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Two decades ago, an experiment at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory pinpointed a mysterious mismatch between established particle physics theory and actual lab measurements. When researchers gauged the behavior of a subatomic particle called the muon, the results did not agree with theoretical calculations, posing a potential challenge to the Standard Model — our current understanding of how the universe works.

Ever since then, scientists around the world have been trying to verify this discrepancy and determine its significance. The answer could either uphold the Standard Model, which defines all of the known subatomic particles and how they interact, or introduce the possibility of an entirely undiscovered physics. A multi-institutional research team (including Brookhaven, Columbia University, and the universities of Connecticut, Nagoya and Regensburg, RIKEN) have used Argonne National Laboratory's Mira supercomputer to help narrow down the possible explanations for the discrepancy, delivering a newly precise theoretical calculation that refines one piece of this very complex puzzle. The work, funded in part by the DOE’s Office of Science through its Office of High Energy Physics and Advanced Scientific Computing Research programs, has been published in the journal Physical Review Letters.

"For a long time, many people thought this contribution, because it was so challenging, would explain the discrepancy. But we found previous estimates were not far off.” — Thomas Blum, study co-author

A muon is a heavier version of the electron and has the same electric charge. The measurement in question is of the muon's magnetic moment, which defines how the particle wobbles when it interacts with an external magnetic field. The earlier Brookhaven experiment, known as Muon g-2, examined muons as they interacted with an electromagnet storage ring 50 feet in diameter. The experimental results diverged from the value predicted by theory by an extremely small amount measured in parts per million, but in the realm of the Standard Model, such a difference is big enough to be notable.

"If you account for uncertainties in both the calculations and the measurements, we can't tell if this is a real discrepancy or just a statistical fluctuation," said Thomas Blum, a physicist at the University of Connecticut who co-authored the paper. "So both experimentalists and theorists are trying to improve the sharpness of their results."

As Taku Izubuchi, a physicist at Brookhaven Lab who is a co-author on the paper, noted, “Physicists have been trying to understand the anomalous magnetic moment of the muon by comparing precise theoretical calculations and accurate experiments since the 1940s. This sequence of work has led to many discoveries in particle physics and continues to expand the limits of our knowledge and capabilities in both theory and experiment.”

If the discrepancy between experimental results and theoretical predictions is indeed real, that would mean some other factor — perhaps some yet-to-be discovered particle — is causing the muon to behave differently than expected, and the Standard Model would need to be revised.

The team's work centered on a notoriously difficult aspect of the anomaly involving the strong force, which is one of four basic forces in nature that govern how particles interact, along with weak, electromagnetic, and gravitational force. The biggest uncertainties in the muon calculations come from particles that interact through the strong force, known as hadronic contributions. These hadronic contributions are defined by a theory called quantum chromodynamics (QCD).

The researchers used a method called lattice QCD to analyze a type of hadronic contribution, light-by-light scattering. "To do the calculation, we simulate the quantum field in a small cubic box that contains the light-by-light scattering process we are interested in," said Luchang Jin, a physicist at the University of Connecticut and paper co-author. "We can easily end up with millions of points in time and space in the simulation."

That's where Mira came in. The team used the supercomputer, housed at the Argonne Leadership Computing Facility (ALCF), to solve the complex mathematical equations of QCD, which encode all possible strong interactions with the muon. The ALCF, a DOE Office of Science User Facility, recently retired Mira to make room for the more powerful Aurora supercomputer, an exascale system scheduled to arrive in 2021.

"Mira was ideally suited for this work," said James Osborn, a computational scientist with the ALCF and Argonne’s Computational Science division. "With nearly 50,000 nodes connected by a very fast network, our massively parallel system enabled the team to run large simulations very efficiently."

After four years of running calculations on Mira, the researchers produced the first-ever result for the hadronic light-by-light scattering contribution to the muon anomalous magnetic moment, controlling for all errors.

"For a long time, many people thought this contribution, because it was so challenging, would explain the discrepancy," Blum said. "But we found previous estimates were not far off, and that the real value cannot explain the discrepancy."

Meanwhile, a new version of the Muon g-2 experiment is underway at Fermi National Accelerator Laboratory, aiming to reduce uncertainty on the experimental side by a factor of four. Those results will add more insight to the theoretical work being done now.

"As far as we know, the discrepancy still stands," Blum said. "We are waiting to see whether the results together point to new physics, or whether the current Standard Model is still the best theory we have to explain nature."

May 5, 2020 -- A study just released by Columbia University Mailman School of Public Health is reporting a blood-DNA-methylation measure that is sensitive to variation in the pace of biological aging among individuals born the same year. The tool - DunedinPoAm -- offers a unique measurement for intervention trials and natural experiment studies investigating how the rate of aging may be changed by behavioral or drug therapy, or by changes to the environment. The study findings are published online in the journal eLife.

"The goal of our study was to distill a measurement of the rate of biological aging based on 12-years of follow-up on 18 different clinical tests into a blood test that can be administered at a single time point." said lead author Daniel Belsky, PhD, assistant professor of epidemiology at Columbia Mailman School and a researcher at the Columbia Aging Center.

Midlife adults measured to be aging faster according to the new measurement showed faster declines in physical and cognitive functioning and looked older in facial photographs. Older adults measured to be aging faster by the tool were at increased risk for chronic disease and mortality. In other analyses, the researchers showed that DunedinPoAm captured new information not measured by proposed measures of biological aging known as epigenetic clocks, that 18-year-olds with histories of childhood poverty and victimization showed faster aging as measured by DunedinPoAm, and that DunedinPoAm predictions were disrupted by a caloric restriction intervention in a randomized trial.

In a 2015 paper, Belsky and colleagues at Duke University, who also collaborated on this study, tracked a battery of clinical tests measured in 954 members of the Dunedin Study birth cohort when the participants were 26, 32, and 38 years old to measure their rate of aging (PNAS paper). A striking finding of that earlier study was that the rate of biological aging was already highly variable in young adults who had not yet developed chronic disease. But the measure the researchers developed in that earlier study, called "Pace of Aging", required long-follow-up time and in-depth clinical assessment. "It wasn't very useful for studies that need to test the impact of a new drug or lifestyle intervention in a matter of a few years," said Belsky.

In their new study, the researchers aimed to develop a blood test that could be given at the start and end of a randomized controlled trial to determine if the treatment had slowed participants' pace of aging. Slowing the pace of aging is an emerging frontier in medical research as a novel approach to preventing multiple chronic diseases.

The authors' analysis focused on DNA samples derived from white blood cells. They analyzed chemical tags on the DNA called methylation marks. DNA methylation is an epigenetic process that can change the way genes are expressed. DNA methylation marks change as we age, with some marks being added and others lost. "We focused our analysis on DNA methylation in white blood cells because these molecular markers are relatively easy to measure and have shown great promise in previous research on aging," explained Belsky.

The study included analysis of data from the NZ-based Dunedin Study, the UK-based Understanding Society and E-Risk Studies, the U.S.-based Normative Aging Study, and the CALERIE randomized trial.

Previous studies have attempted to measure aging by analyzing DNA methylation differences between people of different chronological ages. "One limitation of this approach, noted Belsky, is that individuals born in different years have grown up under different historical conditions, with a possibility of more exposure to childhood diseases, tobacco smoke, airborne lead, and less exposure to antibiotics and other medications, as well as lower quality nutrition, all of which affect DNA methylation. An alternative approach is to study individuals who were all born the same year, and find methylation patterns that differentiate those who have been aging biologically faster or slower than their same-age peers."

The authors used a machine-learning technique called "elastic-net regression" to sift through data on more than 400,000 different DNA methylation marks to find the ones that related to the physiological changes captured in their Pace of Aging measure. In the end, the analysis identified a set of 46 methylation marks that, together, measured Pace of Aging. The 46 marks are combined together according in an algorithm the researchers named "DunedinPoAm" for Dunedin (P)ace (o)f (A)ging in (m)ethylation. The average person has a DunedinPoAm value of 1 - indicating 1 year of biological aging per chronological year. Among Dunedin Study participants, the range of values extend from just above 0.6 (indicating an aging rate nearly 40 percent slower than the norm) to nearly 1.4 (indicating an aging rate 40 percent faster than the norm).

A study of female astronauts has assessed the risk of blood clots associated with spaceflight.

The study, published in Aerospace Medicine and Human Performance, in collaboration with King's College London, the Centre for Space Medicine Baylor College of Medicine, NASA Johnson Space Centre and the International Space University, examines the potential risk factors for developing a blood clot (venous thromboembolism) in space.

The findings, which looked at 38 female astronaut flights between 2000 and 2014, found spaceflight and combined oral contraceptive pill (COCP) use does not appear to increase the risk of venous thromboemoblism (VTE).

Dr Varsha Jain, lead author of the study from King's College London and a Wellbeing of Women Clinical Research Fellow at the Medical Research Council Centre for Reproductive Health at the University of Edinburgh, said: "The first episode of an astronaut developing a blood clot in space was reported earlier this year. It is unknown how spaceflight impacts the risk of an astronaut developing a blood clot. This study aimed to look specifically at the potential blood clot developing risks for female astronauts during spaceflight. We wanted to understand if their use of the hormonal contraceptive pill for menstrual cycle control, increased that risk."

Developing a VTE in space is life threatening and potentially a mission critical risk. The risk may have been further increased by COCP use, however as female astronauts are more fit and healthy than general population, their risk remains low.

The study, which is the first of its kind, proposes more blood tests be carried out during astronaut selection and during medical reviews. There are points during pre-mission training and during spaceflight, such as particular training activities, which may briefly increase the risk of developing a blood clot, and the authors recommend a review of these.

Finally, the study advises a more holistic approach to be taken for contraceptive agent prescribing as women from all professions, including astronauts, may wish to control their menstrual cycles and occupation related risks should be considered during a risk review.

Dr Jain said: "There may be possible time points in an astronaut's pre-mission training or during the space mission itself where blood clot risk may potentially be transiently increased. Due to the potentially life-threatening nature of blood clots, we would advise further targeted research in this area to further understand how an astronaut's risk of developing a blood clot is altered by spaceflight."

Dr Virginia Wotring, associate Professor at the International Space University and senior author of the study, said: "We see a need for continuing studies with female astronauts. Much of the previous biomedical research in space was conducted on mostly male astronauts, because most of the astronauts were male. That has changed, and now we need to understand how the spaceflight environment impacts female physiology."

Twice as many women who experienced a hypertensive disorder during any of their pregnancies were at increased risk of developing heart or kidney diseases earlier in life based on incidence per woman versus per pregnancy, according to a study published today in the Journal of the American College of Cardiology. This is one of the first studies to look at incidence of hypertensive disorders per woman vs. per pregnancy, which accounts for women who are pregnant multiple times.

Hypertensive disorders of pregnancy (HDP) include four categories: preeclampsia, gestational hypertension, chronic hypertension and superimposed preeclampsia (women with chronic hypertension who develop preeclampsia). Women who have preeclampsia during pregnancy are at risk for death from heart disease as early as the first decade after giving birth.

"Despite the rates of HDP increasing over the past three decades, the incidence rates of HDP per-pregnancy and per-woman had not yet been studied," said Vesna D. Garovic, MD, PhD, professor of medicine in the department of internal medicine and obstetrics and gynecology at Mayo Clinic and lead author of the study. "By only looking at HDP rates per-pregnancy, we have been vastly underestimating the number of women who are affected by this condition and may be at risk for future heart or kidney disease. Looking at the per-woman rate allowed us to assess women with more than one pregnancy, who may have had HDP, including preeclampsia, during one of her pregnancies, but not the other."

The researchers used the Rochester Epidemiology Project, a medical record system of all providers in Olmsted County, Minnesota, to compare the risk of heart and kidney disease in pregnant women with and without a history of HDP who delivered (liveborn or stillborn) between 1976 and 1982. The researchers identified 9,862 pregnancies among 7,544 women living in Olmsted County during the assessment period. Each medical chart was screened to determine which women had possible HDP, where a positive screen was defined as two elevated blood pressures taken at any prenatal visit, during delivery or postnatal before hospital discharge.

During the six-year assessment period, 659 women had a total of 719 HDP pregnancies, an incidence rate per-pregnancy of 7.3% for HDP and 3.3% for preeclampsia. To assess HDP incidence rate per-woman, the researchers identified 1,839 women who had sufficient information for all of their pregnancies. The per-woman HDP incidence was twice that of the per-pregnancy rate, at 15.3% (n=281) and 7.5% (n=138) for HDP and preeclampsia, respectively. Women younger than 20 years of age and women older than 35 years of age had the highest incidence rates of preeclampsia and gestational hypertension.

Across a follow-up period of 36.2 years, 571 women with history of HDP developed a chronic condition, including (but not limited to) cardiac arrhythmias, coronary artery disease, heart failure, stroke, chronic kidney disease and hypertension, suggesting that 1 in 6 women may be at an increased risk for heart or kidney disease. Women with HDP developed a chronic condition at an accelerated rate and at earlier age compared with their counterparts.

This study has several limitations, including the lack of diversity in the study population (predominantly white) and looking at a population from four decades ago. A more ethnically diverse contemporary cohort should be pursued. The researchers stress the need for lifestyle interventions and preventive care in this high-risk population.

"With this study, Garovic and colleagues advance our understanding of the burden of HDP-associated multimorbidity," said Michael C. Honigberg, MD, MPP, research fellow in the department of medicine at Massachusetts General Hospital, in an accompanying editorial comment. "The authors have shown that the total HDP burden expressed as incidence per-woman is considerably higher than per-pregnancy. The discovery of effective-targeted risk-reducing interventions for women with HDP would make pregnancy an even more actionable and powerful screening test."

Non-fatal injuries in the US add up to an estimated $1590 and an average of 11 days off work per injured employee every year, indicates an analysis of medical insurance claims and productivity data, published online in the journal Injury Prevention.

These figures exclude people without workplace health insurance, those out of work, and caregivers.

There are more than 30 million annual visits to emergency care for non-fatal injuries every year in the US, with total medical costs exceeding US$133 billion.

Previous estimates of lost productivity attributable to injury have been based on absenteeism associated with injuries sustained only in the workplace and haven't assessed the impact of different types of injury.

To try and rectify this, and calculate the overall value of lost workplace productivity, the researchers mined millions of workplace health insurance claims data (MarketScan) and Health and Productivity Management databases for sick leave taken between 2014 and 2015.

They looked specifically at non-fatal injuries treated in emergency departments for 18-64 year olds with health insurance cover, by injury type and body region affected, as well as the amount of sick leave taken in the year following the injury.

These data were then compared with the number of days of sick leave taken by employees who had not sustained injuries.

The injuries analysed included burns, poisonings, firearm wounds, falls, bites and stings, road traffic collisions, and those caused by machinery and overexertion.

The researchers estimated that the total annual value of lost workplace productivity attributable to all types of non-fatal injury and, initially treated in emergency care, amounted to an average 11 days and US$1590 for each injured employee.

Values ranged from 1.5 days and US$210 for bites and stings to 44 days and US$6196 for motorbike injuries. Days taken off work ranged from 4 for other head, face and neck injuries to almost 20 for traumatic brain injuries.

The researchers admit that their calculations exclude long term disabilities or long term physical and mental illness caused by violent assault. Nor do the figures include injuries among those without workplace health insurance, the jobless, or caregivers.

But they conclude:"Non-fatal injuries are preventable and incur substantial lost work productivity at a high cost to individuals, employers and society."

In a brilliant dance, a cornucopia of flowers, pinecones and acorns connected by wind, rain, insects and animals ensure the reproductive future of seed plants. But before plants achieved these elaborate specializations for sex, they went through millions of years of evolution. Now, researchers have captured a glimpse of that evolutionary process with the discovery of a new ancient plant species.

The fossilized specimen likely belongs to the herbaceous barinophytes, an unusual extinct group of plants that may be related to clubmosses, and is one of the most comprehensive examples of a seemingly intermediate stage of plant reproductive biology. The new species, which is about 400 million years old and from the Early Devonian period, produced a spectrum of spore sizes - a precursor to the specialized strategies of land plants that span the world's habitats. The research was published in Current Biology May 4.

"Usually when we see heterosporous plants appear in the fossil record, they just sort of pop into existence," said the study's senior author, Andrew Leslie, an assistant professor of geological sciences at Stanford's School of Earth, Energy & Environmental Sciences (Stanford Earth). "We think this may be kind of a snapshot of this very rarely witnessed transition period in evolutionary history where you see high variation amongst spores in the reproductive structure."

A major shift

One of the most important time periods for the evolution of land plants, the Devonian witnessed diversification from small mosses to towering complex forests. The development of different spore sizes, or heterospory, represents a major modification to control reproduction - a feature that later evolved into small and large versions of these reproductive units.

"Think of all the different types of sexual systems that are in flowers - all of that is predicated on having separate small spores, or pollen, and big spores, which are inside the seeds," Leslie said. "With two discrete size classes, it's a more efficient way of packaging resources because the big spores can't move as easily as the little ones, but can better nourish offspring."

The earliest plants, from between 475 million to 400 million years ago, lacked reproductive specialization in the sense that they made the same types of spores, which would then grow into little plantlets that actually transferred reproductive cells. By partitioning reproductive resources, plants assumed more control over reproduction, according to the researchers.

The new species, together with the previously described plant group Chaleuria of the same age, represents the first evidence of more advanced reproductive biology in land plants. The next example doesn't appear in the fossil record until about 20 million years later.

"These kinds of fossils help us locate when and how exactly plants achieved that kind of partitioning of their reproductive resources," Leslie said. "The very end of that evolutionary history of specialization is something like a flower."

A fortuitous find

The researchers began analyses of the fossils after they had been stored in the collections at the Smithsonian National Museum of Natural History for decades. From about 30 small chips of rock originally excavated from the Campbellton Formation of New Brunswick in Canada by late paleobotanist and study co-author Francis Hueber, they identified more than 80 reproductive structures, or sporangia. The spores themselves range from about 70 to 200 microns in diameter - about a strand to two strands of hair. While some of the structures contained exclusively large or small spores, others held only intermediate-sized spores and others held the entire range of spore sizes - possibly with some producing sperm and others eggs.

"It's rare to get this many sporangia with well-preserved spores that you can measure," Leslie said. "We just kind of got lucky in how they were preserved."

Fossil and modern heterosporous plants primarily live in wetland environments, such as floodplains and swamps, where fertilization of large spores is most effective. The ancient species, which will be formally described in a follow-up paper, has a medley of spores that is not like anything living today, Leslie said.

"The overarching story in land plant reproduction is one of increased division of labor and specialization and complexity, but that has to begin somewhere - and it began with simply producing small spores and big spores," Leslie said. "With these kinds of fossils, we can identify some ways the plants were able to do that."

Fear is an important survival mechanism and so too is the ability to inhibit fear when it's no longer needed. In order to counter-balance fear, the brain engages in fear extinction. In this process, memories are formed during non-fearful experiences with similar environmental elements. These non-fearful memories then compete with the original fear memory.

Now, in a new paper published in the journal Nature Neuroscience, the University of Queensland's Professor Tim Bredy and his colleagues show that the ability to extinguish fearful memories in this way relies on the flexibility of your DNA.

"DNA can adopt a variety of different structures," says Dr Paul Marshall, a researcher at UQ's Queensland Brain Institute and lead author of the study.

"The most common and most widely recognized form is the 'B-DNA' double helix, which twists in a clockwise direction. But, with a slight rearrangement of how DNA base-pairs connect with one another, DNA can form other helical structures, such as Z-DNA."

Z-DNA is a counter-clockwise twisted version of B-DNA, he explains. Imagine for a moment, that each of your hands is a DNA strand, the thumbs the bases. If you hold both hands out in front of you, palms out, so that your thumbs touch, this is how two bases connect in B-DNA. If you now flip your wrists so that your palms face inward and your pinkies touch, this is how bases flip-out during Z-DNA formation. If you keep rotating your hand and now re-join the thumbs this is what happens when Z-DNA is stabilized into a new twist.

Z-DNA occurs over short regions and only certain sequences can turn inside-out like this. For a long time, no one knew why it existed at all.

"We now know that Z-DNA appears wherever genes are being turned on," says Dr Marshall. "It's a marker of gene activity."

"Scientists have also noticed a connection between Z-DNA and certain diseases, including cancer, and high levels of Z-DNA have been found in the brains of people who had Alzheimer's Disease."

This potential link with memory intrigued Dr Marshall and Professor Bredy, especially since the formation of fear extinction memories involves rapid changes in gene activity.

To find out more, they turned their attention to an enzyme called ADAR1, which recognizes and latches onto Z-DNA. ADAR1 is known to play a role in RNA editing, which is important for modifying protein functions in the cell. Evidence also suggests that ADAR1 can convert Z-DNA back into B-DNA.

"ADAR1 is doing a lot of things at once, but that's what makes it interesting," says Dr Marshall.

He and his colleagues turned off the ADAR1 gene in mice, specifically in a part of the brain known to play a role in fear extinction. As a result, although the mice could still form fear memories, they were unable to form non-fearful memories. In short, they lost the capacity for fear extinction. The researchers observed a similar effect when they mutated ADAR1, so that it didn't work very well.
The findings suggest that Z-DNA forms during fear then, during fear extinction, ADAR1 binds to that Z-DNA and carries out two important jobs: it rapidly increases RNA editing and then flips Z-DNA back into B-DNA.

"It seems that the more easily you can switch between DNA structures, the more plastic your memory is," says Dr Marshall.

"Flexibility of DNA structure, flexibility of memory."

This enables an agile response to our environment, he adds.
"Fear memories need to be plastic. They can be very useful for survival, but they can also get in the way of normal functioning."

The balance between fear and fear-extinction is critical to cognitive flexibility, says Professor Bredy. Indeed, the impairment of fear extinction is a key feature of PTSD and phobias. The more we understand about how fear extinction works, the more chance we have of finding better treatments for those conditions.

PROVIDENCE, R.I. [Brown University] -- For people who live in the Arctic, sea ice that forms along shorelines is a vital resource that connects isolated communities and provides access to hunting and fishing grounds. A new study by Brown University researchers found that climate change could significantly reduce this "shorefast ice" in communities across Northern Canada and Western Greenland.

The study, published in Nature Climate Change, used weather data and near-daily satellite observations of 28 Arctic communities to determine the timing of shorefast ice breakup in each location over the past 19 years. The analysis enabled the researchers to determine the conditions that drive springtime ice breakup. Then they use climate models to predict how that timing might change in each community as the planet warms.

The analysis found that by 2100, communities could see shorefast ice seasons reduced by anywhere from five to 44 days, with the coldest communities in the study seeing the largest reductions. The wide range of potential outcomes was a surprise, the researchers say, and underscores the need to take local factors into account when making policy to prepare for future climate change.

"One of the key takeaways for me is that even though the whole Arctic is going to warm and lose ice, we see very different outcomes from one community to another," said Sarah Cooley, lead author of the study and a Ph.D. student in the Institute at Brown for Environment and Society (IBES). "When you combine that wide range of outcomes with the fact that different communities have lots of social, cultural and economic differences, it means that some communities may experience much larger impacts than others."

For example, the northern Canadian communities of Clyde River and Taloyoak, which are particularly dependent upon shorefast ice for subsistence hunting and fishing, will see some of the most substantial declines in sea ice. On average, these two communities can expect ice to break up 23 to 44 days earlier, respectively by 2100. That could mean "economically and culturally significant activities on the ice will be harder to maintain in the future," the researchers write.

That the coldest regions in the study could see the largest reductions in ice is cause for concern, says study co-author Johnny Ryan, a postdoctoral researcher at IBES.

"Some of these places are considered to be the last remnants of truly polar ecosystems and people talk a lot about preserving these areas in particular," Ryan said. "Yet these are the areas that we find will lose the most ice."

The research is part of a larger research effort aimed at better understanding how climate change in the Arctic will impact the people who live there. In addition to gathering satellite and scientific data, the research team conducted fieldwork in the community of Uummannaq in western Greenland to learn more about how the local population utilizes the ice.

"Shorefast ice is something that's most important from the standpoint of the people who use it," Cooley said. "It has some implications in terms of global climate, but those are fairly small. This is really all about how it affects the people who actually live in the Arctic, and that's why we're studying it."

The fieldwork also provided a first-hand perspective of how things have been changing over the years.

"One of the most powerful things that came out of the field study for me was listening to a hunter talk about how the ice is breaking up earlier than it ever has in his lifetime," Ryan said. "We're only observing this 20-year satellite record. But to be able to learn from locals about what things were like 50 or 60 years ago, it really emphasized how climate change has already impacted the community."

Moving forward, the research team is hopeful that mapping the local effects of regional and global climate patterns will be useful for policy-makers.

"Because shorefast ice is one of many environmental assets important to Arctic communities," the researchers write, "future research combining broad-scale analysis tools with community-level characteristics may help provide more actionable information for Arctic populations facing substantial climatic and social change."

SANTA CRUZ, CA - May 04, 2020 - It's only been three years since UC Santa Cruz researchers proved that long-read human genome assembly using the same nanopore technology developed on campus could be done at all. At the time, it was a monumental effort, requiring 150,000 hours of computing time and weeks of work.

About a year later, using the PromethION nanopore sequencer, a similar effort proved significantly faster, cheaper, and easier, clocking in at about a week. "We sequenced eleven human genomes in nine days, which was unprecedented at the time," said UC Santa Cruz Research Scientist Miten Jain.

Now, researchers at UC Santa Cruz researchers have collaborated on an algorithm designed to accurately and precisely assemble individual, complete human genomes from long-read sequencing data in about six hours and for about $70.

The researchers said they hope their assembler will increase the pace of genomics research and open opportunities. This includes enabling pangenome research to represent the true scale of human diversity, a decidedly more practical pursuit.

Until recently, genomic research has relied exclusively on the reference genome from a single individual selected to represent an entire species. To reflect true human diversity, UC Santa Cruz has embarked on a pangenomic initiative to sequence 350 new, individual human genomes.

As a part of this work, UC Santa Cruz Genomics Institute researchers developed a nanopore long-read sequencing protocol that consistently yields ~60X coverage (~200 gigabases) of a human genome at unprecedented lengths (median read N50 of 42 kb) using three PromethION flow cells. Additionally, ~7X coverage of the genome is in reads exceeding 100 kb in length. This method is highly scalable, both in terms of cost and the number of genomes that can be processed simultaneously. We are now improving this method for higher read lengths and throughput, which will further facilitate our goal of achieving complete, phased, reference-quality genomes.

This large inflow of data necessitated the development of highly efficient software tools, starting with an assembler. "Our new assembler was designed to be cheap and quick, with the goal to be on the cloud," said UC Santa Cruz's Benedict Paten. "It gives us the power to scale nanopore sequencing. Now, I'm confident that we'll be easily assembling hundreds of de novo genomes in the next couple of years."

An extensive team of researchers and developers that was led by Paolo Carnevali from the Chan Zuckerberg Initiative (CZI) -- and included many at the Computational Genomics Lab at the UC Santa Cruz Genomics Institute -- contributed to this solution.

"When I saw the Jain 2018 paper, I was impressed and realized that I could contribute to the computational side of this line of investigation," said Paolo Carnevali. "I had recently met Benedict Paten and decided I wanted to work with his team at UCSC.

The team were soon collaborating. Within months, they had developed and tested the special algorithmic sauce, which they called Shasta.

Shasta is an in-memory computing-driven algorithm that can now help complete a de novo (new, never before processed) human genome assembly in under six hours, the authors say, for an average cost of $70 per sample.

In their paper, "Nanopore sequencing and the Shasta toolkit enable efficient de novo assembly of eleven human genomes," published today in Nature Biotechnology, they describe how Shasta not only yields comparable or better accuracy as its contemporaries but also has the lowest number of misassemblies.

Not satisfied with this milestone, the team saw an opportunity to improve the draft assembly at an affordable cost and turn-around time. "To improve the base-level quality of the assemblies, we used a sequence polisher based on a deep neural network as the final assembly step," explained lead author Kishwar Shafin. "This brought the total cost of the assembly process to less than $200 and 37 hours -- which further reduced the computational overhead of generating long-read assemblies dramatically -- by a factor of five."

The researchers assessed the precision and then validated the accuracy, and noted that they had achieved 99.9% accurate assembly using only nanopore data, a first for the human genome. Further, they generated chromosome-level scaffolds for these polished assemblies using HiC sequencing data.

Research scientist and co-author Karen Miga, who is directing the Data Production Center at UCSC for the Human Pangenome Project, points out the significance of the team's achievements in improved accuracy. "Our aim is not only to expand the diversity of the reference genome but also to resolve the hundreds of gaps that persist across the genome," Miga explains. "Now that we can routinely include these uncharted regions, we have a truly complete assembly of a human genome, and we can begin to explore variations of unknown consequence."

A "step-change" in conservation is needed in order to help save species from extinction in the future, according to an academic at the University of East Anglia (UEA).

Professor of evolutionary genetics Cock van Oosterhout calls for the smart use of genomic data to make populations more resilient to future genetic drift and inbreeding, and proposes a new 'road map' for what needs to be done in conservation to achieve this.

Decades of work by conservation geneticists and international treaties such as the UN Convention on Biological Diversity have attempted to improve the status of biodiversity and maintain genetic diversity across the various forms of life on Earth.

However, according to the most recent global assessment report in 2019, the decline in biodiversity is only accelerating, and one million species are threatened with extinction. The Red List of the International Union for Conservation of Nature (IUCN) also shows that 44.3% of species are currently in decline.

Contributing to this, recent fires in the Amazon and Australia have transformed vast swathes of habitat, climate change places additional pressures on populations, and globally, approximately 75% of the infrastructure planned for 2050 has yet to be built.

Writing in the journal Nature Ecology & Evolution, Prof van Oosterhout, of UEA's School of Environmental Sciences, warns that more needs to be done than just minimizing the loss of biodiversity and genetic variation.

Over the last half century, conservation geneticists have analysed genetic variation and focused on maintaining this in threatened species. While this is important, Prof van Oosterhout says they have ignored an essential part of the genome that is devoid of variation, identical across different species. These are the DNA nucleotides that have been conserved over millions of years of evolution.

These parts of the genome are under strong selection and if mutations occur in these so-called 'ultra-conserved elements', they are bad for the fitness of individuals. When a population declines these mutations become exposed by inbreeding, so the already struggling population is even more at risk.

However, genomics can reveal the presence of this 'mutation load' at the molecular level using tools developed for humans and model animals, such as mice and rats.

Prof van Oosterhout said: "Given that these studies all examine the same ultra-conserved elements, the mutation load can be directly compared between species. Hence, the analyses developed in human genomics could be universally applied across the tree of life, making them very promising tools for conservation genomics.

"We now know the DNA sequences of these ultra-conserved regions in the genomes of threatened species. This means that we can also identify the bad mutations when we sequence these individuals. This has become relatively cheap and it is quick."

Conservation genomics could also help to improve captive breeding in zoos. Rather than just minimising the rate of inbreeding, studbook holders could use the mutation load data of individuals to take on the role of natural selection in the zoo environment.

"With that data and knowledge of which DNA sequences to look out for, we can select against these bad mutations even before they become 'exposed' by inbreeding," said Prof van Oosterhout.

"This would help to prevent - or even turn-back - the deterioration of genepool of the often small zoo populations. Data on the mutation load could also be used to reduce the risk of inadvertently reintroducing harmful mutations into the wild during genetic rescue. Such genomics-informed conservation would make populations more resilient to genetic drift and inbreeding yet to come."

In his paper, Prof van Oosterhout suggests a method that avoids losing valuable genetic variation, an inevitable consequence of selection. It involves selecting the best two offspring of all breeding pairs, so the two with the lowest number of bad mutations. This will reduce the mutation load, maintains the useful genetic variation, and would make the zoo population, and the species, more resilient against current and future inbreeding.

Prof van Oosterhout cautions that there is still work to do to make these genomic approaches reliable, practical tools for conservation. "We still don't know how the mutation load affects the fitness of individuals in the natural environment," he said. "Translating this genomic data into metrics that are relevant to conservation is therefore urgently needed."

"Fortunately, with thousands of genomes currently being sequenced by consortiums, data is rapidly being generated. Together with the rich sample archives that have been collected for some of our threatened species over decades, such as the pink pigeon and the echo parakeet, this would help to translate genomic data into information that is relevant for conservation, for example around the fitness of individuals in their natural environment, and the viability of their populations.

"We should be able to rank individuals, and species, according to their mutation load and relative levels of inbreeding, thereby improving the Red List of animals currently in decline."

Millions more people across the EU could have contracted COVID-19 had strict international travel bans not been implemented, shows a new report by computer modelling experts at Stanford University.

Using a newly developed mathematical epidemiology simulation, the study, published in Computer Methods in Biomechanics and Biomedical Engineering, predicts the huge impact that limiting air travel across the 27 EU nations had on restricting the spread of the disease.

The simulation can show live estimated figures for the growth of spread for each country if we were to remove travel bans today. The images above show how 0.2% of some populations could have become infected by 20th April (when the study was written, 5 April), however these figures change daily.

This new model could now play a vital part in establishing politicians' exit strategies, with the team able to virtually lift travel restrictions between individual communities, states, or countries, to explore the potential gradual changes in spreading patterns and outbreak dynamics.

"There is a well-reasoned fear that easing of current (travel restriction) measures, even slightly, could trigger a new outbreak and accelerate the spread to an unmanageable degree," lead author Ellen Kuhl, Professor of Mechanical Engineering at Standford University comments.

"Global network mobility models, combined with local epidemiology models, can provide valuable insight into different exit strategies. Our results demonstrate that mathematical modelling can provide guidelines for political decision making with the ultimate goal to gradually return to normal while keeping the rate of new COVID-19 infections steady and manageable," says Kevin Linka, lead author and postdoctoral researcher in Dr. Kuhl's group.

From its European origin in Italy, the novel coronavirus spread rapidly via the strongest network connections to Germany, Spain, and France, while slowly reaching the less connected countries, Estonia, Slovakia, and Slovenia.

Currently the levels of population known to be infected with the disease varies from country to country, however as of April 18, with flight being reduced by 89% in Germany, 93% in France, 94% in Italy, and 95% in Spain (Eurostat 2020), the graphs in this study show how the spread has been contained.

"Strikingly, our results suggest that the emerging pattern of the COVID-19 outbreak closely followed global mobility patterns of air passenger travel," confirms Professor Kuhl, whose model can also predict the emerging global diffusion pattern of a pandemic at the early stages of the outbreak.

"Our results suggest that an unconstrained mobility would have significantly accelerated the spreading of COVID-19, especially in Central Europe, Spain, and France."

Unfortunately, the model also confirms how travel bans were introduced too late to stop the Europe-wide outbreak altogether.

"A recent study based on a global metapopulation disease transmission model for the COVID-19 outbreak in China has shown that the Wuhan travel ban essentially came too late, at a point where most Chinese cities had already received many infected travellers (Chinazzi et al. 2020). Our study shows a similar trend for Europe, where travel restrictions were only implemented a week after every country had reported cases of COVID-19 (European Centre for Disease Prevention and Control 2020).

"As a natural consequence, unfortunately, no European country was protected from the outbreak," Professor Kuhl, who is the Robert Bosch Chair of Mechanical Engineering at Standford added.

The first official case of COVID-19 in Europe was reported in France on January 24, 2020, followed by Germany and Finland only three and five days later. Within only six weeks, all 27 countries of the European Union were affected, with the last cases reported in Malta, Bulgaria, and Cyprus on March 9, 2020. At this point, there were 13,944 active cases within the European Union and the number of active cases doubled every three to four days (European Centre for Disease Prevention and Control 2020).

Dr Kuhl adds that although air travel is certainly not the only determinant of the outbreak dynamics, their findings indicate that "mobility is a strong contributor to the global spreading of COVID-19". This is becoming especially important now that many countries are beginning to lift their travel restrictions in an attempt to gradually return to normal.

Other limitations highlighted - like any infectious disease model - include the simulation being subject to data uncertainties from differences in testing, inconsistent diagnostics, incomplete counting, and delayed reporting across all countries.

When cyclones and other natural disasters strike a city or town, the social and economic impacts locally can be devastating. But these events also have ripple effects that can be felt in distant cities and regions -- even globally -- due to the interconnectedness of the world's urban trade networks.

In fact, a new study by researchers at the Yale School of Forestry & Environmental Studies finds that local economic impacts -- such as damage to factories and production facilities -- can trigger secondary impacts across the city's production and trade network. For the largest storms, they report, these impacts can account for as much as three-fourths of the total damage.

According to their findings, published in the journal Nature Sustainability, the extent of these secondary costs depends more on the structure of the production and supply networks for a particular city than on its geographic location. Regional cities that are dependent on their urban network for industrial supplies -- and that have access to relatively few suppliers-- are most vulnerable to these secondary impacts. Larger, global cities such as New York and Beijing, meanwhile, are more insulated from risks.

"Cities are strongly connected by flows of people, of energy, and ideas -- but also by the flows of trade and materials," said Chris Shughrue '18 Ph.D., lead author of the study which is based on his dissertation work at Yale. He is now a data scientist at StreetCred Labs in New York. "These connections have implications for vulnerability, particularly as we anticipate cyclones and other natural hazards to become more intense and frequent as a result of climate change over the coming decades."

The paper was co-authored by Karen Seto, a professor of geography and urbanization science at F&ES, and B.T. Werner, a professor from the Scripps Institution of Oceanography.

"This study is especially important in the context of climate impacts on urban areas," Seto said. "Whereas we tend to consider a city's vulnerability to climate change as limited to local events, this study shows that we need to rethink this conceptualization. It shows that disasters have a domino effect through urban networks."

Using a simulation coupled with a global urban trade network model -- which maps the interdependencies of cities worldwide -- the researchers show how simulated disasters in one location can trigger a catastrophic domino effect.

The global spread of damage was particularly acute when cyclones occurred in cities of North America and East Asia, largely because of their outsize role in global trade networks -- as purchasers and suppliers, respectively -- and because these regions are particularly susceptible to cyclone events.

Often, adverse impacts are primarily caused by a spike in material prices, followed by production losses to purchasers. These production losses eventually can cause industrial shortages, which can then induce additional cycles of price spikes and shortages throughout the production chain.

Similar outcomes have been borne out following real world disasters. For instance, when catastrophic flooding occurred in Queensland, Australia, the impact on coking coal production prompted a 25-percent spike in the global costs. And the economic impacts of Hurricane Katrina extended far beyond New Orleans for several years after the historic storm.

While the example of cyclones can act as a proxy for other isolated disasters -- such as the 2011 tsunami in Japan which caused global economic disruptions, particularly in the auto sector -- the researchers say the findings are particularly relevant in terms of climate-related natural events.

"To be resilient to climate change is not only about building dikes and sea walls, but understanding a city's supply chains and how they are linked to other cities that may be vulnerable," Seto said.

Following the recent Coronavirus outbreak, almost three million people have been infected worldwide, whereas the death toll has already passed the 200,000 mark, according to official reports. Meanwhile, a vaccine remains to be found, and classic medications show low efficacy. Under these conditions, it is up to pharmacologists to do their best in the search of novel treatments. However, laboratory studies are limited by the absence of COVID-19 animal models.

Russian scientists from the Institute of Gene Biology of the Russian Academy of Sciences, the State Virology and Biotechnology Research Center "Vector" and Belgorod University are already working on the development of SARS-CoV-2-sensitive mice to be used as a murine model in tests of potential COVID-19 vaccines and drugs, reports the Office of the Chief State Sanitary Inspector.

To create such a line of mice, researchers have formulated a two-step concept, recently described in the open-access, peer-reviewed scholarly journal Research Results and Pharmacology. Firstly, the mice are to be made biologically safe for routine laboratory practice. Secondly, in order for the mice to be efficient for non-clinical trials, they will need to experience symptoms and pathogenesis as human-like as possible. The scientists believe that they have everything necessary to implement this conception and expect the first results as early as June 2020.

"SARS-CoV-2-inoculated mice will have a human-like pathogenesis and symptoms of the COVID-19. The key difference between a new model and the existing ones will be its biological safety - animals will become sensitive to SARS-CoV-2 only after activation in conditions of a virological laboratory. It makes it possible to nullify the contagion risk for the staff working in nurseries and non-specialised laboratories during a pandemic," the team explains.

Already available data shows that there are two key proteins in the human cells, which are involved in the virus entry. First of all, it is the angiotensin-converting enzyme 2 (ACE2), which is the direct and main target of the coronavirus' "corona". Three lines of transgenic mice with the human ACE2 variant have been found to be susceptible to the SARS-CoV, a causative agent of the SARS outbreak in 2003. However, it was shown that, in addition to ACE2, a molecular pathway of coronavirus invasion contains another important link: the enzyme transmembrane protease serine 2 (TMPRSS2). The blocking of TMPRSS2 prevents SARS-CoV-2 entry on the cell culture in vitro.

To obtain mice with human-like COVID-19 symptoms and pathology, the researchers will introduce human ACE2 and TMPRSS2 genes into the murine genome under the mice's own Tmprss2 promoter. Another key decision on the way of creating the new model is to ensure that SARS-CoV-2 sensitivity is inducible only after the introduction of LoxP sites in front of the human ACE2 and TMPRSS2 genes. As a result, human genes in a murine genome will turn on once a crossbreeding with mice expressing Cre-recombinase occurs.

"The main trick here is that this crossbreed will only happen in specialised virological laboratories, which will prevent the novel line of mice from becoming an infection 'reservoir' in ordinary laboratories," say the researchers.

A study to help determine the rate of novel coronavirus infection in children and their family members in the United States has begun enrolling participants. The study, called Human Epidemiology and Response to SARS-CoV-2 (HEROS), also will help determine what percentage of children infected with SARS-CoV-2, the virus that causes COVID-19, develop symptoms of the disease. In addition, the HEROS study will examine whether rates of SARS-CoV-2 infection differ between children who have asthma or other allergic conditions and children who do not. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is sponsoring and funding the HEROS study.

"One interesting feature of this novel coronavirus pandemic is that very few children have become sick with COVID-19 compared to adults," said NIAID Director Anthony S. Fauci, M.D. "Is this because children are resistant to infection with SARS-CoV-2, or because they are infected but do not develop symptoms? The HEROS study will help us begin to answer these and other key questions."

The HEROS study team will rapidly enroll 6,000 people from 2,000 U.S. families already participating in NIH-funded pediatric research studies in 11 cities. Study participants will include both healthy children and children with asthma or other allergic conditions. The study team will prospectively follow these children and their families for six months to determine who gets infected with SARS-CoV-2, whether the virus is transmitted to other family members, and which family members with the virus develop COVID-19.

Leading the HEROS study is Tina V. Hartert, M.D., M.P.H. Dr. Hartert is director of the Center for Asthma and Environmental Sciences Research, vice president for translational research, the Lulu H. Owen Chair in Medicine and a professor of medicine at the Vanderbilt University School of Medicine in Nashville.

"So far, data on the extent of SARS-CoV-2 infection in the U.S. population have been limited to people who physically interact with the healthcare system: those who are tested?especially those who test positive?and those with severe disease," said Dr. Hartert. "These data provide real-time guidance in a setting of limited test availability, but they don't enable us to understand the full extent of SARS-CoV-2 infection in the entire population. The HEROS study will help fill this knowledge gap and inform public health interventions."

Preliminary evidence suggests that having an allergic condition paradoxically may reduce a person's susceptibility to SARS-CoV-2 infection and severe COVID-19 disease. A NIAID-funded study recently examined upper and lower airway cells for the expression of ACE2, the gene that codes for the receptor that the coronavirus uses to infect cells. ACE2 expression is necessary for a cell to make this receptor, but additional steps also are involved. In both children and adults, respiratory allergy, asthma and controlled allergen exposure were associated with significantly reduced ACE2 expression. The expression of ACE2 was lowest in people with high levels of both asthma and sensitivity to allergens.

The HEROS study will further clarify whether reduced ACE2 gene expression in airway cells of children with allergic diseases correlates with a lower rate of SARS-CoV-2 infection and COVID-19.

The study will be conducted completely remotely. Every two weeks, a caregiver in participating families will collect nasal swabs from the child who is the primary study participant and all other family members who are enrolled in the study, and will mail the samples to a laboratory for analysis. On the same day as the nasal swab, the caregiver will complete online questionnaires about each participant's current symptoms, social distancing practices, recent activities outside the home, and recent exposure to people who are sick.

In addition, if any member of the household develops symptoms of a viral illness, the caregiver will fill out another online questionnaire designed to determine the likelihood that the illness is COVID-19. If COVID-19 is likely, the caregiver will collect nasal swabs from all study participants and a stool sample from the symptomatic participant within 24 hours.

Laboratory analyses of nasal swabs will test for SARS-CoV-2 and assess gene expression in the collected airway-surface cells. Investigators hope that these gene expression studies will reveal patterns that correlate with higher or lower risk of infection, COVID-19 symptom development and SARS-CoV-2 transmission.

A caregiver also will collect a blood sample from each study participant two weeks, 18 weeks and 24 weeks after enrollment as well as three weeks after the family's first likely case of COVID-19, if there is one. The blood will be collected using a new, nearly painless device that extracts a small quantity of blood through the surface of the skin. The blood will be analyzed for antibodies to SARS-CoV-2 once an appropriate antibody test becomes available.

Using high-resolution mass spectrometry, researchers have mapped glycan-processing states of the spike protein complex that allows the SARS-CoV-2 virus to infect human cells - finding that SARS-CoV-2 S glycans differ from typical host glycan processing, which may have implications in vaccine design. As scientists seek to combat the virus that causes COVID-19, the development of vaccines has focused on the spike, a protein complex composed of three protomers that protrudes from the virus and binds to the ACE2 receptor on the surfaces of human cells. Each protomer harbors 22 chemical sites that can undergo glycosylation, a biochemical reaction that adds a glycan compound to a protein. How these sites are glycosylated may affect which cells the virus can infect. The same processes could also shield some regions on the spike from being neutralized by antibodies. Seeking insight, Yasunori Watanabe et al. expressed and purified recombinant glycosylated spike complexes, then used enzymes to cut them into peptides each containing a single glycan but representing all glycan sites. The researchers then used a technique called mass spectrometry to determine the glycan composition at each site. They report that the SARS-CoV-2 S protein is less densely glycosylated than some other viral glycoproteins, possessing a sparse "glycan shield," which may be beneficial for the elicitation of potent neutralizing antibodies. Their analysis provides a benchmark that can be used to measure the quality of the spike antigen as researchers develop new vaccines and antibody tests.