Culture

Mothers leave their mark on their children in many ways - and Australian researchers have discovered a protein called SMCHD1 is involved in this 'imprinting' process.

SMCHD1 switches certain genes off, altering how a cell behaves. The new research has revealed that when an egg cell (or oocyte) is fertilised by a sperm, the egg cell's SMCHD1 lingers within the developing embryo, switching off at least 10 different genes and impacting the embryo's development - which could potentially have a lifelong impact on the offspring.

The research was published in eLife by a WEHI team led by Ms Iromi Wanigasuriya, Dr Quentin Gouil and Professor Marnie Blewitt, in collaboration with WEHI's Dr Matthew Ritchie, Dr Heather Lee from the University of Newcastle and Associate Professor Karla Hutt from Monash Biomedicine Discovery Institute.

At a glance

Some genes have different expression, depending on whether they have been inherited from the mother or father - a phenomenon called genomic imprinting

WEHI researchers have discovered that the protein SMCHD1 is involved in genomic imprinting, with protein from the mother lingering in an embryo and switching ten genes off

The discovery sheds new light on how genomic imprinting occurs, and may reveal new clues to how SMCHD1 contributes to certain developmental and degenerative disorders.

Imprinted genes

We inherit all our genes from our parents - and there are a few genes that behave differently in offspring, depending on whether they are inherited from the mother or the father. This phenomenon is called 'genomic imprinting', and is seen in some genetic diseases, said Ms Wanigasuriya, who undertook the research as a PhD student at WEHI.

"Genomic imprinting occurs because of 'epigenetic marks' on DNA that impact how genes can be used," she said. "When a sperm fertilises an egg, both cells' DNA carries epigenetic marks from the parent to the child, which in some cases have been linked to long-term health impacts," she said. "It is known that proteins found within the egg (proteins that we get from our mum) help to protect these imprinted genes during early embryo development. Therefore, these egg cell proteins can have either a long or a short-term impact on the health of the embryo.".

Professor Blewitt's research team has been studying the SMCHD1 protein, which uses epigenetic modification to 'switch off' or silence certain genes.

"We investigated whether a mother's SMCHD1 protein could be transferred into a newly formed embryo, and how this impacted the expression of imprinted genes," Ms Wanigasuriya said. "Using advanced microscopy to follow a fluorescently tagged version of SMCHD1, we could see that the maternal SMCHD1 protein persisted within embryos for at least five cell divisions. The mother's SMCHD1 altered the imprinted gene expression - potentially leaving a lasting legacy in the offspring."

Understanding SMCHD1

Dr Gouil said the research revealed a critical window of time in early embryonic development during which the mother's SMCHD1 could silence the expression of target genes.

"Using powerful new genomic analysis techniques, we were able to identify ten genes that were switched off by maternal SMCHD1 in the early embryo. This is the first time SMCHD1 from the egg has been identified as having a role in imprinting," he said.

"While the effects we discovered were subtle, we know that events occurring in early embryonic development can have long-term effects on health. As well as extending our understanding of genomic imprinting, this research adds an extra dimension to the many ways we know parents can impact their offspring's health."

Professor Blewitt said the research also helped to explain recently discovered roles of SMCHD1 in certain diseases including developmental disorders such as Prader-Willi Syndrome (PWS) and Bosma arhinia microphthalmia syndrome (BAMS), as well as facioscapulohumeral muscular dystrophy (FSHD), a form of muscular dystrophy.

"Studying SMCHD1 in early embryos has uncovered new gene targets that this protein silences," she said. "This could explain how changes in SMCHD1 activity contribute to diseases. We are currently leading a proprietary drug discovery effort at WEHI to leverage our knowledge around SMCHD1 and design novel therapies to treat developmental and degenerative disorders. This research broadens our understanding of how these novel drug candidates might impact gene expression."

Machine learning could teach us how to make the manufacturing of materials cleaner and more sustainable by taking a holistic view to identify the greenest production method, suggest KAUST researchers.

The quest for sustainability means that scientists worldwide are developing advanced materials to help address issues, including carbon capture, water desalination and energy storage, says Rifan Hardian, a postdoc in Gyorgy Szekely's lab. "Although these materials show promising performance, the materials themselves are often produced in unsustainable ways--using harsh conditions, toxic solvents and energy-intensive processes that generate excessive waste--potentially creating more environmental problems than they solve," Hardian says.

In collaboration with Xiangliang Zhang and his team, Szekely and Hardian have been investigating a more sustainable approach to materials development, called design of experiments (DoE). "Unlike conventional approaches to materials optimization, which vary one factor at a time, DoE is a systematic approach that allows multiple factors to be varied simultaneously," Hardian says.

DoE theoretically allows variables--such as reactant and solvent choice, reaction time and reaction temperature--to be optimized all at once. The procedure cuts the number of experiments conducted and also potentially identifies the greenest possible way to make a material. However, it is challenging to optimize each variable to identify the best reaction protocol from such sparse experimental data. "This is where machine learning comes in," Hardian says.

Machine learning is a form of artificial intelligence that can learn patterns from a limited number of data points to fill in the blanks in the data. "This way, one can view the entire experimental space and pick the one reaction condition that best fits the desired results," Hardian says.

The team combined DoE and machine learning to identify a sustainable method for making a popular metal organic framework (MOF) material called ZIF-8. "ZIF-8 has great potential in applications, such as gas separation, catalysis, heavy metal removal and environmental remediation," Hardian says. The team optimized 10 variables in the electrochemical synthesis of ZIF-8, identifying a high-yielding process that used water as a solvent and generated minimal waste. "Thanks to machine learning, we developed a holistic view of the variables' interactions and identified many unexpected correlations that could have been missed if we had followed a conventional approach," Hardian says.

The next milestone will be to apply DoE and machine learning to large-scale materials production, Szekely says. "Ultimately, our aim is to turn the futuristic vision of an autonomous laboratory system, which can continuously run and self-optimize reaction conditions, into a reality," he says.

A new technique to make cheaper more efficient biological enzyme hybrids could have valuable applications in future water recycling, targeted drug manufacturing and other industries, Flinders University green chemistry researchers say in a new publication.

The model enzyme system, which immobilises a catalyst enzyme hybrid for continuous flow use in the high-speed vortex fluidic device, showed a 16-fold increase in its efficiency, the researchers say in American Chemical Society journal, ASC Applied Materials & Interfaces.

Flinders Professor of Clean Technology Colin Raston, from the Flinders Institute for Nanoscale Science and Technology, with collaborator Professor Greg Weiss at University of California Irvine and other researchers around the world, have extensively used the vortex fluidic device in a wide range of applications - many of which promise to open new frontiers in clean manufacturing and even new industries.

Lead author on the new paper, Flinders University research associate Dr Xuan Luo, says the cost and limited life of enzymes hinders development of enzyme-based biosensors and most enzymes are made inactive during the assay process so cannot be separated for reuse.

"We used an inorganic composite to trap the enzyme on the surface of the vortex fluidic device, essentially making a 'mini factory' where the enzyme was reused under continuous flow," Dr Luo says.

"The technique uses the minimum amount of enzyme, which is less expensive, and monitors the reaction in real-time, also saving time and money on reagents."

Professor Raston, a finalist for South Australian Scientist of the Year 2020, says the paper demonstrates four applications of the vortex fluidic device - fabrication, immobilisation, continuous flow and real-time monitoring.

"In this study, we were able to generate and immobilise laccase nanoflowers into silica hydrogel to greatly simplify the fabrication process, and allow saving of both time and money, along with the ability to reuse the enzyme for further reactions," says co-author Professor Raston says.

"The next steps will be to test the model system with actual samples such as wastewater, and also use this same immobilisation system with other enzymes to see if their efficiency is increased."

The paper describes the immobilisation of hybrid protein-Cu3(PO4)2 nanoflowers to create a new laccase nanoflower immobilisation platform, LNF@silica, which subsequently increased the enzyme efficiency by 16 times and allowed assay monitoring in real-time.

An England-wide case-control study led by Queen Mary University of London has shown that, despite major improvements in diagnostic techniques and treatments, mammography screening continues to play an important role in lowering the risk of dying from breast cancer.

The study of over 23,000 women showed a 37% reduction in breast cancer mortality for women screened at least once, corresponding to approximately nine breast cancer deaths prevented between ages 55 and 79 for every 1000 women attending screening at ages 50-69. The effect of screening within the NHS Breast Screening Programme in England is stronger and longer lasting in women aged 65 or over, but it remains highly relevant for younger women.

Corresponding author Professor Stephen Duffy from Queen Mary University of London said: "The NHS Breast Screening Programme is doing its job in reducing the risk of death from breast cancer. Our results indicate that the benefit persists for 3-4 years in women aged under 65, so slippage of the three-year interval would be unsafe for these women.

"In the current Covid crisis, efforts to reinstate the breast screening programme should continue apace. If difficult decisions about delivery of the programme have to be made in the future, it may be appropriate to consider different intervals between screens for different age groups."

Compared with people who ate meat, vegans with lower calcium and protein intakes on average, had a 43% higher risk of fractures anywhere in the body (total fractures), as well as higher risks of site-specific fractures of the hips, legs and vertebrae, according to a study published in the open access journal BMC Medicine. Vegetarians and people who ate fish but not meat had a higher risk of hip fractures, compared to people who ate meat. However, the risk of fractures was partly reduced once body mass index (BMI), dietary calcium and dietary protein intake were taken into account.

Dr Tammy Tong, Nutritional Epidemiologist at the Nuffield Department of Population Health, University of Oxford, and the lead author said: "This is the first comprehensive study on the risks of both total and site-specific fractures in people of different diet groups. We found that vegans had a higher risk of total fractures which resulted in close to 20 more cases per 1000 people over a 10-year period compared to people who ate meat. The biggest differences were for hip fractures, where the risk in vegans was 2.3 times higher than in people who ate meat, equivalent to 15 more cases per 1000 people over 10 years."

A team of researchers at the Universities of Oxford and Bristol, UK analysed data from nearly 55,000 people in the EPIC-Oxford study, a prospective cohort of men and women living in the UK, who were recruited between 1993 and 2001, many of whom do not eat meat. Prospective cohort studies identify a group of people and follow them over a period of time to understand how certain factors (in this case diet) may affect certain outcomes (in this case fracture risk).

Out of the 54,898 participants included in the present study, 29,380 ate meat, 8,037 ate fish but not meat, 15,499 were vegetarians, and 1,982 were vegans when they were recruited. Their eating habits were assessed initially at recruitment, then again in 2010. Participants were followed continuously for 18 years on average, until 2016 for the occurrence of fractures. During the time of the study, 3,941 fractures occurred in total, including 566 arm, 889 wrist, 945 hip, 366 leg, 520 ankle and 467 fractures at other main sites, defined as the clavicle, ribs and vertebrae.

In addition to a higher risk of hip fractures in vegans, vegetarians and pescetarians than the meat eaters, vegans also had a higher risk of leg fractures and other main site fractures. The authors observed no significant differences in risks between diet groups for arm, wrist or ankle fractures once BMI was taken into account. The authors found that the differences in risk of total and site-specific fractures was partly reduced once BMI, dietary calcium and dietary protein intake had been taken into account.

Dr Tong said: "Previous studies have shown that low BMI is associated with a higher risk of hip fractures, and low intakes of calcium and protein have both been linked to poorer bone health. This study showed that vegans, who on average had lower BMI as well as lower intakes of calcium and protein than meat eaters, had higher risks of fractures at several sites. Well-balanced and predominantly plant-based diets can result in improved nutrient levels and have been linked to lower risks of diseases including heart disease and diabetes. Individuals should take into account the benefits and risks of their diet, and ensure that they have adequate levels of calcium and protein and also maintain a healthy BMI, that is, neither under nor overweight."

The authors caution that they were unable to differentiate between fractures that were caused by poorer bone health (such as fractures due to a fall from standing height or less) and those that were caused by accidents because data on the causes of the fractures were not available. No data were available on differences in calcium supplement use between the different diet groups, and as in all dietary studies the estimates of nutrients such as dietary calcium or dietary protein are subject to measurement error. As the study predominantly included white European participants, generalisability to other populations or ethnicities may be limited, which could be important considering previously observed differences in bone mineral density and fracture risks by ethnicity, according to the authors.

More studies are needed from different populations, including from non-European populations, as well as cohorts with a larger proportion of men to explore possible differences in risk by sex, as around three-quarters of participants in the EPIC-Oxford cohort are women.

VIRTUAL MEETING (CST), November 22, 2020 -- Wear a mask. Stay six feet apart. Avoid large gatherings. As the world awaits a safe and effective vaccine, controlling the COVID-19 pandemic hinges on widespread compliance with these public health guidelines. But as colder weather forces people to spend more time indoors, blocking disease transmission will become more challenging than ever.

At the 73rd Annual Meeting of the American Physical Society's Division of Fluid Dynamics, researchers presented a range of studies investigating the aerodynamics of infectious disease. Their results suggest strategies for lowering risk based on a rigorous understanding of how infectious particles mix with air in confined spaces.

Research early in the pandemic focused on the role played by large, fast-falling droplets produced by coughing and sneezing. However, documented super-spreader events hinted that airborne transmission of tiny particles from everyday activities may also be a dangerous route of infection. Fifty-three of 61 singers in Washington state, for example, became infected after a 2.5-hour choir rehearsal in March. Of 67 passengers who spent two hours on a bus with a COVID-19-infected individual in Zhejiang Province, China, 24 tested positive afterward.

William Ristenpart, a chemical engineer at the University of California, Davis, found that when people speak or sing loudly, they produce dramatically larger numbers of micron-sized particles compared to when they use a normal voice. The particles produced during yelling, they found, greatly exceed the number produced during coughing. In guinea pigs, they observed influenza can spread through contaminated dust particles. If the same is true for the SARS-CoV-2, the researchers said, then objects that release contaminated dust--like tissues--may pose a risk.

Abhishek Kumar, Jean Hertzberg, and other researchers from the University of Colorado, Boulder, focused on how the virus might spread during music performance. They discussed results from experiments designed to measure aerosol emission from instrumentalists.

"Everyone was very worried about flutes early on, but it turns out that flutes don't generate that much," said Hertzberg. On the other hand, instruments like clarinets and oboes, which have wet vibrating surfaces, tend to produce copious aerosols. The good news is they can be controlled. "When you put a surgical mask over the bell of a clarinet or trumpet, it reduces the amount of aerosols back down to levels in a normal tone of voice."

Engineers led by Ruichen He at the University of Minnesota investigated a similar risk-reduction strategy in their study of the flow field and aerosols generated by various instruments. Although the level of aerosols produced varied by musician and instrument, they rarely traveled more than a foot away. Based on their findings, the researchers devised a pandemic-sensitive seating model for live orchestras and described where to place filters and audience members to reduce risk.

While many formerly officebound employees continue to work from home, employers are exploring ways to safely reopen their workplaces by maintaining sufficient social distance between individuals. Using two-dimensional simulations that modeled people as particles, Kelby Kramer and Gerald Wang from Carnegie Mellon University identified conditions that would help avoid crowding and jamming in confined spaces like hallways.

Traveling to and from office buildings in passenger cars also poses an infection risk. Kenny Breuer and his collaborators at Brown University performed numerical simulations of how air moves through passenger car cabins to identify strategies that may reduce infection risk. If air enters and exits a room at points far away from passengers, then it may reduce the risk of transmission. In a passenger car, they said, that means strategically opening some windows and closing others.

MIT mathematicians Martin Bazant and John Bush proposed a new safety guideline built on existing models of airborne disease transmission to identify maximum levels of exposure in a variety of indoor environments. Their guideline depends on a metric called "cumulative exposure time," which is determined by multiplying the number of people in a room by the duration of the exposure. The maximum depends on the size and ventilation rate of the room, the face covering of its occupant, the infectiousness of aerosolized particles, and other factors. To facilitate easy implementation of the guideline, the researchers worked with chemical engineer Kasim Khan to design an app and online spreadsheet that people can use to gauge the risk of transmission in a variety of settings.

As Bazant and Bush wrote in a forthcoming paper on the work, staying six feet apart "offers little protection from pathogen-bearing aerosol droplets sufficiently small to be continuously mixed through an indoor space." A better, flow-dynamics-based understanding of how infected particles move through a room may ultimately yield smarter strategies for reducing transmission.

VIRTUAL MEETING (CST), November 22, 2020 -- Eric Hester has spent the last three years chasing icebergs. A mathematics graduate student at the University of Sydney in Australia, Hester and researchers at Woods Hole Oceanographic Institution in Massachusetts are studying how the shape of an iceberg shapes the way it melts.

"Ice deforms as it melts," said physical oceanographer Claudia Cenedese, who has worked with Hester on the project. "It makes these very weird shapes, especially on the bottom, like the way the wind shapes a mountain on a longer time scale."

At the 73rd Annual Meeting of the American Physical Society's Division of Fluid Dynamics, Hester presented results from his group's experiments aimed at understanding how melting alters the face-changing boundary of a shrinking iceberg--and how those alterations in turn affect the melting.

The dynamics of iceberg melt is missing from most climate models, Cendese said. Including them could help with prediction: icebergs pump fresh water from ice sheets into oceans, boosting communities of living organisms. Icebergs are the dominant source of freshwater in the fjords of Greenland--and a significant contributor to freshwater loss in Antarctica. Icebergs play a critical role in the climate, Cenedese said, and shouldn't be neglected in models. The physics of melting ice is well understood, and some models simulate it accurately, she said. Others don't. "But what you can't do in those simulations is change the shape of the ice."

Icebergs form with a wide range of shapes and sizes, Hester said, and distinct thermodynamic processes affect different surfaces. The base, submerged in water, doesn't melt in the same way as the side. "And each face doesn't melt uniformly," added Cenedese.

Hester conducted his experiments by submerging a dyed block of ice in a flume with a controlled flow of water passing by, and watching it melt. He and his colleagues found that the side facing a current melts faster than sides that run parallel to flow. By combining experimental and numerical approaches, Hester and his collaborators charted the relative influences of factors like relative water velocity and aspect ratio, or the proportion of height to width on a side. Not surprisingly, they found that the bottom had the slowest melt rate.

Cenedese said Hester's project brings together collaborators from a range of disciplines and countries, and that a diverse collaboration was needed for such an interdisciplinary project. "Working in isolation isn't as productive in this case."

Other studies discussed at the conference focused on ice formation, rather than melting. During a session on particle-laden flows, engineer Jiarong Hong from the St. Anthony Falls Laboratory at the University of Minnesota, in Minneapolis, discussed results from experiments showing how turbulence influences both the speed and distribution of snow as it falls and settles. The findings could also help scientists better understand precipitation, Hong said.

Another project, presented by physicist Chao Sun from Tsinghua University in China and his group during a session on convection and buoyancy-driven flows, focused on ice formation in lakes.

Working on a grant from the Natural Science Foundation of China with Ziqi Wang from Tsinghua University, Enrico Calzavarini from the University of Lille in France, and Federico Toschi from Eindhoven University of Technology in the Netherlands, Sun showed how the formation of ice on a lake is closely tied to the fluid dynamics of the water beneath.

A lake may possess layers of water of differing densities and temperatures. "The water density anomalies can induce elaborate fluid dynamics beneath a moving ice front and can drastically change system behaviors," said Sun. "This has often been ignored in previous studies."

Sun's group combined physical experiments, numerical simulations, and theoretical models to investigate the connection between the ice and (turbulent) convective flows. They identified four distinct regimes of different flow dynamics, each of which interacts with other layers and the ice in its own ways. Even with that complexity, though, the group developed an accurate theoretical model that could be used in future studies.

"It made a fair prediction of ice layer thickness and of icing time," said Sun.

Since the formation and melting of ice plays such a critical role in the climate, he said, a better understanding of the fluid dynamics behind the process could help researchers identify and study accurately the markers of a warming world. "The time for ice to form and melt, for example, could potentially provide an indicator of climate change."

Structuring negotiations between insurers and providers, standardizing fee-for-service payments and negotiating prices can lower the United States' health care spending by slowing the rate at which healthcare prices increase, according to a Rutgers study.

The study, published in the journal Health Affairs, examined how other high-income countries that use a fee-for-service model regulate health care costs.

Although the United States has the highest health care prices in the world, the specific mechanisms commonly used by other countries to set and update prices are often overlooked. In most countries with universal health insurance, physicians are paid on a fee-for-service basis, yet health care prices there are lower than in the U.S.
To lower health care spending, American policymakers have focused on eliminating fee-for-service reimbursement, which provides an incentive for performing additional services rather than setting up price negotiations to address the main factor that drives health care spending.

U.S. policy makers emphasize the need to reduce the volume of care that the system provides, but prior research shows that U.S. health care expenditures are higher than in other countries because of the price, not the volume, of services.

The researchers compared policies in France, Germany and Japan where payers and physicians engage in structured fee negotiations and standardized prices in systems where fee-for-service is the main model of outpatient physician reimbursement. They interviewed 37 stakeholders and health policy experts in those three countries to understand the process for creating physician fee schedules and updates, to learn about recent policy changes in physician payment and to identify the remaining challenges in the use of fee-for-service payment to physicians.

"The parties involved, the frequency of fee schedule updates and the scope of the negotiations vary, but all three countries attempt to balance the interests of payers with those of physician associations," said lead author Michael K. Gusmano, lead study author and a professor at the Rutgers School of Public Health and research scholar at The Hastings Center.

Expanding public insurance and creating universal health care coverage for U.S. residents have been popular - even more so during the COVID-19 pandemic. However, addressing the price of health care is crucial for making universal coverage affordable.

The use of fee-for-service physician payment does create issues, but marking fee-for-service as the major cause of high health care spending in the United States is problematic, especially as countries with lower prices and expenditures use fee-for-service systems, while also providing universal health care to its residents. France, Germany and Japan limit the incomes of physicians by standardizing and adjusting the fees they are paid while using a variety of approaches to limit the volume of services provided.

According to Gusmano -- who is also a member of the Rutgers Institute for Health, Health Care Policy and Aging Research and Rutgers Global Health Institute -- regardless of whether the United States will pursue fundamental policy changes such as Medicare for All or incremental expansion of the Affordable Care Act, both would require that policy makers address health care prices.

A new study adds another layer to the remarkable evolutionary transition of life from water to land on Earth.

The international study of the prehistoric 'relic' tetrapods, including salamander and lobe-finned lungfish and coelacanths, adds another perspective to the evolution of other four-legged land animals, including related animals such as frogs and reptiles which live in both terrestrial and aqueous environments.

Using micro-CT and MRI scans to make 3D models of small animal heads, palaeontology researchers from the University of Edinburgh, University of Calgary and Flinders University shone a light on how the eating habits and brains of the some of the first land-based lifeforms prepared them for life on dry land.

The study published in the journal Royal Society Open Science, Flinders University researcher Dr Alice Clement says the transition from water to land by the earliest tetrapods (backboned animals with four legs rather than fins) in the Devonian Period (359-419 million years ago) is seen as one of the greatest steps in evolution. But she says little is known about the changes in brain morphology over this transition.

"Coelacanth and lungfish are the only lobe-finned fish alive today, but their relatives were the lineage of fish that first left the water to colonise land," Dr Clement says.

"Soft tissue, such as brains and muscles, doesn't survive in fossil records so we studied the brains of living animals, and the internal space of the skull or 'endocast' to figure out what brains of fossils animals must have looked like.

"Our main finding is that salamanders and lungfish have brains quite similar in size and shape to each other, while the coelacanth is a real outlier with a tiny brain."

University of Edinburgh researcher Dr Tom Challands says the high-tech scanning of braincase and jaw structure in six sarcopterygians shows a correlation between how tight or loose the brain fills the skull.

"For the first time, we have been able to demonstrate the interplay between how the jaw muscles affect how the brain sits inside the brain cavity," says first author Dr Tom Challands, from University of Edinburgh's Grant Institute of Earth Sciences.

"As animals made their way out of water and on to land, their food sources changed and the brain had to adapt to a completely new way of living - different sensory processing, different control for movement, balance, and so on," he says.

"Each of these plays against each other and our work basically shows the effect of masticatory (eating) changes are balanced with maintaining a skull that can support and protect the brain."

He says some of the features of these earliest land animals is reflected in other modern animals.

"Moreover we see similarities between the fish and land animals, suggesting that some muscle-brain-skull arrangements were already primed for living on land."

Researchers at the University of Tokyo have identified how the architecture of the cell nucleus can change gene activity in plants. This discovery reveals fundamental knowledge about genome regulation and points towards future methods for potentially manipulating the expression of many genes simultaneously.

The long strands of DNA and the protein machinery needed to turn gene expression on or off are contained, floating within the nuclei of cells. The nucleus is essentially a sack made of a flexible, double-membrane envelope that is supported by an inner, fine-mesh frame of proteins called the nuclear lamina.

"DNA does not drift aimlessly within the nucleus. We expect that there is nonrandom spatial positioning of genes around the nuclear lamina," said Professor Sachihiro Matsunaga who led the research project from the University of Tokyo Graduate School of Frontier Sciences, recently published in Nature Communications.

Gene regulation is often studied at the one-dimensional level of reading the DNA sequence. Additional layers of gene regulation exist in 3D by changing the shape of the DNA strand. Examples include the epigenetic code that dictates how tightly to wind up the strands of DNA and the phenomenon of "kissing genes," where distant segments of the DNA strand fold together and change the activity of the genes that touch each other.

These new results provide evidence for another 3D method of gene regulation involving not just the architecture of the genome, but the architecture of its container, the nucleus.

The scientific community has long known that the shape and size of the nucleus can fluctuate dramatically during a cell's life and that these changes can even be timed as an "internal clock" to determine the age of a cell. However, these discoveries have been made using animal cells. Plants do not possess any genes evolutionarily related to the genes responsible for the nuclear lamina in animals.

"Textbooks usually have a few sentences about animal lamina, but nothing at all to say about plant lamina," said Matsunaga.

Prior work in 2013 by some members of the research team identified a group of four proteins known as CROWDED NUCLEI (CRWN) as the most likely components of the plant nuclear lamina.

To confirm the presence of CRWN proteins in the lamina, researchers first attached fluorescent tags onto the proteins and isolated nuclei out of root cells from young thale cress plants, the roadside weed commonly used in research labs. Then they measured the proteins' location in ultrahigh-resolution microscopy images.

These extremely zoomed-in images show weblike patterns formed by the CRWN proteins around the shell of the nucleus.

Healthy plant cells have an oval-shaped nucleus, looking like a large egg in the center of the cell. Plants genetically altered to lack CRWN proteins have nuclei that are smaller and rounder than normal, likely creating a more crowded environment for the DNA inside.

Researchers then screened the genetically altered plants to see if any other genes had different activity levels when crwn genes were inhibited. Multiple genes known to be involved in responding to copper were less active, indicating that somehow the nuclear lamina is connected to copper tolerance.

Plants that lack CRWN proteins grow shorter than healthy plants even in normal soil. Thale cress with inactive crwn genes planted in soil with high copper levels grew even smaller with a significantly weaker appearance, further evidence that the nuclear lamina has a role in plants' response to environmental stress.

Researchers also visualized the physical location of copper tolerance genes within the nucleus of both normal and high copper levels. In healthy plants in the high copper condition, the copper tolerance genes clustered together and moved even closer to the periphery of the nucleus. The copper tolerance genes appeared to spread out and drift around the nuclei in plants with inactive crwn genes.

"If the plant nucleus has distinct regions for active transcription of DNA, it is likely that those regions will be near the nuclear lamina. This is important and interesting because it is opposite to animal cells, which we know have active regions in the center of nuclei while the periphery is inactive," said Matsunaga.

Most gene editing technologies to increase or decrease gene activity work directly at the one-dimensional level of altering the DNA sequence of the individual gene. Understanding how the nuclear lamina affects gene expression could reveal future methods for altering the activity of many genes at the same time by resculpting the genome and nuclear lamina.

Thanks to modern medicine, humans tend to live much longer than before. Unfortunately, this also opens a wider window to develop chronic diseases with late onset, such as neurodegenerative diseases. Despite considerable research being devoted toward developing a cure for diseases like amyotrophic lateral sclerosis, there are currently no effective treatments.

Most of these neurological diseases have one thing in common: an accumulation of abnormal proteins around neurons. Researchers agree that these improperly fabricated proteins become progressively more toxic by interacting with healthy proteins, disrupting their functions. This picture, however, may be incomplete.

In a recent study published in the Journal of Cell Biology, scientists from Daegu Gyeongbuk Institute of Science and Technology, Korea, have discovered the mechanism of action by which abnormal proteins actually unleash the inherent, but normally latent, toxicity of a natural protein in neurons, causing defects in dendrites (branched parts of a neuron that connect to the next neuron). Therefore, their results provide some clarity as to what actually goes on in diseased neurons. Though the researchers focused on Machado-Joseph disease (MJD), the implications of their results are relevant to other diseases as well.

First, they screened existing data to find candidate genes that were abnormally expressed in MJD patients and mice models. Then, based on the results and using MJD flies as animal models, they identified a problematic transcription factor--a protein that controls and regulates the transcription from DNA of other proteins--called NF-κB. Though this transcription factor is essential for the proper functioning and development of dendrites, the researchers found that something went awry with it when abnormal MJD proteins were around.

Through multiple subsequent experiments, they elucidated a long chain of inhibitory/promoting interactions between native proteins that, at a certain point, clashes with the accumulated abnormal proteins and cascades into a "deregulation" of NF-κB. In turn, this improper regulation unlocks the latent toxicity of NF-κB.

Professor Sung Bae Lee, who led the study, remarks: "Our results open-up a new avenue toward finding cures for neurodegenerative diseases by creating inhibition-based drugs that target improperly regulated latent toxic factors." Such new potential treatments would directly target the early stages of neuron damage, stopping neurological disorders right on their tracks.

This study lights a beacon of hope for many countries that are struggling to deal with the problems of an aging society. "Korea will become a super-aged society in the near future and establishing an appropriate social system to care for and treat people with neurodegenerative diseases is turning into an urgent social issue," comments Professor Lee. This might be the first step in a completely new road toward treating these chronic age-related diseases.

A new study in health care workers led by the Barcelona Institute for Global Health (ISGlobal), an institution supported by "la Caixa" Foundation and the Hospital Clínic of Barcelona, shows that IgA and IgM antibodies to SARS-CoV-2 decay quickly, while IgG antibody levels are maintained for at least three months after infection. The longer follow-up of this cohort will provide much-needed information on the duration of different types of antibodies to SARS-CoV-2, the virus that causes COVID-19, as well as their role in protecting from disease and reinfection.

Since the start of the COVID-19 pandemic, there have been two burning questions: how many people have really been infected, and whether infected people are protected from future reinfections or disease. ISGlobal researchers Carlota Dobaño and Alberto García-Basteiro joined forces to help answer these questions with the SEROCOV1 study, which intends to follow-up a cohort of over 550 health care workers at the Hospital Clínic of Barcelona.

The team showed that, at the peak of the COVID-19 pandemic in Spain, the prevalence of SARS-CoV-2 infection among health care workers was 11.2% (9.2% had antibodies and 2% had active infection detected by PCR). This was slightly higher than the antibody prevalence among the general population in Barcelona (7%), estimated by a national seroprevalence study performed shortly after.

In this new study, researchers from ISGlobal and Hospital Clínic present data after 3 months of follow-up of the same cohort of health care workers. As in the first study, an immune assay based on the Luminex technology developed by Dobaño's team was used to measure three main types of antibodies (IgM, IgG and IgA) directed against the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, which allows it to infect human cells.

The results show that, one month after the initial seroprevalence assessment conducted at the beginning of April 2020, the percentage of participants with evidence of previous or current infection had increased to 15% and that around 60% of the new infections detected were asymptomatic. "In one month, we found 25 new infections among the participants, which is quite high, considering that the peak of the pandemic had passed and the population had been confined for more than one month," says García-Basteiro, who is also a medical doctor at the International Health Service of Hospital Clínic.

Of the 82 seropositive participants detected at month 1, 66 were followed up for an additional two months. By month three, most (78%) had no longer detectable levels of IgM, some (24.5%) had no longer detectable IgA, but the majority (97%) maintained detectable levels of IgG. In fact, IgG levels in some of the participants increased as compared to the first analysis. Symptomatic cases had higher levels of IgA but no differences in the speed at which antibodies declined were observed between asymptomatic and symptomatic infections. Overall, IgG1 levels were higher, although high IgG2 levels correlated with a longer duration of symptoms.

"Our findings confirm that IgM and IgA antibodies rapidly decline within the first month or two after infection, which should be kept in mind when performing seroprevalence studies or interpreting serological results" says Gemma Moncunill, first author of the study. "While the duration of detectable IgG antibodies following infection is still unknown, our results show that they remain relatively stable for at least three months," she adds. The SEROCOV1 team (which includes researchers from several ISGlobal's programs and from the departments of Occupational Health, Preventive Medicine and International Health at Hospital Clínic) plans to follow-up this cohort for a longer time, in order to assess the evolution of the seroprevalence in this high risk group, the duration of detectable antibodies, including several isotypes and subclasses to several antigens, and their role in protecting from disease and reinfection.

An extremely powerful assay to measure SARS-CoV-2 antibodies

In fact, Dobaño's team has recently developed and published a multiplex assay for simultaneously measuring IgM, IgA and IgG to a panel of eight different viral fragments (antigens) from SARS-CoV-2 spike (S), nucleoprotein (N) and membrane (M) proteins. The assays show a specificity of 100% and a sensitivity of over 95%, and have been optimized to minimize processing time. By combining multiple markers, these assays can detect a wider range of low-level antibody responses in the population. "In addition to better assessing SARS-CoV-2 immunity in the population, these assays can be of great value for evaluating markers of protection when testing COVID-19 vaccines," says Dobaño.

There is an idea within the coronavirus research field that there is some kind of T cell abnormality in critically ill COVID-19 patients, but specific details have not yet been clarified. To shed light on the problem, a research collaboration based in Kumamoto University (Japan) has performed a genetic analysis of T cells from lung tissue of COVID-19 patients. Their work revealed abnormalities in T cells that resulted in overactivation that may cause severe pneumonia. The researchers believe that their findings will lead to new ways of avoiding severe pneumonia caused by coronavirus infections.

COVID-19 continues to have an enormous impact on daily lives. Why some people become severely ill while the majority of those infected are asymptomatic or very mildly ill is still a major unanswered question. Risk factors for severe disease include old age, diabetes, obesity, and hypertension. We also know that critically ill patients experience an increase in inflammation factors (inflammatory cytokines) and immune system overreaction, whereas the number of T cells, the "command centers" for immune cells, is significantly reduced in the blood. However, the medical implications of these findings are still unclear.

T cells regulate the activity of the immune system by recognizing specific viruses. They also play important roles in virus elimination and the acquisition of immunity. In this study, researchers focused on T cells to determine the causes of severe pneumonia in COVID-19. CD4+ T cells (helper T cells) work to eliminate viruses from the body by promoting the maturation and activation of cytotoxic T cells, which attack virus-infected cells, and B cells, which produce antibodies. On the other hand, when some CD4+ T cells become highly activated, they express the transcription factor FoxP3 and become regulatory T cells which then act as brakes to inhibit T cell responses. This research analyzed genetic data from bronchoalveolar lavage fluids from lungs of patients with COVID-19 from Wuhan, China to characterize the activity and genetic characteristics of the CD4+ T cells present.

Using state-of-the-art bioinformatics techniques, they found that while T cells were markedly activated in the lungs of patients with severe pneumonia, the induction of FoxP3 was inhibited and the T cell braking function stopped working. While T-cell activities are usually balanced between accelerating and braking, one of the most important brakes was not functioning in severe COVID-19 which may have led to severe pneumonia.

"This study has clarified the association between severe pneumonia and T cell abnormalities. We expect that these findings will lead to a better understanding of the mechanisms of severe pneumonia in patients with COVID-19," said study leader, Associate Professor Masahiro Ono. "A more detailed understanding of the pathogenesis based on this research may contribute to the development of drugs to prevent the development of severe COVID-19 and to diagnose the risk of severe disease."

SINGAPORE, 20 November 2020 - Sometimes, too much of a good thing can turn out to be bad. This is certainly the case for the excessive cell growth found in cancer. But when cancers try to grow too fast, this excessive speed can cause a type of cellular ageing that actually results in arrested growth. Scientists at Duke-NUS Medical School have now discovered that a well-known signalling pathway helps cancers grow by blocking the pro-growth signals from a second major cancer pathway.

Inhibiting Wnt signalling with ETC-159 reactivates the hyperactive RAS-MAPK pathway, causing cells to led undergo senescence.Many cancers are driven by activating mutations in the RAS-MAPK signalling pathway which triggers a cascade of proteins that directs cells to grow, divide and migrate. Mutations in proteins involved in this cascade can turn on genes that make this process go into overdrive, causing cells to grow out of control and aggressively invade other parts of the body. However, too much RAS-MAPK signalling causes cancer cells to prematurely age, and eventually stop growing -- a process called cellular senescence.

Publishing in Cancer Research, the Duke-NUS research team found that another important and well-known biochemical pathway, the 'Wnt' (pronounced 'wint') signalling pathway, allows some cancers to grow by dampening RAS-MAPK signalling.

The team made the discovery while investigating how Wnt proteins regulate pancreatic cancers. Scientists have long observed that genetic mutations causing Wnt proteins to be hyperactive drive many common cancers. The long-held thinking had been that this is because Wnt signalling causes cells to grow too fast. The new findings suggest this idea needs re-evaluation.

By making RAS-MAPK signalling "not too hot and not too cold", Wnt signalling enables cancers to grow steadily instead of heading towards the premature ageing that can be caused by excessive RAS-MAPK signalling. These findings support a growing awareness that cancers need a "just-right" level of RAS-MAPK signalling. Disrupting modulating signals like Wnt can cause cancers to stop growing by forcing them to undergo cellular senescence, similar to just getting old.

Assistant Professor Babita Madan, from Duke-NUS Cancer and Stem Cell Biology (CSCB) Programme, a senior co-author of the study, explained, "Using an experimental drug, ETC-159 , to stop Wnts in multiple models of human pancreatic and colorectal cancer, we found that, unexpectedly, Wnt signalling turns off as many genes as it turns on."

Digging deeper, the team made the connection between Wnt signalling and the diminished activity of the RAS-MAPK pathway. Inhibiting Wnt signalling with ETC-159 and other anti-cancer drugs actually activated RAS-MAPK signalling, while inhibiting cancer growth at the same time.

"This makes sense; while activating mutations in the RAS-MAPK pathway are common in cancer, in isolation, they cause cells to stop growing by causing senescence, a form of ageing-induced arrested cell growth," said Professor David Virshup, Director of the CSCB Programme, and also a senior co-author of the study. (Prof Virshup's seminal research on Wnts led to the development of ETC-159.) "By reining in RAS-MAPK signalling, Wnt signalling achieves Goldilocks' goal of getting it not too hot, not too cold, but just right."

One implication of this research is that it opens up additional ways to attack cancers. The traditional way is to kill cancer cells, however this new study shows that stopping cancer cell growth can be achieved by inducing senescence.

"Cancer is the second leading cause of death globally, responsible for an estimated one in six deaths. In Singapore, cancer cases have been rising over the years, and the number of people living with cancer will continue to increase ," noted Professor Patrick Casey, Senior Vice Dean for Research at Duke-NUS. "Studies like these exemplify the importance of robust fundamental science research to guide new approaches and strategies that have the potential to make a major impact on disease."

Glyphosate is the most commonly used broad-spectrum herbicide. Researchers from the University of Turku in Finland have developed a new bioinformatics tool to predict if a microbe, e.g. a human gut bacterium, is sensitive to glyphosate.

"Glyphosate targets an enzyme called EPSPS in the shikimate pathway. This enzyme is crucial to synthesizing three essential amino acids. Based on the structure of the EPSPS enzyme, we are able to classify 80-90% of microbial species into sensitive or resistant to glyphosate," says Docent Pere Puigbò, developer of the new bioinformatics tool.

Based on the analyses using the new bioinformatics tool, 54% of the human core gut bacterial species are potentially sensitive to glyphosate.

"This groundbreaking study provides tools for further studies to determine the actual impact of glyphosate on human and animal gut microbiota and thus to their health," explains Docent Marjo Helander.

Glyphosate is thought to be safe to use because shikimate pathway is found only in plants, fungi and bacteria. However, glyphosate may have a strong impact on bacterial species in the human microbiome, and several recent studies have shown that perturbations in the human gut microbiome are connected to many diseases. Therefore, the widespread use of glyphosate may have a strong effect on gut microbiomes as well as on human health.

The dominance of this herbicide in the pesticide market is mainly attributed to the use of transgenic crops, such as soy, corn and canola, which are often grown as glyphosate-resistant varieties outside Europe. In Europe, glyphosate is commonly used to desiccate cereal, bean and seed crops before harvest. It is also used to eradicate weeds prior to sowing in no-till cropping systems.

The risk to come across glyphosate residue in food that has been grown in Finland is small, because desiccation of the cereal fields by glyphosate is not allowed in Finland.

A rich and diverse microbial community is living in soil, on plant surfaces, and in animal guts. It is possible that even low glyphosate residue may indirectly affect pest and pathogen occurrence in these communities.

"In addition to bioinformatics, we need experimental research to study the effects of glyphosate on microbial communities in variable environments," Helander adds.