Culture

The abrupt shift to hotter and drier conditions over inner East Asia is unprecedented and may herald an irreversible shift to a new climate regime for the region, according to a new study. The findings reveal a positive feedback loop fueled by declining soil moisture, which may have nudged the area's climate over an important tipping point. Extreme heatwaves and droughts are two of society's most pressing concerns as climate change driven by human activity continues unabated. Global warming has already led to recent and rapid shifts in climate worldwide, including inner East Asia, which has experienced some of the most pronounced heatwave-drought concurrences in recent decades. It's thought that such abrupt and substantial changes represent the crossing of critical thresholds within the climate system and signal irreversible shifts from one climate regime to another. But, identifying tipping points and new climate norms is difficult; not only does it require a thorough understanding of a region's natural climate variability over timescales that often exceed available records, regime shifts are likely triggered by complex interactions between a variety of poorly understood factors in the highly dynamic climate system. To determine whether the heatwave-drought trends observed in inner East Asia indeed exceed the range of natural climate variability, Peng Zhang and colleagues used tree-ring data to reconstruct a record of heatwave frequency and soil moisture for the region spanning the past 260 years. Zhang et al. found that the rise in concurrent heatwave-drought events over the last two decades is unique and beyond the natural variability revealed by their centuries-long record. What's more, the authors demonstrate that the rise in heatwave-drought events may be caused by a positive feedback loop between decreasing soil moisture and increasing surface warming - a pattern that's potentially the start of an irreversible trend that's likely to produce more frequent and severe events. While much remains to be understood about the occurrence and mechanisms of climate regime shifts, developing trustworthy long-term climate records is crucial in detecting changes in the interactions of climate variables, discovering past shifts and predicting tipping points of potential future shifts, write Qi-Bin Zhang and Ouya Fang in a related Perspective.

Tortoise refugees with the highest genetic variation are far more likely to survive conservation translocation than tortoises whose genetic diversity is lower, according to a new study. The findings suggest that translocation efforts should account for genetic variation when selecting target individuals rather than focusing solely on those determined to be most geographically or genetically similar to the target populations. Human activity and climate change are driving record numbers of species towards extinction and represent a challenge that is being addressed by a myriad of conservation efforts worldwide. One conservation strategy employed to preserve threatened species is through translocation of individual plants and animals to areas where they've become locally extinct or to new locations where they might bolster declining resident populations. While the approach is becoming increasingly common, it is often reserved as a last resort as the long-term success is often quite poor. An ongoing debate in this area relates to whether such efforts are most successful when they target individuals from environmentally similar regions or genetically close target populations, or when they focus on overall genetic diversity. To test these hypotheses, Peter Scott and colleagues used a long-term dataset of displaced Mojave Desert Tortoises - many previously captive pets - brought to the Desert Tortoise Conservation Center's translocation site in Nevada. Scott et al. analyzed genomic data for 166 desert tortoise refugees that either survived or died over a period of twenty years and found that neither geographical distance nor genetic similarity had any effect on post-translocation survival. Instead, the greatest predictor for success was heterozygosity - individuals with the highest genomic variation survived at much higher rates than others. While the authors note that further research is needed to understand the reasons behind this increased survival, the new insights suggest ways to improve current translocation efforts.

COLUMBUS, Ohio - New research has identified and described a cellular process that, despite what textbooks say, has remained elusive to scientists until now - precisely how the copying of genetic material that, once started, is properly turned off.

The finding concerns a key process essential to life: the transcription phase of gene expression, which enables cells to live and do their jobs.

During transcription, an enzyme called RNA polymerase wraps itself around the double helix of DNA, using one strand to match nucleotides to make a copy of genetic material - resulting in a newly synthesized strand of RNA that breaks off when transcription is complete. That RNA enables production of proteins, which are essential to all life and perform most of the work inside cells.

Just as with any coherent message, RNA needs to start and stop in the right place to make sense. A bacterial protein called Rho was discovered more than 50 years ago because of its ability to stop, or terminate, transcription. In every textbook, Rho is used as a model terminator that, using its very strong motor force, binds to the RNA and pulls it out of RNA polymerase. But a closer look by these scientists showed that Rho wouldn't be able to find the RNAs it needs to release using the textbook mechanism.

"We started studying Rho, and realized it cannot possibly work in ways people tell us it works," said Irina Artsimovitch, co-lead author of the study and professor of microbiology at The Ohio State University.

The research, published online by the journal Science today, Nov. 26, 2020, determined that instead of attaching to a specific piece of RNA near the end of transcription and helping it unwind from DNA, Rho actually "hitchhikes" on RNA polymerase for the duration of transcription. Rho cooperates with other proteins to eventually coax the enzyme through a series of structural changes that end with an inactive state enabling release of the RNA.

The team used sophisticated microscopes to reveal how Rho acts on a complete transcription complex composed of RNA polymerase and two accessory proteins that travel with it throughout transcription.

"This is the first structure of a termination complex in any system, and was supposed to be impossible to obtain because it falls apart too quickly," Artsimovitch said.

"It answers a fundamental question - transcription is fundamental to life, but if it were not controlled, nothing would work. RNA polymerase by itself has to be completely neutral. It has to be able to make any RNA, including those that are damaged or could harm the cell. While traveling with RNA polymerase, Rho can tell if the synthesized RNA is worth making - and if not, Rho releases it."

Artsimovitch has made many important discoveries about how RNA polymerase so successfully completes transcription. She didn't set out to counter years of understanding about Rho's role in termination until an undergraduate student in her lab identified surprising mutations in Rho while working on a genetics project.

Rho is known to silence the expression of virulence genes in bacteria, essentially keeping them dormant until they're needed to cause infection. But these genes do not have any RNA sequences that Rho is known to preferentially bind. Because of that, Artsimovitch said, it has never made sense that Rho looks only for specific RNA sequences, without even knowing if they are still attached to RNA polymerase.

In fact, the scientific understanding of the Rho mechanism was established using simplified biochemical experiments that frequently left out RNA polymerase - in essence, defining how a process ends without factoring in the process itself.

In this work, the researchers used cryo-electron microscopy to capture images of RNA polymerase operating on a DNA template in Escherichia coli, their model system. This high-resolution visualization, combined with high-end computation, made accurate modeling of transcription termination possible.

"RNA polymerase moves along, matching hundreds of thousands of nucleotides in bacteria. The complex is extremely stable because it has to be - if the RNA is released, it is lost," Artsimovitch said. "Yet Rho is able to make the complex fall apart in a matter of minutes, if not seconds. You can look at it, but you can't get a stable complex to analyze."

Using a clever method to trap complexes just before they fall apart enabled the scientists to visualize seven complexes that represent sequential steps in the termination pathway, starting from Rho's engagement with RNA polymerase and ending with a completely inactive RNA polymerase. The team created models based on what they saw, and then made sure that these models were correct using genetic and biochemical methods.

Though the study was conducted in bacteria, Artsimovitch said this termination process is likely to occur in other forms of life.

"It appears to be common," she said. "In general, cells use similar working mechanisms from a common ancestor. They all learned the same tricks as long as these tricks were useful."

In Nevada's dry Ivanpah Valley, just southeast of Las Vegas, a massive unintended experiment in animal conservation has revealed an unexpected result.

From 1997 to 2014, the U.S. Fish and Wildlife Service moved more than 9,100 Mojave desert tortoises to the 100-square-kilometer (about 39 miles square) Large Scale Translocation Site. The newcomers, many of which were abandoned pets or had been displaced by development, joined nearly 1,500 desert tortoises already living there.

Conventional wisdom would suggest that tortoises from areas closest to the translocation site would fare best. But a new UCLA study, published today in Science, found no connection between the tortoises' place of origin and their chances of survival. It did, however, uncover a far better predictor.

Tortoises with lots of genetic variation were much more likely to survive after their relocation, said UCLA conservation ecologist Brad Shaffer, the study's senior author. Like most organisms, tortoises have two copies of their entire genome, with one copy from each parent. The more those copies differ from each other, the higher the organism's heterozygosity.

The researchers compared translocated tortoises that lived or died over the same time period after being relocated to the site. They found that survivors averaged 23% greater heterozygosity than those that perished. Simply put, tortoises with more genetic variation had higher survival rates.

"It flies in the face of what we know from other translocation studies, but lots of genetic variation was hands-down the best predictor of whether a tortoise lived or died," said Shaffer, a professor of ecology and evolutionary biology and director of the UCLA La Kretz Center for California Conservation Science. "Relocating endangered plants and animals is increasingly necessary to counteract the effects of climate change, and this gives us a new tool to increase survival rates."

Although the relationship between heterozygosity and survival was well supported by the study, it's unclear why greater genetic variation is linked to survival rates, said former UCLA postdoctoral scholar Peter Scott, the study's lead author.

"Potentially, individuals with higher heterozygosity have more genomic flexibility," said Scott, who is now an assistant professor at West Texas A&M University. "It's likely that tortoises with more variation have a better chance of having one copy of a gene that works really well in stressful or new environments compared to those individuals with two identical copies that only work really well in their environment of origin."

The researchers wanted to make tortoise conservation efforts more effective, and uncover trends that would help other species as well, Scott said.

"Oftentimes, the chances of success for relocating plants or animals is pretty dismal," he said. "We wanted to understand why, and use that understanding to increase survival."

Over the years, tortoises that were given up as pets, or removed from places like developments in suburban Las Vegas and solar farms in the desert, were surrendered to the U.S. Fish and Wildlife Service.

The agency took blood samples to screen for diseases and marked each animal before releasing them into the Ivanpah Valley site, which enabled the animals to be tracked in later surveys. The UCLA researchers sequenced blood samples drawn from 79 tortoises that were released to the site and were known to be alive in 2015, and from another 87 known to have died after they were released at the site.

Although the Large Scale Translocation Site provided an intriguing dataset, it's not the same as a controlled experiment. Additional studies would be needed to understand why more heterozygous tortoises had a higher survival probability and precisely how much of an increase in genetic variation improves a tortoise's odds of surviving.

"The only reason we could do this study was because the U.S. Fish and Wildlife Service was incredibly forward-thinking when they set up the translocation site and tracked who lived and died," Shaffer said. "Many died, and no one was happy about that. But we can learn a lot from that unfortunate result to help conservation management improve.

"When thinking about moving animals or plants out of danger, or repopulating an area emptied by wildfire, now we can easily and economically measure genetic variability to better gauge the survival probability of those translocated individuals. It's not the only criteria, but it's an important piece of the puzzle."

Twice as much freshwater is stored offshore of Hawai'i Island than was previously thought, according to a University of Hawai'i study with important implications for volcanic islands around the world. An extensive reservoir of freshwater within the submarine southern flank of the Hualālai aquifer has been mapped by UH researchers with the Hawai'i EPSCoR 'Ike Wai project. The groundbreaking findings, published in Science Advances, reveal a novel way in which substantial volumes of freshwater are transported from onshore to offshore submarine aquifers along the coast of Hawai'i Island.

This mechanism may provide alternative renewable resources of freshwater to volcanic islands worldwide. "Their evidence for separate freshwater lenses, stacked one above the other, near the Kona coast of Hawai'i, profoundly improves the prospects for sustainable development on volcanic islands," said UH Mānoa School of Ocean and Earth Science and Technology (SOEST) Dean Brian Taylor.

Paradigm shift

Through the use of marine controlled-source electromagnetic imaging, the study revealed the onshore-to-offshore movement of freshwater through a multilayer formation of basalts embedded between layers of ash and soil, diverging from previous groundwater models of this area. Conducted as a part of the National Science Foundation-supported 'Ike Wai project, research affiliate faculty Eric Attias led the marine geophysics campaign.

"Our findings provide a paradigm shift from the conventional hydrologic conceptual models that have been vastly used by multiple studies and water organizations in Hawai'i and other volcanic islands to calculate sustainable yields and aquifer storage for the past 30 years," said Attias. "We hope that our discovery will enhance future hydrologic models, and consequently, the availability of clean freshwater in volcanic islands."

Co-author Steven Constable, a professor of geophysics at the Scripps Institution of Oceanography, who developed the controlled source electromagnetic system used in the project, said, "I have spent my entire career developing marine electromagnetic methods such as the one used here. It is really gratifying to see the equipment being used for such an impactful and important application. Electrical methods have long been used to study groundwater on land, and so it makes sense to extend the application offshore."

Kerry Key, an associate professor at Columbia University who employs electromagnetic methods to image various oceanic Earth structures, who not involved in this study, said, "This new electromagnetic technique is a game changing tool for cost-effective reconnaissance surveys to identify regions containing freshwater aquifers, prior to more expensive drilling efforts to directly sample the pore waters. It can also be used to map the lateral extent of any aquifers already identified in isolated boreholes."

Two-times more water

Donald Thomas, a geochemist with the Hawai'i Institute of Geophysics and Planetology in SOEST who also worked on the study, said the findings confirm two-times the presence of much larger quantities of stored groundwater than previously thought.

"Understanding this new mechanism for groundwater...is important to better manage groundwater resources in Hawai'i," said Thomas, who leads the Humu?ula Groundwater Research project, which found another large freshwater supply on Hawai'i Island several years ago.

Offshore freshwater systems similar to those flanking the Hualālai aquifer are suggested to be present for the island of O'ahu, where the electromagnetic imaging technique has not yet been applied, but, if demonstrated, could provide an overall new concept to manage freshwater resources.

The study proposes that this newly discovered transport mechanism may be the governing mechanism in other volcanic islands. With offshore reservoirs considered more resilient to climate change-driven droughts, volcanic islands worldwide can potentially consider these resources in their water management strategies.

SASKATOON - In a landmark discovery for global wheat production, a University of Saskatchewan-led international team has sequenced the genomes for 15 wheat varieties representing breeding programs around the world, enabling scientists and breeders to much more quickly identify influential genes for improved yield, pest resistance and other important crop traits.

The research results, just published in Nature, provide the most comprehensive atlas of wheat genome sequences ever reported. The 10+ Genome Project collaboration involved more than 95 scientists from universities and institutes in Canada, Switzerland, Germany, Japan, the U.K., Saudi Arabia, Mexico, Israel, Australia, and the U.S.

"It's like finding the missing pieces for your favorite puzzle that you have been working on for decades," said project leader Curtis Pozniak, wheat breeder and director of the USask Crop Development Centre (CDC). "By having many complete gene assemblies available, we can now help solve the huge puzzle that is the massive wheat pan-genome and usher in a new era for wheat discovery and breeding."

Scientific groups across the global wheat community are expected to use the new resource to identify genes linked to in-demand traits, which will accelerate breeding efficiency.

"This resource enables us to more precisely control breeding to increase the rate of wheat improvement for the benefit of farmers and consumers, and meet future food demands," Pozniak said.

One of the world's most cultivated cereal crops, wheat plays an important role in global food security, providing about 20 per cent of human caloric intake globally. It's estimated wheat production must increase by more than 50 per cent by 2050 to meet an increasing global demand.

In 2018 as part of another international consortium, USask researchers played a key role in decoding the genome for the bread wheat variety Chinese Spring, the first complete wheat genome reference and a significant technical milestone. The findings were published in the journal Science.

"Now we have increased the number of wheat genome sequences more than 10-fold, enabling us to identify genetic differences between wheat lines that are important for breeding," Pozniak said. "We can now compare and contrast the full complement of the genetic differences that make each variety unique."

Nils Stein of the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) and project co-leader from Germany said, "Given the significant impact of the Chinese Spring reference genome on research and application, it is a major achievement that just two years later we are providing additional sequence resources that are relevant to wheat improvement programs in many different parts of the world."

The 10+ Genome study represents the start of a larger effort to generate thousands of genome sequences of wheat, including genetic material brought in from wheat's wild relatives.

The research team was able to track the unique DNA signatures of genetic material incorporated into modern cultivars from several of wheat's undomesticated relatives by breeders over the century.

"These wheat relatives have been used by breeders to improve disease resistance and stress resistance of wheat," said Pozniak. "One of these relatives contributed a DNA segment to modern wheat that contains disease-resistant genes and provides protection against a number of fungal diseases. Our collaborators from Kansas State University and CIMMYT (Mexico) showed that this segment can improve yields by as much as 10 per cent. Since breeding is a continual improvement process, we can continue to cross plants to select for this valuable trait."

Pozniak's team, in collaboration with scientists from Agriculture and Agri-Food Canada and National Research Council of Canada, also used the genome sequences to isolate an insect-resistant gene (called Sm1) that enables wheat plants to withstand the orange wheat blossom midge, a pest which can cause more than $60 million in annual losses to Western Canadian producers.

"Understanding a causal gene like this is a game-changer for breeding because you can select for pest resistance more efficiently by using a simple DNA test than by manual field testing," Pozniak said.

The USask team also included the paper's first author Sean Walkowiak (formerly with Pozniak's team and now with the Canadian Grain Commission), computer scientist Carl Gutwin who developed visualization software and a user-friendly database to compare the genome sequences, and Andrew Sharpe, director of genomics and bioinformatics at the USask Global Institute for Food Security, who did sequencing work through the Omics and Precision Agriculture Laboratory (OPAL), a state-of-the-art laboratory that provides genomics, phenomics and bioinformatics services.

The 10+ Genome Project was sanctioned as a top priority by the Wheat Initiative, a co-ordinating body of international wheat researchers.

"This project is an excellent example of co-ordination across leading research groups around the globe. Essentially every group working in wheat gene discovery, gene analysis and deployment of molecular breeding technologies will use the resource," said Wheat Initiative Scientific Co-ordinator Peter Langridge.

Canadian funding came from the Canadian Triticum Applied Genomics (CTAG2) research project funded by Genome Canada, Genome Prairie, the Western Grains Research Foundation, Government of Saskatchewan, Saskatchewan Wheat Development Commission, Alberta Wheat Commission, Viterra, Manitoba Wheat and Barley Growers Association, and the Canada First Research Excellence Fund through USask's Plant Phenotyping and Imaging Research Centre (P2IRC) initiative.

"This project is a prime example of how genomics can support increased resilience in food production and strengthen Canada's export leadership," said Genome Canada President and CEO Rob Annan.

"Deploying genomics to adapt agricultural production to climate change, address food and nutritional insecurity, and improve crop health is good for farmers and consumers, and our economy will see tangible returns from this research. Genome Canada is immensely proud of the exceptional work by the Canadian researchers and their international collaborators, which underscores the potential of genomics to make a positive impact on the lives of Canadians and others around the world."

The historic NASA Twins Study investigated identical twin astronauts Scott and Mark Kelly and provided new information on the health effects of spending time in space.

Colorado State University Professor Susan Bailey was one of more than 80 scientists across 12 universities who conducted research on the textbook experiment; Mark remained on Earth while Scott orbited high above for nearly one year. The massive effort was coordinated by NASA's Human Research Program.

Bailey has continued her NASA research and now joins more than 200 investigators from dozens of academic, government, aerospace and industry groups to publish a package of 30 scientific papers in five Cell Press journals on Nov. 25.

Jared Luxton, who recently received his doctoral degree in cell and molecular biology at CSU, is the first author of two of the studies. He is now a data scientist with the United States Department of Agriculture in Fort Collins.

The research - including an over-arching paper that covers what the investigators have learned about the fundamental features of space flight - represents the largest set of space biology and astronaut health effects data ever produced.

For Bailey, it is also a milestone marking many years of working with NASA, which included her lead role on basic radiation studies and the honor of being selected as an investigator for the Twins Study and concurrent research projects involving astronauts. During this time, several graduate students in her lab earned doctoral degrees under her mentorship.

"We now have a foundation to build on - things we know to look for in future astronauts, including telomere length changes and DNA damage responses," Bailey said. "Going forward, our goal is to get a better idea of underlying mechanisms, of what's going on during long-duration space flight in the human body and how it varies between people. Not everybody responds the same way. That was one of the good things about having the larger cohort of astronauts in these studies."

Studying the ends of chromosomes, with implications for aging

Bailey is an expert on telomeres and radiation-induced DNA damage, areas of research that were of keen interest around the world when the Twins Study was published. In that study, she and her team found that Scott's telomeres in his white blood cells got longer while in space, and subsequently returned to near normal length after he was back on Earth.

Telomeres are protective "caps" on the ends of chromosomes that shorten as a person ages. Large changes in telomere length could mean a person is at risk for accelerated aging or the diseases that come along with getting older, cardiovascular disease and cancer for example.

In the latest research, Bailey, Luxton, Senior Research Associate Lynn Taylor and team studied a group of 10 unrelated astronauts, including CSU alum Dr. Kjell Lindgren, comparing the results with findings from the Kelly twins. The researchers did not have access to in-flight blood and other samples for all of the crewmembers, but Bailey said they did have blood samples before and after space flight for everyone.

The investigations involved astronauts who spent approximately six months on the International Space Station in low-Earth orbit, which is protected from some space radiation. Despite the protection, scientists found evidence of DNA damage that could be warning signs of potential health effects.

New discovery of oxidative stress

Among the new findings, the research team found that chronic oxidative stress during spaceflight contributed to the telomere elongation they observed. They also found that astronauts in general had shorter telomeres after spaceflight than they did before. The team also observed individual differences in responses.

To gain more insight on these findings, Bailey's team also studied twin mountain climbers who scaled Mt. Everest, an extreme environment on Earth. The non-climbing twins remained at lower altitude, including in Boulder, Colorado. Remarkably, the team found similar evidence of oxidative stress and changes in telomere length in the climbers.

Christopher Mason, associate professor at Weill Cornell Medicine and a co-author with Bailey, performed gene expression analyses on the Mt. Everest climbers. He found evidence of a telomerase-independent, recombination-based pathway of telomere length maintenance known to result in longer telomeres.

Bailey said that when chronic oxidative stress occurs, it damages telomeres.

"Normal blood cells are dying and trying to survive," she said. "They're adapting to their new environment. Some cells will activate an alternative pathway to keep their telomeres going. It's similar to what happens with some tumors. Some of the cells emerge from that process. That's what we think we're seeing during spaceflight as well."

Luxton said the mechanism described above - known as alternative lengthening of telomeres, or ALT - was an unexpected finding.

"You usually see that in cancer or in developing embryos," he said.

Take care of your telomeres

Similar to conclusions from the Twins Study, Bailey said the new findings have implications for future space travelers establishing a base on the Moon or traveling to Mars, or even as a space tourist. Long-duration exploration missions will involve increased time and distance outside of the protection of the Earth.

Although longer telomeres in space might seem like a good thing, perhaps even a "fountain of youth," the scientist said she suspects a somewhat different ending to the story.

"Extended lifespan, or immortality, of cells that have suffered space radiation-induced DNA damage, such as chromosomal inversions, is a recipe for increased cancer risk," she said.

Bailey said she and the team observed increased frequencies of inversions in all crewmembers, during and after spaceflight.

"Telomeres really are reflective of our lifestyles - whether on or off the planet," said Bailey. "Our choices do make a difference in how quickly or how well we are aging. It's important to take care of your telomeres."

Being born early (before 37 weeks' gestation) is associated with a higher risk of hospital admission throughout childhood than being born at full term (40 weeks' gestation), finds a study published by The BMJ today.

Although the risk declined as the children grew up, particularly after age 2, an excess risk remained up to age 10, even for children born at 38 and 39 weeks' gestation, representing many potentially vulnerable children, say the researchers.

Preterm birth is a major contributor to childhood ill health. Existing evidence suggests that the risk of illness associated with preterm birth declines as children grow up, but it remains unclear at what age this begins to happen and how these changes vary by week of gestational age at birth.

To explore this further, a team of UK researchers set out to examine the association between gestational age at birth and hospital admissions to age 10 years and how admission rates change throughout childhood.

Their findings are based on data from more than 1 million children born in NHS hospitals in England between 1 January 2005 and 31 December 2006. Children were monitored from birth until 31 March 2015 (an average of 9.2 years per child), during which time the researchers analysed numbers of hospital admissions.

Gestational age at birth was analysed in weeks, from less than 28 up to 42 weeks.

Over 1.3 million hospital admissions occurred during the study period, of which 831,729 (63%) were emergency admissions. Just over half (525,039) of children were admitted to hospital at least once during the study period.

After taking account of other potentially influential risk factors, such as mother's age, marital status and level of social deprivation, and child's sex, ethnicity and month of birth, the researchers found that hospital admissions during childhood were strongly associated with gestational age at birth.

The hospital admission rate during infancy in babies born at 40 weeks was 28 per 100 person years - this figure was about six times higher in babies born extremely prematurely (less than 28 weeks). By the time the children were aged 7-10 years, the hospital admission rate in children born at 40 weeks was 7 per 100 person years - this figure was about three times higher in those born at less than 28 weeks.

But even children born a few weeks early had higher admission rates. Being born at 37, 38, and 39 weeks' gestation was associated with a difference in the rate of admission of 19, 9, and 3 admissions per 100 person years during infancy, respectively, compared with those born at 40 weeks.

The risk of hospital admission associated with gestational age decreased over time, particularly after age 2. However, an excess risk remained up to age 10, even for children born at 38 and 39 weeks' gestation.

Although this excess risk at 38 and 39 weeks was relatively small, the large number of babies born globally at these gestational ages suggests that they are likely to have a large impact on hospital services, say the researchers.

Infections were the main cause of excess hospital admissions at all ages, but particularly during infancy. Respiratory and gastrointestinal conditions also accounted for a large proportion of admissions during the first two years of life.

This is an observational study, so can't establish cause, and the researchers point to some limitations, such as being unable to take account of several factors that can impact child health like maternal smoking and breastfeeding.

However, they say this was a large study using routinely collected data over a 10 year period, and the findings remained relatively stable after further analyses, suggesting that the results withstand scrutiny.

As such, the researchers say their findings indicate that gestational age at birth "is a strong predictor of childhood illness, with those born extremely preterm being at the greatest risk of hospital admission throughout childhood."

And the finding that infections were the main cause of excess hospital admissions at all ages prompt the researchers to call for targeted strategies to help prevent and better manage childhood infections.

Future research should also consider gestational age as a continuum and explore it for outcomes week by week, they conclude.

New additional research shows that increasing physical activity can counter early death risk linked to long periods of sedentary time

The health harms associated with prolonged sitting can be offset by exceeding weekly recommended physical activity levels, says the World Health Organization (WHO) in new global guidelines on physical activity and sedentary behaviour [1], published in a special dedicated issue of the British Journal of Sports Medicine.

But all physical activity counts and is good for long term health, say the new guidelines.

It's the first time that a recommendation of this kind has been made. It reflects a large and growing body of evidence linking extensive sedentary time to serious ill health and a heightened risk of early death.

New data also released today, and published in the same special issue, [2] show that adults who clock up long hours of sedentary time every day can counter these risks by increasing the amount of physical activity they do.

The new research, involving more than 44,000 people wearing activity trackers from four countries, reveals that a high daily tally of sedentary time (defined in this study as 10 or more hours) is linked to a significantly heightened risk of death, particularly among people who are physically inactive.

But 30 to 40 daily minutes of moderate to vigorous intensity physical activity substantially weakens this risk, bringing it down to levels associated with very low amounts of sedentary time, indicate the findings, which broadly confirm the recommendations set out in the 2020 World Health Organization Global Guidelines on Physical Activity and Sedentary Behaviour.

There's not enough evidence to recommend specific maximum thresholds for sedentary behaviour, say the guidelines. But everyone, irrespective of their age or abilities, should try to limit their daily sedentary time and replace it with physical activity of any intensity.

All physical activity counts. This could be anything from climbing the stairs instead of taking the lift, a walk around the block, a spot of gardening, or some household chores, to going for a run or bike ride, a high intensity interval training work-out, or team sport.

It all adds up to the weekly tally of 150-300 minutes of moderate intensity, or at least 75-100 minutes of vigorous intensity, physical activity, the WHO guidance recommends. But any amount of physical activity is better for health than none, it emphasises.

And those unable to meet these recommendations should start small and gradually build up the frequency, intensity, and duration of their physical activity over time, it says.

Boosting physical activity levels doesn't just benefit mental and physical health, and help to stave off the risk of an early death, it's also likely to benefit the global economy, through lower rates of presenteeism, higher productivity, and lower rates of working age sickness and death, indicates another study in this special issue.[3]

Doing at least 150 minutes of moderate intensity physical activity every week, which is the lower end of the range recommended in the new WHO guidelines, would increase global gross domestic product (GDP) by between 0.15%-0.24% a year between now and 2050, estimate the researchers.

That's worth up to US$314-446 billion a year and US$6.0-8.6 trillion cumulatively over the 30 years in 2019 prices.

The new guidelines, which aim to drive national policy and practice around the globe, involved more than 40 scientists from six continents. They provide a consensus on the latest science on the health impacts of physical activity and sedentary behaviour from early childhood through to older age, and update WHO global recommendations for physical health, published in 2010.

They highlight the importance of regularly undertaking both aerobic and muscle strengthening activities, and for the first time, make specific recommendations for important, but often neglected groups, including those who live with long term conditions or disabilities, pregnant women and new mothers.

Key recommendations for adults, including those living with long term conditions or disabilities at any age:

Aim to do 150-300 mins of moderate intensity, or 75-150 mins of vigorous-intensity physical activity, or some equivalent combination of moderate intensity and vigorous intensity aerobic physical activity every week.

Undertake muscle-strengthening activity (such as weights, core conditioning) at moderate or greater intensity on 2 or more days of the week.

Reduce sedentary behaviour and aim to exceed these weekly recommendations to offset health harms of prolonged sitting.

Older adults (65+) should do physical activity that emphasises functional balance and strength training at moderate or greater intensity on 3 or more days of the week, to enhance functional capacity and prevent falls.

Women should do regular physical activity throughout pregnancy and after the birth, to include various aerobic and muscle-strengthening activities. Gentle stretching may also be beneficial.

Light intensity physical activity doesn't cause a substantial increase in heart rate or breathing and includes activities such as strolling.

Moderate intensity physical activity increases heart rate and induces a degree of breathlessness where it's still possible to talk. Examples include brisk walking, dancing, or raking up leaves.

Vigorous intensity physical activity substantially increases heart rate and breathing rate. Examples include cycling, running/jogging, swimming, carrying heavy objects, walking up the stairs, digging the garden, playing tennis.

"Although the new guidelines reflect the best available science, there are still some gaps in our knowledge. We are still not clear, for example, where exactly the bar for 'too much sitting' is. But this is a fast paced field of research, and we will hopefully have answers in a few years' time," comments special issue co-editor Professor Emmanuel Stamatakis, of the University of Sydney.

He adds: "These guidelines are very timely, given that we are in the middle of a global pandemic, which has confined people indoors for long periods and encouraged an increase in sedentary behaviour.

"But people can still protect their health and offset the harmful effects of physical inactivity. As these guidelines emphasise, all physical activity counts and any amount of it is better than none.

"There are plenty of indoor options that don't need a lot of space or equipment, such as climbing the stairs, active play with children or pets, dancing, or online yoga or Pilates classes."

Co editor of the special issue, and development lead on the guidelines, Professor Fiona Bull of the WHO, adds: "The most recent global estimates show that one in four (27.5%) adults and more than three-quarters (81%) of teenagers don't meet the recommendations for aerobic exercise, as outlined in the 2010 Global Recommendations. So there's an urgent need for governments to prioritise and invest in national initiatives and health and community services that promote physical activity.

"The publication of these new WHO global guidelines can support implementation of policy recommendations set out in the WHO's Global Action Plan on Physical Activity 2018-2030 to achieve its ambitious target of 15% improvement by 2030."

NEW YORK, NY (Nov. 25, 2020)--Decades before the first symptoms of Alzheimer's appear, the brain's neurons start secreting tau proteins, one of the first changes known to occur in the course of the disease.

High levels of secreted forms of tau--which can be detected in spinal fluid and, as recently reported, in blood--are known to be the most reliable predictor of who will eventually develop Alzheimer's disease.

But a critical question about tau has remained unanswered: Why are neurons secreting tau in Alzheimer's disease?

"Since tau secretion is one of the earliest events in Alzheimer's, figuring out why that happens can tell us about the underlying mechanisms of the disease, which is critical for developing therapies. If tau is the smoke, in other words, what is the fire?" says Scott Small, MD, PhD, the Boris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons and director of the Alzheimer's Disease Research Center at Columbia University.

The Neuron's 'Grand Central Station' Is Commonly Defective in Alzheimer's

A new study from Small's laboratory found that, in many patients, tau secretion arises from tiny malfunctioning compartments inside the brain's neurons, suggesting that these malfunctional compartments are commonly involved in the appearance of Alzheimer's disease.

These tiny compartments, called endosomes, function as a 'grand central station' and traffic proteins throughout a cell. The new study provides evidence that endosomal trafficking is disrupted in about 70% of the patients it examined, including those only displaying the first signs of Alzheimer's.

The results provide the first direct evidence that endosomal traffic disruption--which Small, Richard Mayeux, MD, chair of neurology at Columbia, and others had previously identified as one of Alzheimer's root causes--is commonly defective among patients with the disease.

"There was no question that endosomal dysfunction is a component of Alzheimer's, but just how often it's involved had been unknown," says Sabrina Simoes, PhD, assistant professor of neurological sciences at Columbia University Vagelos College of Physicians and Surgeons, who led the study.

"Our study suggests that if drugs that restore endosomal dysfunction can slow Alzheimer's, those drugs could help a large proportion of patients."

Moreover, the study's results and new biomarker tools can be used to investigate which predisposing genes or comorbid diseases, such as obesity and diabetes, disrupt endosomal trafficking and raise the risk of developing Alzheimer's.

What the Study Did

The researchers were looking for biomarkers of endosomal trafficking dysfunction to determine its presence in Alzheimer's patients. Using mice with the same endosomal trafficking defect, the researchers searched the animals' spinal fluid for proteins that differed from that in normal animals. Three proteins stood out: Two were cleaved proteins that are known to be secreted by endosomes, called n-APLP1 and n-CHL1. The third was tau.

The study then examined the spinal fluid of people. First, investigators from Janssen Pharmaceuticals, collaborators in the study, developed new biomarkers of n-APLP1 and n-CHL1. Armed with accurate new biomarkers of these two proteins and with established biomarkers of tau (those that are in current use to diagnose patients), the investigators examined their relationship in healthy people. They found a remarkably tight relationship among the three proteins, suggesting that tau is normally secreted from the endosomal pathway.

The researcher then looked for the proteins in Alzheimer's patients and found that all three proteins are abnormally elevated in spinal fluid in approximately 70% of patients, even in those in the early "prodromal" stage of the disease.

Can Alzheimer's Be Slowed by Restoring Endosome Trafficking?

The study's identification of three new biomarkers of endosomal trafficking disruption can be used to accelerate Alzheimer's drug discovery and clinical trials by identifying patients with malfunctioning endosomes and measuring a drug candidate's ability to restore endosomal operations.

Researchers in Small's lab are working to find ways to improve endosomal trafficking and slow Alzheimer's disease. Several years ago, they identified compounds that do just that in neurons in a dish, and are now trying to develop these compounds as therapeutics. They are also developing gene therapies that can correct endosomal trafficking disruption in the brain.

The researchers are testing these therapeutics to see if they can improve the endosome's trafficking function in animal models of Alzheimer's disease.

More Information

The study appears in a paper titled, "Tau and other proteins found in Alzheimer's Disease spinal fluid are linked to retromer-mediated endosomal traffic," published online Nov. 25 in Science Translational Medicine.

The water-to-land transition is one of the most important and inspiring major transitions in vertebrate evolution. And the question of how and when tetrapods transitioned from water to land has long been a source of wonder and scientific debate.

Early ideas posited that drying-up-pools of water stranded fish on land and that being out of water provided the selective pressure to evolve more limb-like appendages to walk back to water. In the 1990s newly discovered specimens suggested that the first tetrapods retained many aquatic features, like gills and a tail fin, and that limbs may have evolved in the water before tetrapods adapted to life on land. There is, however, still uncertainty about when the water-to-land transition took place and how terrestrial early tetrapods really were.

A paper published November 25 in Nature addresses these questions using high-resolution fossil data and shows that although these early tetrapods were still tied to water and had aquatic features, they also had adaptations that indicate some ability to move on land. Although, they may not have been very good at doing it, at least by today's standards.

Lead author Blake Dickson, PhD '20 in the Department of Organismic and Evolutionary Biology at Harvard University, and senior author Stephanie Pierce, Thomas D. Cabot Associate Professor in the Department of Organismic and Evolutionary Biology and curator of vertebrate paleontology in the Museum of Comparative Zoology at Harvard University, examined 40 three-dimensional models of fossil humeri (upper arm bone) from extinct animals that bridge the water-to-land transition.

"Because the fossil record of the transition to land in tetrapods is so poor we went to a source of fossils that could better represent the entirety of the transition all the way from being a completely aquatic fish to a fully terrestrial tetrapod," said Dickson.

Two thirds of the fossils came from the historical collections housed at Harvard's Museum of Comparative Zoology, which are sourced from all over the world. To fill in the missing gaps, Pierce reached out to colleagues with key specimens from Canada, Scotland, and Australia. Of importance to the study were new fossils recently discovered by co-authors Dr. Tim Smithson and Professor Jennifer Clack, University of Cambridge, UK, as part of the TW:eed project, an initiative designed to understand the early evolution of land-going tetrapods.

The researchers chose the humerus bone because it is not only abundant and well preserved in the fossil record, but it is also present in all sarcopterygians - a group of animals which includes coelacanth fish, lungfish, and all tetrapods, including all of their fossil representatives. "We expected the humerus would carry a strong functional signal as the animals transitioned from being a fully functional fish to being fully terrestrial tetrapods, and that we could use that to predict when tetrapods started to move on land," said Pierce. "We found that terrestrial ability appears to coincide with the origin of limbs, which is really exciting."

The humerus anchors the front leg onto the body, hosts many muscles, and must resist a lot of stress during limb-based motion. Because of this, it holds a great deal of critical functional information related to an animal's movement and ecology. Researchers have suggested that evolutionary changes in the shape of the humerus bone, from short and squat in fish to more elongate and featured in tetrapods, had important functional implications related to the transition to land locomotion. This idea has rarely been investigated from a quantitative perspective - that is, until now.

When Dickson was a second-year graduate student, he became fascinated with applying the theory of quantitative trait modeling to understanding functional evolution, a technique pioneered in a 2016 study led by a team of paleontologists and co-authored by Pierce. Central to quantitative trait modeling is paleontologist George Gaylord Simpson's 1944 concept of the adaptive landscape, a rugged three-dimensional surface with peaks and valleys, like a mountain range. On this landscape, increasing height represents better functional performance and adaptive fitness, and over time it is expected that natural selection will drive populations uphill towards an adaptive peak.

Dickson and Pierce thought they could use this approach to model the tetrapod transition from water to land. They hypothesized that as the humerus changed shape, the adaptive landscape would change too. For instance, fish would have an adaptive peak where functional performance was maximized for swimming and terrestrial tetrapods would have an adaptive peak where functional performance was maximized for walking on land. "We could then use these landscapes to see if the humerus shape of earlier tetrapods was better adapted for performing in water or on land" said Pierce.

"We started to think about what functional traits would be important to glean from the humerus," said Dickson. "Which wasn't an easy task as fish fins are very different from tetrapod limbs." In the end, they narrowed their focus on six traits that could be reliably measured on all of the fossils including simple measurements like the relative length of the bone as a proxy for stride length and more sophisticated analyses that simulated mechanical stress under different weight bearing scenarios to estimate humerus strength.

"If you have an equal representation of all the functional traits you can map out how the performance changes as you go from one adaptive peak to another," Dickson explained. Using computational optimization the team was able to reveal the exact combination of functional traits that maximized performance for aquatic fish, terrestrial tetrapods, and the earliest tetrapods. Their results showed that the earliest tetrapods had a unique combination of functional traits, but did not conform to their own adaptive peak.

"What we found was that the humeri of the earliest tetrapods clustered at the base of the terrestrial landscape," said Pierce. "indicating increasing performance for moving on land. But these animals had only evolved a limited set of functional traits for effective terrestrial walking."

The researchers suggest that the ability to move on land may have been limited due to selection on other traits, like feeding in water, that tied early tetrapods to their ancestral aquatic habitat. Once tetrapods broke free of this constraint, the humerus was free to evolve morphologies and functions that enhanced limb-based locomotion and the eventual invasion of terrestrial ecosystems

"Our study provides the first quantitative, high-resolution insight into the evolution of terrestrial locomotion across the water-land transition," said Dickson. "It also provides a prediction of when and how [the transition] happened and what functions were important in the transition, at least in the humerus."

"Moving forward, we are interested in extending our research to other parts of the tetrapod skeleton," Pierce said. "For instance, it has been suggested that the forelimbs became terrestrially capable before the hindlimbs and our novel methodology can be used to help test that hypothesis."

Dickson recently started as a Postdoctoral Researcher in the Animal Locomotion lab at Duke University, but continues to collaborate with Pierce and her lab members on further studies involving the use of these methods on other parts of the skeleton and fossil record.

A phase 1 trial involving 12 children with relapsed neuroblastoma - a hard-to-treat pediatric cancer - shows that anticancer CAR T cells displayed signs of efficacy against these tumors while avoiding damage to nerve tissue. The results suggest that CAR T cells should be further evaluated as treatments for neuroblastoma and other solid tumors, which have typically been difficult to target with T cell therapies. CAR T cells are immune cells from patients that have been engineered to hunt down cancer cells, and have shown great promise against blood cancers such as leukemia. However, it has been much more difficult to use CAR T cells against solid tumors, which are harder for the cells to penetrate. Here, Karin Straathof and colleagues performed a phase 1 trial to study the safety and performance of CAR T cells against neuroblastoma. They created CAR T cells that target the GD2 protein, which is common on neuroblastoma tumors, and administered the cells to 12 pediatric patients who had failed to respond to standard chemotherapies. None of the children showed measurable drops in the size of their tumors after one month, according to standard X-ray criteria, and some experienced immune-related side effects. However, three patients who also received two conditioning drugs showed some signs of antitumor immunity, and did not display any signs of damage to healthy nerve tissue bearing GD2. Straathof et al. note that further modifications to the CAR T cells will be necessary to boost their persistence within tumors, given the transient nature of the observed antitumor responses.

Pointing toward a much-needed future reservoir of freshwater for the island of Hawai'i in the face of climate-driven drought, electromagnetic images of the island have revealed multilayered basalt, ash and soil formations that serve as a previously unknown conduit to move freshwater offshore to the submarine flank of the island. According to the study by Eric Attias and colleagues, these freshwater-saturated layers may extend as much as 4 kilometers offshore. Attias et al. decided to look more deeply into the transport of freshwater through the island's complex geology after noting a 40% discrepancy in the predicted volume of fresh groundwater. The researchers looked for this missing freshwater using a technique called marine controlled-source electromagnetic (CSEM) imaging, which can distinguish seawater from freshwater through measurements of the electrical resistivity of rock formations. Their images mapped out a pattern of alternating ash/soil and basalt layers of differing porosity that trap layers of fresh groundwater while forcing out seawater. As these layers dip under the ocean, they form a 3.5 cubic kilometer cache of freshwater west of Hawai'i. Electromagnetic studies of other volcanic islands across the globe suggest the presence of similarly layered offshore hydrogeological formations, the researchers note, indicating potential new sources of freshwater for these islands as well.

Research indicates that starting school later in the morning yields health and academic benefits for high schoolers, whose natural body clock tends toward late-to-bed, late-to-rise habits. While parents raise concerns about drowsy driving, irritation and impaired school performance, a new study led by researchers at UC San Francisco suggests another reason to push back the start time.

The researchers found that teens with migraines whose high schools started before 8:30 a.m. experienced an average 7.7 headache days per month. This was close to three more headache days than those with later school start times, the researchers reported in their study, which publishes in Headache: The Journal of Head and Face Pain on Nov. 25, 2020.

"Evidence suggests that there is a relationship between sleep and migraine," said first author Amy Gelfand, MD, a neurologist at the Pediatric Headache Program at UCSF Benioff Children's Hospitals, noting that 8-12 percent of adolescents suffer from the disease. "Getting adequate sleep and maintaining a regular sleep schedule may reduce the frequency of migraines."

The American Academy of Sleep Medicine advises that teens get from eight to 10 hours of sleep a night. In recognition of adolescents' delayed circadian clock, the American Academy of Pediatrics recommends that middle and high schools start no earlier than 8:30 a.m. However, just 18 percent of public middle and high schools adhere to this recommendation, according to the Centers for Disease Control and Prevention.

To quantify what impact, if any, school start times have on migraine frequency, the researchers reached out to high schoolers via social media, offering a $10 gift card to complete a brief survey. Approximately 1,000 9th-12th graders whose headaches fit the criteria for migraine responded to the survey. They comprised 509 students who started school before 8:30 a.m. and 503 who started school after 8:30 a.m.

Both groups had an average 24-minute commute to school, with the earlier-start group waking up at 6:25 a.m. and beginning school at 7:56 a.m., and the later-start group waking up at 7:11 a.m. and beginning school at 8:43 a.m. Of note, the later-start group went to bed earlier on school nights - on average at 10:19 p.m., versus 10:58 p.m. in the earlier-start group.

While the average number of headache days per month averaged 7.7 days for the earlier-start group and 4.8 days for the later-start group, the difference narrowed to 7.1 and 5.8 days when the researchers adjusted for risk factors such as inadequate sleep and skipping breakfast, as well as for gender, grade, homework volume and migraine medication use. Nevertheless, the 1.3 days difference between the two groups remained significant, said Gelfand, who is affiliated with the UCSF Weill Institute for Neurosciences.

"The magnitude of the effect size in this study is similar to that seen in studies of migraine prevention drugs," she said. "For example, in a trial of topiramate (Topamax) versus placebo in 12- to 17-year-olds with episodic migraine, those receiving the drug had an average of two migraine days in the last month, compared with 3.5 migraine days for those on placebo - a difference of 1.5 days."

Similarly, in two studies of adults receiving onabotulinum toxin A (Botox) injections to prevent chronic migraines, the difference between the number of headache days between the two treatment groups and each placebo group was 1.4 days and 2.3 days.

"If our findings are confirmed in future research, shifting to a later high school start time is a modifiable, society-level intervention that could translate to thousands of fewer migraine days and fewer missed days of school for teenagers," said Gelfand, who will be the new editor-in-chief of Headache in January.

In 2019, California became the first state to legislate that high schools begin no earlier than 8:30 a.m., a change that will be implemented in the 2022-23 academic year. "The COVID-19 pandemic has led to widescale changes in how students attend schools," said Gelfand. "As we rethink what a typical school day looks like, the time may be ripe for changing school start time as well."

Among patients reporting to hospital emergency departments (EDs) with suspected COVID-19 infection, important differences in symptoms and outcome exist based on age, sex and ethnicity, according to a new study published this week in the open-access journal PLOS ONE by Steve Goodacre of the University of Sheffield, UK, and colleagues.

Hospital EDs have played a crucial role during the COVID-19 pandemic in receiving acutely ill patients, determining their need for hospital admission, and providing treatment. Appropriate management of the heterogeneous population of patients who are suspected of having COVID-19 is an important challenge that needs to be informed by relevant data.

In the new paper, part of the Pandemic Respiratory Infection Emergency System Triage (PRIEST) study and funded by the National Institute for Health Research (NIHR), researchers collected a mixture of prospective and retrospective data from 22,445 people presenting to 70 EDs across the UK with suspected COVID-19 infection between March 26, 2020 and May 28, 2020. Data on sex, age, ethnicity, presenting symptoms, admission to hospital, COVID-19 result, organ support and death was available for each patient 30 days after initial presentation. This study is one of a number of COVID-19 studies that have been given urgent public health research status by the Chief Medical Officer/ Deputy Chief Medical Officer for England.

On average, those included in the study were 58.4 years old, 50.4% female, and 84.75% white. Adults admitted to the hospital with confirmed COVID-19 were more than twice as likely to die or receive organ support than adults who did not have COVID-19, suggesting a worse outcome from COVID-19 than similar presentations. Compared to children aged 16 years and under, adults were sicker, had higher rates of hospital admission (67.1% vs 24.7%), COVID positivity (31.2% vs 1.2%) and death (15.9% vs 0.3%). Men were also more likely to be admitted to the hospital than women (72.9% vs 61.4%), required more organ support (12.2% vs 7.7%) and were more likely to die (18.7% vs 13.3%).

In addition, ethnicity conveyed some differences--Black and Asian adults tended to be younger than White adults and, while they were less likely to be admitted to the hospital (Black 60.8%, Asian 57.3%, White 69.6%), they were more likely to require organ support (15.9%, 14.3%, 8.9%) and, importantly, more likely to have a positive COVID-19 test (40.8%, 42.1%, 30.0%).

The authors add: "Our findings show that people attending emergency departments with suspected COVID-19 were seriously ill, suggesting that policies aimed at diverting less serious cases away from hospitals were successful. We also showed that admission with COVID-19 carries a much higher risk of death or need for life-saving treatment than admission with similar conditions."