Culture

Southampton researchers have identified a blood profile that could help identify COVID-19 patients at greatest risk of deterioration and direct them towards trials of specific treatments that could modify their immune systems' responses.

A new study jointly led by Professor Tom Wilkinson and Dr Tristan Clark of the University of Southampton, has shown a blood test for five cytokines could help predict those at risk of life-threating overstimulation of immune defences by COVID-19, and potentially tailor their treatment to tackle this.

'Preventing a cytokine storm'

Cytokines are cell signalling molecules with many associated with inflammation released into the bloodstream after an infection, helping to drive protective immune responses.

In patients with severe COVID-19, the immune system can overreact leading to massively increased cytokine levels in the blood - a 'cytokine storm'. Instead of helping the body fight the virus, this overreaction is extremely damaging to the cells and tissues of the body itself and can be fatal.

Identifying those more prone to this response, and tackling the hyperinflammation could be a key route to reducing the severity of COVID-19 and deaths.

'Identifying patients most at risk'

The study, published in Respiratory Research, analysed blood samples from 100 COVID-19 positive patients admitted to University Hospital Southampton NHS Foundation Trust (UHS) between 20 March and 29 April 2020, during the first phase of the pandemic.

They found that high levels of cytokines IL-6, IL-8, TNF, IL-1β and IL-33 in the patients' blood on admission were associated with greater chance of needing intensive care, artificial ventilation and of dying. IL-1β and IL-33 showed the biggest effect.

This study formed part of the CoV-19POC study - a trial led by Dr Clark looking at the clinical impact of molecular point-of-care testing in patients at UHS with suspected COVID-19, including tests that dramatically cut the time taken to diagnose COVID-19.

Combining this cytokine test with a clinical assessment of the patients' condition could help doctors identify and treat those most at risk of deteriorating.

Dr Anna Freeman and Dr Hannah Burke, Respiratory Clinical Research Fellows and joint first authors commented: "This project was a great opportunity for collaboration within the Faculty of Medicine, using resource from both the respiratory and infectious diseases teams.

"As early career researchers this study provided us with a valuable learning opportunity about how to deliver academic impact within the evolving COVID-19 pandemic."

'Investigating new treatments'

Two treatments for those hospitalised with COVID-19 have been found so far, with the steroid dexamethasone shown to reduce deaths by up to a third, in patients needing oxygen. The mechanism for Dexamethasone's protective effects isn't known, but as a non-specific anti-inflammatory it points to the potential benefit of controlling the inflammatory immune response.

The Southampton team hope that by accurately identifying which cytokines are driving hyperinflammation in each COVID-19 patient, doctors could target them (such as with an IL-33 blocker current in UK trials), yielding the biggest benefits for individual patients- an approach known as 'precision medicine'.

Professor Tom Wilkinson said: "These findings, from the ongoing COVID research programme in Southampton, have identified important inflammatory signals which will help steer the development of treatment strategies for this new disease.

"It is increasingly apparent that COVID is highly heterogeneous. Only by applying these techniques to stratify the condition will we be able to target the key mechanisms of disease with the best treatment for that individual."

Dr Tristan Clark said: "Our findings suggest that testing for both COVID-19 and cytokines at the point-of-care is feasible and in the future may identify infected patients and the most appropriate treatment for them, in near real-time."

Dogs' personality changes over time, but these changes occur unevenly during the dogs' life, and each trait follows a distinct age trajectory, according to a study published in Scientific Reports by researchers from the ELTE Eötvös Loránd University, Budapest and the University of Veterinary Medicine, Vienna. The authors also identified some aged dogs with potential age-related impairments, which had very low problem orientation and extremely high levels of activity.

Human personality is characterized by a peculiar dualism: it is both stable and malleable, depending on the point of reference. If we compare ourselves to our peers, it is stable as our personality rankings relative to others remain consistent over time. However, personality changes became obvious if we compare ourselves across time, as people become more conscientious, more emotionally stable, and more agreeable as they get older.

But what about personality stability and change in dogs? "Even though dog personality is a highly popular topic in the literature, there are still gaps about the long-term stability, as well as about the dynamics of personality development. That is, if personality rankings remain consistent over several years, at what age personality changes most prominently occur, and how much dogs actually change throughout their life." - explains Borbála Turcsán, first author of the study (ELTE, Department of Ethology).

To address these gaps, the authors investigated the personality of 217 Border collies across a wide age range (from 6 months to 15 years) using a comprehensive test battery known as the Vienna Dog Personality Test (VIDOPET). The researchers also invited the owners and the dogs back to the lab four years later, and tested 37 subjects again.

Associate Professor Friederike Range (Clever Dog Lab) describes why dogs were re-tested. "Longitudinal studies covering multiple years and using the same method at both time points are very rare in the dog literature. Following up the same dogs across ~4 years allowed us to address not only the question of personality stability, but also if there are individual differences in personality development, that is, if dogs with certain personality profiles change more than others."

The researchers showed that dog personality also has a 'stable' component, the dogs' ranks on all five personality traits remained fairly consistent across the investigated time period. So, for example, the most active individuals in the sample remained the most active 4 years later. However, individuals with a more 'mature' initial personality profile (that were less active, less curious and more oriented to problems) changed less in these traits than their peers - similar to what has been found in humans.

To investigate the general age-related changes in personality the researchers compared the personality of dogs belonging to seven age groups. "We found that dogs' personality changes with age, and these changes occur unevenly during the dogs' life course, just like in humans. Crucially, however, the dynamics of change seem to be specific for each personality trait." - said Zsofia Viranyi (Clever Dog Lab). "For example, the Problem orientation trait, which describes the dogs' attentiveness and ability to solve problems, changes largely during early life, increasing strongly until ~6 years of age, after which further changes became negligible. In contrast, the Novelty seeking trait did not change markedly during the younger life stages, but ~3 years of age their curiosity about novel objects and situations started to decrease which continued until geriatric age."

The Activity-independence of the dogs also decreased continuously over the dogs' life course, but in this trait the most pronounced decrease occurred from puppyhood to adolescence (1-2 years of age). Not all traits showed such a marked change with age. For example, dogs showed only a small tendency to be better at tolerating frustrating situations as they aged, and the dogs' level of Sociability seemed to remain constant throughout the dogs' life course.

Interestingly, the authors also identified some aged dogs with potential age-related impairments, which had very low problem orientation and extremely high levels of activity. "By describing in detail the normative patterns of personality development throughout different life stages, our study can help in the identification of age-related impairments". - explained Enik? Kubinyi, principal investigator at the Senior Family Dog Project (ELTE), supported by an ERC grant. "Dogs are already recognized as a natural model for human cognitive ageing, and our results suggest that similar rules govern the age-related changes in both human and dog personality."

While the ongoing Corona pandemic continues to threaten millions of lives around the world, the first half of 2020 saw an unprecedented decline in CO2 emissions - larger than during the financial crisis of 2008, the oil crisis of the 1979, or even World War II. An international team of researchers has found that in the first six months of this year, 8.8 percent less carbon dioxide was emitted than in the same period in 2019 - a total decrease of 1551 million tonnes. The groundbreaking study not only offers a much more precise look at COVID-19's impact on global energy consumption than previous analyses. It also suggests what fundamental steps could be taken to stabilize the global climate in the aftermath of the pandemic.

"What makes our study unique is the analysis of meticulously collected near-real-time data" explains lead author Zhu Liu from the Department of Earth System Science at Tsinghua University in Beijing. "By looking at the daily figures compiled by the Carbon Monitor research initiative we were able to get a much faster and more accurate overview, including timelines that show how emissions decreases have corresponded to lockdown measures in each country. In April, at the height of the first wave of Corona infections, when most major countries shut down their public life and parts of their economy, emissions even declined by 16.9 %. Overall, the various outbreaks resulted in emission drops that we normally see only on a short-term basis on holidays such as Christmas or the Chinese Spring Festival."

The study, published in the latest issue of Nature Communications, shows which parts of the global economy were most impacted. "The greatest reduction of emissions was observed in the ground transportation sector," explains Daniel Kammen, professor and Chair of the Energy and Resources Group and also professor in the Goldman School of Public Policy, University of California, Berkeley. "Largely because of working from home restrictions, transport CO2 emissions decreased by 40 % worldwide. In contrast, the power and industry sectors contributed less to the decline, with -22 % and -17 %, respectively, as did the aviation and shipping sectors. Surprisingly, even the residential sector saw a small emissions drop of 3 %: largely because of an abnormally warm winter in the northern hemisphere, heating energy consumption decreased with most people staying at home all day during lockdown periods."

To paint this comprehensive and multidimensional picture, the researchers based their estimates on a wide array of data: precise, hourly datasets of electricity power production in 31 countries, daily vehicle traffic in more than 400 cities worldwide, daily global passenger flights, monthly production data for industry in 62 countries as well as fuel consumption data for building emissions in more than 200 countries.

The researchers also found strong rebound effects. With the exception of a continuing decrease of emissions stemming from the transportation sector, by July 2020, as soon as lockdown measures were lifted, most economies resumed their usual levels of emitting CO2. But even if they remained at their historically low levels, this would have a rather minuscule effect on the long-term CO2 concentration in the atmosphere.

Thus, the authors stress that the only valid strategy to stabilize the climate is a complete overhaul of the industry and commerce sector. "While the CO2 drop is unprecedented, decreases of human activities cannot be the answer," says Co-Author Hans Joachim Schellnhuber, founding director of the Potsdam Institute for Climate Impact Research. "Instead we need structural and transformational changes in our energy production and consumption systems. Individual behavior is certainly important, but what we really need to focus on is reducing the carbon intensity of our global economy."

Based on the new study published in Scientific Reports by researchers of the Department of Ethology at Eötvös Loránd University, Budapest, adult, intensively socialised wolves form individualized social bonds with their human handlers.

One of the key features of the dog's success is that they show attachment towards their owners. However, the origin of the ability to form these interspecific bonds is still unclear. To uncover this specific bond we need to investigate the attachment-related behaviours, but to understand its origins it is not enough to take a closer look on the dog's behaviour. Though, it is widely accepted that the common ancestor of the dog and the grey wolf probably was a highly social species, what had an important role during the domestication and the emergence of the dog as a new species, we still know nothing about the evolutionary origin of the dog-human attachment. By studying the dog's closest living relative, the grey wolf, we can have an insight - though indirectly - how the common ancestor's social system might have affected the early domestication process of the dog.

"Attachment is a so-called behaviour-complex, what has several manifestations. For instance, dogs seek protection from their owners in threat or they are calmer in new situations when their owner is present, but they show signs of stress in their absence. We were wondering whether intensively socialised adult wolves show at least some features of the attachment behaviour towards their handlers" - explained Rita Lenkei, the first author of the publication.

The researchers tested hand-raised wolves and family dogs in a separation test, where the subjects were left alone by their handler or by a stranger for three minutes at an unfamiliar place.

"We were surprised how little difference was between the wolves' and dogs' behaviour during the test. When their handler - or owner in case of the dogs - was present they were calmer, they spent their time exploring their vicinity and sniffing around. But when they were left by their handler, they became stressed, whined and pulled the leash towards her hiding place. However, when the stranger disappeared these behaviours barely appeared" - explained Tamás Faragó, leading author of the study.

Naturally, the researchers also found species specific differences, as besides the domestication, the artificial selection and also rearing conditions markedly shaped the dog's behaviour. For instance, dogs were more interested towards humans, regardless of her familiarity. This result is in line with earlier findings that dogs are generally more attracted towards humans from early puppyhood what might be caused by genetic differences between dogs and wolves. Besides, wolves pulled the leash more persistently what the researchers explained with the assumption that owners usually teach their dogs not to pull it from their early age.

Though the dog-human relationship resembles to the offspring-parent bond from several aspects, based on earlier studies wolf puppies do not show attachment towards their human caregivers. As in this experiment the subjects were adult individuals and their handler was not their original caretaker, these results raise the possibility that the evolutional origin of the human-dog attachment is the social bond between the members of the pack. Wolves live in families, usually consisting a mating pair and their offspring of different ages. Presumably the common ancestor also lived in a similar complex social environment what might provide a good basis for developing abilities to easily integrate into human social groups.

"It is important to emphasize the hand-rearing and the intensive socialisation of our wolf subjects. Without this process they would never show these behaviours towards humans. Contrary to them, as a result of genetic changes, dogs are able to form attachment easily from their puppyhood and they can develop it thorough their whole life. Thus, we must keep in mind that though during our test they showed similar behaviour, we are talking about separate species and the dog is not just a tame wolf, while the wolf will never became a pet." - added Lenkei.

Bottom Line:

The histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) in combination with the mTOR inhibitor sirolimus (Rapamune) or everolimus (Afinitor) showed clinical efficacy in patients with relapsed/refractory Hodgkin lymphoma, according to results from a phase I clinical trial.

Journal in Which the Study was Published:

Clinical Cancer Research, a journal of the American Association for Cancer Research

Author:

Filip Janku, MD, PhD, an associate professor at The University of Texas MD Anderson Cancer Center

Background:

"While the majority of patients with Hodgkin lymphoma have favorable outcomes with standard treatment, approximately 20-30 percent of patients with advanced disease develop refractory disease after primary treatment," said Janku. "These patients typically have poor outcomes with five-year survival rates as low as 30 percent."

Histone deacetylases (HDACs) are cellular proteins that regulate gene expression. Aberrant HDAC expression is associated with cancer, and HDAC inhibitors have been approved for the treatment of certain blood cancers. Resistance to HDAC inhibition in Hodgkin lymphoma has been suggested to develop through activation of mTOR signaling, which regulates cellular proliferation and cell death, explained Janku. Thus, combining HDAC inhibition with an mTOR inhibitor could help prevent resistance and improve responses to treatment, he noted.

Prior preclinical research demonstrated that combined inhibition of HDACs and mTOR signaling had antitumor effects against Hodgkin lymphoma. Furthermore, a patient with relapsed/refractory Hodgkin lymphoma who received treatment with vorinostat and sirolimus as part of a phase I clinical trial had a partial response to the treatment.

How the Study was Conducted:

In this study, Janku and colleagues examined the clinical efficacy of vorinostat in combination with either sirolimus or everolimus in a larger cohort of patients with heavily pretreated relapsed/refractory Hodgkin lymphoma who had received a median of five prior therapies. The cohort included 40 adult patients; of these patients, 22 received the vorinostat and sirolimus combination, and 18 received the vorinostat and everolimus combination.

Results:

The objective response rate for patients in the vorinostat and sirolimus arm was 55 percent, with six complete responses and six partial responses. After a median follow-up of 43.3 months, the median progression-free survival was 5.3 months. Median overall survival had not been reached at the time of analysis.

The objective response rate for patients in the vorinostat and everolimus arm was 33 percent, with two complete responses and four partial responses. After a median follow-up of 21 months, the median progression-free survival was 4.8 months. Median overall survival had not been reached at the time of analysis.

All 40 patients were evaluated for adverse events. The most common grade 3 or 4 treatment-related adverse events in both treatment groups were thrombocytopenia, neutropenia, and anemia. There were no treatment-related deaths.

Author's Comments:

"In our study, we observed a relatively high objective response rate in a patient population that would otherwise have poor outcomes," said Janku. "Based on our results, I believe further investigation is warranted for these combination treatments."

Janku added that his future research will examine the efficacy of these combinations with immune checkpoint inhibition. "There is evidence that both mTOR and HDAC inhibitors affect the tumor microenvironment, so there may be a benefit to combining these inhibitors with immunotherapy," he noted.

Study Limitations:

A limitation of the study is that it was conducted prior to the approval of immune checkpoint inhibitors for relapsed/refractory Hodgkin lymphoma and therefore does not account for prior treatment with immune checkpoint inhibitors. An additional limitation is that the trial was conducted at a single institution.

What if you could instruct a swarm of robots to paint a picture? The concept may sound far-fetched, but a recent study in open-access journal Frontiers in Robotics and AI has shown that it is possible. The robots in question move about a canvas leaving color trails in their wake, and in a first for robot-created art, an artist can select areas of the canvas to be painted a certain color and the robot team will oblige in real time. The technique illustrates the potential of robotics in creating art, and could be an interesting tool for artists.

Creating art can be labor-intensive and an epic struggle. Just ask Michelangelo about the Sistine Chapel ceiling. For a world increasingly dominated by technology and automation, creating physical art has remained a largely manual pursuit, with paint brushes and chisels still in common use. There's nothing wrong with this, but what if robotics could lend a helping hand or even expand our creative repertoire?

"The intersection between robotics and art has become an active area of study where artists and researchers combine creativity and systematic thinking to push the boundaries of different art forms," said Dr María Santos of the Georgia Institute of Technology. "However, the artistic possibilities of multi-robot systems are yet to be explored in depth."

This latest study looks at the potential for robot swarms to create a painting. The researchers designed a system whereby an artist can designate different regions of a canvas to be painted a specific color. The robots interact with each other to achieve this, with individual robots traversing the canvas and leaving a trail of colored paint behind them, which they create by mixing paints of different colors available on-board.

"The multi-robot team can be thought of as an "active" brush for the human artist to paint with, where the individual robots (the bristles) move over the canvas according to the color specifications provided by the human," explained Santos.

In their experiments, the researchers used a projector to simulate a colored paint trail behind each robot, although they plan to develop a robot that can handle paint in the future. They found that even when some robots didn't have access to all the colors required to create the assigned color, they were still able to work together and approximate the color reasonably well.

This system could allow artists to control the robot swarm as it creates the artwork in real time. The artist doesn't need to provide instructions for each individual robot, or even worry whether they have access to all the colors needed, allowing them to focus on creating the painting.

In the current study, the resulting images are abstract, and resemble a child's crayon drawing. They show unique areas of color that flow into each other, revealing the artist's input, and are pleasing to the eye. Future versions of the system may allow for more refined images.

Most importantly, the images confirm that it is possible for an artist to successfully instruct a robot swarm to paint a picture. The technique may also have potential in other fields where easily controlling the actions of a swarm of robots could be valuable. Robot orchestra, anyone?

It might look like a little game at the molecular scale.

Filament-like proteins in heart muscle cells have to be exactly the same length so that they can coordinate perfectly to make the heart beat.

Another protein decides when the filament is the right size and puts a wee little cap on it. But, if that protein makes a mistake and puts the cap on too early, another protein, leiomodin, comes along and knocks the cap out of the way.

This little dance at the molecular scale might sound insignificant, but it plays a critical role in the development of healthy heart and other muscles. Reporting in the journal, Plos Biology, a WSU research team has proven for the first time how the mechanism works.

The finding could someday lead to improved diagnostics and medical treatments for serious and sometimes devastating hereditary heart conditions that come about from genetic mutations in the proteins. One of these conditions, cardiomyopathy, affects as many as one in 500 people around the world and can often be fatal or have lifetime health consequences. A similar condition called nemaline myopathy affects skeletal muscles throughout the body with often devastating consequences.

"Mutations in these proteins are found in patients with myopathy," said Alla Kostyukova, associate professor in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering and leader of the project. "Our work is to prove that these mutations cause these problems and to propose strategies for treatment."

Heart muscle is made of tiny thick and thin filaments of proteins. With the help of electrical signals, the rope-like filaments bind and unbind in an intricate and precise architecture, allowing heart muscle to contract and beat.

The thin filaments are made of actin, the most abundant protein in the human body. Tropomysin, another protein, wraps itself around the actin filaments. Tropomyosin together with two other proteins, tropomodulin and leiomodin, at the end of the actin filaments act as a sort of cap and determine the filament length.

"It's beautifully designed," said Kostyukova, whose research is focused on understanding protein structures.

And, tightly regulated.

To keep heart muscle healthy, the actin filaments, which are about a micron long, all have to be the exact same length. In families with cardiomyopathy, genetic mutations result in formation of filaments that are either too short or too long. Those affected can have significant heart problems that cause disability, illness and death.

In a project that spanned seven years, the researchers proved that leiomodin attaches to the end of the actin filament and kicks out the other protein, tropomodulin, to assure the actin filament's proper length.

"This is the first time that this has been shown with the atomic-level precision," said Dmitri Tolkatchev, research assistant professor in the Voiland School and lead author on the paper. "Previously, several laboratories attempted to solve this problem with very little success. With our data we finally have a direct proof."

The researchers used state-of-the-art approaches to make the key proteins and study them at the molecular and cellular level.  The work entailed designing the molecules, constructing them at the gene level in a plasmid, and then producing them into bacterial or cardiac cells. The researchers used nuclear magnetic resonance, which works on the same physical principle as Magnetic Resonance Imaging (MRIs), to understand the proteins' binding at the atomic level.  They also used molecular dynamic simulation to model them.

"The probability of being able to show this mechanism was not high, but the impact of the discovery is," said Tolkatchev, an expert in nuclear magnetic resonance. "This was a very important problem to study and could have a significant impact in the field of muscle mechanics."

The researchers hope to continue the work, identifying additional components and molecular mechanisms that regulate thin filament architecture, whether diseased or healthy.

New research from the University of North Carolina at Chapel Hill suggests that a strain of coronavirus that has recently alarmed the swine industry may have the potential to spread to humans as well.

The coronavirus strain, known as swine acute diarrhea syndrome coronavirus (SADS-CoV), emerged from bats and has infected swine herds throughout China since it was first discovered in 2016. Outbreaks of such an illness have the potential to wreak economic havoc in many countries across the globe that rely on the pork industry.

The virus' potential threat to people was demonstrated in lab tests showing SADS-CoV efficiently replicated in human airway and intestinal cells. The findings were published Oct. 12 in PNAS.

Though it is in the same family of viruses as the betacoronavirus SARS-CoV-2, which causes the respiratory illness COVID-19 in humans, SADS-CoV is an alphacoronavirus that causes gastrointestinal illness in swine. The virus causes severe diarrhea and vomiting and has been especially deadly to young piglets.

SADS-COV is also distinct from two circulating common cold alphacoronaviruses in humans, HCoV-229E and HCoV-NL63.

"While many investigators focus on the emergent potential of the betacoronaviruses like SARS and MERS, actually the alphacoronaviruses may prove equally prominent -- if not greater -- concerns to human health, given their potential to rapidly jump between species," said Ralph Baric, professor of epidemiology at UNC-Chapel Hill Gillings School of Global Public Health.

While SADS-CoV has not been known to affect humans to-date, the COVID-19 pandemic serves as a potent reminder that many coronavirus strains found in animals have the potential to infect humans as well - an effect known as spillover.

The Baric lab worked with Caitlin Edwards, a research specialist and master of public health student at UNC-Chapel Hill, on the study which suggests humans may be susceptible to spillover of SADS-CoV.

Edwards, the study's first author, tested several types of cells by infecting them with a synthetic form of SADS-CoV to understand just how high the risk of cross-species contamination could be.

Evidence from the study indicates that a wide range of mammalian cells, including primary human lung and intestinal cells, are susceptible to infection. According to Edwards, SADS-CoV shows a higher rate of growth in intestinal cells found in the human gut, unlike SARS-CoV-2, which primarily infects lung cells.

Cross-protective herd immunity often prevents humans from contracting many coronaviruses found in animals. However, results from the testing done by Edwards and her team suggest that humans have not yet developed such immunity to SADS-CoV.

"SADS-CoV is derived from bat coronaviruses called HKU2, which is a heterogenous group of viruses with a worldwide distribution," Edwards said. "It is impossible to predict if this virus, or a closely related HKU2 bat strain, could emerge and infect human populations. However, the broad host range of SADS-CoV, coupled with an ability to replicate in primary human lung and enteric cells, demonstrates potential risk for future emergence events in human and animal populations."

In response to these findings, Edwards and colleagues tested the broad-spectrum antiviral remdesivir as a potential method of treatment for the infection.

Working with Gilead Sciences, remdesivir was developed by the Baric Lab to combat all known coronaviruses, including SADS-CoV. It is currently being used to treat COVID-19 infections in humans, including the United States president. Preliminary results from this study show that it has robust activity against SADS-CoV, though Edwards cautions that more testing is necessary on additional cell types and in animals to confirm these findings.

"Promising data with remdesivir provides a potential treatment option in the case of a human spillover event," she said. "We recommend that both swine workers and the swine population be continually monitored for indications of SADS-CoV infections to prevent outbreaks and massive economic losses."

SADS-CoV could also pose a threat to the U.S. economy, which was third in global pork production in 2019. In 2012, the U.S. pork industry was devastated by different swine coronavirus that emerged from China.

"Not surprisingly, we are currently looking for partners to investigate the potential of SADS-CoV vaccine candidates to protect swine," Baric said. "While surveillance and early separation of infected piglets from sows provide an opportunity to mitigate larger outbreaks and the potential for spillover into humans, vaccines may be key for limiting global spread and human emergence events in the future."

Researchers at Institut national de la recherche scientifique (INRS) have discovered a cost-effective way to tune the spectrum of a laser to the infrared, a band of great interest for many laser applications. They collaborated with Austrian and Russian research teams to develop this innovation, which is now the subject of a patent application. The results of their work were recently published in Optica, the flagship journal of the Optical Society (OSA).

In this field of study, many laser applications have a decisive advantage if the laser wavelength is located and possibly tunable in the infrared region. However, this is still hardly the case with current ultrafast laser technologies, and scientists need to explore various nonlinear processes to shift the emission wavelength. In particular, the Optical Parametric Amplifier (OPA) has so far been the only well-established tool to reach this infrared window. Although OPA systems offer a broad range of tunability, they are complex, often made of multiples stages, and quite expensive.

The team of Professor Luca Razzari, in collaboration with Professor Roberto Morandotti, has demonstrated that large wavelength tunability can also be achieved with a simple and much less expensive system: a hollow-core (capillary) fiber filled with nitrogen. In addition, this approach readily delivers optical pulses shorter than those of the input laser and with high spatial quality. The researchers also had the benefit of INRS expertise in this field, since the special system to stretch and hold such fibers is marketed by the startup few-cycle.

Asymmetrical spectral broadening

Usually, hollow-core fibers are filled with a monatomic gas such as argon in order to symmetrically broaden the spectrum of the laser and then recompress it into a much shorter optical pulse. The research team discovered that by using a molecular gas such as nitrogen, spectral broadening was still possible, but in an unexpected manner.

"Rather than spreading symmetrically, the spectrum was impressively shifted toward less energetic infrared wavelengths. This frequency shift is the result of the nonlinear response associated with the rotation of the gas molecules and, as such, it can be easily controlled by varying the gas pressure (i.e., the number of molecules) in the fiber," explains Dr. Riccardo Piccoli, who led the experiments in Razzari's team.

Once the beam is broadened toward the infrared, the researchers filter the output spectrum to keep only the band of interest. With this approach, energy is transferred into the near-infrared spectral range (with efficiency comparable to that of OPAs) in a pulse three times shorter than the input, without any complex apparatus or additional pulse post-compression system.

An international collaboration

To complete the research, the INRS scientists joined with Austrian and Russian colleagues. "We pooled our expertise after discovering at a conference how similar the phenomena our two groups had observed were," says Razzari.

The team of researchers based in Vienna headed by Professor Andrius Baltuska and Dr. Paolo A. Carpeggiani had a complementary strategy to that of INRS. They also used a nitrogen-filled hollow-core fiber, but rather than filtering the spectrum, they compressed it in time with mirrors capable of adjusting the phase of the broadened pulse. "In this case, the overall shift in the infrared was less extreme, but the final pulse was much shorter and more intense, perfectly suited to attosecond and strong-field physics" says Dr. Carpeggiani.

The Moscow-based team, led by Professor Aleksei Zheltikov, focused on developing a theoretical model to explain these optical phenomena. By combining these three approaches, the researchers were able to fully understand the complex underlying dynamics as well as achieve not only the extreme red shift using nitrogen, but also efficient pulse compression in the infrared range.

The international team believes the method could very well meet the increasing demand for long-wavelength ultrafast sources in laser and strong-field applications, starting with less expensive industrial-grade tunable systems based on the emerging ytterbium laser technology.

WEST LAFAYETTE, Ind. - Tandem mass spectrometry is a powerful analytical tool used to characterize complex mixtures in drug discovery and other fields.

Now, Purdue University innovators have created a new method of applying machine learning concepts to the tandem mass spectrometry process to improve the flow of information in the development of new drugs. Their work is published in Chemical Science.

"Mass spectrometry plays an integral role in drug discovery and development," said Gaurav Chopra, an assistant professor of analytical and physical chemistry in Purdue's College of Science. "The specific implementation of bootstrapped machine learning with a small amount of positive and negative training data presented here will pave the way for becoming mainstream in day-to-day activities of automating characterization of compounds by chemists."

Chopra said there are two major problems in the field of machine learning used for chemical sciences. Methods used do not provide chemical understanding of the decisions that are made by the algorithm, and new methods are not typically used to do blind experimental tests to see if the proposed models are accurate for use in a chemical laboratory.

"We have addressed both of these items for a methodology that is isomer selective and extremely useful in chemical sciences to characterize complex mixtures, identify chemical reactions and drug metabolites, and in fields such as proteomics and metabolomics," Chopra said.

The Purdue researchers created statistically robust machine learning models to work with less training data - a technique that will be useful for drug discovery. The model looks at a common neutral reagent - called 2-methoxypropene (MOP) - and predicts how compounds will interact with MOP in a tandem mass spectrometer in order to obtain structural information for the compounds.

"This is the first time that machine learning has been coupled with diagnostic gas-phase ion-molecule reactions, and it is a very powerful combination, leading the way to completely automated mass spectrometric identification of organic compounds," said Hilkka Kenttämaa, the Frank Brown Distinguished Professor of Analytical Chemistry and Organic Chemistry. "We are now introducing many new reagents into this method."

The Purdue team introduces chemical reactivity flowcharts to facilitate chemical interpretation of the decisions made by the machine learning method that will be useful to understand and interpret the mass spectra for structural information.

UCLA researchers say a blood test commonly used to detect fetal genetic abnormalities may help predict complications associated with pregnancy before symptoms develop. Their preliminary study, appearing in Epigenetics, links certain cell-free DNA signatures to adverse outcomes in pregnancy, including ischemic placental disease and gestational diabetes.

The findings are the first to show that genetic material shed from the placenta into the mother's blood (circulating cell-free nucleic acids) during the first trimester of pregnancy could potentially be used to predict these potentially serious complications.

Although the analysis of genetic material in the mother's blood has been used to screen for genetic abnormalities in a pregnancy, this is the first time these specific methods have been used as a way of a more accurate prediction.

"Our research points to a promising approach that could improve outcomes for mothers and their babies using existing technologies," said Dr. Sherin Devaskar, lead author of the study and physician-in-chief of UCLA Mattel Children's Hospital and distinguished professor of pediatrics at the David Geffen School of Medicine. "If confirmed in larger studies, cell-free DNA blood tests may help identify issues in the placenta as an indicator of a healthy mother and fetus."

Researchers followed a diverse group of pregnant women between February 2017 and January 2019, testing their blood periodically throughout gestation. By the end of the study, 160 participants had given birth, with 102 maternal and 25 cord plasma samples taken along the way. They found that during the first-to-early second trimester, placenta-specific DNA increased among those women who went on to develop gestational diabetes. They also identified several differently expressed genes and were able to create a model with a predictive value for adverse pregnancy outcomes.

"The novelty of this research is being able to break down a mother's DNA and be able to hone in on the health of the placenta - something that researchers have never been able to do before," added Devaskar. "This research warrants application of automated methodologies in multi-center trials to improve future testing and screening for all women."

WASHINGTON, DC--Just one month before an election in which climate change may be a key issue, new survey results show that climate change may be less politically polarizing than many might expect.

Climate Insights 2020: Partisan Divide--the fourth installment in a series of survey reports by researchers at Stanford University, Resources for the Future, and ReconMR--illustrates climate-related beliefs, attitudes, and policy preferences across the political spectrum. The survey, which polled 999 American adults from May to August 2020, identifies the issues on which political groups agree--and disagree. And although there are situations in which opinions differ along party lines, there is also bipartisan support on a number of issues related to climate change.

Topline Findings

94% of Democrats believe climate change has been happening, as do 67% of Republicans.

Majorities of Republicans (56%), Independents (77%), and Democrats (86%) believe that they have personally seen the effects of climate change.

Majorities of Republicans (53%), Independents (71%), and Democrats (96%) favor pursuing the goals of the Paris Agreement.

Majorities of all three groups think that the US government should act to deal with climate change.

43% of Democrats attach extreme personal importance to climate change, compared to 22% of Independents and 4% of Republicans.

"While some observers have claimed that climate change is a deeply partisan issue, the data show more nuance--majorities of all three groups of Americans agree on the existence, causes, and threat of climate change, as well as on various government policies that could be used to mitigate future warming," report co-author Jon Krosnick said. "And the partisan gap dividing American public opinion on this issue is smaller than it is on many other important issues facing the country."

To learn more about these findings, read the partisan divide installment of Climate Insights 2020 by Bo MacInnis, lecturer at Stanford University and PhD economist, and Jon Krosnick, social psychologist at Stanford University and RFF university fellow. The Climate Insights 2020 interactive data tool also allows users to explore the data in greater depth.

Future report installments in this series will focus on electric vehicles and a state-level breakdown. Previous installments of reports focus on overall trends, natural disasters, and climate policies.

Gliding movements to invade host cells

In biological terms, gliding refers to the type of movement during which a cell moves along a surface without changing its shape. This form of movement is unique to parasites from the phylum Apicomplexa, such as Plasmodium and Toxoplasma. Both parasites, which are transmitted by mosquitoes and cats, have an enormous impact on global heath. Plasmodium causes 228 million malaria infections and around 400,000 deaths per year. Toxoplasma, which infects even one third of the human population, can cause severe symptoms in some people, and is particularly dangerous during pregnancy.

Gliding enables the Apicomplexa parasites to enter and move between host cells. For example, upon entering the human body through a mosquito bite, Plasmodium glides through human skin before crossing into human blood vessels. This type of motion relies on actin and myosin, which are the same proteins that enable muscle movement in humans and other vertebrates. Myosin has a form of molecular 'legs' that 'march' along actin filaments and thereby create movement.

In Apicomplexa, myosin interacts with several other proteins, which together form a complex called the glideosome. The exact mechanism by which the glideosome works is not well understood, among other reasons because the molecular structure of most glideosome proteins are unknown. Yet understanding this mechanism could aid the development of drugs that prevent the assembly of the glideosome and thereby stop the progression of diseases such as malaria and toxoplasmosis.

Molecular stilts facilitate gliding

Scientists at EMBL Hamburg analysed the molecular structure of essential light chains (ELCs), which are glideosome proteins that bind directly to myosin. It is known that they are necessary for gliding, but their exact structure and role were unknown until now. The researchers now obtained molecular structures of ELC bound to myosin A in Toxoplasma gondii and Plasmodium falciparum using X-ray crystallography and nuclear magnetic resonance (NMR).

Their study, published in Communications Biology, shows that ELCs work like 'molecular stilts' - upon binding myosin A, the ELCs become rigid, and start to act as its lever arm. This stiffening lets myosin makes longer steps, which likely accelerates the parasite's gliding movements.

The researchers also investigated the role of calcium, a presumed gliding regulator, in the interaction between ELCs and myosin A. Surprisingly, they discovered that calcium does not influence the structure of ELCs. It does, however, increase the stability of the ELC-myosin A complex. This unexpected result shows that the glideosome architecture still hides many unknowns.

"This work has provided the first glimpse of how these organisms move around," says Matthew Bowler, an EMBL Grenoble researcher not involved in this study, who investigates Toxoplasma's strategies to control the immune system after invading cells.

"It is fascinating to see new molecular details emerge on how these parasites work outside of the host cell. The beautiful structures show how the motor that drives this motion is put together, and could provide a basis to develop new medicines to treat these diseases," continues Bowler.

Maria Bernabeu, who leads research on vascular dysfunction in cerebral malaria at the EMBL site in Barcelona, adds: "Plasmodium passage through the skin is the first stage of human infection. The advantage of targeting Plasmodium at that stage is that only about a hundred parasites are present. Understanding the parasite's gliding motility might help to develop drugs or vaccines that target Plasmodium before it multiplies."

Interdisciplinary collaboration

The work is a result of interdisciplinary collaboration between structural biologists (Löw group) and parasitologists (Gilberger group) from the European Molecular Biology Laboratory in Hamburg and Centre for Structural Systems Biology (CSSB), as well as scientists from the Bernhard Nocht Institute for Tropical Medicine, University of Hamburg and Martin-Luther-University Halle-Wittenberg. It demonstrates the potential of interdisciplinary collaborations in contributing to our understanding of biological processes and possible future strategies to combat parasitic diseases.

"Entering malaria research has been an exciting endeavour - regular exchange with experts and the interdisciplinary environment helped us to explore the field of parasitology," says Christian Löw.

Bacteria are a dominant form of life that inhabit every environment on Earth. This includes human bodies, where they outnumber our cells and genes and regulate our existence for good or bad. Bacteria are regularly viewed as simple, single-celled organisms. As bacteria are ancient, it is widely accepted that a bacteria-like, unicellular being was the first life. Recent work published in 'Molecular Biology and Evolution' by an international research team challenges these views.

In this paper the researchers took evolutionary tools to study the growth of biofilms, the most common bacterial lifestyle characterized by the tight clustering of bacterial cells on surfaces. "Surprisingly, we found that the development of bacterial biofilms is comparable to animal embryogenesis. This means that bacteria are true multicellular organisms just like we are. Considering that the oldest known fossils are bacterial biofilms, it is quite likely that the first life was also multicellular, and not a single-celled creature as considered so far," explains Prof Tomislav Domazet-Lošo from the Rudjer Boskovic Institute and the Catholic University of Croatia in Zagreb who led the research.

Secret life of bacterial biofilms

Macroscopic organisms like animals and plants are never germ-free. They are always accompanied by bacteria and other microorganisms that persist on their inner and outer surfaces. Yet, these symbiotic bacteria are just a tiny fraction of the bacterial diversity that occupy every bit of the biosphere including vast subterranean habitats in the Earth's crust. In all of these sites bacterial cells are locally organized in morphologically structured clusters known as biofilms. Beside natural habitats, biofilms are also extremely important in industrial and biomedical settings where they often lead to biofouling or persistent infections that are resistant to therapies.

For some time, microbiologist have recognized that bacterial cells live a rich social life in biofilms, however it has remained obscure if these diverse interactions make a multicellular organism. "Evolutionary methods to study collective behavior of cells in animal development were at hand, but no one tried to transfer this technology from animal embryos to bacterial biofilms. Perhaps people were uncomfortable to challenge the special status of animal multicellularity, the idea that is culturally hardwired," emphasises Domazet-Lošo.

Technology translation

Previous work of Domazet-Lošo and his team was focused on evolutionary genomics and animal development. They were able to show that the evolution is mirrored in embryos, thus confirming more than 150 years old conjecture that ontogeny parallels phylogeny in animals. To reach these findings, they developed a computational approach, named genomic phylostratigraphy, that allows evolutionary dating of genes and proteins on the large scale. Now together with researchers from University of Zagreb, Chalmers University and Technical University of Denmark they further refined this tool to meet specifics of bacteria. "We generated the first phylostratigraphic maps of bacteria and this allowed us to link bacterial phenotypes in biofilms to evolutionary information," continues Domazet-Lošo.

Bacillus biofilms behave like animal embryos

In order to feed their new bioinformatic pipeline, researchers sampled biofilms of Bacillus subtilis, a model organism for biofilm research that inhabits soil as well as human gut. Using transcriptome sequencing and protein quantification they established transcript and protein expression levels for all Bacillus genes during the process of biofilm growth.

"Surprisingly, we found that evolutionary younger genes were increasingly expressed towards the later timepoints of biofilm growth. In other words, we found that Bacillus ontogeny strongly recapitulates phylogeny. So far, these patterns have been considered the signature of embryo development in complex eukaryotes." stresses Domazet-Lošo. The research team then followed the trail and looked for other features of embryogenesis in biofilms like stage-organized architecture, increased use of multicellularity genes and molecular links to morphology changes, and to their excitement they found these properties as well.

Towards the control of biofilms

These findings challenge the special status of eukaryotic multicellularity and show that bacteria are more complex than we thought. The tools developed in this study could also help in finding efficient procedures for biofilm control - a largely unsolved problem in industry and medicine.

"Our results point that a biofilm should be viewed as a multicellular individual, and not as a pile of individual cells. Like in animal embryogenesis, every developmental phase has its own peculiarities. Critical transition stages in biofilm growth could now be targeted via their stage-specific genes that we detected. This could be a game changer in treating biofilm related diseases, and in preventing industrial losses." concludes Domazet-Lošo.

Without directly invading the brain or nerves, the virus responsible for COVID-19 causes potentially damaging neurological injuries in about one in seven infected, a new study shows. These injuries range from temporary confusion due to low body-oxygen levels, to stroke and seizures in the most serious cases, say the study authors.

Led by researchers at NYU Grossman School of Medicine, the study showed no cases of brain or nerve inflammation (meningitis or encephalitis), indicating no immediate invasion of these organs by the pandemic virus, SARS-CoV-2.

While this should reassure patients, the neurological complications of COVID-19 should be taken seriously because they dramatically raise a patient's risk of dying while still in hospital (by 38 percent), researchers say. Such adverse effects also raise a coronavirus patient's likelihood (by 28 percent) of needing long-term or rehabilitation therapy immediately after their stay in hospital.

"The results of our study showed no signs that the coronavirus directly attacks the nervous system," says study lead investigator Jennifer Frontera, MD. "The neurological complications seen in COVID-19 are predominately the secondary effects of being severely ill and suffering from low oxygen levels in the body for prolonged periods of time," says Frontera, a professor in the Department of Neurology at NYU Langone Health.

Published in the journal Neurology online Oct. 5, the study closely monitored the progress of 606 COVID-19 adult patients diagnosed with brain or other nerve-related medical conditions at any of four NYU Langone hospitals in New York City and Long Island between March 10 and May 20, when coronavirus infections were at their peak in the region.

Frontera says that ahead of the pandemic, dozens of NYU Langone neurologists and trainees had deployed across its medical centers to assist with the expectant surge of COVID-19 patients.

Early reports from Asia and Europe, where infections had spiked before rising in the United States, she says, had also "raised the alarm" about possible brain damage from coronavirus infection. Because of this, the research team was ready to look for any signs of neurological dysfunction among the thousands of patients being admitted to hospital in the spring. Among all the hospitals, 4,491 patients tested positive for COVID-19 during that time.

Among the study's other key results was that common neurological problems, such as confusion caused by chemical electrolyte imbalances, severe infection or kidney failure, usually arose within 48 hours of developing general COVID-19 symptoms, including fever, difficulty breathing, and cough.

Half of those neurologically affected were over the age of 71, which researchers say is significantly older than the other 3,885 patients with COVID-19 (at a media age of 63) who did not experience brain dysfunction. Most were men (66 percent) and white (63 percent). Frontera notes that the study results do suggest that Blacks are not at greater risk of neurological complications than other COVID-19 patients, which is "welcome news," given that Blacks are widely known to be at greater risk of death from coronavirus infection. However, she says this potentially important observation requires further investigation.

While the coronavirus is known to attack other organs, including blood vessels and the heart, researchers say its main target is the lungs, where it makes breathing difficult, starving the body of oxygen it needs to stay alive. Low levels of oxygen in the body and brain was another common neurological problem, study results showed, that could lead to confusion, coma, or permanent brain damage.

"Our study results suggest that physicians need to be more aggressive in stabilizing body oxygen levels in patients with COVID-19 as a potentially key therapy for stopping, preventing and/or possibly reversing neurological problems," says study senior investigator Steven Galetta, MD.