images very quickly, in an automated way, these kind of data sources can immediately be fed into the machine-learning model," Buehler says. "We really think that the future will be one where we have a lot more integration between experiment and simulation, much more than we have in the past."

The system could be applied not just to fracturing, as the team did in this initial demonstration, but to a wide variety of processes unfolding over time, he says, such as diffusion of one material into another, or corrosion processes. "Anytime where you have evolutions of physical fields, and we want to know how these fields evolve as a function of the microstructure," he says, this method could be a boon.

CAMBRIDGE, MA -- MIT scientists have identified a potential new strategy for treating Fragile X syndrome, a disorder that is the leading heritable cause of intellectual disability and autism.

In a study of mice, the researchers showed that inhibiting an enzyme called GSK3 alpha reversed many of the behavioral and cellular features of Fragile X. The small-molecule compound has been licensed for further development and possible human clinical trials.

From the mouse studies, there are signs that this compound may not have the same limitations of another class of Fragile X drugs that failed in human clinical trials a few years ago, says Mark Bear, the Picower Professor of Neuroscience, a member of MIT's Picower Institute for Learning and Memory, and one of the senior authors of the study.

GSK3 inhibitors might also be useful against other diseases in which GSK3 plays a role, including Alzheimer's disease, he says.

Florence Wagner, director of medicinal chemistry at the Broad Institute's Stanley Center for Psychiatric Research, is also a senior author of the study, which appears today in Science Translational Medicine. The lead authors are MIT postdoc Patrick McCamphill, former MIT graduate student Laura Stoppel, and former MIT postdoc Rebecca Senter.

Many targets

Fragile X affects about 1 in 2,500 to 4,000 boys and 1 in 7,000 to 8,000 girls, and is caused by a genetic mutation of a protein called Fragile X mental retardation protein (FMRP). In addition to intellectual disability, symptoms include epilepsy, attention deficit and hyperactivity, hypersensitivity to noise and light, and autistic behaviors such as hand-flapping.

Bear's lab, which has been studying Fragile X for about two decades, has previously shown that protein synthesis at synapses, the specialized junctions between neurons, is stimulated by a neurotransmitter receptor called metabotropic glutamate receptor 5 (mGluR5). FMRP normally regulates this protein synthesis. When FMRP is lost, mGluR5-stimulated protein synthesis becomes overactive, and this can account for many of the varied symptoms seen in Fragile X.

In studies of mice, Bear and others have found that compounds that inhibit the mGluR5 receptor could reverse most of the symptoms of Fragile X. However, none of the mGluR5 inhibitors that have been tested in clinical trials have succeeded.

In the meantime, the MIT team, along with many other research groups, has been searching for other molecules that could be targeted to treat Fragile X.

"We and many other labs have been chipping away at this and trying to understand the key molecular players. There's quite a large number now, and there have been different manipulations in the signaling pathway that can correct Fragile X phenotypes in animals," Bear says. "We like to refer to this as a target-rich environment. If at first you don't succeed therapeutically, you have many other shots on goal."

Some studies suggested that GSK3 was overactive in Fragile X mouse models and that this activity could be turned down using lithium. However, the required dosage of lithium has adverse side effects in children. Pharmaceutical companies developed other small-molecule drugs that inhibit GSK3, but these triggered an accumulation of a protein called beta-catenin, which can lead to cancerous cell proliferation.

The GSK3 enzyme comes in two forms, alpha and beta, so Wagner, along with Edward Holson, former director of medicinal chemistry at the Stanley Center, and Edward Scolnick, chief scientist emeritus at the Stanley Center, set out to develop drugs that would inhibit either one or the other.

"Studies had been published showing that if you selectively knock out either alpha or beta, it wouldn't trigger beta-catenin accumulation," Wagner says. "GSK3 inhibitors had been tested in Fragile X models before, but it's never gone anywhere because of the toxicity issue."

After a screen of more than 400,000 drug compounds, Wagner identified a handful that inhibited both forms of GSK3. By slightly altering their structures, she then came up with versions that could target selectively the alpha or beta forms.

Bear's lab tested the selective inhibitors in genetically engineered mice that lack the FMRP protein, and found that the inhibitor specific to GSK3 alpha eliminated one of the common Fragile X symptoms -- seizures induced by loud tones. Following that, they found that the GSK3 alpha inhibitor also successfully reversed several other symptoms of Fragile X, while the GSK3 beta inhibitor did not.

These symptoms include overproduction of protein as well as altered synaptic plasticity, impairment of some types of learning and memory, and hyperexcitability of some neurons.

"It checked off all the boxes that we would have expected from inhibiting mGluR5 or the signaling pathway downstream," Bear says. "It's really amazing that if you can correct the excess protein synthesis with a drug compound, a dozen other phenotypes are going to be corrected."

Exploring side effects

GSK3 is a kinase, which means that it controls other proteins by adding chemical groups called phosphates to them, but its exact role in Fragile X is not yet known. In this study, the researchers found that GSK3 is part of the same signaling pathway controlled by mGluR5, but GSK3 appears to act later in the pathway.

The initial findings in mice suggest that GSK3 alpha inhibitors do not have some of the complications that may have caused the mGluR5 inhibitors to fail in clinical trials, Bear says. In those trials, mGluR5 inhibitors were found to cause hallucinations in some people, which limits the dose that can be given. (In mice, hallucinations cannot be directly measured, but there are techniques for indirectly testing hallucinogenic potential.) Mouse studies of mGluR5 inhibitors did show that potential for causing hallucination, but studies of GSK3 alpha inhibitors have not shown it.

Another side effect seen in mouse studies of mGluR5 inhibitors is the development of resistance to long-term treatment, for some of the symptoms of the disorder.

"We don't know whether the mGluR trials failed because of treatment resistance, but it's a viable hypothesis," Bear says. "What we do know is with the GSK3 alpha inhibitor, we do not see that in mice, to the extent that we've looked at it."

GSK3 inhibitors may also hold promise for treating other diseases in which GSK3 plays a role. In a Science Translational Medicine study published last year, also co-authored by Wagner, researchers at the Broad Institute and Dana-Farber Cancer Institute showed that selective GSK3 inhibitors could be effective against acute myeloid leukemia.

GSK3 could also be a potential target for Alzheimer's treatment, as it is responsible for phosphorylating Tau, a protein that forms tangles in the brains of Alzheimer's patients.

What The Study Did: Researchers looked at whether patients with nonfatal intentional opioid overdoses would be more likely to die by suicide than patients with unintentional overdoses with an analysis of deaths following nonfatal opioid overdoses of intentional, unintentional and undetermined intent in California from 2009 to 2011.

Authors: Mark Olfson, M.D., M.P.H., of Columbia University in New York, 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.2020.1045)

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