Culture

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.

Cancer is a group of diseases characterised by uncontrolled cell growth caused by mutations, and other alterations in the genome of cells. A tumour can present from hundreds to thousands of mutations, but only a few are vital for its tumorigenic capacity. These key mutations affect the function of cancer driver genes. Finding the genes that harbour this cancer driver mutations is one of the main goals in cancer research.

Researchers from IRB Barcelona's Biomedical Genomics Lab, led by ICREA researcher Nuria Lopez-Bigas, have performed an extensive computational analysis of around 28,000 tumours from 66 types of cancer and have identified 568 cancer driver genes. These pivotal genes play specific roles in the regulation of cell growth, the cell cycle and DNA replication, among others. Mutations in these genes, confer malignant cells the capacity to reproduce rapidly and endlessly, evade the immune system and other defence systems, spread and invade other tissues, and modify the environment to their benefit, among other capabilities.

"The compendium of driver genes provides cancer researchers, both in the clinical and basic research setting, with crucial knowledge and it has an important impact on clinical decision-making," says López-Bigas. "For instance, if we know that the tumorigenic capacity of a tumour relies on a specific protein, an approved targeted therapy -i.e., antibodies or other inhibitors hindering its function- may be employed by oncologists to treat the patient", she adds.

Most cancer driver genes are highly specific

With the identification of the 568 cancer driver genes, the researchers have observed that most are highly specific and with their mutations capable of triggering only a few tumour types. However, there is a small group, accounting for less than 2% of those identified, that is very versatile and can drive more than 20 different types of cancer. "Although it's been known that cancer driver genes have different degree of specificity since they were first identified, having this snapshot of the compendium has allowed us to address this question it in an unbiased way," says Abel González Perez, Research Associate in the Biomedical Genomics Lab, who also led the study.

Previous studies by other groups have shown that cancers are caused by an average of 4 key mutations in cancer driver genes. Some types of cancer, characterised by a low number of mutations, present only one mutation in these genes, while others that typically present many mutations, such as colorectal and uterus tumours, hold up to 10. Other genomic alterations, such as structural variants, changes in the number of copies of genes, and mutations affecting non-coding areas of the genome also contribute to tumorigenesis.

Positive selection as an indicator

Surprising mutational patterns in a gene, different from the expected under neutrality, constitute signals that they are under positive selection in tumorigenesis. IRB Barcelona researchers use these signals of positive selection to identify mutational driver genes. To compute these signals, the accumulation of mutations under neutrality needs to be accurately modelled for all genes, so that deviations of any gene from the expected pattern may be readily spotted.

Signals of positive selection that are exploited to identify mutational driver genes are, for example, the abnormally high number of mutations in a gene or an unexpected distribution of mutations along the sequence of a gene. In this latest article, published in the journal Nature Reviews Cancer, the researchers present an update of the open-access IntOGen platform, including the values computed for these signals across all mutational driver genes. "The IntOGen platform provides the ideal infrastructure for the systematic update of the compendium, as more tumour sequencing data are released into the public domain," says first author Francisco Martínez-Jiménez, postdoctoral researcher in the Biomedical Genomics Lab.

Enriching the Cancer Genome Interpreter

The Biomedical Genomics Lab previously developed a platform called the Cancer Genome Interpreter, aimed at supporting clinical decision-making in oncology. The recently published compendium of driver genes in each cancer type, as well as their mutational patterns across tumours, will feed the new version of Cancer Genome Interpreter, under development, thus refining its capability of identifying mutations that may be key for an individual's tumour, and which constitute therapeutic targets. The snapshot of the compendium of driver genes, and the computational system used to produce it are freely available to clinical and basic cancer researchers for exploration and download.

Remarkable progress in our understanding of phosphate metabolism has been made over the last two decades, and this in turn has led to significant advances in the knowledge and management of diseases such as hypo- and hyperphosphatemia and tumour-induced osteomalacia, among other related disorders.

A special issue of Calcified Tissue International now features 10 invited reviews that elucidate the latest knowledge and noteworthy progress on phosphate metabolism. The issue has been curated by guest editors, Professors S. Minisola and ML Brandi, renowned experts in rare skeletal diseases.

Professors René Rizzoli and Stuart Ralston, Editors of Calcified Tissue International, noted: "These state-of-the-art reviews give insights into the physiology and pathology of phosphate metabolism as well as the important advances that have been made to date at the translational and clinical level. Importantly, they point to new directions for future research which are expected to benefit patients who suffer from phosphate wasting and related disorders. We sincerely thank the authors of these outstanding reviews for providing important and timely updates."

The prevalence of the highly infectious coronavirus disease, COVID-19, has caused massive health and socio-economic upheavals worldwide. Major slumps in industrial production due to stringent lockdown measures and export restrictions have led to severe logistical challenges and drastic disruptions to the global supply chains. Rising to the challenges and unprecedented demands, the 3D printing technology has demonstrated operational resilience with timely and innovative responses to help in the global supply efforts.

In an article published in Nature Reviews Materials, researchers from the Singapore University of Technology and Design (SUTD), Nanyang Technological University, Cedars-Sinai Medical Center and HP Inc examined how the digital versatility and quick prototyping of 3D printing has enabled the swift mobilization of the technology and a rapid response to emergencies in a closed loop economy.

The researchers explained how 3D printing has enabled product customization, complex designs and on-demand manufacturing using any decentralized 3D printing facility in the world by leveraging designs shared online. This has led to the broad spectrum of 3D printing applications in the fight against COVID-19 including the printing of personal protective equipment (PPE), medical and testing devices, personal accessories, visualization aids, and emergency dwellings.

For instance, due to severe shortages of ventilator machines, continuous positive airways pressure (CPAP) machines were used as substitutes for COVID-19 patients who require sub-intensive therapy. A 3D printable mask connector design, the Charlotte valve, was produced and it was specially designed to fit and connect Decathlon's Easybreath snorkelling masks to CPAP machines.

3D printing also served as an alternative and more efficient manufacturing option to keep up with the demand for nasopharyngeal (NP) swabs. The 3D printed NP swabs were fabricated with complex tip structures for enhanced sample collection efficacy, hence eliminating the need to apply flocks at the tips. Separately, 3D printing has even been used to fabricate temporary emergency dwellings to isolate those under quarantine, relieving the overloaded medical infrastructures.

The article additionally discussed technological suitability, accountability of new approved designs, copyright infringements as well as regulations and guidelines that 3D print manufacturers need to abide by to ensure safe and effective performance of 3D-printed medical devices and translate the good intentions of individuals into meaningful contributions.

"The agility and precision of 3D printing has allowed for innovative solutions amidst the supply chain pressures that we are facing globally. This has resulted in rapidly deployable built environment, healthcare medical devices and training tools which have been crucial in the fight to save lives and contain this virus," said corresponding author Professor Chua Chee Kai from SUTD.

Stroke, Parkinson's disease and depression - these medical illnesses have one thing in common: they are caused by changes in brain functions. For a long time, research has therefore been conducted into ways of influencing individual brain functions without surgery in order to compensate for these conditions.

Scientists at the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany, have taken a decisive step. They have succeeded in precisely influencing the functioning of a single area of the brain. For a few minutes, they inhibited exactly the area that processes the sense of touch by specifically intervening in its rhythm. As a result, the area that was less networked with other brain regions, its so-called functional connectivity, decreased, and thus also the exchange of information with other brain networks.

This was possible because the researchers had previously determined each participant's individual brain rhythm that occurs when perceiving touch. With the personal frequency, they were able to modulate the targeted areas of the brain one at a time in a very precise manner using what is known as transcranial alternating current stimulation. "This is an enormous advance," explains Christopher Gundlach, first author of the underlying study. "In previous studies, connectivity fluctuated extensively when the current was distributed in different areas of the brain. The electrical current randomly sought its own path in the brain and thus affected different brain areas simultaneously in a rather imprecise manner.

In a preliminary study, the neuroscientists had already observed that this form of stimulation not only reduces the exchange of the targeted brain networks with other networks, it also affects the brain's ability to process information, in this case the sense of touch. When the researchers inhibited the responsible somatosensory network, the perception threshold increased. The study participants only perceived stimuli when they were correspondingly strong. When, on the other hand, they stimulated the region, the threshold value dropped and the study participants already felt very gentle electrical stimuli.

"The deliberate change in brain rhythm lasted only briefly. As soon as the stimulation is switched off, the effect disappears again," explains study leader Bernhard Sehm. "Nevertheless, the results are an important step towards a targeted therapy for diseases or disorders caused by disturbed brain functions". Targeted brain stimulation could help to improve, direct and, if necessary, attenuate the flow of information.

The development of chemotherapeutic agents with selective anti-cancer activities is increasingly unattractive due to the emergence of resistance, poor targeting of cancer tissues, and subsequent metastasis. Among tumor characteristic cell types, cancer stem cells are increasingly associated with cancer progression and metastasis, reflecting self-renewal and their propensity to enter the circulation.

Scientists at Japan Advanced Institute of Science and Technology (JAIST) have created a regulation technology of fatal cancer stemness using the combination of nanotechnology and genetic engineering called as "photothermogenetics" that allows for effective cancer elimination.

Developed by Associate Professor Eijiro Miyako and his team from JAIST, photo-active functional nanocarbon complexes, which made of polyethylene glycol (PEG)-modified carbon nanohorns (CNH) with an antibody against the receptor potential vanilloid family type 2 (TRPV2), showed high potential as a targeting cancer chemotherapeutic agent.

In fact, the nanocomplexes are effectively heated by biologically permeable near-infrared light. After application to cancer cells and mice tumor models, these complexes photo-thermally triggered calcium influx into target cells overexpressing TRPV2 (temperature-responsive membrane protein), resulting in increased cancer cell death and effective regulation of cancer stemness. The present experiments warrant further consideration of this novel chemotherapeutic approach using the best combination of nanotechnology and genetic engineering for the treatment of refractory cancers and control of fatal cancer stemness.

Tropical Storm Josephine weakened on Aug. 16 in the North Atlantic Ocean and satellite imagery showed the storm had become elongated and stretched out into a trough of low pressure a couple of hundred miles north of Puerto Rico.

Early on Sunday, Aug. 16, the Moderate Resolution Imaging Spectroradiometer or MODIS instrument aboard NASA's Aqua satellite provided infrared temperatures of the storm's cloud tops and revealed the storm had become more disorganized over the last day. Coldest cloud top temperatures were near minus 70 degrees Fahrenheit and were displaced from the center. At the time, the National Hurricane Center said, "Josephine's low-level center has raced out over 100 nautical miles to the west of a remnant area of deep convection, which itself is shrinking and becoming more disorganized."

Later in the day, at 1:30 p.m. EDT, the MODIS instrument aboard NASA's Terra satellite provided a visible image of Josephine as it was degenerating into a trough (elongated area) of low pressure about 175 miles (280 km) north of San Juan, Puerto Rico. The MODIS image showed a low-level swirl that became less defined later in the day. Wind data on the afternoon of Aug. 16 indicated Josephine had degenerated into a trough of low pressure.

Josephine's Final Advisory

The NHC posted its final advisory on Josephine on Sunday, Aug. 16 at 5 p.m. EDT (2100 UTC). At that time, the remnants of Josephine were located near latitude 20.9 degrees north and longitude 65.8 degrees west. The remnants were moving toward the west-northwest near 12 mph (19 kph), and is expected to turn toward the northwest.

Maximum sustained winds are near 35 mph (55 kph) with higher gusts. The maximum winds associated with the remnants are forecast to continue to decrease over the next day or two. The remnants are forecast to recurve toward the north and northeast Tuesday and Tuesday night.

About NASA's Worldview and Terra Satellite

NASA's Earth Observing System Data and Information System (EOSDIS) Worldview application provides the capability to interactively browse over 700 global, full-resolution satellite imagery layers and then download the underlying data. Many of the available imagery layers are updated within three hours of observation, essentially showing the entire Earth as it looks "right now." One of the satellites providing data is NASA's Terra Satellite. Terra is one in a fleet of NASA satellites that provide data for hurricane research.

Tropical cyclones/hurricanes are the most powerful weather events on Earth. NASA's expertise in space and scientific exploration contributes to essential services provided to the American people by other federal agencies, such as hurricane weather forecasting.

For updated forecasts, visit: http://www.nhc.noaa.gov

By Rob Gutro
NASA's Goddard Space Flight Center