Culture

Much like investors on the stock market, cell populations prepare for changes in the environment by spreading the risk. The tool box they use contains a repertoire of sensory receptors on the surface of individual cells. These receptors can be tweaked to make individual members of the population responsive to different environmental signals. It was thought that cells could only modify this diversity relatively slowly, by producing new receptor proteins or degrading them. Scientists at AMOLF (Amsterdam, the Netherlands) and Yale University (New Haven, CT) now report the discovery of a mechanism that enables cell populations to tune their diversity much faster, by a combination of physical and chemical interactions between existing proteins. The findings are published in the journal Science Advances on November 13th.

The new experimental findings reveal that populations of E. coli bacteria cells maintain a high diversity in their sensory portfolio when environmental signals are absent, but this diversity decreases drastically (by a factor of 10) when subjected to new environmental signals. "This makes a lot of sense," explains Tom Shimizu, a group leader at AMOLF and senior author of the study. "When environmental signals are scarce, uncertainty about the future is at a maximum, so the smart thing to do is to spread your bets broadly across many possible new signals. But the game changes once you sense a certain stimulus. Evidently, cell populations use that new information to 'focus' their attention to a particular signal, so that the whole population can respond together."

What was surprising, however, was how rapidly cells could switch to this new strategy. In biological cells, updates of the portfolio of sensory capabilities were until now assumed to require changes in gene expression, a time consuming process that involves the synthesis of new protein molecules or degradation of old ones. "However, these cell populations could adjust the way they spread their bets over different sensory modes within seconds," says Keita Kamino, lead author of the study who initiated the study at AMOLF and finished it at Yale. "This immediately ruled out the possibility that the cells were updating their bets by gene expression, which takes minutes to hours". To investigate the mechanism at work, the team then built a mathematical model of the observed diversity, based on known interactions between receptors and other molecules that process and relay signals across the cell. Although the model does not include a way for cells to change their gene expression, they found that it very accurately predicts the changes in the sensory diversity of cells observed in the earlier experiments. "Remarkably, diversity tuning emerges from the a combination of allosteric interactions and covalent modifications between protein molecules", says Thierry Emonet, Professor at Yale University and co-corresponding author of the study, referring to the physical influence of proteins in contact with one another to cause changes in their shape (known as "allosteric interactions"), and the addition and removal of chemical groups to those same receptors (known as "covalent modification"). "Although a model capturing these interactions had already been established by a large body of experimental work, the consequences of this allostery for diversity tuning had not been appreciated."

Thus, the team identified a simple explanation for the fast changes in risk spreading achieved by the cell population. Instead of building and breaking down protein molecules, the mechanism works through chemical modifications of existing proteins and their effects on the physical cross-talk between those proteins, thus allowing a much faster shift. Such protein modifications are used widely to process and relay signals inside individual cells, but it was not previously known that they could also play a role in the diversification of entire cell populations. Because such modifications are so prevalent throughout cells of all organisms, the authors believe this basic mechanism for fast changes in cellular diversity could be at work in many cell types across biology.

Researchers from the Hubrecht Institute and Utrecht University developed an advanced technique that makes it possible to monitor a virus infection live. The researchers from the groups of Marvin Tanenbaum and Frank van Kuppeveld expect that the technique can be used to study a wide variety of viruses, including SARS-CoV-2 - the virus responsible for the current pandemic. The technique named VIRIM ('virus infection real-time imaging') is therefore very valuable for gaining insights in virus infection in the human body. Eventually, this can lead to more targeted treatments for viral infection. The results were published in the leading scientific journal Cell on the 13th of November.

Viruses have a large negative impact on society. This is demonstrated once again by the enormous consequences of the current global outbreak of SARS-CoV-2 for our physical- and mental health and for the economy.

Intruder

RNA-viruses represent a large group of viruses, which carry their genetic information in the form of RNA: a molecule that is similar to DNA, the genetic material of humans. After infection of a host cell, an RNA-virus hijacks many of the host cell's functions and turns it into a virus-producing factory. This way, the intruder can quickly replicate inside cells in the body. The new virus particles are subsequently released through the respiratory tract and can infect other people. Examples of RNA-viruses include coronaviruses, the hepatitis C virus, the zika virus, and enteroviruses - a group of viruses that includes rhinoviruses, causing the common cold, coxsackieviruses, that are an important cause of viral meningitis and encephalitis, and the poliovirus, that causes paralytic poliomyelitis.

Live stream

Until now, available techniques could only provide a snapshot of virus-infected cells. In other words, researchers could see the infected cells at a certain point in time, but it was not possible to monitor the process of virus infection from beginning to end. The newly developed microscope technology VIRIM ('virus infection real-time imaging') changes that: researchers from the groups of Marvin Tanenbaum (Hubrecht) and Frank van Kuppeveld (Utrecht University) developed this advanced method with which the entire course of a virus infection can be visualized in the lab with great precision. "This new method enables us to address many important questions about viruses", says Sanne Boersma, first author of the study.

Fluorescent virus

The method uses SunTag - a technology previously developed by Tanenbaum - in an enterovirus, a group of viruses in which Van Kuppeveld has extensive expertise. The SunTag is introduced into the RNA of the virus and labels viral proteins with a very bright fluorescent tag. Using this fluorescent tag, viral proteins can be seen using a microscope, allowing researchers to see when, where and how quickly a virus produces it proteins and replicates in its host cell. VIRIM is much more sensitive than other methods: protein production from a single viral RNA can be detected. This allows researchers to track the course of the infection from the very beginning.

Competition

The building blocks of our bodies -cells -have their own defense system to detect and eliminate a virus upon infection. Once a virus enters a cell, a competition arises between the virus and the host cell: the virus aims to hijack the cell to replicate itself, while the host tries very hard to prevent this. Using VIRIM, researchers were able to see the outcome of this competition. They found that in a subset of cells, the host cell won the competition. Boersma: "These host cells were infected by a virus, but the virus failed to replicate." This triggered the curiosity of Boersma and her colleagues and led to a new experiment.

Achilles' heel of the virus

The researchers helped host cells by boosting their defense system. As it turned out, the very first viral replication often failed in the cells that had received the boost, which prevented the virus from taking over the host. "The first step in the replication process is the Achilles' heel of this virus: this moment determines whether the virus can spread further", Boersma explains. "If the host cell does not manage to eliminate the virus at the very beginning of an infection, the virus will replicate and win the competition." Boersma and her colleagues used a picorna virus for the development of VIRIM. Members of this virus family can cause diseases ranging from the common cold to severe diseases such as Polio.

Wide variety of viruses

VIRIM enables the identification of the vulnerable phases of a wide variety of viruses. The researchers expect the technique to be valuable for research into many life-threatening viruses, including SARS-CoV-2. Boersma explains: "Understanding viral replication and -spreading can help us determine the Achilles' heel of a virus. This knowledge can contribute to the development of treatments, for example a treatment that intervenes during a vulnerable moment in the virus' life. That allows us to create more efficient therapies and hopefully mitigate the impact of viruses on society."

* LDL Cholesterol Lowering Drugs Benefit Older and Younger Patients Equally: Older individuals face an increased incidence of cardiovascular events compared to younger individuals. Paradoxically, however, proven lipid-lowering therapies remain underused in older patients because these individuals have typically comprised small subsets of clinical trials and thus there has been a less persuasive evidence base. A new systematic review and meta-analysis of 29 trials which included 244,090 patients including 21,492 patients aged 75 years or older found that lipid-lowering therapies reduced the risk of major cardiovascular events in older patients just as much as they did in younger patients, with a 26 percent reduction in major cardiovascular events per 1 mmol/L reduction of LDL cholesterol (LDL-C). The benefit of LDL-C lowering in the elderly was consistent for cardiovascular death, myocardial infarction, stroke, and coronary revascularization and consistent, per 1 mmol/L reduction in LDL-C, for statin and non-statin lipid-lowering therapies (ezetimibe and the PCSK9 inhibitors, evolocumab and alirocumab).

"Our analysis indicates that these therapies, which are affordable drugs that have reduced risk of heart disease for millions of people worldwide, are as effective in reducing cardiovascular events and deaths in older people as they are in younger people," said corresponding author Marc Sabatine, MD, MPH, of the Division of Cardiovascular Medicine at the Brigham. "We found no offsetting safety concerns and, together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and non-statin therapy, in elderly people."

The study will be presented Nov. 13 at 10 a.m. EST and published simultaneously in The Lancet.

* Over 80 Percent of Heart Failure Patients Eligible for Treatment with Recently FDA-Approved Therapy: In May 2020, the U.S. Food and Drug Administration (FDA) approved dapagliflozin, a blood sugar-lowering drug, as a therapy for patients with heart failure with reduced ejection fraction (HFrEF). While the drug, a type of SGLT2 inhibitor, was originally developed to treat type 2 diabetes, there is increasing evidence that SGLT2 inhibitors reduce risks of cardiovascular events in patients with and without diabetes. To determine what proportion of HFrEF patients might be candidates for dapagliflozin treatment according to the new FDA labeling, Brigham researchers and collaborators analyzed data from 154,714 patients hospitalized with HFrEF at over 400 hospital centers across the U.S. participating in the American Heart Association's Get With The Guidelines-Heart Failure registry. They found that 81.1 percent of participants would be eligible for dapagliflozin, with the most common explanation for non-candidacy being advanced kidney disease. HFrEF patients with type 2 diabetes had a lower proportion of eligibility (75.6 percent) compared to those without type 2 diabetes, of whom 85.5 percent were eligible.

"Despite accelerating scientific discoveries, few patients with heart failure are being treated with the best available treatment options in 2020," said lead author Muthiah Vaduganathan, MD, MPH, of the Division of Cardiovascular Medicine at the Brigham. "While SGLT2 inhibitors were first developed for treatment of diabetes, these therapies have now been recognized to reduce mortality, prevent worsening heart failure events, and improve health-related quality of life in patients with HFrEF, including those without diabetes. Our data suggest that effective implementation of SGLT2 inhibitors is poised to impact a large at-risk population across a broad range of US health systems."

The study will be presented Nov. 13 at 10 a.m. EST and published simultaneously in JAMA Cardiology. This work is the first of a series of studies under a new collaboration called TRANSLATE-HF led by Vaduganathan and investigators at 10 different institutions nationwide that is being launched by the American Heart Association and AstraZeneca to better understand how new therapies for heart failure can best be implemented in clinical practice to improve patient outcomes.

* Cardiothoracic Organ Transplantations Increase Among Non-U.S. Citizens, With No Evidence of Worse Outcomes: In the past decade, cardiothoracic organ transplants have increased in the United States for both citizens and non-citizens, with non-U.S. citizens now representing between 3 and 4 percent of heart- and lung-transplant recipients. However, federal funding for transplant and post-transplant care for non-US citizens is restricted and varies by residency status. While citizenship-based disparities in liver and kidney transplant outcomes were not identified in recent studies, similar investigations into cardiothoracic transplant outcomes have not been pursued. Brigham researchers and collaborators studied 31,033 transplant recipients from 2013-2018 from the United Network for Organ Sharing and found that non-U.S. citizens who received heart and lung transplants experienced similar rates of risk-adjusted graft failure and mortality compared to U.S. citizens.

"Our study shows that non-U.S. citizens and U.S. citizens have similar outcomes at one year after heart or lung transplant," said co-first author Lauren Sinnenberg, MD, of the Division of Cardiovascular Medicine at the Brigham. "It remains unknown whether there exist disparities in access to transplantation for non-U.S. citizens. This will be an important focus of future work."

According to the study, more non-U.S. citizens are now receiving cardiothoracic transplants than ever before. The absolute proportion of transplantations is growing steadily by 0.3 percent annually according to the researchers' data. Non-U.S. citizens in the study were more likely to be Hispanic (comprising 40 percent of recipients, versus 8 percent of U.S. recipients) and more likely to be supported by Medicaid (22 percent vs. 13 percent). U.S. citizens receiving transplants were more likely to be white (70 percent vs. 37 percent) and more likely to be supported by private insurance (46 percent vs. 35 percent).

The study will be presented Nov. 13 at 10 a.m. EST and paper will be published simultaneously in Circulation: Heart Failure.

An international study led by scientists at the University of Sussex has provided strong evidence for an effective new target for breast cancer treatment. The five-year study, called "The structure-function relationship of oncogenic LMTK3" to be published in Science Advances, involved researchers from seven institutions across three countries including the UK's Diamond Light Source. It suggests that LMTK3 inhibitors could be effectively used for the treatment of breast cancer, and potentially other types of cancer. The structure of oncogenic LMTK3 (Lemur Tyrosine Kinase 3 ) determines its role and functions allowing drug inhibition as a new therapeutic strategy

It is hoped the research will allow the further development and optimisation of LMTK3 inhibitors as a new type of orally-administered anticancer drug for patients and have potential value not only for breast cancer patients but also for lung, stomach, thyroid and bladder cancer patients.

LMTK3 is a protein implicated in the development and progression of different malignancies and other diseases (eg. central nervous system related), which is not typically included in commercial kinase screening assays. The research successfully demonstrates that LMTK3 is an active kinase and reports a compound which binds to, and effectively inhibits, this protein resulting in anticancer effects in cells and in breast cancer models in mice.

Georgios Giamas, Professor of Cancer Cell Signalling at the University of Sussex, who led the research, says: "By solving the crystal structure of LMTK3, we have demonstrated that it possesses all of the hallmarks of an active protein kinase. LMTK3 plays a pivotal role in controlling cellular processes, and we have previously shown that active LMTK3 makes some cancer treatments (eg. chemotherapy and endocrine therapies) less effective."

"We are now in the process of taking this research to the next stage by developing LMTK3 specific drugs. We hope that in the next five years we will be undertaking clinical trials, which is incredibly quick for this type of process."

It is expected that the development of oral LMTK3 inhibitors may have the potential for broad clinical utility, either as a monotherapy, or as a combinational therapy, for example combined with chemotherapy, immunotherapy or endocrine treatments. Consequently, an LMTK3 inhibitor could be used alongside complementary therapies to increase the therapeutic efficacy and help overcome mechanisms of resistance to existing cancer therapies.

The researchers say that the work is a great example of international science collaboration with several groups coming together to help with a challenging project. In particular the OPPF (Oxford Protein Production Facility) and the UK's synchrotron, Diamond Light Source worked with the groups to produce their protein of interest (LMTK3) and to help solve its crystal structure. "It is often difficult to obtain large well diffracting crystals and LMTK3 was no exception. Through close collaboration between the OPPF and I24 and exploiting the microfocused X-ray beam at I24 to collect wedges of data from multiple crystals we were able to obtain diffraction data key to the study," commented Robin Owen, Principal Beamline Scientist of MX beamline I24 at Diamond. This research project is also a great demonstration of the powerful synergy between Diamond and its neighbouring research institutes like the Research Complex at Harwell which housed sample preparation.

What The Study Did: This Viewpoint discusses the need for new and better testing for COVID-19 to help prevent community transmission, and it explains the limitations of such testing, including performance in the asymptomatic phase and access in resource-limited communities.

Authors: Yukari C. Manabe, M.D., of Johns Hopkins University in Baltimore, is the corresponding author.

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

(doi:10.1001/jama.21694)

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

What The Study Did: The rare incidence of nosocomial SARS-CoV-2 infection is reviewed in this Viewpoint, which also discusses ways it can be minimized, including use of surgical masks, proper ventilation, physical distancing, eye protection, regular testing and the availability of sick leave for health care workers.

Authors: Aaron Richterman, M.D., of the Hospital of the University of Pennsylvania in Philadelphia, is the corresponding author.

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

(doi:10.1001/jama.2020.21399)

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

SINGAPORE, 3 Nov 2020 - Long RNA molecules carrying DNA codes that don't get translated into proteins have long been a mystery of the human genome. Now, scientists at Duke-NUS Medical School have found a way to systematically investigate their functions and discovered some could play a role in pancreatic cancer. Their findings, published in the journal Genome Medicine, highlight the importance of investigating long non-coding RNAs (lncRNAs) in living organisms.

RNA had long been considered an intermediary molecule; DNA codes for RNA, which, in turn, codes for protein. More recently, scientists found that of the three billion bases in the human genome, only two per cent encode proteins. Much of the remaining 98 per cent of the genome are non-coding, and once thought to be the 'dark matter' of the human genome, with no known functions. Some lncRNAs, a major component of this genomic dark matter, have been shown to play key roles in diverse biological processes, ranging from development to diseases.

"By combining several advanced tools, we were able to investigate the role and function of 'the dark matter that matters' in pancreatic cancer," said the study's lead author, Mr Shiyang Liu, who is an MD/PhD student at Duke-NUS.

Specifically, the research team wanted to identify lncRNAs that were regulated by a well-known pathway called Wnt signalling. This pathway regulates many genes that code for proteins, but its influence on lncRNAs has been unclear.

Wnt signalling is known to fuel the growth of some pancreatic cancers. Turning off this pathway could not only help treat pancreatic cancer but also help researchers identify the parts of the genome that are regulated by it.

To do this, the research team turned to a ETC-159, a made-in-Singapore Wnt-suppressing drug jointly developed by Duke-NUS and the Agency for Science, Technology and Research (A*STAR), which is currently progressing through clinical trials as a treatment for a range of cancers, including pancreatic.

The scientists compared what happened to lncRNAs when ETC-159 turned off Wnt signalling in preclinical model of pancreatic cancer and in pancreatic cancer cells cultured in the laboratory. They found it changed the expression of 1,503 lncRNAs in the former but only changed the expression of half that number in the latter. This highlights the importance of studying lncRNAs within the context of a more natural environment, the researchers say.

The team then used the gene editing tool CRISPR to study what happened when the 1,503 Wnt-regulated lncRNAs were turned off in the preclinical model and in pancreatic cell cultures. Twenty-one lncRNAs were found to be able to modify pancreatic cancer cell growth in the living model, whereas only half that number were identified in the cancer cell culture tests.

"Our study provides a unique window in the largely unknown role of the dark matter of the genome that plays a functional role in pancreatic cancer, and will be a valuable resource for the scientific community studying Wnt-regulated lncRNAs in cancer," said Professor David Virshup, director of Duke-NUS' Cancer and Stem Cell Biology Programme, a senior co-author of the study. Prof Virshup's seminal research on Wnts led to the development of ETC-159. "Understanding that a subset of Wnt-regulated lncRNAs can act as mediators of the oncogenic function of Wnt signalling in cancers provides potential new targets for precision cancer therapies."

Associate Professor Enrico Petretto, from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, also a senior co-author of the study, said, "Compared with previous studies we identified twice as many lncRNAs in vivo than what you might detect in vitro, and many of these are important for cancer cell growth only in vivo, providing important clues for the development of more effective cancer treatments."

How hot is the Universe today? How hot was it before? A new study by an international team of researchers, including members of the Kavli Institute for the Physics and Mathematics of the Universe (Kavli IPMU), suggests that the mean temperature of gas in large structures of the Universe has increased about 3 times in the last 8 billion years, to reach about two million Kelvin today.

The large-scale structure of the Universe refers to the global pattern of how galaxies and galaxy clusters are distributed in space. This cosmic net formed from tiny irregularities in the matter distribution in the early Universe, which were amplified through gravitational attraction. "As the Universe evolves, gravity pulls dark matter and gas in space together into galaxies and clusters of galaxies," said Yi-Kuan Chiang, the lead author of the study, and a research fellow at the Ohio State University Center for Cosmology and AstroParticle Physics. "The drag is violent--so violent that more and more gas is shocked and heated up."

This heated gas can then be used to measure the mean temperature of the Universe over cosmic time. In particular, the researchers used the so-called "Sunyaev-Zeldovich" effect, named after Rashid Sunyaev, director emeritus at the Max Planck Institute for Astrophysics, and Soviet-era physicist Yakov Zeldovich, who first predicted this phenomenon theoretically. This effect arises when low-energy photons of the cosmic microwave background radiation are scattered by hot electrons in the large-scale structure of the Universe. The scattering transfers energy from electrons to photons, making the hot electron gas visible. The intensity of the Sunyaev-Zeldovich effect is proportional to the thermal pressure of the gas, which, in turn, is proportional to the temperature of electrons.

While this measurement is straightforward in principle, collecting the necessary data was a major undertaking. The study, which has been published in the Astrophysical Journal, was done in a collaboration of researchers at the Kavli IPMU, the Ohio State University, the Johns Hopkins University, and the Max Planck Institute for Astrophysics.

The researchers used data collected by two observatories, the Planck satellite and the Sloan Digital Sky Survey (SDSS). Planck is the European Space Agency mission which measured the cosmic microwave background radiation. SDSS collected detailed images and light spectra of galaxies. Combining the two data sets, the scientists were able to measure the amount of thermal pressure around the locations of galaxies and clusters of galaxies.

"It took astronomers more than 15 years to collect the necessary data using a telescope on the ground and one in space," said Brice Ménard who led the analysis with Chiang. Ménard, who has been a visiting scientist at the Kavli IPMU since 2011, added: "On the analysis side, our team spent four years developing the algorithms necessary to extract the signal from these data."

What's more, interpretation of the data required a physical model, which was provided by Ryu Makiya, a research fellow at the Kavli IPMU. "Combining the latest data with a state-of-the-art theoretical model, we were able to reveal how the temperature of the Universe evolved, and how it was linked to formation of the large-scale structure of the Universe," Makiya said. "The next goal is to understand details of the physics of thermal and non-thermal phenomena."

Chiang, from the Ohio Stated University, added: "Our new measurement provides a direct confirmation of the seminal work by Jim Peebles--the 2019 Nobel Laureate in Physics--who laid out the theory of the emergence of large-scale structure of the Universe."

The study determined that about eight billion years ago (at a redshift z=1), the mean electron temperature was some 700,000 Kelvin, rising to about two million Kelvin today. Furthermore, the scientists determined that its evolution is almost entirely driven by the growth of structures, as gas is shock heated in collapsing large-scale structures.

Back in 2000, Eiichiro Komatsu, a Principal Investigator at the Kavli IPMU and Director at the Department of Physical Cosmology at the Max Planck Institute for Astrophysics, was also involved in a previous effort to calculate how the temperature of the Universe evolved. "For 20 years, we have been studying how to measure this using the Sunyaev-Zeldovich effect," he remembered. "We now have finally measured the temperature of the Universe, not only thanks to the remarkable progress in observational data, but also due to the dedicated efforts of brilliant young scientists such as Yi-Kuan Chiang and Ryu Makiya. This is very satisfying," Komatsu added.

Researchers from the University of Helsinki, Finland, examined 48 Staffordshire Bull Terriers, of which eight dogs - four healthy and four atopic - were selected for RNA sequencing where their skin gene expression was compared between both atopic and healthy dogs as well as between dogs that ate dry food or raw food.

The diet appears to make a great difference in skin gene expression.

"Before the dietary intervention comparing atopic and healthy dogs, only a total of eight genes functioning in a range of ways in the skin were found, but the intervention increased this figure manifold. In other words, dietary intervention is extremely important for actual differences in gene expression to emerge," says researcher Johanna Anturaniemi from the Faculty of Veterinary Medicine, University of Helsinki.

The effect of the diet on skin gene expression was mostly associated with the immune system, antioxidants and inflammatory processes. Raw food appeared to activate the skin's immune defence system as well as the expression of genes that increase antioxidant production or that have anti-inflammatory effects.

"A previously conducted study also demonstrated that diets based on raw meat engender an anti-inflammatory effect on blood gene expression," Anturaniemi says.

In terms of puppyhood, the researchers consider a particularly important finding the fact that the immune defence of dogs whose diet is based on raw food is activated. What is known is that in people suffering from atopic dermatitis the development of immunity has been disturbed and that diverse exposure to microbes in childhood reduces the risk of becoming atopic.

The differences in skin gene expression between atopic and healthy dogs highlighted the possibility of deficiencies in the lipid metabolism and keratinocyte proliferation of atopic individuals. Both hold a key role in the normal functioning of the skin barrier.

Additionally, the expression of genes that boost the formation of new blood vessels, a phenomenon known to be associated with the inflammatory response of the skin, was seen to have increased in atopic dogs. The findings support those made in prior studies.

"We identified several genes whose link with canine atopic dermatitis had not been reported earlier. Some of them are associated with previously known disturbed metabolic pathways, while the role of others in atopic dermatitis requires further investigation. Since the number of dogs involved in the study was small, the results can be considered preliminary. Indeed, the aim is to confirm them at a later date by utilising the rest of the skin samples collected," Anturaniemi says.

The dietary intervention trial on Staffordshire Bull Terriers was carried out at the Faculty of Veterinary Medicine, University of Helsinki. In the trial, the dogs were divided into groups whose diet was based on either dry food or raw food for approximately four months. A total of 48 dogs were involved in the trial, of which eight were selected for RNA sequencing. Four of the eight dogs were healthy, and they represented both dietary groups equally, as did the other four dogs selected for sequencing that suffered from atopic dermatitis.

Algorithms have shown that the compositional structure of Western landscape paintings changed "suspiciously" smoothly between 1500 and 2000 AD, potentially indicating a selection bias by art curators or in art historical literature, physicists from the Korea Advanced Institute of Science and Technology (KAIST) and colleagues report in the Proceedings of the National Academy of Sciences (PNAS).

KAIST statistical physicist Hawoong Jeong worked with statisticians, digital analysts and art historians in Korea, Estonia and the US to clarify whether computer algorithms could help resolve long-standing questions about design principles used in landscape paintings, such as the placement of the horizon and other primary features.

"A foundational question among art historians is whether artwork contains organizing principles that transcend culture and time and, if yes, how these principles evolved over time," explains Jeong. "We developed an information-theoretic approach that can capture compositional proportion in landscape paintings and found that the preferred compositional proportion systematically evolved over time."

Digital versions of almost 15,000 canonical landscape paintings from the Western renaissance in the 1500s to the more recent contemporary art period were run through a computer algorithm. The algorithm progressively divides artwork into horizontal and vertical lines depending on the amount of information in each subsequent partition. It allows scientists to evaluate how artists and various art styles compose landscape artwork, in terms of placement of a piece's most important components, in addition to how high or low the landscape's horizon is placed.

The scientists started by analysing the first two partitioning lines identified by the algorithm in the paintings and found they could be categorized into four groups: an initial horizontal line followed by a second horizontal line (H-H); an initial horizontal line followed by a second vertical line (H-V); a vertical followed by horizontal line (V-H); or a vertical followed by a vertical line (V-V) (see image 1 and 2). They then looked at the categorizations over time.

They found that before the mid-nineteenth century, H-V was the dominant composition type, followed by H-H, V-H, and V-V. The mid-nineteenth century then brought change, with the H-V composition style decreasing in popularity with a rise in the H-H composition style. The other two styles remained relatively stable.

The scientists also looked at how the horizon line, which separates sky from land, changed over time. In the 16th century, the dominant horizon line of the painting was above the middle of the canvas, but it gradually descended to the lower middle of the canvas by the 17th century, where it remained until the mid-nineteenth century. After that, the horizon line began gradually rising again.

Interestingly, the algorithm showed that these findings were similar across cultures and artistic periods, even through periods dominated by a diversity in art styles. This similarity may well be a function, then, of a bias in the dataset.

"In recent decades, art historians have prioritized the argument that there is great diversity in the evolution of artistic expression rather than offering a relatively smoother consensus story in Western art," Jeong says. "This study serves as a reminder that the available large-scale datasets might be perpetuating severe biases."

The scientists next aim to broaden their analyses to include more diverse artwork, as this particular dataset was ultimately Western and male biased. Future analyses should also consider diagonal compositions in paintings, they say.

An international team led by the University of Geneva (UNIGE) has studied which types of forest, in terms of biodiversity, are the most effective in storing carbon. Inventory data from natural forests on five continents show that species diversity is optimal for equatorial and tropical rainforests, and that, conversely, in forests located in cold or dry regions, it is the abundance of trees and not their diversity that favours the recapture of CO2. The results of the study, published in Nature Communications, are valuable in defining natural strategies to combat climate change.
Global warming is stressing forests through higher mean annual temperatures, longer-lasting droughts and more frequent and extreme weather events. At the same time, forests – and the wood they produce – can trap and store carbon dioxide (CO2), they therefore play a crucial role in mitigating climate change. Trees and forests remove carbon dioxide from the atmosphere and convert it to carbon during photosynthesis, which they then store in the form of wood and vegetation, a process referred to as «carbon sequestration». However, not all forests have the same capacity to capture and store carbon.

Opposite Assumptions

In recent decades, researchers have suggested that species diversity allows for denser stacking and niche compartmentalisation that promotes the abundance of trees within a forest and that this abundance increases the forest’s carbon storage capacity. But another hypothesis suggests that it is not diversity that allows tree abundance but the availability of energy substrate. Areas with higher energy content allows more trees to thrive per unit area and thus increase carbon recapture. While these two hypotheses question the scientific community on the relationship between diversity and abundance, knowing the answer could pragmatically guide the fight against CO2 emissions.
An international team around Jaime Madrigal-Gonzalez, scientific collaborator at the Institute for Environmental Sciences of the Sciences Faculty of UNIGE, investigated which of these hypotheses is more likely and under which climatic conditions one is more likely than the other. The question was addressed using inventory data from natural forests from five continents.

Forests of the Five Continents

“Having more species may not always be what is needed to achieve greater carbon storage in forests”, states Dr. Madrigal-Gonzalez. Instead, this relation only seems to prevail in the most productive forest regions of the planet that are basically restricted to equatorial and tropical rain forests, and some temperate forests – in regions where deforestation and human-induced forest fires have ravaged pristine environments lately. On the contrary, in the forests located in the coldest or driest regions on Earth, it is seemingly the abundance, promoted by productivity, that determines the diversity. Here, any increase in the number of species will not necessarily result in more trees and will not therefore have a big contribution to carbon storage.
The findings of these studies are of substantial practical relevance as they will aid decision makers identifying nature-based climate change mitigation strategies and to successfully use forests and their sequestration of carbon to reach the climate goals defined in the Paris Agreement. “Increasing climatic stress in the most productive forests of the planet could diminish or even collapse the role of diversity against climate change” says Prof. Markus Stoffel, Professor at the Institute for Environmental Sciences of the UNIGE.

Kyoto, Japan -- Scanning lasers -- from barcode scanners at the supermarket to cameras on newer smartphones -- are an indispensable part of our daily lives, relying on lasers and detectors for pinpoint precision.

Distance and object recognition using LiDAR -- a portmanteau of light and radar -- is becoming increasingly common: reflected laser beams record the surrounding environment, providing crucial data for autonomous cars, agricultural machines, and factory robots.

Current technology bounces the laser beams off of moving mirrors, a mechanical method that results in slower scanning speeds and inaccuracies, not to mention the large physical size and complexity of devices housing a laser and mirrors.

Publishing in Nature Communications, a research team from Kyoto University's Graduate School of Engineering describe a new beam scanning device utilizing 'photonic crystals', eliminating the need for moving parts.

Instead of arranging the lattice points of the crystals in an orderly array, the researchers found that varying the lattice points' shapes and positions caused the laser beam to be emitted in unique directions.

"What results is a lattice of photonic crystals that looks like a slab of Swiss cheese, where each crystal is calculated to emit the beam in a specific direction," explains Susumu Noda, who led the team.

"By eliminating mechanical mirrors, we've made a faster and more reliable beam-scanning device."

Photonic crystal lasers are a type of 'semiconductor laser' whose lattice points can be regarded as nanoscale antennae, which can be arranged to cause a laser beam to be emitted perpendicularly from the surface. But initially the beam would only go in a single direction on a two-dimensional plane; the team needed more area to be covered.

Arranging the antennae positions cyclically resulted in a successful direction change, but a decrease in power output and deformed shape made this solution unviable.

"Modulating the antennae positions caused light emitted from adjacent antennae to cancel each other out," continues Noda, "leading us to try changing antenna sizes."

"Eventually, we discovered that adjusting both position and size resulted in a seemingly random photonic crystal, producing an accurate beam without power loss. We called this a 'dually modulated photonic crystal'."

By organizing these crystals -- each designed to emit a beam in a unique direction -- in a matrix, the team was able to build a compact, switchable, two-dimensional beam scanner without the need for any mechanical parts.

The scientists have successfully constructed a scanner that can generate beams in one hundred different directions: a resolution of 10×10. This has also been combined with a diverging laser beam, resulting in a new type of LiDAR with enhanced scope to detect objects.

The team estimates that with further refinements, the resolution could be increased by a factor of 900: up to a 300×300 resolution range.

"At first there was a great deal of interest in whether a structure that is seemingly so random could actually work," concludes Noda. "We now believe that eventually we will be able to develop a LiDAR system small enough to hold on a fingertip."

New Rochelle, NY, November 12, 2020--Future human missions to Mars depend on field research in an environment similar to that of Mars. It will enable the evaluation of operational concepts and optimization of strategies. The goals and results of the AMADEE-18 Mars analog mission are detailed in a special collection of articles in the peer-reviewed journal Astrobiology. Click here to read the articles now.

The AMADEE-18 expedition was designed in preparation for future human missions to the Mars surface. The mission took place in the Dhofar Desert in the Sultanate of Oman and was directed by a Mission Support Center in Austria. Brief descriptions of some of the papers in the collection follow.

A comprehensive overview of the mission, describing its technical and organizational infrastructure, is provided by Gernot Groemer, Austrian Space Forum, and coauthors. They describe the proposed workflow for coordinating the timing and location of the instruments and experiments. "In validation of this workflow, the decision-making interaction between the field and the Mission Support Center was studied," state the authors.

A performance metrics analysis is presented by Sophie Gruber, Austrian Space Forum, and coauthors. Their aim is to develop a benchmarking tool for mission planning and evaluation. "We propose a method to compare analog missions across agencies, disciplines, and complexities/fidelities to improve scientific output and mission safety and maximize effectiveness and efficiency," say the authors.

Methods to localize an unmanned aerial vehicle on Mars, such as an autonomous helicopter, were tested by Eren Allak, University of Klagenfurt, and coauthors. "In the absence of a global positioning system, a computationally efficient localization technology that can be applied on Mars is visual-inertial odometry (VIO). The AMADEE-18 mission provided an opportunity to test the feasibility of a state-of-the-art VIO algorithm and the camera in a Mars-like analog environment," state the authors.

Alzheimer's disease is the most common cause of dementia. Still incurable, it directly affects nearly one million people in Europe, and indirectly millions of family members as well as society as a whole. In recent years, the scientific community has suspected that the gut microbiota plays a role in the development of the disease. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) in Switzerland, together with Italian colleagues from the National Research and Care Center for Alzheimer's and Psychiatric Diseases Fatebenefratelli in Brescia, University of Naples and the IRCCS SDN Research Center in Naples, confirm the correlation, in humans, between an imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of the neurodegenerative disorders characteristic of Alzheimer's disease. Proteins produced by certain intestinal bacteria, identified in the blood of patients, could indeed modify the interaction between the immune and the nervous systems and trigger the disease. These results, to be discovered in the Journal of Alzheimer's Disease, make it possible to envisage new preventive strategies based on the modulation of the microbiota of people at risk.

The research laboratory of neurologist Giovanni Frisoni, director of the HUG Memory Centre and professor at the Department of Rehabilitation and Geriatrics of the UNIGE Faculty of Medicine, has been working for several years now on the potential influence of the gut microbiota on the brain, and more particularly on neurodegenerative diseases. &laquoWe have already shown that the gut microbiota composition in patients with Alzheimer's disease was altered, compared to people who do not suffer from such disorders,» he explains. &laquoTheir microbiota has indeed a reduced microbial diversity, with an over-representation of certain bacteria and a strong decrease in other microbes. Furthermore, we have also discovered an association between an inflammatory phenomenon detected in the blood, certain intestinal bacteria and Alzheimer's disease; hence the hypothesis that we wanted to test here: could inflammation in the blood be a mediator between the microbiota and the brain? »

The brain under influence

Intestinal bacteria can influence the functioning of the brain and promote neurodegeneration through several pathways: they can indeed influence the regulation of the immune system and, consequently, can modify the interaction between the immune system and the nervous system. Lipopolysaccharides, a protein located on the membrane of bacteria with pro-inflammatory properties, have been found in amyloid plaques and around vessels in the brains of people with Alzheimer's disease. In addition, the intestinal microbiota produces metabolites - in particular some short-chain fatty acids - which, having neuroprotective and anti-inflammatory properties, directly or indirectly affect brain function.

&laquoTo determine whether inflammation mediators and bacterial metabolites constitute a link between the gut microbiota and amyloid pathology in Alzheimer's disease, we studied a cohort of 89 people between 65 and 85 years of age. Some suffered from Alzheimer's disease or other neurodegenerative diseases causing similar memory problems, while others did not have any memory problems,» reports Moira Marizzoni, a researcher at the Fatebenefratelli Center in Brescia and first author of this work. &laquoUsing PET imaging, we measured their amyloid deposition and then quantified the presence in their blood of various inflammation markers and proteins produced by intestinal bacteria, such as lipopolysaccharides and short-chain fatty acids.»

A very clear correlation

&laquoOur results are indisputable: certain bacterial products of the intestinal microbiota are correlated with the quantity of amyloid plaques in the brain,» explains Moira Marizzoni. &laquoIndeed, high blood levels of lipopolysaccharides and certain short-chain fatty acids (acetate and valerate) were associated with both large amyloid deposits in the brain. Conversely, high levels of another short-chain fatty acid, butyrate, were associated with less amyloid pathology.»

This work thus provides proof of an association between certain proteins of the gut microbiota and cerebral amyloidosis through a blood inflammatory phenomenon. Scientists will now work to identify specific bacteria, or a group of bacteria, involved in this phenomenon.

A strategy based on prevention

This discovery paves the way for potentially highly innovative protective strategies - through the administration of a bacterial cocktail, for example, or of pre-biotics to feed the &laquogood» bacteria in our intestine. &laquoHowever, we shouldn't be too quick to rejoice,» says Frisoni. &laquoIndeed, we must first identify the strains of the cocktail. Then, a neuroprotective effect could only be effective at a very early stage of the disease, with a view to prevention rather than therapy. However, early diagnosis is still one of the main challenges in the management of neurodegenerative diseases, as protocols must be developed to identify high-risk individuals and treat them well before the appearance of detectable symptoms.» This study is also part of a broader prevention effort led by the UNIGE Faculty of Medicine and the HUG Memory Centre.

A team of immunology experts from research organisations in Belgium and the UK have come together to apply their pioneering research methods to put individuals' COVID-19 response under the microscope. Published today in the journal Clinical and Translational Immunology, their research adds to the developing picture of the immune system response and our understanding of the immunological features associated with the development of severe and life-threatening disease following COVID-19. This understanding is crucial to guide the development of effective healthcare and 'early-warning' systems to identify and treat those at risk of a severe response.

One of the most puzzling questions about the global COVID-19 pandemic is why individuals show such a diverse response. Some people don't show any symptoms, termed 'silent spreaders', whereas some COVID-19 patients require intensive care support as their immune response becomes extreme. Age and underlying health conditions are known to increase the risk of a severe response but the underlying reasons for the hyperactive immune response seen in some individuals is unexplained, although likely to be due to many factors contributing together.

To investigate the immune system variations that might explain the spectrum of responses, teams of researchers from the VIB Centre for Brain and Disease Research and KU Leuven in Belgium and the Babraham Institute in the UK worked with members of the CONTAGIOUS consortium to compare the immune system response to COVID-19 in patients showing mild-moderate or severe effects, using healthy individuals as a control group.

Professor Adrian Liston, senior group leader at the Babraham Institute in the UK, explains: "One of our main motivations for undertaking this research was to understand the complexities of the immune system response occurring in COVID-19 and identify what the hallmarks of severe illness are. We believe that the open sharing of data is key to beating this challenge and so established this data set to allow others to probe and analyse the data independently."

The researchers specifically looked at the presence of T cells - immune cells with a diverse set of functions depending on their sub-type, with 'cytotoxic' T cells able to kill virus-infected cells directly, while other 'helper' T cell types modulate the action of other immune cells. The researchers used flow cytometry to separate out the cells of interest from the participants' blood, based on T cell identification markers, cell activation markers and cytokine cell signalling molecules.

Surprisingly, the T cell response in the blood of COVID-19 patients classified as severe showed few differences when compared to healthy volunteers. This is in contrast to what would usually be seen after a viral infection, such as the 'flu. However, the researchers identified an increase in T cells producing a suppressor of cell inflammation called interleukin 10 (IL-10). IL-10 production is a hallmark of activated regulatory T cells present in tissues such as the lungs. While rare in healthy individuals, the researchers were able to detect a large increase in the number of these cells in severe COVID-19 patients.

Potentially, monitoring the level of IL-10 could provide a warning light of disease progression, but the researchers state that larger-scale studies are required to confirm these findings.

"We've made progress in identifying the differences between a helpful and a harmful immune response in COVID-19 patients. The way forward requires an expanded study, looking at much larger numbers of patients, and also a longitudinal study, following up patients after illness. This work is already underway, and the data will be available within months," says Professor Stephanie Humblet-Baron, at the KU Leuven in Belgium.

"This is part of an unprecedented push to understand the immunology of COVID-19", concludes Professor Liston. "Our understanding of the immunology of this infection has progressed faster than for any other virus in human history - and it is making a real difference in treatment. Clinical strategies, such as switching to dexamethasone, have arisen from a better understanding of the immune pathology of the virus, and survival rates are increasing because of it".