Culture

The global movement of goods and people, in its modern form, has many unwanted side effects. One of these is that animal and plant species travel around the world with it. Often they fail to establish themselves in the ecosystems of the destination areas. Sometimes, however, due to a lack of effective management, they multiply to such an extent in the new environment that they become a threat to the entire ecosystem and economy. Thousands of alien species are currently documented worldwide. A quarter of them are in highly vulnerable, aquatic habitats.

So far, research has mainly focused on the ecological consequences of these invasions. In a first global data analysis, 20 scientists from 13 countries led by GEOMAR Helmholtz Centre for Ocean Research Kiel have now compiled the economic costs caused specifically by aquatic invaders. "We come to the conclusion that invasive aquatic species that have established themselves in their new habitats have cost at least 345 billion US dollars since the 1970s," says Dr Ross Cuthbert from GEOMAR. He is lead author of the study, which has now been published in the journal Science of the Total Environment.

Economic costs occur, for example, when invasive species decimate commercially exploited fish stocks, spread deadly diseases or damage infrastructures. "Good examples include invasive mussels that clog intake pipes of factories, power plants or water treatment plants. Or, alien parasites that cause catastrophic declines in commercial fisheries," explains Dr Cuthbert.

For the study, the team used cases recorded in the existing literature and standardized them in a comprehensive database. Invertebrates (62%) accounted for the largest proportion of costs that could be detected in this way, followed by vertebrates (28%) and plants (6%). The largest costs were reported in North America (48 %) and Asia (13 %) and were mainly due to damages to resources such as physical infrastructures, healthcare systems and fisheries. Worryingly, over ten-times less was spent on management actions, such as prevention of future invasions, than damages.

"However, our figures are vastly underestimated due to knowledge gaps. Costs were never reported for many countries and known damaging invasive species, especially in Africa and Asia. So, we can assume that the damages are actually much higher," Dr Cuthbert points out. A comparison with the costs caused by invaders on land confirms this assumption. While aquatic species make up a quarter of the documented invasive species, the economic costs they cause comprise only a twentieth of what is known for terrestrial species.

The team also identified a clear trend that costs have increased significantly in recent years. In 2020 alone, they amounted to at least 23 billion US dollars.

"So, the costs of aquatic invaders are significant, but probably under-reported. Costs have increased over time and are expected to continue to increase with future invasions," Dr Cuthbert summarises the study. The team of authors therefore calls for increased and improved cost reporting by managers, practitioners and researchers to reduce knowledge gaps. It also urges more money to be invested in invasion management and prevention. "This would be money well spent to prevent and limit current and future damage," Dr Cuthbert emphasises.

LAWRENCE -- An international trade law expert at the University of Kansas argues in a pair of new articles that human rights and trade are now inextricably linked, as evidenced by U.S. and international reactions to actions in China, and asserts that approach is an appropriate use of trade.

Raj BhalaAfter the United States, then Canada and the Netherlands, declared the Chinese Communist Party's actions against Uyghur Muslims as genocide, the nations followed with various trade sanctions. Likewise, countries have adopted trade measures in response to China's violation of its one-country, two-systems agreement with Hong Kong. Raj Bhala, Brenneisen Distinguished Professor of Law at the KU School of Law, details both situations in two new companion case studies, argues the linking of trade to human rights is correct and examines future possibilities for such measures.

"Most people think human rights are to be separated from trade. In fact, that's not true," Bhala said. "There are no express, comprehensive provisions for human rights in the World Trade Organization or General Agreement on Tariffs and Trade, but we're seeing the link come up in U.S. trade policy and some regional free trade agreements. We're entering an era of invigorated enhancements of human rights through trade policy."

Bhala wrote an article on China's treatment of Uyghur Muslims and American trade response, published in India's Journal of the National Human Rights Commission, and another on Hong Kong's democracy, China's violation thereof and American trade response, forthcoming in the Kansas Journal of Law & Public Policy.

Former President Donald Trump's disputes with China and resulting trade war were widely debated and criticized. But, Bhala points out the sometimes-overlooked trade reactions to the events in Xinjiang and Hong Kong are distinct, and defensible, actions. While thoroughly detailing the economic and legal actions of each case, he points out how the United States and China are in a new era of great power competition. He also outlines how, historically, trade and human rights were considered separate matters, and he chronicles how and why the earliest connections between the two issues occurred.

"The articles make the point that the two issues, international trade and human rights, are now inextricably linked," Bhala said. "In one situation, we have what three governments have already called genocide, and what the world generally agrees is a violation of China's one-country, two-systems policy in Hong Kong in the other."

The former system involves genocide of a religious minority, while the latter involves legally codified human rights such as direct elections and peaceful assembly in Hong Kong. The United States has taken various trade actions, such as banning imports of Chinese products like cotton and tomatoes from Xinjiang in the first case, and freezing assets of Chinese Communist Party officials on the mainland in the second.

Bhala argues that such sanctions and related actions are appropriate. The World Trade Organization does not provide for trade remedies to human rights violations or crimes against humanity, hence options through that multilateral venue are limited.

"If we don't use trade measures like sanctions in these two egregious instances, then when would we?" Bhala said.

In addition to outlining in the articles the legal responses and arguing they are justified, Bhala examines how the United States and other nations will most likely continue to use such measures in the future. Numerous contexts, including China's actions toward Tibet, Taiwan and across the South China Sea and its self-declared Nine Dash Line, will most likely cause disagreement and conflict between the two world powers. He also emphasizes the conflicts are not with the Chinese people, but with the actions and policies of their government.

"We know the Chinese people are not monolithic in their views of their own government," Bhala said. "There are many people in Hong Kong and on the mainland who are concerned with what has happened in Xinjiang with the Uyghur population, and also in respect to what has happened in Tibet and Taiwan."

While it may be too early to know what the long-term results of trade remedies to human rights violations may be, or whether they will escalate tensions, the ongoing situations are confirmation that international trade and human rights are two sides of the same coin.

"If we've learned nothing else, it's that trade policy is national security policy is human rights policy," Bhala said. "Our national security is based on our values. We express our values partly through who we decide to trade with, and the terms on which we trade with them. Trade is not only about trade."

Ann Arbor, April 6, 2021 - New data from the Centers for Disease Control and Prevention (CDC) show that one in four adults with HIV in the United States has experienced intimate partner violence (IPV), which disproportionately affects women and LGBT populations. Further, people with HIV who experienced IPV in the past 12 months were more likely to engage in behaviors associated with elevated HIV transmission risk, were less likely to be engaged in routine HIV care and more likely to seek emergency care services and have poor HIV clinical outcomes. The findings are reported in the American Journal of Preventive Medicine, published by Elsevier.

Lead Investigator Ansley B. Lemons-Lyn, MPH, and colleagues from the CDC's National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention and the National Center for Injury Prevention and Control in Atlanta, GA, USA, used data from the Medical Monitoring Project, an annual survey used to produce national estimates of sociodemographic, behavioral, and clinical characteristics of adults diagnosed with HIV. Analysts estimated the prevalence of respondents who had ever experienced IPV and those who experienced IPV within the last 12 months and compared that with sociodemographic information, behavioral characteristics, clinical outcomes, and the use of emergency or inpatient medical services in the past year.

Among individuals with HIV, 26.3 percent had at least one experience of IPV. Significant differences were found by race/ethnicity and age; 35.6 percent of women, 28.9 percent of transgender people, and 23.2 percent of men had experienced IPV. There were also significant differences based on gender and sexual identity. Although women overall experienced the highest prevalence of IPV, bisexual women experienced the highest proportion (51.5 percent) compared with all gender and sexual identity groups.

Overall, 4.4 percent of people with HIV had experienced IPV in the last 12 months. Statistically significant differences were found by sociodemographic characteristics, such as age and gender/sexual identify but not by race/ethnicity or gender identity. The study found that compared with individuals with HIV who did not experience IPV in the last 12 months, those who did engaged in riskier behavior such as binge drinking, use of injection drugs, and transactional sex. They were more likely to report not receiving additional needed services.

These findings suggest that screening people with HIV for IPV and linking them to services, not only during HIV testing but also during routine HIV care, is important. A higher proportion of individuals reporting IPV in the last 12 months were not receiving HIV medical care, were not taking antiretroviral therapy, and were more likely to miss HIV-related medical appointments. They were also more likely to have more than one emergency room visit or hospital admission in the past 12 months.

The study suggests that when IPV is identified, the safety and health of people with HIV can be improved with supportive services. IPV is preventable, especially when efforts begin early. The investigators note that most IPV and protection programs are tailored for heterosexual women. Given the extent to which the study found risk to other gender/sexual identity groups and racial/ethnic minorities, investigators suggest that programming should be tailored for marginalized groups.

Sea urchins receive a lot of attention in California. Red urchins support a thriving fishery, while their purple cousins are often blamed for mowing down kelp forests to create urchin barrens. Yet for all the notice we pay them, we know surprisingly little about the microbiomes that support these spiny species.

Researchers at UC Santa Barbara led by geneticist Paige Miller sought to uncover the diversity within the guts of these important kelp forest inhabitants. Their results reveal significant differences between the microbiota of the two species, as well as between individuals living in different habitats. The study, which appears in Limnology and Oceanography Letters, represents the first step in understanding the function of urchins' microbial communities, including the possibility that urchins may be able to 'farm' microbes in their guts to create their own food sources.

California hosts two common species of sea urchin: red and purple. They generally consume algae, but are actually fairly opportunistic omnivores that will eat decaying plant and animal matter, microbial mats and even other urchins if need be. The microbiome in their guts might help urchins handle such a varied diet, but it hasn't been examined until now.

"It's very important to understand what animals eat and why," Miller said, "and we think the microbiome could play an important role in why species thrive despite all the variation in food availability that's out there in the ocean." However, scientists are only beginning to investigate the microbiota of ocean animals, let alone the function these microorganisms serve in their hosts.

To begin their investigation, Miller and her team collected red and purple urchins from three habitats in the Santa Barbara Channel. Some came from lush kelp forests; others from urchin barrens; and a few came from one of the channel's many hydrocarbon seeps, where they scratch a living feeding on mats of microbes that thrive off of petroleum compounds.

Key to this study's success was the researchers' stringent protocol. They used meticulous techniques to remove each specimen's stomach and guts in order to avoid contamination from microbes in the lab, elsewhere on the animal, and even in the sea water.

The researchers were then able to sequence a particular region of the genetic code that scientists commonly use to identify microbes. This enabled them to compare what they found with several comprehensive taxonomic databases that scientists use for genetic identification of microbial life.

The team found significant differences between the bacterial communities living within the two urchin species. However, they saw just as much variation between the microbiomes of individuals from the same species living in different habitats.

Purple sea urchin closeup

Comparing the microbiome of purple (pictured) and red sea urchins points toward differences between the similar species.

Photo Credit: KATIE DAVIS

"Our study is the first to examine the microbiome in these extremely common, and really ecologically important, species," said coauthor Robert (Bob) Miller, a researcher at the university's Marine Science Institute. "We're just scratching the surface here, but our study shows how complex these communities are."

One group of bacteria that was prevalent in both species is the same group that helps break down wood in the guts of termites, and could help the urchins digest algae. Previous research indicates that these microbes could potentially be autotrophic. "Some members of this group can create their own food, like photosynthetic plants, for example," explained Paige Miller, "only they don't use sunlight for energy, they use hydrogen."

Although the authors caution against jumping to conclusions, ascertaining whether urchins can produce their own food would be a huge revelation. "We know that the urchins can survive a long time without food," Bob Miller said. "And they can survive almost indefinitely in these barren areas that have very low food supplies. So, this could really help them out, if they have their own little farmed food supply in their gut."

The findings also stress the oversight of conflating these similar species. People often treat species like the red and purple sea urchins as equivalent when making decisions about resource use and management, Paige Miller explained. Even ecologists can fall into this line of reasoning. "But it's very important to look at how these things actually function," she noted. "And as we saw, the red and purple sea urchins are not necessarily functioning the same way, or eating the same things, if their microbiome is an indicator."

Understanding the makeup and function of microbiota could help researchers recognize the subtle differences between superficially similar species. "More recently, people have begun considering the microbiome as another trait that these species have," Bob Miller said. "We wanted to find out whether this is a hidden source of variation that's separating these two species."

This study provides a launch point for additional research. In the future, the Millers and their coauthors plan to further investigate the function of the different microbes in urchin guts. For now, there's still more work to do simply identifying what species reside in the prickly critters.

"This is a new subfield of ecology," said Paige Miller, "trying to understand what these microbiomes do and the role they play in the living organism out in the wild."

Philadelphia, April 6, 2021 - Since the discovery of leptin in the 1990s, researchers have wondered, how does leptin, a hormone made by body fat, suppress appetite? Despite tremendous gains in the intervening three decades, many questions still remain. Now, a new study in mice describes novel neurocircuitry between midbrain structures that control feeding behaviors that are under modulatory control by leptin. The study appears in Biological Psychiatry, published by Elsevier.

John Krystal, MD, Editor of Biological Psychiatry, said of the findings, "Omrani and colleagues shed light on how, in non-obese animals, leptin puts the brakes on overeating."

Leptin acts as a critical link between the body and the brain, providing information about metabolic state and exerting control over energy balance. The importance of leptin is illustrated by the finding that animals deficient for leptin rapidly become obese without its regulatory stop on feeding behavior.

Roger Adan, PhD, of the Department of Translational Neuroscience, University Medical Center Utrecht and University Utrecht, the Netherlands, who led the study, said, "This process is shaped by communication between bodily fat storages (via a hormone called leptin) and the brain's dopamine reward system. This leptin-dopamine axis is critically important for body weight control, but its modes of action were not well understood."

Leptin suppresses eating by signaling to brain regions that control eating behaviors, but it also decreases the reward value inherent in foods, engaging the brain's dopamine (DA) reward system. That food-reward pathway was known to involve dopaminergic neurons of the ventral tegmental area (VTA) signaling to the nucleus accumbens (NAc), but most of those DA neurons do not contain receptors for leptin.

The work used a combination of powerful technologies, including optogenetics, chemogenetics and electrophysiology to map the new microcircuitry.

"Although leptin receptors are present on [some] dopamine neurons that signal food reward," said Professor Adan, also of the Department of Translational Neuroscience, University Medical Center Utrecht and University Utrecht, "we discovered that leptin receptors are also present on inhibitory neurons that more strongly regulate the activity of dopamine neurons. Some of these inhibitory neurons suppressed food seeking when [animals were] hungry, whereas others [did so] only when [animals were] in a sated state."

Dr. Krystal said of the study, "It turns out that leptin plays key modulatory roles in an elegant circuit that unites midbrain and limbic reward circuitry. By inhibiting hypothalamic neurons and ultimately suppressing the activity of dopamine neurons in the midbrain that signal reward and promote feeding, leptin reduces food intake in animals under conditions when caloric intake has exceeded energy use."

Ultimately, Professor Adan said, "Targeting these neurons may provide a new avenue for the treatment of anorexia nervosa and to support dieting in people with obesity."

Biophysicists from Ludwig-Maximilians-Universitaet (LMU) in Munich have shown that a phenomenon known as diffusiophoresis, which can lead to a directed particle transport, can occur in biological systems.

In order to perform their biological functions, cells must ensure that their logistical schedules are implemented smoothly, such that the necessary molecular cargoes are delivered to their intended destinations on time. Most of the known transport mechanisms in cells are based on specific interactions between the cargo to be transported and the energy-consuming motor proteins that convey the load to its destination. A group of researchers led by LMU physicist Erwin Frey (Chair of Statistical and Biological Physics) and Petra Schwille of the Max Planck Institute for Biochemistry has now shown for the first time that a form of directed transport of particles can take place in cells, even in the absence of molecular motors. Furthermore, this mechanism can sort the transported particles according to their size, as the team reports in the latest issue of Nature Physics.

The study focuses on the MinDE system from the bacterium E. coli, which is an established and important model for biological pattern formation. The two proteins MinD and MinE oscillate between the poles of the rod-shaped cell and their mutual interaction on the cell membrane ultimately restricts the plane of cell division to the center of the cell. In this case, the researchers reconstructed the pattern forming MinDE system in the test-tube, using the purified Min proteins and artificial membranes. As expected from previous experiments, when the energy-rich molecule ATP was added to this system, the Min proteins recapitulated the oscillatory behavior seen in bacterial cells. More importantly, the experimenters went on to demonstrate that many different kinds of molecules could be caught up in the oscillatory waves as they traversed the membranes - even molecules that have nothing to do with pattern formation and are not found in cells at all.

A sorting machine for DNA origami

In order to analyze the transport mechanism in greater detail, the team turned to cargoes that consisted of DNA origami, and could be anchored to the membrane. This strategy allows one to create molecular structures of varying sizes and shapes, based on programmable base-pairing interactions between DNA strands. "These experiments showed that this mode of transport depends on the size of the cargo, and that MinD can even sort structures on the basis of their size," says Beatrice Ramm, a postdoc in Petra Schwille's department and joint first author of the new study. With the aid of theoretical analyses, Frey's group went on to identify the underlying transport mechanism as diffusiophoresis - the directed motion of particles along a concentration gradient. In the Min system, the friction between the cargo and the diffusing Min proteins is responsible for the transport of the freight. Thus, the crucial factor in this context is not a specific set of biochemical interactions - as in the case of transport via motor proteins in biological cells - but the effective sizes of the particles involved. "Particles that are more strongly affected by friction, owing to their large size, are also transported further - that's what accounts for sorting on the basis of size," says Andriy Goychuk, also joint first author of the paper.

With these results, the team has demonstrated the involvement of a purely physical (as opposed to a biological) form of transport based on diffusiophoresis in a biological pattern-forming system. "This process is so simple and fundamental that it seems likely that it also plays a role in other cellular processes, and might even have been employed in the earliest cells at the origin of life," says Frey. "And in the future, it might also be possible to make use of it to position molecules at specific sites within artificial minimal cells," he adds.

As part of an international collaboration, researchers from ELTE Eötvös Loránd University developed a new animal model to study a rare genetic disease that can lead to blindness at the age of 40-50. The new model could open up new perspectives in our understanding of this metabolic disease and will also help to identify new potential drug candidates, according to the recent study published in Frontiers in Cell and Developmental Biology.

Pseudoxanthoma elasticum (PXE) is a rare genetic disease with symptoms that usually manifest in adolescence or in early adulthood. The symptoms are caused by the appearance of hydroxyapatite crystal deposits in the subcutaneous connective tissue and retina and later can also appear in the vascular system. Excessive calcification in the retina can lead to blindness, while the crystals in the walls of the blood vessels result in the loss of their elasticity and in the development of severe vascular diseases.

The researchers of the DanioLab Research Group at the Department of Genetics of the ELTE Eötvös Loránd University, supported by the Diagnostics and Therapy Excellence Program, collaborated with researchers from the ELKH-RCNS Institute of Enzymology, Semmelweis University Institute of Physiology, and the US National Human Genome Research Institute (NHGRI) to create a new model for PXE. The researcher used zebrafish (Danio rerio), a popular model of genetic research, to gain a better understanding of this rare genetic disease.

Why is zebrafish a good animal model?

PXE usually develops in patients carrying mutations in the ABCC6 gene, encoding a cell membrane transporter protein. The zebrafish genome harbors three variants (so-called paralogues) of this gene: abcc6a is located on chromosome 6, while abcc6b.1 and abcc6b.2 are located on chromosome 3. Closer examination of the three paralogues, using new sequencing methods, revealed that only abcc6a and abcc6b.1 have a protein-coding function. In contrast, abcc6b.2 has lost its active role and is present as a pseudogene in the genome of the zebrafish.

The research team at ELTE Eötvös Loránd University successfully created and characterized mutant lines in the two protein-coding ABCC6 paralogues using the CRISPR/Cas9 genome-editing system, to understand if they have synergistic effects in the fish. "To our surprise, only abcc6a homozygous mutant animals showed defects in calcification. These could be observed relatively early, already at larval stages, indicating that loss of function of this gene in zebrafish affects calcification similarly to that seen in human patients. By adulthood, the skeletal system of the mutant animals was severely distorted. The spine is spectacularly twisted due to the excessive calcification between the vertebrae" - said Máté Varga, the head of the DanioLab Research Group at ELTE Eötvös Loránd University.

The new model will provide new opportunities for a better understanding of this metabolic disease and could become an important asset for future clinical research. The mutant lines created in the project will be used to test drug candidates with the potential to ameliorate PXE symptoms.

The universe is expanding at an ever-increasing rate, and while no one is sure why, researchers with the Dark Energy Survey (DES) at least had a strategy for figuring it out: They would combine measurements of the distribution of matter, galaxies and galaxy clusters to better understand what's going on.

Reaching that goal turned out to be pretty tricky, but now a team led by researchers at the Department of Energy's SLAC National Accelerator Laboratory, Stanford University and the University of Arizona have come up with a solution. Their analysis, published April 6 in Physical Review Letters, yields more precise estimates of the average density of matter as well as its propensity to clump together - two key parameters that help physicists probe the nature of dark matter and dark energy, the mysterious substances that make up the vast majority of the universe.

"It is one of the best constraints from one of the best data sets to date," says Chun-Hao To, a lead author on the new paper and a graduate student at SLAC and Stanford working with Kavli Institute for Particle Astrophysics and Cosmology Director Risa Wechsler.

An early goal

When DES set out in 2013 to map an eighth of the sky, the goal was to gather four kinds of data: the distances to certain types of supernovae, or exploding stars; the distribution of matter in the universe; the distribution of galaxies; and the distribution of galaxy clusters. Each tells researchers something about how the universe has evolved over time.

Ideally, scientists would put all four data sources together to improve their estimates, but there's a snag: The distributions of matter, galaxies, and galaxy clusters are all closely related. If researchers don't take these relationships into account, they will end up "double counting," placing too much weight on some data and not enough on others, To says.

To avoid mishandling all this information, To, University of Arizona astrophysicist Elisabeth Krause and colleagues have developed a new model that could properly account for the connections in the distributions of all three quantities: matter, galaxies, and galaxy clusters. In doing so, they were able to produce the first-ever analysis to properly combine all these disparate data sets in order to learn about dark matter and dark energy.

Improving estimates

Adding that model into the DES analysis has two effects, To says. First, measurements of the distributions of matter, galaxies and galaxy clusters tend to introduce different kinds of errors. Combining all three measurements makes it easier to identify any such errors, making the analysis more robust. Second, the three measurements differ in how sensitive they are to the average density of matter and its clumpiness. As a result, combining all three can improve the precision with which the DES can measure dark matter and dark energy.

In the new paper, To, Krause and colleagues applied their new methods to the first year of DES data and sharpened the precision of previous estimates for matter's density and clumpiness.

Now that the team can incorporate matter, galaxies and galaxy clusters simultaneously in their analysis, adding in supernova data will be relatively straightforward, since that kind of data is not as closely related with the other three, To says.

"The immediate next step," he says, "is to apply the machinery to DES Year 3 data, which has three times larger coverage of the sky." This is not as simple as it sounds: While the basic idea is the same, the new data will require additional efforts to improve the model to keep up with the higher quality of the newer data, To says.

"This analysis is really exciting," Wechsler said. "I expect it to set a new standard in the way we are able to analyze data and learn about dark energy from large surveys, not only for DES but also looking forward to the incredible data that we will get from the Vera Rubin Observatory's Legacy Survey of Space and Time in a few years."

During the early phase of the pandemic, approximately 40% of the COVID-19 literature was shared as preprints - freely available manuscripts that are shared prior to peer-review. In a new study publishing in the open access journal PLOS Biology, researchers led by Dr Jonathon Coates (Queen Mary University of London), Dr Nicholas Fraser (Leibniz Information Centre for Economics, Germany) and Dr Liam Brierley (University of Liverpool) explore the crucial role of preprint servers in hosting COVID-19 related science and how these preprints have been used to disseminate knowledge of COVID-19, leading to cultural shifts in journalistic and policy practices.

There has been a rapid and incredible scientific response to the COVID-19 pandemic, with research being shared less than a month after the first reported case, and vaccines being developed in less than a year. The researchers find that this has been matched by a striking change in the way in which research is accessed and communicated; preprints describing COVID-19 research are downloaded and accessed at unprecedented levels (up to 10-fold more than research unrelated to the pandemic) and are being heavily used by reporters and policy makers for the first time.

According to the study's lead author, Dr Jonathon Coates, "The pandemic has shone a light on the benefits of preprints over more traditional publishing and it was clear early in the pandemic that something was happening with preprint usage".

When the researchers explored how preprints were being shared, they found that COVID-19 preprints were being shared across online platforms such as Twitter at a rate of over 7 times that of non-COVID-19 preprints. Although traditionally rarely referenced by official policy documents or reported on by journalists, preprints describing COVID-19 research are frequently being cited in policy and reported in news media, bringing active research closer to policymakers as well as the general public than ever before.

"Prominent public officials, such as Dr Fauci, have stated that preprints have been important in accelerating our understanding of COVID-19. Our data provides evidence to support these statements and reveals a clear cultural shift in the use of preprints by scientists, the general public, journalists and policy makers" says Dr Coates, "What we hope is that the cultural shifts reported in this paper will remain after the pandemic and the biomedical community will continue to turn to preprint servers for disseminating new studies".

A new large-scale study led by UC Davis Health and UC San Francisco researchers assessed the risks of leukemia in children with Down syndrome. It pointed to stronger than expected associations between Down syndrome and acute myeloid leukemia (AML), one type of blood cancer.

Down syndrome is one of the most common genetic conditions in the U.S. and Canada. According to the U.S. Centers for Disease Control and Prevention, about 6,000 babies with Down syndrome are born in the United States each year. That's approximately one in every 700 babies born in the U.S. and one in 750 newborns in Canada.

Children with Down syndrome have a substantially increased risk of multiple health conditions compared to the general population. They have a particularly elevated risk (estimated 150-fold) of developing AML before age 5.

The study, published in The Journal of Pediatrics, confirmed that Down syndrome is a strong risk factor for childhood leukemia.

Study findings on leukemia in children with Down syndrome

The researchers examined medical data of more than 3.9 million children born 1996-2016 in seven U.S. healthcare systems or in Ontario, Canada. The data included the children's health information from birth to cancer diagnosis, death, age of 15 years, disenrollment, or Dec. 30, 2016.

"One main strength of this study is its large cohort with more leukemia cases in children with Down syndrome than most previous studies," said Emily Marlow, first author and a recent graduate from UC Davis Department of Public Health Sciences and Graduate Group in Epidemiology. "This allowed more precise risk estimation, especially for rare leukemia types such as AML-7, previously estimated from small case reports."

The study estimated the incidence and hazard ratios of leukemia for children with Down syndrome and other children, adjusting for health system, child's age at diagnosis, birth year and sex. It found that 2.8% of children with Down syndrome were diagnosed with leukemia, compared to 0.05% of other children.

Compared to other children, kids with Down syndrome had a higher risk of AML before age 5 and a higher risk of acute lymphoid leukemia (ALL) regardless of age. In children with Down syndrome, ALL was more common between ages 2-4 years, while AML was more common in younger kids - the highest incidence during the first year of life. For other children, AML incidence remained very low through age 14 years, whereas ALL peaked at age 3 years and steadily declined until age 8 years.

The study also found that males and Hispanic children were more likely to be diagnosed with Down syndrome and more likely to develop leukemia than their counterparts. White children have a higher incidence rate of ALL and more likely to have Down syndrome than Black children.

Catching leukemia in kids

The researchers urged parents with kids with Down syndrome to keep an eye for signs of leukemia. Common symptoms include fatigue or pale skin, infections and fever, easy bleeding or bruising, shortness of breath and coughing. Parents are advised to talk to the pediatrician if their children exhibit any of these symptoms.

"The good news is that childhood leukemia can be very treatable if caught early," said co-senior author Diana L. Miglioretti, professor and division chief of biostatistics at the UC Davis Department of Public Health Sciences and affiliate investigator with Kaiser Permanente Washington Health Research.

Imaging technologies and leukemia

A steep rise in medical imaging over the past two decades, particularly in computed tomography (CT) exams, increased children's exposure to higher levels of radiation. Previous studies have shown that CT scanning increases leukemia risk.

"Given the potential for ionizing radiation to increase leukemia risk in children with Down syndrome, other non-ionizing radiation modes of imaging, such as ultrasound and MRI, should be used as the first line image tests," said co-senior author Rebecca Smith-Bindman, a UCSF School of Medicine professor with the Departments of Radiology and Biomedical Imaging and of Epidemiology and Biostatistics.

Tweets about Russia by Donald Trump during his presidency caused short but noticeable depreciations of the rouble. Meanwhile, the introduction of new sanctions, upon which the president did not comment, had no such effect. This was the finding of a group of researchers, which included Elena Fedorova, Professor of the Faculty of Economic Sciences of HSE University. The group published their findings in in the Journal of Economic Behavior and Organization.

With the growing influence of social media, officials, politicians, and entrepreneurs increasingly express their positions on various issues directly (for example, using Facebook or Twitter), and their messages serve as an independent source of financial and business information. When global political and economic processes depend on the decisions of this person (as in the case of the President of the United States), their social media posts can even affect indicators such as oil prices or the rouble exchange rate. Researchers have already examined the impact of Trump's tweets on the stock market.

To see if there is a connection between the former US president's tweets and the exchange rate of the Russian currency, researchers collected 5,548 of Trump's tweets posted from October 2016 to August 2018. Of these, the authors chose those that mentioned Russia, Moscow, the Kremlin, sanctions, the rouble, and other key words. For the remaining 296 tweets, they rated the tonality of the text (neutral, positive, or negative; those falling in the latter category were the most frequent).

'To assess the tonality of the English-language tweets, we used five already proven dictionaries, and as part of a textual analysis project group with undergraduate and graduate students, we are working on a toolkit for assessing economic and financial texts in Russian. So, I think there will be similar studies on the Russian market,' said Elena Fedorova, article co-author and professor of economics at HSE University.

Using mathematical methods, the authors of the study assessed the impact on the rouble exchange rate of several control variables reflecting oil prices; Central Bank policy; the intensity of sanctions imposed by the United States, the European Union, and other states; and the attention of the media to relations between Russia and Western countries. These were considered beyond the period of the tweets to make sure that the rouble exchange rate was in fact responding specifically to the tweets, and not these other factors.

The researchers found that of the two 'political' variables (tweets and the degree of sanctions), only the tweets affected the exchange rate. The authors of the work highlighted several episodes when, after Trump tweeted anti-Russia statements, the rouble exchange rate dropped and the drop lasted for several days. The researchers note that all these episodes coincide with the announcement of new sanctions. However, in cases where sanctions were introduced, but Trump did not comment on them on Twitter, the rouble did not fall.

Calculations of both Russian and foreign researchers show that if sanctions affect the Russian economy, they do so to a much lesser extent than fluctuations in oil prices. New research confirms this conclusion and additionally shows that the emotional reaction to the sanctions of various players affects the exchange rate more than the restrictions themselves. Based on the results of the analysis, the authors suggest that the way market participants assess the severity of the new sanctions and their consequences for the Russian economy is rather strongly influenced by the president's tweets and the reaction of the press.

'Our research, on the one hand, draws upon the contemporary field of behavioural finance. On the other hand, it partially touches upon the philosophical theories of Marxism-Leninism about the role of personality in history (which people of my generation studied both in school and college). Who would have thought more than a hundred years ago that now, with the development of technology for assessing the textual tonality, it would be possible to quantify the impact of statements made by important politicians on the financial and economic market!' said Elena Fedorova.

"On a scale of one to 10, how much pain are you in?"

In a recent study published by the Journal of Pain, co-authored by Elizabeth Losin, assistant professor of psychology and director of the Social and Cultural Neuroscience lab at the University of Miami, researchers found that a patient's pain responses may be perceived differently by others based on their gender.

According to "Gender biases in estimation of others' pain," when male and female patients expressed the same amount of pain, observers viewed female patients' pain as less intense and more likely to benefit from psychotherapy versus medication as compared to men's pain, exposing a significant patient gender bias that could lead to disparities in treatments.

The study consisted of two experiments. In the first, 50 participants were asked to view various videos of male and female patients who suffered from shoulder pain performing a series of range of motion exercises using their injured and uninjured shoulders. Researchers pulled the videos from a database that contains videos of actual shoulder injury patients, each experiencing a range of different degrees of pain. The database included patients' self-reported level of discomfort when moving their shoulders.

According to Losin, the study likely provides results more applicable to patients in clinical settings compared to previous studies that used posed actors in their stimuli videos.

"One of the advantages of using these videos of patients who are actually experiencing pain from an injury is that we have the patients' ratings of their own pain," she explained. "We had a ground truth to work with, which we can't have if it's a stimulus with an actor pretending to be in pain."

The patients' facial expressions were also analyzed through the Facial Action Coding System (FACS)--a comprehensive, anatomically based system for describing all visually discernible facial movements. The researchers used these FACS values in a formula to provide an objective score of the intensity of the patients' pain facial expressions. This provided a second ground truth for the researchers to use when analyzing the data.

The study participants were asked to gauge the amount of pain they thought the patients in the videos experienced on a scale from zero, labeled as "absolutely no pain," and 100, labeled as "worst pain possible."

In the second experiment, researchers replicated the first portion of this study with 200 participants. This time, after viewing the videos, perceivers were asked to complete the Gender Role Expectation of Pain questionnaire, which measures gender-related stereotypes about pain sensitivity, the endurance of pain, and willingness to report pain.

Perceivers also shared how much medication and psychotherapy they would prescribe to each patient and which of these treatments they believed would be more effective in treating each patient.

The researchers analyzed the results of the participants' responses to the videos compared to the patient's self-reported level of pain and the facial expression intensity data. The ability to analyze observers' perceptions relative to these two ground truth measures of the patients' pain in the videos allowed the researchers to measure bias more accurately, Losin explained. That is because bias could be defined as different ratings for male and female patients despite the same level of responses.

Overall, the study found that female patients were perceived to be in less pain than the male patients who reported, and exhibited, the same intensity of pain. Additional analyses using participants' responses to the questionnaire about gender-related pain stereotypes allowed researchers to conclude that these perceptions were partially explained by these stereotypes.

"If the stereotype is to think women are more expressive than men, perhaps 'overly' expressive, then the tendency will be to discount women's pain behaviors," Losin said. "The flip side of this stereotype is that men are perceived to be stoic, so when a man makes an intense pain facial expression, you think, 'Oh my, he must be dying!' The result of this gender stereotype about pain expression is that each unit of increased pain expression from a man is thought to represent a higher increase in his pain experience than that same increase in pain expression by a woman."

What's more, psychotherapy was chosen as more effective than medication for a higher proportion of female patients compared to male patients.

Additionally, the study concluded that the gender of the perceivers did not influence pain estimation. Both men and women interpreted women's pain to be less intense.

The idea to study disparities in the perception of pain based on a patient's gender was derived from previous research, Losin said, that found women are often prescribed less treatment than men and wait longer to receive that treatment as well.

"There's a pretty wide literature showing demographic differences in pain report, the prevalence of clinical pain conditions, and then also a demographic difference in pain treatments," Losin pointed out. "These differences manifest as disparities because it seems that some people are getting undertreated for their pain based on their demographics."

Moving forward, Losin and her fellow researchers hope this study is a step in identifying and addressing gender disparities in health care. Co-authors of the study included the study's lead author, Lanlan Zhang, Guangzhou Sport University; Yoni K. Ashar, Weill Cornell Medical College; Leonie Koban, Paris Brain Institute; and senior author Tor D. Wager, Dartmouth College.

"I think one critical piece of information that could be conveyed in medical curricula is that people, even those with medical training in other studies, have been found to have consistent demographic biases in how they assess the pain of male and female patients and that these biases impact treatment decisions," Losin remarked. "Critically, our results demonstrate that these gender biases are not necessarily accurate. Women are not necessarily more expressive than men, and thus their pain expression should not be discounted."

Glycine regulates neuronal activity in the brain

Glycine is the smallest amino acid - one of the building blocks of proteins. It acts also as a neurotransmitter in the brain, enabling neurons to communicate with each other and modulating neuronal activity. Many researchers have focused on increasing glycine levels in synapses to find an effective treatment for schizophrenia. This could be done using inhibitors targeting Glycine Transporter 1 (GlyT1), a protein that sits in neuronal cell membranes and is responsible for the uptake of glycine into neurons. However, the development of such drugs has been hampered because the 3D structure of GlyT1 was not known.

To determine the structure of GlyT1, researchers at the Danish Research Institute of Translational Neuroscience (DANDRITE), which is part of the Nordic EMBL Partnership for Molecular Medicine, F. Hoffmann-La Roche, EMBL Hamburg, the University of Zurich, Aarhus University, and Linkster Therapeutics joined forces. "This project required multidisciplinary collaboration and unique expertise from different labs over several years," says Azadeh Shahsavar, first author of the study and now an assistant professor at DANDRITE. She performed the measurements for the study during her time as a postdoc in the EMBL Interdisciplinary Postdocs (EIPOD) programme, during which she worked at EMBL Hamburg, DANDRITE and Roche.

Poul Nissen, Director of DANDRITE and a senior researcher in the study, comments: "We are immensely grateful for the EMBL's EIPOD scheme and the Nordic EMBL Partnership to keep us on track for so long and allow us to explore very difficult approaches. We would not have succeeded without it, and without Azadeh's persistence of course!"

Overcoming challenges in studying Glycine Transporter 1

GlyT1 turned out to be particularly challenging to study, because it is unstable when extracted from the cell membrane. To stabilise it, scientists combined several approaches, such as creating more stable variants of the protein. To catch the transporter in a clinically relevant state, the team used a chemical created by Roche that binds and stabilises GlyT1 from the inside, and designed a synthetic mini-antibody (sybody) that binds it from the outside.

The scientists tested 960 different conditions and managed to obtain GlyT1 crystals in one of them. "The crystals were very small and difficult to image. We chose to measure them at EMBL Hamburg's beamline P14, which is well suited for challenging experiments like this one," says Azadeh. The X-ray beam at P14 is particularly strong and focused, and its equipment has features tailored for work with even micrometre-sized crystals. Yet the quality of the crystals was variable, which made data collection challenging. Eventually, Azadeh's perseverance paid off. "I remember when I saw electron density of the inhibitor for the first time. I was so excited, I couldn't sleep for two nights," she says. "You live for those rewarding moments."

The final challenge was the data analysis. While the crystals were giving only weak diffraction patterns due to their small size, the strong X-rays destroyed the crystals in less than a second. A single crystal would yield only partial information about the structure, so Azadeh had to collect data from hundreds of crystals. "Processing such a huge amount of data was possible thanks to the unique infrastructure at EMBL Hamburg," she says. Combining partial datasets was complex for the existing software, but the Schneider group at EMBL Hamburg wrote software specifically designed for such cases. It enabled Azadeh to merge datasets into a full picture of GlyT1 at 3.4 Å resolution (1 Å, or ångström, is one ten-billionth of a metre - about the size of a typical atom). "I really enjoyed working with people with different scientific backgrounds. Everybody contributed their unique expertise that made this study possible," says Azadeh.

For Thomas Schneider, Joint Head of Research Infrastructures at EMBL Hamburg, the study is a perfect example highlighting the importance of both scientific excellence and the availability of cutting-edge infrastructures for progressing research. "For challenging projects like this, we are happy to put the methodological expertise of our staff to work and to make full use of the technological capabilities of our beamlines and sample preparation facilities. The high-intensity microfocused beam produced by the PETRA III synchrotron on the DESY campus and the versatile high-precision diffractometer that was developed in a collaboration between EMBL Hamburg, EMBL Grenoble, and ARINAX were key for this project."

Azadeh agrees. "The excellence, infrastructure, hardware, and software provided by EMBL are of the highest quality, and they are constantly being improved," she adds.

Blueprint for new therapeutics

The analysis revealed an unexpected structure of GlyT1. In contrast to other neurotransmitter transporters, which are bound by their inhibitors from the outer side of the cell membrane, GlyT1 is bound by its inhibitor from the inner side. "The structure was a surprise for us. It seems that the GlyT1 inhibitor must first cross the cell membranes before it can access GlyT1 from the inside of the neurons," says Roger Dawson, a senior author in the study.

"This structure provides a blueprint for developing new inhibitors of GlyT1, be they organic molecules or antibodies," explains Roger. "The sybody developed for this study binds GlyT1 at a previously unknown binding site and locks it in a state in which it cannot transport glycine any more. We could use this knowledge to develop drugs targeting not only GlyT1, but also other membrane transport proteins in the future."

The adage goes, "Two is better than one." Well, that might be true for endeavors involving human heads, but when it comes to ears, hybrid maize tends to have a superior advantage over the parental stocks in most cases. This phenomenon, called hybrid vigor or "heterosis," has been used by agriculturalists across ages to create higher-yielding, more resistant varieties of maize all over the world.

But what are the factors contributing to the increased hybrid vigor of maize? Several different genetic models have been proposed to explain heterosis in varied crops including maize, but none have hitherto been able to comprehensively unravel the mystery of heterosis.

A possible reason for this may be the complex genetic origin of the present-day maize species--Zea mays. Maize is supposed to have diverged from sorghum during an ancient speciation event, following which there was a duplication of the entire chromosomal materials or the genomic set in the ancestral stock via a process called polyploidization, giving rise to an ancestral tetraploid, or a plant with four genomic sets, i.e., double the usual number. Each genomic set in this tetraploid maize ancestor, called a subgenome, underwent dramatic breaks and fusion to eventually give rise to the current diploid genome (which bears two sets of genetic materials). During this genomic reorganization, redundant copies of genes from both subgenomes were lost through a process called fractionation.

In plants where such fractionation has been identified, including maize, there is a tendency for one subgenome to experience more gene loss than the other--a process called fractionation bias. For instance, the two subgenomes in present-day maize, termed maize1 and maize2, show differential expression of constituent genes, with maize1 typically identified as the dominant between the two.

It could be that differential expression of proteins coded by the maize subgenomes is responsible for the increased vigor of the hybrid maize lines, which are referred to as F1. However, this has not been clearly established. Until now.

Now, researchers in China have explored the transcriptome (the full complement of protein-coding mRNA molecules derived from information coded in DNA) and translatome (the actual mRNA set that gets translated to proteins in cell) of maize to identify factors that may be potentially responsible for heterosis in maize.

Using the new ribosome profiling technique, the researchers, led by Professor Lin Li of National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, evaluated the maize parental lines B73 and Mo17, and their F1 offspring. Their findings, published in The Crop Journal, suggest the presence of prominent subgenome bias at the translation level, especially skewed towards translated subgenome maize1 genes, which had a nonadditive effect on heterosis in F1 plants.

Furthermore, some genes switched to the dominant form in the hybrid than in the parental lines, quite surprisingly. As Prof. Li observes, "More genes switched the dominant isoforms between the F1 and the two parents than between the two parents. This observation indicates that the best gene variant is more likely to be selectively utilized in hybrids for a given environment, leading to higher efficiency of protein accumulation in the hybrids."

Moreover, the switched gene isoforms mostly belonged to subgenome maize2, while the conserved gene isoforms belonged to subgenome maize1. This knowledge, the researchers suggest, can help in selective breeding for further improving hybrid vigor.

Additionally, the researchers found evidence for additive effects of gene expression at both the transcriptome and the translatome levels in the hybrid. According to Prof. Li, "All these results are in accordance with the 'Goldilocks hypothesis,' suggesting that additive expression is advantageous for both transcriptome and translatome."

These findings suggest the potential role of asymmetric subgenome translation as an important factor contributing to heterosis in maize. These insights can provide crop breeders with effective gene manipulation tools to increase yield of not just maize, but other food crops, which might serve to address the looming food scarcity in face of the growing human population across the world.

Pain will lessen over time

Results include longer distance and walking time

8.5 million people in U.S., 250 million worldwide, have PAD

CHICAGO --- No pain means no gain when it comes to reaping exercise benefits for people with peripheral artery disease (PAD), reports a new Northwestern Medicine study.

In people with peripheral artery disease, walking for exercise at an intensity that induces ischemic leg pain (caused by restricted blood flow) improves walking performance -- distance and length of time walking -- the study found. Walking at a slow pace that does not induce ischemic leg symptoms is no more effective than no exercise at all, the study showed.

This randomized trial is the first to show that a home-based walking exercise program improved walking ability in people with peripheral artery disease when exercise was conducted at a high intensity that induced ischemic leg symptoms but not when the exercise was conducted at a low intensity without ischemic leg symptoms.

"We've shown you have to walk to elicit ischemic leg pain to reap the benefits," said lead investigator Dr. Mary McDermott, professor of medicine at Northwestern University Feinberg School of Medicine. "It will lessen over time, and most people eventually will be able to walk further without discomfort."

The study was published in JAMA April 6, 2021.

McDermott's previous research suggested that pain during exercise prevented many people with PAD from walking.

While the trial did not identify the biological changes that lead to walking improvement, McDermott said prior research shows intensive exercise stimulates certain biologic pathways that promote improved mitochondrial activity, the cell's chemical energy source.

"Perhaps for people with PAD, the exercise promotes growth of new small blood vessels to their muscles," McDermott said.

About 8.5 million in the United States and about 250 million people worldwide have lower extremity peripheral artery disease (PAD). People with PAD have blockages in their arteries that slow or stop the blood flood flow to their legs. As a result, they have pain and difficulty walking even short distances. It is comparable to angina for people who have symptomatic heart disease. Few therapies exist to treat it.

The first month consisted of weekly in-person visits with the coach. These sessions helped the participants to learn the difference between walking at high versus low intensity, allowed them to learn to use the technology used to monitor their exercise intensity at home and helped them get started with their exercise activity. The program then consisted of telephone calls and remote monitoring by a coach.

The remote monitoring aspect is important, McDermott said. Although supervised exercise is covered by Medicare and other insurance companies, most people with PAD do not participate in supervised exercise because of the burden associated with traveling three times weekly to the medical center for participation.

For the study, 305 people with peripheral artery disease at four medical centers were randomized to high-intensity exercise, low-intensity exercise or a control group that got telephone calls that were not about exercise. Those randomized to an exercise intervention were asked to walk up to 50 minutes per session, five days a week. Those in high intensity were asked to walk at a pace that was fast enough to elicit ischemic leg symptoms during exercise. Those randomized to low intensity were asked to walk at a comfortable pace that did not induce ischemic leg symptoms.

Intensity was monitored remotely using an ActiGraph activity monitor that participants wore during exercise. These data were uploaded to the study website and viewed by study coaches. The six-minute walk, treadmill testing and patient-reported outcomes were measured at baseline and at 12-month follow-up.

Patients who participated in high-intensity walking exercise significantly improved the distance they could walk in six minutes compared to either the low-intensity group or the control group. The high-intensity exercise group also significantly improved the length of time they could walk on the treadmill at the end of the study, compared to each of the other two groups.

"Patients with PAD should be advised to walk for exercise at a pace that induces ischemic leg symptoms in order to get a benefit," McDermott said. "Exercise is the most effective non-invasive therapy to improve walking in people with PAD."

The next step in the research is to determine the biologic explanation for the finding that ischemia of the lower extremities appears necessary to gain benefit from walking exercise in people with PAD.