Protein-based Vaccine Candidate Combined With Potent Adjuvant Yields Effective SARS-CoV-2 Protection (Medicine)

A new protein-based vaccine candidate combined with a potent adjuvant provided effective protection against SARS-CoV-2 when tested in animals, suggesting that the combination could add one more promising COVID-19 vaccine to the list of candidates for human use.

The protein antigen, based on the receptor binding domain (RBD) of SARS-CoV-2, was expressed in yeast instead of mammalian cells – which the authors say could enable a scalable, temperature-stable, low-cost production process well suited for deployment in the developing world.

In a study by Maria Pino and colleagues, the adjuvant – a TLR7/TLR8 agonist named 3M-052, formulated with alum – substantially improved performance of the vaccine compared with vaccine adjuvanted with alum alone, inducing stronger antibody and T cell responses in vaccinated rhesus macaques.

The vaccine and adjuvant combination also significantly reduced the quantity of virus in the respiratory tracts of macaques challenged by infection with SARS-CoV-2, and reduced lung inflammation as well.

Pino et al. vaccinated 5 macaques with the RBD protein and the 3M-052/alum adjuvant and another 5 with the RBD protein and alum alone, each at 0, 4, and 9 weeks; they also included 5 unvaccinated macaques as controls. The vaccine and adjuvant combination induced more neutralizing antibodies with higher binding affinity for the virus RBD and also enhanced CD4+ and CD8+ T cell responses compared with the alum-only formulation.

About one month after the third round of vaccinations, the researchers then infected the macaques with SARS-CoV-2, and noted the macaques vaccinated with the novel adjuvant formulation showed a reduced viral load in their nasal mucus and lung fluid, as well as fewer inflammatory cytokines in their plasma.

Featured image: The RBD+3M-052-alum vaccine induces robust humoral immunity in RMs. © Authors

Reference: Maria Pino, Talha Abid, Susan Pereira Ribeiro, Venkata Viswanadh Edara, Katharine Floyd, Justin C. Smith, Muhammad Bilal Latif, Gabriela Pacheco-Sanchez, Debashis Dutta, Shelly Wang, Sanjeev Gumber, Shannon Kirejczyk, Joyce Cohen, Rachelle L. Stammen, Sherrie M. Jean, Jennifer S. Wood, Fawn Connor-Stroud, Jeroen Pollet, Wen-Hsiang Chen, Junfei Wei, Bin Zhan, Jungsoon Lee, Zhuyun Liu, Ulrich Strych, Neeta Shenvi, Kirk Easley, Daniela Weiskopf, Alessandro Sette, Justin Pollara, Dieter Mielke, Hongmei Gao, Nathan Eisel, Celia C. LaBranche, Xiaoying Shen, Guido Ferrari, Georgia D. Tomaras, David C. Montefiori, Rafick P. Sekaly, Thomas H. Vanderford, Mark A. Tomai, Christopher B. Fox, Mehul S. Suthar, Pamela A. Kozlowski, Peter J. Hotez, Mirko Paiardini, Maria Elena Bottazzi, Sudhir Pai Kasturi, “A yeast expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates”, Science Immunology  15 Jul 2021: Vol. 6, Issue 61, eabh3634 DOI:

Provided by AAAS

Why Oxygenation Tends To Fluctuate In The Brain? (Neuroscience)

Adequate blood flow supplies the brain with oxygen and nutrients, but the oxygenation tends to fluctuate in a distinct, consistent manner. The root of this varied activity, though, is poorly understood.

Now, Penn State researchers have identified one cause of the fluctuations: inherent randomness in the flow rate of red blood cells through tiny blood vessels called capillaries. According to the researchers, this randomness could have potential implications for understanding the biological build-up mechanisms underlying neurodegenerative diseases, such as Alzheimer’s disease. They published their findings in PLOS Biology today (July 15).

“These oxygenation fluctuations also occur in other tissues, like muscle,” said Patrick Drew, Huck Distinguished Associate Professor of Engineering Science and Mechanics, Neurosurgery and Biomedical Engineering.?”The question we had was: Are these fluctuations caused by neural activity or something else?”

The fluctuations resemble 1/f-like noise, a statistical pattern showing large fluctuations made up of many small fluctuations and naturally occurring in a variety of phenomena, from stock-market prices to river heights. The researchers investigated the fluctuations in mice due to their brains’ similarities to those of humans, according to Drew, who also serves as associate director of the Penn State Neuroscience Institute.

First, the researchers monitored the blood flow, oxygenation and electrical signals produced by brain activity — the first time the latter two had been tracked simultaneously, according to Drew — in awake mice. They collected the data as mice moved on a spherical treadmill for up to 40 minutes at a time.

Next, to investigate the relationship between brain activity and oxygenation fluctuations, the researchers used pharmacological compounds to temporarily and reversibly silence neural signals in the mice’s brains. Despite the silencing, the fluctuations continued, showing little correlation between neural activity and oxygenation.

The passage of red blood cells, however, told a different story. Using two-photon laser scanning microscopy, an imaging technique used to visualize cells deep inside living tissue, the researchers could visualize the passage of individual red blood cells through capillaries.

“It’s like traffic,” Drew said. “Sometimes there are a lot of cars going by, and the traffic gets plugged up, and sometimes there aren’t. And red blood cells go either way when they approach a junction, so this random flow can lead to bottlenecks and stalls in the vessel.”

Importing experimental data into a statistical model allowed the researchers to run further simulations and make inferences based on massive amounts of data produced by the model. The researchers discovered that these random red blood cell stoppages contributed to the fluctuations in oxygenation, further supporting a relationship between the flow of red blood cells through capillaries and the tiny changes in oxygenation that formed larger trends.

Better understanding the regulation of blood flow and subsequent transport of oxygen can help researchers improve medical technology and explore causes of diseases such as Alzheimer’s, according to Drew. While the researchers identified the link between red blood cell transport and oxygenation, further research is needed to investigate additional contributors to oxygenation fluctuations that could play a role in neurodegenerative diseases.

Kyle Gheres, a graduate student in the intercollege Graduate Program in Molecular Cellular and Integrative Biosciences, also contributed to this paper. Qingguang Zhang, assistant research professor of engineering science and mechanics, served as first author on the paper. This work was supported by the National Institutes of Health.

Featured image: The researchers found that red blood cell “traffic” (top grey bar) appears to contribute to oxygenation fluctuations (white line), which are not correlated to changes in neural activity (bottom blue peaks) in mice brains (top right). © Drew Lab and Yongsoo Kim Lab

Reference: Zhang Q, Gheres KW, Drew PJ (2021) Origins of 1/f-like tissue oxygenation fluctuations in the murine cortex. PLoS Biol 19(7): e3001298. doi:10.1371/journal.pbio.3001298

Provided by Penn State University

Abell 1775: Chandra Catches Slingshot During Collision (Cosmology)

  • Abell 1775 is a system where a smaller galaxy cluster has plowed into a larger one.
  • Using X-rays from Chandra and data from other telescopes astronomers are piecing together details of this collision.
  • Features in the data, including a curving tail of hot gas and a “cold front”, are clues.
  • Scientists will likely need more observations and modeling to get the full picture of Abell 1775.

When the titans of space — galaxy clusters — collide, extraordinary things can happen. A new study using NASA’s Chandra X-ray Observatory examines the repercussions after two galaxy clusters clashed.

Galaxy clusters are the largest structures in the Universe held together by gravity, containing hundreds or even thousands of individual galaxies immersed in giant oceans of superheated gas. In galaxy clusters, the normal matter — like the atoms that make up the stars, planets, and everything on Earth — is primarily in the form of hot gas and stars. The mass of the hot gas between the galaxies is far greater than the mass of the stars in all of the galaxies. This normal matter is bound in the cluster by the gravity of an even greater mass of dark matter.

Because of the huge masses and speeds involved, collisions and mergers between galaxy clusters are among the most energetic events in the Universe.

In a new study of the galaxy cluster Abell 1775, located about 960 million light years from Earth, a team of astronomers led by Andrea Botteon from Leiden University in the Netherlands announced that they found a spiral-shaped pattern in Chandra’s X-ray data. These results imply a turbulent past for the cluster.

When two galaxy clusters of different sizes have a grazing collision, the smaller cluster will begin to plow through the larger one. (Because of its superior mass, the bigger cluster has the upper hand when it comes to gravitational pull.) As the smaller cluster moves through, its hot gas is stripped off due to friction. This leaves behind a wake, or tail, that trails behind the cluster. After the center of the smaller cluster passes by the center of the larger one, the gas in the tail starts to encounter less resistance and overshoots the center of its cluster. This can cause the tail to “slingshot” as it flies to the side, curving as it extends away from the cluster’s center.

The newest Chandra data contains evidence — including the brightness of the X-rays and the temperatures they represent — for one of these curving “slingshot” tails. Previous studies of Abell 1775 with Chandra and other telescopes hinted, but did not confirm, that there was an ongoing collision in this system.

A new image of Abell 1775 contains X-rays from Chandra (blue), optical data from the Pan-STARRS telescope in Hawaii (blue, yellow, and white), and radio data from the LOw Frequency ARray (LOFAR) in the Netherlands (red). The tail is labeled in this image along with a region of gas with a curved edge, called a “cold front,” that is denser and cooler than the gas it is plowing into. The tail and the cold front all curve in the same direction, creating a spiral appearance. A separate labeled image shows the field of view of the Chandra data.

Abell 1775 image with labels
Labeled Multiwavelength Image of Abell 1775 © Chandra X-ray

Astronomers previously found that Abell 1775 contains an enormous jet and radio source, which is also seen in this new composite image. This jet is powered by a supermassive black hole in a large elliptical galaxy in the cluster’s center. New data from LOFAR and the Giant Metrewave Radio Telescope (GMRT) in India reveals that the radio jet is actually 2.6 million light years long. This is about twice as long as astronomers thought it was before and makes it one of the longest ever observed in a galaxy cluster. The structure of the jet changes abruptly as it crosses into the lower density gas in the upper part of the image, across the edge of the cold front, implying that the collision has affected it.

According to the new study, the gas motions inside the cluster could be responsible for other structures detected by observing Abell 1775 in radio waves, such as two filaments located near the origin of the jet (one of these is labeled). The LOFAR and Chandra data have also enabled the researchers to study in great detail the phenomena that contribute to accelerating electrons both in this galaxy’s jet and in the radio emission near the center of the larger cluster.

There is an alternate explanation for the appearance of the cluster. As a small cluster approaches a larger one, the dense hot gas of the larger cluster will be attracted to it by gravity. After the smaller cluster passes the center of the other cluster, the direction of motion of the cluster gas reverses, and it travels back towards the cluster center. The cluster gas moves through the center again and “sloshes” back and forth, similar to wine sloshing in a glass that was jerked sideways. The sloshing gas ends up in a spiral pattern because the collision between the two clusters was off-center.

The Botteon team favors the slingshot tail scenario, but a separate group of astronomers led by Dan Hu of Shanghai Jiao Tong University in China favors the sloshing explanation based on data from Chandra and ESA’s XMM-Newton. Both the slingshot and sloshing scenarios involve a collision between two galaxy clusters. Eventually the two clusters will fully merge with each other to form a single, larger galaxy cluster.

Further observations and modeling of Abell 1775 are required to help decide between these two scenarios.

A paper describing the results by Botteon’s team has been published in the journal Astronomy and Astrophysics and is available online. The separate work on the “sloshing” theory led by Dan Hu has been accepted for publication in The Astrophysical Journal and is also available online.

NASA’s Marshall Space Flight Center manages the Chandra program. The Smithsonian Astrophysical Observatory’s Chandra X-ray Center controls science from Cambridge, Massachusetts, and flight operations from Burlington, Massachusetts.

Featured image: Abell 1775. Credit X-ray: NASA/CXC/Leiden Univ./A. Botteon et al.; Radio: LOFAR/ASTRON; Optical/IR:PanSTARRS

Provided by Chandra X-ray Observatory

Engineers Find Imaging Technique Could Become Treatment For Deep Vein Thrombosis (Medicine)

Penn State College of Engineering researchers set out to develop technology capable of localizing and imaging blood clots in deep veins. Turns out their work may not only identify blood clots, but it may also be able to treat them.

The team, led by Scott Medina, assistant professor of biomedical engineering, published its results in Advance Healthcare Materials.

“Deep vein thrombosis is the formation of blood clots in deep veins, typically in a person’s legs,” said Medina. “It’s a life-threatening blood clotting condition that, if left unaddressed, can cause deadly pulmonary embolisms — when the clot travels to the lungs and blocks an artery. To manage DVT, and prevent these life-threating complications, it’s critical to be able to rapidly detect, monitor and treat it.”

The challenge, according to Medina, is that current diagnostic imaging methods lack the resolution required to precisely pinpoint potential breeding grounds for clots and monitor the clots in real time. DVT can sometimes present as swelling and aching in a person’s leg, which can then be examined via ultrasound.

“Ultrasound isn’t great for diagnosing DVT,” Medina said. “It can tell you that a region of fluid flow may look odd, which might be related to a clot — but maybe not. You follow up with blood tests to look for specific factors, and, together, you might be able to diagnose a clot.”

Once a clot is diagnosed, a clinician may order either pharmaceuticals to help break it apart or a procedure that involves snaking a probe to the clot to grab it and physically remove it from the body. The pharmaceuticals may not be enough to break the clot apart, though, or they could trigger bleeding issues elsewhere in the body, while the procedure option is invasive and carries risks, including potential infection.

To better identify the location, composition and size of clots, which informs how to treat them, Medina and his team used a particle approach they developed in 2017. Called nanopeptisomes (NPeps), the particles comprise a shell around a droplet of fluorine-based oil similar to liquid Teflon. The surface of the shell holds a molecule that finds and binds a protein on the surface of activated platelets, a key cellular component of clots.

“The particles bind to the surface of the clots, we apply the ultrasound, and the droplet turns to gas and forms a bubble under the shell,” said Medina. “It gives an excellent contrast for imaging. The bubbles appear exactly where the clots are forming.”

But, Medina said, a mystery unfolded as they tested their technique. To analyze how to diagnose and treat clots, the researchers first induce clots in bovine veins by injecting an enzyme that triggers clot formation.

“The enzyme induces clot formation generally 100% of the time — but when we applied the particles, we only saw clot formation about 30% of the time,” Medina said. “We had to wonder: were the particles not only binding to the clots, but somehow breaking them down?”

The team tested its hypothesis, but the researchers would lose the bubble signal after 15 minutes of ultrasound every time.

“We think that once our particles start to decorate the clot, they saturate the surface and inhibit the mechanisms of further clot growth,” said Medina. “And under the ultrasound, the particles are disrupting the clot or inhibiting its mechanism to persist. While we don’t understand the underlying mechanism yet, it’s clear that these particles can image and help treat clots in real time.”

The researchers plan to continue investigating how the particles are disrupting the clots, as well as develop more control over how the particles behave.

Medina is also affiliated with the Materials Research Institute and the Huck Institutes of Life Sciences. Other contributors include Janna N. Sloand, Connor T. Watson, Michael A. Miller, Keefe B. Manning, all with the Department of Biomedical Engineering; Eric Rokni and Julianna C. Simon, both with the Graduate Program in Acoustics.

The National Science Foundation Faculty Early Career Development Program, a Penn State Multidisciplinary Seed Grant and a Penn State Graduate Research Fellowship supported this work in part.

Featured image: Penn State researchers developed particles that target blood clots and visualize their structures well compared to traditional ultrasound imaging. These images show blood flowing from left to right: The top image does not have the particles, while the bottom one does. © Penn State/Scott Medina

Reference: Sloand, J. N., Rokni, E., Watson, C. T., Miller, M. A., Manning, K. B., Simon, J. C., Medina, S. H., Ultrasound-Responsive Nanopeptisomes Enable Synchronous Spatial Imaging and Inhibition of Clot Growth in Deep Vein Thrombosis. Adv. Healthcare Mater. 2021, 2100520.

Provided by Penn State

Researchers Create Reptile-derived ‘Super Glue’ That Stops Bleeding in Seconds Using Visible Light (Engineering)

Indiana Jones hates snakes. And he’s certainly not alone. The fear of snakes is so common it even has its own name: ophidiophobia.

Kibret Mequanint © Western news

Kibret Mequanint doesn’t particularly like the slithery reptiles either (he actually hates them too) but the Western University bioengineer and his international collaborators have found a novel use for snake venom: a body tissue ‘super glue’ that can stop life-threatening bleeding in seconds.

Over the past 20 years, Mequanint has developed a number of biomaterials-based medical devices and therapeutic technologies – some of which are either licensed to medical companies or are in the advanced stage of preclinical testing.

His latest collaborative research discovery is based on a blood clotting enzyme called reptilase or batroxobin found in the venom of lancehead snakes (Bothrops atrox), which are amongst the most poisonous snakes in South America.

Bothrops atrox © Western news

Taking advantage of this clotting property, Mequanint and the international research team designed a body tissue adhesive that incorporates the special enzyme into a modified gelatin that can be packaged into a small tube for easy, and potentially life-saving, application.

“During trauma, injury and emergency bleeding, this ‘super glue’ can be applied by simply squeezing the tube and shining a visible light, such as a laser pointer, over it for few seconds. Even a smartphone flashlight will do the job,” said Mequanint, a Western engineering professor.

Compared to clinical fibrin glue, considered the industry gold standard for clinical and field surgeons, the new tissue sealant has 10 times the adhesive strength to resist detachment or washout due to bleeding. The blood clotting time is also much shorter, cutting it in half from 90 seconds for fibrin glue to 45 seconds for the new snake venom ‘super glue.’

This new biotechnology translates to less blood loss and more life-saving. The super-sealant was tested in models for deep skin cuts, ruptured aortae, and severely injured livers – all considered as major bleeding situations.

“We envision that this tissue ‘super glue’ will be used in saving lives on the battlefield, or other accidental traumas like car crashes,” said Mequanint. “The applicator easily fits in first aid kits too.”

In addition, the new snake venom ‘super glue’ can be used for suture-free, surgical wound closures.

Snake extract–laden hemostatic bioadhesive gel cross-linked by visible light was published today in the journal Science Advances. For the discovery, Mequanint collaborated with bioengineers, scientists and medical practitioners at the University of Manitoba and Army Medical University in Chongqing, China.

“The next phase of study which is underway is to translate the tissue ‘super glue’ discovery to the clinic,” said Mequanint.

Provided by University of Western Ontario

Fossil Rodent Teeth Add North American Twist To Caribbean Mammals Origin Story (Paleontology)

Two fossil teeth from a distant relative of North American gophers have scientists rethinking how some mammals reached the Caribbean Islands.

The teeth, excavated in northwest Puerto Rico, belong to a previously unknown rodent genus and species, now named Caribeomys merzeraudi. About the size of a mouse, C. merzeraudi is the Caribbean’s smallest known rodent and one of the region’s oldest, dating back about 29 million years.

It also represents the first discovery of a Caribbean rodent from a North American lineage, a finding that complicates an idea that has persisted since Darwin – that land-dwelling mammals colonized the islands from South America. The presence of C. merzeraudi in Puerto Rico suggests a second possibility: Some species may have rafted from North America.

The tiny rodent joins two other types of animals, an extinct rhinoceros-like species and bizarre, venomous shrews known as Solenodons, as the only known examples of Caribbean land-dwelling mammals with North American roots.

“This discovery demonstrates that overwater dispersal from North America was also a potential pathway to the Caribbean,” said study co-author Jorge Velez-Juarbe, associate curator of mammalogy at the Natural History Museum of Los Angeles County. “This challenges what we thought we knew about the origins of Antillean terrestrial mammals.”

(article continues below image)

illustration of position of rodent teeth in model skull
This artist’s reconstruction shows the likely position of these fossil molars in Caribeomys merzeraudi’s skull. These two teeth are the only evidence of this species thus far.ILLUSTRATION COURTESY OF JORGE VELEZ-JUARBE
image of CT scan of rodent molar
Researchers believe this molar came from an old adult because of its advanced state of wear. This tooth is the holotype of Caribeomys merzeraudi, meaning that the species description is based on this specimen.IMAGE COURTESY OF THE PALAEONTOLOGICAL ASSOCIATION
image of CT scan of rodent molar
This tooth likely belonged to a newborn. A thick layer of enamel helped preserve the teeth during fossilization.IMAGE COURTESY OF THE PALAEONTOLOGICAL ASSOCIATION

While Caribbean ecotourism brochures generally don’t feature splashy images of rats, the islands were once home to a rich representation of rodents, including spiny rats, chinchillas, rice rats and hutias – all descendants of South and Central American forebears.

Fossil and molecular evidence suggest these rodents arrived in the islands in multiple waves over time, though how they got there – whether by scurrying over an ancient land bridge, island-hopping or rafting – has been hotly contested. The paucity of fossils from the early years of the Caribbean Islands further obscures the picture of the region’s past biodiversity.

Caribeomys merzeraudi’s teeth were so unusual that researchers initially struggled to discern what kind of animal they had come from, said study co-author Lazaro Viñola Lopez, a doctoral student in vertebrate paleontology at the Florida Museum of Natural History.

“We didn’t know what it was for several months,” he said. “We wondered whether this could be some other rodent from the Caribbean or even some kind of strange fish. It was so puzzling because they’re not similar to anything else we had found in that region.”

paleontologists excavating fossils
Scientists on the research team excavate fossils from a layer of grey, silty claystone in Puerto Rico: from top, Lazaro Viñola Lopez, Jorge Velez-Juarbe, François Pujos and Laurent Marivaux. Velez-Juarbe was part of a group of undergraduate students that discovered the site in 2006. He has returned to it each year.PHOTO COURTESY OF PIERRE-OLIVIER ANTOINE

The team eventually pinpointed several tooth characteristics that are hallmarks of rodents known as geomorphs, a group that includes kangaroo rats, pocket mice and gophers. Caribeomys merzeraudi is the first geomorph found outside North America.

An exceptionally thick layer of tooth enamel, among other features, sets C. merzeraudi apart from its relatives and could indicate these rodents belonged to a distinct West Indian branch that evolved in isolation over several million years, Viñola Lopez said.

Scientists found the teeth while screen-washing sediment collected from a river outcrop in San Sebastian, a site that has yielded fossil sharks and rays, fish, turtles, a gharial, sea cows and the oldest known frog in the Caribbean, a coquí. In 2019, the team excavated fossil evidence of two large chinchillas, which likely grew up to 30 pounds. These South American rodents once shared Puerto Rico with the humble C. merzeraudi, which weighed less than a quarter pound.

Today, hutias, bats and Solenodons are the “last survivors of what was once a much more diverse group of Caribbean mammals” that included sloths and primates, Velez-Juarbe said.

Discovering C. merzeraudi opens up the tantalizing possibility that Caribbean mammals with North American origins may not be as exceptional as previously thought, Viñola Lopez said. But there’s only one way to find out: “Go back to the locality and see what else we can find.”

The researchers published their findings in Papers in Palaeontology.

Featured image: A paleontologist stands on an outcrop next to the Rio Guatemala, which flows through the township of San Sebastian, Puerto Rico. The site has yielded an abundance of fossils. including two teeth that belonged to a rodent with North American roots.PHOTO COURTESY OF JORGE VELEZ-JUARBE

Reference: Marivaux, L., Vélez-Juarbe, J., Viñola López, L.W., Fabre, P.-H., Pujos, F., Santos-Mercado, H., Cruz, E.J., Grajales Pérez, A.M., Padilla, J., Vélez-Rosado, K.I., Cornée, J.-J., Philippon, M., Münch, P. and Antoine, P.-O. (2021), An unpredicted ancient colonization of the West Indies by North American rodents: dental evidence of a geomorph from the early Oligocene of Puerto Rico. Pap Palaeontol.

Provided by Florida Museum

What Does The Sleeping Brain Think About? (Neuroscience)

Thanks to a unique system that decodes brain activity during sleep, a UNIGE team is deciphering the neuronal mechanisms of memory consolidation.

We sleep on average one third of our time. But what does the brain do during these long hours? Using an artificial intelligence approach capable of decoding brain activity during sleep, scientists at the University of Geneva (UNIGE), Switzerland, were able to glimpse what we think about when we are asleep. By combining functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), the Geneva team provides unprecedented evidence that the work of sorting out the thousands of pieces of information processed during the day takes place during deep sleep. Indeed, at this time, the brain, which no longer receives external stimuli, can evaluate all of these memories in order to retain only the most useful ones. To do so, it establishes an internal dialogue between its different regions. Moreover, associating a reward with a specific information encourages the brain to memorise it in the long term. These results, to be discovered in the journal Nature Communications, open for the first time a window on the human mind in sleep.

In the absence of tools capable of translating brain activity, the content of our sleeping thoughts remains inaccessible. We however do know that sleep plays a major role in memory consolidation and emotional management: when we sleep, our brain reactivates the memory trace built during the day and helps us to regulate our emotions. “To find out which brain regions are activated during sleep, and to decipher how these regions allow us to consolidate our memory, we developed a decoder capable of deciphering the activity of the brain in deep sleep and what it corresponds to”, explains Virginie Sterpenich, a researcher in the laboratory of Professor Sophie Schwartz in the Department of Basic Neurosciences at UNIGE Faculty of Medicine, and the principal investigator of this study. “In particular, we wanted to see to what extent positive emotions play a role in this process.”

During deep sleep, the hippocampus – a structure of the temporal lobe which stores temporary traces of recent events – sends back to the cerebral cortex the information it has stored during the day. A dialogue is established which allows the consolidation of memory by replaying the events of the day and therefore reinforce the link between neurons.  

Combining MRI, electroencephalography and artificial intelligence

To conduct their experiment, the scientists placed volunteers in an MRI in the early evening and had them play two video games – a face-recognition game similar to ‘Guess Who?’ and a 3D maze from which the exit must be found. These games were chosen because they activate very different brain regions and are therefore easier to distinguish in the MRI images. In addition, the games were rigged without the volunteers’ knowledge so that only one of the two games could be won (half of the volunteers won one and the other half won the second), so that the brain would associate the game won with a positive emotion.

The volunteers then slept in the MRI for one or two hours – the length of a sleep cycle – and their brain activity was recorded again. “We combined EEG, which measures sleep states, and functional MRI, which takes a picture of brain activity every two seconds, and then used a ‘neuronal decoder’ to determine whether the brain activity observed during the play period reappeared spontaneously during sleep”, Sophie Schwartz explains.  

Even when asleep, the brain likes rewards

By comparing MRI scans of the waking and sleeping phases, the scientists observed that during deep sleep, the brain activation patterns were very similar to those recorded during the gaming phase. “And, very clearly, the brain relived the game won and not the game lost by reactivating the regions used during wakefulness. As soon as you go to sleep, the brain activity changes. Gradually, our volunteers started to ‘think’ about both games again, and then almost exclusively about the game they won when they went into deep sleep”, says Virginie Sterpenich.

Two days later, the volunteers performed a memory test: recognising all the faces in the game, on the one hand, and finding the starting point of the maze, on the other. Here again, more the brain regions related to the game were activated during sleep, better were the memory performances. Thus, memory associated to reward is higher when it is spontaneously reactivated during sleep. With this work, the Geneva team opens a new perspective in the study of the sleeping brain and the incredible work it does every night.  

This research is published in
Nature Communications
DOI: 10.1038/s41467-021-24357-5

Featured image: During deep sleep, the brain replay important events of the previous day. It reactivates spontaneously the memories associated to reward. © UNIGE, Virginie Sterpenich

Provided by University of Geneve

Autophagy May Be The Key To Finding Treatments For Early Huntington’s Disease (Neuroscience)

Autophagy disruption may be at the root of early cognitive changes in Huntington’s disease and is a potential target for disease-modifying therapies, report scientists in the Journal of Huntington’s Disease

Huntington’s Disease (HD) is a progressive neurodegenerative condition characterized by motor, cognitive, and psychiatric symptoms, and motor symptoms are often preceded by cognitive changes. Recent evidence indicates that autophagy plays a central role in synaptic maintenance, and the disruption in autophagy may be at the root of these early cognitive changes. Understanding this mechanism better may help researchers develop treatments for patients with HD early in their disease progression, report scientists in a review article published in the Journal of Huntington’s Disease.

In this review, experts describe how autophagy, the cellular process responsible for clearing old or damaged parts of the cell, plays a critical role supporting synaptic maintenance in the healthy brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease. The line of research discussed in this review represents a previously unexplored avenue for identifying potential disease-modifying therapies for HD.

“Like many neurodegenerative conditions affecting primarily cognition, such as Alzheimer’s disease, preclinical and clinical data indicate that synapses, the part of brain cells responsible for communication between cells, are affected early in HD,” explained Hilary Grosso Jasutkar, MD, PhD, Department of Neurology, Columbia University, and Ai Yamamoto, PhD, Departments of Neurology and Pathology and Cell Biology, Columbia University, New York, NY, USA. “We have long thought that autophagy played a role in the pathophysiology of HD, but what this role is has been unclear until recently. Recent evidence indicates that autophagy may be important in maintaining the synapse. This line of research has the potential to lead to identification of a drug target to treat HD early in the disease process.”

The authors first explore how cognitive dysfunction is an early manifestation of HD, and that similarly to other neurodegenerative diseases that primarily affect cognition, such as Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, early deficits in synaptic function may underlie these cognitive symptoms. Next, they review the growing evidence that the lysosome-mediated degradation pathway autophagy plays a central role in synaptic maintenance, and how the disruption in autophagy may contribute to early cognitive changes in HD.

The authors conclude that there are pathologic and imaging data in individuals with mutations in the Huntingtin protein (mHtt), as well as evidence from animal models with HD, that suggest that synapse dysfunction may occur early in HD, prior to cell death.

“Autophagy plays a specialized role in the maintenance and function of the synapse, and mHtt may disrupt this function, leading to the early synaptic changes seen in HD patients and model systems,” explained Dr. Grosso Jasutkar. “These synaptic changes may then manifest as impairments in synaptic plasticity and thus cognitive changes early in the disease course. Given that neurons rely on synaptic input and feedback for cell health, it is possible that this disruption in synaptic signaling in and of itself contributes to cell death in HD.”

“There is much work yet to be done in this field,” added Dr. Yamamoto. “Although various groups have demonstrated individual components of this pathway, a direct causal relationship of mutant Htt leading to synaptic dysfunction and, in turn, cognitive impairments, has yet to be demonstrated.”

“If the model described here is borne out, therapeutics aimed at enhancing the efficiency of synaptic autophagy early in the course of HD could be protective against early cognitive changes and potentially degeneration itself,” concluded the authors.

HD is a fatal genetic neurodegenerative disease that causes the progressive breakdown of nerve cells in the brain. An estimated 250,000 people in the United States are either diagnosed with, or at risk for, the disease. Symptoms include personality changes, mood swings and depression, forgetfulness and impaired judgment, unsteady gait, and involuntary movements (chorea). Every child of an HD parent has a 50% chance of inheriting the gene. Patients typically survive 10-20 years after diagnosis.

Featured image: Proposed pathway of mutant huntingtin (mHtt) contribution to cognitive dysfunction and cell death through impairments in synaptic autophagy: the Huntingtin protein (mHtt) interferes with autophagic efficiency, leading to a decline in synaptic autophagy. This may in turn interfere with synaptic plasticity, causing both cognitive dysfunction and loss of normal synaptic input to post-synaptic cells and feedback to presynaptic cells. Loss of normal synaptic feedback and input may then contribute to cell death. Credit: Journal of Huntington’s Disease.

Reference: Grosso Jasutkar, Hilary and Yamamoto, Ai. ‘Do Changes in Synaptic Autophagy Underlie the Cognitive Impairments in Huntington’s Disease?’ 1 Jan. 2021 : 227 – 238.

Provided by IOS Press

RUDN University Chemists Propose a One-step Synthesis of Substances for Medicine (Chemistry)

The RUDN University chemists have discovered a reaction for the synthesis of acetimidamides, heterocyclic compounds with biological activity that can be used for the synthesis of hormones, anti-inflammatory and other medical drugs. The reaction goes in one step with an efficiency of up to 96%. The results are published in the journal Molecules.

Traditional chemical synthesis goes in several stages and requires the isolation and purification of intermediates at each stage. It is not efficient and not environmentally friendly as it increases the loss of substances and the consumption of solvents, and there is a problem of waste disposal. Therefore, modern chemistry is trying to replace multi-stage reactions with multicomponent ones, in which several compounds react to form a product in a single stage. Reactions with isocyanides are the most popular in multicomponent chemistry. Isocyanides are organic compounds with high reactivity. RUDN University chemists have discovered a new three-component reaction with isocyanides that results in a heterocyclic compound with biological activity, acetimidamides. They contain a fragment of indole, which is used for the synthesis of hormones, indomethacin, and other drugs. This work is a development of the famous Ugi reaction.

“Isocyanide-based multicomponent reactions play an outstanding role in the syntheses of heterocycles, biologically relevant compounds and for diversity-oriented synthesis. In the case of the famous Ugi reaction, isocyanide interacts with iminium salt generated in situ. The potency of methods, based on the Ugi reaction, increases with the possibility of subsequent modification or cyclization of obtained products of multicomponent reaction. This is promising from the point of view of medical chemistry”, said Nikita Golantsov, PhD, Professor of the Department of Organic Chemistry of the RUDN University.

Apart from isocyanides, the new three-component reaction involves a 3-arylidenindoleninium salt and an amine. In total chemists used 8 salts and 13 amines. To choose the optimal reaction conditions, they tested 6 types of solvents, alternated the reaction time and temperature. After the reaction was completed, the chemists isolated the final product by treatment with a saturated baking soda solution followed by chromatography and studied its composition and structure using various methods, including nuclear magnetic resonance (NMR) spectroscopy.

In total, the RUDN University chemists obtained 16 acetimidamides. When using isocyanoacetic ester, imidamides were further cyclized with the formation of an imidazolone fragment. Thus, a series of 19 imidazolones containing an indole substituent was synthesized. The most suitable solvent was acetonitrile. It allowed to minimize the formation of by-products. After three hours at a temperature of 20?, the reaction yield (the ratio of the actual mass of the product obtained to the theoretical one), was 75%. And after 12 hours, the output reached 96%. Chemists tried to accelerate the reaction by increasing the temperature, but this attempt was unsuccessful due to a tar formation and an increase in the amount of the by-product.

“These reactions furnish a new practical synthetic approach to a series of compounds with a privileged indole scaffold, which are prospective choices for seeking new physiologically active compounds”, said Nikita Golantsov, PhD, Professor of the Department of Organic Chemistry of the RUDN University.

Featured image: The RUDN University chemists have discovered a reaction for the synthesis of acetimidamides, heterocyclic compounds with biological activity that can be used for the synthesis of hormones, anti-inflammatory and other medical drugs. The reaction goes in one step with an efficiency of up to 96%. © RUDN University

Reference: Nguyen, H.M.; Golantsov, N.E.; Golubenkova, A.S.; Rybakov, V.B.; Voskressensky, L.G. Three-Component Reactions of 3-Arylidene-3H-Indolium Salts, Isocyanides and Amines. Molecules 2021, 26, 2402.

Provided by RUDN University