Culture

Periods of lockdown during the COVID-19 situation likely to exacerbate problems with mood regulation, say experts at the University of Oxford.

Mood varies from hour-to-hour, day-to-day and healthy mood regulation involves choosing activities that help settle one's mood. However, in situations where personal choices of activities are constrained, such as during periods of social isolation and lockdown, this natural mood regulation is impaired which might result in depression. New research, published today in JAMA Psychiatry, from the Department of Psychiatry, University of Oxford suggests a new target for treating and reducing depression is supporting natural mood regulation.

This new study looked at 58,328 participants from low, middle and high income countries, comparing people with low mood or a history of depression with those of high mood. In a series of analyses, the study investigated how people regulate their mood through their choice of everyday activities. In the general population, there is a strong link between how people currently feel and what activities they choose to engage in next. This mechanism - mood homeostasis, the ability to stabilise mood via activities - is impaired in people with low mood and may even be absent in people who have ever been diagnosed with depression.

Guy Goodwin, Professor Emeritus of Psychiatry, University of Oxford, said, 'When we are down we tend to choose to do things that cheer us up and when we are up we may take on activities that will tend to bring us down. However, in our current situation with COVID-19, lockdowns and social isolation our choice of activity is very limited. Our research shows this normal mood regulation is impaired in people with depression, providing a new, direct target for further research and development of new treatments to help people with depression.'

One in five people will develop major depression at some point in their life. The current lockdown strategies used by different countries to control the COVID-19 pandemic is expected to cause even more depressions. About 50% of people will not see their symptoms improve significantly with an antidepressant and the same applies to psychological treatments. The total annual cost of depression in the UK is about £8 billion. A key priority for mental health research is therefore to develop new treatments or optimise existing ones for depression.

Maxime Taquet, Academic Foundation Doctor, University of Oxford, said, 'By training people to increase their own mood homeostasis, how someone naturally regulates their mood via their choices of activities, we might be able to prevent or better treat depression. This is likely to be important at times of lockdown and social isolation when people are more vulnerable to depression and when choices of activities appear restricted. Our research findings open the door to new opportunities for developing and optimising treatments for depression and this could potentially be well adapted to treatments in the form of smartphone apps, made available to a large population which sometimes lack access to existing treatments.'

Using computer simulations, this study also showed that low mood homeostasis predicts more frequent and longer depressive episodes. Research suggests that by monitoring mood in real time, intelligent systems could make activity recommendations to increase mood regulation and such an intervention could be delivered remotely, improving access to treatment for patients for whom face-to-face care is unavailable, including low and middle income countries.

Importantly, some associations between activities and mood were highly culture-specific, for example, exercise led to the highest increase in mood in high income countries, whereas religion did so in low and middle income countries. Interventions aimed at improving mood regulation will need to be culture specific, or even individual specific, as well as account for people's constraints and preferences.

On a global scale, more than 264 million people of all ages suffer from depression and the majority of cases, 80 per cent, are in low and middle income countries despite the scarcity of research performed in those countries. Major depressive disorder is a more important cause of disability worldwide than diabetes or lung cancer (in terms of disability-adjusted life years).

By studying a cohort of 190 children, a research team has discovered important clues that could help explain why some children with respiratory syncytial virus (RSV) infections get mild cases while others get more severe disease and require hospitalization. The results identify important features in the immune response to RSV and could inform the development of a historically elusive vaccine for the disease. RSV is a common disease in children and represents the most frequent cause of hospitalization in newborns in developed countries, although it most often causes only mild symptoms. Studies have hinted that factors ranging from age to viral load can influence the severity of infections, but scientists had not fully understood how these factors affect the course of the disease on the biological level. Researchers also suspect that more severe cases are tied to abnormal responses from the immune system. To investigate, Santtu Heinonen and colleagues compared immune signatures in blood samples taken from a group of 190 young children, including 125 children with RSV infections and 65 healthy controls. Surprisingly, the authors saw that children who developed mild cases actually harbored higher viral loads compared with children who required hospitalization and had a higher likelihood of being infected with rhinovirus or another respiratory virus. The children with mild cases also displayed higher activity of genes involved in the production of interferons - molecules that are important in the innate immune response - but had less expression of inflammatory genes. The authors say their findings support a key role for innate immunity in determining the severity of RSV infections, and believe their results could help the design of clinical studies to evaluate new vaccines and antivirals against RSV.

A nationwide intervention to replace regular household salt with potassium-enriched salt substitutes in China could prevent nearly half a million cardiovascular deaths per year, according to a new modelling study published in the British Medical Journal.

The study found that overall, the blood pressure lowering effects of salt substitution could prevent around 460,000 cardiovascular disease (CVD) deaths each year, including 208,000 due to stroke and 175,000 due to heart disease.

They were also estimated to prevent some 743,000 non-fatal CVD events each year, including 365,000 strokes and 147,000 heart attacks, and decrease rates of chronic kidney disease (CKD) by around 120,000 each year, or almost seven percent of new cases.

Dr Jason Wu, one of the study's senior authors and Program Head of Nutrition Science at The George Institute said that replacing regular salt with potassium-enriched salt substitutes combines the blood pressure lowering effects of reduced sodium and increased potassium intake.

"While potassium intake in China is low, intake of sodium is well above recommended levels, mainly coming from salt used at home, in cooking or at the table," he said.

"Salt substitution is therefore a promising strategy to reduce blood pressure and related diseases like CVD and CKD in China, where over two million deaths were attributed to elevated blood pressure in 2015. Our findings suggest that a nationwide intervention to encourage use of potassium-enriched salt substitutes could prevent nearly one in nine CVD deaths in China."

An important part of this study was to look at the potential benefits of blood pressure reduction at the same time as the possible risk to people with CKD from increased potassium intakes. Lead author, Senior Research Fellow at The George Institute and now research assistant professor at the Friedman School of Nutrition Science and Policy at Tufts University, Matti Marklund, PhD, said that concerns about the potential risk of increased potassium intakes in people with CKD were particularly relevant in China where most people with CKD are unaware of their condition.

"Our modelling study suggests that with this type of intervention, the benefits greatly outweigh the harms in the overall population. In fact, even among individuals with CKD, there are substantial net benefits," he said.

Among an estimated 17.2 million people with CKD, the blood pressure lowering effects of the intervention could prevent around 32,000 CVD deaths, but the increased potassium intake and higher blood potassium levels could potentially cause some 11,000 additional CVD deaths, resulting in an estimated 21,000 deaths avoided overall.

"The finding of net cardiovascular benefits in those with CKD suggests that encouraging them to avoid potassium-enriched salt substitutes in a national intervention could result in overall harm as they would then miss the benefits of reduced blood pressure. However, alternative approaches like improving screening for CKD and closer monitoring of potassium levels in diagnosed patients should be evaluated to minimize potential risks," added Dr Marklund.

Eating too much salt increases blood pressure, which is one of the biggest contributors to premature death from stroke or heart disease. Worldwide, excess salt intake is estimated to cause about three million deaths each year.

In China, sodium intake is more than double the WHO-recommended limit, and nearly half of Chinese people aged 35-75 have high blood pressure. Almost 30 percent of fatal strokes in Chinese people aged under 70 are attributable to high sodium consumption.

In contrast to most Western countries the largest contributor of dietary sodium in China is discretionary salt (i.e., salt added in the home during cooking or at the table), contributing to about two thirds of sodium intake.

"Our study suggests that a national program to replace regular salt with lower-sodium 'salt substitutes' for home cooking, could have a large impact on the burden of CVD in China." said Dr Marklund.

New research demonstrates unsustainable levels of soil erosion in the UK.

The study examined more than 1,500 existing records and found 16% relating to arable (crop-growing) land showed erosion above "tolerable" levels - meaning rates of soil loss are significantly greater than new soil formation.

This may not reflect the national picture, as the study has highlighted that existing studies are frequently biased towards places which have eroded in the past.

However, the findings still show that erosion can occur at problematic levels under a range of conditions, meaning soil resources are at risk in the medium to long term.

"Unsustainable rates of erosion reduce soil fertility and can have devastating environmental impacts downstream in waterways," said lead author Dr Pia Benaud, of the University of Exeter.

"If we don't manage it properly in the UK and around the world, it will affect our ability to feed our growing population.

"Soil run-off also leads to significant extra sediment in waterways, increasing the damage to ecology and risk of flooding downstream."

Land management affects erosion rates. For example, leaving fields bare, ploughing up and down a hill (instead of across it) or growing arable crops on steep slopes raise the risk of erosion during heavy rain.

Soil types and local geography also affect erosion rates, though erosion is shown to occur on any soil that is intensively farmed, especially when rainfall is extreme.

"Current UK legislation, particularly existing farm subsidies, pay for land to be managed in a way that leads to unsustainable erosion, with public funding," Dr Benaud said.

"We argue that this should be addressed as a matter of urgency by policymakers, with soil protection at the heart of forthcoming environmental land management schemes."

Despite raising concerns about UK erosion above the "tolerable" rate of one metric tonne per hectare per year, the study says erosion rates in the UK are relatively low compared to the rest of Europe, demonstrating that erosion is a serious global problem.

The highest UK erosion rate found was more than 140 tonnes per hectare per year - recorded on a single field in West Sussex in the early 1990s.

"Analysing existing research, as we have done here, it is difficult to define what constitutes a soil erosion 'problem', and to know how serious an issue this is in the UK," said Professor Richard Brazier, a co-author on the paper and Director of Exeter Centre for Environmental Resilience, Water and Waste.

"What is clear, however, is that soil erosion rates of the order reported will lead to serious impacts on soil productivity if left unchecked.

"More information is needed to fill the gaps in understanding; the open access geodatabase and interactive web-map published alongside this paper offer a platform for the development and sharing of soil erosion research, which will hopefully allow for the formulation of effective policy and better protection of our soil, which is so critical to food production and genuine ecosystem services such as carbon storage."

From two seeds grew a thousand plants.

University of Guelph researchers used advanced cloning techniques to give the threatened Hill's thistle a fighting chance.

This cutting-edge propagation method could rejuvenate the population of other threatened and endangered plant species, said lead researcher Prof. Praveen Saxena, Department of Plant Agriculture.

Published recently in the journal PLOS ONE, the three-year study used the CPR (Conservation, Propagation, Redistribution) method to preserve the genetic material of germ cells, known as germplasm, and use that material to produce large quantities of plants in a controlled environment.

"A very small amount of plant material can produce large numbers of plants for conservation purposes," said Saxena, who heads the Gosling Research Institute for Plant Preservation (GRIPP) at U of G.

The conventional method of planting seeds to reintroduce Hill's thistle has shown limited success due to low flowering and low germination rates.

"The major goal of our research is to preserve threatened and endangered plant biodiversity through the application of in vitro culture technologies that can be used to prevent species loss in the field," said, Saxena, who worked on the study with fellow GRIPP researchers Bita Sheikholeslami, Christina Turi and Mukund Shukla. "We wanted to test our model for its practical utility in a real-life situation, when lab-generated plants are transferred to harsh natural sites."

Parks Canada provided the team with 29 seeds, of which only two germinated. Those two seeds sprouted enough plant material to grow 1,000 plants in the lab; 300 were transplanted back into the Bruce Peninsula National Park in southern Ontario.

The 300 plants were planted in 12 sites in the national park in summer 2017. The survival rate ranged from 67 to 99 per cent, with nearly all of these plants surviving the winter. Shoot regeneration and flowering occurred in most sites.

"Micropropagation is a good approach for Hill's thistle because germplasm can be stored for long-term in our GRIPP facility to conserve the limited genetic diversity, while the threats to the declining populations can be managed through reintroduction of micropropagated plants," said Shukla. "This extensive study provides solid evidence of the usefulness of in vitro-grown plants."

The Hill's thistle grows in scarce Great Lakes areas known as open alvar grasslands. In Ontario, the flowering plant, which supports the life cycles of rare bees and other pollinators, is found mostly on the Bruce Peninsula and Manitoulin Island.

It is listed as a threatened plant species in the province, and one likely to become endangered if steps are not taken to protect it. A lack of suitable habitat due to the encroachment of trees and shrubs, as well as cottage development and quarrying activity in its natural habitat, have contributed to the decline.

"In general, plant biodiversity is important for human lives, as well as animals and microbes, as it is critical to their survival because of the oxygen, food and medicine they provide," Saxena said. "A complete ecological system is not possible without plant biodiversity. We are optimistic that the CPR model will prove to be an important tool in saving plant diversity, including important food and medicinal crops."

Researchers from the Department of Pharmacology, Paediatrics and Radiology at the University of Seville, in collaboration with Dr. Rodriguez from the International University of Catalonia, have confirmed that Orujo Olive OIL (POCTA), when introduced into the diet, produces a significant reduction in obesity and vascular and inflammatory complications in obese mice. In addition, given that POCTA has been obtained from a by-product of olive oil, orujo, which is considered as industrial waste, this study helps to increase its biological and nutritional value as a functional food, being its main source of bioactive compounds, the triterpenic acids.

To carry out this research, a comparative study was made over the course of 10 weeks in mice with two types of diets; a diet high in saturated fats, called "prejudicial" fat, and another, with the same calorie content, but with orujo olive oil. After this time was over, a significant reduction in weight was observed (around 30%) in the mice fed with POCTA in comparison with the group fed with the high-fat diet.

This study shows for the first time that POCTA, "does not only reduce body weight in obese animals, but also reduces body fat (adipose tissue), hepatic inflammation, while, at the same time, reducing resistance to insulin and vascular dysfunction associated with obesity", explains the University of Seville researcher Carmen Maris Claro Cala.

These preliminary studies in animals provide very important information about the traditional use of orujo olive oil as a functional food due to its content of triterpenic acids, such as oleanolic acid and maslinic acid as bioactive molecules. However, the researcher indicates that "before being able to establish the therapeutic potential of these molecules, controlled clinical trials should be carried out so as to be able to arrive at conclusions about their action in humans and any repercussions on health".

Other oils on the market

Unlike other types of oils, like coconut or palm oil, the oil obtained from the orujo of the olive, a product forgotten in recent years, has shown itself to be a source of bioactive molecules with great therapeutic potential against obesity and the metabolic dysfunctions developed with Metabolic Syndrome. The results of this study "open a new line of research in investigating the Mediterranean diet", the researcher adds.

The common view of heredity is that all information passed down from one generation to the next is stored in an organism's DNA. But Antony Jose, associate professor of cell biology and molecular genetics at the University of Maryland, disagrees.

In two new papers, Jose argues that DNA is just the ingredient list, not the set of instructions used to build and maintain a living organism. The instructions, he says, are much more complicated, and they're stored in the molecules that regulate a cell's DNA and other functioning systems.

Jose outlined a new theoretical framework for heredity, which was developed through 20 years of research on genetics and epigenetics, in peer-reviewed papers in the Journal of the Royal Society Interface and the journal BioEssays. Both papers were published on April 22, 2020.

Jose's argument suggests that scientists may be overlooking important avenues for studying and treating hereditary diseases, and current beliefs about evolution may be overly focused on the role of the genome, which contains all of an organism's DNA.

"DNA cannot be seen as the 'blueprint' for life," Jose said. "It is at best an overlapping and potentially scrambled list of ingredients that is used differently by different cells at different times."

For example, the gene for eye color exists in every cell of the body, but the process that produces the protein for eye color only occurs during a specific stage of development and only in the cells that constitute the colored portion of the eyes. That information is not stored in the DNA.

In addition, scientists are unable to determine the complex shape of an organ such as an eye, or that a creature will have eyes at all, by reading the creature's DNA. These fundamental aspects of anatomy are dictated by something outside of the DNA.

Jose argues that these aspects of development, which enable a fertilized egg to grow from a single cell into a complex organism, must be seen as an integral part of heredity. Jose's new framework recasts heredity as a complex, networked information system in which all the regulatory molecules that help the cell to function can constitute a store of hereditary information.

Michael Levin, a professor of biology and director of the Tufts Center for Regenerative and Developmental Biology and the Allen Discovery Center at Tufts University, believes Jose's approach could help answer many questions not addressed by the current genome-centric view of biology. Levin was not involved with either of the published papers.

"Understanding the transmission, storage and encoding of biological information is a critical goal, not only for basic science but also for transformative advances in regenerative medicine," Levin said. "In these two papers, Antony Jose masterfully applies a computer science approach to provide an overview and a quantitative analysis of possible molecular dynamics that could serve as a medium for heritable information."

Jose proposes that instructions not coded in the DNA are contained in the arrangement of the molecules within cells and their interactions with one another. This arrangement of molecules is preserved and passed down from one generation to the next.

In his papers, Jose's framework recasts inheritance as the combined effects of three components: entities, sensors and properties.

Entities include the genome and all the other molecules within a cell that are needed to build an organism. Entities can change over time, but they are recreated with their original structure, arrangement and interactions at the start of each generation.

"That aspect of heredity, that the arrangement of molecules is similar across generations, is deeply underappreciated, and it leads to all sorts of misunderstandings of how heredity works," Jose said.

Sensors are specific entities that interact with and respond to other entities or to their environment. Sensors respond to certain properties, such as the arrangement of a molecule, its concentration in the cell or its proximity to another molecule.

Together, entities, sensors and properties enable a living organism to sense or 'know' things about itself and its environment. Some of this knowledge is used along with the genome in every generation to build an organism.

"This framework is built on years of experimental research in many labs, including ours, on epigenetics and multi-generational gene silencing combined with our growing interest in theoretical biology," Jose said. "Given how two people who contract the same disease do not necessarily show the same symptoms, we really need to understand all the places where two people can be different--not just their genomes."

The folly of maintaining a genome-centric view of heredity, according to Jose, is that scientists may be missing opportunities to combat heritable diseases and to understand the secrets of evolution.

In medicine, for instance, research into why hereditary diseases affect individuals differently focuses on genetic differences and on chemical or physical differences in entities. But this new framework suggests researchers should be looking for non-genetic differences in the cells of individuals with hereditary diseases, such as the arrangement of molecules and their interactions. Scientists don't currently have methods to measure some of these things, so this work points to potentially important new avenues for research.

In evolution, Jose's framework suggests that organisms could evolve through changes in the arrangement of molecules without changes in their DNA sequence. And in conservation science, this work suggests that attempts to preserve endangered species through DNA banks alone are missing critical information stored in non-DNA molecules.

Jose acknowledged that there will be much debate about these ideas, and experiments are needed to test his hypotheses. But, he said, preliminary feedback from scientists like Levin and other colleagues has been positive.

"Antony Jose's generalization of memory and encoding via the entity-sensor-property framework sheds novel insights into evolution and biological complexity and suggests important revisions to existing paradigms in genetics, epigenetics and development," Levin said.

ABERDEEN PROVING GROUND, Md. -- The Army has a new type of multi-polymer filament for commonly-used desktop 3-D printers. This advance may save money and facilitate fast printing of critical parts at the point of need.

The research is also the cover story of the April edition of Advanced Engineering Materials, a monthly peer-reviewed scientific journal.

Parts produced with these printers historically have had poor strength and toughness, which prevented affordable printers from being used to resupply military parts on demand, especially at deployed locations, until now. The Army's new material overcomes those deficiencies, potentially allowing Soldiers to use low-cost printers to create parts that, once subjected to a few hours of heat, can achieve mechanical properties robust enough to withstand the rigors of field operations.

This breakthrough is an important step forward for Army expeditionary manufacturing, said Dr. Eric D. Wetzel, who leads the Emerging Composites team and serves as the research area leader for Soldier Materials at the U.S. Army Combat Capabilities Development Command's Army Research Laboratory.

Wetzel's research encompasses a wide range of technological solutions that could increase Soldier lethality by enhancing the way warfighters shoot, move, communicate, protect and sustain themselves.

"The Army would like to be able to print parts in the field to simplify logistics by carrying digital part files instead of physical parts, but to date, the technologies for producing high-strength parts have not been practical in an expeditionary setting. These printers are too large, energy-hungry, delicate or messy for starters, and their feedstocks can require specialized storage requirements."

This technology may enable the Army to use affordable, simple printers to produce high-quality parts.

According to the paper, fused filament fabrication or FFF, is the most common additive manufacturing technology, but parts fabricated using FFF lack sufficient mechanical integrity for most engineering applications.

The research team used a novel thermal draw process to fabricate a dual material filament comprising acrylonitrile butadiene styrene, known as ABS, with a star?shaped polycarbonate core.

This dual material filament is then used as feedstock in a conventional FFF printer to create 3-D solid bodies with a composite ABS/polycarbonate core meso?structure.

This novel DM filament can revolutionize additive manufacturing allowing low?cost printers to produce parts with mechanical properties competitive with injection?molded plastics, as referenced in the paper.

In ongoing experiments, the Army's research team is experimenting with new material pairings, print conditions and annealing protocols to further improve mechanical properties and reduce processing times. Their goal is to reduce current annealing times of 24-48 hours to four hours or less.

Researchers are using a pilot manufacturing line to produce larger quantities of the filament over the next few months to provide material samples to a variety of Army transition partners.

"Having the option to additively manufacture parts from a high strength polymer via the FFF process, at the field, division, and/or depot level will certainly provide warfighters with the ability to produce better temporary parts much quicker - hours versus days or weeks - and at significantly lower costs - often pennies compared to tens of dollars, said Jeff Wallace, a mechanical engineer with the Army's C5ISR Center at APG. "Additionally, Soldiers tend to improvise as needed, often finding their own design solutions to the issues they face. As such, offering them a higher strength polymer material that can be used in the desktop printers they have access to, affords them the opportunity to innovate on-the-fly, as necessary to temporarily solve greater numbers of supply and design challenges. Their designs would then be sent to the proper Engineering Support Activity for evaluation."

The lab has filed multiple patent applications on the technology, and a license has already been granted for one aspect of the technology: thermally drawn filaments using a specialty polymer for use in additive manufacturing. The Army is looking for additional commercial partners to accelerate development and fielding of this technology, which could hold broad applicability to a wide range of additively manufactured thermoplastic parts.

Inquiries regarding partnerships and licensing should be directed to Jason Craley, CCDC ARL Tech Transfer, (410) 306-1275.

Yehuda Shoenfeld is the world's leading expert in the research, treatment and prevention of autoimmune diseases. Professor Shoenfeld noted that the hyperferritinemic syndrome was thoroughly studied a while ago: 'We have already published the data on this clinical condition. In 50% of cases, patients with exceptionally high ferritin levels die. In fact, what we are witnessing at present with the new coronavirus infection is reminiscent of the situation with the hyperferritinemic syndrome.'

Ferritin is a major intracellular iron storage protein in all organisms. It binds free ions of the trace element, neutralising its toxic properties and increasing its solubility. In the soluble form, the body is able to expend iron as needed, in particular for regulation of cellular oxygen metabolism. Low ferritin levels result in lower iron concentrations and iron deficiency anaemia. Elevated levels of ferritin, or hyperferritinemia, indicate the presence of viruses and bacteria into the body. Hyperferritinemia can also be caused by a genetic mutation. In this case, it leads to neurological disorders and vision problems.

Recent studies by Italian scientists have shown that ferritin is able to activate macrophages. The latter are a type of white blood cell of the immune system that play a critical role in innate immunity, being the body's first line of defence.

This is evidenced by hyperferritinemia in patients with septic shock, catastrophic antiphospholipid syndrome, and other medical conditions characterised by macrophage activation. Similar observations have been reported by scientists from China and the United States.

'When activated, macrophages begin to secrete cytokines. These are a category of signalling molecules that mediate and regulate immunity. At low concentrations, they are safe for the body and help to protect it against viruses and bacteria. At high levels, the so called "cytokine storm" develops, which can be lethal for half of the patients, especially for the elderly,' explains Yehuda Shoenfeld. 'Thus, hyperferritinemia has been associated with increased illness severity and adverse outcomes, including COVID-19. Our task is to find a way to combat it.'

The scientist identified a further important indicator of macrophage activation and a high probability of complications. This is marker CD163. In the Laboratory of the Mosaic of Autoimmunity at St Petersburg University, the scientists are searching for a way to reduce circulating ferritin levels. In addition, they are studying possible methods of inhibiting the synthesis of CD163 and other macrophage signalling molecules using antibodies. Similar work is currently underway around the world.

Additionally, Professor Shoenfeld and his colleagues are working on a vaccine against COVID-19. The researchers are developing a method of using virus particles, surface proteins of the virus as the main components of the vaccine. Since these fragments cannot be found in the human body, they are not able to produce an undesirable immune response, which makes them promising candidates for the vaccine.

Researchers from Russia, the Netherlands, Sweden, and the U.S. have revealed the structure of the protein responsible for vitamin B12 import into the cells of the bacterium that causes tuberculosis. The research findings were published in Nature.

Vitamin B12, also known as cobalamin, is vital to the proliferation of Mycobacterium tuberculosis, which causes TB. But while that vitamin can be synthesized internally, it is much easier for the pathogen to import B12 from the environment, and cobalamin consumption by the bacterium is directly associated with TB progression.

However, no known B12 importer has been discovered in the pathogen's genome, only three cobalamin-associated proteins. While one of them -- Rv1819c -- was regarded as a candidate for B12 transport, the amino acid sequence analysis suggested that it likely functions in a different way: as an exporter.

The authors of the recent paper in Nature addressed this contradiction: They found that the protein is indeed capable of importing B12 and used single-particle cryo-electron microscopy to explain how it works.

The experiment involved a cell line of Escherichia coli, manipulated so as to lack any B12 transporters. Placed in a cobalamin-rich culture medium, the bacteria did not grow until the researchers endowed them with the Rv1819c protein from Mycobacterium tuberculosis, which made them proliferate. The team also used a mutated cell line to establish that the Rv1819c-mediated transport depends on ATP hydrolysis.

The team resolved the 3D structure of the protein. It consists of two unevenly sized interconnected chambers, with the larger one located in the cell membrane and the smaller one protruding on the inside. The region between the two chambers is narrow, constricted by a loop of 17 amino acids.

The large cavity has a volume of about 7.7 cubic nanometers, which is enough to accommodate six or seven vitamin B12 molecules. A cap seals off the chamber on the outside, perhaps opening spontaneously to capture molecules from the external environment. Since the cavity is inlaid with negatively charged and polar amino acids, it is attractive for hydrophilic molecules.

This explains why the Rv1819c transporter, despite not being very selective, was found to favor polar and positively charged substrates. For example, the scientists showed that besides B12, the protein can transport a cancer medication called bleomycin. At the same time, it did not work with biotin, probably due to the latter molecule bearing negatively charged groups.

The part of the protein inside the cell is sealed with a bivalved gate, which communicates with the sites where the cell generates energy by breaking down ATP molecules. Two of them have to be consumed to open the gate, which explains why Rv1819c-mediated transport is ATP-dependent.

Study co-author Albert Guskov, who heads the Laboratory of Structural Electron Microscopy of Biological Systems at the Moscow Institute of Physics and Technology, commented on the findings: "Our study takes us one step further in understanding how tuberculosis develops. We now know how the pathogen acquires vitamin B12, which is vital for it. Importantly, the mechanism we humans use to import cobalamin is very different, making Rv1819c an excellent target for developing anti-TB drugs."

"The discovery of this unexpected function of the protein that has been regarded as an exporter rather than an importer offers insights into the possible mechanisms of antibiotic delivery into pathogen cells," the researcher went on. "Aminoglycosides, for example, are positively charged, so they cannot freely penetrate the membrane. Previously, we only knew these drugs somehow got into the cell. We can now say that Rv1819c and similar proteins might well be the transporters involved."

The study featured researchers from the University of Groningen in the Netherlands, SLAC National Accelerator Laboratory and Stanford University in the U.S., and Stockholm University in Sweden.

Reef fish species uniquely respond to climate change, with some more vulnerable than others.

Five Great Barrier Reef fish species each activated different genetic responses to a marine heatwave in the Australian summer of 2015-16. This finding could help further understanding of climate change impacts on wild fish distributions.

"Scientists have extensively studied heatwave impacts on coral reefs because they are very sensitive to temperature and can easily bleach in warming conditions," says former KAUST postdoc, Moisés Bernal, now an assistant professor at Auburn University, USA. "Previous studies have measured the effects of heatwaves on fish as a side effect of coral bleaching. Our study is novel in that it applies molecular techniques to directly understand the mechanisms used by different fish to cope with elevated temperatures."

Bernal worked with international and KAUST colleagues to sequence RNA from the livers of fish species from reefs of Lizard Island, Australia. Samples were collected from fish before (December 2015), during (February and March 2016) and after (July 2016) the heatwave. The researchers aimed to find out which genes were turned on at different times during the heatwave in different fish species. Samples were taken from two damselfish species, the spiny chromis damselfish and the lemon damselfish, and from three cardinalfish species, the yellow-striped, Doederlein's and five-lined cardinalfish.

"Unexpectedly, we found that all species reacted differently, using different genes to respond to warming conditions," says former postdoc Celia Schunter, now at the University of Hong Kong. "There was an overlap, however, in the functions performed by these genes."

The team found, for example, that the spiny chromis damselfish had the largest number of differentially expressed genes (3000) across the four time points, while the five-lined cardinalfish had the smallest (992). All five species, however, had activated molecular pathways associated with increased oxygen uptake, the energy-generating electron transport chain in cells, and cellular stress responses.

"Another surprising result was that there were large differences in the genes that were activated in February and March," adds Schunter. "These two time points were separated by four weeks, but experienced similar temperatures, suggesting that both the intensity and duration of a heatwave are important for evaluating the responses of marine organisms."

The study's findings suggest that some species are more sensitive to climate change, while others are more resistant, possibly as a result of differences in their geographic ranges and evolutionary histories.

The study does, however, have some limitations. For example, the researchers did not have a baseline reference for liver gene expression in the five fish species from previous years. Also, the heatwave affected seasonal food availability, which could also influence gene expression.

Further studies could investigate how repeated heatwaves influence fish fitness and their long-term adaptation.

CAMBRIDGE, MA -- Researchers at MIT; the Ragon Institute of MGH, MIT, and Harvard; and the Broad Institute of MIT and Harvard; along with colleagues from around the world have identified specific types of cells that appear to be targets of the coronavirus that is causing the Covid-19 pandemic.

Using existing data on the RNA found in different types of cells, the researchers were able to search for cells that express the two proteins that help the SARS-CoV-19 virus enter human cells. They found subsets of cells in the lung, the nasal passages, and the intestine that express RNA for both of these proteins much more than other cells.

The researchers hope that their findings will help guide scientists who are working on developing new drug treatments or testing existing drugs that could be repurposed for treating Covid-19.

"Our goal is to get information out to the community and to share data as soon as is humanly possible, so that we can help accelerate ongoing efforts in the scientific and medical communities," says Alex K. Shalek, the Pfizer-Laubach Career Development Associate Professor of Chemistry, a core member of MIT's Institute for Medical Engineering and Science (IMES), an extramural member of the Koch Institute for Integrative Cancer Research, an associate member of the Ragon Institute, and an institute member at the Broad Institute.

Shalek and Jose Ordovas-Montanes, a former MIT postdoc who now runs his own lab at Boston Children's Hospital, are the senior authors of the study, which appears today in Cell. The paper's lead authors are MIT graduate students Carly Ziegler, Samuel Allon, and Sarah Nyquist; and Ian Mbano, a researcher at the Africa Health Research Institute in Durban, South Africa.

Digging into data

Not long after the SARS-CoV-2 outbreak began, scientists discovered that the viral "spike" protein binds to a receptor on human cells known as angiotensin-converting enzyme 2 (ACE2). Another human protein, an enzyme called TMPRSS2, helps to activate the coronavirus spike protein, to allow for cell entry. The combined binding and activation allows the virus to get into host cells.

"As soon as we realized that the role of these proteins had been biochemically confirmed, we started looking to see where those genes were in our existing datasets," Ordovas-Montanes says. "We were really in a good position to start to investigate which are the cells that this virus might actually target."

Shalek's lab, and many other labs around the world, have performed large-scale studies of tens of thousands of human, nonhuman primate, and mouse cells, in which they use single-cell RNA sequencing technology to determine which genes are turned on in a given cell type. Since last year, Nyquist has been building a database with partners at the Broad Institute to store a huge collection of these datasets in one place, allowing researchers to study potential roles for particular cells in a variety of infectious diseases.

Much of the data came from labs that belong to the Human Cell Atlas project, whose goal is to catalog the distinctive patterns of gene activity for every cell type in the human body. The datasets that the MIT team used for this study included hundreds of cell types from the lungs, nasal passages, and intestine. The researchers chose those organs for the Covid-19 study because previous evidence had indicated that the virus can infect each of them. They then compared their results to cell types from unaffected organs.

"Because we have this incredible repository of information, we were able to begin to look at what would be likely target cells for infection," Shalek says. "Even though these datasets weren't designed specifically to study Covid, it's hopefully given us a jump start on identifying some of the things that might be relevant there."

In the nasal passages, the researchers found that goblet secretory cells, which produce mucus, express RNAs for both of the proteins that SARS-CoV-2 uses to infect cells. In the lungs, they found the RNAs for these proteins mainly in cells called type II pneumocytes. These cells line the alveoli (air sacs) of the lungs and are responsible for keeping them open.

In the intestine, they found that cells called absorptive enterocytes, which are responsible for the absorption of some nutrients, express the RNAs for these two proteins more than any other intestinal cell type.

"This may not be the full story, but it definitely paints a much more precise picture than where the field stood before," Ordovas-Montanes says. "Now we can say with some level of confidence that these receptors are expressed on these specific cells in these tissues."

Fighting infection

In their data, the researchers also saw a surprising phenomenon -- expression of the ACE2 gene appeared to be correlated with activation of genes that are known to be turned on by interferon, a protein that the body produces in response to viral infection. To explore this further, the researchers performed new experiments in which they treated cells that line the airway with interferon, and they discovered that the treatment did indeed turn on the ACE2 gene.

Interferon helps to fight off infection by interfering with viral replication and helping to activate immune cells. It also turns on a distinctive set of genes that help cells fight off infection. Previous studies have suggested that ACE2 plays a role in helping lung cells to tolerate damage, but this is the first time that ACE2 has been connected with the interferon response.

The finding suggests that coronaviruses may have evolved to take advantage of host cells' natural defenses, hijacking some proteins for their own use.

"This isn't the only example of that," Ordovas-Montanes says. "There are other examples of coronaviruses and other viruses that actually target interferon-stimulated genes as ways of getting into cells. In a way, it's the most reliable response of the host."

Because interferon has so many beneficial effects against viral infection, it is sometimes used to treat infections such as hepatitis B and hepatitis C. The findings of the MIT team suggest that interferon's potential role in fighting Covid-19 may be complex. On one hand, it can stimulate genes that fight off infection or help cells survive damage, but on the other hand, it may provide extra targets that help the virus infect more cells.

"It's hard to make any broad conclusions about the role of interferon against this virus. The only way we'll begin to understand that is through carefully controlled clinical trials," Shalek says. "What we are trying to do is put information out there, because there are so many rapid clinical responses that people are making. We're trying to make them aware of things that might be relevant."

BROOKLYN, New York, Wednesday, April 22, 2020 – A newly discovered connection between control theory and network dynamical systems could help estimate the size of a network even when a small portion is accessible.

Understanding the spread of coronavirus may be the most alarming and recent example of a problem that could benefit from a fuller knowledge of network dynamical systems, but scientists and mathematicians have been grappling for years with ways to draw accurate inferences about these complex systems by working with partial data from available measurements.

In a new Physical Review Letters paper, New York University Tandon School of Engineering Institute Professor Maurizio Porfiri demonstrates a profound connection between mathematical control theory and the problem of determining the size of a network dynamical system from the time series of some accessible units. For homogeneous networks — in which every unit plays the same — accessing a mere 10% of the units could be sufficient to exactly infer the size of the entire network, Porfiri concludes.

But the same approach fails for heterogeneous networks, which are far more common in the field of complex systems: Think of the early stage of the novel coronavirus outbreak, in which every person experienced a widely different range of contacts due to their social and professional lives. Hence, the author recommends prudence in the inference of the size of a network dynamical system from available measurements when information on the nature of the network is lacking.

“From natural to technological settings, network dynamical systems constitute a powerful approach to study collective dynamics. The size of the system is arguably its most fundamental property, but seldom do we have access to such critical information,” Porfiri explained. His research provides mathematical proof for a model-free approach published last year by researchers from the University of Oldenberg and the Technical University of Dresden.

Porfiri holds appointments in NYU Tandon’s Departments of Mechanical and Aerospace Engineering; Biomedical Engineering; and Civil and Urban Engineering, as well as its Center for Urban Science and Progress.

“Validity and Limitations of the Detection Matrix to Determine Hidden Units and Network Size from Perceptible Dynamics” is available at journals.aps.org. The National Science Foundation funded the research.

About the New York University Tandon School of Engineering

The NYU Tandon School of Engineering dates to 1854, the founding date for both the New York University School of Civil Engineering and Architecture and the Brooklyn Collegiate and Polytechnic Institute (widely known as Brooklyn Poly). A January 2014 merger created a comprehensive school of education and research in engineering and applied sciences, rooted in a tradition of invention and entrepreneurship and dedicated to furthering technology in service to society. In addition to its main location in Brooklyn, NYU Tandon collaborates with other schools within NYU, one of the country’s foremost private research universities, and is closely connected to engineering programs at NYU Abu Dhabi and NYU Shanghai. It operates Future Labs focused on start-up businesses in Brooklyn and an award-winning online graduate program. For more information, visit engineering.nyu.edu.

Journal

Physical Review Letters

DOI

10.1103/PhysRevLett.124.168301

New calculations by HSE University researchers show that technological growth passed its peak in the early 21st century and will soon obtain new acceleration, although it will be followed by a new slowdown in the second half of the century. The researchers believe these progress rate fluctuations are largely due to a global demographic transition--the ageing of the planet's population, which many developed countries have already faced.

The history of civilization, particularly in recent centuries, can be considered a history of science and technology achievements--above all in information technology. This is why modelling the long-term trends of technology progress is so important.

Andrey Korotayev of HSE University together with his peers from the RAS Institute of Oriental Studies in Moscow and the MPGU [Moscow Pedagogical State University] Institute of Education in Social Sciences and Humanities undertook a quantitative analysis of the long-term dynamics of technological progress from 40,000 BC and offered projections through the 22nd century.

The authors based their research on the theory of production principles, which outlines three super-long cycles in the human history, each of which is characterized by a technology revolution:

Agricultural (or Neolithic), which happened sometime between 12,000 BC and 3,000 BC;

Industrial, which took place between the last third of the 15th century and the first third of the 19th century;

Cybernetic, which started in the 1950s and will end approximately in 2060-70.

Each of these cycles is described by a hyperbolic curve with exponential acceleration. At a certain moment, it reaches its peak--a singularity--which is interpreted by many as an exit point at infinity. Some futurologists believe that for humanity, this point will literally mean the loss of human control over progress.

However, Korotayev and colleagues believe that such an interpretation is incorrect and that the peak will be followed by a decline. Their calculations demonstrate that in fact, in the current, second stage of our cybernetic revolution a singularity already occurred in 2018.

But soon enough, in 2030, progress is expecting a new wave of acceleration, the third stage of the cybernetic revolution, which may become an era of 'smart' self-regulating systems. In the fourth stage, in 2055, these systems will start improving rapidly and will occupy a central position in the new production process. Medicine will be at its forefront.

The key driver of technology growth will be the structural change inherent in the ageing of the global population, which is also called the 'third demographic transition'. Acceleration at this moment will be similar to that of the 1950s and 1960s.

The Gerontological Society of America's highly cited, peer-reviewed journals are now publishing scientific articles on COVID-19. The following were published between March 31 and April 20; all are free to access:

COVID-19 through the lens of gerontology: Editorial in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences by David G. Le Couteur, MBBS, PhD, Rozalyn M. Anderson, PhD, and Anne B. Newman, MD, MPH

Aging in Times of the COVID-19 Pandemic: Avoiding Ageism and Fostering Intergenerational Solidarity: Editorial in The Journals of Gerontology, Series B: Psychological Sciences and Social Sciences by Liat Ayalon, PhD, Alison Chasteen, PhD, Manfred Diehl, PhD, Becca Levy, PhD, Shevaun D. Neupert, PhD, Klaus Rothermund, PhD, Clemens Tesch-Römer, PhD, and Hans-Werner Wahl, PhD

A geroscience perspective on COVID-19 mortality [https://doi.org/10.1093/gerona/glaa094]: Research/brief report in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences by Daniel E.L. Promislow, DPhil

"We're staying at home." Association of self-perceptions of aging, personal and family resources and loneliness with psychological distress during the lock-down period of COVID-19: Research report in The Journals of Gerontology, Series B: Psychological Sciences and Social Sciences by Andrés Losada-Baltar, PhD, Lucía Jiménez-Gonzalo, MA, Laura Gallego-Alberto, PhD, María del Sequeros Pedroso-Chaparro, MA, José Fernandes-Pires, MA, and María Márquez-González, PhD

Clinical characteristics and outcomes of older patients with coronavirus disease 2019 (COVID-19) in Wuhan, China (2019)[https://doi.org/10.1093/gerona/glaa089]: Research article in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences by TieLong Chen, MD, Zhe Dai, MD, Pingzheng Mo, MD, Xinyu Li, MD, Zhiyong Ma, MD, Shihui Song, MD, Xiaoping Chen, MD, Mingqi Luo, MD, Ke Liang, MD, Shicheng Gao, MD, Yongxi Zhang, MD, Liping Deng, MD, and Yong Xiong, MD

The Impact of the COVID-19 Pandemic on Disabled and Hospice Home Care Patients: Letter to the editor in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences by Tzyy-Guey Tseng, MD, Hui-Ling Wu, Hui-Chuan Ku, Chi-Jung Tai, MD

Assessing the impact of the covid-19 pandemic and accompanying mitigation efforts on older adults: Letter to the editor in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences by Peggy Cawthon, MPH, PHD, Eric Orwoll, MD, Kristine Ensrud, MD, Jane A. Cauley, DrPH, Stephen B. Kritchevsky, PhD, Steven R. Cummings, MD, and Anne B. Newman, MD

New preventative measures against coronavirus disease 2019 for home care aides in Taiwan: Letter to the editor in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences by Cheng-Chie Weng, MD, Yueh-Er Lin, Yu-Chin Lin, and Wei Chen, MD, PhD

The Gerontological Society of America (GSA) is the nation's oldest and largest interdisciplinary organization devoted to research, education, and practice in the field of aging. The principal mission of the Society -- and its 5,500+ members -- is to advance the study of aging and disseminate information among scientists, decision makers, and the general public. GSA's structure also includes a policy institute, the National Academy on an Aging Society, and an educational section, the Academy for Gerontology in Higher Education.