Culture

Researchers at the Hong Kong University of Science and Technology (HKUST) have identified new therapeutic targets for Alzheimer's disease (AD) by studying the patients' brain with a newly-developed methodology. This novel approach also enables researchers to measure the effects of potential drugs on AD patients, opening new directions for AD research and drug development.

Although the pathological mechanisms of AD have been studied for decades, the disease remains incurable. One reason is that conventional research approaches have limited capability to identify molecular targets for drug development. Molecular and pathological pathway analysis generally examines AD patients' brain as a single unit, which usually underestimates the contributions of different brain cell types to AD and any abnormalities in them. This is especially the case with less-common cell types such as microglia (the brain's resident immune cells) and neurovascular cells (specifically endothelial cells), which only account for less than 5% and 1% of the total brain cell population, respectively.

However, a team led by Prof. Nancy Ip, Vice-President for Research and Development, Director of the State Key Laboratory of Molecular Neuroscience, and Morningside Professor of Life Science at HKUST, has more than circumvented this problem--they have also identified several new potential molecular targets in endothelial cells and microglia for AD drug development.

The team examined the functions of specific cell types in the postmortem brains of AD patients, which is typically impossible with conventional approaches, by using cutting-edge, single-cell transcriptome analysis, which can be used to characterize of the molecular changes in single cells. This yielded a comprehensive profile of the cell-type-specific changes in the transcriptome in the brains of AD patients. Subsequent analysis identified cell subtypes and pathological pathways associated with AD, highlighting a specific subpopulation of endothelial cells found in the brains' blood vessels. Accordingly, the team discovered that increased angiogenesis (the formation of new blood vessels from current ones) and immune system activation in a subpopulation of endothelial cells are associated with the pathogenesis of AD, suggesting a link between the dysregulation of blood vessels and AD. The researchers also identified novel targets for restoring neural homeostasis (the ability to maintain a relatively stable internal state despite external changes) in AD patients.

The team also leveraged their single-cell transcriptome analysis to study the mechanism by which the cytokine interleukin-33 (IL-33), an important protein for immune signaling, exerts beneficial actions, making it a possible AD therapeutic intervention. The researchers found that IL-33 reduces AD-like pathology by stimulating the development of a specific subtype of microglia that helps clear amyloid-beta, a neurotoxic protein found in AD brains. The team is also the first to capture data on the mechanisms by which microglia transform into an amyloid-beta-consuming phagocytic state, which is a major cellular mechanism for the removal of pathogens.

"The complex and heterogeneous cell composition within the brain makes it difficult to study disease mechanisms," Prof. Ip explained. "The advancement of single-cell technology has enabled us to identify specific cell subtypes and molecular targets, which is critical for developing new interventions for Alzheimer's disease."

The team has recently published their work in the prestigious scientific journals Proceedings of the National Academy of Sciences U S A (PNAS) and Cell Reports.

AD, the predominant form of dementia, currently affects over 50 million individuals worldwide and is projected to afflict 150 million people by 2050. Its pathological hallmarks include the accumulation of extracellular amyloid-beta depositions and neurofibrillary tangles. Over time, ineffective clearance of these pathological hallmarks leads to cellular dysfunction in AD, resulting in memory loss, communication problems, reduced physical abilities, and eventually death.

A new study from the University of Eastern Finland shows that individualised and family-based physical activity and dietary counselling considerably slows down the development of insulin resistance, which is a precursor of type 2 diabetes, in 6-9-year-old children. Published in Diabetologia, the study focused on predominantly normal-weight children.

Insulin resistance refers to the body's weakened metabolic response to insulin in the target tissues, i.e. in skeletal muscles, adipose tissue and the liver. Insulin resistance is usually the first sign of disturbed glucose metabolism, developing much earlier than abnormalities in pancreatic insulin secretion, elevated glucose levels and, eventually, type 2 diabetes. Earlier studies have shown that physical activity and dietary counselling reduces insulin resistance in overweight and obese children. This new study from the University of Eastern Finland is significant not only scientifically, but also in terms of public health and clinical practice, because it is the first to show that a combination of physical activity and dietary counselling can be used to slow down the long-term development of insulin resistance in children who were predominantly normal-weight at baseline.

More than 500 Finnish children aged between 6 and 9 years at baseline participated in the Physical Activity and Nutrition in Children (PANIC) study ongoing at the University of Eastern Finland. Children and their caregivers in the intervention group were given individualised and family-based physical activity and dietary counselling over a period of two years. Children and their caregivers in the control group, on the other hand, were given instructions on physical exercise and nutrition as per the national guidelines, but no actual lifestyle counselling. At baseline and two years later, the researchers analysed children's physical activity and sedentary behaviour using the Actiheart sensor that measures heart rate and body movements. Physical activity was also assessed by the PANIC Physical Activity Questionnaire, and dietary factors were assessed by a 4-day food record over four days. Children's body fat percentage and lean body mass were measured by dual-energy x-ray absorptiometry, DXA. Fasting serum insulin and HOMA-IR were used as indicators of insulin resistance.

The study showed that during the two-year follow-up, increase of insulin resistance was roughly 35% lower in the group that was given individualised and family-based physical activity and dietary counselling than in the control group. The attenuating effect of counselling on insulin resistance was explained especially by changes in physical activity and sedentary behaviour, and slightly less by changes in overall dietary quality and in the consumption of high-fat spreads. Counselling did not have an effect on body fat percentage or lean body mass, i.e. changes in body composition did not mediate the beneficial effect of intervention on insulin resistance.

"This is an interesting finding. The attenuating effect of physical activity and dietary counselling on insulin resistance in children is likely caused by the fact that physical activity and a healthy diet boost metabolism in skeletal muscles, adipose tissue and in the liver, and not so much by a lower body fat percentage or lean body mass," Professor Timo Lakka, the lead author of the study, says.

Although type 2 diabetes usually develops in adulthood, research suggests that its prevention is best begun already in childhood.

"Increasing physical activity, reducing sedentary behaviour and eating food of better quality should be a priority for all children, not just for those who are overweight," Professor Lakka points out.

Professor Lakka points out that in addition to body composition measurements, all children should also be asked about their physical activity, sedentary behaviour and diet when they visit a child health clinic or a school nurse.
"Identifying children who have unhealthy lifestyle habits and who are at an increased risk of type 2 diabetes in adulthood would allow a better targeting of measures that are geared towards preventing type 2 diabetes. The best way to collect lifestyle-related data is to use scientifically validated, well-proven digital applications. This would allow the data to be optimally used for promoting children's health and well-being, and for making scientifically informed decisions," Professor Lakka says.

For the first time, researchers have compared air pollution in urban and suburban areas across all of China. Using data from the China National Environmental Monitoring Center (CNEMC), the researchers found that one air pollutant, called particulate matter (PM2.5), may be overestimated in winter, while another pollutant, called ozone (O3), is significantly underestimated.

They published their results in the peer-reviewed journal Advances in Atmospheric Sciences (https://doi.org/10.1007/s00376-020-0054-2).

"Since the urban region accounts for only 2% of the whole country's area, the urban-dominant air quality data from the CNEMC network may overestimate winter PM2.5 but underestimate winter O3 over the vast domain of China," said paper author Xu Yue, professor at Nanjing University of Information Science & Technology. "The study suggests that the CNEMC monitoring data should be used with caution for evaluating chemical models and assessing ecosystem health, which require more data outside urban areas."

Both PM2.5 and Ozone are respiratory hazards and can be detrimental to human and animal health, as well as ecosystems.

"The differences between urban and non-urban areas, such as the intensity of human and plant activities, can lead to differences of ozone and PM2.5 concentrations between land types," Yue said. "Our study tries to answer the question: How different is the air pollution between urban and non-urban areas in China?"

The researchers examined air quality data from 1,171 urban and 110 suburban sites built by the CNEMC during an observational period from 2015 to 2018. "The pattern whereby the non-urban ozone concentrations and the urban PM2.5 level are higher dominates across time and space," Yue said. "Such contrast is significant in winter but insignificant in summer."

Since most of the data is available from urban sites, it does not likely apply uniformly across the rest of the country, according to Yue. This can be problematic when it comes to designing efforts to improve pollution and conserve plant life in suburban or rural areas.

"We suggest that more nonurban sites are necessary to build for better representation of air pollution level over the vast domain in China," Yue said. Ultimately, the researchers plan to improve their analysis model to achieve the most accurate estimation of air pollution impacts on ecosystem functions in China.

Plants can be infected by multiple viruses at once. However, the composition of the pathogen community varies, even if individuals belong to the same species and the same population. Ecologists at the University of Zurich have now shown that these differences are primarily due to genetic variation among the hosts. The loss of genetic diversity could thus render species more vulnerable to infections and extinction.

Viruses are ubiquitous across the plant and animal kingdoms - but most of them are still unknown to science. Researchers have only recently developed improved analysis techniques and statistical tools to tackle one of the key questions: Why are some individuals more susceptible to viruses, while others remain unharmed?

Combination of pathogens is important

It is already known that genetic differences can make animals or plants more resistant to a specific virus. However, it is becoming increasingly clear that most organisms do not only harbor one kind of pathogen but complex communities made up of different microbes. "Accounting for this diversity of infection is necessary to understand and predict disease dynamics and costs of infection for the host," says Professor Anna-Liisa Laine from the Department of Evolutionary Biology and Environmental Studies at the University of Zurich. For example, the first arriving pathogen could confer resistance to a second pathogen. But so far, little is known about the factors that shape the composition of virus communities.

With her research team at the Universities of Zurich and Helsinki, Laine has now shown that genetic differences have a major impact on the diversity of the virus community each individual supports. "This suggests that depletion of genetic diversity within a species can have significant consequences for the risk of virus infection," says Laine.

Identical plants in different environments

For their study, the team used the common weed Plantago lanceolata, also known as ribwort plantain. Individuals of this plant can be cloned by propagation of the roots - resulting in genetically identical offspring. With this method, the researchers generated 80 clones from each of four different genetic variants of ribwort plantain and placed them among populations of naturally occurring ribwort plantain at four locations in the Åland archipelago in the Baltic Sea. The cloned plants were thus exposed to virus attacks under natural conditions. "By placing identical plants in different environments and keeping everything else constant, we could rigorously test the role of genetics," explains Laine.

After two and seven weeks respectively, the researchers collected leaves and determined which of five frequently occurring plant viruses had infected the clones. They found that about two thirds of the plants were infected with at least one virus, while almost a quarter of those carried multiple viruses. Altogether, they found 17 different combinations, ranging from two to five viruses per plant.

Hereditary factors most significant

Sophisticated statistical modelling then allowed the researchers to discern how strongly the various factors ? genetics, location, plant size, damage by herbivores and interaction among the viruses - influenced the composition of the virus communities. The results revealed that host genetic differences explained most of the observed variation. "Although we had suspected that genotype would play a role, we were very surprised that it turned out to be the most important determinant," says Laine. Another important factor was the local environment, whereas others such as plant size and herbivores showed only minor effects.

"This demonstrates for the first time that genetic differences, most likely in immunity genes, are critical for how these diverse pathogen communities assemble inside hosts," says Laine. "One of the next steps will now be the identification of the underlying genes."

Genetic diversity makes species stronger

The results highlight the importance of genetic diversity within species. The loss of diversity makes species much more susceptible to virus infections, with far-reaching consequences for biodiversity. The genetic diversity of natural populations is already being increasingly depleted due to human destruction of natural habitats.

According to Laine, these findings could also be applied in agriculture to improve pathogen resistance in crop plants: "Incorporating genetic diversity to crop systems should be embraced as a sustainable means of controlling disease in agriculture. Not only individual pests, but entire communities of pathogens."

An analysis of aging in Down syndrome and hypercholesterolemia mouse models has suggested that a Down syndrome-associated gene, DSCR-1, protects against abnormal vascularization of the cornea and associated corneal opacity (blindness) by suppressing oxidized LDL cholesterol production and new downstream angiogenic signaling in patients with chronic high cholesterol. Epidemiological data suggests that, while the neurological pathology of Down syndrome patients worsens with age, they are also less susceptible to age-related vascular diseases. The responsible genes and mechanisms have not yet been clarified, but DSCR-1 appears to be a strong candidate for a wide range of vascular diseases, such as atherosclerosis and hypertension.

Down syndrome, the most common congenital disease in human genetics, has seen dramatic increases in longevity with advances in modern medicine. Unfortunately, new problems associated with this increased longevity have emerged, such early Alzheimer's, reduced vision, and muscle weakness. However, unlike the nervous system, the vascular system in Down syndrome patients is very resistant to aging pathologies like solid cancers (as opposed to blood cancers such as leukemia), atherosclerosis, hypertension, and Kawasaki disease--a systemic vasculitis that some researchers say has a connection to SARS-CoV-2, the virus that causes COVID-19. It has therefore become important to conduct comprehensive genomic and pathological analyses, including secondary analyses of gene expression on Down syndrome chromosomes and changes due to different chromosome numbers, to determine its cause.

Down syndrome occurs when there is an extra chromosome 21 instead of the usual two. DSCR-1 is located on chromosome 21 and suppresses signals related to angiogenesis. A research group based in Kumamoto University (Japan) crossed hypercholesterolemia (ApoE-deficient) mice with those that highly expressed DSCR-1 and those that were DSCR-1-deficient to analyze the effects of aging. By examining the pathological signals produced by high cholesterol, they hoped to determine why corneal opacity (prominent in ApoE deficiency) is protected against by high DSCR-1 expression and exacerbated by DSCR-1 deficiency.

DSCR-1-deficient mice showed slight age-related corneal opacity, which was dramatically exacerbated when crossed with ApoE-deficient mice, and increased corneal inflammation. DSCR-1 protects postnatal homeostasis based on its inhibitory and antioxidant effects on the NFAT transcription factor--a major factor in the development of Down syndrome. DSCR-1 deficiency results in the abnormal activation of NFAT and the signal transduction function of SDF-1 and its receptor CXCR4, which has an angiogenic effect in peripheral blood vessels. This results in increased angiogenesis and lymphangiogenesis in the corneal area.

Researchers further clarified that DSCR-1 deficiency increases oxidized LDL cholesterol which, in turn, increases SDF-1 production in the endothelium and the production of the angiogenesis-promoting factor VEGF in infiltrating macrophages, thus resulting in pathological angiogenesis (and clouding) in the cornea. This condition was greatly alleviated by the administration of antibodies that neutralize the function of SDF-1.

"This study shows that, in addition to suppressing cancer growth and cytokine storms in sepsis, DSCR-1 may have a protective effect on pathological angiogenesis under high cholesterol conditions," said study leader, Professor Takashi Minami. "We have also obtained data on NFAT/DSCR-1 signaling in patients with human corneal lesions, suggesting that drugs that block NFAT and its downstream SDF-1 function may be effective in protecting against age-related vascular disease."

Researchers from the Universities of Melbourne, York, Warwick and Oxford have shed light on how encapsulated viruses like hepatitis B, dengue and SARS-CoV-2 hijack the protein manufacturing and distribution pathways in the cell - they have also identified a potential broad spectrum anti-viral drug target to stop them in their tracks.

The findings have been published in PNAS today and are important to efforts to develop broad-spectrum antiviral agents.

Professor Spencer Williams from the School of Chemistry at Bio21 said the research will help define a new 'host-directed' approach for treating infections by encapsulated viruses.

"One approach to treating viral infections is to make a new drug for each virus that comes along. But it is slow. An alternative and attractive approach is to make a drug against a human target that viruses need to replicate. The same drug can then be used and reused against many different viruses, even ones that have yet to emerge," he said.

The findings result from work by Professor Gideon Davies and his UK team who clarified how the structure of the catalytic domain of human enzyme that trims sugar molecules from proteins during their production and Professor Williams' and his Bio21 team, who developed a series of inhibitors to block the enzyme.

When tested in human cell lines, these inhibitors where shown to reduce infection in dengue viruses.

"Encapsulated viruses tend to harness the 'glycosylation' step of protein production, whereby glycans, or sugar molecules coat newly assembled proteins," said Professor Williams.

"The sugar molecules provide instructions for proteins to fold into their correct 3D structure as well as transport instructions for the protein to be brought to its next destination within the cell. Glycosylation is facilitated by various enzymes that synthesize, trim, check and modify these sugar molecules."

Our body's cells contain around 42 million protein molecules. Protein production is a complex, multi-step process within the cell. Like products on a factory assembly-line, all proteins pass through 'quality control' check points where they are inspected before they are transported to their destination, to carry out their functions.

Viruses are not living organisms, but biological programs encoded in ribonucleic acid (RNA) or deoxyribonucleic acid (DNA).

They come to life when they enter a living cell and hijack the protein production systems. Viruses use the cell's machinery to copy their DNA or RNA (in the case of SARS-CoV2, it's RNA) and to produce the proteins they need to make copies of themselves.

The viral proteins produced in an infected cell undergo the 'glycosylation' and then pass through the quality control steps, which involves 'trimming' by an enzyme called 'MANEA'.

"Trimming is a crucial quality control step and when it does not occur, client proteins are marked for degradation. MANEA represents a key target for broad spectrum drug development against encapsulated viruses, as inhibitors will trigger destruction of their proteins," said Professor Davies.

Because viruses hijack this unusual biosynthetic pathway, it makes it a good potential drug target.

Researchers at the University of Warwick and University of Oxford studied the effect of the best inhibitors on viral replication.

Musculoskeletal disorders--which affect muscles, tendons, ligaments, bones, and joints--can severely affect individuals' physical and mental health, and they're especially prevalent among aging adults. Although many researchers are studying these conditions and their rates in different regions of the world, no study to date has provided an overview of the burden of all musculoskeletal disorders. Investigators have now done so in Arthritis & Rheumatology, an official journal of the American College of Rheumatology.

For the analysis, researchers examined data from the Global Burden of Disease Study 2017, which assessed the extent of diseases and injuries across 21 regions and 195 countries and territories from 1990 to 2017. Musculoskeletal disorders included rheumatoid arthritis, osteoarthritis, low back pain, neck pain, gout, and related conditions.

The team found that there were approximately 1.3 billion prevalent cases and 121,300 deaths due to musculoskeletal disorders in 2017, as wells as 138.7 million disability-adjusted life years, or the number of years lost due to ill-health, disability, or early death. The burden of these diseases generally increased with age for both sexes, was more prevalent among females, and was higher in developed countries.

"Our study describes the enormous global burden of disability from musculoskeletal conditions in a single paper," said senior author Rachelle Buchbinder, MD, of the Cabrini Institute and Monash University, in Australia. "These conditions are under-recognized despite their enormous costs to individuals, the economy, and the health system. Also, there has been a lack of any significant decline in the burden from these conditions over time, which means that there is still insufficient emphasis on addressing the problem."

Dr. Buchbinder noted that policy makers must be made aware of the size of this growing problem, especially in light of rapidly aging populations around the world. "A global response is needed, and this should be integrated with other strategies that can address some of the modifiable and important risk factors of musculoskeletal disorders, including obesity, poor nutrition, smoking, and sedentary lifestyles," she said. "As well, there should be an emphasis on reducing low-value care for some of the most burdensome conditions such as low back pain and osteoarthritis that is contributing to the problem."

The authors also stressed the need for standardized methods for collecting data on the prevalence and impact of musculoskeletal disorders across the world.

Researchers from University of North Carolina-Chapel Hill and Tilburg University published a new paper in the Journal of Marketing that explores the rise of click-and-collect services and examines their most appropriate settings.

The study, forthcoming in the Journal of Marketing, is titled "Navigating the Last Mile in Grocery Shopping: The Click and Collect Format" and is authored by Katrijn Gielens, Els Gijsbrechts, and Inge Geyskens.

Big box stores have spent years developing technology capabilities to compete with Amazon and other digitally savvy competitors. While no one could have foreseen Covid-19, these chains' investments in click-and-collect technology allowed them to cash in when the coronavirus pushed sales online.

Order fulfilment is a costly and difficult challenge that must be mastered for online grocery success. The rise of click-and-collect services help overcome this roadblock by having shoppers help fulfill the goods by placing orders online and picking up the goods themselves.

Click-and-collect services can be offered in different ways and through different formats, all of which come with vastly different levels of investments and cost structures. Not surprisingly, many retailers, rushing into the click-and-collect fray, are opting for the lower cash- and capital-intensive options such as in-store and curbside pickup. However, not all click-and-collect formats offer the same convenience benefits to shoppers. Sales outcomes may therefore widely differ. Retailers may thus want to contemplate how to organize these click-and-collect services in a sustainable and profitable way to safeguard the longer-run success and viability of the format. The study offers advice to retailers on whether and how to implement click-and- collect. To that end, the researchers gauged how shoppers' online and total spending changes after they start using three different click-and collect formats, specifically: (1) in-store, i.e. pickup at existing stores; 2) near-store, i.e., pickup at outlets adjoining stores, also known as 'curbside'; and 3) stand-alone click-and-collect, i.e. pickup at free-standing locations.

Do these click-and-collect types address the same needs? Gielens says the answer is, No! "The different formats address fundamentally different shopper needs in terms of fulfillment convenience." Fulfillment convenience touches upon three different benefits offered to shoppers:

Access convenience: the reduction of time to, at, and from a click-and-collect location.

Collection convenience: the reduction of physical effort to collect the order.

Adjustment convenience: the ease with which shoppers can adjust their online orders by adding, returning, or replacing items.

Depending on shoppers' needs for these different convenience benefits, click-and-collect results in vastly different performance outcomes. This calls for judicious alignment of the right click-and-collect format with local-market needs.

Overall, does click-and-collect increase shoppers' online and total spending? The study shows that click-and-collect can be an effective means to boost online spending at the retailer. Hence, click-and-collect may indeed be the long-awaited road to online success for grocery retailers, overcoming the last-mile problems associated with home delivery. Moreover, by blending the convenience benefits of home delivery and brick-and-mortar, click-and-collect can also enhance households' total spending at the retailer and thus constitute a profitable addition to the retailer's channel mix.

What is the best click-and-collect format for access-convenience-oriented markets? In markets with high access-convenience needs, such as rural markets with many weekend shoppers, both in-store and stand-alone click-and-collect do well. The time-efficient pickup of stand-alones stimulates these shoppers to spend more at the retailer online. In-store pickup, in turn, leads to positive spillovers to the retailer's brick-and-mortar stores and, hence, an increase in total spending.

What is the best click-and-collect format for collection-convenience-oriented markets? Stand-alone click-and-collects best serve needs in these markets with a predominance of large-basket shoppers buying more bulky items. In these markets, the lower physical shopping effort combined with the time-savings of not having to drive to a regular store, make stand-alones particularly appealing - resulting in the highest extra total spending at the retailer.

What is the best click-and-collect format for adjustment-convenience-oriented markets? Stand-alone and near-store yield the highest total retailer sales in these markets where larger households that shop more for perishables and buy more on impulse tend to live. While in-store leads shoppers in these markers to spend more online, it also cannibalizes their brick-and-mortar purchases. Even worse, it may even decrease total spending at the retailer and should therefore be avoided.

What are the key takeaways for practitioners? Gijsbrechts explains that "We provide grocery retailers with insights on how to avoid costly mistakes when kick starting click-and-collect. As retailers race to build click-and-collects, they are mostly opting for fulfillment within existing stores for the sake of quick, low-cost roll-out. Indeed, since in-store click-and-collect can rely on existing infrastructure and processes, it is the easiest to implement. However, the pursuit of speed without knowing which type is best in terms of demand may lead to the demise of the format." Also, while most retailers tend to opt for one type of click-and-collect across all markets, a one-size-fits-all approach is not advisable. Instead, the impact depends on shoppers' needs for fulfillment convenience. This study helps retailers find the right mix.

The first fossils of a duckbilled dinosaur have been discovered in Africa, suggesting dinosaurs crossed hundreds of kilometres of open water to get there.

The study, published in Cretaceous Research, reports the new dinosaur, Ajnabia odysseus, from rocks in Morocco dating to the end of the Cretaceous, 66 million years ago. Ajnabia was a member of the duckbill dinosaurs, diverse plant-eating dinosaurs that grew up to 15 meters long. But the new dinosaur was tiny compared to its kin - at just 3 meters long, it was as big as a pony.

Duckbills evolved in North America and eventually spread to South America, Asia, and Europe. Because Africa was an island continent in the Late Cretaceous, isolated by deep seaways, it seemed impossible for duckbills to get there.

The discovery of the new fossil in a mine a few hours from Casablanca was "about the last thing in the world you would expect," said Dr Nicholas Longrich, of the Milner Centre for Evolution at the University of Bath, who led the study. Dr Longrich said: "It was completely out of place, like finding a kangaroo in Scotland. Africa was completely isolated by water - so how did they get there?"

Study of Ajnabia's distinctive teeth and jawbones show it belonged to Lambeosaurinae, a subfamily of duckbills with elaborate bony head crests. Lambeosaurs evolved in North America before spreading to Asia and Europe, but have never been found in Africa before.

Reconstructing duckbill evolution, they found the lambeosaurs evolved in North America, then spread over a land bridge to Asia. From there, they colonised Europe, and finally Africa.

Because Africa was isolated by deep oceans at the time, duckbills must have crossed hundreds of kilometres of open water- rafting on debris, floating, or swimming - to colonise the continent. Duckbills were probably powerful swimmers - they had large tails and powerful legs, and are often found in river deposits and marine rocks, so they may have simply swum the distance.

"Sherlock Holmes said, once you eliminate the impossible, whatever remains, no matter how improbable, must be the truth," said Longrich. "It was impossible to walk to Africa. These dinosaurs evolved long after continental drift split the continents, and we have no evidence of land bridges. The geology tells us Africa was isolated by oceans. If so, the only way to get there is by water."

In reference to this feat, the dinosaur is named "Ajnabia odysseus". Ajnabi being Arabic for "foreigner", and Odysseus referring to the Greek seafarer.

Ocean crossings are rare, improbable events, but have been observed in historic times. In one case, green iguanas travelled between Caribbean islands during a hurricane borne on debris. In another, a tortoise from the Seychelles floated hundreds of kilometres across the Indian Ocean to wash up in Africa.

"Over millions of years," said Longrich, "Once-in-a-century events are likely to happen many times. Ocean crossings are needed to explain how lemurs and hippos got to Madagascar, or how monkeys and rodents crossed from Africa to South America."

But the fact that duckbills and other dinosaur groups spread between continents, even with high sea levels, suggests dinosaurs travelled across oceans as well. "As far as I know, we're the first to suggest ocean crossings for dinosaurs," said Longrich.

The international team of scientists was led by the University of Bath with researchers from the University of the Basque Country UVP/EHU (Spain), George Washington University (USA) and the Natural History Museum of Sorbonne University (France) / Universite Cadi Ayyad (Morocco).

Dr Nour-Eddine Jalil, from the Natural History Museum of Sorbonne University (France) said: "The succession of improbable events (crossing an ocean by a dinosaur, fossilization of a terrestrial animal in a marine environment) highlights the rarity of our find and therefore its importance.

"Ajnabia shows us that hadrosaurs have set foot on African land, telling us that ocean barriers are not always an insurmountable obstacle."

Fungus farming is a fascinating symbiosis that has evolved multiple times in social insects: once in ants, once in termites, and several times in weevils (beetles) from the subfamilies Scolytinae and Platypodinae. The behavior of these "ambrosia beetles" - over 3,000 species - is poorly known, because they live inside galleries in wood, making observation hard. Here, a study focuses for the first time on the division of labor within colonies of ambrosia beetles. The author shows that in Xyleborus affinis, unlike in ants and termites, social behavior such as brood and fungus care is mostly by fertile "helper" females who reproduce alongside their mother, the colony foundress. He also shows that a specialized fungus in the genus Raffaelea is probably the only food source for the larvae.

"Beetles are the most diverse insect order, but social beetles are relatively rare. Our successful development of laboratory rearing of X. affinis allows us to design experiments to determine why some beetle helpers refrain from reproduction, yielding important insights into the early evolutionary stages of insect sociality," says Prof Peter H. Biedermann from the Albert-Ludwigs-University in Freiburg, Germany, the sole author of the new study, which is published in Frontiers in Ecology and Evolution.

The scolytid ambrosia beetle X. affinis ranges across the Americas and has been further spread by humans to (sub-)tropical regions around the world. Despite its common name, sugarcane shot-hole borer, it doesn't have any special affinity for sugarcane - it typically nests inside moist, fallen logs and stems of around 250 plant species in natural forests. Females have a special pouch in their mouth, which contains fungal spores from their natal nest. They use these spores to start gardens along the galleries they excavate, tended by themselves and their offspring. Different species are known to grow different fungi, but the identity of the fungal symbiont and the specificity of the association is seldom known.

Here, Biedermann collected 23 mated X. affinis females (foundresses) from forests in Louisiana and let them dig inside glass tubes (1.8 cm wide, 15 cm long) filled with a sterile medium based on sawdust. Inside, the foundresses grew fungus gardens and produced offspring. The behavior of larvae and adults could be observed in detail when the wrapping around the tubes was temporarily removed. Between 51-61 days after colony foundation, Biedermann determined the number of males and females of all developmental stages, their spatial distribution, the reproductive status of adult females by dissecting their ovaries, and the taxonomic identify of the fungus gardens by plating them onto diagnostic growth media.

Biedermann shows that only one fungus, an asexual Raffaelea species from the ascomycete family Ophiostomataceae, occurs in all parts of each nest, strongly suggesting that it has been domesticated by X. affinis as its main food crop. Four less frequent fungi might represent alternative crops, parasites, or commensals.

The results also suggest that females grow eggs inside their ovaries in response to an opportunity to breed, such as greater amount of food per larva. Fertile females may either fly out to disperse or stay inside the nest, typically near the brood, to reproduce in competition with their mother. Both non-fertile and fertile females help their mother with hygienic tasks and brood and fungus care, but fertile ones are more prone to do such work. Males don't work but wait inside side galleries to mate with sisters.

"Here I showed that X. affinis has convergently evolved a facultative eusocial system very similar to wasps and bees that lack castes. In ambrosia beetles, egg-laying females work more than their non-fertile sisters, whereas females in distinctive sterile castes do all the work in in ants and termites. Also, farming has evolved convergently in ambrosia beetles, ants, and termites, in that a single asexual fungus seems to be the main domesticated food source in all these insect farmers," says Biedermann.

Vitamin D supplementation eased the symptoms experienced by children with severe atopic dermatitis, or eczema, in a recent randomized controlled trial published in Pharmacology Research & Perspectives.

Investigators reported on the results of 86 patients with the inflammatory skin condition who completed the trial and received either oral daily vitamin D or placebo, in addition to standard care, for 12 weeks.

"Vitamin D supplementation could be an effective adjuvant treatment that improves the clinical outcomes in severe atopic dermatitis," the authors wrote.

Researchers from John Carroll University and University of Kansas published a new paper in the Journal of Marketing that investigates how recipients respond to charities' pre-giving incentives to determine if they are worth the investment.

The study forthcoming in the Journal of Marketing is titled "Coins are Cold and Cards are Caring: The Effect of Pre-giving Incentives on Charity Perceptions, Relationship Norms and Donation Behavior" and is authored by Bingqing (Miranda) Yin, Yexin Jessica Li, Surendra Singh.

Many nonprofits include a small gift with their appeals, such as pennies, dimes, address labels, and greeting cards, in hopes of persuading recipients to donate. PGIs such as coins and greeting cards are included in approximately 40% of the total non-profit mail volume. In fact, inclusion of monetary PGIs is so popular that the strategy has its own moniker: "the coin trick." However, these monetary and non-monetary pre-giving incentives (PGIs) cost time, money, and other resources that are already scarce for charities. Yin explains that "Our research examines the effect of monetary versus non-monetary PGIs on multiple outcomes of interest to charitable organizations. Results indicate that PGIs have different effects on different outcomes and that the best strategy depends on what the charity wants to achieve."

Opening rate - If the goal is to raise awareness and help the charity gain exposure, enclosing a monetary PGI appears to be an effective strategy. Results suggest that enclosing a monetary PGI not only persuades recipients to open the letter, but to read it, particularly among people not familiar with the charity.

Response rate - Enclosing a monetary PGI may help organizations achieve the goal of enlarging the donor pool for future campaigns. Results show that a monetary PGI leads to a significantly higher response rate than both a non-monetary PGI and no PGI. However, no response rate difference is found for the annual campaign for recurring donors. Therefore, monetary PGIs may be especially beneficial for lesser known charities just starting to build a donor list.

Average donation - If the primary goal is to maximize the contribution of each donor, results consistently show that a monetary PGI is a bad idea. Non-monetary PGIs perform no better than no incentives. In fact, including them, even when the researchers increase their value, leads to the same average donations as when no PGI is included.

Total donations - Charities may have the goal of raising the most money possible. Across all seven studies, the no-PGI appeals result in the most money raised, followed by the non-monetary PGI appeals, and the monetary PGI appeals. The effectiveness of PGIs on total donations depends on who the recipients are. For donor acquisition, the monetary PGI appeal works best (perhaps due to the higher opening rate), whereas for recurring donors, the no PGI appeal raises the most money.

Return on investment - If the goal is to minimize losses or yield a higher return on investment, it is more effective to not include a PGI. Specifically, for donor acquisition, where ROIs for all conditions are negative, enclosing a monetary PGI leads to an additional $.27 cents net loss per mailing, which is more than twice the net loss with no PGI. Enclosing a non-monetary PGI results in an additional $.24 net loss per mailing. Similar results are found with recurring donors. Enclosing a monetary PGI results in a $2.19 lower ROI per person compared to no PGI, while a non-monetary PGI (versus no PGI) results in a $1.41 lower ROI per person.

Charity perceptions - Enclosing a monetary PGI leads people to perceive the charity as less communal and more exchange-oriented, which directly harms donations. Enclosing a non-monetary PGI does not affect donors' communality perception of the charity. Li says "We expect this is because an immediate ask for help accompanying the gift offsets any increase in communality from the gift itself. Net communality is significantly lower when participants are asked for a donation immediately after receiving a PGI than when they were given a gift without a donation request. So, if charities want to enhance communal norms, we suggest sending a gift with a delayed request for help." Additionally, enclosing a monetary PGI leads people to perceive the charity as more manipulative and less efficient.

Working together with researchers from the University of Tübingen, the University of Tromsø, the UC Davis and the Sainsbury Laboratory in Norwich, biologists from Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) have discovered how tomato plants identify Cuscuta as a parasite. The plant has a protein in its cell walls that is identified as 'foreign' by a receptor in the tomato.

Cuscuta spp., also known as dodder, is a parasitic vine which grafts to the host plant using special suckers to obtain water, minerals and carbohydrates. The parasite also attacks and damages crops such as oilseed rape, sweetcorn, soy, flax or clover. Although the infection generally goes undetected by the host, some species of tomato actively defend themselves by forming wooden tissue which prevents the suckers from penetrating the plant. In earlier research, the biologists at FAU discovered that these tomatoes possess a special receptor, the Cuscuta receptor 1 (CuRe1), which triggers the defence mechanism. However, until now it was unclear how the receptor recognises the danger posed by the dodder.

The researchers have now succeeded in answering this question: the dodder possesses a specific marker in its cellular wall, a glycine-rich protein (GRP). Using its receptor CuRe1, the tomato is able to recognise the molecular pattern of the GRP and identify the dodder as a pathogen, and triggers the immune reaction as a result. The new findings concerning the molecular dialogue between the Cuscuta marker and the tomato receptor may help to increase the resistance of crop plants against parasitic plants.

Researchers from University of Georgia, University of South Carolina, and University of Arkansas published a new paper in the Journal of Marketing that analyzes how asymmetries in pre-alliance network ties between a firm and its alliance partner affect the focal firm's financial performance and financial performance uncertainty.

The study, forthcoming in the Journal of Marketing, is titled "Effect of Alliance Network Asymmetry on Firm Performance and Risk" and is authored by Anindita Chakravarty, Chen Zhou, and Ashish Sharma.

Persistent high failure rates of new product alliances call for an identification of factors that might improve alliance outcomes. This research analyzes how asymmetries in pre-alliance network ties between a firm and its alliance partner affect the focal firm's financial performance and financial performance uncertainty. The research team discovered that direct-tie asymmetry has an inverted U-shaped effect on the focal firm's abnormal returns and a U-shaped effect on its risk. Indirect-tie asymmetry also has a U-shaped effect on the focal firm's risk. However, the focal firm's innovation quality and preexisting ties with its partner flatten these curvilinear effects.

Results suggest the following in dollar terms. To interpret the inverted U-shaped effect, in order to set a reference point let us assume that a moderate increase in direct-tie asymmetry increases market capitalization of a firm by $100MM. A high increase in direct-tie asymmetry will lead to a lower increase of $78.2MM in market capitalization. The above findings are the interpretation of the main effects. To interpret the interaction effects of innovation quality at moderate increases in direct-tie asymmetry, begin with the $100MM lift in market capitalization due to a moderate increase in direct-tie asymmetry. In this scenario, if innovation quality of the firm is high, it can achieve a $100.57MM increase in market capitalization. However, if innovation quality of the focal firm is low, it can achieve a $98.04MM increase in market capitalization. To interpret the interaction effects of total interdependence, consider the $100 MM increase in market capitalization due to a moderate increase in direct tie asymmetry. In this scenario, if the total interdependence of the firm is high, it can achieve a $114.08MM increase in market capitalization. However, if the total interdependence of the focal firm is low, it can achieve a $101.6MM increase in market capitalization.

In order to interpret the interaction effects of innovation quality at high increases in direct-tie asymmetry, begin with the $78.2MM lift in market capitalization due to a high increase in direct-tie asymmetry as shown above. In this scenario, if the innovation quality of the firm is high, it can achieve a $102.41MM increase in market capitalization. However, if the innovation quality of the focal firm is low, it can achieve a $34.10 MM increase in market capitalization. To interpret the interaction effects of total interdependence, begin the $78.2MM increase in market capitalization due to a high increase in direct-tie asymmetry. In this scenario, if the total interdependence of the firm is high, it can achieve a $113.47MM increase in market capitalization. However, if the total interdependence of the focal firm is low, there is a decrease of market capitalization by $64.23MM.

Chakravarty summarizes this as "A worst-case scenario managers should avoid--a combination of high direct tie-asymmetry and low total interdependence with the potential alliance partner."

Regarding risks associated with alliance formation, managers should note the importance of a potential alliance partner's indirect ties, specifically how well these ties are interconnected relative to the interconnectivity of their firm's own indirect ties. The research team calculates changes in the focal firm's predicted risk from a moderate increase in indirect tie asymmetry and finds a 68.7% decrease in the focal firm's risk. The corresponding decrease in risk is 24% when indirect tie asymmetry has a high increase. When high and low levels of the moderators are calculated, all combinations reduce predicted risk to different degrees, but one specific combination highlights a worst-case scenario. Specifically, a focal firm's predicted risk increases by 56.8% with a combination of high increase in indirect-tie asymmetry and low total interdependence.

Zhou explains that "In terms of risk, a worst-case scenario emerges that managers should avoid--a combination of high indirect-tie asymmetry and low total interdependence with a potential alliance partner."

This study highlights the need to assess a potential alliance partner's direct ties and indirect ties. Indirect ties of alliance partners are important to assess and direct and indirect ties relative to an alliance partner directly affect the focal firm's market capitalization.

Argonne computational resources supported the largest comprehensive analysis of COVID-19 genome sequences in the U.S. and helped corroborate growing evidence of a protein mutation.

Before COVID-19 first entered the United States in March, Houston Methodist Hospital had already begun preparations to test for and sequence the virus on a large scale, given the news coming out of Wuhan, China.

Between March 5, when the first case turned up in metropolitan Houston, and July 7, physician/researchers at Houston Methodist sequenced the genome of over 5,085 strains of the virus. These accounted for nearly 10 percent of the COVID-19 cases that came through the 2,400-bed Houston Methodist health system, during two distinct waves that occurred in that time frame.

“99 percent isn’t 100 percent. If there is a mutation that accounts for just one percent of the population, and you suppress or eradicate the majority, you can drive up some trait of that one percent, whether it’s virulence or transmissibility, and then it’s a different ballgame.” — James Davis, Argonne staff scientist

Collaborators from the University of Texas at Austin, Weill Cornell Medical College, the University of Chicago and the U.S. Department of Energy’s (DOE) Argonne National Laboratory worked together to analyze the data and try to correlate patient outcomes with viral traits.

“This is the largest viral sequence analysis in the U.S. right now and it’s one of the most comprehensive, continual snapshots of sequences that dates to the beginning of the outbreak,” said James Davis, a staff scientist in Argonne’s Data Science and Learning division. “It also provides a much clearer picture of how the strains are evolving.”

During the course of the research, the group helped solidify mounting observations and concerns internationally that a mutation in the virus’s spike protein had become dominant, driving COVID-19’s transmissibility rates as witnessed by the second wave that surged through Houston around mid-May.

A paper describing their methods and results was published in the journal mBio on October 30.

That mutation in the spike — responsible for infiltrating the human immune system and the current target of vaccine research — was in an amino acid called Gly614 and was the result of one protein, aspartic acid, mutating into another, glycine.

During the earliest parts of the pandemic, March through April, Gly614 was just one variant among many others. But during the second wave in May, Davis recalls, all of the cases they were sequencing at Houston Methodist showed that Gly614 had proliferated to the point of becoming the dominant amino acid in the spike protein.

In fact, it was found in over 99 percent of the sequenced variants.

“The SARS-CoV-2 virus is remarkably conserved, so whenever you see changes like this it’s more remarkable because you don’t tend to see that many mutations,” he said. “I’m not sure if it makes the virus more virulent or easier to transmit, but the study does show some data suggesting that patients with the Gly614 mutation have a larger viral load, though they aren’t necessarily sicker.”

Coincident with the Gly614 takeover in the second wave, patients tended to be younger, showed less severe symptoms, were more likely to be Hispanic/Latino, and lived in areas of lower median incomes. Still, the reasons were unclear and they’d hoped that Argonne’s computational resources would open a door on the causes.

A working relationship already in place, Houston Methodist approached Argonne for help with genome sequence analyses of the 5,000-plus COVID strains, as well as phylogenetic analyses, which look at changes in an organism or a specific feature over time.

Through its Bioinformatics Resource Center Project, supported by the National Institute of Allergy and Infectious Diseases, Argonne provides computational and technical resources to collaborators conducting large biological-based data projects. In this case, it managed the sequencing components, and included quality control, genome alignments and the building of phylogenetic trees.

“For a virus, it has a pretty big genome,” noted Davis, “so, the process became computationally expensive.” But with its arsenal of computers, both large and super, Argonne was prepared to handle the influx of data.

Another aspect of that work involved the artificial intelligence technique called machine learning. While the focus of machine learning among many research institutions, including Argonne, has focused on determining how drugs might interact with COVID-19, Marcus Nguyen hoped to predict whether the sequence of the virus could ultimately predict patient outcome or patient demographics.

Nguyen, a research specialist with a joint appointment at Argonne and the University of Chicago, looked at correlations between the genome sequences and patient information.

The process trained a machine learning algorithm on the genomic sequences from Houston Methodist, as well as past patient outcomes — length of hospital stay, need for mechanical ventilation, mortality — to potentially determine those outcomes.

“Unfortunately, we didn’t get the results we were hoping for,” said Nguyen. “Although there have been a few correlations found in different pieces of patient metadata, I don’t think there is anything in the genome that is indicative of patient outcome, so there has to be something else going on.”

While the group did observe other variations in the spike, research continues on Gly614 to understand its dynamics and determine what role, if any, it might play in treatment therapies.

“It should be helpful in vaccine development because it shows so many different sequences and so many variants that you get a pretty good picture of what to look for in terms of what variants are dominant in the population,” said Davis.

Though the virus has remained somewhat stable, to date, this study — and natural history — have shown that it only takes one mutation to create a powerful impact on life, both large and diminutive.

“99 percent isn’t 100 percent,” Davis pointed out. “If there is a mutation that accounts for just one percent of the population, and you suppress or eradicate the majority, you can drive up some trait of that one percent, whether it’s virulence or transmissibility, and then it’s a different ballgame.”