Culture

In a new study published in Cell Research, Chen-Yu Zhang's group at Nanjing University School of Life Sciences, China, reports that SIDT1 in the mammalian stomach mediates host uptake of dietary and orally administered microRNAs (miRNAs), thus exerting biological functions in the host.

In previous studies, Chen-Yu Zhang's group has demonstrated that intact plant miRNA in foods can be absorbed through the mammalian digestive system and mediate cross-kingdom gene regulation. The discoveries also provide new insight into the oral administration of RNA therapeutic drugs. Although accumulated evidences showing the existence of intact dietary miRNAs within mammalian host, the absorption of dietary miRNAs in animal gastrointestinal tract has been frequently questioned, mainly due to the unknown mechanism of absorption.

In the current study, they show that SID-1 transmembrane family member 1 (SIDT1), mammalian homolog of SID-1 expressed on gastric pit cells in the stomach is required for the absorption of dietary miRNAs. SIDT1-deficient mice show reduced basal levels and impaired dynamic absorption of dietary miRNAs. Notably, they identified the stomach as the primary site for dietary miRNA absorption, which is dramatically attenuated in the stomachs of SIDT1-deficient mice. Mechanistic analyses revealed that the uptake of exogenous miRNAs by gastric pit cells is SIDT1 and low-pH dependent. Furthermore, oral administration of plant-derived miR2911 retards liver fibrosis, and the protective effect was abolished in SIDT1-deficient mice. This study not only reveals the major mechanism of dietary miRNA absorption, uncovers a novel physiological function of the mammalian stomach, but also shed light on orally delivered small-RNA therapeutics.

This work is important for the following reasons:

1. In this study, they demonstrated the molecular mechanism of mammalian dietary miRNA absorption, which is one of the most groundbreaking as well as most controversial discoveries in the field of extracellular RNA research in the last decade. Identification of the absorption mechanism provides strong evidence of the physiological existence and functionality of mammalian dietary miRNA absorption, thus ending the 10-year debate on this topic.
2. This work also newly found that the stomach not only absorbs water and alcohol, as is broadly known in classic physiology, but also senses and takes up functional dietary miRNAs. This provides a unique new understanding of digestion physiology.
3. A low-pH condition is required for efficient exogenous miRNA uptake via SIDT1. This finding reveals an evolutionary explanation for functional dietary miRNA absorption, in which the stability of dietary miRNAs is granted in stomach, where RNase activity is largely absent in this low-physiological-pH gastric environment.
4. By oral administration, plant-derived miR2911 can be absorbed via SIDT1 and can subsequently alleviate liver fibrosis in mice, providing a new therapeutic strategy for small-RNA-based treatment. This natural mammalian absorption pathway of dietary miRNA will be easily harnessed for the oral delivery of therapeutic miRNAs, which could be a potential direction in for the development of RNA-based medicine.

Most of modern medicine has physical tests or objective techniques to define much of what ails us. Yet, there is currently no blood or genetic test, or impartial procedure that can definitively diagnose a mental illness, and certainly none to distinguish between different psychiatric disorders with similar symptoms. Experts at the University of Tokyo are combining machine learning with brain imaging tools to redefine the standard for diagnosing mental illnesses.

"Psychiatrists, including me, often talk about symptoms and behaviors with patients and their teachers, friends and parents. We only meet patients in the hospital or clinic, not out in their daily lives. We have to make medical conclusions using subjective, secondhand information," explained Dr. Shinsuke Koike, M.D., Ph.D., an associate professor at the University of Tokyo and a senior author of the study recently published in Translational Psychiatry.

"Frankly, we need objective measures," said Koike.

Challenge of overlapping symptoms

Other researchers have designed machine learning algorithms to distinguish between those with a mental health condition and nonpatients who volunteer as "controls" for such experiments.

"It's easy to tell who is a patient and who is a control, but it is not so easy to tell the difference between different types of patients," said Koike.

The UTokyo research team says theirs is the first study to differentiate between multiple psychiatric diagnoses, including autism spectrum disorder and schizophrenia. Although depicted very differently in popular culture, scientists have long suspected autism and schizophrenia are somehow linked.

"Autism spectrum disorder patients have a 10-times higher risk of schizophrenia than the general population. Social support is needed for autism, but generally the psychosis of schizophrenia requires medication, so distinguishing between the two conditions or knowing when they co-occur is very important," said Koike.

Computer converts brain images into a world of numbers

A multidisciplinary team of medical and machine learning experts trained their computer algorithm using MRI (magnetic resonance imaging) brain scans of 206 Japanese adults, a combination of patients already diagnosed with autism spectrum disorder or schizophrenia, individuals considered high risk for schizophrenia and those who experienced their first instance of psychosis, as well as neurotypical people with no mental health concerns. All of the volunteers with autism were men, but there was a roughly equal number of male and female volunteers in the other groups.

Machine learning uses statistics to find patterns in large amounts of data. These programs find similarities within groups and differences between groups that occur too often to be easily dismissed as coincidence. This study used six different algorithms to distinguish between the different MRI images of the patient groups.

The algorithm used in this study learned to associate different psychiatric diagnoses with variations in the thickness, surface area or volume of areas of the brain in MRI images. It is not yet known why any physical difference in the brain is often found with a specific mental health condition.

Broadening the thin line between diagnoses

After the training period, the algorithm was tested with brain scans from 43 additional patients. The machine's diagnosis matched the psychiatrists' assessments with high reliability and up to 85 percent accuracy.

Importantly, the machine learning algorithm could distinguish between nonpatients, patients with autism spectrum disorder, and patients with either schizophrenia or schizophrenia risk factors.

Machines help shape the future of psychiatry

The research team notes that the success of distinguishing between the brains of nonpatients and individuals at risk for schizophrenia may reveal that the physical differences in the brain that cause schizophrenia are present even before symptoms arise and then remain consistent over time.

The research team also noted that the thickness of the cerebral cortex, the top 1.5 to 5 centimeters of the brain, was the most useful feature for correctly distinguishing between individuals with autism spectrum disorder, schizophrenia and typical individuals. This unravels an important aspect of the role thickness of the cortex plays in distinguishing between different psychiatric disorders and may direct future studies to understand the causes of mental illness.

Although the research team trained their machine learning algorithm using brain scans from approximately 200 individuals, all of the data were collected between 2010 to 2013 on one MRI machine, which ensured the images were consistent.

"If you take a photo with an iPhone or Android camera phone, the images will be slightly different. MRI machines are also like this - each MRI takes slightly different images, so when designing new machine learning protocols like ours, we use the same MRI machine and the exact same MRI procedure," said Koike.

Now that their machine learning algorithm has proven its value, the researchers plan to begin using larger datasets and hopefully coordinate multisite studies to train the program to work regardless of the MRI differences.

Emerging technologies can be harnessed to use the strengths of hot, humid coastal deserts of the Middle East and North Africa (MENA) region to grow food and other crops.

KAUST researchers are calling for a new generation of vast greenhouse complexes, supported by novel solar panels, air-cooling technologies, and advances in salt-tolerant agriculture. Their concept could kickstart a sustainable agriculture revolution in coastal desert regions across the world.

"Controlled environment agriculture (CEA) uses integrated systems to facilitate sustainable, local crop growth on a large scale," says Kyle Lauersen, synthetic biologist. "Our vision combines several technologies currently in development at KAUST: energy-efficient, transparent solar panels; low-energy desiccant cooling; salt-tolerant edible plants; and algal biotechnology."

Coastal locations in the MENA region have ample access to seawater and year-round intense sunlight. CEA makes it possible to use seawater to use grow salt-tolerant crops, such as newly identified varieties of tomatoes and green vegetables. Mixed irrigation means that CEA would have a lower impact on municipal supplies. To source extra freshwater, the researchers plan to harvest from humid air.

"We are excited by developments in cooling technologies that leverage liquid desiccants," says research scientist Ryan Lefers. "Desiccants are highly concentrated substances that absorb water from the air--think of the silica packs found in electronic packaging. When humid air is pumped through a liquid desiccant system, it uses a highly saline liquid solution to absorb the moisture."

The air released by the system is drier and cooler and can be circulated in the greenhouses, while the captured freshwater is recovered. The buildup of excessive heat inside greenhouses is a major concern in the MENA region. One solution comes from KAUST start-up iyris: which uses semitransparent solar panels as windows. Such panels allow visible light through for plant growth, while converting infrared energy (heat) into electricity.

The researchers also hope to combine plant and algae growth to generate not just food, but also biomass feedstocks for aquaculture, animal feed, chemical industry products and bioplastics. Algae can be grown in photobioreactors inside CEA, and this co-cultivation would increase the system's value output.

"We see incredible potential for regionally inspired mixtures of salt-tolerant and freshwater species in different facilities, depending on market demands," says Lauersen. "It's becoming increasingly important to produce food and products in closer proximity to communities that need it. CEA will also provide food security, jobs and an economic base for year-round exports."

"This is where multidisciplinary research comes into its own," says plant scientist Mark Tester. "A pilot CEA greenhouse is under construction at KAUST as part of our spin-off company Red Sea Farms, and we will collaborate with colleagues across the university and beyond to demonstrate the exciting potential for CEA."

With the increasing miniaturization of electronic components, researchers are struggling with undesirable side effects: In the case of nanometer-scale transistors made of conventional materials such as silicon, quantum effects occur that impair their functionality. One of these quantum effects, for example, is additional leakage currents, i.e. currents that flow "astray" and not via the conductor provided between the source and drain contacts. It is therefore believed that Moore's scaling law, which states that the number of integrated circuits per unit area doubles every 12-18 months, will reach its limits in the near future because of the increasing challenges associated with the miniaturisation of their active components. This ultimately means that the currently manufactured silicon-based transistors -- called FinFETs and equipping almost every supercomputer -- can no longer be made arbitrarily smaller due to quantum effects.

Two-dimensional beacons of hope

However, a new study by researchers at ETH Zurich and EPF Lausanne shows that this problem could be overcome with new two-dimensional (2-D) materials -- or at least that is what the simulations they have carried out on the "Piz Daint" supercomputer suggest.

The research group, led by Mathieu Luisier from the Institute for Integrated Systems (IIS) at ETH Zurich and Nicola Marzari from EPF Lausanne, used the research results that Marzari and his team had already achieved as the basis for their new simulations: Back in 2018, 14 years after the discovery of graphene first made it clear that two-dimensional materials could be produced, they used complex simulations on "Piz Daint" to sift through a pool of more than 100,000 materials; they extracted 1,825 promising components from which 2-D layers of material could be obtained.

The researchers selected 100 candidates from these more than 1,800 materials, each of which consists of a monolayer of atoms and could be suitable for the construction of ultra-scaled field-effect transistors (FETs). They have now investigated their properties under the "ab initio" microscope. In other words, they used the CSCS supercomputer "Piz Daint" to first determine the atomic structure of these materials using density functional theory (DFT). They then combined these calculations with a so-called Quantum Transport solver to simulate the electron and hole current flows through the virtually generated transistors. The Quantum Transport Simulator used was developed by Luisier together with another ETH research team, and the underlying method was awarded the Gordon Bell Prize in 2019.

Finding the optimal 2-D candidate

The decisive factor for the transistor's viability is whether the current can be optimally controlled by one or several gate contact(s). Thanks to the ultra-thin nature of 2-D materials -- usually thinner than a nanometer -- a single gate contact can modulate the flow of electrons and hole currents, thus completely switching a transistor on and off.

Structure of a single-gate FET with a channel made of a 2-D material. Arranged around it are a selection of 2-D materials that have been investigated. (Mathieu Luisier/ETH Zürich)

"Although all 2-D materials have this property, not all of them lend themselves to logic applications," Luisier emphasizes, "only those that have a large enough band gap between the valence band and conduction band." Materials with a suitable band gap prevent so-called tunnel effects of the electrons and thus the leakage currents caused by them. It is precisely these materials that the researchers were looking for in their simulations.

Their aim was to find 2-D materials that can supply a current greater than 3 milliamperes per micrometre, both as n-type transistors (electron transport) and as p-type transistors (hole transport), and whose channel length can be as small as 5 nanometres without impairing the switching behaviour. "Only when these conditions are met can transistors based on two-dimensional materials surpass conventional Si FinFETs," says Luisier.

The ball is now in the experimental researchers' court

Taking these aspects into account, the researchers identified 13 possible 2-D materials with which future transistors could be built and which could also enable the continuation of Moore's scaling law. Some of these materials are already known, for example black phosphorus or HfS2, but Luisier emphasizes that others are completely new -- compounds such as Ag2N6 or O6Sb4.

"We have created one of the largest databases of transistor materials thanks to our simulations. With these results, we hope to motivate experimentalists working with 2-D materials to exfoliate new crystals and create next-generation logic switches," says the ETH professor. The research groups led by Luisier and Marzari work closely together at the National Centre of Competence in Research (NCCR) MARVEL and have now published their latest joint results in the journal ACS Nano. They are confident that transistors based on these new materials could replace those made of silicon or of the currently popular transition metal dichalcogenides.

A research team from the University Hospital at Ruhr-Universität Bochum (RUB) has developed a test that provides information on the immune response to the novel coronavirus in patients who need to take immunosuppressive drugs. This is necessary, for instance, following an organ transplantation. "We were able to show that these patients can achieve a good immune response to Sars-Cov-2 despite immunosuppression," says Professor Nina Babel, Head of the Centre for Translational Medicine at Marien Hospital Herne. Immunosuppressive therapy can be adapted individually during a Covid-19 infection using the test. The researchers report in the American Journal of Transplantation on 10 August 2020.

Risk for organ transplant patients twice as high

Chronically ill patients with impaired immune defences have an increased risk of suffering from a severe Covid-19 infection. Transplant patients are affected in several ways: in addition to the chronic illness that led to organ failure and subsequent transplantation, transplant patients need to take medications that suppress the defences of their own immune system.

"These immunosuppressants are necessary to prevent the body from rejecting transplanted organs. However, they can lead to an abundance of viral infections," explains Nina Babel, who, together with Professor Timm Westhoff, Director of Medical Clinic I at Marien Hospital Herne, led the team, including researchers from the Department of Molecular and Medical Virology at RUB and the Surgical Clinic at Knappschaftskrankenhauses Langendreer. "Until now, it has not been known whether our transplant patients are capable of forming a sufficient immune response to the new coronavirus," emphasises Timm Westhoff.

Immune response despite suppressing drugs

With the help of the test established in the Marien Hospital's immunodiagnostics laboratory, the team demonstrated that transplant patients are very capable of achieving a good immune response despite immunosuppression. In addition to high antibody titres, large quantities of T lymphocytes, which are responsible for killing infected cells, were found in the current case study.

The test is of great clinical relevance for transplant patients: the information provided by this goes far beyond a pure antibody test. "The data obtained help us to deal with immunosuppression during the current pandemic," emphasises Timm Westhoff. "The test allows us to individually adjust immunosuppression when a patient is suffering from Covid-19."

In an aging society, one of the most important and urgent tasks of scientific research is to counteract the decline in motor function and muscle weakness that accompanies the aging process.

A research group led by Professor Yuji Yamanashi of the Institute of Medical Science, the University of Tokyo, conducted experiments using aged mice to demonstrate that muscle denervation at the neuromuscular junction (NMJ, *1) could be appreciably offset by an NMJ formation-enhancing treatment that strengthened the motor function and muscle of aged mice.

The results of this study suggest that NMJ formation-enhancing treatment may be effective to overcome motor impairment and muscle weakness associated with human aging.

The results of this research were published in iScience on August 5, 2020.

The NMJ is the only "bond" that connects motor nerves to skeletal muscles

In order to move the body, precise control of skeletal muscle contraction via motor nerves is required. The NMJ is the only "bond" that connects motor nerves to skeletal muscles (the neuromuscular synapse), and its loss means that motor functions including breathing cease to work.

The research group focused on "nerve detachment" aka "denervation" at NMJs, in which the motor nerve becomes separated from the NMJ, a process that progresses with aging.

As a result of the treatment given to aged mice to enhance the formation of NMJs, the following three points were verified:

1) The motor nerve connection was enhanced.

2) Stronger response of skeletal muscle to motor nerve stimulation was observed.

3) Motor function and muscle strength were enhanced in treated mice.

According to the research group, muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment.

They previously demonstrated that the muscle protein Dok-7 (*2) plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, they show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice.

Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared to the controls, suggesting enhanced NMJ transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.

For details of the research, please see the paper.

Possibility of opening the way to NMJ formation-enhancing therapy using compounds

Yuji Yamanashi, the corresponding author of this research, Professor at the Institute of Medical Science, The University of Tokyo, said, "In this new study with mice, NMJ augmentation treatment was shown to be effective for age-related motor impairment and muscle weakness, which are serious problems in an aging society. It has great social significance in terms of presenting the possibilities."

In addition, this study is not only a basic study of gene therapy using AAV-D7 (*3), but also serves as a proof of principle for opening the way to NMJ formation-enhancing therapy using compounds.

The research group hopes that the findings of this research will be used in the future to promote many research efforts from various perspectives, such as translational research to overcome age-related motor impairment and muscular weakness, together with development of compounds with NMJ formation-enhancing effect.

The simultaneous stimulation of the motor nerves of the brain and limbs (paired associative stimulation) has yielded promising research results. Research conducted at the BioMag Laboratory, operated by the University of Helsinki, Helsinki University Hospital and Aalto University, has previously demonstrated that simultaneous transcranial magnetic stimulation of the brain and electrical stimulation of the limb nerves constitute a useful method of motor rehabilitation in patients suffering from spinal cord injuries.

Prior case studies have shown that synchronised stimulation of the brain and limb nerves strengthens neural connections and, thus, can restore patients' mobility.

Now, researchers at the laboratory have, for the first time, looked into the potential of paired associative stimulation therapy in treating incomplete paraplegia, investigating how stimulation therapy can promote the recovery of walking ability when combined with walking rehabilitation.

The results of the recently completed case study have been published in the Spinal Cord Series and Cases journal.

"We demonstrate for the first time that paired associative stimulation helped a paraplegic patient walk and promoted his walking rehabilitation. Stimulation therapy has already previously been found to be a potential mode of treatment for spinal cord injuries. These findings spur us on to continue investigating paired associative stimulation," says Anastasia Shulga, a neuroscientist and medical doctor from the University of Helsinki who headed the case study.

A spinal cord injury patient regained the ability to walk independently with the help of a rolling walker

In the case study, stimulation therapy was given to a 47-year-old male whose lower limbs were partially paralysed due to a spinal cord injury. The patient's right leg had spontaneously recovered almost all of its function in the year after the injury, but the left leg's functionality had recovered only partially, leaving the patient unable to walk. A year after the trauma, his left leg received stimulation treatment for three months. This three-month treatment was repeated two years after the trauma.

Prior to the stimulation treatment, the patient was unable to stand without considerable body weight support. As it was considered fruitless, conventional walking rehabilitation was not initiated.

After the first three-month stimulation period, the patient was able to stand for 1.5 minutes and take 13 steps on parallel bars without weight support. Thanks to this improvement, the patient was enrolled into walking rehabilitation after the treatment period, achieving independent walking ability with the help of a rollator.

During the second three-month treatment period, his walking distance grew 2.4 times faster compared to the previous period when he received no stimulation. Furthermore, the left leg had recovered its strength to a considerable degree, while the score for the measure describing the patient's independent functioning had also improved. No adverse effects were caused by the treatment.

Paired associative stimulation investigated as a treatment for incomplete injuries

Most spinal cord injuries are incomplete, with great variance between individual cases. Certain patients can remain completely paralysed from the neck down, while the best cases can make an almost full or full recovery. Recovery depends on the level and severity of the injury.

"One year on from the trauma, the speed of recovery slows down markedly and there is little spontaneous recovery," Shulga explains.

New therapies are needed for treating traumatic spinal cord injuries, since the only method currently in clinical use is the surgical stabilisation of the spine, only carried out when necessary, and subsequent rehabilitation.

Shulga has gained promising results in investigating paired associative stimulation therapy through patient cases and series where the therapy has been trialled on incomplete injuries. In the studies, the functionality of the upper or lower limbs of nearly 20 patients has been successfully improved. Shulga points out that in the case of complete spinal cord injury, paired associative stimulation is not an appropriate therapy.

At the moment, she is carrying out a randomized double-blind placebo-controlled trial where only 1-4 months has passed from the trauma that caused the tetraplegia of the patients participating in the study. The goal of the study is to improve the function of the patients' upper limbs, while a similar study is being planned for paraplegic patients.

"We are investigating the effectiveness of synchronised electrical and magnetic stimulation, with the aim of introducing a technique for clinical use by increasing the strength of the evidence", Shulga says.

Sea trout get no peace. They're constantly exposed to new diseases and ailments, many of which are due to climate change and human activity.

Now researchers want to find out which diseases are affecting the fish in order to know how to help them. The researchers plan to explore the entire coast of Norway, but have started on a smaller scale.

"We've investigated viruses, bacteria and parasites on 160 sea trout in the Skjerstadfjord and the Tosenfjord in Nordland county," says associate professor Jan Grimsrud Davidsen in the Department of Natural History at the Norwegian University of Science and Technology's (NTNU) University Museum.

The research group has looked at what diseases the fish have and how they affect fish behaviour.

The research group searched for 46 different disease-causing factors, so-called pathogens, and found 11 of them.

"The most important thing was that we found out the method works. But we didn't really find much disease on the fish in either the Skjerstadfjord or the Tosenfjord," says Davidsen.

The researchers had to use an analysis method developed for fish in the Pacific Ocean - because that was the only existing option. It wasn't an ideal solution.

"We think the analysis results weren't completely accurate, because we didn't screen for the correct pathogens. The problem is that we don't quite know what diseases we're looking for. Currently we still know very little about which pathogens affect sea trout on the Norwegian coast. But we hope to learn more about that in the follow-up project to map the entire coast," Davidsen says.

The studies of the two rivers in Nordland were a pilot project. The researchers have now received 1.1 million Euros from the Research Council of Norway to continue and expand the project.

The research institute NORCE, the Institute of Marine Research, NINA, fisheries authorities in Canada and the NTNU University Museum will survey the spread of sea trout diseases and parasites along the entire Norwegian coast over the next several field seasons.

"So far, we've looked at data that we had already collected. Now we'll be collecting the first new data from the Beiarfjord in Nordland and a fjord in Western Norway," says Davidsen.

The researchers plan to tag 150 fish with traceable electronic tags.

"Then we'll be able to examine both the activity level and the migration pattern of the fish, to see how diseases affect their behaviour and energy consumption," he says.

In practical terms, the researchers take a cell sample from the gills of the sea trout, which are fitted with electronic ID tags. The gill sample is only the size of a pinhead, but yields a lot of information that is quite fascinating.

"Using a completely new DNA method, we can screen this sample for traces of 90 different viruses, parasites and bacteria," says Davidsen.

These analysis methods are the most advanced available and will enable the researchers to detect whether the sea trout is just a carrier of the disease or is actually sick.

"We can link this information to sea trout behaviour. We register their behaviour using the electronic ID tags and listening stations that we set up in the fjords. Then we can see if sea trout with various diseases or parasites behave differently from other sea trout," he said.

So why is this research important?

"Sea trout in Norway and the rest of Europe are in decline. The main reason lies in the ocean. We know very little about the effect of pathogens, and it's important to find out the role they play," says Davidsen.

The aquaculture industry in Norway is growing. We know that this also contributes to an increase of pathogens in wild fish, and so it is important to find out what effect they have on sea trout. Researchers have already ascertained that salmon lice have an effect on wild fish. Now they want to look at other diseases and parasites as well.

"If we figure out what is afflicting the wild fish the most, we may be able to do something about it. Maybe this knowledge will help us build up the sea trout population again," Davidsen says.

With potential application diagnosing cancer or predicting how viruses, such as HIV, attack human cells, machine learning is opening promising new areas of application for bioinformatics - the data science of molecular biology. Dr Pengyi Yang from the Charles Perkins Centre and School of Mathematics and Statistics with colleagues has summarised the latest developments in this emerging field in a review article in Nature Machine Intelligence.

Latest techniques are bringing together two previously disparate approaches to machine learning: ensemble methods and deep learning.

Just like 'many heads are better than one', ensemble deep learning combines multiple 'computer brains' to achieve high levels of performance. Dr Yang summarises the latest developments in ensemble deep learning and its application in a range of biological and biomedical fields; highlights achievements unattainable by traditional methods; and maps out its potential to revolutionise molecular biological and biomedical sciences.

Lack of Continuing Research Into Infectious Disease Epidemics Endangers Pandemic Responses, According to Ben-Gurion University Researchers

BEER-SHEVA, Israel, August 17, 2020 - While the volume of research of infectious coronavirus diseases is very high after an outbreak, it drops substantially upon containment, which prevents a full understanding of coronavirus management and prevention, according to a new study by Ben-Gurion University of the Negev researchers.

In the study published in GigaScience, the researchers developed and analyzed a dataset of 35 million papers over 20 years that revealed the comparatively limited research conducted on emerging infectious diseases. Moreover, the research peaked after epidemics, but then dropped off precipitously within two years of the initial outbreak.

"The COVID-19 outbreak has revealed how little we know about emerging coronaviruses," says Dr. Michael Fire, a lecturer in the BGU Department of Software and Information Systems Engineering (SISE) and the founder of the Data Science for Social Good Lab. "There has been no sustained research into these types of infections, merely peaks following specific outbreaks. That pattern has left us woefully unprepared for the COVID-19 pandemic. If we want to be ready for the next pandemic, we must maintain a steady pace of research, even after the current pandemic subsides. The path to understanding is a marathon, not a sprint."

Dr. Fire, together with Dima Kagan, his Ph.D. student and Prof. Jacob Moran-Gilad of the Department of Health Systems Management at BGU's School of Public Health constructed and analyzed the novel dataset of research articles on emerging diseases.

The researchers also discovered that there have been few international collaborations to study emerging infectious diseases. Moreover, 73% of the coronavirus studies were centered in only six countries, far fewer than other investigated diseases, with the majority of research emanating from the U.S. and China.

The coronavirus was also studied considerably less than blood borne viruses like Hepatitis B or C and H.I.V. and its research community has less prolific researchers than the other investigated diseases. This translates into limited collaborations and a non-sustained investment in research on coronaviruses. Such a short-lived investment also reduces funding and may slow down important developments such as new drugs, vaccines or preventive strategies.

"We believe the lessons learned from the scientometrics of previous epidemics argue that regardless of the outcome of COVID-19, efforts to sustain research in this field should be made," Fire says. "More specifically, in 2017 and 2018, SARS and MERS were considered to be priority diseases in WHO's R&D Blueprint, but their research rate did not grow relative to other diseases. Therefore, the translation of international policy and public health priorities into a research agenda should be continuously monitored and enhanced."

Neutron stars are the smallest and densest astrophysical objects with visible surfaces in the Universe. They form after gravitational collapses of the iron nuclei of massive (with masses about ten solar masses) stars at the end of their nuclear evolution. We can observe these collapses as supernovae explosions.

The masses of neutron stars are typical for normal stars, about one and half solar masses, but their radii are extremely small in comparison with normal stars - they are between ten and fifteen kilometers. For comparison, the radius of the Sun is about 700,000 km. It means that the average matter density of neutron stars is a few times larger than the density of atomic nuclei, namely about 1 billion tons per cubic centimeter.

The neutron star matter consists mainly of close up neutrons, and the repulsive forces between neutrons prevent neutron stars from collapsing into a black hole. Theoretical quantitative des­cription of these repulsive forces is not possible at the moment, and it is a fundamental problem of the nuclear physics and astrophysics. This problem is also known as the equation of state of the superdense cold matter problem. Astrophysical observations of neutron stars can limit the existing different theoretical models of the equation of state, because the neutron star radii depend on the repulsive forces.

One of the most suitable astrophysical objects for neutron star radii measurements are X-ray bursting neutron stars. They are components of close binary systems, so called low-mass X-ray binaries. In such systems, the secondary component, which is a normal solar-like star, losses its matter, and the neutron star accretes the matter. The matter flows from the normal star onto the surface of the neutron star. The surface gravity on a neutron star is very high, hundred billion times higher than on the Earth's surface. As a result, the conditions for exploding thermonuclear burning arise on the bottom of the fresh accreted matter. It's these explosions that we observe as X-ray flashes in low-mass X-ray binaries.

Durations of the most X-ray flashes are about 10 to 100 seconds. After the maximum, the X-ray brightness decays almost exponentially. An X-ray bursting neutron star emits as a black body with some temperature (about ten million degrees), and this temperature decreases together with the brightness decreasing. But the connection between the brightness and the temperature is not fixed. It depends on the physical structure of the upper layers of the emitting neutron star envelope (the atmosphere). The model atmospheres of X-ray bursting neutron stars can be computed for various masses and radii of, as well as for a given X-ray flash brightness, and some time ago the co-authors computed the extended grid of such model atmospheres.

The comparison of joint observational decreasing of the temperature and the X-ray brightness in some X-ray flashes with the model predictions allows to find the mass and radius of a neutron star. This method, which was named the cooling tail method, was suggested more than ten years ago. The authors of this method are Valery Suleimanov, Juri Poutanen, Mike Revnivtsev, and Klaus Werner, three of whom are the co-authors of this current publication. Further development of this approach and its application to the many X-ray flashes allowed them to limit the neutron star radii in the range from 11 to 13 km (see, for instance, https://ui.adsabs.harvard.edu/abs/2017A%26A...608A..31N/abstract). All the following determinations, including an observation of the merging of two neutron stars by gravitational wave detectors, gave values inside of this range.

In the method, the researchers assumed that the neutron star is not rotating and has a spherical shape with a uniform temperature distribution over the surface. But the neutron stars in the considered binary systems can rotate rapidly with the typical period a few milliseconds.

In particular, the fastest rotating neutron star in the system 4U 1608-52 has a spin period of 0.0016 seconds. Shapes of such rapidly rotating neutron stars are far from spherical. They have larger radii at the equators than at the poles, and the surface gravity and the surface temperature are larger at the poles than at the equators. Therefore, there are systematic uncertainties in the method of the neutron star masses and radii determination. The obtained neutron star radii can be systematically overestimated due to their rapid rotation.

Recently Valery Suleimanov, Juri Poutanen, and Klaus Werner developed a fast approximate approach for computing the emergent radiations of rapidly rotating neutron stars. They extended the cooling tail method for thermonuclear flashes on the rapidly rotating neutron star surfaces. This extended method was applied to the X-ray burst on the surface of the neutron star in the system SAX 1810.8-2609, which is rotating with the period of about 2 milliseconds. The study showed that the radius of this neutron star can be overestimated on the value in the range from one to a half kilometer depending on the inclination angle of the rotation axis to the line of sight. It means that the systematic corrections are not crucial and can be ignored in the first approximation. The plan is to apply this method to the fastest rotating neutron star in the system 4U 1608-52.

DA has become an important component of the methodology of ESS and has improved the observability and predictability of the Earth system. The rigorous and beautiful mathematical framework of DA reflects the harmony between reason and experience.

A research entitled "Harmonizing models and observations: Data assimilation in Earth system science", with Xin Li as the first author, Feng Liu and Miao Fang as co-authors, is published in Science China Earth Sciences. The researchers review the application of DA in the main branches of ESS, trace the coordinated evolution of DA with the methodologies of rationalism and empiricism, and present an outlook on the challenges facing the development of a uniform DA for ESS.

Figure 1 shows that DA has been extensively applied in the different branches of ESS. This research briefly reviews the application of DA in the main branches of ESS, namely, atmosphere, ocean, land, and solid Earth sciences. "It is worth noting that while DA will develop with specific features of various fields", said the researchers, "its core methodology remains consistent, i.e., combining dynamic models and multisource observational data to obtain more accurate, more consistent analysis and improve the prediction accuracy and predictability of models".

The methodology of DA reflects the evolution of the philosophy of science. Models and observations represent the rationalism and empiricism origins of the modern and contemporary philosophy of science, respectively, which are two scientific ideological trends that had once competed but eventually became complementary to one another. DA follows the same evolutionary path and the methodology of the modern philosophy of science, with specific DA methods founded on Bayesian theory, the least squares method, the calculus of variations, and cybernetics (Fig.2).

Chinese researchers have achieved innovative progress in nonlinear non-Gaussian Bayesian recursive filtering, representativeness error estimation, and the combination of variation and ensemble filter-based methods. In the meantime, China has made marked progress in the application of DA, specifically in the development of atmospheric, ocean, and land-surface data assimilation systems.

Figure 3 shows the development history of DA in ESS. "Regardless of how DA develops in various branches of ESS, a uniform DA system for the Earth system will eventually be devised", said the researchers.

"DA theories and methods will continue to evolve and provide an increasingly mature methodology for enhancing the understanding and prediction of Earth as a system", said the researchers. Future trends and challenges will include: (1) Generalized and rigorous mathematical framework for DA; (2) Human-nature system DA; (3) Research on uncertainties in DA; and (4) Conforming to the development trend of the big data and artificial intelligence (AI) era.

Antibodies targeting the normal PrP version of the prion protein have been found in humans selected at random with no history of any associated transmissible spongiform encephalopathies. The significance is that prion proteins can be converted into a disease-causing infectious particle like PrPSc, an aggregated version or isoform resistant to degradation by protease enzymes. Resulting prion diseases, like other neurodegenerative syndromes such as Alzheimer's disease and Parkinson's disease, are associated with accumulation of misfolded and aggregated proteins in the central nervous system. Antibodies against such proteins may be beneficial and offer potential for therapies against such diseases by targeting the pathological aggregates for degradation by phagocytic cells.

In EMBO Molecular Medicine, researchers at the University of Zurich and Novartis Institutes for BioMedical Research in Switzerland report on active antibodies against PrP at high levels in a small proportion of individuals, 21 of 37,894 hospital patients screened for presence of anti-PrP IgGs, the most common form of immunoglobulin. There was strong evidence from lack of any past history of disease among these individuals that these antibodies were not themselves neurotoxic. That, combined with the lack of such antibodies among people who do carry disease-causing mutations in the PRNP gene coding for prion proteins, suggests they might have cleared unwanted nascent disease prions early in life.

Earlier research had already shown that anti-PrP antibodies are effective in mice infected with prions and also some human cells, suggesting they might represent a viable therapeutic strategy. However, it has also been demonstrated that the biological effect of anti-PrP antibodies depends critically on which part, or epitope, of the PrP prion recognized by the immune system is targeted. Therefore, the latest work sought to produce a high-resolution map of neuroprotective epitopes, with the ultimate goal of identifying immunotherapeutics that might be effective, as well as safe by avoiding neurotoxic effects. This was achieved by discovering antibodies that targeted both the main globular domain (GD) of the prion protein and its flexible tail (FT). This suggested there was a polyclonal antibody response, offering further evidence for the existence of naturally occurring antibodies against the prion protein in humans.

The resulting immune response capable of clearing nascent infectious prions may then operate analogously to immune surveillance for neoplastic cells that cause cancer. At the very least, generation of antibodies to the whole set of PrP epitopes provides new tools for studying the mechanism of neurodegeneration conveyed by prions.

A novel receptor protein that binds to the SARS-CoV-2 virus and prevents it from entering cells may hold promise for treating COVID-19 and other coronavirus-related diseases, according to research published online Aug. 4 in the journal SCIENCE.

As scientists race to find treatments for COVID-19, many are focused on a specific protein called angiotensin-converting enzyme 2, or ACE2, which is found on various cell surfaces throughout the human body. Its purpose is to generate smaller proteins that regulate functions within the cell. Using the spike-like protein on its surface, the SARS-CoV-2 virus binds to ACE2 prior to entry and infection of cells. Thus, ACE2 acts as a receptor for the virus that causes COVID-19.

In the study, Dr. Erik Procko and scientists at the University of Illinois engineered a novel receptor that resembles ACE2, with the intent of using it as a "decoy" that can bind to the virus before it can latch onto ACE2 at the cell surface and invade the cell. First, Procko examined more than 2,000 ACE2 mutations and created cells with the mutant receptors on their surfaces. By analyzing how these interacted with the coronavirus spike protein, he found a combination of three mutations that made a receptor that bound to the virus more strongly and made it a more "attractive" target for the virus.

After Procko posted his findings to a preprint server, a colleague connected him with the U.S. Army Medical Research Institute of Infectious Diseases. USAMRIID scientists, including Dr. Andrew Herbert of The Geneva Foundation, agreed to test the receptor in cells using live SARS-CoV-2.

"We were already in the process of testing several therapeutic candidates for SARS-CoV-2, and Erik's approach seemed novel--and certainly compelling enough to give it a shot," commented Herbert.

USAMRIID's team determined that the decoy receptor has potent neutralizing activity against SARS-CoV-2, activity that is on par with the best neutralizing antibodies identified to date. Furthermore, they found that the decoy receptor not only neutralizes SARS-CoV-2, but also acts to neutralize SARS-CoV-1, a closely related virus that uses the same cellular receptor.

"Once we confirmed neutralizing activity against SARS-CoV-2, it made sense to test for pan-coronavirus activity against other coronaviruses that also use ACE2 to enter cells," said Herbert.

Additional research is required to determine whether the decoy receptor could be used to effectively treat or prevent COVID-19 and related coronavirus diseases, according to Herbert. The team hopes to secure funding for animal studies to help answer those questions.

Monash Biomedicine Discovery Institute (BDI) scientists have discovered a previously unknown method used by bacteria to evade immune responses.

The study, published in Nature Microbiology, points to potential new ways of countering bacterial infections, which are becoming increasingly resistant to antibiotics.

First author Dr Pankaj Deo said researchers in Dr Thomas Naderer's laboratory took a different approach to understanding the process by which bacteria release toxins that disarm the 'power-house' mitochondria in immune cells.

The study showed that immune cells sense that their mitochondria are no longer functional during infections, which triggers apoptosis. "Ironically, it is the activation of host cell death factors that deliver the final blow to mitochondria which induces apoptosis, not the bacterial toxins themselves," Dr Pankaj said.

The researchers genetically targeted apoptotic factors and showed that they were able to reduce inflammation in mice, which increased health outcomes.

They used the bacterial pathogens Neisseria gonorrhoeae, uropathogenic Escherichia coli and the deadly Pseudomonas aeruginosa, prevalent in hospitals and which can be multi-drug resistant. However, the findings would apply to other species of bacteria too, Dr Deo said.

Dr Naderer, who oversaw the research, said that understanding the ways some bacterial infections evade immune response by targeting mitochondria opens new therapeutic possibilities.

"There's been a lot of effort trying to block endotoxins that kill immune cells but this study really shifts the focus onto different toxins that might be more important," Dr Naderer said.

"It gives us a few good leads that we can look at as a next step," he said.

"We've shown in this paper that we can accelerate the immune response," he said. "The other side is that if that response persists and we get constant inflammation - which is usually associated with bacterial infection and which causes a lot of tissue damage - we have a new way to shut down that tissue-damaging inflammation."

"What scientists have thought before is that when endotoxins are released by bacteria they induce an inflammatory type of programmed cell death called pyroptosis in immune cells," Dr Deo said. Endotoxins are part of the external cell wall of essentially all Gram-negative bacteria.

"We've found that the pathogenic bacteria use a similar mechanism to release additional toxins," he said. "They kill immune cells by releasing small surface structures called outer membrane vesicles - packages of toxins that target mitochondria. The mitochondria are disarmed, become dysfunctional then die according to apoptosis or cellular suicide."

The scientists will investigate drugs that are now advancing to the clinic, and at re-purposing drugs already in use, perhaps as anti-cancer treatments, to see if they can be used to clear bacterial infections.