Need to increase diversity within genetic data sets

Current polygenic scores are significantly better in predicting the risk of common diseases for people of European ancestry than those of African ancestry.

Polygenic scores can predict a person's risk for conditions like coronary artery disease, breast cancer, and type 2 diabetes (T2D) with great accuracy, even in patients who lack common warning signs. This new genome analysis tool holds promise for physicians, who may be able to intervene earlier to help prevent common disease for at-risk individuals.

According to a new study, however, polygenic scores developed by studying Europeans do a better job at predicting disease risk for people of European ancestry than for those of other ancestries.

Researchers from the Broad Institute of MIT and Harvard and Massachusetts General Hospital (MGH) led a team that used large-scale genetic data from UK Biobank to develop prediction scores for height, body mass index, T2D, and certain other traits and diseases.

The researchers found that polygenic scores, calculated based on data from UK Biobank, had a 4.5 times higher prediction accuracy for people of European ancestry than those of African ancestry, and two times higher accuracy than those of East Asian ancestry.

"From a clinical context, this means that current polygenic scores are significantly better in predicting the risk of common diseases for people of European ancestry than those of African ancestry," said Alicia Martin, the lead author of the study and an affiliate of the Program in Medical and Population Genetics and the Stanley Center for Psychiatric Research at the Broad Institute.

Martin, who is now an instructor in investigation at MGH, started this work while she was a postdoctoral researcher in the lab of Mark Daly, institute member and co-director of the Program in Medical and Population Genetics at the Broad Institute.

These findings are published in Nature Genetics.

With advances in genome sequencing technology, studies in people of European ancestry have grown rapidly in the last few years, while the proportion of non-Europeans in these genomic studies have stagnated since 2014, the authors report. As of 2016, 80 percent of participants in genetic studies are of European descent, even though Europeans constitute only 16 percent of the world population.

UK Biobank is one of the largest publicly available genetic data sets. It contains information for half a million people, about 94 percent of whom are of European ancestry. Fewer than 10 percent are of African, South Asian, East Asian, and Hispanic or Latino ancestry.

However, Martin and her team also developed separate polygenic scores using data from the BioBank Japan Project, an East Asian data set, and found that scores calculated from this data set were almost 50 percent more accurate in predicting disease risk for East Asians than scores based on UK Biobank data.

"This further confirms that risk predictors are more precise if they are drawn from genetic data derived from a similar ancestry," Martin said. "It is crucial that researchers should recruit more minority populations in future genetic studies and also make data from such studies accessible and open. Failure to do this will lead to further inequities in our healthcare system."

In recent years, Sekar Kathiresan, an institute member and director of the Cardiovascular Disease Initiative at the Broad Institute, and his colleagues have advanced research in polygenic scoring, increasing their predictive power tremendously, and they are working to implement clinically meaningful risk predictors.

"Though health disparities are currently related to social determinants of health rather than genetic testing, it will be important for the biomedical community to ensure that all ethnic groups have access to genetic risk prediction of comparable quality," said Kathiresan, who is also director of the Center for Genomic Medicine at MGH and a professor of medicine at Harvard Medical School. "This will require undertaking or expanding large genomic studies in non-European ethnic groups."

This study was funded by the National Institutes of Health.

Making waves: Researchers shed light on how cilia work

The body motion is cancelled and basis of the cilium is fixed. The blue line corresponds to the mathematical description of the position of the cilium. The red circle corresponds to the basis of the cilium. The video is slowed by a factor of 40.

Human bodies have some built-in systems to care for themselves. The cells that line our lungs, nose, brain and reproductive system have cilia, which are tiny, hair-like structures designed to sweep out fluids, cells and microbes to stay healthy. But the mechanisms behind their motion are not well understood.

A team of researchers in the McKelvey School of Engineering and the School of Medicine at Washington University in St. Louis wanted to determine how length affected the mechanical efficiency of beating cilia. They found that most mechanical metrics, including force, torque and power, increased in proportion to the length of the cilia, but there was a "sweet spot" in terms of efficiency. The findings give insight into cilia in humans and how defects lead to disease, such as primary ciliary dyskinesia, which is associated with chronic respiratory infections, changes in the right-left axis and heart defects. The results will be published in the April 9 issue of Biophysical Journal.

The study was led by Mathieu Bottier, a postdoctoral researcher in the lab of Philip Bayly, the Lilyan & E. Lisle Hughes Professor of Mechanical Engineering and chair of the Department of Mechanical Engineering & Materials Science; and the lab of Susan K. Dutcher, professor of genetics and of cell biology and physiology at the School of Medicine. The researchers used high-speed video microscopy to analyze a model for cilia to determine their mechanical metrics. After analyzing nearly 400 videos, the team found that the most efficient beating of cilia was at its natural length of 10-12 microns, or about one-fifth the width of a human hair.

"Something we did not expect is that the short cilia would not be periodic," Bottier said. "The cilia are all moving, but we find no actual pattern of beating -- nothing was synchronized -- and that was our first discovery."

The team used Chlamydomonas reinhardtii, a single-cell green alga that normally swims with two propulsive tails and is frequently used as a model for mammalian cilia. Bottier and Kyle Thomas, a senior undergraduate student majoring in biomedical engineering, used a mutant with only one cilium that spins in place, allowing longer video recording. They removed the cilium, then recorded the regrowth by video. The cilium took about 90 minutes to return to its normal length, and while its waveform varied slightly from that of the standard cilia, its key characteristics were similar.

"We wanted to see the cilium beating, which we did with the video," Bottier said. "Then we asked how we could describe it, and the best way was to look at the average beat. We recorded five or six cycles of beating that repeat periodically, and from those five or six, we can reconstruct one average, which will remove the eventual outliers."

The cilium's beating takes place via a series of bends that begin at its base and extend to the tip. The team found that periodic beating begins when cilia become longer than two to four microns, which means that a critical length is necessary for the cilia to beat. In previous research, scientists had not studied cilia shorter than five or six microns, Bottier said. Another new observation is that the beat frequency in periodically-beating cilia is quite consistent over the normal range of cilium length, although it decreases slightly as length increases from four microns to 12 microns, Bayly said.

This work may help to understand human mutations that make cilia short and how short cilia will impact the patient's outcome, Dutcher said.

Thomas said the research provides a better understanding of how cilia operate and what causes the oscillations.

"There are a lot of different models presented on what drives this bending pattern, so this study helped to learn which models are more accurate and which may have inaccuracies, so we can understand when there is a cilia dysfunction, what causes it because that could spark some conversations on how we go about treating it," Thomas said.

Exercise is more critical than diet to maintain weight loss

A new study from the University of Colorado Anschutz Health and Wellness Center (AHWC) at the CU Anschutz Medical Campus revealed physical activity does more to maintain substantial weight loss than diet.

The study, published in the March issue of Obesity, was selected as the Editor's Choice article.

"This study addresses the difficult question of why so many people struggle to keep weight off over a long period. By providing evidence that a group of successful weight-loss maintainers engages in high levels of physical activity to prevent weight regain -- rather than chronically restricting their energy intake -- is a step forward to clarifying the relationship between exercise and weight-loss maintenance," said Danielle Ostendorf, PhD, a postdoctoral fellow at the CU Anschutz Health and Wellness Center.

The findings reveal that successful weight-loss maintainers rely on physical activity to remain in energy balance (rather than chronic restriction of dietary intake) to avoid weight regain. In the study, successful weight-loss maintainers are individuals who maintain a reduced body weight of 30 pounds or more for over a year.

Key findings include:

• The total calories burned (and consumed) each day by weight-loss maintainers was significantly higher (300 kcal/day) compared with that in individuals with normal body weight controls but was not significantly different from that in the individuals with overweight/obesity.
• Notably, of the total calories burned, the amount burned in physical activity by weight-loss maintainers was significantly higher (180 kcal/day) compared with that in both individuals of normal body weight and individuals with overweight/obesity. Despite the higher energy cost of moving a larger body mass incurred by individuals with overweight/obesity, weight-loss maintainers were burning more energy in physical activity, suggesting they were moving more.
• This is supported by the fact that the weight-loss maintainer group also demonstrated significantly higher levels of steps per day (12,000 steps per day) compared to participants at a normal body weight (9,000 steps per day) and participants with overweight/obesity (6,500 steps per day).

"Our findings suggest that this group of successful weight-loss maintainers are consuming a similar number of calories per day as individuals with overweight and obesity but appear to avoid weight regain by compensating for this with high levels of physical activity," said Victoria A. Catenacci, MD, a weight management physician and researcher at CU Anschutz Medical Campus.

The study looked at successful weight-loss maintainers compared to two other groups: controls with normal body weight (Body Mass Index (BMI) similar to the current BMI of the weight-loss maintainers); and controls with overweight/obesity (whose current BMI was similar to the pre-weight-loss BMI of the maintainers). The weight-loss maintainers had a body weight of around 150 pounds, which was similar to the normal weight controls, while the controls with overweight and obesity had a body weight of around 213 pounds.

This study is one of the few to measure total daily energy expenditure in weight-reduced individuals using the gold standard doubly labeled water method. This method allows researchers to precisely determine an individual's energy expenditure through collecting urine samples over one to two weeks after people are given a dose of doubly labeled water. Doubly labeled water is water in which both the hydrogen and the oxygen atoms have been replaced (i.e. labeled) with an uncommon isotope of these elements for tracing purposes.

The measure of total daily energy expenditure from doubly labeled water also provides an estimate of energy intake when people are weight stable, as they were in this study. Prior studies used questionnaires or diet diaries to measure energy intake, which have significant limitations.

The researchers also measured each individual's resting metabolic rate in order to understand how much of the total daily energy expenditure is from energy expended at rest versus energy expended during physical activity. Prior studies used self-reported measures or activity monitors to measure physical activity, which are techniques that cannot provide the same accuracy.

The findings are consistent with results from the longitudinal study of "The Biggest Loser" contestants, where physical activity energy expenditure was strongly correlated with weight loss and weight gain after six years.

Supercomputers help supercharge protein assembly

Using supercomputers, scientists are just starting to design proteins that self-assemble to combine and resemble life-giving molecules like hemoglobin.

Using proteins derived from jellyfish, scientists assembled a complex sixteen protein structure composed of two stacked octamers by supercharging alone. This research could be applied to useful technologies such as pharmaceutical targeting, artificial energy harvesting, 'smart' sensing and building materials, and more. Computational modeling through XSEDE allocations on Stampede2 (TACC) and Comet (SDSC) refined measurements of structure.

Red blood cells are amazing. They pick up oxygen from our lungs and carry it all over our body to keep us alive. The hemoglobin molecule in red blood cells transports oxygen by changing its shape in an all-or-nothing fashion. Four copies of the same protein in hemoglobin open and close like flower petals, structurally coupled to respond to each other. Using supercomputers, scientists are just starting to design proteins that self-assemble to combine and resemble life-giving molecules like hemoglobin. The scientists say their methods could be applied to useful technologies such as pharmaceutical targeting, artificial energy harvesting, 'smart' sensing and building materials, and more.

A science team did this work by supercharging proteins, which means that they changed the subunits of proteins, the amino acids, to give the proteins an artificially high positive or negative charge. Using proteins derived from jellyfish, the scientists were able to assemble a complex sixteen protein structure composed of two stacked octamers by supercharging alone, findings that were reported in January of 2019 in the journal Nature Chemistry.

The team then used supercomputer simulations to validate and inform these experimental results. Supercomputer allocations on Stampede2 at the Texas Advanced Computing Center (TACC) and Comet at the San Diego Supercomputer Center (SDSC) were awarded to the researchers through XSEDE, the Extreme Science and Engineering Discovery Environment funded by the National Science Foundation (NSF).

"We found that by taking proteins that don't normally interact with each other, we can make copies that are either highly positively or highly negatively charged," said study co-author Anna Simon, a postdoctoral researcher in the Ellington Lab of UT Austin. "Combining the highly positively and negatively charged copies, we can make the proteins assemble into very specific structured assemblies," Simon said. The scientists call their strategy 'supercharged protein assembly,' where they drive defined protein interactions by combining engineered supercharged variants.

"We exploited a very well-known and basic principle from nature, that opposite charges attract," added study co-author Jens Glaser. Glaser is an assistant research scientist in the Glotzer Group, Department of Chemical Engineering at the University of Michigan. "Anna Simon's group found that when they mix these charged variants of green fluorescent protein, they get highly ordered structures. That was a real surprise," Glaser said.

The stacked octamer structure looks like a braided ring. It's composed of 16 proteins -- two intertwined rings of eight that interact in very specific, discreet patches. "The reason why it's so hard to engineer proteins that interact synthetically is that making these interacting patches and having them all line up right such that they'll allow the proteins to assemble into bigger, regular structures is really hard," explained Simon. They got around the problem by adding many positive and negative charges to engineer variants of green fluorescent protein (GFP), a well-studied 'lab mouse' protein derived from the Aequorea victoria jellyfish.

The positively charged protein, which they called cerulean fluorescent protein (Ceru) +32, had additional opportunities to interact with the negatively charged protein GFP -17. "By giving these proteins all these opportunities, these different places where they could potentially interact, they were able to choose the right ones," Simon said. "There were certain patterns and interactions that were there, available, and energetically favored, that we didn't necessarily predict beforehand that would allow them to assemble into these specific shapes."

To get the engineered charged fluorescent proteins, Simon and co-authors Arti Pothukuchy, Jimmy Gollihar, and Barrett Morrow encoded their genes, including a chemical tag used for purification on portable pieces of DNA called plasmids in E. coli, then harvested the tagged protein that E. coli grew. The scientists mixed the proteins together. They initially thought the proteins might just interact to form large, irregularly structured clumps. "But then, what we kept on seeing was this weird, funny peak around 12 nanometers, that was a lot smaller than a big clump of protein, but significantly bigger than the single protein," Simon said.

They measured the size of the particles that formed using a Zetasizer instrument at the Texas Materials Institute of UT Austin, and verified that the particles contained both cerulean and GFP proteins Förster Resonance Energy Transfer (FRET), which measures the energy transfer between different colored fluorescent proteins produce fluorescence in response to different energies of light to see if they are close together. Negative stain electron microscopy identifed the specific structure of the particles, conducted by the group of David Taylor, assistant professor of molecular biosciences at UT Austin. It showed that the 12 nm particle consisted of a stacked octamer composed of sixteen proteins. "We found that they were these beautifully shaped flower-like structures," Simon said. Co-author Yi Zhou from Taylor's group of UT Austin increased the resolution even further using cryo-electron microscopy to reveal atomic-level details of the stacked octamer.

Computational modeling refined the measurements of how the proteins were arranged into a clear picture of the beautiful, flower-like structure, according to Jens Glaser. "We had to come up with a model that was complex enough to describe the physics of the charged green fluorescent proteins and present all the relevant atomistic details, yet was efficient enough to allow us to simulate this on a realistic timescale. With a fully atomistic model, it would have taken us over a year to get a single simulation out of the computer, however fast the computer was," Glaser said.

They simplified the model by reducing the resolution without sacrificing important details of the interactions between proteins. "That's why we used a model where the shape of the protein is exactly represented by a molecular surface, just like the one that's measured from the crystallographic structure of the protein," Glaser added.

"What really helped us turn this around and improve what we were able to get out of our simulations was the cryo-EM data," said Vyas Ramasubramani, a graduate student in chemical engineering at the University of Michigan. "That's what really helped us find the optimal configuration to put into these simulations, which then helped us validate the stability arguments that we were making, and hopefully going forward make predictions about ways that we can destabilize or modify this structure," Ramasubramani said.

The scientists required lots of compute power to do the calculations on the scale that they wanted.

"We used XSEDE to basically take these huge systems, where you have lots of different pieces interacting with each other, and calculate all of this at once so that when you start moving your system forward through some semblance of time, you could get an idea for how it was going to evolve on somewhat real timescales," Ramasubramani said. "If you tried to do the same kind of simulation that we did on a laptop, it would have taken months if not years to really approach understanding whether or not some sort of structure would be stable. For us, not being able to use XSEDE, where you could use essentially 48 cores, 48 compute units all at once to make these calculations highly parallel, we would have been doing this much slower."

The Stampede2 supercomputer at the TACC contains 4,200 Intel Knights Landing and 1,736 Intel Skylake X compute nodes. Each Skylake node has 48 cores, the basic unit of a computer processor. "The Skylake nodes of the Stampede2 supercomputer were instrumental in achieving the performance that was necessary to compute these electrostatic interactions that act between the oppositely-charged proteins in an efficient manner," Glaser said. "The availability of the Stampede2 supercomputer was at just the right point in time for us to perform these simulations."

Initially, the science team tested their simulations on the Comet system at the SDSC. "When we were first figuring out what kind of model to use and whether this simplified model would give us reasonable results, Comet was a great place to try these simulations," Ramasubramani said. "Comet was a great testbed for what we were doing."

Looking at the bigger scientific picture, the scientists hope that this work advances understanding of why so many proteins in nature will oligomerize, or join together to form more complex and interesting structures.

"We showed that there doesn't need to be a very specific, pre-distinguished set of plans and interactions for these structures to form," Simon said. "This is important because it means that maybe, and quite likely we can take other sets of molecules that we want to make oligomerize and generate both positively charged and negatively charged variants, combine them, and have specifically ordered structures for them."

Natural biomaterials like bone, feathers, and shells can be tough yet lightweight. "We think supercharged protein assembly is an easier way to develop the kind of materials that have exciting synthetic properties without having to spend so much time or having to know exactly how they're going to come together beforehand," Simon said. "We think that will accelerate the ability to engineer synthetic materials and for discovery and exploration of these nanostructured protein materials."

The Serengeti-Mara squeeze -- One of the world's most iconic ecosystems under pressure

The migration of wildebeest is being disrupted.

Increased human activity around one of Africa's most iconic ecosystems is 'squeezing the wildlife in its core', damaging habitation and disrupting the migration routes of wildebeest, zebra and gazelle, an international study has concluded.

The Serengeti-Mara ecosystem is one of the largest and most protected ecosystems on Earth, spanning 40,000 square kilometres and taking in the Serengeti National Park and Maasai Mara National Reserve in East Africa.

Every year a million wildebeest, half a million gazelle and 200,000 zebra make the perilous trek from the Serengeti national park in Tanzania to the Maasai Mara reserve in Kenya in their search for water and grazing land.

Now, an international team of scientists have discovered that increased human activity along the boundaries is having a detrimental impact on plants, animals, and soils.

The findings are published in the journal Science.

The study looked at 40 years of data, and revealed that some boundary areas have seen a 400 per cent increase in human population over the past decade, while larger wildlife species in key areas in Kenya have declined by more than 75 per cent.

The study reveals how population growth and an influx of livestock in the buffer zones of the parks has squeezed the area available for migration of wildebeest, zebra and gazelles, causing them to spend more time grazing less nutritious grasses than they did in the past. This has reduced the frequency of natural fires, changing the vegetation and altering grazing opportunities for other wildlife in the core areas.

The study shows that the impacts are cascading down the food chain, favouring less palatable plants and altering the beneficial interactions between plants and microorganisms that enable the ecosystem to capture and utilize essential nutrients.

The effects could potentially make the ecosystem less resilient to future shocks such as drought or further climate change, the scientists warn.

The authors conclude that, even for reasonably well-protected areas like the Serengeti and Mara, alternative strategies may be needed that sustain the coexistence and livelihood of local people and wildlife in the landscapes surrounding protected areas. The current strategy of increasingly hard boundaries may be a major risk to both people and wildlife.

The study was led by the University of Groningen with collaborators at 11 institutions around the world, including the universities of York, Glasgow and Liverpool.

Dr Colin Beale, from the University of York's Department of Biology, said: "Protected areas across East Africa are under pressure from a wide range of threats. Our work shows that encroachment by people should be considered just as serious a challenge as better known issues such as poaching and climate change."

Dr Michiel Veldhuis, lead author of the study from the University of Groningen, said: "There is an urgent need to rethink how we manage the boundaries of protected areas to be able to conserve biodiversity. The future of the world's most iconic protected area and their associated human population may depend on it."

Dr Simon Mduma, Director of the Tanzanian Government's Wildlife Research Institute added: "These results come at the right time, as the Tanzanian government is now taking important steps to address these issues on a national level."

"This paper provides important scientific evidence of the far ranging consequences of the increased human pressures around the Serengeti-Mara ecosystem, information that is now urgently needed by policy makers and politicians."

Galápagos islands have nearly 10 times more alien marine species than once thought

The bryozoan Amathia verticillata. Known in other parts of the world for fouling pipes and fishing gear and killing seagrasses, its discovery in the Galapagos is especially concerning for scientists.

Over 50 non-native species have found their way to the Galápagos Islands, almost 10 times more than scientists previously thought, reports a new study in Aquatic Invasions published Thursday, March 28.

The study, a joint effort of the Smithsonian Environmental Research Center, Williams College, and the Charles Darwin Foundation, documents 53 species of introduced marine animals in this UNESCO World Heritage Site, one of the largest marine protected areas on Earth. Before this study came out, scientists knew about only five.

"This increase in alien species is a stunning discovery, especially since only a small fraction of the Galápagos Islands was examined in this initial study," said Greg Ruiz, a co-author and marine biologist with the Smithsonian Environmental Research Center.

"This is the greatest reported increase in the recognition of alien species for any tropical marine region in the world," said lead author James Carlton, an emeritus professor of the Maritime Studies Program of Williams College-Mystic Seaport.

The Galápagos lie in the equatorial Pacific, roughly 600 miles west of Ecuador. Made famous by Charles Darwin's visit in 1835, the islands have long been recognized for their remarkable biodiversity. But with their fame, traffic has spiked. In 1938, just over 700 people lived on the Galápagos. Today, more than 25,000 people live on the islands, and nearly a quarter-million tourists visit each year.

Carlton and Ruiz began their study in 2015, with Inti Keith of the Charles Darwin Foundation. They conducted field surveys on two of the larger Galápagos Islands: Santa Cruz and Baltra, where they hung settlement plates from docks one meter underwater to see what species would grow on them. They also collected samples from mangrove roots, floating docks and other debris and scoured the literature for previous records of marine species on the islands.

The team documented 48 additional non-native species in the Galápagos. Most of them (30) were new discoveries that could have survived on the islands for decades under the radar. Another 17 were species scientists already knew lived on the Galápagos but previously thought were native. One final species, the bryozoan Watersipora subtorquata, was collected in 1987 but not identified until now.

Sea squirts, marine worms and moss animals (bryozoans) made up the majority of the non-native species. Almost all of the non-natives likely arrived inadvertently in ships from tropical seas around the world. Some of the most concerning discoveries include the bryozoan Amathia verticillata -- known for fouling pipes and fishing gear and killing seagrasses -- and the date mussel Leiosolenus aristatus, which researchers have already seen boring into Galápagos corals.

"This discovery resets how we think about what's natural in the ocean around the Galápagos, and what the impacts may be on these high-value conservation areas," Carlton said.

To reduce future invasions, the Galápagos already have one of the most stringent biosecurity programs in the world. International vessels entering the Galápagos Marine Reserve may anchor in only one of the main ports, where divers inspect the vessel. If the divers find any non-native species, the vessel is requested to leave and have its hull cleaned before returning for a second inspection.

Still, the authors say, the risks remain high. The expansion of the Panama Canal in 2015 may bring the Indo-Pacific lionfish -- a major predator in the Caribbean -- to the Pacific coast of Central America. Once there, it could make its way to the Galápagos, where the likelihood of its success would be very high. Another possible arrival is the Indo-Pacific snowflake coral, which has already caused widespread death of native corals on the South American mainland.

Seeds inherit memories from their mother

This is a seed of Arabidopsis thaliana at the beginning of germination.

Seeds remain in a dormant state -- a temporary blockage of their germination -- as long as environmental conditions are not ideal for germination. The depth of this sleep, which is influenced by various factors, is inherited from their mother, as researchers from the University of Geneva (UNIGE), Switzerland, had previously shown. Today, they reveal in the journal eLife how this maternal imprint is transmitted through small fragments of so-called 'interfering' RNAs, which inactivate certain genes. The biologists also reveal that a similar mechanism enables to transmit another imprint, that of the temperatures present during the development of the seed. The lower this temperature was, the higher the seed's dormancy level will be. This mechanism allows the seed to optimize the timing of its germination. The information is then erased in the germinated embryo, so that the next generation can store new data on its environment.

Dormancy is implemented during seed development in the mother plant. This property allows the seeds to germinate during the appropriate season, to prevent all the offspring of a plant from developing in the same place and competing for limited resources, and to promote plant dispersal. Seeds also lose their dormancy at variable times. "Subspecies of the same plant can have different levels of dormancy depending on the latitudes at which they are produced, and we wanted to understand why," explains Luis Lopez-Molina, Professor at the Department of Botany and Plant Biology of the UNIGE Faculty of Science.

The paternal gene is silenced

Like all organisms with sexual reproduction, the seed receives two versions of each gene, a maternal and a paternal allele, which may have different levels of expression. The UNIGE biologists had shown in 2016 that the dormancy levels of Arabidopsis thaliana, a model organism used in laboratories, are inherited from the mother. Indeed, in the seed, the level of expression of a dormancy regulating gene called allantoinase (ALN) is the same as that of the maternal allele. This implies that it is the maternal allele of ALN that is mainly expressed, to the detriment of the paternal allele.

In the current study, the researchers show that this maternal imprint is transmitted by an epigenetic mechanism, which influences the expression of certain genes without altering their sequence. The paternal allele of ALN is 'silenced' by biochemical modifications called methylations, which are carried out in the promoter region of the gene in order to inactivate it.

"These methylations are themselves the result of a process in which different enzymatic and factor complexes are involved, as well as small fragments of so-called 'interfering' RNA. This is a unique example of genomic imprinting, because it is made in the absence of the enzyme usually responsible for methylation," says Mayumi Iwasaki, researcher in the Geneva group and the first author of the article.

The imprint of past cold prevents the seed from awakening

The environmental conditions present during the seed formation also leave their mark, as its dormancy level increases with decreasing temperatures. "We have discovered that, in this case, both alleles of the ALN gene are strongly repressed in the seed. This is due to a similar epigenetic mechanism, but not all of the actors are the same as those used to silence the paternal allele," says Luis Lopez-Molina.

This imprint of the cold enables the seed to keep information on past temperatures, in order to include them in the choice of the optimal time of germination. After germination, the ALN gene is reactivated in the embryo. The memory of the cold will then be cleared, allowing the counters to be reset for the next generation.

"Studying how maternal and environmental factors cause dormant seeds to awaken is of crucial importance for agriculture, especially to prevent early germination in an environment subject to climate change," concludes Mayumi Iwasaki. The ecological stakes are also high, because increasing temperatures could reduce the dormancy of the seed bank and thus modify the distribution of plant species under a given latitude. This would have multiple consequences, both direct and indirect, for native animal and plant species.

Biophysicists use machine learning to understand, predict dynamics of worm behavior

Caenorhabditis elegans 

Biophysicists have used an automated method to model a living system -- the dynamics of a worm perceiving and escaping pain. The Proceedings of the National Academy of Sciences (PNAS)published the results, which worked with data from experiments on the C. elegans roundworm.

"Our method is one of the first to use machine-learning tools on experimental data to derive simple, interpretable equations of motion for a living system," says Ilya Nemenman, senior author of the paper and a professor of physics and biology at Emory University. "We now have proof of principle that it can be done. The next step is to see if we can apply our method to a more complicated system."

The model makes accurate predictions about the dynamics of the worm behavior, and these predictions are biologically interpretable and have been experimentally verified.

Collaborators on the paper include first author Bryan Daniels, a theorist from Arizona State University, and co-author William Ryu, an experimentalist from the University of Toronto.

The researchers used an algorithm, developed in 2015 by Daniels and Nemenman, that teaches a computer how to efficiently search for the laws that underlie natural dynamical systems, including complex biological ones. They dubbed the algorithm "Sir Isaac," after one of the most famous scientists of all time -- Sir Isaac Newton. Their long-term goal is to develop the algorithm into a "robot scientist," to automate and speed up the scientific method of forming quantitative hypotheses, then testing them by looking at data and experiments.

While Newton's Three Laws of Motion can be used to predict dynamics for mechanical systems, the biophysicists want to develop similar predictive dynamical approaches that can be applied to living systems.

For the PNAS paper, they focused on the decision-making involved when C. elegans responds to a sensory stimulus. The data on C. elegans had been previously gathered by the Ryu lab, which develops methods to measure and analyze behavioral responses of the roundworm at the holistic level, from basic motor gestures to long-term behavioral programs.

C. elegans is a well-established laboratory animal model system. Most C. elegans have only 302 neurons, few muscles and a limited repertoire of motion. A sequence of experiments involved interrupting the forward movement of individual C. elegans with a laser strike to the head. When the laser strikes a worm, it withdraws, briefly accelerating backwards and eventually returning to forward motion, usually in a different direction. Individual worms respond differently. Some, for instance, immediately reverse direction upon laser stimulus, while others pause briefly before responding. Another variable in the experiments is the intensity of the laser: Worms respond faster to hotter and more rapidly rising temperatures.

The researchers fed the Sir Isaac platform the motion data from the first few seconds of the experiments -- before and shortly after the laser strikes a worm and it initially reacts. From this limited data, the algorithm was able to capture the average responses that matched the experimental results and also to predict the motion of the worm well beyond these initial few seconds, generalizing from the limited knowledge. The prediction left only 10 percent of the variability in the worm motion that can be attributed to the laser stimulus unexplained. This was twice as good as the best prior models, which were not aided by automated inference.

"Predicting a worm's decision about when and how to move in response to a stimulus is a lot more complicated than just calculating how a ball will move when you kick it," Nemenman says. "Our algorithm had to account for the complexities of sensory processing in the worms, the neural activity in response to the stimuli, followed by the activation of muscles and the forces that the activated muscles generate. It summed all this up into a simple and elegant mathematical description."

The model derived by Sir Isaac was well-matched to the biology of C. elegans, providing interpretable results for both the sensory processing and the motor response, hinting at the potential of artificial intelligence to aid in discovery of accurate and interpretable models of more complex systems.

"It's a big step from making predictions about the behavior of a worm to that of a human," Nemenman says, "but we hope that the worm can serve as a kind of sandbox for testing out methods of automated inference, such that Sir Isaac might one day directly benefit human health. Much of science is about guessing the laws that govern natural systems and then verifying those guesses through experiments. If we can figure out how to use modern machine learning tools to help with the guessing, that could greatly speed up research breakthroughs."

New approach could boost energy capacity of lithium batteries

Molecular diagram shows the structure of molybdenum sulfide, one of the materials used to create the new kind of cathode for lithium-sulfur batteries.

Researchers around the globe have been on a quest for batteries that pack a punch but are smaller and lighter than today's versions, potentially enabling electric cars to travel further or portable electronics to run for longer without recharging. Now, researchers at MIT and in China say they've made a major advance in this area, with a new version of a key component for lithium batteries, the cathode.

The team describes their concept as a "hybrid" cathode, because it combines aspects of two different approaches that have been used before, one to increase the energy output per pound (gravimetric energy density), the other for the energy per liter (volumetric energy density). The synergistic combination, they say, produces a version that provides the benefits of both, and more.

The work is described today in the journal Nature Energy, in a paper by Ju Li, an MIT professor of nuclear science and engineering and of materials science and engineering; Weijiang Xue, an MIT postdoc; and 13 others.

Today's lithium-ion batteries tend to use cathodes (one of the two electrodes in a battery) made of a transition metal oxide, but batteries with cathodes made of sulfur are considered a promising alternative to reduce weight. Today, the designers of lithium-sulfur batteries face a tradeoff.

The cathodes of such batteries are usually made in one of two ways, known as intercalation types or conversion types. Intercalation types, which use compounds such as lithium cobalt oxide, provide a high volumetric energy density -- packing a lot of punch per volume because of their high densities. These cathodes can maintain their structure and dimensions while incorporating lithium atoms into their crystalline structure.

The other cathode approach, called the conversion type, uses sulfur that gets transformed structurally and is even temporarily dissolved in the electrolyte. "Theoretically, these [batteries] have very good gravimetric energy density," Li says. "But the volumetric density is low," partly because they tend to require a lot of extra materials, including an excess of electrolyte and carbon, used to provide conductivity.

In their new hybrid system, the researchers have managed to combine the two approaches into a new cathode that incorporates both a type of molybdenum sulfide called Chevrel-phase, and pure sulfur, which together appear to provide the best aspects of both. They used particles of the two materials and compressed them to make the solid cathode. "It is like the primer and TNT in an explosive, one fast-acting, and one with higher energy per weight," Li says.

Among other advantages, the electrical conductivity of the combined material is relatively high, thus reducing the need for carbon and lowering the overall volume, Li says. Typical sulfur cathodes are made up of 20 to 30 percent carbon, he says, but the new version needs only 10 percent carbon.

The net effect of using the new material is substantial. Today's commercial lithium-ion batteries can have energy densities of about 250 watt-hours per kilogram and 700 watt-hours per liter, whereas lithium-sulfur batteries top out at about 400 watt-hours per kilogram but only 400 watt-hours per liter. The new version, in its initial version that has not yet gone through an optimization process, can already reach more than 360 watt-hours per kilogram and 581 watt-hours per liter, Li says. It can beat both lithium-ion and lithium-sulfur batteries in terms of the combination of these energy densities.

With further work, he says, "we think we can get to 400 watt-hours per kilogram and 700 watt-hours per liter," with that latter figure equaling that of lithium-ion. Already, the team has gone a step further than many laboratory experiments aimed at developing a large-scale battery prototype: Instead of testing small coin cells with capacities of only several milliamp-hours, they have produced a three-layer pouch cell (a standard subunit in batteries for products such as electric vehicles) with a capacity of more than 1,000 milliamp-hours. This is comparable to some commercial batteries, indicating that the new device does match its predicted characteristics.

So far, the new cell can't quite live up to the longevity of lithium-ion batteries in terms of the number of charge-discharge cycles it can go through before losing too much power to be useful. But that limitation is "not the cathode's problem"; it has to do with the overall cell design, and "we're working on that," Li says. Even in its present early form, he says, "this may be useful for some niche applications, like a drone with long range," where both weight and volume matter more than longevity.

"I think this is a new arena for research," Li says.

Hubble watches spun-up asteroid coming apart

This Hubble Space Telescope image reveals the gradual self-destruction of an asteroid, whose ejected dusty material has formed two long, thin, comet-like tails. The longer tail stretches more than 500,000 miles (800,000 kilometers) and is roughly 3,000 miles (4,800 kilometers) wide. The shorter tail is about a quarter as long. The streamers will eventually disperse into space.

A small asteroid has been caught in the process of spinning so fast it's throwing off material, according to new data from NASA's Hubble Space Telescope and other observatories.

Images from Hubble show two narrow, comet-like tails of dusty debris streaming from the asteroid (6478) Gault. Each tail represents an episode in which the asteroid gently shed its material -- key evidence that Gault is beginning to come apart.

Discovered in 1988, the 2.5-mile-wide (4-kilometer-wide) asteroid has been observed repeatedly, but the debris tails are the first evidence of disintegration. Gault is located 214 million miles (344 million kilometers) from the Sun. Of the roughly 800,000 known asteroids between Mars and Jupiter, astronomers estimate that this type of event in the asteroid belt is rare, occurring roughly once a year.

Watching an asteroid become unglued gives astronomers the opportunity to study the makeup of these space rocks without sending a spacecraft to sample them.

"We didn't have to go to Gault," explained Olivier Hainaut of the European Southern Observatory in Germany, a member of the Gault observing team. "We just had to look at the image of the streamers, and we can see all of the dust grains well-sorted by size. All the large grains (about the size of sand particles) are close to the object and the smallest grains (about the size of flour grains) are the farthest away because they are being pushed fastest by pressure from sunlight."

Gault is only the second asteroid whose disintegration has been strongly linked to a process known as a YORP effect. (YORP stands for "Yarkovsky-O'Keefe-Radzievskii-Paddack," the names of four scientists who contributed to the concept.) When sunlight heats an asteroid, infrared radiation escaping from its warmed surface carries off angular momentum as well as heat. This process creates a tiny torque that can cause the asteroid to continually spin faster. When the resulting centrifugal force starts to overcome gravity, the asteroid's surface becomes unstable, and landslides may send dust and rubble drifting into space at a couple miles per hour, or the speed of a strolling human. The researchers estimate that Gault could have been slowly spinning up for more than 100 million years.

Piecing together Gault's recent activity is an astronomical forensics investigation involving telescopes and astronomers around the world. All-sky surveys, ground-based telescopes, and space-based facilities like the Hubble Space Telescope pooled their efforts to make this discovery possible.

The initial clue was the fortuitous detection of the first debris tail, observed on Jan. 5, 2019, by the NASA-funded Asteroid Terrestrial-Impact Last Alert System (ATLAS) telescope in Hawaii. The tail also turned up in archival data from December 2018 from ATLAS and the Panoramic Survey Telescope and Rapid Response System (Pan-STARRS) telescopes in Hawaii. In mid-January, a second shorter tail was spied by the Canada-France-Hawaii Telescope in Hawaii and the Isaac Newton Telescope in Spain, as well as by other observers. An analysis of both tails suggests the two dust events occurred around Oct. 28 and Dec. 30, 2018.

Follow-up observations with the William Herschel Telescope and ESA's (European Space Agency) Optical Ground Station in La Palma and Tenerife, Spain, and the Himalayan Chandra Telescope in India measured a two-hour rotation period for the object, close to the critical speed at which a loose "rubble-pile" asteroid begins to break up.

"Gault is the best 'smoking gun' example of a fast rotator right at the two-hour limit," said team member Jan Kleyna of the University of Hawaii in Honolulu.

An analysis of the asteroid's surrounding environment by Hubble revealed no signs of more widely distributed debris, which rules out the possibility of a collision with another asteroid causing the outbursts.

The asteroid's narrow streamers suggest that the dust was released in short bursts, lasting anywhere from a few hours to a few days. These sudden events puffed away enough debris to make a "dirt ball" approximately 500 feet (150 meters) across if compacted together. The tails will begin fading away in a few months as the dust disperses into interplanetary space.

Based on observations by the Canada-France-Hawaii Telescope, the astronomers estimate that the longer tail stretches over half a million miles (800,000 kilometers) and is roughly 3,000 miles (4,800 kilometers) wide. The shorter tail is about a quarter as long.

Only a couple of dozen active asteroids have been found so far. Astronomers may now have the capability to detect many more of them because of the enhanced survey capabilities of observatories such as Pan-STARRS and ATLAS, which scan the entire sky. "Asteroids such as Gault cannot escape detection anymore," Hainaut said. "That means that all these asteroids that start misbehaving get caught."

The researchers hope to monitor Gault for more dust events.

Deep groundwater may generate surface streams on Mars

Recurrent Slope Linae on the Palikir Crater walls on Mars

In mid-2018, researchers supported by the Italian Space Agency detected the presence of a deep-water lake on Mars under its south polar ice caps. Now, researchers at the USC Arid Climate and Water Research Center (AWARE) have published a study that suggests deep groundwater could still be active on Mars and could originate surface streams in some near-equatorial areas on Mars.

The researchers at USC have determined that groundwater likely exists in a broader geographical area than just the poles of Mars and that there is an active system, as deep as 750 meters, from which groundwater comes to the surface through cracks in the specific craters they analyzed.

Heggy, who is a member of the Mars Express Sounding radar experiment MARSIS probing Mars subsurface, and co-author Abotalib Z. Abotalib, a postdoctoral research associate at USC, studied the characteristics of Mars Recurrent Slope Linea, which are akin to dried, short streams of water that appear on some crater walls on Mars.

Scientists previously thought these features were affiliated with surface water flow or close subsurface water flow, says Heggy.

"We suggest that this may not be true. We propose an alternative hypothesis that they originate from a deep pressurized groundwater source which comes to the surface moving upward along ground cracks," Heggy says.

"The experience we gained from our research in desert hydrology was the cornerstone in reaching this conclusion. We have seen the same mechanisms in the North African Sahara and in the Arabian Peninsula, and it helped us explore the same mechanism on Mars," said Abotalib Z. Abotalib, the paper's first author.

The two scientists concluded that fractures within some of Mars' craters, enabled water springs to rise up to the surface as a result of pressure deep below. These springs leaked onto the surface, generating the sharp and distinct linear features found on the walls of these craters. The scientists also provide an explanation on how these water features fluctuate with seasonality on Mars.

The study, to be published on March 28, 2018, in Nature Geoscience, suggests that groundwater might be deeper than previously thought in areas where such streams are observed on Mars. The findings suggest that the exposed part of these ground fractures associated with these springs as the primary location candidates to explore Mars' habitability. Their work suggests that new probing methods should be developed to study these fractures.

Method:

Previous research to explore groundwater on Mars relied on interpreting the returned electromagnetic echoes sent from the radar-probing experiments from orbit onboard Mars Express and Mars Reconnaissance Orbiter. These experiments measured the reflection of the waves from both the surface and the subsurface whenever penetration was possible. However, this earlier method did not yet provide evidence of groundwater occurrence beyond the 2018 South Pole detection.

The authors of this current Nature Geoscience study used hi-resolution optical images and modeling to study the walls of large impact craters on Mars. The goal was to correlate the presence of fractures with the sources of streams that generate short water flows.

Heggy and Abotalib, who have long studied subsurface aquifers and groundwater flow movement on Earth and in desert environments, found similarities between the groundwater moving mechanisms in the Sahara and on Mars.

"Groundwater is strong evidence for the past similarity between Mars and Earth -- it suggest they have a similar evolution, to some extent," says Heggy.

He says this deep source of groundwater is the most convincing evidence of similarities between the two planets -- it suggest both may have had wet periods long enough to create such an active groundwater system.

For Heggy, an advocate for water science and water science education in arid areas, this particular study is not about colonization. But he says these rare and puzzling water flows on Mars are of big interest to the science community.

"Understanding how groundwater has formed on Mars, where it is today and how it is moving helps us constrain ambiguities on the evolution of climatic conditions on Mars for the last three billion years and how these conditions formed this groundwater system. It helps us to understand the similarities to our own planet and if we are going through the same climate evolution and the same path that Mars is going. Understanding Mars' evolution is crucial for understanding our own Earth's long-term evolution and groundwater is a key element in this process. "

The new study suggests that the groundwater that is the source of these water flows could be at depths starting at 750 meters deep. "Such depth requires us to consider more deep-probing techniques to look for the source of this groundwater versus looking for shallow sources of water, " says Heggy.

The work is funded under NASA Planetary Geology and Geophysics Program.

Quantum optical cooling of nanoparticles

A tightly focused laser field traps a nanoparticle between two highly reflecting mirrors, i.e. an optical cavity. Preferential scattering along this optical resonator allows to induce cooling of the nanoparticle motion in all three directions.

One important requirement to see quantum effects is to remove all thermal energy from the particle motion, i.e. to cool it as close as possible to absolute zero temperature. Researchers  are now one step closer to reaching this goal by demonstrating a new method for cooling levitated nanoparticles.

Tightly focused laser beams can act as optical "tweezers" to trap and manipulate tiny objects, from glass particles to living cells. The development of this method has earned Arthur Ashkin the last years Nobel prize in physics. While most experiments thus far have been carried out in air or liquid, there is an increasing interest for using optical tweezers to trap objects in ultra-high vacuum: such isolated particles not only exhibit unprecedented sensing performance, but can also be used to study fundamental processes of nanoscopic heat engines, or quantum phenomena involving large masses.

A key element in these research efforts is to obtain full control over the particle motion, ideally in a regime where the laws of quantum physics dominate its behavior. Previous attempts to achieve this, have either modulated the optical tweezer itself, or immersed the particle into additional light fields between highly reflecting mirror configurations, i.e. optical cavities. However, laser noise and large required laser intensities have posed a substantial limit to these methods. "Our new cooling scheme is directly borrowed from the atomic physics community, where similar challenges for quantum control exist," says Uros Delic, lead author of the recent study published in Physical Review Letters by researchers at the University of Vienna, the Austrian Academy of Sciences and the Massachusetts Institute of Technology (MIT), which was headed by Markus Aspelmeyer. The idea goes back to early works from Innsbruck physicist Helmut Ritsch and from US physicists Vladan Vuletic and Steve Chu, who realized that it is sufficient to use the light that is scattered directly from the optical tweezer itself if the particle is kept inside an initially empty optical cavity.

A nanoparticle in an optical tweezer scatters a tiny part of the tweezer light in nearly all directions. If the particle is positioned inside an optical cavity a part of the scattered light can be stored between its mirrors. As a result, photons are preferentially scattered into the optical cavity. However, this is only possible for light of specific colors, or said differently, specific photon energies. If we use tweezer light of a color that corresponds to a slightly smaller photon energy than required, the nanoparticles will "sacrifice" some of their kinetic energy to allow photon scattering into the optical cavity. This loss of kinetic energy effectively cools its motion. The method has been demonstrated for atoms before by Vladan Vuletic, a coauthor of this work. This is, however, the first time it has been applied to nanoparticles and used to cool in all three directions of motion.

"Our cooling method is much more powerful than all the previously demonstrated schemes. Without the constraints imposed by laser noise and laser power quantum behavior of levitated nanoparticles should be around the corner," says Delic.

Discovery of life-extension pathway in worms demonstrates new way to study aging

Caenorhabditis elegans 

An enzyme-blocking molecule can extend the lifespan of Caenorhabditis elegans roundworms by as much as 45 percent, largely by modulating a cannabinoid biological pathway, according to a study from scientists at Scripps Research.

The scientists, whose work is published on March 25 in Nature Chemical Biology, also showed that the lifespan-extending cannabinoid pathway in C. elegans is related in unexpected ways to cannabinoid pathways found in humans and other mammals.

"This study reveals a new life-extension pathway, but more broadly, it introduces a powerful method for applying chemical probes to lab animals such as worms to discover biology that may be relevant to humans," says study senior author Benjamin Cravatt, PhD, Professor and Gilula Chair of Chemical Biology at Scripps Research.

Cravatt is known for his development of advanced "chemical proteomics" methods for studying enzymes and the biological pathways they regulate. In the new study his team deployed these methods to investigate aging in C. elegans roundworms. The tiny worms normally live for just a few weeks -- compared to two or three years for lab mice -- making them, in principle, more practical for lifespan studies.

Lifespan studies using C. elegans worms typically involve the deletion or silencing of a particular gene in the embryonic stage of life to see if that extends the average lifespan of affected animals. The Cravatt team's approach, by contrast, was to use small-molecule compounds to disrupt enzyme-related pathways in adult worms, in the hope that this would uncover pathways that regulate lifespan.

"The beauty of this approach is that any lifespan-extending compounds we identify can be useful tools to study whether the same mechanisms and targets also modulate aging in mammals," says study co-author Michael Petrascheck, PhD, associate professor in the Department of Molecular Medicine at Scripps Research.

The team used a library of about 100 such compounds, all known to inhibit enzymes called serine hydrolases in mammals. "Metabolic processes are very important in determining the rate of aging and lifespan, and serine hydrolases are major metabolic enzymes, so we thought there was a good chance we'd find an important aging-related enzyme this way," says study first author Alice Chen, a graduate student in the Cravatt lab.

After finding ways to get the compounds through the tough outer skin of the worms, Chen tested them on worms that were 1 day into adulthood, and found that some of the compounds extended average worm lifespan by at least 15 percent. One, a carbamate compound called JZL184, extended worm lifespan by 45 percent at the optimal dose. More than half the worms treated with JZL184 were still alive and apparently healthy at 30 days, a time when virtually all untreated worms were dead of old age.

JZL184 was originally developed by the Cravatt lab as an inhibitor of the mammalian enzyme monoacylglycerol lipase (MAGL), whose normal job includes the breakdown of a molecule called 2-AG. The latter is an important neurotransmitter and is known as an endogenous cannabinoid ("endocannabinoid") because it activates one of the receptors hit by the main psychoactive component in cannabis.

Curiously however, a corresponding MAGL enzyme does not exist in C. elegans worms, so JZL184's target in these animals was a mystery. Chen soon found, though, that one of the main target enzymes for JZL184 in worms was fatty acid amide hydrolase 4 (FAAH-4). Although FAAH-4 and MAGL are not related in terms of their amino-acid sequences or 3-D folds, further experiments revealed, surprisingly, that FAAH-4 in worms does what MAGL does in humans and other mammals: it breaks down 2-AG.

2-AG has been linked to aging in mammals; one recent study found evidence that its levels fall in the brains of aging mice, likely due to greater MAGL activity. The results suggest, then, that studying the FAAH-4/2-AG pathway in worms could one day yield lifespan-extending strategies for humans.

"It seems at least plausible at this point that both worms and mammals have a cannabinoid-related signaling pathway that affects longevity and possibly aging-related disorders," Cravatt says.

The study demonstrates more generally how libraries of small-molecule compounds and associated proteomics techniques can be used to reveal biological pathways that evolutionarily distant lab animals such as worms have in common with humans.

"In principle, with this approach one can quickly find a compound that has a desired biological effect and also find the target through which it works, all in a live and relatively complex model organism," Cravatt says.

The authors of the study, "Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan," were Alice Chen, Kenneth Lum, Daisuke Ogasawara, Armand Cognetta, Alan To, William Parsons, Gabriel Simon, Michael Petrascheck, Liron Bar-Peled, and Benjamin Cravatt, all of Scripps Research; and Pablo Lara-Gonzalez and Arshad Desai of the University of California-San Diego.

The research was supported by the National Institutes of Health (DA033760, CA215249), the Damon Runyon Cancer Research Foundation, and Abide Therapeutics, Inc.