Earth

The beginning of the end started with violent shaking that raised giant waves in the waters of an inland sea in what is now North Dakota.

Then, tiny glass beads began to fall like birdshot from the heavens. The rain of glass was so heavy it may have set fire to much of the vegetation on land. In the water, fish struggled to breathe as the beads clogged their gills.

The heaving sea turned into a 30-foot wall of water when it reached the mouth of a river, tossing hundreds, if not thousands, of fresh-water fish -- sturgeon and paddlefish -- onto a sand bar and temporarily reversing the flow of the river. Stranded by the receding water, the fish were pelted by glass beads up to 5 millimeters in diameter, some burying themselves inches deep in the mud. The torrent of rocks, like fine sand, and small glass beads continued for another 10 to 20 minutes before a second large wave inundated the shore and covered the fish with gravel, sand and fine sediment, sealing them from the world for 66 million years.

This unique, fossilized graveyard -- fish stacked one atop another and mixed in with burned tree trunks, conifer branches, dead mammals, mosasaur bones, insects, the partial carcass of a Triceratops, marine microorganisms called dinoflagellates and snail-like marine cephalopods called ammonites -- was unearthed by paleontologist Robert DePalma over the past six years in the Hell Creek Formation, not far from Bowman, North Dakota. The evidence confirms a suspicion that nagged at DePalma in his first digging season during the summer of 2013 -- that this was a killing field laid down soon after the asteroid impact that eventually led to the extinction of all ground-dwelling dinosaurs. The impact at the end of the Cretaceous Period, the so-called K-T boundary, exterminated 75 percent of life on Earth.

"This is the first mass death assemblage of large organisms anyone has found associated with the K-T boundary," said DePalma, curator of paleontology at the Palm Beach Museum of Natural History in Florida and a doctoral student at the University of Kansas. "At no other K-T boundary section on Earth can you find such a collection consisting of a large number of species representing different ages of organisms and different stages of life, all of which died at the same time, on the same day."

In a paper to appear next week in the journal Proceedings of the National Academy of Sciences, he and his American and European colleagues, including two University of California, Berkeley, geologists, describe the site, dubbed Tanis, and the evidence connecting it with the asteroid or comet strike off Mexico's Yucatan Peninsula 66 million years ago. That impact created a huge crater, called Chicxulub, in the ocean floor and sent vaporized rock and cubic miles of asteroid dust into the atmosphere. The cloud eventually enveloped Earth, setting the stage for Earth's last mass extinction.

"It's like a museum of the end of the Cretaceous in a layer a meter-and-a-half thick," said Mark Richards, a UC Berkeley professor emeritus of earth and planetary science who is now provost and professor of earth and space sciences at the University of Washington.

Richards and Walter Alvarez, a UC Berkeley Professor of the Graduate School who 40 years ago first hypothesized that a comet or asteroid impact caused the mass extinction, were called in by DePalma and Dutch scientist Jan Smit to consult on the rain of glass beads and the tsunami-like waves that buried and preserved the fish. The beads, called tektites, formed in the atmosphere from rock melted by the impact.

Tsunami vs. seiche

Richards and Alvarez determined that the fish could not have been stranded and then buried by a typical tsunami, a single wave that would have reached this previously unknown arm of the Western Interior Seaway no less than 10 to 12 hours after the impact 3,000 kilometers away, if it didn't peter out before then. Their reasoning: The tektites would have rained down within 45 minutes to an hour of the impact, unable to create mudholes if the seabed had not already been exposed.

Instead, they argue, seismic waves likely arrived within 10 minutes of the impact from what would have been the equivalent of a magnitude 10 or 11 earthquake, creating a seiche (pronounced saysh), a standing wave, in the inland sea that is similar to water sloshing in a bathtub during an earthquake. Though large earthquakes often generate seiches in enclosed bodies of water, they're seldom noticed, Richards said. The 2011 Tohoku quake in Japan, a magnitude 9.0, created six-foot-high seiches 30 minutes later in a Norwegian fjord 8,000 kilometers away.

"The seismic waves start arising within nine to 10 minutes of the impact, so they had a chance to get the water sloshing before all the spherules (small spheres) had fallen out of the sky," Richards said. "These spherules coming in cratered the surface, making funnels -- you can see the deformed layers in what used to be soft mud -- and then rubble covered the spherules. No one has seen these funnels before."

The tektites would have come in on a ballistic trajectory from space, reaching terminal velocities of between 100 and 200 miles per hour, according to Alvarez, who estimated their travel time decades ago.

"You can imagine standing there being pelted by these glass spherules. They could have killed you," Richards said. Many believe that the rain of debris was so intense that the energy ignited wildfires over the entire American continent, if not around the world.

"Tsunamis from the Chicxulub impact are certainly well-documented, but no one knew how far something like that would go into an inland sea," DePalma said. "When Mark came aboard, he discovered a remarkable artifact -- that the incoming seismic waves from the impact site would have arrived at just about the same time as the atmospheric travel time of the ejecta. That was our big breakthrough."

At least two huge seiches inundated the land, perhaps 20 minutes apart, leaving six feet of deposits covering the fossils. Overlaying this is a layer of clay rich in iridium, a metal rare on Earth, but common in asteroids and comets. This layer is known as the K-T, or K-Pg boundary, marking the end of the Cretaceous Period and the beginning of the Tertiary Period, or Paleogene.

Iridium

In 1979, Alvarez and his father, Nobelist Luis Alvarez of UC Berkeley, were the first to recognize the significance of iridium that is found in 66 million-year-old rock layers around the world. They proposed that a comet or asteroid impact was responsible for both the iridium at the K-T boundary and the mass extinction.

The impact would have melted the bedrock under the seafloor and pulverized the asteroid, sending dust and melted rock into the stratosphere, where winds would have carried them around the planet and blotted out the sun for months, if not years. Debris would have rained down from the sky: not only tektites, but also rock debris from the continental crust, including shocked quartz, whose crystal structure was deformed by the impact.

The iridium-rich dust from the pulverized meteor would have been the last to fall out of the atmosphere after the impact, capping off the Cretaceous.

"When we proposed the impact hypothesis to explain the great extinction, it was based just on finding an anomalous concentration of iridium -- the fingerprint of an asteroid or comet," said Alvarez. "Since then, the evidence has gradually built up. But it never crossed my mind that we would find a deathbed like this."

Key confirmation of the meteor hypothesis was the discovery of a buried impact crater, Chicxulub, in the Caribbean and off the coast of the Yucatan in Mexico, that was dated to exactly the age of the extinction. Shocked quartz and glass spherules were also found in K-Pg layers worldwide. The new discovery at Tanis is the first time the debris produced in the impact was found along with animals killed in the immediate aftermath of the impact.

"And now we have this magnificent and completely unexpected site that Robert DePalma is excavating in North Dakota, which is so rich in detailed information about what happened as a result of the impact," Alvarez said. "For me, it is very exciting and gratifying!"

Tektites

Jan Smit, a retired professor of sedimentary geology from Vrije Universiteit in Amsterdam in The Netherlands who is considered the world expert on tektites from the impact, joined DePalma to analyze and date the tektites from the Tanis site. Many were found in near perfect condition embedded in amber, which at the time was pliable pine pitch.

"I went to the site in 2015 and, in front of my eyes, he (DePalma) uncovered a charred log or tree trunk about four meters long which was covered in amber, which acted as sort of an aerogel and caught the tektites when they were coming down," Smit said. "It was a major discovery, because the resin, the amber, covered the tektites completely, and they are the most unaltered tektites I have seen so far, not 1 percent of alteration. We dated them, and they came out to be exactly from the K-T boundary."

The tektites in the fishes' gills are also a first.

"Paddlefish swim through the water with their mouths open, gaping, and in this net, they catch tiny particles, food particles, in their gill rakers, and then they swallow, like a whale shark or a baleen whale," Smit said. "They also caught tektites. That by itself is an amazing fact. That means that the first direct victims of the impact are these accumulations of fishes."

Smit also noted that the buried body of a Triceratops and a duck-billed hadrosaur proves beyond a doubt that dinosaurs were still alive at the time of the impact.

"We have an amazing array of discoveries which will prove in the future to be even more valuable," Smit said. "We have fantastic deposits that need to be studied from all different viewpoints. And I think we can unravel the sequence of incoming ejecta from the Chicxulub impact in great detail, which we would never have been able to do with all the other deposits around the Gulf of Mexico."

"So far, we have gone 40 years before something like this turned up that may very well be unique," Smit said. "So, we have to be very careful with that place, how we dig it up and learn from it. This is a great gift at the end of my career. Walter sees it as the same."

Low levels of oxygen in the womb - which can be caused by smoking or conditions such as pre-eclampsia - may cause problems with fertility later in life, a study carried out in rats suggests.

The research, led by scientists at the University of Cambridge, found that exposing fetuses to chronic hypoxia (low oxygen levels) during development led to them having advanced ageing of the ovaries and fewer eggs available.

Hypoxia in the womb can be caused by a number of factors, including smoking, pre-eclampsia, maternal obesity, and living at high altitude. The condition is already known to have potential long term effects on the health of offspring, including increased risk of heart disease. However, this study, published today in The FASEB Journal, is the first time it has been shown to affect fertility.

To investigate the effects of hypoxia, researchers from the Metabolic Research Laboratories at the University of Cambridge placed pregnant female rats in reduced levels of oxygen (13%, compared to the standard 21% found in air) from day six to day 20 of their pregnancy. They then examined the reproductive tract of their female pups at age four months.

Rats are a useful model for studying pregnancy. As a mammal, their bodies and underlying biology share some key similarities with those of humans. However, their gestation period and lifecycles are much shorter than those of humans, making them an ideal animal model in which to study pregnancy and fetal development.

When the team examined the pups, they found a decrease in the number of ovarian follicles in the reproductive tract. Females are born with fixed numbers of follicles, each with the potential of developing into an egg. In humans, women usually expend all their eggs around the age of fifty, at which point they will enter menopause.

The researchers also looked at telomere length in the pups' ovarian tissue. Telomeres are found at the end of chromosomes and prevent the chromosome from deteriorating - they are often compared to the plastic that seals the end of shoe laces. As we age, telomeres become shorter and shorter, and hence their length can be used as a proxy to measure ageing. The researchers found that telomeres in the ovarian tissue of pups exposed to hypoxia were shorter than in unexposed pups.

"It's as if low levels of oxygen caused the female's ovarian tissue to age faster," says Dr Catherine Aiken from the University of Cambridge. "Biologically, the tissue appears older and the female would run out of eggs - in other words, become infertile - at a younger age."

Although the research was carried out in rats, Dr Aiken says there is every reason to expect that the findings could be translated to humans as previous studies looking at hypoxia during pregnancy in relation to other conditions such as heart disease have been shown to be relevant in humans.

While women are recommended not to smoke during pregnancy, other causes of hypoxia, such as pre-eclampsia and living in a high altitude, are beyond their control. However, says Dr Aiken, the findings of her team's research may prove helpful to women who were exposed to low levels of oxygen during their mother's pregnancy.

"Now that we've seen a link between hypoxia and fertility problems in rats, we know what to look for in women," she says. "If the same turns out to be true for them, then women at risk will be able to take action: by having children earlier in life or looking to assisted reproduction, such as IVF, there should be no reason why these women cannot have children."

Dr Aiken is also involved in research looking at whether anti-oxidant medication may help undo any damage caused by hypoxia.

Paper-based diagnostic tests are cheap, convenient and biodegradable. However, their use is limited by conventional dyes - which are not bright enough to show trace amounts of analyte, are prone to fading, and can be environmentally toxic.

Now researchers are using quantum physics to overcome these limitations, says a review published in Frontiers in Bioengineering and Biotechnology. The bizarre optical properties of tiny metal particles - smaller than light waves - can be captured on paper to detect even a single target molecule in a test sample. These hyper-sensitive testing devices could be assembled and customized at the point of use in low-resource environments, with virtually limitless applications spanning medicine, forensics, manufacturing and environmental safety.

"A new generation of paper-based analytical devices is being developed, which use metal nanoparticles for analyte identification," says lead author Dr. Eden Morales-Narváez of the Center for Optics Research in Mexico. "These will allow low-cost testing in low-resource settings from clinics to crime scenes to contaminated water sources."

Paper-based diagnostics are smart but not bright

Paper is an ideal medium for cheap, accessible diagnostic devices - and has come a long way already from pregnancy-test-style strips that simply mix a sample with a test chemical.

"Paper devices can filter, concentrate and mix reagents with controlled timing and sequence - by using guidelines that can be scored, drawn or even printed on," explains Morales-Narváez. "Some groups have even used origami to vary flow direction and add processing steps that allow more sophisticated, duplicate or parallel reactions using a single paper device."

The real difficulty comes in reading the results of these paper-based tests.

"Test reactions are set up so that if the substance of interest or 'analyte' - a biomarker or pollutant, for instance - is present in a sample, a colored pigment is produced or altered.

"The problem is that conventional pigments produce colors by selectively absorbing some wavelengths and simply reflecting others - for example, red ink appears red because it absorbs strongly in the blue and green spectral regions.

"This means that for a visible color change to occur, relatively large amounts of analyte are required. In other words, the test is not very sensitive."

To make matters worse, the test result cannot be saved as a record because pigments are prone to fading, and in some cases cannot be safely discarded because of pigment toxicity.

A quantum physics solution

What paper-based tests need is an ultra-bright color indicator. Cue metal nanoparticles (MNPs).

"MNPs are can give a brighter, lasting color signal, since they dramatically amplify a particular wavelength of light - rather than simply reflecting it," sums up Morales-Narváez.

As the name suggests, MNPs are nanometer-sized pieces of metal. At about 10-100 times smaller than light waves, their behavior enters the strange realm of quantum physics.

"Put simply: metals consist of a fixed lattice of positive ions, which share a "cloud" of negatively charged free electrons.

"In nanometer-sized pieces of metal, certain wavelengths of light make these free electrons vibrate with respect to the fixed positive ions in the metal. This vibration amplifies the light, emitting a brighter color."

Still confused? Remember that light is a visible electromagnetic field. Imagine a cube of metal placed inside this field. Electrons, being negatively charged, will move to positive pole of the field, uncovering positive metal ions at the negative pole. When the field is gone (or rather as it - the light wave - oscillates) the electrons move in the opposite direction, repelled by each other and attracted back towards the uncovered positive metal ions. The electrons oscillate back and forth in this way with the changing polarity of the electromagnetic field.

Ultra-sensitive paper-based diagnotics

Crucially, the particular wavelength that causes the free electrons to vibrate is tuneable - so the color amplified by MNPs depends on their shape, size and spacing, as well as the type of metal and surrounding medium.

As a result, there are various ways to couple a paper-based test reaction to a change in MNP color.

"You can make MNPs that bind the analyte, then let these flow in solution over fixed biorecognition elements on the paper such as antibodies, that also bind the analyte. A positive test will cause the MNPs to accumulate and so change their spacing and surroundings.

"Alternatively, MNPs can be released from a holding molecule when this reacts with an analyte.

"Some analytes can even erode MNPs, causing a color change directly. For example, ammonia and other volatile compounds from food spoilage, or UV radiation from sun exposure."

The result: ultra-sensitive paper diagnostics.

"MNPs can produce visible color changes at even attomolar concentrations of analyte," confirms Morales-Narváez.

That's about 30 molecules per drop of test sample. But if the paper test is read by a special machine rather than the human eye, the sensitivity is even higher still.

"Combined with a scanning technique called Raman spectroscopy, MNPs can report detection of a single molecule of analyte."

With over 10,000 research articles exploring the use of MNPs published in 2018 alone, it may not be long before quantum physics-powered paper diagnostic devices enter the mainstream.

A new technique developed by scientists at the Broad Institute of MIT and Harvard gives an unprecedented view of the cellular organization of tissues. Known as Slide-seq, the method uses genetic sequencing to draw detailed, three-dimensional maps of tissues, revealing not only what cell types are present, but where they are located and what they are doing.

Because it does not require specialized imaging equipment, the technique can be employed by scientists across diverse fields of biology, genetics, and medicine who want to look at the cellular structure of tissues, or to observe where particular genes are active in a tissue, an organ, or even whole organisms.

Such a platform offers unparalleled views of the cellular structure of tissues, the roles played by genes in different tissues, and the effects of injury or other perturbations on tissue, giving researchers rich maps of tissue function that have never before been possible.

The Slide-seq method was developed in the labs of Broad associate member Evan Macosko, also an assistant professor of psychiatry at Harvard, and Fei Chen, a Schmidt fellow at the Broad.

The work appears online in Science.

In the 19th century, neurobiologist Santiago Ramón y Cajal thrilled the scientific world with his detailed drawings of human tissue, demonstrating that the brain is made up of individual cells. The development of antibodies in the mid-20th century later allowed researchers to peek at proteins - a few at a time - in cells and tissue. In recent years, RNA sequencing has enabled scientists to identify which cell types are present in a tissue and which genes are turned on across the genome, but not where those cells are precisely located.

Slide-seq can be seen as the latest advance in this technological evolution.

The technique begins with a rubber-coated glass slide, or "puck," that is packed with microparticles, or "beads," covered in unique DNA barcodes. The Broad team sequences each of those barcodes, generating data that later allows users to determine where the sequencing reads originated on the bead array.

"It's like a cellular form of GPS," said Robert Stickels, co-first author and a graduate student in the Macosko lab. "When we built this technology, we wanted to make it easy for our collaborators to use. We do all the imaging and array generation upfront, and give the arrays to the end user so they don't need to have specialized expertise in microscopy."

In a few hours of work with arrays provided by the Broad, researchers can transfer slices of fresh-frozen tissue onto the bead surface and dissolve the tissue, leaving mRNA transcripts bound to barcoded beads. The barcoded RNA library is then sequenced on commercial instruments. Software developed by the Broad team and provided to end users assigns locations to each sequencing read, which can be plotted to generate high-resolution maps of cell types or gene expression, with richer information than that of standard microscopy images.

To demonstrate the tool's capabilities, the team used Slide-seq to localize cell types within the cerebellum and hippocampus in the mouse brain, highlighting detailed structures including a one-cell-thick layer of cells. Applying Slide-seq to slices of mouse cerebellum, the team revealed bands of gene activity variation across the tissue, patterns that indicate spatially defined subpopulations that were not discernable using traditional single-cell sequencing.

The team also showed that Slide-seq can be useful to test the effects of perturbations, using it to monitor the responses of specific cell types in a mouse model of traumatic brain injury. By filtering the data to show expression of individual genes, they found some genes turned on in neurons based on proximity to the injury even long after the injury occurred.

The researchers also demonstrated that stacking a series of tissue slices can reveal three-dimensional tissue organization and cellular function by generating an animated 3D reconstruction of mouse hippocampus, which can be customized to display different cell types or expression of individual genes.

"Single-cell RNA sequencing is really good at telling you what kind of cells are in your sample," said co-first author Samuel Rodriques, an affiliate in the Chen lab and an MIT graduate student in the lab of Broad associate member Ed Boyden. "But Slide-seq is a fundamentally new tool that adds a whole different dimension by telling us where cells are in the tissue. We're excited to work with collaborators in many fields to answer some novel scientific questions."

WASHINGTON, D.C. March 28, 2019 -- While many advancements have been in improving its efficiency, the refrigerator still consumes considerable amounts of energy each year.

"Energy efficiency of a normal refrigerator is affected by the heat-insulating property of the thermal barriers of the freezer. This is due to its low inner temperature," explained Jingyu Cao at the University of Science and Technology of China. "There is a significant difference in temperature between the freezer of a traditional refrigerator and ambient air temperature and the normal thermal barrier of the freezer causes considerable cold loss."

Cao and his team hypothesized that using part of the cold loss to cool the fresh food compartment could be a promising solution in improving the efficiency of the refrigerator. They describe their findings in the Journal of Renewable and Sustainable Energy, from AIP Publishing.

"The evaporating temperature of the refrigeration cycle depends only on the freezer temperature and appropriate reduction of the evaporator area in the fresh food compartment will not decrease the overall efficiency," explained Cao.

"Most families need one or two refrigerators and they are always on 24 hours a day, 365 days a year. That wastes a lot of energy. Even if we can save a little energy, that helps the human race be more energy-efficient," said Cao.

Cao and his team are not the first scientists to attempt to improve the efficiency of household refrigeration. Extensive experiments by many different scientists have looked at various parts of the refrigerator to improve energy consumption, but a definitive solution has not yet been found. In Cao's study, a novel refrigerator with a loop thermosyphon is put forward to decrease the heat transfer between the freezer and ambient air.

"One of the surprises was how much energy we saved. The energy-saving ratio of the improved walls got close to 30 percent -- more than we had expected. This technology even works in hot climates like the desert."

Although Cao's study is currently based on theoretical calculation, the results are promising. "It has great potential to be popularized as a sustainable energy technology or applied in the renewable energy field, considering its significant energy-saving effect, simple structure and low cost," said Cao.

Scientists at the Department of Energy's Oak Ridge National Laboratory are working to understand both the complex nature of uranium and the various oxide forms it can take during processing steps that might occur throughout the nuclear fuel cycle. An improved understanding of uranium oxides, which fuel the vast majority of the U.S nuclear power fleet, could lead to the development of improved fuels or waste storage materials.

ORNL researchers approached this problem computationally with help from the lab's Compute and Data Environment for Science (CADES). Through CADES, ORNL staff members have access to computing resources that engineers tailor to specific projects, enabling management and analysis of massive datasets too cumbersome to tackle otherwise.

Amorphous uranium oxides are common, but the lack of a consistent structural order within them can be difficult to model. To address this challenge and accelerate the process of identifying novel uranium oxide phases, scientists in ORNL's Nuclear Security Advanced Technologies Group evaluated the energy of 4,600 different potential crystal structures of uranium oxide compositions.

Using genetic algorithms--computational tools designed to efficiently solve problems according to the theory of natural selection--the team studied these structures on a CADES high-performance computing cluster called Metis, a two-cabinet Cray XK7 system.

This method helped them build statistical relationships between structural stability and the local uranium environment, two factors that affect the crystallinity of solid forms. Interpreting this information could lead to a more concrete understanding of how crystalline and amorphous uranium materials form in the nuclear fuel cycle.

"Our main goal is to try to understand some of these amorphous phases for uranium oxides," said Ashley Shields, an ORNL postdoctoral associate. "They arise during the nuclear fuel cycle and are difficult to study, but we hope that our computational approach will help us better characterize samples of these materials."

After determining that the project required a significant amount of computing power, CADES personnel provided Shields and her team with exclusive access to the entire Metis system for 15 days to evaluate these structures using the Universal Structure Predictor Evolutionary Xrystallography (USPEX) software package and the Vienna ab initio Simulation Package (VASP).

"Given the sheer number of calculations we had to execute to build this database of structures, we really needed the help of the CADES team," Shields said. "Without their support, as well as recent advances in computing power and research from other groups to develop genetic algorithms specifically applied to structure prediction problems, this project wouldn't have been possible."

Shields and her team identified a potentially stable crystalline phase for a material, U2O7, which has only been observed experimentally as an amorphous phase. To learn more about this phase, they studied 2,700 possible crystal geometries for U2O7 in addition to the 4,600 original structures. Their findings are published in Optical Materials.

Because an amorphous U2O7 material can be made from amorphous UO3, NSAT's Andrew Miskowiec and Jennifer Niedziela led experiments aiming to crystallize U2O7 from samples of UO3. To support this effort, Shields compared the simulated effects of pressure on known phases of UO3 and the predicted U2O7 structure, identifying pressures where experimentally observable structural changes may take place.

"We haven't found crystalline U2O7 in the lab yet, but what we did find was really unusual pressure behavior in amorphous UO3, which led us to some really interesting physics that we're still working to fully understand," Shields said.

Despite lacking definitive proof of crystalline U2O7's existence, the team noted features in the predicted structure that correspond well with features in amorphous U2O7. They identified potential coordination geometries, or atomic patterns, in line with the material. Most striking among these observations was the discovery of peroxide units in the predicted structure.

"It's already proven useful to have this database of structures because clearly just looking at known crystalline phases for one material like UO3 does not provide enough information to explain all the behaviors of an amorphous sample of the same material," Shields said.

Linux Systems Engineer Ketan Maheshwari and Computer Systems Analyst Michael Galloway of CADES helped set up the computational components involved in the project, from modifying source code to make USPEX run more efficiently on Metis to creating post-processing scripts--tiny operations that extract information from computational results--to decipher scientific output.

"To help the team run at such a large scale and successfully use GPUs, we installed and tested VASP at scale on Metis and troubleshot the jobs as needed to ensure the work was done in a timely and efficient manner," Maheshwari said.

Shields anticipates that this ongoing project will continue for at least another year and looks forward to other studies that apply machine learning and artificial intelligence concepts to uranium chemistry research. Currently, she is compiling a similar database composed of uranium fluorides, another key subset of materials involved in the nuclear fuel cycle.

Researchers at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and the University of Massachusetts Medical School have developed a strategy to treat two of the most common inherited blood diseases -- sickle cell disease and beta thalassemia -- applying CRISPR-Cas9 gene editing to patients' own blood stem cells. Described this week in Nature Medicine and in a January report in the journal Blood, their approach overcomes prior technical challenges, editing blood stem cells more efficiently than in the past.

The two studies show that the gene-edited cells generate genetically corrected red blood cells producing functional hemoglobin.

"We think our work defines a strategy that could lead to the cure of common hemoglobin disorders," says Daniel Bauer, MD, PhD, an attending physician with Dana-Farber/Boston Children's and a senior author on both papers. "Combining gene editing with an autologous stem-cell transplant could be a therapy for sickle-cell disease, beta-thalassemia and other blood disorders."

Together, sickle cell disease and beta-thalassemia affect 332,000 conceptions or births worldwide each year, according to the World Health Organization. Both diseases involve mutations in the gene for beta globin protein. In beta-thalassemia, the mutations prevent red blood cells from producing enough of the oxygen-carrying hemoglobin molecule, leading to anemia. In sickle cell disease, the mutation causes hemoglobin to change shape, distorting red blood cells into stiff "sickle" shapes that block up blood vessels.

More efficient editing

The Nature Medicine study used CRISPR-Cas9 technology, in particular a Cas9 protein modified by a team led by Scot Wolfe, PhD at UMass Medical School, to optimize gene editing. In previous attempts to edit the genomes of human blood stem and progenitor cells, the efficiency, specificity and long-term stability of the edits once the cells engraft in the bone marrow have varied. The new technique improves the targeting and durability of the edits.

"Efficient editing of the blood stem cell population -- ideally at rates approaching 100 percent -- is critical to achieve a durable therapeutic effect for patients," says Wolfe, a professor in the Department of Molecular, Cell and Cancer Biology at UMass Medical School. "Progress toward this goal has been advancing through the contributions of multiple laboratories in the scientific community. My research team, in collaboration with the Bauer laboratory, focused on improving the efficiency of delivery and nuclear entry of the CRISPR-Cas9 technology to achieve nearly complete therapeutic editing of the entire blood stem cell population."

Bauer's team used the strategy to make a highly targeted edit. Previous work at Boston Children's had showed that inactivating a gene called BCL11A allows red blood cells to keep producing a fetal form of hemoglobin even after birth. Fetal hemoglobin doesn't sickle and can stand in for defective "adult" hemoglobin. More recently, Bauer found a safer target: a genetic enhancer of BCL11A that is active only in red blood cells.

"With our new very efficient protocol, we can edit the BCL11A enhancer in nearly all blood stem cells we collect, overcoming some of the technical challenges of editing these cells," says Bauer. "In our experiments, more than 95 percent of copies of the enhancer sequence were changed in a way we expect would be therapeutic."

The strategy enabled mice carrying blood stem cells from patients with sickle cell disease to produce red blood cells with enough fetal hemoglobin to prevent cell sickling. The team showed that the gene-edited cells, infused back into the bloodstream, engrafted in the bone marrow and produced genetically corrected red blood cells. Later, when blood stem cells were isolated from these mice and transplanted into other mice, the cells engrafted again, still carrying the therapeutic gene changes.

Applied to blood stem cells from patients with beta-thalassemia, the same strategy restored the normal balance of the globin chains that make up hemoglobin.

The other study, published in Blood, used a similar gene editing protocol to target forms of beta-thalassemia that involve splicing mutations -- errors in bits of DNA near the beta-globin gene that change how the gene is read out to assemble beta-globin protein. In this study, nine patients with beta thalassemia donated their cells, which were manipulated in a dish. For some patients, the UMass team produced a different enzyme, Cas12a, to more effectively target their mutations. The CRISPR system efficiently made edits and restored normal splicing of the beta-globin protein in blood cells from each of the patients.

Setting the stage for a clinical trial

The investigators are taking steps to take their BCL11A enhancer editing strategy to the clinic. They are developing a clinical-grade, scaled up protocol for cell product manufacturing, and performing safety studies necessary for regulatory approval from the FDA. They plan to seek funding from the National Heart, Lung and Blood Institute's Cure Sickle Cell initiative to launch a clinical trial in patients.

Dana-Farber/Boston Children's has already begun a clinical trial of gene therapy for sickle cell disease. That approach increases fetal hemoglobin production by exposing patients' blood stem cells to a lentivirus carrying instructions to knock down the BCL11A gene in red-blood-cell precursors.

Bauer believes it's important to keep pursuing both approaches. "These conditions are very common inherited diseases and occur especially often in parts of the world where resources are quite limited," he says. "So we need a broad set of therapeutic options to make treatment available to as many patients as possible."

Yuxuan Wu and Jing Zeng of Dana-Farber/Boston Children's are co-first authors on the Nature Medicine paper; Bauer is corresponding author. Shuqian Xu of Dana Farber/Boston Children's is first author on the Blood paper; Bauer and Wolfe are co-corresponding authors.

The work was supported by the Translational Research Program at Boston Children's Hospital, the National Institutes of Health (NHLBI, NHGRI, NIAID, NIGMS, NIDDK), bluebird bio, the Harvard Stem Cell Institute, the St. Jude Children's Research Hospital Collaborative Research Consortium, the Burroughs Wellcome Fund, the American Society of Hematology and the Doris Duke Charitable, Charles H. Hood and Cooley's Anemia Foundations.

Boston Children's Hospital> is an equity holder in bluebird bio, and several authors have applied for patents related to therapeutic gene editing.

Boston Children's Hospital may gain financial benefits if the technology being studied proves to be of benefit. As in all research studies, the Hospital has taken, and will continue to take, all necessary steps to ensure research subject safety, and the validity and integrity of the information obtained by this research.

As we go about our daily lives, we are constantly bombarded by a steady stream of sensory information. Take a typical morning routine for example- roused from sleep by a shrill alarm, the strong aroma of freshly brewed coffee, and the brake lights and traffic horns of rush hour. In the course of a single day, we experience thousands of different cues across all senses.

Despite the numerous chaotic cues we encounter, our brains do a remarkable job assembling and processing them; allowing us to make sense of the world around us. This processing can take shape in very noticeable ways, such as our vision and hearing, but also occurs more subtly and unexpectedly. For instance, when learning a new movement, our brain is constantly keeping track of the sensory cues around us. This sensory snapshot helps to instruct and guide motor learning so that when we encounter the same context again, we'll be more likely to perform the movement in better way.

Though there is a wealth knowledge supporting the idea that sensory cues benefit motor learning, the precise brain circuitry and mechanisms tying these two together has been debated in recent years. Shedding new light on this topic, a recently published paper in Neuron from the lab of Dr. Jason Christie, Research Group Leader at the Max Planck Florida Institute for Neuroscience (MPFI), has revealed that a special input pathway into the cerebellum seems to hold the key to coding sensory information.

The cerebellum is a unique structure within the brain that plays a critically important role in motor coordination and learning that improves movements. By receiving many inputs from various regions of the brain, the cerebellum integrates and sends refined information out through a single neuron type called a Purkinje cell. One significant input to the Purkinje cells, are long-range projections called climbing fibers.

"Climbing fibers are very well-known and extensively studied in the field." describes Dr. Michael Gaffield, Research Fellow in the Christie Lab and first author of the publication. "These fibers form long-range connections with the cerebellum and are thought to deliver instructive motor signals and relay sensory information. But in the past few years it's been suggested that local circuits within the cerebellum, such as parallel fibers or molecular layer interneurons, may also play a part in coding of sensory information."

To investigate, the team used two-photon calcium imaging to monitor the activity of Purkinje cells within the cerebellum of mice while presenting various sensory stimuli (auditory, visual and somatosensory). They then isolated and assessed changes in Purkinje cell activity that directly corresponded to the timing of each individual stimulus and climbing fiber input.

"Within each Purkinje cell, we saw a consistent enhancement of activity whenever a sensory stimulus was presented. But the enhancement wasn't the exact same across all three sensory types, it varied depending on the type of stimulus presented" explains Gaffield.

Next MPFI scientists examined if other cell types besides climbing fibers, contributed directly to the sensory enhanced activity seen in the Purkinje cells. Using the techniques of optogenetic inactivation (suppression of neural activity using light) and chemogenetic inhibition (suppression of neural activity using drugs), the team was able to inhibit individual cell types in the local cerebellar circuitry. Despite altering the local activity, no change occurred to the sensory enhanced activity of the Purkinje cells. However, by inhibiting climbing fiber activity directly, the enhancement was abolished; indicating that climbing fibers alone are responsible for conveying sensory information to the cerebellum.

Taking their investigation a step further, the Christie lab pioneered a novel technique allowing them to monitor the activity of climbing fiber axonal projections themselves. They discovered that when presenting sensory stimuli, the graded changes in the presynaptic activity of climbing fibers was accurately represented in the Purkinje cells; stronger activity in the climbing fiber was precisely mirrored by stronger activity in the Purkinje cells they connect with.

"Our results actually came as a bit of a surprise" notes Dr. Christie. "Traditionally it was thought that sensory signals arriving in the cerebellum were integrated and processed by Purkinje cells using local connections. Our findings demonstrate that Purkinje cells are merely reflecting what the climbing is doing. This means that a more distal region of the brain is doing the actual processing of sensory information and simply relaying it to the cerebellum. "

"Since Purkinje cell activity is critically important for motor learning, we are now in the process looking at sensory-derived activity during more complex motor behaviors" describes Dr. Christie. "Hopefully we will be able to uncover the neural mechanisms that underlie the climbing fiber's unique ability to convey sensory information and how learning benefits from this coding scheme."

Your chances of getting a nasty migraine increase following a spinal cord injury, thanks to a chemical messenger in the brain that spikes to toxic levels, past studies have suggested.

For treatment to get any better, researchers need to catch that split-second spike in action and closely follow its path of destruction.

Purdue University engineers have built a tiny, flexible sensor that is faster and more precise than past attempts at tracking this chemical, called glutamate. The sensor, an implantable device on the spinal cord, is primarily a research tool for testing in animal models, but could find future clinical use as a way to monitor whether a drug for neurotrauma or brain disease is working.

The group's work appears in a forthcoming issue of Biosensors and Bioelectronics.

"When you feel like you're running a fever, it doesn't matter when you check your temperature - it will probably be the same for several hours. But a glutamate spike is so fast that if you don't capture it at that moment, you miss the whole opportunity to get data," said Riyi Shi, a professor of neuroscience and biomedical engineering in Purdue's Department of Basic Medical Sciences, College of Veterinary Medicine and Weldon School of Biomedical Engineering.

Impact, such as from a car accident or tackle in football, can injure the spinal cord - also injuring the nerve structures that transport glutamate, which sends signals to excite nerve tissue for performing functions such as learning and memorizing.

Damaged nerve structures means that loads of glutamate leak out into spaces outside of cells, over-exciting and damaging them. Brain diseases, including Alzheimer's and Parkinson's, also show elevated levels of glutamate.

Devices so far either haven't been sensitive enough to detect glutamate, fast enough to capture its spike or affordable enough for long-term research projects.

Purdue researchers are addressing these issues through implantable sensors that they have 3D printed and laser-micromachined - processes that are already used regularly in the lab and industry. A YouTube video is available at https://youtu.be/hyn9SM1wdz0.

"We wanted to create a low-cost and very fast way to build these sensors so that we can easily provide researchers with a means to measure glutamate levels in vivo," said Hugh Lee, a Purdue assistant professor of biomedical engineering, who focuses on implantable microtechnologies.

The technique allows researchers to rapidly change the size, shape and orientation of the sensors and then test in animal models without having to go through the more expensive process of microfabrication.

Measuring levels in vivo would help researchers to study how spinal cord injuries happen, as well as how brain diseases develop.

"How big of a problem is a migraine? Is too much glutamate really behind the pain, or is it that the system that cleans up glutamate is down?" Shi said.

The researchers implanted the device into the spinal cord of an animal model and then injured the cord to observe a spike. The device captured the spike immediately, whereas for current devices, researchers have had to wait 30 minutes to get data after damaging the spinal cord.

In the future, the researchers plan to create a way for the biosensors to self-clear of inflammatory cells that the body recruits to protect itself. These cells typically form a fibrous capsule around the biosensor, which blocks its sensitivity.

The technology could also allow for implanting more sensors along the spinal cord, which would help researchers to know how far glutamate spreads and how quickly.

The researchers have filed a patent application for this device with the Purdue Research Foundation Office of Technology Commercialization. The work was supported by the Global Research Outreach program of the Samsung Advanced Institute of Technology, the National Institutes of Health, and sponsored in part by the National Science Foundation under grant CNS-1726865.

This research aligns with Purdue's Giant Leaps celebration, acknowledging the university's global advancements made in health, longevity and quality of life as part of Purdue's 150th anniversary. This is one of the four themes of the yearlong celebration's Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.

The cocktail of man-made chemicals that we are exposed to daily is a health risk which current regulations and risk assessment overlook. This is the conclusion of the EU Horizon 2020 EDC-MixRisk project that is now being presented.

We are exposed to a large number of man-made chemicals in our everyday life. This creates combinations of chemical mixtures, to which we are subjected during our whole lifespan. Current risk assessment and management practices, however, focus mainly on exposure to single substances. Exposure to hazardous substances, especially endocrine disrupting chemicals (EDCs), during the foetal period is of particular concern, as it can lead to irreversible changes in the development of organs and tissues and increased susceptibility to diseases later in life.

The EDC-MixRisk project was initiated to investigate how effects caused by real-life relevant mixtures could be studied. The project developed a novel approach based on identifying and testing EDC mixtures associated with adverse health outcomes in humans.

An overarching conclusion from the EDC-MixRisk project is that current regulations of man-made chemicals systematically underestimate health risks associated with combined exposures to EDCs or potential EDCs.

Effects caused by exposure during the foetal period

By using epidemiology data from the Swedish pregnancy cohort SELMA (a cohort of more than 2300 pregnant women), reference mixtures were created to mimic real life exposures (at concentrations found in the pregnant women). These mixtures were tested in various experimental (cell and animal) models, and the toxicological data from these tests were used to establish new methods and strategies for mixture risk assessment in order to better account for complex environmental exposures.

Professor Åke Bergman at Stockholm University and coordinator of the project, says "the novel whole mixture approach applied in EDC-MixRisk has allowed us to assess the number of mothers in the SELMA cohort that are at risk for effects in their children, effects related to growth and metabolism, neurodevelopment and sexual development".

Researchers in Professor Testa's laboratory in Milano spearheaded the use of human brain organoids to directly assess the impact of such mixtures on the closest available model of the developing human brain. They uncovered that even at real life concentrations, EDCs interfere with the same regulatory networks that are already involved in the genetic forms of autism spectrum disorder and intellectual disability. "This new method enables the investigation of relevant chemical exposures on equally relevant windows of sensitivity during human brain development", Professor Testa points out.

In Paris, the team of Professor Demeneix investigated whether the mixtures interfered with brain development and growth through modulation of thyroid hormone signalling. Professor Demeneix underlines that "Thyroid hormone is essential for brain development and children born to mothers that have insufficient thyroid hormone also have increased risk of autism spectrum disorder and IQ loss.

Thyroid hormone signalling and numerous thyroid hormone dependent genes were disrupted by the mixture in the different models tested. These findings reveal a mechanism whereby brain development is affected by exposure to the chemicals at relevant human exposure levels."

Tokyo, Japan - A team at The University of Tokyo described in unprecedented detail the rare phenomenon called "liquid-to-liquid phase transitions" in a pure substance. By showing how a liquid made of just one type of molecule can switch between liquid and glassy states, this research may lead to a novel way to control the transport properties of a liquid.

Phase transitions are a familiar part of daily life. Whenever you see ice melting (solid to liquid), or steam coming from a teakettle (liquid to gas), you've just experienced a phase transition. However, the study of how one arrangement of molecules changes into another reveals complex details about the strength of their interactions. In conventional phase transitions, as with an iron bar melting into molten metal, added heat causes the atoms to vibrate so violently that they break free of their solid lattice arrangement and assume a liquid form. The team at The University of Tokyo studied a much rarer type of phase transition: from one liquid state to another. In this research, they found that, even without changing temperature, relatively free-flowing triphenyl phosphite could gradually vitrify into a glassy state, in which the molecules remain disordered but are much less mobile. The different phases were identifiable experimentally based on how quickly the molecules could relax after being perturbed.

"Contrary to intuition, there has been a growing body of experimental and theoretical evidence that even a single-component substance may have multiple liquid states," says lead author Hajime Tanaka. They found that the phase transition can occur in two very different ways. The first is called "nucleation and growth," a slow process that requires the emergence of one phase in the other overcoming a barrier to get started. The other type is spinodal decomposition, in which the transition can smoothly proceed without any barrier. The researchers also discovered a critical temperature, above which only nucleated growth could occur, but below this temperature, spinodal decomposition was possible.

"From the viewpoint of practicality, triphenyl phosphite may be one of the best systems for studying liquid-to-liquid transitions, since the transformation takes place at ambient pressure and moderate temperatures," says first author Ken-ichiro Murata. "Phase transitions, particularly those that involve a change from a liquid to a glassy state, are often used in the manufacturing of polymers. This research may greatly enhance our ability to optimize and control these processes."

Barnacles that hitch rides on the backs of humpback and gray whales not only record details about the whales' yearly travels, they also retain this information after they become fossilized, helping scientists reconstruct the migrations of whale populations millions of years in the past, according to a new University of California, Berkeley, study.

Oxygen isotope ratios in barnacle shells change with ocean condition and allow scientists to chart the migration of the host whale, for example to warmer breeding grounds or colder feeding grounds. Now, marine paleobiologists led by UC Berkeley doctoral student Larry Taylor have discovered that barnacles retain this information even after they fall off the whale, sink to the ocean bottom, and become fossils."

As a result, the travels of fossilized barnacles can serve as a proxy for the peregrinations of whales in the distant past, like GPS trackers from the Pleistocene.

"One of the more exciting things about the paper, in my mind, is that we find evidence for migration in all of these ancient populations, from three different sites and time periods, but also from both humpback and gray whale lineages, indicating that these animals, which lived hundreds of thousands of years ago, were all undertaking migrations similar in extent to those of modern-day whales," Taylor said.

One surprise finding is that the coast of Panama has been a meeting ground for different subpopulations of humpback whales for at least 270,000 years and still is today. Whales visit Panama from as far away as Antarctica and the Gulf of Alaska.

This information about ancient migration will help scientists understand how migration patterns may have affected the evolution of whales over the past 3 to 5 million years, how these patterns changed with changing climate and help predict how today's whales will adapt to the rapid climate change happening today.

"We want to understand how malleable migratory behavior has been through time, how rapidly whales have adapted to previous climate changes, and see if this can give us some clues as to how they might respond to the current changes in Earth's climate," he said. "How will whales cope with that, how will the food base shift, how will the whales themselves respond?"

Taylor and his colleagues, senior author Seth Finnegan, a UC Berkeley associate professor of integrative biology, Aaron O'Dea of the Smithsonian Tropical Research Institute in Panama and Timothy Bralower of Pennsylvania State University in University Park, will publish their findings this week in the journal Proceedings of the National Academy of Sciences.

Riding the whales

Barnacles are crustaceans, like crabs, lobsters and shrimp, that remain stuck in one place their whole lives, encased in a protective hard shell and sticking out their legs to snatch passing food. Most glue themselves to rocks, boats or pilings, but whale barnacles attach to a whale's skin by boring down into it. Some whales have been estimated to carry up to 1,000 pounds of barnacles, which are visible when they breech. Clusters of barnacles are used to identify individual whales.

"This gives the barnacle several advantages: a safe surface to live on, a free ride to some of the richest waters in the world and a chance to meet up with other (barnacles) when the whales get together to mate," O'Dea said.

Taylor's technique works because different species of whale barnacle hitch rides on different species of whale, so paleontologists can know, when they find a fossilized barnacle, which species it rode with. Normally, the barnacles stay with a whale between one and three years, until they fall or are brushed off, often at whale breeding grounds. At least 24 fossil assemblages of whale barnacles have been found around the world, Taylor said.

The new discovery means that the fossilized barnacles recovered at these sites can tell about ancient migrations of humpbacks, gray whales and perhaps other baleen whales (toothed whales, such as sperm whales, do not host many barnacles), potentially turning up previously unsuspected feeding and breeding areas.

The technique is based on measuring the oxygen isotopes in the calcium carbonate, or calcite, shell of the barnacle. The ratio of oxygen-18 to oxygen-16 goes up as the temperature drops. Since barnacles lengthen their shells by a few millimeters a month as they try to stay attached to whales in the face of the mammals' shedding skin, the composition of the new shell reflects the ocean temperature and general isotopic composition where it formed.

Taylor built on previous work showing that barnacles attached to living gray whales record a chemical signature of their migrations. He confirmed that the isotopic composition of the humpback whale barnacle (Coronula diadema) also tracks its environment today during the whales' yearly migration, showing monthly changes. He then demonstrated that fossilized barnacles from Panama and from the California coast could be analyzed similarly, and that they showed isotopic changes similar to that of today's whales."

This technique will be particularly valuable for studying prehistoric humpback populations, Taylor said, because the humpback was and is more cosmopolitan than the California gray whale, cruising widely through the Pacific and Atlantic oceans. Scientists theorize that whale migration began as food sources became more scattered as the climate changed 5 million years ago. Modern Pacific whales migrate tens of thousands of miles annually, visiting several known feeding areas and returning to warm waters off Central and South America or Hawaii to breed.

"We plan to push this approach further back in time and across different whale populations," Finnegan said. "We hope that by analyzing other aspects of the geochemistry of the barnacles shells we might ultimately be able to figure out what areas different ancient whale populations were migrating to."

ANN ARBOR, Mich. - Picking what book to read isn't the only choice families now make at story time - they must also decide between the print or electronic version.

But traditional print books may have an edge over e-books when it comes to quality time shared between parents and their children, a new study suggests.

The research, led by University of Michigan C.S. Mott Children's Hospital and involving 37 parent-toddler pairs, found that parents and children verbalized and interacted less with e-books than with print books. The findings appear in journal Pediatrics, which is published by the American Academy of Pediatrics.

"Shared reading promotes children's language development, literacy and bonding with parents. We wanted to learn how electronics might change this experience," says lead author Tiffany Munzer, M.D., a fellow in developmental behavioral pediatrics at Mott.

"We found that when parents and children read print books, they talked more frequently and the quality of their interactions were better."

The parent-toddler pairs in the study used three book formats: print books, basic electronic books on a tablet and enhanced e-books featuring additions like sound effects and animation. With e-books, not only did the pairs interact less but parents tended to talk less about the story and more about the technology itself. Sometimes this included instructions about the device, such as telling children not to push buttons or change the volume.

Munzer notes that many of the interactions shared between parents and young children while reading may appear subtle but actually go a long way in promoting healthy child development.

For example, parents may point to a picture of an animal in the middle of a story and ask their child "what does a duck say?"

Or, parents may relate part of a story to something the child has experienced with comments like "Remember when we went to the beach?" Reading time also lends itself to open-ended questions, such as asking children what they thought of the book or characters.

Munzer says these practices, involving comments and questions that go beyond content, are believed to promote child expressive language, engagement, and literacy.

"Parents strengthen their children's ability to acquire knowledge by relating new content to their children's lived experiences," Munzer says. "Research tells us that parent-led conversations is especially important for toddlers because they learn and retain new information better from in-person interactions than from digital media."

However, such practices occurred less frequently with electronic books, with parents asking fewer simple questions and commenting less about the storyline compared with print books.

The study suggests that electronic book enhancements were likely interfering with parents' ability to engage in parent-guided conversation during reading.

Munzer adds that nonverbal interactions, including warmth, closeness and enthusiasm during reading time also create positive associations with reading that will likely stick with children as they get older.

Authors recommend that future studies examine specific aspects of tablet-book design that support parent-child interaction. Parents who do choose to read electronic books with toddlers should also consider engaging as they would with the print version and minimize focus on elements of the technology itself.

"Reading together is not only a cherished family ritual in many homes but one of the most important developmental activities parents can engage in with their children," says senior author Jenny Radesky, M.D., developmental behavioral pediatrician at Mott.

"Our findings suggest that print books elicit a higher quality parent-toddler reading experience compared with e-books. Pediatricians may wish to continue encouraging parents to read print books with their kids, especially for toddlers and young children who still need support from their parents to learn from any form of media."

AUSTIN, TEXAS (March 24, 2019)--Smart speakers that are customarily used in your living room can be programmed to act as an aid to physicians in hospital operating rooms, according to new research presented today at the Society of Interventional Radiology's 2019 Annual Scientific Meeting. Smart speakers, such as the Amazon Echo and Google Home, offer a conversational voice interface that allows interventional radiology (IR) physicians to ask questions and retrieve information needed for their patient treatments without breaking sterile scrub.

"During treatment, IRs rely on nuanced medical information delivered in a timely manner. When you're in the middle of a procedure, you need to remain sterile, so you lose the ability to use a computer," said Kevin Seals, MD, a fellow in interventional radiology at the University of California, San Francisco (UCSF) and lead author of the study. "This smart speaker technology helps us to quickly and intelligently make decisions relevant to a patient's specific needs."

The researchers at UCSF developed a device-sizing application for the Google Home smart speaker. The application processes questions from a human voice and provides recommendations on the precise sizing of medical devices. For example, if an IR needs to know what size sheath to use to implant a stent in a patient's blood vessel, the smart speaker can quickly and accurately communicate the correct size based on the specific circumstances, which helps the physician in making a final decision.

"There are hundreds of devices, with more being introduced every day, making it difficult to determine the correct sizing or materials needed in every circumstance. This technology allows physicians to concentrate more closely on the care of their patients, devoting less time and mental energy to device technicalities," said Seals.

In developing the application, size specifications were acquired using literature reviews for 475 IR devices, such as catheters, sheaths, stents, vascular plugs and others. Natural language processing was implemented using Dialogflow, which extracted the information of interest from an input query. Logic operations and other data processing were performed using a Python script deployed to the cloud.

The researchers plan to continue to build on this technology and expand its scope to include information on material costs and inventory databases. Having this information readily available will make treatments more efficient, cost-effective and beneficial to patients. Further research will look to yield information for physicians in other specialties and provide information from electronic health records and patient clinical data, such as allergies or prior surgeries.

NEW ORLEANS--Young women are more likely to experience sleep disruption in the days leading up to their menstrual period, according to a new study that will be presented Saturday at ENDO 2019, the annual meeting of the Endocrine Society, in New Orleans, La.

"Sleep is more disrupted in the several days directly prior to menses in young healthy women," said Anne E. Kim, a medical student at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Cleveland, Ohio. "Increased sleep disruption was found in the late luteal phase, which corresponds with the days directly prior to menses." Menstrual phase affected sleep efficiency, wake after sleep onset (WASO), number of awakenings per night, and sleep fragmentation index, in keeping with increased sleep disruption in the late luteal phase. Compared with the early follicular phase, sleep efficiency decreased by 3.3 percent, WASO increased by 15 minutes, and number of awakenings per night increased by three in the late luteal phase.

Kim and her colleagues collected daily sleep data from 10 healthy women between the ages of 18 and 28 who had regular menstrual cycles. The researchers tracked the women's sleep during two of their cycles. The women wore actigraphic sensors on their wrist to record patterns of activity and rest over 578 sleep episodes and they provided morning urine samples for measurement of concentrations of luteinizing hormone (LH), estrone-3-glucuronide (E1G), and pregnanediol-3-glucuronide (PDG). All participants ovulated in both cycles.

The women also completed five-day diets during the early follicular phases of each cycle. The diet during one cycle contained neutral energy availability, and the diet during the other cycle contained 55 percent fewer calories. Menstrual cycle lengths were standardized to 14-day follicular and 14-day luteal phases, centered on the day of ovulation.

"Short-term caloric restriction had negative effects on sleep in both the late follicular phase, just before ovulation, and in the late luteal phase, just before the onset of menses," said Kim, who performed this study at the National Institute of Environmental Health Sciences (NIEHS). Decreased energy availability increased sleep disruption, with less sleep efficiency, greater WASO, and higher sleep fragmentation index in the late follicular phase in addition to the effects noted above in the late luteal phase.

It is likely these effects are mediated by the dynamic changes in ovarian hormones across the menstrual cycle. Their study found that E1G was linked with more awakenings, and PDG was linked with a trend toward higher sleep fragmentation index.

According to the National Sleep Foundation, 25 percent to 33 percent of menstruating women in the United States have reported more disrupted sleep during the weeks before and/or during menses. This study by Kim and colleagues validates these perceptions using objective measures, and further documents the negative impact of dieting on sleep.

"These findings suggest that women need to be particularly cognizant of practicing good sleep hygiene in the week before menses and with decreased caloric intake," Kim noted.