Culture

CAMBRIDGE, MA -- Twenty years ago this month, the first draft of the human genome was publicly released. One of the major surprises that came from that project was the revelation that only 1.5 percent of the human genome consists of protein-coding genes.

Over the past two decades, it has become apparent that those noncoding stretches of DNA, originally thought to be "junk DNA," play critical roles in development and gene regulation. In a new study published today, a team of researchers from MIT has published the most comprehensive map yet of this noncoding DNA.

This map provides in-depth annotation of epigenomic marks -- modifications indicating which genes are turned on or off in different types of cells -- across 833 tissues and cell types, a significant increase over what has been covered before. The researchers also identified groups of regulatory elements that control specific biological programs, and they uncovered candidate mechanisms of action for about 30,000 genetic variants linked to 540 specific traits.

"What we're delivering is really the circuitry of the human genome. Twenty years later, we not only have the genes, we not only have the noncoding annotations, but we have the modules, the upstream regulators, the downstream targets, the disease variants, and the interpretation of these disease variants," says Manolis Kellis, a professor of computer science, a member of MIT's Computer Science and Artificial Intelligence Laboratory and of the Broad Institute of MIT and Harvard, and the senior author of the new study.

MIT graduate student Carles Boix is the lead author of the paper, which appears today in Nature. Other authors of the paper are MIT graduate students Benjamin James and former MIT postdocs Yongjin Park and Wouter Meuleman, who are now principal investigators at the University of British Columbia and the Altius Institute for Biomedical Sciences, respectively. The researchers have made all of their data publicly available for the broader scientific community to use.

Epigenomic control

Layered atop the human genome -- the sequence of nucleotides that makes up the genetic code -- is the epigenome. The epigenome consists of chemical marks that help determine which genes are expressed at different times, and in different cells. These marks include histone modifications, DNA methylation, and how accessible a given stretch of DNA is.

"Epigenomics directly reads the marks used by our cells to remember what to turn on and what to turn off in every cell type, and in every tissue of our body. They act as post-it notes, highlighters, and underlining," Kellis says. "Epigenomics allows us to peek at what each cell marked as important in every cell type, and thus understand how the genome actually functions."

Mapping these epigenomic annotations can reveal genetic control elements, and the cell types in which different elements are active. These control elements can be grouped into clusters or modules that function together to control specific biological functions. Some of these elements are enhancers, which are bound by proteins that activate gene expression, while others are repressors that turn genes off.

The new map, EpiMap (Epigenome Integration across Multiple Annotation Projects), builds on and combines data from several large-scale mapping consortia, including ENCODE, Roadmap Epigenomics, and Genomics of Gene Regulation.

The researchers assembled a total of 833 biosamples, representing diverse tissues and cell types, each of which was mapped with a slightly different subset of epigenomic marks, making it difficult to fully integrate data across the multiple consortia. They then filled in the missing datasets, by combining available data for similar marks and biosamples, and used the resulting compendium of 10,000 marks across 833 biosamples to study gene regulation and human disease.

The researchers annotated more than 2 million enhancer sites, covering only 0.8 percent of each biosample, and collectively 13 percent of the genome. They grouped them into 300 modules based on their activity patterns, and linked them to the biological processes they control, the regulators that control them, and the short sequence motifs that mediate this control. The researchers also predicted 3.3 million links between control elements and the genes that they target based on their coordinated activity patterns, representing the most complete circuitry of the human genome to date.

Disease links

Since the final draft of the human genome was completed in 2003, researchers have performed thousands of genome-wide association studies (GWAS), revealing common genetic variants that predispose their carriers to a particular trait or disease.

These studies have yielded about 120,000 variants, but only 7 percent of these are located within protein-coding genes, leaving 93 percent that lie in regions of noncoding DNA.

How noncoding variants act is extremely difficult to resolve, however, for many reasons. First, genetic variants are inherited in blocks, making it difficult to pinpoint causal variants among dozens of variants in each disease-associated region. Moreover, noncoding variants can act at large distances, sometimes millions of nucleotides away, making it difficult to find their target gene of action. They are also extremely dynamic, making it difficult to know which tissue they act in. Lastly, understanding their upstream regulators remains an unsolved problem.

In this study, the researchers were able to address these questions and provide candidate mechanistic insights for more than 30,000 of these noncoding GWAS variants. The researchers found that variants associated with the same trait tended to be enriched in specific tissues that are biologically relevant to the trait. For example, genetic variants linked to intelligence were found to be in noncoding regions active in the brain, while variants associated with cholesterol level are in regions active in the liver.

The researchers also showed that some traits or diseases are affected by enhancers active in many different tissue types. For example, they found that genetic variants associated with coronary heart disease (CAD) were active in adipose tissue, coronary arteries, and the liver, among many other tissues.

Kellis' lab is now working with diverse collaborators to pursue their leads in specific diseases, guided by these genome-wide predictions. They are profiling heart tissue from patients with coronary artery disease, microglia from Alzheimer's patients, and muscle, adipose, and blood from obesity patients, which are predicted mediators of these disease based on the current paper, and his lab's previous work.

Many other labs are already using the EpiMap data to pursue studies of diverse diseases. "We hope that our predictions will be used broadly in industry and in academia to help elucidate genetic variants and their mechanisms of action, help target therapies to the most promising targets, and help accelerate drug development for many disorders," Kellis says.

A new technique has taken the first images of muon particle beams. Nagoya University scientists designed the imaging technique with colleagues in Osaka University and KEK, Japan and describe it in the journal Scientific Reports. They plan to use it to assess the quality of these beams, which are being used more and more in advanced imaging applications.

Muons are charged particles that are 207 times the mass of electrons. They naturally form when cosmic rays strike atoms in the upper atmosphere, showering down onto every part of Earth's surface. They can penetrate through hundreds of meters of solids before being absorbed.

Scientists have used naturally occurring muon particles as a way to peek through huge solid structures. For example, in 2017 scientists announced they had found a hidden chamber inside the Khufu Pyramid of Giza by comparing the muon intensities measured by detectors located inside and outside the pyramid. Particle accelerator facilities can now also generate muon beams, which are used in a variety of applications, like non-destructive X-ray fluorescence spectroscopy. Muon beams are also expected to be adapted for cancer radiotherapy.

Nagoya University biomedical nuclear scientist Seiichi Yamamoto and colleagues developed a new imaging technique that they say shows promise for quality assessment and research of muon beams, and should be of benefit for muon radiotherapy in the future.

The technique depends on a phenomenon that occurs when charged particles travel through transparent media, like water. Water slows light down relative to high-energy particles. Particles moving faster than light cause something similar to the sonic boom we hear when a jet plane breaks through the sound barrier. In the case of the particles, an 'optical boom', called the Cherenkov effect, causes a brief flash.

Yamamoto and his colleagues imaged this effect with a special camera when a muon beam was directed through water or a plastic scintillator block. The technique allowed them to image muons and the positrons that form when muons decay. This helped them measure the beam's range through the water or plastic scintillator, and the deviation of its momentum, as well as clarify the direction of positron movement.

"The system is compact, low cost and easy to use, showing promise as a tool for quality assessment in muon beam facilities," says Yamamoto.

After the Chernobyl disaster of 1986, the 2011 Fukushima Daiichi nuclear power plant (FDNPP) disaster was the second worst nuclear incident in history. Its consequences were tremendous for the Japanese people and now, almost a decade later, they can still be felt both there and in the rest of the world. One of the main consequences of the event is the release of large amounts of cesium-137 (137Cs)--a radioactive "isotope" of cesium--into the atmosphere, which spread farther away from the power plant through wind and rainfall.

Considering the massive threat posed by 137Cs to the health of both humans and ecosystems, it is essential to understand how it has distributed and how much of it still lingers. This is why the International Atomic Energy Agency (IAEA) has recently published a technical document on this specific issue. The fifth chapter of this "Technical Document (TECDOC)," titled "Forest ecosystems," contains an extensive review and analysis of existing data on 137Cs levels in Fukushima prefecture's forests following the FDNPP disaster.

The chapter is based on an extensive study led by Assoc. Prof. Shoji Hashimoto from the Forestry and Forestry Products Research Institute, Japan, alongside Dr. Hiroaki Kato from the University of Tsukuba, Japan, Kazuya Nishina from the National Institute of Environmental Studies, Japan, Keiko Tagami from the National Institutes for Quantum and Radiological Science and Technology, Japan, George Shaw from the University of Nottingham, UK, and Yves Thiry from the National Agency for Radioactive Waste Management (ANDRA), France, and several other experts in Japan and Europe.

The main objective of the researchers was to gain a better understanding of the dynamics of 137Cs flow in forests. The process is far from straightforward, as there are multiple elements and variables to consider. First, a portion of 137Cs-containing rainfall is intercepted by trees, some of which is absorbed, and the rest eventually washes down onto the forest floor. There, a fraction of the radiocesium absorbs into forest litter and the remainder flows into the various soil and mineral layers below. Finally, trees, other plants, and mushrooms incorporate 137Cs through their roots and mycelia, respectively, ultimately making it both into edible products harvested from Fukushima and wild animals.

Considering the complexity of 137Cs flux dynamics, a huge number of field surveys and gatherings of varied data had to be conducted, as well as subsequent theoretical and statistical analyses. Fortunately, the response from the government and academia was considerably faster and more thorough after the FDNPP disaster than in the Chernobyl disaster, as Hashimoto explains: "After the Chernobyl accidents, studies were very limited due to the scarce information provided by the Soviet Union. In contrast, the timely studies in Fukushima have allowed us to capture the early phases of 137Cs flow dynamics; this allowed us to provide the first wholistic understanding of this process in forests in Fukushima."

Understanding how long radionuclides like 137Cs can remain in ecosystems and how far they can spread is essential to implement policies to protect people from radiation in Fukushima-sourced food and wood. In addition, the article also explores the effectiveness of using potassium-containing fertilizers to prevent the uptake of 137Cs in plants. "The compilation of data, parameters, and analyses we present in our chapter will be helpful for forest remediation both in Japan and the rest of the world," remarks Hashimoto.

When preventive measures fail, the only remaining option is trying to fix the damage done--in the case of radiation control, this is only possible with a comprehensive understanding of the interplay of factors involved.

In this manner, this new chapter will hopefully lead to both timely research and more effective solutions should a nuclear disaster happen again.

Tampa, FL (Feb. 3, 2021) -- A preclinical study by a University of South Florida Health (USF Health) Morsani College of Medicine research team has discovered a new mechanism for how Zika virus can pass from mothers to their children during pregnancy - a process known as vertical transmission.

The researchers showed, for the first time, that specialized cells lining the uterus (maternal decidual cells) act as reservoirs for trimester-dependent transmission of the virus through the placenta - accounting for both the fetus's greater susceptibility to first-trimester Zika infection and for the more serious congenital defects observed in early versus late pregnancy. They also report that the agent tizoxanide inhibits ZIKA virus in maternal decidual cells grown in the lab, offering promise for preventing perinatal transmission that can cause devastating malformations and brain damage in developing fetuses and infants.

The findings appeared Dec. 1, 2020 in the Journal of Immunology.

The study was led by co-principal investigators Ozlem Guzeloglu-Kayisli, PhD, a USF Health associate professor of obstetrics and gynecology, and Charles J. Lockwood, MD, USF Health senior vice president, dean of the Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine.

"If we can better understand Zika virus vertical transmission and successfully block infection in maternal (decidual) cells early in the pregnancy, the virus will not pass through the placenta to reach the fetus and it is less likely to cause severe abnormalities," said Guzeloglu-Kayisli, the paper's lead author.

The widespread global alarm caused by the spread of mosquito-borne Zika virus throughout the Americas in 2015-2016 dissipated after the virus all but disappeared in 2017. Yet, resurgence remains possible in areas where the Aedes aegypti mosquito is prevalent, and there is no treatment or vaccine available for Zika virus infection.

While most Zika-infected adults show no symptoms, the virus can cause minor flu-like symptoms, and in rare cases has been associated with Guillain-Barre syndrome. However, Zika poses the most concern for pregnant women, because up to one in 10 newborns of affected mothers suffer Zika-associated birth defects, including smaller than normal head size (microcephaly) that can lead to developmental disabilities and other health problems. Zika has also been linked to pregnancy complications, including preterm birth, preeclampsia and miscarriage. Moreover, timing appears important. Mothers infected in the first trimester are much more likely to have babies with severe Zika birth defects than mothers infected in the third semester.

The placenta, the organ supplying maternal oxygen and nutrients to the growing fetus, has ways to prevent most pathogens, including viruses, from crossing its protective maternal-fetal barrier. A subtype of fetally-derived placental cells known as syncytiotrophoblasts, in direct contact with maternal blood, are assumed to be the site where the Zika virus enters the placenta, leading to potential fetal infection. However, Dr. Ozlem Guzeloglu-Kayisli said, these particular trophoblasts resist Zika virus attachment and replication.

To learn more about how Zika gets through the placental wall, the USF Health team began by investigating the cellular and molecular mediators of Zika virus replication. Among their key findings, the researchers:

- Showed that specialized uterine cells from both pregnant and nonpregnant women were highly infectable by Zika virus. These immunologically active decidual cells, which line the uterus in preparation for and during pregnancy, form the maternal part of the placenta closest to the fetus.

- Identified a more than 10,000-fold higher expression of the Zika virus attachment-entry receptor in the maternal decidual cells than in the fetal trophoblasts. Once inside the maternal cells, the Zika virus (an RNA virus) hijacks the cellular machinery to make proteins needed to copy its genetic material and churn out new viral particles. The proliferation of viral particles released from the maternal cells are then transmitted through branch-like vascular projections (villi) on the placenta's surface layer where they can infect fetal trophoblast cells otherwise resistant to Zika virus.

- Found that the efficiency of viral replication was significantly greater in first-trimester decidual cells than in those from term pregnancies.

- Concluded that maternal (decidual) cells likely serve as the source for initial Zika virus infection and enhance subsequent transmission through the placenta to the fetus. "Moreover, trimester-dependent responses of decidual cells to Zika virus help to explain why pregnant women are susceptible to Zika infection and why the subsequent effects are more detrimental in the first trimester than in late pregnancy," the study authors wrote.

- Demonstrated that tizoxanide, the active metabolite of FDA-approved antiparasitic drug nitazoxanide, effectively impeded Zika virus infection in both maternal decidual cells and fetal trophoblast cells. The drug has been shown preclinically to inhibit a broad range of flu-like viruses and is being tested clinically against coronavirus. The finding warrants further testing of tizoxanide to block perinatal transmission of Zika virus and thereby protect the fetus from harmful outcomes, the researchers conclude.

The SARS-CoV-2, the new coronavirus behind the current pandemic, infects humans by binding its surface-exposed spike proteins to ACE2 receptors exposed on the cell membranes.

Upon a vaccination or a real infection, it takes several weeks before the immunity develops antibodies that can selectively bind to these spike proteins. Such antibody-labeled viruses are neutralized by the natural killer and T cells operated by the human immunity.

An alternative approach to train the immunity response is offered by researchers at the University of Illinois Chicago and California State University at Sacramento who have developed a novel strategy that redirects antibodies for other diseases existing in humans to the spike proteins of SARS-CoV-2.

In their study published by the Journal of Physical Chemistry Letters, the team proposes using peptide-based double-faced "booster" inhibitors, with one face binding to the spike proteins of SARS-CoV-2 and the other face binding to generic hepatitis B antibodies.

"Once the SARS-CoV-2 viruses become labeled by the hepatitis B antibodies via intermediate boosters, the viruses will be neutralized. This universal approach allows a dramatic shortening of the response time upon real infections, which can be critical in certain patients or conditions," said Petr Král, UIC professor of chemistry, physics, pharmaceutical sciences and chemical engineering, and senior author on the paper.

Král and Yanxiao Han, who recently earned a Ph.D. in chemistry at UIC and is first author on the paper, believe the study could provide guidance in the preparation of generic therapeutics against emerging pathogens with the combined advantages of small-protein and antibody therapies.

"The dramatic impact which novel viruses can have on humans could be fast mitigated in the absence of their vaccination if generic antibodies present within them are temporarily retrained to recognize these viruses," the researchers wrote.

In a study published last spring, Král and Han extracted different peptides from ACE2 that interact directly with the viral spike protein.

"We investigated potential COVID-19 therapeutics using computer simulations based on the X-ray crystal structure of the receptor-binding domain of SARS-CoV-2 when it is bound to ACE2," Král said. "Similar to our latest study, identifying these kinds of inhibitors could lead to new treatments to combat the coronavirus."

A higher diversity of flowering plants increases the breeding success of wild bees and may help compensate for the negative effects of insecticides. This is what researchers from the Universities of Göttingen and Hohenheim, as well as the Julius Kühn Institute, have found in a large-scale experimental study. The results have been published in the scientific journal Ecology Letters.

In their experiment, the researchers investigated how successfully the wild bee Osmia bicornis (red mason bee) reproduced. Red mason bees are important for both ecological and economic reasons. The wild bees were experimentally kept in more than 50 large enclosure cages with flower mixtures of varying wild plant diversity and insecticide-treated oilseed rape. Subsequently, the reproductive success of the wild bees, as measured by the number of their brood cells and emerged offspring, was investigated over several months.

The research team found that the number of cells that the wild bees created for their offspring where species-rich flowering mixtures were available was twice that of wild bees where only oilseed rape was available. The reproductive success of the wild bees, which have to supply their offspring with pollen and nectar, increased both in cages with a large diversity of flowering plants and where there were particularly important plant species. In contrast, if oilseed rape treated with clothianidin (from the neonicotinoid class of insecticides), was available to the bees, this had a negative effect on their reproductive success. However, this negative effect of the insecticide only occurred in cages with oilseed rape monocultures, which suggests that such effects can be mitigated by alternative food resources from species-rich flowering mixtures.

The study shows that both the diversity of flowering plants and exposure to insecticides significantly influence the reproductive success of wild bees, and shows that a high diversity of flowering plants could compensate for the negative effects of insecticides. "One possible explanation is that bee larvae benefit from additional nutrients, and are exposed to fewer insecticides, when the pollen of other plant species besides oilseed rape is available to them," explains Felix Klaus, first author of the study and PhD student in the Agroecology Group at Göttingen University. "Our results emphasise the important role of species-rich resources of flowers for wild bees," adds Professor Ingo Grass, head of the Department of Ecology of Tropical Agricultural Systems at the University of Hohenheim. "If sufficiently diverse flowers are available in the agricultural landscape, this could counteract the negative effects of monocultures and insecticides," says Professor Teja Tscharntke, Head of the Agroecology Group at Göttingen University.

Researchers in Costa Rica have found that some bacteria on the skin of amphibians prevent growth of the fungus responsible for what has been dubbed 'the amphibian apocalypse'.

Published in the journal Microbiology, the research identified a number of bacteria which could growth of the fungus Batrachochytrium dendrobatidis (Bd). One particularly dangerous strain of the fungus, called BdGPL-2, is responsible for mass amphibian die-offs around the world.

The fungus infects the skin of amphibians, breaking down the cells. As amphibians breathe and regulate water through their skin, infection is often deadly. It is believed that almost 700 species of amphibian are vulnerable to the fungus, and Bd has led to the extinction of 90 amphibian species.

In order to investigate why some amphibian populations in Costa Rica were more resilient to Bd that others, a research group led by Dr Adrian Pinto, Professor at the University of Costa Rica sampled the circulating strains of Bd and the skin microbiome of amphibians at different sites.

To do this, the research group collected wild amphibians from areas of Costa Rica which had a history of Bd outbreaks. "Bd has previously been widely detected in Costa Rica, but this is the first study to isolate and compare the characteristics of different isolates," said Dr Pinto, "our work showed that the circulating strains of the pathogenic fungus belong to a highly virulent global strain known as BdGPL-2."

They found that the bacteria on the skin of some surviving amphibians prevented growth of the fungus in the lab. "Amphibian species that survived decline harbor bacteria on their skin capable of inhibiting the growth of the pathogen. However, this inhibitory capacity varies according to which strain of the fungus is being tested," said Dr Pinto. "These findings suggest that locally adapted skin bacteria may offer protection from the disease."

Although the researchers expected to see the highly virulent strain BdGPL-2 in Costa Rica, they did not expect to see so much variation in circulating strains. "We were surprised of the phenotypic variations among the pathogen isolates, including their different responses to the antagonistic bacteria," said Dr Pinto. "Local pathogen adaptations must be considered when designing mitigation strategies for this disease."

Dr Pinto hopes to combine their findings with other disease control strategies to protect amphibian populations from decimation by Bd: "We will further study the ability of skin bacteria to protect amphibians against disease, as another tool to combat this plague alongside the creation of climate shelters and fostering the amphibians' own immune system," he said.

Costa Rica is one of the countries that suffered a dramatic loss of amphibian species between the 1980 and 1990. In Costa Rica, there are currently 64 species of amphibians in some risk category according to the International Union for the Conservation of Nature. Species classified as critically endangered include the Holdridge's Toad (Incilius holdridgei), a native species found only in the mountain ranges of the central region; The Variable Harlequin Frog (Atelopus varius), a river species very sensitive to Bd, and several species of river tree frogs of the genus Isthmohyla that live in cold currents in high areas, a habitat where Bd proliferates successfully.

Amphibians are one of the most diverse groups in the tropics and represent crucial links in food webs. Protecting them keeps ecosystems healthy since biological diversity is the basis for resilient forests, thus helping control pests and zoonotic infections.

A group of scientists led by Drs Toshinori Kinoshita and Maoxing Zhang (Institute of Transformative Bio-Molecules,Nagoya University, Japan) and Dr Yiyong Zhu (Jiangsu Collaborative Innovation Center for Solid Organic Waste Utilization, Nanjing Agricultural University, China) have developed a method which, by increasing the number of a plasma membrane proton pump gene in rice, simultaneously increases nutrient uptake through the roots and stomatal opening, thus increasing the yield of paddy field grown rice by over 30%.

In their previous research, the group had found that the plasma membrane proton pump played an important role in influencing stomatal opening. When they created a variant of rice with an overexpression of a particular plasma membrane proton pump gene, they found that nutrient uptake through the roots increased by over 20%, and photosynthesis by over 20%. Growth experiments at four separate rice farms with different growth conditions showed an increase in overall rice yield of over 30%. The success of this research is a groundbreaking achievement, with its simultaneous effect upon nutrient uptake and stomatal opening, and is expected to see a variety of practical uses in the future.

As they take in mineral nutrients such as nitrogen, phosphorous and potassium through their roots, plants simultaneously absorb carbon dioxide through the stomata on their leaves, and grow through photosynthesis. Photosynthesis enables not only the farming of plants for food, but the exchange of carbon dioxide and management of the earth's environment. CO2 intake in plants occurs exclusively through the stomata, which are holes on the surface of the leaves. Thus, if it were possible to open the stomata wider, increase the nutrient uptake through the roots, and thus increase the rate of photosynthesis, not only would it be possible to speed up growth and increase yield of plants, but also to reduce CO2 levels and the use of fertilizers.

With that in mind, in this study, they created a variant of the rice plant with an increased expression of the plasma membrane proton pump gene OSA1 and carried out an analysis of its phenotype. They found that the proton pump overexpressed rice, when compared to a wild strain, took up over 20% more mineral nutrients, and opened its stomata over 25% wider when exposed to light (Figure 2). On further analysis, they found that its carbon dioxide storage capacity (the indicator of photosynthesis activity) was increased by over 25%, and that its dry weight (biomass) increased by 18-33% in hydroponic laboratory growth.

With this determined, the researchers set out to find if the results could be replicated under realistic growing conditions. They conducted yield measurement exercises at four separate rice farms over the course of two years, finding that the rice with the overexpressed OSA1 gene had a yield over 30% higher than that of the wild strain. Even more interestingly, they discovered that even if the level of nitrogen fertilizer was reduced by half, it still produced a greater yield than the wild strain did with normal levels of nitrogen.

The success of this revolutionary piece of research points to a future in which food supply and CO2 overproduction issues can be solved through use of these proton pump gene overexpression plants. While these early stage models have been created through genetic modification, it is anticipated that future generations not reliant on GM but instead using genome editing or chemical engineering will be realized.

Modern-day robots are often required to interact with humans intelligently and efficiently, which can be enabled by providing them the ability to perceive touch. However, previous attempts at mimicking human skin have involved bulky and complex electronics, wiring, and a risk of damage. In a recent study, researchers from Japan sidestep these difficulties by constructing a 3D vision-guided artificial skin that enables tactile sensing with high performance, opening doors to innumerable applications in medicine, healthcare, and industry.

Robots have come a long way since their original inception for high-speed automation. Today, robots can be found in a wide variety of roles in medicine, rehabilitation, agriculture, and marine navigation. Since a lot of these roles require human contact, robots are expected to become adept at interacting with humans in a safe and intelligent manner.

One way to accomplish this goal is by endowing robots with the ability to perceive touch. Accordingly, attempts have been made to develop artificial "skins" capable of inducing tactile sensations and allowing robots to be more aware of their surrounding environment, in the same way humans are. However, despite great advances in tactile sensor technology, the endeavor remains challenging. "The main challenge lies in mimicking the inherent complexity of natural skin structure that has a particularly high density of mechanoreceptors with specialized functions such as sensing pressure, vibrations, temperature, and pain," says Associate Professor Van Anh Ho from Japan Advanced Institute of Science and Technology, where he leads a laboratory working on soft haptic technology. He adds, "All approaches so far have only focused on developing a skin-like structure with a matrix of different sensors without considering the bulk of wires, electronic components, and the risk of damage from frequent contact."

In a new study published in IEEE Transactions on Robotics, Prof. Ho and his colleague Lac Van Duong, a doctoral student at JAIST, developed a high-performance, vision-based artificial sensing system that is low-cost, has a relative simple structure, and is scalable. Named TacLINK, this system can process tactile information and even determine contact force and contact geometry upon interacting with the surroundings.

The researchers based the structure of TacLINK essentially on a transparent acrylic tube (serving as a rigid bone frame) covered by a continuous soft artificial skin with a sensing area of about 500 cm2. They used silicone rubber to fabricate the artificial skin due to its high elasticity and smoothness. Moreover, the material could be inflated to change its form and stiffness. The researchers printed an array of markers on the surface of this skin to track its deformation instead of embedding sensors or electronic components inside the skin. This greatly reduced its bulkiness, cost, and chances of possible damage.

The vision system consisted of two co-axial cameras arranged to form a stereo camera that tracked the 3D displacement of the markers on the inner wall of the skin. In addition, researchers employed a finite element model (FEM) to estimate the structural stiffness of the skin. By combining the data from both these sources, they were able to reconstruct the contact geometry and contact force distribution simultaneously. Moreover, unlike in previous studies, this method worked for multiple contact points.

With such positive outcomes, Prof. Ho is hopeful about the creation of a future generation of touch-sensing-enabled robotic devices. "The artificial skin used in our study can be easily fabricated by the casting method and can, therefore, be implemented on other parts of robots, such as fingers, legs, chests, and heads, and even for smart prosthetics for humans, allowing a disabled person to perceive sensations the same way as a normal human," comments Prof. Ho excitedly. "In addition, it can also be used to design various sensory devices in medicine, healthcare, and industry. In fact, it is especially suited for the development of robotic systems in the post-COVID era to enable remote service with robotic avatars."

It certainly seems like the robots of the near future will be "touching" human lives more than ever before!

Modern immunotherapeutic anti-cancer drugs support a natural mechanism of the immune system to inhibit the growth of cancer cells. They dock onto a specific receptor of the killer cell and prevent it from being switched off by the cancer cells. This is a complex molecular process, which is known but has not yet been fully understood. In a molecular dynamics study conducted by the group led by medical information scientist Wolfgang Schreiner and gynaecologists Heinz Kölbl and Georg Pfeiler from MedUni Vienna, working with biosimulation expert Chris Oostenbrink from the University of Natural Resources and Applied Life Sciences (Boku) Vienna, has now, for the first time, analysed this mechanism for the drugs nivolumab and pembrolizumab. It was found that tiny molecular motions are of key significance. The study has been published in the leading journal Cancers.

The human immune system protects the body against bacteria, viruses and damaged cells, such as cancer cells. Specialised immune cells, such as natural killer cells (NK cells), work together to identify and eliminate these threats. Sometimes these killer cells inadvertently target healthy cells, and this can result in severe autoimmune reactions. If this happens, the immune system deploys a safeguard measure, so-called "programmed cell death" (apoptosis). This is triggered when the endogenous surface molecule PD-L1 binds to the receptor expressed on the killer cell, the PD- molecule. In this process, the (immuno-checkpoint) receptor acts like an emergency off switch. If cells are attacked in error, they produce PD-L1 molecules and reach towards the killer cells, thus killing them. Cancer cells are also able to express PD-L1 and these bind to the checkpoint, thereby causing the killer cells to die and allowing the tumour to grow.

This is exactly where modern immunotherapeutic anti-cancer drugs (checkpoint inhibitors) come in. They resemble the surface molecule PD-L1 and bind to the PD-1 receptor, but the triggered mechanism is different, as the killer cells are not sent into cell death. Although the checkpoints are blocked, they are not activated. Cancer cells are no longer able to bind to the blocked receptors and the killer cells retain their ability to destroy cancer cells. Immunotherapy exploits this phenomenon, even though it was hitherto not fully understood exactly how the binding occurred without a switching process.

Wolfgang Schreiner from the Center for Medical Statistics, Informatics and Intelligent Systems at MedUni Vienna's Institute of Biosimulation and Bioinformatics, gynaecologists Georg Pfeiler and Heinz Kölbl, who is also Director of MedUni Vienna's Department of Obstetrics and Gynecology, and Chris Oostenbrink from Boku Vienna, have now investigated the key differences between the natural PD-L1 and the drugs used for treating various cancers such as breast cancer, lung cancer and melanoma in a molecular dynamics model by means of computer simulation. The motions of individual atoms and their reciprocal influence were calculated and mathematically analysed on the "supercomputer" belonging to Vienna Scientific Cluster (VSC). In this way it was possible to identify the smallest differences in the molecular motions between the natural molecule PD-L1 and those of the drugs.

Schreiner explains: "One can virtually make a precise mathematical assessment of the "facial expressions" of the molecules in slow motion, up close and personal. It was found that some loops of the PD-1 molecule deform in a different way, depending on their binding partner." These small differences would be directed inside the killer cell by the PD-1 molecule and produce the desired effect, namely that, although the drugs would bind to the receptor, they would not activate it like the natural surface molecule PD-L1.

What initially appears to be a slight difference is actually the basis for our continually growing understanding of cellular processes. The more we know about these, the more specific we can be in the development of checkpoint inhibitors. Research findings of this kind are highly promising, particularly in the area of gynaecological oncology, says Pfeiler: "Of course, checkpoint inhibitors can only work if the corresponding surface molecules (PD-1, PDL-1) that are to be inhibited, are actually expressed. This therapy is then a good option for triple negative breast cancer, for example. Interestingly, to date, only the expression of PDL-1 has been observed pre-therapeutically but not the expression of PD-1. This raises manifold research questions in terms of precision medicine."

To date, research in the field of combinatorial catalysts has relied on serendipitous discoveries of catalyst combinations. Now, scientists from Japan have streamlined a protocol that combines random sampling, high-throughput experimentation, and data science to identify synergistic combinations of catalysts. With this breakthrough, the researchers hope to remove the limits placed on research by relying on chance discoveries and have their new protocol used more often in catalyst informatics.

Catalysts, or their combinations, are compounds that significantly lower the energy required to drive chemical reactions to completion. In the field of "combinatorial catalyst design," the requirement of synergy--where one component of a catalyst complements another--and the elimination of ineffective or detrimental combinations are key considerations. However, so far, combinatorial catalysts have been designed using biased data or trial-and-error, or serendipitous discoveries of combinations that worked. A group of researchers from Japan has now sought to change this trend by trying to devise a repeatable protocol that relied on a screening instrument and software-based analysis.

Their new study, published in ACS Catalysis, details the identification of effective catalyst combinations, using the proposed protocol, for the oxidative coupling of methane (OCM). OCM is a widely used chemical reaction used to convert methane into useful gases in the presence of oxygen and the catalyst. Elaborating on the motivations behind the study, Dr. Toshiaki Taniike, Professor at the School of Materials Science, Japan Advanced Institute of Science and Technology and corresponding author of the study, says, "Combinatorial catalyst design is hardly generalizable, and the empirical aspect of the research has biased the literature data toward accidentally found combinations".

To derive a bias-free dataset from OCM for devising the protocol, the researchers sampled randomly 300 solid catalysts from a vast materials space containing upwards of 36,000 catalysts! Screening such a large number of catalysts is near impossible by human standards. Hence, the team used a high-throughput screening instrument to evaluate their performance at facilitating OCM. The obtained dataset was used to outline the novel protocol, aimed at providing a guideline for catalyst design. This was implemented in the form of a "decision tree classification," which is a form of machine learning that helped in understanding the efficiency of the selected catalyst combinations, in giving better OCM yield. This, in turn, helped in drawing up the required catalyst design guidelines.

Interestingly, the results showed that, even with random sampling, 51 out of the 300 catalysts gave a better OCM yield when compared to the alternative non-catalytic process. Explaining the potential implications of their discovery, Dr. Keisuke Takahashi, Associate Professor at Hokkaido University and co-author of this study, says, "The combination of high throughput experimentation and data science has already demonstrated the power of bias-free catalyst big data in finding novel catalysts as well as a catalyst design guideline. It is also important to state the essentiality of these approaches for implementing such a demanding study in a realistic time frame. By equipping all the essential techniques of the study, truly nonempirical catalyst developments could be realized".

Indeed, we can hope, along with the scientists, that this strategy will "catalyze" several future material science discoveries!

Life changes influence the amount of physical activity in a person, according to a recent study by the University of Jyväskylä. The birth of children and a change of residence, marital status and place of work all influence the number of steps of men and women in different ways. For women, having children, getting a job and moving from town to the countryside reduce everyday exercise.

A study conducted by the Faculty of Sports & Health Sciences found that the birth of the first child significantly reduces the number of everyday steps in women. As children grow, women's aerobic steps, in turn, increase. Although the birth of children did not have a statistically significant effect on the number of steps in men, changes were also observed in men.

"With the birth of both the first and second child, the trend of aerobic steps declined in men," says postdoctoral researcher Kasper Salin. "However, with the birth of the second child, the number of everyday steps began to rise. This can be explained by, for example, a decrease in exercise hobbies."

Aerobic steps are movements of longer duration, lasting at least 10 minutes, with a step rate of at least 60 steps per minute. Aerobic steps are important for, among other things, heart health. The adult population should have at least 150 minutes of moderate to vigorous exercise per week. Everyday steps describe other active movement on a daily basis.

"Steps can accumulate many times during the day if we just allow," Salin explains it. "To increase your number of steps, you may not have to exercise separately each day. Instead, attention should be paid to everyday choices and, for example, choose stairs instead of the elevator or walk to the store instead of driving."

Where we live influences the amount of physical activity

The study also examined the impact of one's place of residence and of changing it. Moving from the city to the countryside reduced the overall steps and everyday steps of women, but no similar effect was observed for men. For men living permanently in rural areas, both aerobic steps and total steps were at a lower level than those of men living permanently in the city.

The researchers also found that in women, employment reduced aerobic steps.

"Work provides a rhythm for the day and this can influence how, for example, it is possible to participate in various scheduled hobbies," Salin says. "However, it should be noted that the change in total steps was not statistically significant among the employed, as the change in everyday steps was correspondingly positive for those who were employed.

The importance of physical activity for health is well known, but longer-term observations of how changes in life are related to physical activity have so far relied only on self-reported exercise.

An international research team including members from The University of Manchester has shown that a rapidly rotating neutron star is at the core of a celestial object now known as PSR J2039?5617

The international collaboration used novel data analysis methods and the enormous computing power of the citizen science project Einstein@Home to track down the neutron star's faint gamma-ray pulsations in data from NASA's Fermi Space Telescope. Their results show that the pulsar is in orbit with a stellar companion about a sixth of the mass of our Sun. The pulsar is slowly but surely evaporating this star. The team also found that the companion's orbit varies slightly and unpredictably over time. Using their search method, they expect to find more such systems with Einstein@Home in the future.

Searching for the so-called 'Spider' pulsar systems - rapidly spinning neutron stars whose high-energy outflows are destroying their binary companion star, required 10 years of precise data. The pulsars have been given arachnid names of 'Black widows' or 'Redbacks', after species of spider where the females have been seen to kill the smaller males after mating.

New research published in, Monthly Notices of the Royal Astronomical Society, details how researchers found a neutron star rotating 377 times a second in an exotic binary system using data from NASA's Fermi Space Telescope.

The astronomer's findings were uniquely boosted by the Einstein@Home project, a network of thousands of civilian volunteers lending their home computing power to the efforts of the Fermi Telescope's work.

The group's search required combing very finely through the data in order not to miss any possible signals. The computing power required is enormous. The search would have taken 500 years to complete on a single computer core. By using a part of the Einstein@Home resources it was done in 2 months.

With the computing power donated by the Einstein@Home volunteers, the team discovered gamma-ray pulsations from the rapidly rotating neutron star. This gamma-ray pulsar, now known as J2039?5617, rotates about 377 times each second.

"It had been suspected for years that there is a pulsar, a rapidly rotating neutron star, at the heart of the source we now know as PSR J2039?5617," says Lars Nieder, a PhD student at the Max Planck Institute for Gravitational Physics (Albert Einstein Institute; AEI) in Hannover. "But it was only possible to lift the veil and discover the gamma-ray pulsations with the computing power donated by tens of thousands of volunteers to Einstein@Home," he adds.

The celestial object has been known since 2014 as a source of X-rays, gamma rays, and light. All evidence obtained so far pointed at a rapidly rotating neutron star in orbit with a light-weight star being at the heart of the source. But clear proof was missing.

The first step to solving this riddle were new observations of the stellar companion with optical telescopes. They provided precise knowledge about the binary system without which a gamma-ray pulsar search (even with Einstein@Home's huge computing power) would be unfeasible.

The system's brightness varies during an orbital period depending on which side of the neutron star's companion is facing the Earth. "For J2039-5617, there are two main processes at work," explains Dr. Colin Clark from Jodrell Bank Centre for Astrophysics, lead author of the study. "The pulsar heats up one side of the light-weight companion, which appears brighter and more bluish. Additionally, the companion is distorted by the pulsar's gravitational pull causing the apparent size of the star to vary over the orbit. These observations allowed the team to get the most precise measurement possible of the binary star's 5.5-hour orbital period, as well as other properties of the system."

With this information and the precise sky position from Gaia data, the team used the aggregated computing power of the distributed volunteer computing project Einstein@Home for a new search of about 10 years of archival observations of NASA's Fermi Gamma-ray Space Telescope. Improving on earlier methods they had developed for this purpose, they enlisted the help of tens of thousands of volunteers to search Fermi data for periodic pulsations in the gamma-ray photons registered by the Large Area Telescope onboard the space telescope. The volunteers donated idle compute cycles on their computers' CPUs and GPUs to Einstein@Home.

The new knowledge of the frequency of the gamma-ray pulsations also allowed collaborators to detect radio pulsations in archival data from the Parkes radio telescope. Their results, also published in Monthly Notices of the Royal Astronomical Society, show that the pulsar's radio emission is often eclipsed by material that has been blown off the companion star by its nearby Redback pulsar.

Washington, DC / New Delhi, India - Researchers at CDDEP have released, The State of the World's Antibiotics in 2021, which presents extensive data on global antimicrobial use and resistance as well as drivers and correlates of antimicrobial resistance, based on CDDEP's extensive research and data collection through ResistanceMap, a global repository that has been widely used by researchers, policymakers, and the media.

Since the first State of the World's Antibiotics report in 2015, antimicrobial resistance has leveled off in some high-income countries but continues to rise in many low- and middle-income countries (LMICs), where access to antibiotics has risen with increases in gross domestic product per capita. Per capita antibiotic consumption in LMICs is lower than in high-income countries, despite a higher infectious disease burden; however, consumption rates are rapidly converging. These trends reflect both better access to antibiotics for those who need them and increases in inappropriate antibiotic use.

An important driver of resistance is antibiotic use in humans and in terrestrial and aquatic animals raised for human consumption. Global antibiotic consumption in humans increased by 65 percent between 2000 and 2015, whereas consumption in animals is expected to increase by 11.5 percent between 2017 and 2030. If nothing changes to alter these trajectories, antibiotic consumption is likely to increase worldwide by 200 percent between 2015 and 2030.

The approaches to addressing AMR are to reduce the need for antibiotics (through prevention of infections), to reduce the use of antibiotics (by better use of diagnostics and antibiotic stewardship), and to innovate to find new methods of disease prevention and treatment. All three strategies are needed so that a strong arsenal of effective antibiotics can be maintained.

This report introduces country-level dashboards that capture progress on indicators that track AMR and show what remains to be done to decrease the need for antibiotics and their inappropriate use.

"We are optimistic that future generations will also witness the miracle of antibiotics. To ensure that privilege, it is incumbent on us to treat the crown jewels of modern medicine with care and respect," said Dr. Laxminarayan, Director at CDDEP.

The State of the World's Antibiotics in 2021 is published in CDDEP's website and is available for download here: https://cddep.org/blog/posts/the-state-of-the-worlds-antibiotics-report-in-2021/

It is being launched at a global webinar featuring Dame Sally Davies, and Professors Otto Cars, Abdoulaye Djimde, and Ramanan Laxminarayan.

Mothers are at increased risk of mental health problems as they struggle to balance the demands of childcare and remote working in COVID-19 lockdowns, according to new research from an international team of researchers.

The findings, published in the journal Psychological Medicine, were drawn from a comprehensive, online survey of mothers in China, Italy and the Netherlands.

Changes to their working lives, family strife and loss of social networks emerged as common factors affecting the mental health of mothers in all three countries.

The study was carried out by a team from Radboud University, Peking University, Tilburg University, Vrije Universiteit Amsterdam, and Padua University, to compare the factors affecting and protecting mothers' metal health in lockdown across countries and cultures.

A total of 900 Dutch, 641 Italian, and 922 Chinese mothers with children aged between one and 10 years participated in the study and reported on their mental health, family functioning, the support they received, and their demographic characteristics during the first lockdown in April and May 2020.

The researchers found women in all three countries shared three big risk factors: changes to work through unemployment, reduced job security and the shift to remote working; marital problems and conflict with other family members, and what the researchers called pandemic-related distress, caused by reduced access to food and essentials, healthcare and social networks.

There were also smaller risks to mental health, which differed across the three countries.

In the Netherlands, unemployed mothers reported high levels of mental health problems, possibly because of financial insecurity. At the same time, highly educated Dutch mothers also reported more symptoms. The researchers suggest this may be because of the need to combine demanding work, often remotely, with child care responsibilities.

In China, highly educated or high income mothers, single mothers, and mothers with poor physical health all reported more mental health symptoms, while in Italy, lower maternal age and poor physical health emerged as risk factors.

Regardless of country, the researchers found mothers who were more resilient and generally able to cope effectively with stressful events experienced lower mental health problems during the lockdown. In China, a large number of children as well as support in childcare from grandparents living in the same household decreased the risk of mental health problems. The researchers conclude that an extended family may be a source of resilience as the unexpected burden of the pandemic is shared among more people.

Dr Madelon Riem, from Radboud University, said: "With closures of schools and day care centres, COVID-19 continues to drastically impact the lives of parents. The burden of the pandemic may be disproportionality placed on women who are still often the primary caregiver. Mothers are, therefore, at increased risk for mental health problems."

Her colleague, Jing Guo, from Peking University, said: "These findings may inform future interventions aimed at improving maternal mental health during future pandemics. For instance, the current lockdown policies may ignore the advantages of grandparental childcare that support mother's mental health, as shown in China.

"Families without grandparental support show a clear need of childcare facilities during lockdowns. Improving maternal mental health not only benefits mothers, but also their children. For mothers who are disproportionately burdened by the pandemic, good mental health may be a necessary prerequisite for providing adequate care of their children."