Culture

What The Study Did: Researchers in this observational study of 43,000 twins born in Scotland used linked maternal and educational data to identify the optimal gestation week for the birth of infant twins associated with the lowest risk of short- and long-term adverse outcomes, specifically perinatal death and special education needs later on in school.

Author: Sarah Murray, Ph.D., M.R.C., of the University of Edinburgh in Scotland, is the corresponding author.

 To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapediatrics.2019.6317)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

In a new publication in Nature Plants, assistant professor of Plant Science at the University of Maryland Yiping Qi has established a new CRISPR genome engineering system as viable in plants for the first time: CRISPR-Cas12b. CRISPR is often thought of as molecular scissors used for precision breeding to cut DNA so that a certain trait can be removed, replaced, or edited. Most people who know CRISPR are likely thinking of CRISPR-Cas9, the system that started it all. But Qi and his lab are constantly exploring new CRISPR tools that are more effective, efficient, and sophisticated for a variety of applications in crops that can help curb diseases, pests, and the effects of a changing climate. With CRISPR-Cas12b, Qi is presenting a system in plants that is versatile, customizable, and ultimately provides effective gene editing, activation, and repression all in one system.

"This is the first demonstration of this new CRISPR-Cas12b system for plant genome engineering, and we are excited to be able to fill in gaps and improve systems like this through new technology," says Qi. "We wanted to develop a full package of tools for this system to show how useful it can be, so we focused not only on editing, but on developing gene repression and activation methods."

It is this complete suite of methods that has ultimately been missing in other CRISPR systems in plants. The two major systems available before this paper in plants were CRISPR-Cas9 and CRISPR-Cas12a. CRISPR-Cas9 is popular for its simplicity and for recognizing very short DNA sequences to make its cuts in the genome, whereas CRISPR-Cas12a recognizes a different DNA targeting sequence and allows for larger staggered cuts in the DNA with additional complexity to customize the system. CRISPR-Cas12b is more similar to CRISPR-Cas12a as the names suggest, but there was never a strong ability to provide gene activation in plants with this system. CRISPR-Cas12b provides greater efficiency for gene activation and the potential for broader targeting sites for gene repression, making it useful in cases where genetic expression of a trait needs to be turned on/up (activation) or off/down (repression).

"When people think of CRISPR, they think of genome editing, but in fact CRISPR is really a complex system that allows you to target, recruit, or promote certain aspects already in the DNA," says Qi. "You can regulate activation or repression of certain genes by using CRISPR not as a cutting tool, but instead as a binding tool to attract activators or repressors to induce or suppress traits."

This ability gives CRISPR-Cas12b an edge over CRISPR-Cas12a, particularly when gene activation is the goal. Additionally, the system retains all the positives that were inherent in CRISPR-Cas12a for plants, including the ability to customize cuts and gene regulation across a broad range of applications. In fact, Qi and his lab were even able to repurpose the CRISPR-Cas12b system for multiplexed genome editing, meaning that you can simultaneously target multiple genes in a single step.

"Added complexity allows targeting of more specific or other effectors for gene activation, repression, or even epigenetic changes," says Qi. "This system is more versatile because we can play with more modifications, more domains, and there are therefore more opportunities to engineer the whole system. Only when you have this kind of hybrid system with more complexity do you get the most robust gene activation and editing capabilities."

The initial work for CRISPR-Cas12b completed in this paper was conducted in rice, which is already a major global crop. However, Qi and his lab hope to explore more systems to further enhance and improve plant genome engineering, including developing applications to additional crops.

"This type of technology helps increase crop yield and sustainably feed a growing population in a changing world. In the end, we are talking about broad impact and public outreach, because we need to bridge the gap between what researchers are doing and how those impacts affect the world," stresses Qi.

A research group led by Simone Fabiano at the Laboratory of Organic Electronics, Linköping University, has created an organic material with superb conductivity that doesn't need to be doped. They have achieved this by mixing two polymers with different properties.

In order to increase the conductivity of polymers, and in this way obtain higher efficiency in organic solar cells, light-emitting diodes and other bioelectronic applications, researchers have until now doped the material with various substances. Typically, this is done by either removing an electron or donating it to the semiconductor material with a dopant molecule, a strategy that increases the number of charges and thereby the conductivity of the material.

"We normally dope our organic polymers to improve their conductivity and the device performance. The process is stable for a while, but the material degenerates and the substances we use as doping agents can eventually leach out. This is something that we want to avoid at any cost in, for example, bioelectronic applications, where the organic electronic components can give huge benefits in wearable electronics and as implants in the body", says Associate Professor Simone Fabiano, head of the Organic Nanoelectronics group within the Laboratory of Organic Electronics at Linköping University.

The research group, with scientists from five countries, has now succeeded in combining the two polymers, producing a conducting ink that does not require any doping to conduct electricity. The energy levels of the two materials perfectly match, such that charges are spontaneously transferred from one polymer to the other.

The results have been published in Nature Materials.

"The phenomenon of spontaneous charge transfer has been demonstrated before, but only for single crystals on a laboratory scale. No one has shown anything that could be used at an industrial scale. Polymers consist of large and stable molecules that are easy to deposit from solution, and that's why they are well suited for large-scale use as ink in printed electronics", says Simone Fabiano.

Polymers are simple and relatively cheap materials, and are commercially available. No foreign substances leach out from the new polymer mixture. It remains stable for a long time and withstands high temperatures. These properties are important for energy harvesting/storage devices as well as wearable electronics.

"Since they are free of doping agents, they are stable over time and can be used in demanding applications. The discovery of this phenomenon opens completely new possibilities for improving the performance of light-emitting diodes and solar cells. This is also the case for other thermoelectric applications, and not least for research within wearable and close-body electronics", says Simone Fabiano.

"We have involved scientists at Linköping University and Chalmers University of Technology, and experts in the US, Germany, Japan, and China. It has been a really great experience to lead this work, which is a large and important step in the field", he says.

Principal funding for the research has come from the Swedish Research Council and the Wallenberg Wood Science Center. It has also been conducted within the framework for the strategic initiative in advanced functional materials, AFM, at Linköping University.

"Fundamentally, doping in conducting polymers, generating high electrical conductivity, has so far only been achieved by combining a non-conducting dopant with a conducting polymer. Now, for the first time, the combination of two conducting polymers renders a composite system that is highly stable and highly conducting. This discovery defines a major new chapter in the field of conducting polymers, and will spark many novel applications and interest world-wide", says professor Magnus Berggren, director of Laboratory of Organic Electronics at Linköping University.

Astronomers working on 'first light' results from a newly commissioned telescope in Chile made a chance discovery that led to the identification of a rare eclipsing binary brown dwarf system.

The discovery, published today in Nature Astronomy, was led by an international team of researchers, including scientists at the University of Birmingham, working on the SPECULOOS (Search for habitable Planets EClipsing ULtra-cOOl Stars) project. SPECULOOS involves the University of Birmingham in collaboration with the University of Liège, the University of Cambridge, the University of Bern, the Institute of Astrophysics of the Canaries, the Massachusetts Institute of Technology, and other partner institutions.

SPECULOOS' mission is to investigate planets surrounding ultra-cool dwarfs, a category that includes the smallest stars that exist, as well as objects called 'brown dwarfs'. Brown dwarfs are 'sub-stellar' objects, meaning they have less mass than a star but more than a planet. Brown dwarfs are unable to sustain the fusion of hydrogen into helium, a process that powers the light from normal stars like the Sun.

Astronomers predict that these ultra-cool dwarfs should host large populations of close-by, potentially habitable rocky planets, offering a wealth of opportunity to explore a diversity of atmospheres and climates. An example is the 7-planet system TRAPPIST-1, which was discovered by members of the same team.

Soon after the construction the first SPECULOOS telescopes, and during testing observations, the team targeted the known brown dwarf 2MASSW J1510478-281817, since renamed 2M1510, in the constellation Libra. The SPECULOOS observations picked up a distinct signal that led the researchers to speculate that 2M1510 might be two brown dwarfs instead of one, in orbit around each other.

Dr Michaël Gillon, Principal Investigator of the SPECULOOS project, said: "Among the first test observations we performed, we turned one of our telescopes to a known brown dwarf. But suddenly the object appeared to get dimmer for about 90 minutes, which indicated an eclipse just took place."

Artem Burdanov, a postdoctoral researcher at MIT added: "We rapidly realised that we were probably looking at two eclipsing brown dwarfs, one passing in front of the other, a configuration which is much rarer than planetary systems."

The researchers were able to confirm their hypothesis using two more powerful telescopes, the 10m Keck Telescope in Hawaii, and the 8m Very Large Telescope in Chile. The VLT is based at the same site as the SPECULOOS telescopes used to make the observations. Keck and VLT have sensitive spectrometers that can be used to measure the velocities of celestial objects. In the case of 2M1510, the astronomers detected the velocities of both brown dwarfs as they orbit one another.

"From the very first spectrum we obtained, we could tell we had an exciting binary discovery," says Adam Burgasser, professor of Physics at the University of California, San Diego, who led the spectroscopic analysis. "It was thrilling to see the absorption lines move back and forth in perfect synchronicity, and this allowed us to measure the mass of the binary."

The detection of eclipsing brown dwarfs is extremely rare - only one other such system has been identified to date. These systems provide astronomers the opportunity to measure the brown dwarfs' radii and masses directly, which are fundamental quantities for theoretical models. 2M1510 is also special in that it is among the very few brown dwarfs that has a known age, due to its membership in a nearby cluster of young stars called the Argus moving group.

"Collecting a combination of mass, radius and age is really rare for a star, let alone a brown dwarf," said Dr Amaury Triaud, from the School of Physics & Astronomy of the University of Birmingham, who was the lead author of the study. "Usually one or more of these measurements is missing. By drawing all these elements together, we were able to verify theoretical models for how brown dwarfs cool, models which are over 30 years old. We found the models match remarkably well with the observations, a testament to human ingenuity."

Researchers at Princeton University have identified a set of human proteins that the hepatitis B virus (HBV) uses to establish itself permanently inside liver cells. The study, published in the journal Nature Microbiology, could suggest new directions for therapies to treat chronic HBV infection, a condition that increases the risk of developing liver cancer and is responsible for almost 900,000 deaths worldwide each year.

Over 250 million people are chronically infected with HBV. The condition remains incurable and patients currently require lifelong treatment with antiviral drugs that still leave them at an increased risk of developing not only liver cancer but also other liver diseases, including liver cirrhosis.

When HBV first enters its host's liver cells, its DNA genome contains several gaps and other imperfections that need to be repaired before the virus can establish a permanent infection. To do this, HBV must enlist the help of its host cell's DNA repair machinery, but exactly which components of this machinery the virus needs has remained a mystery for decades.

To identify the components required to repair HBV DNA, Alexander Ploss, an associate professor of molecular biology at Princeton, and postdoctoral fellow Lei Wei recreated the process in a test tube. The researchers tested dozens of DNA repair factors and found that a set of just five factors purified from human cells was sufficient for the repair process. Removing even one of these five factors prevented the repair process from being successfully completed, suggesting that targeting any of these five factors can potentially prevent HBV infection.

One of the essential repair factors, an enzyme known as DNA polymerase delta, is inhibited by a drug called aphidicolin. Wei and Ploss found that aphidicolin treatment can prevent the repair of HBV DNA, not only in the test tube but also in virally infected liver cells.

Ploss hopes that further studies will reveal exactly how the five repair factors work together to fix the HBV genome. "Our study is an excellent starting point to finally answer the decades-old question of how the stable form of the virus's DNA is generated," Ploss said. "Until we understand this process, which is crucial for HBV persistence, targeted clinical therapies that can completely clear the infection will remain out of reach."

Skin diseases affect half of the world's population, but many treatments are not effective, require frequent injections, or cause significant side effects. But what if there was a treatment that eliminated injections, reduced side effects, and increased drug effectiveness? A skin therapy with these properties may be on the horizon from Mark Prausnitz's Drug Delivery Lab at the Georgia Institute of Technology.

In a study to be published on March 9, 2020, in the journal Nature Medicine, Prausnitz and his team of researchers report on research using a skin cream infused with microscopic particles, named STAR particles. To the naked eye, STAR particles look like a powder, but closer inspection reveals tiny microneedle projections sticking out from the particles like a microscopic star. A particle-containing cream could potentially facilitate better treatment of skin diseases including psoriasis, warts, and certain types of skin cancer.

Following the successful study of his microneedle patches for vaccination, Prausnitz and postdoctoral scholar Andrew Tadros have advanced the technology with the objective of treating skin conditions by simply rubbing STAR particles on the skin. In a study in mice, skin cancer tumors were treated with 5-fluorouracil, a cancer therapy drug that works by limiting replication of abnormal cells. Tumor growth was inhibited only when the drug was rubbed on the skin above the tumor in combination with STAR particles, whereas the drug without STAR particles was much less effective.

"Andrew [Tadros] and I teamed up to adapt the microneedle technology and make it useful, especially in dermatology," said Prausnitz, Regents Professor and J. Erskine Love Jr. Chair in the Georgia Tech School of Chemical and Biomolecular Engineering. "Microneedle patches are good at administering drugs or vaccines to a small area of skin, but many dermatological conditions are spread over larger areas. Rather than trying to make really big patches, which would be difficult to use, we ultimately arrived at STAR particles that can be rubbed on the skin - just like any skin lotion - and poke tiny holes in the skin to better deliver drugs."

STAR particles are mixed into a therapeutic cream or gel and applied to the skin, painlessly creating micropores in the skin's surface that dramatically - but temporarily - increase skin permeability to drugs.

The problem is that most drugs are not absorbed well into skin, so often a drug needs to be given to the whole body by pill or injection just to treat the skin. Exposing the whole body to dermatological drugs often leads to unwanted side effects such as nausea or organ damage. Fortunately, the barrier layer of skin - called the stratum corneum - is thinner than the width of a human hair. While STAR particles are tiny, they are large enough to poke through this barrier layer when rubbed on the skin and let drugs enter the body through the micropores without pain.

More effectively delivering medicine directly to where it's needed could improve treatments for patients dealing with many kinds of skin diseases. Oral methotrexate is a common course of treatment for psoriasis - a dermatological condition in which skin cells build up and form scales and itchy, dry patches - but because the therapy is systemic, it exposes the whole body to a drug that can cause serious side effects like diarrhea, hair loss, and liver problems.

Prausnitz said doctors must weigh the costs of exposing the whole body to a drug versus treating psoriasis topically, which may be less effective. That's where STAR particles could provide value.

"Based on our studies, you could feasibly combine methotrexate with STAR particles into a cream and localize the therapy where it is needed," Tadros said. "The STAR particles in the cream would enable drugs to get into skin and treat diseases locally, right where it needs to be treated, and without exposing the whole body to the drug."

Skin creams that deliver drug therapies could widen the range of compounds administered topically, Prausnitz and Tadros suggested. Non-medicinal creams infused with STAR particles have been tested on humans, who generally reported experiencing a mild and comfortable tingling sensation, but no pain or skin irritation.

Each STAR particle is no larger than a millimeter, with sharp and strong microneedle structures protruding from the surface that are 100 to 300 microns long. While the particles are barely perceptible to the human eye, the microneedles on them are not. Moreover, when mixed in with a cream, the STAR particles disappear from sight. The research team uses a laser to make the particles from ceramic materials like titanium dioxide, a common ingredient in sunscreens and other cosmetic products.

"Titanium dioxide is a common material that we have adapted to make STAR particles," said Prausnitz. "The material is well established, but it's the star-shaped geometry of the particle that's new."

Prausnitz said he hopes to scale the STAR particles for commercial use not only in dermatology, but for cosmetic purposes as well, where they could potentially deliver anti-aging treatments without injections or other harsh procedures.

"Our research philosophy is to develop an understanding of biomedical science and engineering technology, and then bring them together to create something that is practical and can benefit patients," Prausnitz said.

Prausnitz and Tadros have started a new company called Microstar Biotech that's working to commercialize the STAR particle technology.

"Georgia Tech has been instrumental in enabling us to bring this research to the forefront of the medical field, but universities can only do so much," said Prausnitz. "Commercialization by a company is the mechanism to bring this novel research to the public for their benefit, and I'm hopeful for the future of STAR particles."

St. Jude Children's Research Hospital scientists have discovered a gene associated with about half of glucocorticoid resistance in children with the most common pediatric cancer. Researchers have also identified a drug that may counter resistance. The research appears today in the journal Nature Cancer.

St. Jude researchers developed a novel strategy to identify genes that cause leukemia cells to be resistant to chemotherapy. The approach extends the momentum generated by whole genome sequencing and shows the power of incorporating other dimensions of the genome.

Investigators used the method to identify a new gene, CELSR2, associated with acute lymphoblastic leukemia (ALL) resistance to glucocorticoids. It is one of 14 newly identified genes implicated in resistance to steroids, drug that are essential for curing ALL. The findings led investigators to the drug venetoclax and evidence that it may reverse resistance.

"Drug resistance is a major cause of treatment failure for children and adults with disseminated cancers like leukemia," said corresponding author William Evans, Pharm.D., of the St. Jude Department of Pharmaceutical Sciences. Although about 90% of children and adolescents with acute lymphoblastic leukemia (ALL) now become long-term survivors, ALL remains a leading cause of pediatric cancer deaths and is less curable in adults.

"Steroids play an essential role in the treatment of acute lymphoblastic leukemia," Evans said. "About 20% of children with acute lymphoblastic leukemia and twice as many adults are highly resistant. Yet, the underlying cause of resistance often remains unknown."

Mining data for answers

For answers, researchers measured six types of genomic and epigenetic features in leukemia cells, then created a computational pipeline to aggregate each genetic feature to individual genes. The goal was to determine which genes were most strongly associated with steroid resistance.

Then researchers used cutting-edge methods like CRISPR gene editing and a sophisticated statistical tool to prioritize genes for further investigation.

This study focused on leukemia resistance to steroids such as prednisone and dexamethasone. The pipeline is also being used to study leukemia resistance to 14 other cancer drugs.

The methods included analyzing and validating data from about 500 St. Jude patients newly diagnosed with ALL. Investigators looked for connections between steroid resistance and gene variations, gene expression, gene regulation and other factors.

Co-author Cheng Cheng, Ph.D., of the St. Jude Department of Biostatistics and his colleagues developed a statistical tool to rank the contribution of more than 19,700 genes to steroid resistance. The tool is called truncated aggregation of P-values or TAP.

Working in a human ALL cell line, investigators used CRISPR gene editing to knock out genes across the genome as another way to recognize drug resistance.

Along with identifying novel genes, the strategy identified 78% of the 38 genes known to cause steroid resistance and 100% of the molecular pathways involved.

Foiling steroid resistance

CELSR2 was the gene most strongly associated with steroid resistance. Decreased CELSR2 expression in leukemia cells from patients and ALL cells in the lab was associated with increased steroid resistance. About half of steroid-resistant ALL in children and adults in this study had reduced CELSR2 expression.

Researchers showed that reduced levels of CELSR2 protein likely contributes to steroid resistance by promoting increased expression of the protein BCL2. The protein inhibits a cell death pathway. Venetoclax, a drug commonly used to treat leukemia subtypes common in older adults, inhibits BCL2.

In a model system in the laboratory and in mice with human ALL expressing low CELSR2, venetoclax mitigated steroid resistance by inhibiting BCL2. Mice with steroid-resistant human ALL lived longer when steroid treatment was combined with venetoclax.

"The findings point to the potential benefit of combining venetoclax with current remission-induction therapy as a strategy to overcome steroid resistance and improve the effectiveness of ALL chemotherapy," Evans said.

A master control region of a protein linked to Parkinson's disease has been identified for the first time.

The finding, made by scientists from the University of Leeds' Astbury Centre for Structural Molecular Biology, provides a new target for the development of therapies to try and slow down or even prevent the disease.

Parkinson's affects more than 10 million people across the world, causing neurodegeneration and difficulties with movement, which increase over time. There is currently no cure for the disease.

The study focused on a protein called alpha-synuclein, which is linked to the onset and progression of Parkinson's disease.

Alpha-synuclein is found in healthy cells in the nervous system, but problems arise when it clumps together, or aggregates, into plaques known as amyloid that can disrupt normal function.

A short region of the alpha-synuclein protein, known as NAC, was assumed to be key to Parkinson's disease, as it is particularly aggregation-prone.

In this study, researchers Dr Ciaran Doherty and PhD researcher Sabine Ulamec from the Astbury Centre at Leeds, found that two regions outside of NAC play a critical role in controlling amyloid formation of alpha-synuclein.

Removing these regions switched off aggregation in a laboratory setting, even though NAC was still present.

To investigate the importance of these 'master controller' regions in protein aggregation in living cells, the team joined forces with Dr Patricija van Oosten Hawle and her students, also members of the Astbury Centre in Leeds.

They inserted alpha-synuclein and a variant of the protein lacking the master controller regions in to the muscle cells of nematode worms and monitored aggregation of the proteins and their effects on the mobility of the worms - a commonly used model organism in research into neurodegenerative disorders.

When the control regions were deleted in the worms, alpha-synuclein no longer formed aggregates, and the worms were healthier and more mobile, even in old age, compared to worms expressing the normal alpha-synuclein protein.

Their findings are published today in Nature Structural and Molecular Biology.

Investigator Professor Sheena Radford, FMedSci FRS, Director of the Astbury Centre for Structural Molecular Biology at the University of Leeds, said: "In trying to tackle diseases like Parkinson's, the first problem is identifying the key areas to target with small-molecules or protein-based medicines, as these proteins do not have a fixed structure, ruling out traditional methods of structure-based drug design.

"Finding a previously over-looked target to focus future efforts on is very exciting.

"Our discovery of master controller regions may open up new opportunities to understand how mutating the protein sequence that causes disease could help us find the Achilles heel for these proteins to target for future therapeutic intervention."

The research was funded by the Biotechnology and Biological Sciences Research Council, European Research Council, Wellcome Trust and NC3Rs.

Function vs malfunction

Whilst alpha-synuclein is linked to Parkinson's disease, it is also thought to be involved in signalling across nerves in the brain. This involves the release of neurotransmitters which occurs when small carrier structures called vesicles, containing vital signalling molecules, fuse with cellular membranes to release their cargo. This is important for signalling in the nervous system.

To investigate whether the master controller regions identified in alpha-synuclein are also important for its function, the researchers looked at whether the modified protein could still fuse vesicles together.

They found that while removing the master control region prevented aggregation, it also prevented vesicle fusion. This suggests a tug-of-war between the function and harm - aggregation - of the master controller region.

Fine tuning of this balance may enable therapeutic opportunity to reduce aggregation whilst maintaining function, and it is the need to rebalance these two opposing roles of the master controller region that will be the next challenge.

The co-investigator of the study, Dr David Brockwell, said: "Our hope is that future research might target this master controller, to allow the development of a therapy which could tweak the conformation or stickiness of alpha-synuclein in the brain with only minimal changes to its function."

"We hope that such a strategy might be able to help people with early signs of Parkinson's, by reducing the formation of amyloid plaques in the brain, and to delay the progression of the disease."

Understanding life in molecular detail

To study how the master controller region affects aggregation, the team of researchers used a powerful technology called nuclear magnetic resonance (NMR) spectroscopy.

Following more than £5 million investment in 2016, the University's Astbury Centre for Structural Molecular Biology was able to purchase and install a powerful 950MHz NMR instrument, one of the most powerful in the country. This NMR machine allows researchers to advance our knowledge of how changes in protein structure can trigger diseases like Parkinson's.

Ms Ulamec said: "Our state-of-the-art NMR machines allowed us to map the interactions made between the master controller region and the rest of the protein. This has revealed a surprising complexity in a protein commonly thought to be without a fixed structure.

"Using NMR we have managed to build a detailed picture of this master controller region, which exerts its effect over NAC by forming key interactions that drive aggregation.

"Future research can also look at whether other proteins involved in different diseases also have master controller regions of aggregation, which could open up new avenues for therapeutic development in several neurodegenerative diseases which involve the aggregation of disordered proteins like alpha-synuclein."

Patients in a hospital's intensive care unit are kept under close observation: clinicians continuously monitor their vital signs such as their pulse, blood pressure and blood oxygen saturation. This furnishes doctors and nurses with a wealth of data about the condition of their patients' health. Nevertheless, using this information to predict how their condition will develop or to detect life-threatening changes far in advance is anything but easy.

Researchers at ETH Zurich and Inselspital, Bern University Hospital, have now developed a method that cleverly combines a patient's various vital signs with other medically relevant information. Fusing this data enables critical circulatory failure to be predicted several hours before it occurs. In future, the aim is to use the method for real-time evaluation of hospital patients' vital signs to provide an early warning system for the medical staff on duty, who, in turn, can take appropriate action at an early stage.

Extensive dataset

The researchers were able to develop this approach thanks to the wealth of data supplied by the Department of Intensive Care Medicine at Bern University Hospital. In 2005, it became the first large intensive care unit in Switzerland to start storing granular, high-resolution data for intensive care patients in digital form. For their study, the researchers used anonymised data from 36,000 admissions to intensive care units, which came exclusively from patients who agreed to their data being used for research purposes.

On the initiative of Tobias Merz, research associate and former senior physician at the Department of Intensive Care Medicine at the University Hospital in Bern and who now works at Auckland City Hospital, researchers led by ETH professors Gunnar Rätsch and Karsten Borgwardt analysed this data using machine learning methods. "The algorithms and models we developed were able to predict 90 percent of all circulatory failures in the dataset we used. In 82 percent of the cases, the prediction came at least two hours in advance, which would have given doctors at least two hours to intervene," explains Rätsch, Professor of Biomedical Informatics at ETH Zurich.

Relatively few variables required

For each patient in their study, the researchers had several hundred different variables combined with other medical information at their disposal. "However, we were able to show that just 20 of these variables are sufficient to make accurate predictions. These include blood pressure, pulse, various blood values, the patient's age and the medication administered," explains Borgwardt, Professor of Data Mining at ETH Zurich.

To further improve the quality of the predictions, the researchers plan to incorporate patient data from other large hospitals into future analyses. In addition, they will make the anonymised dataset, the algorithms and the models available to other scientists.

Small number of highly relevant alarms

"Preventing circulatory failure is a crucial aspect of patient treatment in intensive care. Even short periods of inadequate circulation significantly increase the mortality of patients," Merz says. "In intensive care units today, we have to deal with a multitude of alarm systems, but they're not very accurate. Often, they trigger false alarms or they give us only a short advance warning, which can delay initiation of adequate measures to support a patients circulation," he says. With their approach, the researchers aim to replace the large number of alarms with a few, highly relevant and early alarms. This is possible, as the study showed that the new method could cut the number of alarms by 90 percent.

Some further development work is required to make the method ready for use as an early warning system. Rätsch explains that the first prototype already exists, but before the system can be employed in everyday clinical practice, its reliability must be demonstrated in clinical studies.

Québec City, March 9, 2020 - Bacteria may be involved in the development of type 2 diabetes, according to a study published today in Nature Metabolism by researchers from Université Laval, the Québec Heart and Lung Institute (IUCPQ), and McMaster University.

The authors found that the blood, liver, and certain abdominal fat deposits in diabetics have a different bacterial signature than in non-diabetics.

The researchers demonstrated this using blood and tissue samples from 40 patients suffering from severe obesity taken during bariatric surgery. Half of the participants suffered from type 2 diabetes, while the other subjects showed insulin resistance without being diabetic.

The researchers identified the bacterial genetic material in each of the tissues sampled, which came from the liver and three abdominal fat deposits. Based on the type of bacteria present and their relative abundance, the researchers were able to determine the bacterial signature for each tissue.

Their analysis revealed that the bacterial signature in diabetics was not the same as in non-diabetics. It also showed that the total number of bacteria varied from one tissue to another, and was highest in the liver and the greater omentum (a fatty tissue connecting the stomach and the transverse colon), two areas that play an important role in metabolic regulation.

"Our findings suggest that in people suffering from severe obesity, bacteria or fragments of bacteria are associated with the development of type 2 diabetes," said the lead author, André Marette, professor at Université Laval's Faculty of Medicine and researcher at the IUCPQ research centre.

According to the study, the bacterial genetic material detected in the tissues most likely comes from the intestine.

"We know that the intestinal barrier is more permeable in obese patients," said Professor Marette. "Our hypothesis is that living bacteria and bacterial fragments cross this barrier and set off an inflammatory process that ultimately prevents insulin from doing its job, which is to regulate blood glucose levels by acting on metabolic tissues."

Fernando Forato Anhê, an author on the paper and a postdoctoral research fellow at McMaster, added: "Location, location location...Beyond knowing the names of bacteria, their location is key to understanding how gut microbes influence host metabolism."

Professor Marette and his collaborators will be able to pursue their research further thanks to a $2 million grant they were recently awarded by the Canadian Institutes of Health Research.

"Our next objective is to determine if the bacteria found in the liver and fat deposits of people suffering from severe obesity are also present in those who are overweight or moderately obese," said André Marette.

"We also want to see if certain pathogenic bacteria found in the tissues can trigger type 2 diabetes in an animal model. And lastly, we want to find out if certain beneficial bacteria found in these tissues can be used to prevent the development of the disease. If so, they might lead us to a new family of probiotic bacteria or a source of bacteria-based treatments to help fight diabetes," he said.

Natural environments are constantly changing. If the change is a familiar one--like the shift from day to night or fluctuation in food supply--organisms use gene regulation to adapt, allowing individual genes to be turned on and off as needed. However, an organism may face fundamentally new conditions for which it has not yet evolved an adequate gene regulation mechanism. The evolution of such a mechanism takes a very long time--up to millions of years--, as the process depends on rare point mutations to occur, and the right mutations may not happen fast enough if conditions change rapidly. PhD students Isabella Tomanek and Rok Grah from the groups of Calin Guet and Gašper Tkačik at the Institute of Science and Technology Austria (IST Austria) and Jonathan Bollback at University of Liverpool, UK, were thus wondering if another evolutionary solution--gene copying--may step in to support the survival of a bacterial population under rapidly changing conditions.

Copy/paste and delete create genetic diversity

Like any other mutation, the copying of genes happens spontaneously and all the time. "A typical bacterial population will contain a large fraction of cells with a duplication somewhere in their chromosome", explains Isabella Tomanek. "We looked at over 40 generations of individual bacteria and visualized these duplications, but we also saw that they are quite unstable: The second copy of a gene may be amplified further in the next generations to come and thus lead to large copy numbers, but the duplication may also be deleted again right away, and the individual falls back to the original single-gene state." This instability causes variation in gene copy numbers and thus in gene expression levels of a population (as any extra gene copy boosts the expression of a gene). In turn, selection could act on the resulting diversity of copy numbers--and pick those bacteria with the "right" amount of copies/level of gene expression.

Quick changes ask for quick strategies

To test their hypothesis, the scientists investigated the expression of a model gene relevant for the growth of Escherichia coli in two different sugar environments: galactose on the one hand, selecting for high expression of the model gene to support growth (environment A), and a chemical analog of galactose on the other hand, which supports growth only when gene expression is low (environment B). By switching between these two opposing environments following a 24-hour rhythm, the scientists simulated a relatively rapid change of growth conditions selecting for the regulation of the model gene. As expected, Tomanek et al. observed that the populations tuned their gene expression to the two environments as needed--high gene expression in environment A as opposed to low gene expression in environment B.

These experimental results were taken up by Rok Grah from the biophysics theory group of Gašper Tkačik, who cast the data into a population-dynamics model. Uniting their work in this study, the three groups have demonstrated for the first time that gene copying serves as a strategy to tune the level of gene expression when gene regulation is required but no other genetic regulatory mechanism is in place. Rok Grah: "Most notably, the copy/paste and delete strategy comes into effect on ecological timescales, i.e. before slower evolutionary solutions like gene regulation on the level of single cells can evolve by adaptation through point mutations. And, as we could show in our model, since any genomic region can basically be amplified, the described mechanism cannot only act on any bacterial gene but it is also applicable, in principle, to any other organism."

Implications for antibiotic resistance

The broad applicability of the genetic mechanism described in this study has potential implications for an equally diverse number of biological phenomena. For instance, it may lead to failure of antibiotics because, due to a difference in copy numbers, bacteria from one and the same patient show different levels of antibiotic resistance. This phenomenon called heteroresistance makes it hard for physicians to estimate just how much antibiotic is needed to successfully fight a bacterial infection.

CHAPEL HILL, NC - March 9, 2020 - Scientists at the UNC School of Medicine and colleagues created a new computational tool called H-MAGMA to study the genetic underpinnings of nine brain disorders, including the identification of new genes associated with each disorder.

The research, published in Nature Neuroscience, revealed that genes associated with psychiatric disorders are typically expressed early in life, highlighting the likelihood of this early period of life as critical in the development of psychiatric illnesses. The researchers also discovered that neurodegenerative disorder-associated genes are expressed later in life. Lastly, the scientists linked these disorder-associated genes to specific brain cell types.

"By using H-MAGMA, we were able to link non-coding variants to their target genes, a challenge that had previously limited scientists' ability to derive biologically meaningful hypotheses from genome-wide association studies of brain disorders," said study senior author Hyejung Won, PhD, assistant professor of genetics at the UNC School of Medicine and member of the UNC Neuroscience Center. "Additionally, we uncovered important biology underlying the genetics of brain disorders, and we think these molecular mechanisms could serve as potential targets for treatment."

Brain disorders such as schizophrenia and Alzheimer's disease are among the most burdensome disorders worldwide. But there are few treatment options, largely due to our limited understanding of their genetics and neurobiological mechanisms. Genome-wide association studies (GWAS) have revolutionized our understanding of the genetic architecture related to many health conditions, including brain-related disorders. GWAS is a technique that allows researchers to compare genetic sequences of individuals with a particular trait - such as a disorder - to control subjects. Researchers do this by analyzing the genetic sequences of thousands of people.

"To date, we know of hundreds of genomic regions associated with a person's risk of developing a disorder," Won said. "However, understanding how those genetic variants impact health remained a challenge because the majority of the variants are located in regions of the genome that do not make proteins. They are called non-coding genetic variants. Thus, their specific roles have not been clearly defined."

Prior research suggested that while non-coding variants might not directly encode proteins, they can interact with and regulate gene expression. That is, these variants help regulate how genes create proteins, even though these variants do not directly lead to - or code for - the creation of proteins.

"Given the importance of non-coding variants, and that they make up a large proportion of GWAS findings, we sought to link them to the genes they interact with, using a map of chromatin interaction in the human brain," Won said. Chromatin is the tightly packed structure of DNA and proteins inside cells, folded in the nucleus in a way to maintain normal human health.

Won and colleagues used this map to identify genes and biological principles underlying nine different brain disorders, including psychiatric conditions such as schizophrenia, autism, depression, and bipolar disorder; and neurodegenerative disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).

Using the computational tool H-MAGMA, Won and colleagues could link non-coding variants to their interacting genes - the genes already implicated in previous GWAS findings.

Another important question in brain disorders is to identify cellular etiology - the cells involved in the root cause of disease. This is especially critical as the brain is a complex organ with many different cell types that may act differently in response to treatment. In the attempt of finding critical cell types for each brain disorder, the researchers found that genes associated with psychiatric disorders are highly expressed in glutamatergic neurons, whereas genes associated with neurodegenerative disorders are highly expressed in glia, further demonstrating how the two disorder clusters diverge from each other.

"Moreover, we classified biological processes central to the disorders," Won said. "From this analysis, we found that the generation of new brain cells, transcriptional regulation, and immune response as being essential to many brain disorders."

Won and colleagues also generated a list of shared genes across psychiatric disorders to describe common biological principles that link psychiatric disorders.

"Amongst the shared genes, we once again identified the brain's early developmental process as being critical and upper layer neurons as being the fundamental cell-types involved," Won said "We unveiled the molecular mechanism that underscores how one gene can affect two or more psychiatric diseases."

H-MAGMA is publicly available so that the tool can be widely applicable and available to the genetics and neuroscience community to help expand research, with the ultimate goal of helping people who suffer with brain-related conditions.

Boston, MA - Proposed changes to the federal Supplemental Nutrition Assistance Program (SNAP) may result in as many as one in ten U.S. families losing SNAP benefits, and potential impacts are unknown. A new study led by the Harvard Pilgrim Health Care Institute examines the potential effects of the proposed SNAP eligibility changes on health and health care affordability. The study, "Socioeconomic and Health Characteristics of Families at Risk for Losing Supplemental Nutrition Assistance Program Benefits", appears in JAMA Internal Medicine on March 9.

SNAP is a U.S. federal aid program that serves 40 million persons annually with health, nutrition, and financial benefits. Families can be eligible for the SNAP program under federal rules or categorical eligibility rules that extend SNAP support to otherwise ineligible families who receive benefits under certain social assistance programs, such as Temporary Assistance for Needy Families. In July 2019, the U.S. Department of Agriculture proposed new rules that would limit qualifications via categorical eligibility. Although these rules have not been finalized, it is estimated that one in ten U.S. families currently participating in SNAP may lose their benefits.

"These proposed changes to SNAP raise concerns for adverse effects on health, nutrition, and ability to pay for health care," said Alon Peltz, MD, lead author and Instructor of Population Medicine at the Harvard Pilgrim Health Care Institute and Harvard Medical School. "We wanted to investigate the potential ramifications of these changes to help inform policymakers of the vulnerabilities of the people who are dependent on SNAP benefits and may be at risk for disenrollment if the proposed rules are implemented."

Peltz and co-investigators used national survey data of U.S. households, researchers compared the vulnerabilities of those at risk of losing SNAP benefits and those not impacted by the proposed rules. Despite being subject to different financial standards under federal or categorical eligibility, researchers found few differences between the groups. Those at risk of losing benefits under the proposed rules were found to face high rates of health, nutritional, and financial vulnerabilities, such as high rates of chronic illness, fair to poor health status, and challenges affording health care services. Food insecurity, despite the moderating effects of SNAP, remained high in both groups.

Regarding next steps, Dr. Peltz adds, "proposed and future SNAP eligibility policies should consider the potential effects on families who, despite slightly higher incomes, have substantial health, nutrition, and financial needs."

A star that pulsates on just one side has been discovered in the Milky Way about 1500 light years from Earth. It is the first of its kind to be found and scientists expect to find many more similar systems as technology to listen inside the beating hearts of stars improves.

"What first caught my attention was the fact it was a chemically peculiar star," said co-author Dr Simon Murphy from the Sydney Institute for Astronomy at the University of Sydney. "Stars like this are usually fairly rich with metals - but this is metal poor, making it a rare type of hot star."

Dr Murphy shared the find with international collaborators to discover others had started to study the star, known as HD74423, which is about 1.7 times the mass of the Sun.

Together they have published their findings today in Nature Astronomy.

"We've known theoretically that stars like this should exist since the 1980s," said co-author Professor Don Kurtz from the University of Central Lancashire in Britain.

"I've been looking for a star like this for nearly 40 years and now we have finally found one," said Professor Kurtz, who is the inaugural Hunstead Distinguished Visitor at the University of Sydney.

Stars that pulsate have been known in astronomy for a long time. Our own Sun dances to its own rhythms. These rhythmic pulsations of the stellar surface occur in young and in old stars, and can have long or short periods, a wide range of strengths and different causes.

There is however one thing that all these stars had thus far in common: the oscillations were always visible on all sides of the star. Now an international team, including researchers from the University of Sydney, has discovered a star that oscillates largely over one hemisphere.

The scientists have identified the cause of the unusual single-sided pulsation: the star is located in a binary star system with a red dwarf. Its close companion distorts the oscillations with its gravitational pull. The clue that led to its discovery came from citizen scientists poring over public data from NASA's TESS satellite, which is hunting for planets around distant stars.

The orbital period of the binary system, at less than two days, is so short that the larger star is being distorted into a tear-drop shape by the gravitational pull of the companion.

Professor Gerald Handler from the Nicolaus Copernicus Astronomical Centre in Poland and lead author said: "The exquisite data from the TESS satellite meant that we could observe variations in brightness due to the gravitational distortion of the star as well as the pulsations."

To their surprise the team observed that the strength of the pulsations depended on the aspect angle under which the star was observed, and the corresponding orientation of the star within the binary. This means the pulsation strength varies with the same period as that of the binary.

"As the binary stars orbit each other we see different parts of the pulsating star," said Dr David Jones at the Instituto de Astrofisica de Canarias and co-author of the study. "Sometimes we see the side that points towards the companion star, and sometimes we see the outer face."

This is how the astronomers could be certain that the pulsations were only found on one side of the star, with the tiny fluctuations in brightness always appearing in their observations when the same hemisphere of the star was pointed towards the telescope.

The discovery of the unusual behaviour of the star was initially made by citizen scientists. These amateur astronomy sleuths painstakingly inspected the enormous amounts of data that TESS regularly supplies, as they search for new and interesting phenomena.

While this is the first such star to be found where only one side is pulsating, the authors believe there must be many more such stars.

Mitochondria cannot autonomously cope with stress and must instead call on the cell for help. Molecular geneticists at Ludwig-Maximilians-Universitaet (LMU) in Munich have identified the long-sought signaling pathway which enables the organelles to do so.

Mitochondria are membrane-bounded intracellular organelles that supply the energy needed to power the biochemical operations required for cell function and survival. The energy is provided in the form of a compound called ATP, which can be hydrolyzed by specific enzymes to drive chemical reactions. When mitochondria are subjected to stress - owing to the accumulation of misfolded proteins, for example - their functional capacities are diminished. Degradation of mitochondrial function can have serious consequences for the affected cells, and potentially for the whole organism. In order to activate protective measures, mitochondria must transmit a distress signal into the surrounding cytosol. In a paper that appears in the leading scientific journal Nature, researchers led by Professor Lucas Jae at the LMU Gene Center now report that they have characterized the elusive signaling pathway that triggers the response to mitochondrial stress in human cells. Mitochondrial dysfunction is at the root of many serious disorders, and functional deterioration of these organelles is regarded as a major component of the aging process. The new findings are therefore of considerable significance in the search for new therapeutic approaches to the treatment of age-related diseases.

Although mitochondria retain a small set of genes required for their primary role as energy generators, they are unable to autonomously resolve stress. Instead, they must alert the cell to the developing emergency by sending a specific signal into the cytosol. This signal then triggers mechanisms that either dissipate the source of stress, or activate programmed cell death once the level of stress exceeds a specific threshold. Landmark studies in the nematode worm Caenorhabditis elegans have elucidated how this organism monitors the state of its mitochondria. However, the results show that the mode of action in worms differs from that in humans. Human cells respond to mitochondrial stress - and various other insults - by inducing a rather unspecific reaction known as the Integrated Stress Response (ISR) in the cytosol. "The signaling pathway that relays mitochondrial stress to the cell has eluded identification through classical biochemical approaches for over 20 years," says Jae. "So we decided to use a genetic strategy to tackle the problem."

Since normal human genomes contain two copies each of virtually every gene, Jae and his colleagues made use of 'haploid' cells, in which genes are present in only one copy. This allowed the researchers to randomly introduce millions of knockout mutations throughout the genome that would not be compensated for by the presence of a second gene copy. They then subjected the resulting mutant cells to mitochondrial stress and recovered mutants that responded aberrantly. "This unbiased genome-wide screening procedure revealed two mitochondrial key factors that are essential for the ability of the mitochondria to activate the cellular stress response. One of these is the enzyme OMA1, which can cleave target proteins, and the other is a barely studied protein called DELE1," Jae explains.

When mitochondria are exposed to stress, OMA1 becomes activated and induces the cleavage of the DELE1 protein into a shorter fragment. This fragment is then redistributed to the cytosol, where it binds to another enzyme called HRI, which in turn triggers the ISR. "HRI was thus far believed to be primarily required for the formation of red blood cells," says Jae. "Our study has now shown that it can also be activated by DELE1 in the context of mitochondrial perturbation."

According to the authors, these findings might open up new opportunities for therapeutic regulation of cellular stress responses. These could be relevant for conditions that are associated with mitochondrial malfunction - including debilitating, age-related neurodegenerative disorders, such as Parkinson's disease. Recently, drugs have been developed that can globally shut down the ISR. Although not tailored to a specific type of ISR-inducing stress, such compounds have been shown to have positive effects on cognition and learning in mice. However, unspecific inhibition of the ISR might also have undesirable effects, as the ISR, for instance, also mediates antiviral protection during infection. "In an alternative scenario, the cellular response to mitochondrial stress could be selectively modulated by manipulating the factors we have now identified," says Jae.