Culture

Maximizing the protection of life on Earth requires knowledge of the global patterns of biodiversity at multiple dimensions, from genetic diversity within species, to species and ecosystem diversity. Yet, the lack of genetic sequences with geographic information at global scale has so far hindered our ability to map genetic diversity, an important, but hard to detect, biodiversity dimension.

In a new study, researchers from the Universities of Copenhagen and Adelaide have collected and georeferenced a massive amount of genetic data for terrestrial mammals and evaluated long-standing theories that could explain the global distribution of genetic diversity. They found that regions of the world rich in deep evolutionary history, such as Northern Andes, the Eastern Arc Mountains, Amazonia, the Brazilian Atlantic forest, the central America jungles, sub-Saharan Africa and south-eastern Asia are also strongholds of genetic diversity. They also show that the relatively stable climate in these regions during the past 21'000 years contributes significantly to this intraspecific richness.

"Genetic diversity within species is a critical component of biodiversity, playing two important roles at the same time. It reflects species evolutionary history and defines their capacity to adapt under future environmental change. However, and despite the predictions of major biodiversity theories, the actual global distribution of genetic diversity remained, so far, a mystery. Recent collective efforts to populate public databases with genetic sequences and their localities allowed us to evaluate these theories and generate the first global maps of genetic diversity in terrestrial mammal assemblages", says Spyros Theodoridis, Postdoctoral Researcher at the Center for Macroecology, Evolution and Climate, GLOBE Institute, and lead author of the study.

"The tropics, and more specifically tropical mountain regions, host large amounts of the global pool of genetic diversity. These arks of biodiversity are under a high pressure today due to climate and land-use change. The conservation of genetic diversity in these areas should be a priority in on-going conservation efforts", says David Nogues-Bravo, the senior author of the study and Associate Professor at the University of Copenhagen.

The study also evaluated the effects of climate change during the last 21'000 years in shaping current patterns of genetic diversity. Regions of the world that experienced less severe change in temperature and precipitation harbor higher levels of genetic diversity, potentially due to reduced population extinctions. It also suggests that past inter-annual precipitation variability contributes to higher genetic diversity possibly through population adaptive divergence.

"While we show that areas of high genetic diversity tend to occur in regions where climates have remained relatively unchanged during past periods of global-scale climate change, many of these regions are forecast to experience major climate disturbances in the near future. Unfortunately, this is likely to lead to a loss of genetic diversity in many biodiversity hotspots", says Damien Fordham, Associate Professor at The University of Adelaide's Environment Institute and a coauthor of the study.

"The identified correlations of genetic diversity with evolutionary history and past climate change allowed us to develop predictive models at global scale, particularly in regions that lack sufficient data, such as the tropics. These predictions constitute a first step towards filling major gaps of knowledge for genetic diversity, and can inform and be further validated by field-work campaigns in data-poor regions of the Earth", says Carsten Rahbek, head of the Center for Macroecology, Evolution and Climate.

Russian researchers from HSE University and Open University for the Humanities and Economics have demonstrated that artificial intelligence is able to infer people's personality from 'selfie' photographs better than human raters do. Conscientiousness emerged to be more easily recognizable than the other four traits. Personality predictions based on female faces appeared to be more reliable than those for male faces. The technology can be used to find the 'best matches' in customer service, dating or online tutoring.

The article 'Assessing the Big Five personality traits using real-life static facial images' will be published on May 22 in Scientific Reports.

Physiognomists from Ancient Greece to Cesare Lombroso have tried to link facial appearance to personality, but the majority of their ideas failed to withstand the scrutiny by modern science. The few established associations of specific facial features, such as facial width-to-height ratio, with personality traits are quite weak. Studies asking human raters to make personality judgments based on photographs have produced inconsistent results, suggesting that our judgments are too unreliable to be of any practical importance.

Nevertheless, there are strong theoretical and evolutionary arguments to suggest that some information about personality characteristics, particularly, those essential for social communication, might be conveyed by the human face. After all, face and behaviour are both shaped by genes and hormones, and social experiences resulting from one's appearance may affect one's personality development. However, the recent evidence from neuroscience suggests that instead of looking at specific facial features, the human brain processes images of faces in a holistic manner.

Researchers from two Moscow universities, HSE University (Higher School of Economics) and Open University for the Humanities and Economics, have teamed up with a Russian-British business start-up BestFitMe to train a cascade of artificial neural networks to make reliable personality judgments based on photographs of human faces. The performance of the resulting model was above that discovered in previous studies which used machine learning or human raters. The artificial intelligence was able to make above-chance judgments about conscientiousness, neuroticism, extraversion, agreeableness, and openness based on 'selfies' the volunteers uploaded online. The resulting personality judgments were consistent across different photographs of the same individuals.

The study was done in a sample of 12 thousand volunteers who completed a self-report questionnaire measuring personality traits based on the "Big Five" model and uploaded a total of 31 thousand 'selfies'. The respondents were randomly split into a training and a test group. A series of neural networks were used to preprocess the images to ensure consistent quality and characteristics, and exclude faces with emotional expressions, as well as pictures of celebrities and cats. Next, an image classification neural network was trained to decompose each image into 128 invariant features, followed by a multi-layer perceptron that used image invariants to predict personality traits.

The average effect size of r = .24 indicates that AI can make a correct guess about the relative standing of two randomly chosen individuals on a personality dimension in 58% of cases as opposed to the 50% expected by chance. In comparison with the meta-analytic estimates of correlations between self-reported and observer ratings of personality traits, this indicates that an artificial neural network relying on static facial images outperforms an average human rater who meets the target in person without prior acquaintance. Conscientiousness emerged to be more easily recognizable than the other four traits. Personality predictions based on female faces appeared to be more reliable than those for male faces.

There are a vast number of potential applications to be explored. The recognition of personality from real-life photos can complement the traditional approaches to personality assessment in situations where high speed and low cost are more important than high accuracy. Artificial intelligence can be used to propose products that are the best fit for the customer's personality or to select the possible 'best matches' for individuals in dyadic interactions, such as customer service, dating or online tutoring.

Meiosis is essential to sexual reproduction. For almost 15 years, it has been commonly held that retinoic acid, a molecule derived from vitamin A, triggers meiosis in mammalian germ cells. Yet, in joint articles published in Science Advances ( 22 May 2020 ), french researchers from the Institut de Biologie Valrose (CNRS / INSERM / Université Côte d'Azur) and the IGBMC (CNRS / INSERM / University of Strasbourg), with their colleagues, demonstrate that meiosis in mice begins and proceeds normally even in the absence of retinoic acid. These findings set the stage for new research in the field of reproductive biology.

Meiosis is an essential process that results in novel assortments of chromosomes for the transmission of unique sets of genes to offspring. Beginning with a diploid[1] germ cell (an oogonium in females or a spermatogonium in males), it yields haploid[2] gametes (oocytes in females or spermatozoa in males). The union of an oocyte and a spermatozoon combines both parental haploid genomes in a single diploid cell destined to give rise to an embryo, marking the start of the next generation.

In mammals, cells found in developing gonads (ovaries in females or testes in males) provide germ cells with structural support, nourishment, and protection. They also emit molecular signals that determine what will become of the germ cells. One of the signalling molecules is retinoic acid, widely thought to trigger germ cell meiosis. Despite the 2011 publication of findings casting doubt on this assumption, the idea that retinoic acid is a switch for meiosis has risen to the status of dogma.

Together with colleagues,[3] scientists from the Institut de Biologie Valrose in Nice and the IGBMC in Strasbourg conducted two complementary studies of the mouse foetal ovary to clarify the role of this molecule, by (i) inhibiting its synthesis and (ii) removing its receptors. Neither approach prevented normal initiation of meiosis in germ cells. Furthermore, viable infant mice were born after fertilization of oocytes lacking retinoic acid receptors, proving that these cells are functionally intact.

These twin studies therefore refute the dogma of a retinoic acid trigger for meiosis in germ cells, ending a debate that has lasted nearly a decade and a half. By dismissing a long-held tenet, these findings invite the scientific community to reconsider its working assumptions and investigate new leads in the search for the real signals controlling initiation of germ cell meiosis.

Organisms carry long-term "memories" of their ancestral homelands that help them adapt to environmental change, according to a new study that involved raising chickens on the Tibetan Plateau and an adjacent lowland site.

The study provides new insights into how creatures adapt to changing environments, a topic that's especially relevant today in the context of rapid climate change, which is creating challenges for plants and animals worldwide.

The chicken was domesticated from the red jungle fowl in South Asia and Southeast Asia at least 4,000 to 4,500 years ago. It was brought to the Tibetan Plateau by about 1,200 years ago, where it acquired high-altitude adaptations such as an increase in oxygen-carrying red blood cells.

In a set of experiments by University of Michigan biologists and their Chinese colleagues, researchers hatched and reared hundreds of chickens on the Tibetan Plateau, at an elevation of nearly 11,000 feet, and at an adjacent lowland site in China's Sichuan Province. Some of the eggs from lowland chickens were hatched on the plateau, and some high-altitude eggs were hatched at a site 2,200 feet above sea level.

The goal was to assess the relative contributions of two types of phenotypic change--meaning changes to an organism's observable physical characteristics or traits--to the process of environmental adaptation. "Plastic" phenotypic changes involve altered gene activity but no rewriting of the genetic code in DNA molecules, while mutations cause altered gene activity by modifying the sequence of letters in the code itself.

Evolutionary biologists have debated the relative roles of plastic and mutation-induced changes in adaptation, and whether the former serve as stepping stones to the latter.

In the chicken study, researchers were specifically interested in how organisms readapt when reintroduced to ancestral environments. They found that plastic changes play a more prominent role when organisms return to an ancestral home than when they adapt to new environments.

"These findings reveal a mechanism by which past experience affects future evolution," said Jianzhi Zhang, the study's senior author and a professor in the U-M Department of Ecology and Evolutionary Biology.

"Our findings contribute to the recent debate on the relative roles of plastic and genetic changes in adaptation and reveal the importance of considering whether the environment is changing to a novel or ancestral one."

The findings are scheduled for publication May 22 in the journal Science Advances.

To study the relative roles of plastic and DNA-sequence changes, the researchers looked at gene-expression differences between lowland and Tibetan chickens in five tissue types: brain, liver, lung, heart and muscle. To do that, they analyzed RNA transcriptomes from cells in those tissues.

The genome is made of DNA that contains the instructions needed to build an organism. For those instructions to be carried out, DNA must be read and transcribed into messenger RNA molecules.

By analyzing the entire collection of RNA sequences in a cell, known as the transcriptome, researchers can determine when and where genes are turned on and off. Gene-expression studies provide snapshots of actively expressed genes under various conditions.

Changes in gene activity alter an organism's phenotype, which includes its morphology, behavior and physiology. The term phenotypic plasticity refers to environmentally induced phenotypic changes that do not involve genetic mutations.

In the chicken study, the researchers found that while many mutation-induced phenotypic changes were necessary when the animals first adapted to the Tibetan Plateau, plastic changes largely transformed the transcriptomes to the preferred state when Tibetan chickens were brought back to the lowland.

A similar result was seen with egg "hatchability," the fraction of fertilized chicken eggs that hatched in the study.

When lowland eggs were incubated on the unfamiliar Tibetan Plateau, hatchability was significantly lower than that of Tibetan chicken eggs. But when Tibetan eggs were incubated in the lowland--an environment familiar from the distant past--there was no significant difference in hatchability between the two groups.

The egg result suggests that adaptive mutational changes are needed when an organism is brought to an unfamiliar environment for the first time, while plastic changes will do the trick when those same creatures return to an ancestral home.

Zhang's team also analyzed transcriptomes from previous studies of guppies and E. coli bacteria and found comparable results--regardless of whether the new environment was more stressful or less stressful than the ancestral environment.

"In summary, our work uncovers a phenomenon conserved from bacteria to vertebrates that organisms remember their ancestral environments in the form of phenotypic plasticity," the authors wrote.

Bottom Line: Patients with metastatic pancreatic cancer who had germline or somatic mutations in DNA repair genes had better clinical outcomes after platinum-based chemotherapy, as compared with patients without these mutations.

Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research

Authors: The senior author was Eileen O'Reilly, MD, medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC). The lead author was Wungki Park, MD, medical oncologist at MSKCC.

Background: Metastatic pancreatic cancer is associated with a challenging prognosis with a relative five-year survival rate of 2.9 percent. The current standard of care for metastatic pancreatic cancer includes platinum-based chemotherapy. "Unfortunately, there are no validated biomarkers to predict which patients might benefit from standard treatment," said O'Reilly.

Biomarkers are biological features, such as DNA mutations, that can be used to predict prognosis or response to treatment. DNA mutations may be found in one or both copies of the gene. Furthermore, mutations may be germline mutations, which are inherited and are found in every cell of the body, or they may be somatic, which arise after conception and are not found in every cell.

Approximately 5 to 9 percent of patients with pancreatic cancer have germline or somatic mutations in the BRCA1, BRCA2, and/or PALB2 genes, according to O'Reilly. The proteins encoded by these genes are involved in a form of DNA repair known as homologous recombination (HR). Results from recent clinical trials showed that patients with germline mutations in BRCA1, BRCA2, and/or PALB2 had clinical responses to platinum-based chemotherapy or the PARP inhibitor olaparib (Lynparza).

"These studies demonstrate that germline mutations in BRCA1, BRCA2, or PALB2 are valuable biomarkers to predict response to treatment," said Park. "This led us to ask whether the benefit was limited to germline mutations only, or whether somatic mutations in these genes or mutations in other HR genes are also associated with responses to platinum-based chemotherapy."

How the Study was Conducted: In this study, Park, O'Reilly, and colleagues analyzed the association between mutations in HR genes and clinical outcome. The study included 262 patients with metastatic pancreatic cancer, who underwent both germline and somatic sequencing using the MSK-IMPACT sequencing test. The researchers analyzed 17 HR genes included in both the somatic and germline panels of the MSK-IMPACT gene set. Analysis of sequencing data allowed the researchers to determine whether mutations were germline or somatic, in core HR genes (BRCA1, BRCA2, or PALB2) or in noncore HR genes (such as ATM, CHEK2, BAP1, RAD51, FANCA, and 9 others), and in one or both copies of each gene.

Results: Out of 262 patients, 50 patients had mutations in HR genes; 40 patients had germline mutations, and 10 had somatic mutations. Thirty-one patients had mutations in core genes, while 19 patients had mutations in noncore genes. Twenty-nine patients had mutations in both copies of a gene, and 21 patients had mutations in only one gene copy.

The median overall survival for the entire cohort of 262 patients was 15.5 months. Overall survival was similar between patients with germline mutations and those with somatic mutations. Thus, these subgroups were combined in the ensuing analyses.

The authors found that for the 35 patients who were treated with first-line platinum-based chemotherapy, those with mutations in HR genes had greater overall survival compared with those without mutations in these genes (25.1 months vs. 15.3 months), suggesting that mutations in HR genes may be associated with enhanced overall survival. Furthermore, patients with HR mutations had a 44 percent lower risk of disease progression than patients without these mutations after first-line treatment with platinum-based chemotherapy. The lower risk of disease progression was observed regardless of whether the mutations were in core or noncore HR genes.

Among patients with mutations in HR genes, those who were treated with platinum-based chemotherapy had higher progression-free survival (PFS) than those who received non-platinum treatment (12.6 months vs. 4.4 months). For the patients with mutations in both gene copies, those who were treated with platinum-based chemotherapy had greater PFS than those treated with other therapies (13.3 months vs. 3.8 months). This association was not observed for patients with mutations in only one gene copy, suggesting that platinum-based chemotherapy may provide a greater clinical benefit in patients with mutations in both copies of HR genes.

Author's Comments: "Our data support the use of platinum-based chemotherapy as first-line treatment for patients with defects in various HR genes," said O'Reilly. "The results underscore the importance of genetic testing in newly diagnosed patients to help refine treatment decisions."

"HR deficiency defined by pathogenic mutation of core HR genes and loss of both copies of either core or noncore HR genes confers the greatest platinum sensitivity," said Park. "Patients with these deficiencies represent the optimal subgroup for therapies that target DNA repair pathways, such as platinum-based chemotherapy." He noted that these deficiencies could also be predictive of response to other targeted developmental therapeutics in DNA repair pathways, to other PARP inhibitors, and to immunotherapy, although additional research into these will be needed.

"Identifying factors associated with treatment response may also help us understand why some patients' tumors do not respond to treatment and why some that respond ultimately develop resistance," Park added.

Study Limitations: A limitation of the study is that the analysis was performed on a highly selected group of patients and therefore may not represent all patients with pancreatic cancer. "While the data are very compelling, we need to validate the results prospectively in wider and larger datasets," noted O'Reilly.

Additional challenges included low sample purity, limited tissue availability, and other technical limitations.

A team of researchers from the University of Southampton, the University of Bath and King's College London, have provided compelling evidence of the impact of adversity in childhood on neuropsychological functioning in adulthood. They also showed that neuropsychological difficulties may explain why early adversity is linked to attention deficit hyperactivity disorder (ADHD) in later life.

Their study, published in the journal Psychological Medicine, analysed neuropsychological function in 70 young adults who were exposed to severely depriving conditions in Romanian orphanages during Nicolae Ceausescu's regime and subsequently adopted by British families. The adoptees were compared to 22 British adoptees of similar ages who had not suffered childhood deprivation.

As part of the research, the adoptees were asked to carry out tests to assess their neuropsychological functioning in five areas: controlling their responses (inhibitory control), prospective memory, decision-making, emotional recognition and cognitive ability (IQ). Prospective memory is the ability to remember to do something in the future, such as remembering to go to an appointment or what you need to buy if you don't have a shopping list. ADHD and autism spectrum disorder (ASD) symptoms were assessed through questionnaires completed by their parents.

The results showed that the Romanian adoptees had lower IQs and performed less well on the other four tests when compared to the adoptees who had not suffered deprivation. The adoptees with the lowest IQs and the greatest problems in prospective memory were more likely to show ADHD symptoms in adulthood than those without neuropsychological difficulties. The researchers found no direct link between ASD symptoms and neuropsychological performance.

The latest research is part of the wider English and Romanian Adoptees study, a collaborative study between the University of Southampton and King's College London which began shortly after the fall of the communist regime in Romania.

Children living in the institutions were subjected to extremely poor hygiene, insufficient food, little affection and no social or cognitive stimulation. The study analyses the mental health and brain development of 165 children who spent time in Romanian institutions and who were adopted by families in the UK when aged between two weeks and 43 months.

The principal investigator of the study is Professor Edmund Sonuga-Barke, who began the study whilst working at the University of Southampton and is now based at the Institute of Psychiatry, Psychology & Neuroscience at King's College London.

Speaking of the latest research, Professor Sonuga-Barke said: "This study contributes to our changing understanding of the power of the early environment to shape brain development -showing that the effects of institutional deprivation on cognition can still be seen after more than twenty years of positive experience in high functioning and loving adoptive families leads us to acknowledge that there are limits to the brain's recuperative powers."

Dr Dennis Golm, Lecturer in Psychology at the University of Southampton, said: "The study highlights that institutional deprivation can have long-lasting effects on a range of neuropsychological functions that are important in everyday life, such as memory and general intellectual ability. Our findings also emphasise the importance of improving the quality of care for children in institutions."

DURHAM, N.C. -- Much like people, fruit flies must decide when the time and place are right to make a move on a mate. Male fruit flies use cues such as age and pheromones to gauge their chances of success, but just how they do that on a molecular level was a mystery.

New research suggests that the answer lies, in part, in their DNA. A new study finds that the scent of other flies, coupled with signals from a male's internal hormones, alter the activity of a gene that controls how turned on he is by pheromones when he reaches maturity.

A female fruit fly's outer shell -- her "cuticle" -- gives off waxy-smelling molecules that act as aphrodisiacs. Normal male fruit flies follow a female around to get a whiff before deciding to pursue her further.

But previous studies found that males raised alone, deprived of the odor of other flies, can't pick up the scent as well when they reach adulthood. Scent-deprived males show less interest in females, and are more likely to lose a girl to another guy.

It makes sense because growing up alone could signal that future mating options may be slim -- why put in the effort? On the other hand, males raised in groups respond more strongly to pheromones than their socially isolated counterparts, presumably because they may face stiff competition later on, and must step up their game with the ladies.

In the new study, published May 22 in Science Advances, researchers have figured out how males dial their scent sensitivity up or down to court when conditions are right for mating.

Fruit flies don't have noses to smell with -- they use their antennae. There, olfactory neurons detect odor molecules wafting past and send the information to the brain.

Duke University biologist Pelin Volkan and colleagues raised some male fruit flies in groups, and isolated others in separate vials.

The researchers found that when a male grows up in a group, around the odors of other flies, a "courtship" gene called fruitless is switched on in his olfactory neurons as he ages. This makes him better at detecting the scent of other flies and more likely to outcompete rival males for mates.

A key trigger for this activity is the loosening of a coiled material called chromatin that controls access to the fruitless gene's "on" switch.

In contrast, social isolation keeps this region of chromatin packed so tightly that the gene can't be read off by the cell.

The researchers also found that the effects were reversible. When they wafted pheromone by the socially isolated males, or transferred them to vials with other flies, the chromatin unwound and returned the fruitless gene to its "open for business" state.

"People always ask: how does this relate to human sexuality?" Volkan said.

The connection between what happens in fruit flies and sexual behavior in humans isn't clear-cut, Volkan said. Humans don't have a fruitless gene, for one. And the chain of causation from genes and hormones to behavior is much more complex. But by understanding the epigenetic changes that allow organisms to selectively tune into sensory input, or block it out, researchers say the work could point to new ways to treat people with autism and other sensory processing disorders.

Astronomers using the Atacama Large Millimeter/submillimeter Array (ALMA) found quasi-periodic flickers in millimeter-waves from the center of the Milky Way, Sagittarius (Sgr) A*. The team interpreted these blinks to be due to the rotation of radio spots circling the supermassive black hole with an orbit radius smaller than that of Mercury. This is an interesting clue to investigate space-time with extreme gravity.

"It has been known that Sgr A* sometimes flares up in millimeter wavelength," tells Yuhei Iwata, the lead author of the paper published in the Astrophysical Journal Letters and a graduate student at Keio University, Japan. "This time, using ALMA, we obtained high-quality data of radio-wave intensity variation of Sgr A* for 10 days, 70 minutes per day. Then we found two trends: quasi-periodic variations with a typical time scale of 30 minutes and hour-long slow variations."

Astronomers presume that a supermassive black hole with a mass of 4 million suns is located at the center of Sgr A*. Flares of Sgr A* have been observed not only in millimeter wavelength, but also in infrared light and X-ray. However, the variations detected with ALMA are much smaller than the ones previously detected, and it is possible that these levels of small variations always occur in Sgr A*.

The black hole itself does not produce any kind of emission. The source of the emission is the scorching gaseous disk around the black hole. The gas around the black hole does not go straight to the gravitational well, but it rotates around the black hole to form an accretion disk.

The team focused on short timescale variations and found that the variation period of 30 minutes is comparable to the orbital period of the innermost edge of the accretion disk with the radius of 0.2 astronomical units (1 astronomical unit corresponds to the distance between the Earth and the Sun: 150 million kilometers). For comparison, Mercury, the solar system's innermost planet, circles around the Sun at a distance of 0.4 astronomical units. Considering the colossal mass at the center of the black hole, its gravity effect is also extreme in the accretion disk.

"This emission could be related with some exotic phenomena occurring at the very vicinity of the supermassive black hole," says Tomoharu Oka, a professor at Keio University.

Their scenario is as follows. Hot spots are sporadically formed in the disk and circle around the black hole, emitting strong millimeter waves. According to Einstein's special relativity theory, the emission is largely amplified when the source is moving toward the observer with a speed comparable to that of light. The rotation speed of the inner edge of the accretion disk is quite large, so this extraordinary effect arises. The astronomers believe that this is the origin of the short-term variation of the millimeter emission from Sgr A*.

The team supposes that the variation might affect the effort to make an image of the supermassive black hole with the Event Horizon Telescope. "In general, the faster the movement is, the more difficult it is to take a photo of the object," says Oka. "Instead, the variation of the emission itself provides compelling insight for the gas motion. We may witness the very moment of gas absorption by the black hole with a long-term monitoring campaign with ALMA." The researchers aim to draw out independent information to understand the mystifying environment around the supermassive black hole.

If we took a journey from Earth's surface to the center, the midway point locates roughly at 1900 km depth in the lower mantle. The lower mantle ranges from 660 to 2900 km depth and occupies 55% of our planet by volume. The chemical composition of the lower mantle is rather simple. It has long been pictured as being made up of 2 major minerals (~95%), namely bridgmanite and ferropericlase. Until recently, this model is directly challenged by a set of discoveries in the lower mantle.

"One of the major lower mantle compositions, ferropericlase (Mg,Fe)O, turns into a pyrite-type structure upon meeting water. This intriguing chemical reaction only occurs at Earth's deep lower mantle which is defined in depths between 1900 and 2900 km" said Qingyang Hu from HPSTAR. "The reaction produces so-called oxygen excessive phases, or simply superoxides. The lower mantle is oxidized in the presence of water." Generally, when all the oxygen atoms in a compound are bonded with metal atoms, they are called oxides. However, if a compound has paired oxygen atoms, like oxygen-oxygen bonding, it becomes a superoxide. Although superoxide is rarely found in nature, it might be common in Earth's deep lower mantle.

"We also found that olivine and its high-pressure phase wadsleyite, the dominating minerals in the upper mantle, decompose to generate superoxides when subducting down into the deep mantle with water." added by Jin Liu from at HPSTAR. Few approaches are available for scientists to probe into the lower mantle mineralogy given its depth. "Our experiments are very challenging. We input appropriate parameters like pressure, temperature, and starting minerals. Then we investigated the outputs including chemical reactions, new mineral assemblages, and their density profiles. Those parameters allow us to better constrain the nature of the lower mantle and its oxidation state." Contrary to the paradigm that the lower mantle is highly reduced, our results indicate that the deep lower mantle is at least locally oxidized wherever water is present.

The team members proceeded with minerals existing on Earth's surface, by squeezing them between two pieces of diamond anvils to generate about 100,000,000 times the atmospheric pressure at sea level, heating them up using infrared laser, before analyzing the samples using a battery of x-ray and electron probes. The experiments have mimicked the extreme pressure-temperatures conditions found in Earth's deep lower mantle.

Previous experiments explored a dry mineral assembly in the absence of water. Those experiments reported that bridgmanite (and/or post-bridgmanite) and ferropericlase are the most abundant and stable minerals throughout the lower mantle. However, when water is introduced, ferropericlase would be partially oxidized to superoxide under the deep lower mantle conditions. The superoxide is verified to stay in harmony with bridgmanite and post-bridgmanite.

This new water-mantle chemistry can be closely linked to the water cycling in the solid Earth. Every year, billions of tons of ocean water falls into the deep Earth at tectonic plate boundaries. While some water returns via underwater volcanoes and hot vents, others goes deep into the Earth's interiors. "Our experiments indicate the deep water is an essential part of mantle chemistry. The water cycling can extend to the deep lower mantle where water has extraordinary oxidation power, producing highly oxidized superoxide and releasing hydrogen." suggested by Dr. Ho-kwang Mao from HPSTAR. "The lower mantle can be oxidized and reduced at the same time."

Lugano, Switzerland, 22 May 2020 - Cancer-related fatigue is a prevalent and potentially persistent issue among breast cancer survivors, which can prevent them from returning to their previous life well after treatment ends and they are declared free of disease. A study, to be presented at the ESMO Breast Cancer Virtual Meeting 2020 (23-24 May), has now shown that existing recommendations and proven strategies for reducing fatigue, which can have physical, emotional as well as cognitive dimensions, may not be sufficiently adhered to by early breast cancer patients. (1)

Explaining the background to the analysis, study author Dr. Antonio Di Meglio of Gustave Roussy in Villejuif, France, stated: "Cancer-related fatigue is an issue that many patients complain about in the clinic, sometimes for years after the completion of treatment. Although there is a lot that we still don't know about the different mechanisms underpinning fatigue, we now have specific, evidence-based recommendations for treating it: the first is to initiate or maintain adequate levels of physical activity and limit sedentary time as much as possible. Data also supports the use of psychosocial interventions such as cognitive behavioural therapy, which can help address maladaptive thoughts like over-dramatising or feelings of helplessness. Our aim with this study was to assess the real-world uptake of these recommendations."

To do this, the research team drew on data from the CANTO cohort study, (2) which assessed long-term toxicities in early breast cancer patients from 26 French cancer centres for at least five years from the time of diagnosis. According to Di Meglio, "CANTO is unique in the field of survivorship research, as it enrolled over 10,000 breast cancer patients nationwide, of which we were able to include more than 7,000 in our analysis. The wealth of clinical, patient-reported and biological data collected makes it an ideal database to answer a lot of questions about cancer-related fatigue." Di Meglio and his colleagues included in their analysis only women who had completed primary treatment and were free of disease, and examined patients' reported utilisation of recommended strategies to treat fatigue over 12 months after a baseline assessment.

Uptake of physical activity recommendations hindered by severe fatigue

"These are patients who were free of disease and whom we would expect to return to their pre-cancer state within six to 12 months after the end of treatment. What we found, however, was that over a third of patients (36%) reported fatigue that we classify as severe at three to six months after treatment," Di Meglio reported. "A majority of study participants (64%) complied with physical activity recommendations in the year that followed, but that still leaves a concerning proportion of women (36%) who were not sufficiently active or completely inactive during this period."

The results additionally showed that patients who reported severe levels of fatigue at baseline were less likely than those with non-severe symptoms to adhere to recommendations of physical activity (60% versus 67%) in the year following the assessment. "The message here is that we need to work harder to encourage patients to stay active, and to make them understand that even if it seems counter-intuitive, it is exercise, not rest, that will help them to overcome fatigue," said Di Meglio.

Supportive care underutilised across the board, with differences observed by fatigue domain

The analysis further brought to light that overall reported utilisation of supportive care was low in this patient population, with only one out of 10 women consulting a psychologist, one out of 12 seeing an acupuncturist and one out of 14 seeking help from a homeopath. "The striking fact here is that patients seem to be using strategies that we have robust evidence for and can refer them to, like psychotherapy, at roughly the same rates as approaches for which we do not have sufficient efficacy data and therefore cannot recommend, like homeopathy," Di Meglio observed. "This suggests that patients may not be sufficiently aware of what the recommendations are, and that we as oncologists need to ensure they are educated about the options at their disposal to reduce fatigue. Better education may also help to diminish the fears and stigma that are still too often associated with psychosocial interventions."

Patients' physical activity uptake and utilisation of supportive care were additionally evaluated for different dimensions of fatigue, revealing differences in women's behaviour depending on whether their fatigue was more physical, cognitive or emotional in nature. "Most notably, we found that patients with severe physical fatigue were less likely to adhere to physical activity recommendations, at 59% compared to 67% of those with non-severe physical fatigue, while high levels of emotional fatigue were more strongly linked to utilisation of psychological consultations, at 17% compared to 8% of non-severe patients in this domain," Di Meglio reported.

He continued: "We also expected women experiencing severe overall fatigue to rely much more heavily on supportive care measures, but in fact they were only 1.3 times more likely to seek out the help of a psychologist, for example, than patients with non-severe fatigue. This may be explained in part by the fact that psychosocial interventions in this context usually come with out-of-pocket costs for patients. That is something our findings may contribute to changing in the future - especially considering that untreated cancer-related fatigue can have long-term social and financial consequences for survivors, some of whom we know never return to their previous life."

Prof. Gabriella Pravettoni, Director of the Psycho-Oncology Division at the European Institute of Oncology (IEO) in Milan, Italy, commented on the findings: "The fact that the strategies patients adopt to manage side-effects are strongly correlated to the type of fatigue they are suffering from is particularly interesting, because patients experiencing significant physical fatigue, for example, may actually benefit substantially from seeing a psychologist. We know that physical activity is proven to reduce cancer-related fatigue, but on its own it does not guarantee the inner healing of the individual."

Pravettoni continued: "By focusing too much on physical activity as the primary remedy for cancer-related fatigue, we are omitting the importance of working on patients' motivation and resilience to help them maintain that activity level and recover fully in the long term. If we leave these women without psychological support, other interventions are almost certain to be less effective as a result. What is truly needed is a 360-degree approach whereby healthcare professionals make therapeutic recommendations in line with patients' unique characteristics and needs. This is all the more important in the context of the current health emergency, which can cause patients to experience strong negative emotions like fear and uncertainty and add to their existing psychological burden from potentially traumatic experiences related to their cancer diagnosis and treatment."

Age, male sex, obesity, and underlying illness have emerged as risk factors for severe covid-19 or death in the UK, according to the largest cohort study to date published by The BMJ today.

The risk of death increases in the over 50s, as does being being male, obese, or having underlying heart, lung, liver and kidney disease.

As the largest prospective observational study reported worldwide to date, it provides a comprehensive picture of the characteristics of patients hospitalised in the UK with covid-19 and their outcomes.

Because the study is ongoing, it has now recruited over 43,000 patients. The findings will help health professionals learn more about how the illness progresses and enable us to compare the UK with other countries, say the researchers.

Studies in China have reported risk factors associated with severe covid-19, but studies describing the features and outcomes of patients with severe covid-19 who have been admitted to hospital in Europe are lacking.

To address this knowledge gap, a team of UK researchers analysed data from 20,133 patients with covid-19 admitted to 208 acute care hospitals in England, Wales, and Scotland between 6 February and 19 April 2020.

This represents around a third of all patients admitted to hospital with covid-19 in the UK. The average age of patients in the study was 73 years, and more men (12,068; 60%) were admitted to hospital than women (8,065; 40%).

Besides increasing age, and underlying heart, lung, liver and kidney disease - factors already known to cause poor outcomes - the researchers found that obesity and gender were key factors associated with the need for higher levels of care and higher risk of death in hospital.

At the time of publication, just over a quarter (26%) of all covid-19 patients in hospital had died, 54% were discharged alive, and a third (34%) remained in hospital. Outcomes were poorer for those requiring mechanical ventilation: 37% had died, 17% had been discharged alive, and 46% remained in hospital.

The pattern of disease we describe broadly reflects the pattern reported globally, say the researchers. However, obesity is a major additional risk factor that was not highlighted in data from China. They suspect that reduced lung function or inflammation associated with obesity may play a role.

This is an observational study, so can't establish cause, and the researchers point to some limitations that may have affected their results. Nevertheless, they say this is the largest study of its kind outside of China and clearly shows that severe covid-19 leads to a prolonged hospital stay and a high mortality rate.

"Our study identifies sectors of the population that are at greatest risk of a poor outcome, and shows the importance of forward planning and investment in preparedness studies," they write.

These results have already been shared with the UK Government and World Health Organisation, and are being compared with data from other countries around the world.

At the outset of the covid-19 pandemic, it was natural to focus first on the people with severe disease who might need potentially scarce resources in hospital and intensive care, write US researchers in a linked editorial.

Cohort studies of such patients are important, they say, and this study is a testament to good planning and preparation before, and implementation of data collection during a pandemic.

But they add that if we are going to be managing covid-19 for the next several years, "we need to understand and optimize care before, during, and beyond the hospital."

Lugano, Switzerland, 22 May 2020 - Two novel biomarkers have been found to correlate with improved outcomes with immunotherapy in metastatic breast cancer and may help to identify the patients most likely to benefit from this treatment, according to exploratory studies reported at the ESMO Breast Cancer Virtual Meeting 2020 (1,2). The biomarkers are an increase in the number of programmed death ligand-1 (PDL1/CD274) genes measured by copy number alteration (CNA) and the PD-L1 combined positive score (CPS), which assesses PD-L1 expression on both tumour and immune cells.

"Metastatic breast cancer remains incurable, with many unmet needs and challenges. Triple negative breast cancer has the poorest prognosis among breast cancer subtypes and limited treatment options, mainly involving chemotherapy," said Prof. Sherene Loi, Medical Oncologist and Head of Translational Breast Cancer Genomics and Therapeutics at the Peter MacCallum Cancer Centre, Melbourne, Australia, commenting on the relevance of the new studies. "Immunotherapy has resulted in long durations of disease control and even cures with improved quality of life compared with chemotherapy in other cancers. We are hoping this might also be applicable for some breast cancer patients".

"Previous studies show that not all patients with metastatic breast cancer benefit from immunotherapy. Pre-existing immunity, which can be detected by PD-L1 expression, is required for response to PD-1 or PD-L1 targeting immunotherapy agents. The key question is whether we can identify further patients with metastatic breast cancer that respond to immunotherapy using biomarkers other than just PD-L1 expression."

To explore new potential biomarkers for immunotherapy in advanced breast cancer, researchers assessed the predictive value of copy number alteration (CNA) for the PDL1 gene, which measures whether the gene number has decreased, remained the same (2 copies, one on each chromosome) or increased. (1) They measured CNA values in tumour tissue collected from 126 patients with metastatic breast cancer taking part in the SAFIR-IMMUNO study, the first randomised trial comparing immunotherapy with durvalumab to maintenance chemotherapy in this setting.

"The main predictive markers of immunotherapy efficacy in metastatic breast cancer to date are the absence of hormone receptors and PD-L1 positivity on immune cells," said lead author Prof. Thomas Bachelot, Director of the Breast Cancer Unit, Leon Berard Centre, Lyon, France. But he warned, "Immunohistochemistry analysis of PDL1 expression is not standardised and a more robust predictor of response to immunotherapy is needed."

Results showed that nearly one in four (23.8%) of the patients had copy gain (3 or 4 copies) or amplification (> 4 copies) of the PDL1 gene. Improvement of overall survival with durvalumab was limited to this group, with a median overall survival of 9 months (95% confidence interval [CI] 4-18) in the chemotherapy arm and not reached in the durvalumab arm (hazard ratio 0.17, 95% CI 0.05-0.55).

"This exploratory translational analysis suggested a higher efficacy of durvalumab as maintenance treatment for patients with PDL1 copy gain or amplification," said Bachelot. He suggested: "PDL1 copy number alteration could be an important predictive marker for PD-L1 inhibitor efficacy. If confirmed in larger series, this could have important implications for the development of immunotherapy in patients with metastatic breast cancer, enabling us to better identify patients that are sensitive to PD-L1 inhibitors than current testing for PD-L1 positivity on immune cells."

"At the moment patients with ER-positive breast cancer are not treated with immunotherapy because results of trials were poor. But maybe if we can select the subpopulation that will benefit - the 10% of patients with CNA abnormalities - and show immunotherapy is beneficial for them too, then this would be important," he explained.

Commenting on the potential relevance of the data, Loi said, "The study suggests that PD-L1 amplification may be a predictor for benefit to durvalumab monotherapy, interestingly in all subtypes as well as in triple negative breast cancer." But she cautioned, "It was an unplanned, retrospective analysis so requires further validation in larger studies. There was no analysis presented of whether PD-L1 amplification was associated with overexpression at the protein level, which would be important to understand the underlying biological mechanism of this observation."

Improved health-related quality of life

A second study looked at health-related quality of life (HRQOL) in patients with metastatic triple negative breast cancer randomised to the PD-L1 inhibitor pembrolizumab or chemotherapy in the KEYNOTE-119 trial. (2) Efficacy results for the trial showed no significant difference in overall survival (3) but this analysis described patient reported outcomes for patients by their PD-L1 combined positive score (CPS). CPS is a novel biomarker that assesses PD-L1 expression on both tumour cells and immune cells in contrast to PD-L1 tumour proportion score (TPS), which has been used as a biomarker for immunotherapy in other cancers but fails to take account of immune cell PD-L1 expression. (4)

"The benefit of pembrolizumab versus chemotherapy was observed in nearly all prespecified patient reported outcome endpoints," said lead author Prof. Peter Schmid, Lead of the Centre for Experimental Medicine at Barts Cancer Institute, Queen Mary University of London, UK. "Importantly, time to deterioration score for global health status/QoL scale was longer for patients treated with pembrolizumab compared to those treated with chemotherapy," he reported. The median time to deterioration was 4.3 months for pembrolizumab versus 1.7 months with chemotherapy (hazard ratio 0.70, 95% CI 0.46, 1.05). Scores for symptom scales for fatigue, nausea and vomiting, pain, dyspnoea and loss of appetite all increased with chemotherapy but remained stable or improved slightly with immunotherapy.

"In this CPS-enriched population of patients with metastatic triple negative breast cancer receiving second- and third-line treatments, health-related quality of life was better for patients receiving pembrolizumab than those receiving chemotherapy," said Schmid.

He added: "We are still learning a lot about immunotherapy in metastatic breast cancer. Trials for single agent immunotherapy in the first-line setting have not been positive. But these results clearly show there is a group of patients who do at least as well with single agent immunotherapy as chemotherapy in terms of survival and probably better in terms of quality of life."

Loi commented: "Patients who expressed high levels of PD-L1 protein according to their CPS score had better overall survival with pembrolizumab compared with chemotherapy, and pembrolizumab was far better tolerated than chemotherapy according to HRQOL measures. This underscores the importance of PD-L1 testing in the advanced setting as well as identifying other biomarkers that can help identify those who do best with pembrolizumab monotherapy given its favourable HRQOL impact."

High-entropy alloys (HEAs) are at the frontier of the metal materials community. They are used as alternative materials in the production of high-temperature turbine blades, high-temperature molds and dies, hard coatings on cutting tools or even components of 4th generation nuclear reactors.

By screening proper combinations of HEAs' constituent elements and regulating their proportions, HEAs can exhibit remarkable mechanical properties at high temperatures and display exceptional strength, ductility and fracture toughness at cryogenic temperatures.

Meanwhile, the development of HEAs for 3D printing has also been advancing rapidly, ramping up great potential for the manufacturing of such geometrically complex HEA products with desirable performances.

However, there is a lack of comprehensive understanding on the 3D printing of HEAs. To tackle this issue, researchers from Singapore University of Technology and Design (SUTD), Nanyang Technological University (NTU), Huazhong University of Science and Technology and Hunan University collaborated to publish a thorough review of the recent achievements on 3D printing of HEAs (refer to image). The study was published in Advanced Materials.

The review paper includes the production processes for HEA powders, 3D printing processes for HEA products, and the microstructure, mechanical properties, functionalities and potential applications of the printed products.

"3D printing of HEAs has been undergoing explosive growth in the academia and will gain extensive interest from industry. In our review, laser-based directed energy deposition, selective laser melting and electron beam melting are validated for their applicability to print various high-quality HEA products. It allows for a combination of material selection, design and manufacturing freedoms for lightweight, customizable and non-assembly required products," explained lead author Professor Chua Chee Kai from SUTD.

"The ultrafast cooling rates of certain 3D printing techniques are expected to prevent the formation of undesirable intermetallic compounds in HEA products, thereby enhancing their mechanical properties. The different cooling rates of these printing processes would induce substantial variations in both the microstructures and macroscopic performances of the products," said first author Dr Han Changjun from NTU.

"We believe that this paper serves as a valuable comprehensive review to deepen our understanding of the 3D printing of HEAs by focusing on its unique merits. Hopefully, more researchers would be encouraged to explore this highly interesting field," added corresponding author Associate Professor Zhou Kun from NTU.

Multidisciplinary study of the COVID-19 pandemic and its wide-ranging impact has become an urgent endeavor worldwide. To further and deepen global understanding of the crisis, the Harvard Data Science Review (an open access platform of the Harvard Data Science Initiative) is publishing a special issue examining the novel coronavirus and its impact through the lens of data science.

The issue covers a wide range of topics addressing the societal, epidemiological, political, and educational issues that have rapidly emerged from the SARS-CoV2 pandemic. Articles include:

A Conversation About Covid-19 With Biostatisticians and EpidemiologistsDavid Banks (Duke University), Susan Ellenberg (University of Pennsylvania), Thomas Fleming (University of Washington), M. Elizabeth Halloran (University of Washington), Andrew Lawson (Medical University of South Carolina), and Lance Waller (Emory University)Five leading biostatisticians and epidemiologists debate the probable scope and duration of the pandemic, the kinds of medical responses that we need, and some of the impacts they foresee on the U.S. and on the world. They also discuss the pandemic’s likely effect on higher education.

The Coronavirus Exponential: A Preliminary Investigation into the Public’s UnderstandingAlexander Podkul (Optimus), Scott Tranter (Optimus), Liberty Vittert (Washington University, St. Louis), Alex Alduncin (Optimus)The reasons why we are currently “socially distancing” are based on an understanding of exponential growth and the idea of “flattening the curve.” The authors present and discuss a pair of survey experiments that explore the public’s statistical literacy by examining its ability to calculate and understand exponential growth. These findings may be used to help better ground effective communication strategies aimed at the general public.

Bayesian Adaptive Clinical Trials for Anti-Infective Therapeutics During Epidemic OutbreaksShomesh Chaudhuri (QLS Advisors), Andrew W. Lo (MIT), Danying Xiao (MIT), and Qingyang Xu (MIT)In the midst of the COVID-19 pandemic, how should regulatory agencies adapt their normally lengthy clinical trial and approval process to address the urgency of finding treatments and saving lives? The authors propose a Bayesian adaptive patient-centered framework to optimize the clinical trial development path for anti-infective therapies and vaccines. Their research provides a rational, systematic, transparent, repeatable, and practical framework for regulators, policymakers, and clinical researchers to evaluate the efficacy of anti-infective therapeutics during the course of any epidemic outbreak when the cost of false negatives far outweighs the cost of false positives.

Estimating Probabilities of Success of Vaccine and Other Anti-Infective Therapeutic Development ProgramsAndrew W. Lo (MIT), Kien Wei Siah (MIT), Chi Heem Wong (MIT)The economic value of a drug or medical device development program is typically computed by assessing the program’s cumulative revenues if successful, and companies rely on this data to make business decisions about which programs to pursue and how to fund them.
In this article, the authors provide estimates of clinical trial outcomes for vaccines and other anti-infective therapeutics using 43,414 unique triplets of clinical trial, drug, and disease between January 1, 2000, and January 7, 2020, yielding 2,544 vaccine programs and 6,829 non-vaccine programs targeting infectious diseases—the largest dataset of its kind. As governments around the world begin to formulate a more systematic strategy for dealing with pandemics beyond COVID-19, these estimates can be used by policymakers to identify areas most likely to be undeserved by private-sector engagement and in need of public-sector support.

Tackling Covid-19 through Responsible AI Innovation: Five Steps in the Right DirectionDavid Leslie (The Alan Turing Institute)Innovations in data science and artificial intelligence (AI) have a central role to play in supporting global efforts to combat COVID-19 and address a broad range of biomedical, epidemiological, and socio-economic challenges. However, this wide-reaching scientific capacity also raises ethical challenges.
The authors present a practice-based path to responsible AI design and discovery centered on open, accountable, equitable, and democratically governed processes and products. When taken from the start, these steps will not only enhance the capacity of innovators to tackle Covid-19 responsibly, they will help to set the data science and AI community down a path that is both better prepared to cope with future pandemics and better equipped to support a more humane, rational, and just society of tomorrow.

The special issue will be published on a rolling/continuous basis with new articles appearing weekly through the beginning of July 2020.

Journal

Harvard Data Science Review

DOI

10.1162/99608f92.1b77b932

There are an estimated 2 million older adults who are homebound or unable to leave their homes due to multiple chronic conditions and functional impairment. Home-based primary care provides access to care for these patients and has been shown to save costs for the Medicare program. The federal government's Centers for Medicare and Medicaid Services (CMS) is currently moving from volume-based reimbursement -- where health care providers are paid based on the quantity of care supplied -- to value-based reimbursement -- where providers are rewarded with incentive payments for the quality of care their patients receive. To successfully achieve the shift, it's critical that CMS quality measures include ones focused on medical care provided in the home by physicians.

In a report published in the May 19, 2020, issue of the Annals of Internal Medicine, researchers at Johns Hopkins Medicine and four other U.S. medical institutions examined the performance quality measures used by the CMS Merit-based Incentive Payment System (MIPS) to determine if they appropriately addressed home-based medical care.

In their review of 257 overall quality measures on the CMS 2019 MIPS list, the researchers found that of the 78 potentially appropriate quality measures for home-based care, only 50% (39) included certain codes that enable physicians to report they provided services in a patient's home. These codes indicate that the services are eligible for quality-based incentives.

"This is unfortunate, because strong evidence exists that improving care for frail older adults, particularly those who are homebound, can help improve care and reduce health care costs," says lead author Bruce Leff, M.D., director of the Center for Transformative Geriatric Research and professor of medicine at the Johns Hopkins University School of Medicine. "Currently," he adds, "only 12% of homebound patients receive their medical care at home."

Based on their findings, the researchers recommend that (1) the CMS add home visit codes to all MIPS quality measures relevant to such care; (2) that quality measure developers consider home-based primary care when designing new standards; and (3) that research initiatives foster this development. They also support the establishment of a national learning collaborative and practice-based research network focused on home-based medical care.