Culture

BIRMINGHAM, Ala. - A bout with flu virus can be hard, but when Streptococcus pneumonia enters the mix, it can turn deadly.

Now researchers have found a further reason for the severity of this dual infection by identifying a new virulence mechanism for a surface protein on the pneumonia-causing bacteria S. pneumoniae. This insight comes more than three decades after discovery of that surface protein, called pneumococcal surface protein A, or PspA.

This new mechanism had been missed in the past because it facilitates bacterial adherence only to dead or dying lung epithelial cells, not to living cells. Heretofore, researchers typically used healthy lung cell monolayers to search for bacterial adhesins that aid infection. Virus killing of lung cells during flu was found to set the stage for S. pneumonia attachment to the airway, thereby worsening disease and pneumonia.

The research, published in the journal Cell Reports, was led by Carlos Orihuela, Ph.D., and David Briles, Ph.D., professor and professor emeritus in the University of Alabama at Birmingham Department of Microbiology. Orihuela and Briles say their findings provide further explanation for how an infection by influenza A flu virus -- followed by S. pneumoniae superinfection -- causes severe pneumonia and a high death rate. The mechanism also points to possible improvements for disease treatment and vaccination.

A historical example of the deadly synergy of flu infection followed by S. pneumoniae superinfection is found in banked lung samples from the 1918 Spanish influenza pandemic that killed 40 million to 50 million people -- the vast majority of these samples showed co-infection or secondary infection with S. pneumonia.

The UAB research on PspA began with some head-scratching results from experimental lung infections of mice with influenza A, followed by either wild-type S. pneumonia that has the intact PspA gene, or a mutant S. pneumoniae that lacks PspA. Lung homogenates from mice infected with the wild-type had much higher numbers of S. pneumonia bacteria than lungs infected with the mutant. However, when researchers washed the interiors of the lungs and collected that bronchoalveolar lavage fluid, they counted similar numbers of the wild-type S. pneumonia and the mutant.

"This unexpected result was interpreted to mean that wild-type S. pneumoniae were more resistant to dislodgement than S. pneumonia with a pspA gene deletion, and it served as rationale for further experimentation," Orihuela said.

From this clue, the researchers were able to show that PspA functions as an adhesin to dying host cells, in addition to its several other previously established virulence mechanisms. The researchers also detailed the molecular mechanism of this bacterial adherence.

Both influenza A infection and release of the S. pneumoniae toxin pneumolysin cause death of lung epithelial cells. As they are dying, cells' phosphatidylserine residues get flipped to the outer cell membrane, where they bind the host enzyme glyceraldehyde-3-phosphate dehydrogenase, or GAPDH. In turn, the S. pneumoniae PspA on the surface of the bacteria binds to the GAPDH. PspA-GAPDH-mediated binding to lung cells increased S. pneumoniae localization in the lower airway, and this was enhanced by pneumolysin exposure or co-infection with influenza A virus.

Tests with fragments of the PspA protein showed that a 52-amino acid portion of the protein -- from amino acid 230 to 281 -- was required for GAPDH binding. Instilling one of those binding fragments into the lungs of influenza-infected mice reduced the disease severity of S. pneumoniae superinfection, presumably through binding competition.

"Our findings support the targeting of regions of PspA for therapeutic and vaccine development against influenza A/Streptococcus pneumoniae superinfections," Orihuela said. "Importantly, and despite more than 30 years since its discovery, PspA was not previously shown to function as an adhesin. Thus, our finding of PspA's role in adherence substantially advances our knowledge on the interactions of S. pneumoniae with its host."

Ultrasound can overcome some of the detrimental effects of ageing and dementia without the need to cross the blood-brain barrier, Queensland Brain Institute researchers have found.

Professor Jürgen Götz led a multidisciplinary team at QBI's Clem Jones Centre for Ageing Dementia Research who showed low-intensity ultrasound effectively restored cognition without opening the barrier in mice models.

The findings provide a potential new avenue for the non-invasive technology and will help clinicians tailor medical treatments that consider an individual's disease progression and cognitive decline.

"Historically, we have been using ultrasound together with small gas-filled bubbles to open the almost-impenetrable blood-brain barrier and get therapeutics from the bloodstream into the brain," Professor Götz said.

The new research involved a designated control group who received ultrasound without the barrier-opening microbubbles.

"The entire research team was surprised by the remarkable restoration in cognition," he said.

"We conclude therapeutic ultrasound is a non-invasive way to enhance cognition in the elderly."

Ageing is associated with impaired cognition and a reduction in the learning induced plasticity of the signalling between neurons called long-term potentiation (LTP).

Dr Daniel Blackmore, senior postdoctoral researcher on the team, said the new research aimed to use ultrasound to restore LTP and improved spatial learning in aged mice.

Professor Götz said the brain was "not particularly accessible", but ultrasound provided a tool for overcoming challenges like the blood-brain barrier.

"Using ultrasound could enhance cognition independently of clearing amyloid and tau, which form plaques and tangles in people with Alzheimer's disease," he said.

"Microbubbles will continue to be used in combination with ultrasound in ongoing Alzheimer's research."

About 400,000 people in Australia have dementia and numbers are projected to increase to one million by 2050, with ageing the single biggest risk factor.

Previous research has shown the long-term safety of ultrasound technology and that pathological changes and cognitive deficits could be improved by using ultrasound to treat Alzheimer's disease.

Professor Götz said there were still questions about the differences between normal "physiological" ageing and the "pathological" ageing that happens in Alzheimer's disease.

''We believe there may be some overlap between physiological and pathological ageing in the brain and the potential for this to be corrected with ultrasound is meaningful for those living with Alzheimer's disease," he said.

''We are taking these findings and implementing them in our Alzheimer's research as we go forward to clinical trials.''

Professor Götz's research team aims to understand how brain diseases begin and their progression at molecular and cellular levels in the hope of ultimately developing therapies.

The research has been published in Nature journal Molecular Psychiatry.

Are the traditional practices tied to endangered species at risk of being lost? The answer is yes, according to the authors of an ethnographic study published in the University of Guam peer-reviewed journal Pacific Asia Inquiry. But the authors also say a recovery plan can protect both the species as well as the traditional CHamoru practice of consuming them.

Else Demeulenaere, lead author of the study and associate director of the UOG Center for Island Sustainability, presented on their findings during the Marianas Terrestrial Conservation Conference on June 8.

Strong cultural ties

The researchers interviewed CHamorus about their recollections of preparing and eating the endangered fanihi, the fruit bat found only in the Mariana Islands, and the endangered fadang, a cycad endemic to Micronesia, as sources of food.

"Gathering and processing the [fadang] seeds into titiyas fadang was a family activity. Manåmko' spoke vividly about their exquisite taste and smell during my ethnobotanical research," Demeulenaere said. "CHamoru conservation managers told me they were afraid their kids would never acquire the taste of fanihi and hoped that one day the fanihi population would be restored so they could hunt them sustainably and restore this traditional practice."

Important roles in the ecosystem

Demeulenaere said the CHamoru culture's strong ties to these species only makes a stronger argument for preserving what are both ecologically important species in their own rights and important players in Guam's biodiversity.

"The fadang is a very special tree, as it belongs to the ancient genus Cycas, which originated during the Triassic Period, when dinosaurs were around. The leaves were most likely dinosaur food," Demeulenaere said.

The fadang, known scientifically as Cycas micronesica, was once the most common tree in Guam's limestone forests, but "an invasive scale insect has caused a rapid decline in the health of the cycad populations, which is further exacerbated by habitat loss," Demeulenaere said.

The fanihi, known scientifically as Pteropus mariannus, is an important seed disperser, she said, in particular for fadang seeds.

"They love to eat the seed coat of the fadang [...]," Demeulenaere said. "Restoration efforts consist of adding food sources for the fanihi in degraded forests. [Restoring the] fadang [population] is an important part of this effort."

Today, it is estimated that only 45 to 50 fruit bats remain in the wild in Guam -- down from 400-500 in 1984 and around 3,000 in the 1950s -- because of poaching and habitat destruction, according to the U.S. Fish & Wildlife Service.

Restoration work moving forward

Most of the study's interviewees said they would like to eat fanihi again once the populations are restored. Endemic foods can also significantly contribute to food security in the region, the paper states. But scientist-led protection and restoration of limestone habitats as well as snake suppression are important to recover the species and make sustainable harvest possible.

Moving forward, Demeulenaere said, "A co-production of knowledge consisting of traditional holders and scientists can outline harvesting practices and the recovery actions."

In the recent decade, scientists have paid more attention to studying light harvest for producing novel bionic materials or integrating naturally biological components into synthetic systems. Inspiration is the imitation of natural photosynthesis in green plants, algae, and cyanobacteria to convert light energy into chemical energy. Photosystem II (PSII) is a light-intervened protein complex responsible for the light harvest and water splitting to release O2, protons, and electrons. The development of PSII-based biomimetic assembly in vitro is favorable for the investigation of photocatalysis, biological solar cells, and bionic photosynthesis, further help us reveal more secret of photosynthesis.

The combination of PSII and artificially synthetic structures is successful for making biohybrid assemblies to harvest light. The evolution of material science advances the development of PSII-based assemblies, PSII-mimicking hybrid systems, and utilization of PSII-related products for energy conversion. Relative applications and explorations occur through coupling PSII within lipid membranes, multilayer polymeric structures, and nanoparticles to maximize the efficient range of light absorbance and offer a high PSII payload yield.

The desired light-harvest performance enables a dramatic energy conversion from sunlight to electric power or biochemical energy. Apart from integrating with synthetic materials, naturally active components, photosystem I (PSI), bacteriorhodopsin (BR), or ATP synthase (ATPase), attain in vitro reassembly with PSII to form artificial chloroplasts and achieve partial natural photosynthesis process, including electron generation and transfer as well as ATP synthesis. Subsequent studies found that manipulation of light absorption range is critical to improving the photosynthetic activity of PSII. Synthetic luminescent materials (e.g., fluorescent polymers, quantum dots) are applied to help PSII or chloroplast convert UV light into visible light, resulting in productivity improvement of ATP synthesis.

At present, although reassembly of PSII-based hybrid systems is successful, this system suffers from typical drawbacks shares by common protein species in terms of stability, durability, biological activity, and environmental restrictions for applying PSII-based systems in the near future. Therefore, efforts and explorations still focus on investigating PSII-based biomimetic assembly to challenge these above weaknesses.

This Reviews Article published in National Science Review by Prof. Junbai Li's group at Beijing National Laboratory for Molecular Sciences, CAS Key Lab of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry of Chinese Academy of Sciences, summarizes recent studies on how PSII protein complex combines with artificial structures via molecular assembly, and highlights PSII-based semi-natural biosystems. Moreover, they discuss this biomimetic systems regarding the remaining problem, challenges, and outlooks.

Toxoplasma gondii, the parasite responsible for toxoplasmosis, is capable of infecting almost all cell types. It is estimated that up to 30% of the world's population is chronically infected, the vast majority asymptomatically. However, infection during pregnancy can result in severe developmental pathology in the unborn child. Like the other members of the large phylum of Apicomplexa, Toxoplasma gondii is an obligate intracellular parasite which, to survive, must absolutely penetrate its host's cells and hijack their functions to its own advantage. Understanding how the parasite manages to enter host cells offers new opportunities to develop more effective prevention and control strategies than those currently available. A team from the University of Geneva (UNIGE), in collaboration with the University of Zurich (UZH) and the Paul Scherrer Institute (PSI) in Villigen, Switzerland, have identified the key role of RON13, a protein of the parasite, which is essential for the invasion process. The three-dimensional structure and the site of action of this enzyme are atypical, thus offering the possibility of designing specific inhibitors to stop the infection. These results are published in the journal Nature Communications.

Specific types of enzymes named kinases are key regulators of a wide range of basic biological processes. "These enzymes modify proteins by adding or removing phosphate groups that, like a switch, turn cellular functions on or off as needed", explains Oscar Vadas, a lecturer in the Department of Microbiology and Molecular Medicine at UNIGE Faculty of Medicine, a specialist in protein biochemistry and co-author of this study. "Kinases are great targets for drug development because, on the one hand, they are relatively easy to inhibit and, on the other hand, they are involved in many pathologies. They are therefore the subject of intense research." Identifying a kinase essential to the survival of a pathogen would thus pave the way for the development of new therapies.

A kinase seen from all its angles

The identification of RON13, a Toxoplasma gondii kinase, quickly became a very attractive subject of study in light of its major role in the invasive capacity of the parasite. "To understand the biological processes controlled by this enzyme, both at the cellular and molecular level, we combined several state-of-the-art technologies", explains Professor Adrian Hehl of UZH. Cryo-electronic microscopy identified an additional modular structure that was absent in all other kinases previously studied, but essential for RON13 activity. Expansion microscopy demonstrated morphological changes in the parasite using high-resolution images. In addition, proteomics was used to identify the kinase targets that are released into host cells to promote its invasion, and genetics was performed to study the impact of the absence of this kinase on the parasite's growth.

"These sophisticated analyses were also made possible thanks to the high-precision technology facilities of the UNIGE Faculty of Medicine, which were made available to the research teams", says Dominique Soldati-Favre, Director of UNIGE Faculty of Medicine Department of Microbiology and Molecular Medicine, who directed this work. "By pooling together all our expertise, we were able to identify precisely the interactions at work and understand the structure of this kinase at the atomic level", underlines Volodymyr Korkhov, a professor at PSI.

Without RON13, there is no invasion

RON13 is a kinase located in a unique compartment of the parasite, an organelle containing proteins to be injected into the host. Without RON13, host cells infection is impossible. "To confirm these results, we infected mice with a strain of the parasite that does not express RON13: it became completely harmless, to the extent that the mice did not show any specific immune response", explains Dominique Soldati-Favre.

Moreover, these very particular characteristics make RON13 insensitive to an inhibitor that is effective on the majority of kinases. "From a therapeutic point of view, this is excellent news", says Oscar Vadas. "This means that we can target it very precisely without affecting human kinases, thus limiting the side effects of the treatment." Moreover, although this work focused on the toxoplasmosis parasite, other pathogens of the Apicomplexa phylum share the same invasion process. It is therefore conceivable that a kinase similar to RON13 plays an essential role in infection by other parasites, and in particular by Plasmodium falciparum, the agent responsible for malaria.

This work was carried out thanks to the support of the Carigest SA Foundation and the Swiss National Science Foundation (SNSF).

An international study led by Helmholtz Zentrum München has revealed the structure of a membrane-remodeling protein that builds and maintains photosynthetic membranes. These fundamental insights lay the groundwork for bioengineering efforts to strengthen plants against environmental stress, helping to sustaining human food supply and fight against climate change.

Plants, algae, and cyanobacteria perform photosynthesis, using the energy of sunlight to produce the oxygen and biochemical energy that power most life on Earth. They also adsorb carbon dioxide (CO?) from the atmosphere, counteracting the accumulation of this greenhouse gas. However, climate change is exposing photosynthetic organisms to increasing environmental stress, which inhibits their growth, and in the long term, endangers the food supply of humankind.

The important first steps of photosynthesis are performed within the thylakoid membranes, which contain protein complexes that harvest sunlight. For decades, it has been known that the protein VIPP1 (vesicle-inducing protein in plastids) is critical for forming thylakoid membranes in almost all photosynthetic organisms - from plants on land to algae and cyanobacteria in the ocean. However, it has remained a mystery how VIPP1 performs this essential function. In the latest issue of the journal Cell, a new study by an international consortium of researchers led by Ben Engel from the Helmholtz Pioneer Campus at Helmholtz Zentrum München reveals the structure and mechanism of VIPP1 with molecular detail.

Building and protecting photosynthetic membranes

The researchers used cryo-electron microscopy to generate the first high-resolution structure of VIPP1. Combining this structural analysis with functional assays revealed how VIPP1 assembles into an interwoven membrane coat that shapes the thylakoid membranes. The research group also used the cutting-edge approach of cryo-electron tomography to image VIPP1 coats within the native environment of algae cells. By using the structural information to make specific mutations to VIPP1, the researchers observed that the interaction of VIPP1 with thylakoid membranes is critical to maintain the structural integrity of these membranes under high-light stress. "Our study shows how VIPP1 plays a central role in both thylakoid biogenesis and adaptation of thylakoids to environmental changes," explains first author Tilak Kumar Gupta from the Max Planck Institute of Biochemistry.

This study lays the foundation for a mechanistic understanding of thylakoid biogenesis and maintenance. It also provides new opportunities for engineering plants that are more resistant to extreme environmental conditions. "Insights into the molecular mechanisms controlling thylakoid remodeling are an important step towards developing crops that not only grow faster, have higher yield and resistance to environmental stress, but also absorb more atmospheric CO? to counteract climate change," says study leader Ben Engel.

International team research

This interdisciplinary study brought together the talents of research teams from the Technische Universität Kaiserslautern (Michael Schroda), Philipps-Universität Marburg (Jan Schuller), Ludwig-Maximilians-Universität München (Jörg Nickelsen), Okayama University in Japan (Wataru Sakamoto), McGill University in Canada (Mike Strauss), Ruhr-Universität Bochum (Till Rudack), the Max Planck Institute of Biochemistry (Wolfgang Baumeister and Jürgen Plitzko) and Helmholtz Zentrum München. "Our study covers a lot of new ground using a wide variety of techniques. This was only possible thanks to the tremendous collective efforts of the researchers in our international consortium," says Ben Engel.

Men - more often than women - need passion to succeed at things. At the same time, boys are diagnosed as being on the autism spectrum four times as often as girls.

Both statistics may be related to dopamine, one of our body's neurotransmitters.

"This is interesting. Research shows a more active dopamine system in most men" than in women, says Hermundur Sigmundsson, a professor at the Norwegian University of Science and Technology's (NTNU)Department of Psychology.

He is behind a new study that addresses gender differences in key motivating factors for what it takes to become good at something. The study uses men's and women's differing activity in the dopamine system as an explanatory model.

"We looked at gender differences around passion, self-discipline and positive attitude," Sigmundsson says.

The study refers to these qualities as passion, grit and mindset. The researchers also applied theories to possible links with dopamine levels.

Dopamine is linked to learning, attention and our ability to focus.

Dopamine is a neurotransmitter that is released in the brain. It can contribute to a feeling of satisfaction.

Men normally secrete more dopamine, which is often called the "happy hormone," but it plays a far more complex role than that. The effects of dopamine are linked to learning, attention and our ability to focus.

Previous studies on Icelandic students have shown that men are more dependent on passion in order to succeed at something. This study confirms the earlier findings. Men require more passion. In six out of eight test questions, men score higher on passion than women.

However, the association with dopamine levels has not been established previously.

"The fact that we've developed a test to measure passion for goal achievement means that we can now relate dopamine levels to passion and goal achievement," says Sigmundsson.

Women, on the other hand, may have greater self-discipline - or grit - and be more conscientious, according to other studies. Their level of passion may not be as pronounced in general, but they still are able to do what it takes to be good.

The results for the women, however, are somewhat more ambiguous than men's strong need to burn for something, and this study found no such gender difference.

Nor did the researchers find any difference between the sexes in terms of growth mindset.

In the past, the dopamine system has been associated with many different conditions, such as ADHD, psychoses, manias and Parkinson's disease. But it may also be related to a certain form of autistic behaviour.

Some individuals with autism may become very interested in certain topics, which can be a bit unusual, or even strange, for most people. People on the autism spectrum can focus intensely on these topics or pursuits, at least for a while. Dopamine may play a role.

"Other research in neuroscience has shown hyperactivity in the dopamine system in individuals with autism, and boys make up four out of five children on the autism spectrum. This, and dopamine's relationship to passion, might be a mechanism that helps to explain this behaviour," says Sigmundsson.

The research group tested 917 people aged 14 to 77, consisting of 502 women and 415 men. This is considered a major study in this context.

Sigmundsson collaborated with Stéfan Guðnason from the University of Akureyri and Sigurrós Jóhannsdóttir from the Icelandic State Diagnostic and Counselling Centre (SDCC).

Researchers from Skoltech and their colleagues have shown that adaptation to similar environments hardly involves similar genomic positions when species are distantly related. The team investigated recurrent adaptations of wildlife birds' mitochondria to high altitude, migration, diving, wintering, and flight. Repeatable substitutions are rather a coincidence than adaptation, which confirms the scientific opinion that distant species "choose" different ways of similar trait evolution. The paper was published in the journal Genome Biology and Evolution.

If an organism wants to survive in unusual conditions, such as oxygen starvation typical for high altitudes or elevation of metabolism rate due to extreme temperatures, it has to adapt. If different species meet similar environment conditions, they will adapt independently and could even do it by same substitutions in identical genomic positions - this is called single-position molecular convergence.

"Convergent evolution is one of most fascinating topics of evolutionary biology: from a practical point of view, it helps to find particular genomic positions associated with adaptation; from a more theoretical one, it shows how repeatable evolution is. Yet detection of adaptive convergent single-position mutations is known to be hard, especially in phylogenetically distant species: scientists continue to argue about whether it is possible at all," Skoltech PhD graduate Valentina Burskaia says.

Burskaia, Professor Georgii Bazykin and their colleagues designed an unusually large dataset of 415 species in which similar traits appear independently dozens of times. The dataset allowed them to examine the problem deeply, as previous attempts to detect convergent single-nucleotide mutations in phylogenetically distant species were often limited by few numbers of convergent phenotype acquisitions.

"Mitochondrial genome was chosen for the study as it is small and thus sequenced for many species, yet full of extremely important genes. Mitochondrial genes are responsible for hypoxia and metabolism level tuning: this guided our selection of phenotypic traits of interest," Burskaia notes.

The team looked at birds who live at high altitudes and diving birds (likely to face hypoxia). To study adaptations which affect metabolism rate changes, scientists considered four groups of species: birds with outstanding flight abilities, long-distance migrants, flightless birds and wintering birds. By running powerful phylogenetic methods, where species are placed on a "tree" and coincident changes in phenotype and genotype are counted, the researchers were able to show that the majority of convergence events can be explained by random coincidences rather than adaptation.

The study, being conceptually close to recent attempts to search for single-position convergences in echolocating bats and marine mammals, confirms that evolutionary landscape at between-order distances is too different for single-position adaptive convergence.

Other organizations involved in this research include Lomonosov Moscow State University, Kharkevich Institute for Information Transmission Problems of the Russian Academy of Sciences, and Hong Kong University of Science and Technology.

Osaka, Japan - Scientists from the Department of Physics and the Research Center for Nuclear Physics (RCNP) at Osaka University, in collaboration with Kyoto University, used alpha particle inelastic scattering to show that the theorized "5α condensed state" does exist in neon-20. This work may help us obtain a better understanding the low-density nucleon many-body systems.

All elements besides hydrogen and helium must have been fused inside the nuclear furnace of a star. The yield during these reactions of carbon-12, which has six protons and six neutrons, is increased by an unusual quirk in that 12 is divisible by 4. This means that given a little extra energy, the nucleons in carbon can form three alpha particles, consisting of two protons and two neutrons each, and these alpha particles can be condensed into the lowest-energy orbit in carbon-12. The existence of an alpha condensed state in heavier isotopes with atomic weights divisible by four, such as neon-20, has been theorized, but remained uncertain. These condensed states would provide a unique window into the world of nuclear physics. This is because the densities of most normal nuclei are very similar to each other, while the alpha condensed state would be an example of a low-density many-body system. Measuring the properties of protons and neutrons in such a dilute state would be very helpful for understanding the nature of low-density nuclear matter that exists on the surface of neutron stars.

Now, a team of researchers led by Osaka University have provided experimental evidence that these excited states do exist in neon-20. By firing alpha particles at a neon gas, they observed that the decay products indicated the existence of specific energy states in the original nucleus. These matched very well with predictions of the 5α condensed state, in which the 10 protons and 10 neutrons are grouped into five alpha particles in the lowest-energy orbit.

"We were able to obtain such precise results because we were able to measure the decay particles from the excited state," first author Satoshi Adachi explains. "We developed an isotopically enriched neon-20 gas target system with an ultra-thin gas-sealing window made of SiNx. We found it was crucial to measure inelastically scattered alpha particles at very forward angles including 0 degrees, where the alpha condensed state was selectively excited. This measurement was very difficult, but a high-quality beam provided by the well-tuned cyclotrons at RCNP enabled us to conduct it." These techniques allowed the scientists to carry out a detailed comparison between the statistical decay-model calculations and the experiment.

"We expect that this research will accelerate progress in our understanding of extreme environments, like the surface of a neutron star," senior author Takahiro Kawabata says. The work can also be extended to even heavier isotopes that follow the "divisible by four" pattern.

When cancers metastasize, cells from the primary tumor break away, travel through the blood or lymph system,
and form new tumors in other body parts. Although metastasis are responsible for more than 90% of all cancer
deaths, limited progress has been made in treating cancers that have spread.

Besides DNA, RNA is the other molecule of life. For several years now, RNA has become just as important as DNA in understanding the book of life. Especially, messenger RNA (mRNA), the basis of the Covid-19 vaccines, has been put in the spotlight. Just as with DNA, in addition to the 4 well known letters (A, U, G, C), there are further letters defining the RNA alphabet or 'RNA epigenetics'. One of these RNA letters, m6A plays a key role in gene regulation through an enzyme called FTO.

The newest work of the Laboratory of Cancer Epigenetics at the Faculty of Medicine at Université libre de Bruxelles and the ULB Cancer Research Center (U-CRC), led by Prof. François Fuks and Dr. Jana Jeschke, has revealed that FTO plays a key role in the deadly process of cancer metastasis. Analyzing data from thousands of cancer patients, the ULB researchers discovered that FTO is produced at lower levels in cancers than in healthy tissues. When they experimentally lowered the levels of FTO in cancer cells grown in plastic dishes or in animal models, they observed that these cells grew and spread faster than control cells. In cancer patients, they discovered a similar pattern in which low FTO levels correlated with more aggressive tumors, metastasis and earlier death. Using a new sequencing technology, which allows to measure m6A within all mRNAs, Prof. Fuks and Dr. Jeschke found that in FTO-low cancer cells m6A is enriched specifically in mRNAs that belong to a program, termed WNT signaling, that promotes metastasis.

As WNT signaling has been found upregulated in many cancers, therapies that aim to block this program have been developed and are currently tested in clinical trials. When the ULB researchers experimented with this new type of therapy, they observed that cancer cells or tumors with lowered FTO levels and enhanced WNT activity were more sensitive to WNT inhibitors. Thus, although FTO-low tumors are more aggressive and deadly, they are better treatable with Wnt inhibitor therapy. The findings were initially made in breast cancer but can be generalized to many other tumors, such as prostate, cervix or lung cancers.

Overall, the team of Prof. Fuks identified a new key regulator of cancer metastasis and a new therapeutic strategy to block the deadly spread of cancer. Details of this work, which offers encouraging prospects for cancer research and therapy, are published in the 23d June 2021 issue of the Nature Cancer journal.

Discovering and engineering nanobodies with properties suitable for treating human diseases ranging from cancer to COVID-19 is a time-consuming, laborious process.

To that end, University of Michigan researchers found a simple method for identifying nanobodies with drug-like properties suitable for preventing SARS-CoV-2 infections. They demonstrated the approach by generating nanobodies that neutralized the SARS-CoV-2 virus more potently than an antibody isolated from an infected patient and a nanobody isolated from an immunized animal.

Nanobodies are small antibody fragments which bind strongly to their target molecules and block their functions. Currently, antibody and nanobody discovery involves selecting initial lead antibody candidates, followed by time- and labor-intensive modifications to make them suitable for therapeutic applications, said Jennifer Zupancic, doctoral candidate in chemical engineering and co-first author, with Alec Desai, doctoral candidate in chemical engineering. The study is in Cell Chemical Biology.

"A key advantage to this method, both in terms of addressing pandemics and nanobody development more generally, is the ability to select nanobodies that bind strongly more rapidly than with current methods," said Zupancic.

"This unexpected discovery appears to be a key step toward addressing a long-standing challenge in the field, namely the rapid and simple generation of high-affinity agents (agents that bind strongly) such as nanobodies, without the need for extensive screening and optimization," said Peter Tessier, the Albert M. Mattocks Professor in Pharmaceutical Sciences and Chemical Engineering, and senior author. He's also a member of the U-M Biointerfaces Institute,

Nanobodies and antibodies bind to their targets via multiple flexible binding loops called the complementarity-determining regions. Researchers discovered that one or more of the individual binding loops from different lead nanobodies could be combined into single nanobody mutants with improved properties, Zupancic said. That process is called complementarity-determining region swapping.

"This process of CDR swapping resulted in substantial changes to the nanobodies we initially started out to modify," she said. "It was surprising to us that such large changes not only did not hinder the nanobodies' ability to bind and neutralize the SARS-CoV-2 virus, but actually greatly improved it."

Researchers discovered the method accidentally, but found and reported that the technique is simple to perform in a systematic manner.

Generally, approved antibody drugs must demonstrate drug-like properties, including high stability, specificity and solubility, and must also bind strongly to their target. Often, there are tradeoffs between these properties, which frustrate therapeutic antibody development.

"However, we observe that our nanobodies have drug-like properties and also bind to and neutralize the SARS-CoV-2 virus strongly," she said.

The new method likely can be used to develop nanobodies against other viruses and disease targets. That work is ongoing in the lab now, Zupancic said.

Many people don't realize that the trillions of bacteria, viruses, and fungi residing within the gastrointestinal tract--collectively called the gut microbiome-- are connected to overall health, and specifically to cancer.

Manipulating the gut microbiome to produce "beneficial" commensal microbes, which protect the host from pathogens and can boost immune responses, among other things, could potentially help patients respond better to cancer drugs called immune checkpoint inhibitors, a type of immunotherapy.

To that end, researchers at the University of Michigan have developed a new dietary fiber formulation that improves the potency of immunotherapies against cancer by modulating the gut microbiome. In the future, cancer patients treated with immune checkpoint blockers may benefit from consuming this inulin gel dietary fiber, said James Moon, the John G. Searle Associate Professor of Pharmaceutical Sciences in the College of Pharmacy. The findings appear in the June 24 issue Nature Biomedical Engineering.

Inulin, a dietary fiber found in chicory root, Jerusalem artichoke and other plants, is a prebiotic that helps produce colon-residing commensal bacteria. By formulating inulin into a more colon-targeted inulin gel formulation, the team was able to provide a rich source of nutrients to allow beneficial gut microbes to expand more in the gastrointestinal tract.

The inulin gel improved immune checkpoint inhibitor therapy in rodents with colon carcinoma as well as melanoma. For instance, when inulin gel was combined with an immune checkpoint inhibitor in a colon carcinoma rodent model, the rate of tumor eradication doubled (100% improvement), compared with the immune checkpoint inhibitor therapy alone.

"Consumption of the inulin gel expanded and increased the number of beneficial microbes in tumor-bearing mice," said Kai Han, postdoctoral fellow and first author of the study. "These are beneficial commensal microbes that are found in cancer patients who respond well to immune checkpoint inhibitors.

"The current approaches to restoring a healthy gut microbiome include oral ingestion of defined probiotics or fecal microbiota transplantation," Han said. "However, it would be very challenging to develop these as pharmaceutical products due to scale-up manufacturing and quality control."

The human microbiome has recently emerged as the next frontier in drug development. Intense research interest in the microbiome is driven by evidence linking the potential health benefits of modulating gut microbiota to treating various diseases, including cancer, diabetes, obesity and neurodegenerative diseases. In particular, a series of recent studies showed that the gut microbiome plays a crucial role in cancer patients' response rate to immune checkpoint inhibitors, Moon said.

"We and others have shown that the gut microbiome has a crucial role in our immune responses," Han said. "Close to 70% of lymph nodes in our bodies are located in the gastrointestinal tract and therefore, microbes residing in the gastrointestinal tract closely interact with our immune cells. Maintaining a healthy gut microbiome nurtures our immune system so that our immune cells can effectively fight against cancer."

The group chose inulin because it wanted something that could be readily translated to the clinic. Inulin is a dietary fiber that is widely consumed by the public and is present in many plants. It's used as a sugar substitute and in candies and butter. By making inulin into inulin gel, researchers found that inulin gel coats the gastrointestinal tract much better, leaving more nutrients to the commensal microbes.

The inulin gel also works with anti-PD-1 plus anti-CTLA-4 combo-therapy, (widely used immune checkpoint inhibitors) that treat many types of cancer, Han said.

Roughly 10-30% of cancer patients respond to immune checkpoint inhibitors, depending on the types of cancer, and there is risk of serious immune-related complications and side-effects, Moon said. For instance, inflammation in the gastrointestinal tract and skin are common. Previous studies have shown that inulin consumption may alleviate gastrointestinal inflammation, such as colitis and IBD.

"So, inulin gel may alleviate gastrointestinal inflammation induced by immune checkpoint inhibitors and we are testing this idea now," Moon said.

"Generation of systemic anti-tumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel"

A cluster of comet fragments believed to have hit Earth nearly 13,000 years ago may have shaped the origins of human civilisation, research suggests.

Possibly the most devastating cosmic impact since the extinction of the dinosaurs, it appears to coincide with major shifts in how human societies organised themselves, researchers say.

Their analysis backs up claims that an impact occurred prior to start of the Neolithic period in the so-called Fertile Crescent of southwest Asia.

During that time, humans in the region - which spans parts of modern-day countries such as Egypt, Iraq and Lebanon - switched from hunter-gatherer lifestyles to ones centred on agriculture and the creation of permanent settlements.

It is thought that the comet strike - known as the Younger Dryas impact - also wiped out many large animal species and ushered in a mini ice age that lasted more than 1,000 years.

Since it was proposed in 2007, the theory about the catastrophic comet strike has been the subject of heated debate and much academic research. Now, researchers from the University of Edinburgh have reviewed evidence assessing the likelihood that an impact took place, and how the event may have unfolded.

The team says a large body of evidence supports the theory that a comet struck around 13,000 years ago. Researchers analysed geological data from four continents, particularly North America and Greenland, where the largest fragments are thought to have struck.

Their analysis highlights excess levels of platinum, signs of materials melted at extremely high temperatures and the detection of nanodiamonds known to exist inside comets and form during high-energy explosions. All of this evidence strongly supports the impact theory, researchers say.

The team says further research is needed to shed more light on how it may have affected global climate and associated changes in human populations or animal extinctions.

The research is published in the journal Earth-Science Reviews. An Open Access version of the paper is available here: https://www.research.ed.ac.uk/en/publications/the-younger-dryas-impact-hypothesis-review-of-the-impact-evidence

Dr Martin Sweatman, of the University of Edinburgh's School of Engineering, who led the study, said: "This major cosmic catastrophe seems to have been memorialised on the giant stone pillars of Göbekli Tepe, possibly the 'World's first temple', which is linked with the origin of civilisation in the Fertile Crescent of southwest Asia. Did civilisation, therefore, begin with a bang?"

The Third Pole centered on the Tibetan Plateau is home to the headwaters of multiple rivers in Asia. Despite the importance of these rivers, scientists have not known exactly how much water flows out of the mountains of the Third Pole as river runoff.

Now, however, researchers from the Institute of Tibetan Plateau Research (ITP) of the Chinese Academy of Sciences have quantified the total river runoff of 13 major rivers in the region.

The study was published in the Bulletin of the American Meteorological Society and was based on data from an observational network of "water meters" at mountain outlets in the Third Pole.

The network generates comprehensive discharge data for 13 major Third Pole rivers and was established by Pan-TPE, a research program under the Chinese Academy of Sciences. The water meters integrate both ground-based observations and numerical simulations.

"Monitoring changes in river runoff at mountain outlets in the Third Pole is particularly important because rivers in this region support millions of people in Asia and are very sensitive to climate change," said Prof. WANG Lei from ITP, lead author of the study.

Using data from the network, the scientists made the first-ever estimate of annual total river runoff for the 13 Third Pole rivers. The results, for 2018, peg total runoff at 656 ± 23 billion m3.

The scientists also found that the annual readings of the water meters varied widely among the different rivers, ranging from 2 to 176 billion m3. The higher values mainly corresponded to rivers in the Indian monsoon domain in the southern Third Pole, rather than in the westerly domain in the northern Third Pole.

Readings from these water meters offer valuable information about regional water resources. They also provide information relevant to hazard risk management. This is particularly important in the context of climate change since river runoff has significantly changed as a result of increasingly rapid snow and glacial melting in the region.

"We also plan to collect and process data for major rivers in the region prior to 2018 and improve the accuracy of discharge estimates, so that better cryosphere-hydrology models can be built for different river basins across the Third Pole," said Prof. YAO Tandong, co-author of the study and chief scientist at Pan-TPE.

In a new study published in Circulation Research, Chen-Yu Zhang and Xiaohong Jiang's group from Nanjing University and Dongjin Wang's group from Nanjing Drum Tower Hospital reported a critical role of PGC1α in maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) and highlighted the therapeutic potential of PGC1α for atherosclerosis.

The traditional view holds that aberrant proliferation of VSMCs promotes plaque formation after vessel injury and inflammation, whereas the presence of VSMCs in the fibrous cap of the plaque is beneficial. Although it has long been assumed that these seemingly contradictory functions of VSMCs during atherosclerosis arise from their remarkable plasticity, direct evidence that VSMCs undergo phenotypic switching during atherogenesis in vivo has only been proven recently by rigorous lineage tracing studies. These studies showed that the contribution of VSMCs to atherosclerosis has been greatly underestimated. Despite the importance of VSMC phenotypic modulation in lesion pathogenesis and plaque composition, the underlying molecular mechanisms remain to be elucidated.

Among the different animal models that have been used to study atherosclerosis, rabbits not only have provided many insights into the pathogenesis of human AS but also have contributed greatly to translational research. Rodents, such as mice and rats, are quite resistant to atherosclerosis due to high levels of HDL in circulation. Like humans but unlike rodents, rabbits are considered LDL mammals, which are sensitive to dietary cholesterol and spontaneously develop AS. However, due largely to the relative ease of their genetic manipulation and breeding, compared with those of rabbits, mice--such as ApoE-/- and LDLR-/- mice--are still the most wildly used laboratory models. However, owing to their unique features of lipoprotein metabolism, which are pathophysiologically more similar to those of primates than those of rodents, transgenic rabbits have still been used during the past decades to study humans atherosclerosis in order to bridge the gaps between mice and humans; thus, rabbits are an indispensable model for studying human atherosclerosis.

Although aberrant expression of PGC1α, a master regulator of mitochondrial biogenesis, has been shown to be associated with cardiovascular diseases, the role of PGC1α overexpression in VSMCs in the formation of atherosclerotic lesions has not been elucidated. In the current study, Wei et al. generated Tg rabbits with SMC-specific PGC1α overexpression and showed that overexpression of PGC1α in VSMCs significantly ameliorated high cholesterol diet-induced atherosclerotic plaque formation. After feeding cholesterol rich diet, the VSMCs from Tg rabbits exhibited a more contractile phenotype than their non-Tg littermates, which resulted in decreased macrophage infiltration, vascular inflammation, ROS production, vascular senescence, and VSMC proliferation. In addition, similar vasoprotective effects were observed in cultured human aortic SMCs and clinical samples. Collectively, their findings demonstrate a beneficial role for PGC1α in modulating VSMC phenotype and the pathogenesis of atherosclerosis.

This work is essential for the following reasons:

1. As the first and one of the best animal models for investigating AS, the rabbit model is a better overall approximation to humans. However, to date, only 22 lines of Tg rabbits have been established to study CVD due to the relative difficulty of genetically manipulating and breeding rabbits compared with mice. Most of these exogenous genes were either systemically or specifically expressed in rabbit liver cells and directly participated in lipoprotein metabolism, for example, apolipoproteins and their associated enzymes. Although many lipid metabolism related factors have been expressed in rabbit livers and macrophages, models with artery-specific overexpression of genes are lacking. By generating transgenic rabbits that expressed PGC1α under the control of a minimal SM22 promoter, whose activity was constitutive in arterial SMCs. Zhang's group found that after HCD feeding, although Tg rabbits developed hypercholesterolemia similar to that in their non-Tg littermates, the mean aortic lesion size in Tg rabbits was markedly reduced. This finding is consistent with previous observations in vitro studies in cultured VSMCs, indicating a direct atheroprotective role of PGC1α in arterial VSMCs.

2. As a powerful orchestrator of energy metabolism, PGC1α is highly expressed in energy demanding tissues, such as brown fat, liver, brain, and muscles. The function of PGC1α is less studied in VSMCs, the ultimate effectors of vasomotion and a major cell type present at all stages of AS than in skeletal muscle and cardiac muscle cells. Although previous in vitro studies showed that PGC1α can inhibit pathological factor-induced VSMC proliferation and senescence, increased local PGC1α expression in AS has not been conclusively demonstrated in vivo. In the present study, based on RNA-seq analysis and a set of experimental assays of the aortic media from HCD-fed control and Tg rabbits, they found that the PGC1α level was positively associated with the VSMC-restricted contractile gene expressions, but negatively correlated with the atherogenic synthetic phenotype-related features of VSMCs, such as increased expression of proinflammatory factors and MMPs, enhanced ROS production and senescence, and elevated VSMC proliferation. These in vivo observations were also confirmed in cultured VSMCs, hence revealing the novel role of PGC1α in preserving the beneficial contractile phenotype of VSMCs and bolstering its antiatherogenic function.

3. Their data indicated a potential atheroprotective role of PGC1α in clinical atherosclerotic samples, yet further studies with more accurate lineage identification techniques are needed to address this possibility, and regulating PGC1α itself or increasing the level of PGC1α in VSMCs might be feasible therapeutic strategies for atherosclerosis.