Posts Tagged ‘brain’


Paul Tesar, professor of genetics and genome sciences, School of Medicine


Regeneration of myelin in the brain, shown in blue, after ASO drug treatment

A team led by Case Western Reserve University medical researchers has developed a potential treatment method for Pelizaeus-Merzbacher disease (PMD), a fatal neurological disorder that produces severe movement, motor and cognitive dysfunction in children. It results from genetic mutations that prevent the body from properly making myelin, the protective insulation around nerve cells.

Using mouse models, the researchers identified and validated a new treatment target—a toxic protein resulting from the genetic mutation. Next, they successfully used a family of drugs known as ASOs (antisense oligonucleotides) to target the ribonucleic acid (RNA) strands that created the abnormal protein to stop its production. This treatment reduced PMD’s hallmark symptoms and extended lifespan, establishing the clinical potential of this approach.

By demonstrating effective delivery of the ASOs to myelin-producing cells in the nervous system, researchers raised the prospect for using this method to treat other myelin disorders that result from dysfunction within these cells, including multiple sclerosis (MS).

Their research was published online July 1 in the journal Nature.

“The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment,” said Paul Tesar, principal investigator on the research, a professor in the Department of Genetics and Genome Sciences at the School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics. “Our results open the door for the development of the first treatment for PMD as well as a new therapeutic approach for other myelin disorders.”

Study co-authors include an interdisciplinary team of researchers from the medical school, Ionis Pharmaceuticals Inc., a Carlsbad, California-based pioneer developer of RNA-targeted therapies, and Cleveland Clinic. First author Matthew Elitt worked in Tesar’s lab as a Case Western Reserve medical and graduate student.

PMD attacks the young

PMD is a rare, genetic condition involving the brain and spinal cord that primarily affects boys. Symptoms can appear in early infancy and begin with jerky eye movements and abnormal head movements. Over time, children develop severe muscle weakness and stiffness, cognitive dysfunction, difficulty walking and fail to reach developmental milestones such as speaking. The disease shortens life-expectancy, and people with the most severe cases die in childhood.

The disease results from errors in a gene called proteolipid protein 1 (PLP1). Normally, this gene produces proteolipid protein (PLP) a major component of myelin, which wraps and insulates nerve fibers to allow proper transmission of electrical signals in the nervous system. But a faulty PLP1 gene produces toxic proteins that kill myelin producing cells and prevent myelin from developing and functioning properly—resulting in the severe neurological dysfunction in PMD patients.

PMD impacts a few thousand people around the world. So far, no therapy has lessened symptoms or extended lifespans.

For nearly a decade, Tesar and his team have worked to better understand and develop new therapies for myelin disorders. They have had a series of successes, and their myelin-regenerating drugs for MS are now in commercial development.

Latest research

In the current laboratory work, the researchers found that suppressing mutant PLP1 and its toxic protein restored myelin-producing cells, produced functioning myelin, reduced disease symptoms and extended lifespans.

After validating that PLP1 was their therapeutic target, the researchers pursued pre-clinical treatment options. They knew mutations in the PLP1 gene produced faulty RNA strands that, in turn, created the toxic PLP protein.

So they teamed with Ionis Pharmaceuticals, a leader in RNA-targeted therapeutics and pioneer of ASOs. These short strings of chemically modified DNA can be designed to bind to a specific RNA target and block production of its protein product.

And that’s exactly what happened in their studies. The result was improved myelin and locomotion, and substantial extension of lifespan. “ASOs provided an opportunity to cut the disease-causing protein off at its source,” Elitt said.

The successful clinical use of ASOs is relatively new, yet recent developments seem promising. In 2016, the U.S. Food and Drug Administration approved the first ASO drug for a neurological disorder, spinal muscular atrophy. The drug, Spinraza, was developed by Ionis and commercialized by Biogen Inc. More ASO therapies are in development, and clinical trials and hold promise for addressing many neurological diseases that as of now have no effective treatment options.

Tesar said that ongoing and planned experiments in his laboratory will help guide future clinical development of ASO therapy for PMD. For example, researchers want to understand more about how well the treatment works after the onset of symptoms, how long it lasts, how often treatment needs to be given and whether it might be effective for all PMD patients, regardless of their specific form of the disease.

“While important research questions remain, I’m cautiously optimistic about the prospect for this method to move into clinical development and trials for PMD patients,” Tesar said. “I truly hope our work can make a difference for PMD patients and families.”

Case Western Reserve University-led team develops new approach to treat certain neurological diseases

by DAVID NIELD

We already know that our brains have a waste disposal system that keeps dead and toxic neurons from clogging up our biological pathways. Now, scientists have managed to capture a video of the process for the first time, in laboratory tests on mice.

There’s still a lot we don’t know about how dead neurons are cleared out, and how the brain reacts to them, so the new research could be a significant step forward in figuring some of that out – even if we’ve not yet confirmed that human brains work in the exact same way.

“This is the first time the process has ever been seen in a live mammalian brain,” says neurologist Jaime Grutzendler from the Yale School of Medicine in Connecticut.

Further down the line, these findings might even inform treatments for age-related brain decline and neurological disorders – once we know more about how brain clean-up is supposed to work, scientists can better diagnose what happens when something goes wrong.

The team focussed in on the glial cells responsible for doing the clean-up work in the brain; they used a technique called 2Phatal to target a single brain cell for apoptosis (cell death) in a mouse and then followed the route of glial cells using fluorescent markers.

“Rather than hitting the brain with a hammer and causing thousands of deaths, inducing a single cell to die allows us to study what is happening right after the cells start to die and watch the many other cells involved,” says Grutzendler.

“This was not possible before. We are able to show with great clarity what exactly is going on and understand the process.”

Three types of glial cells – microglia, astrocytes, and NG2 cells – were shown to be involved in a highly coordinated cell removal process, which removed both the dead neuron and any connecting pathways to the rest of the brain. The researchers observed one microglia engulf the neuron body and its main branches (dendrites), while astrocytes targeted smaller connecting dendrites for removal. They suspect NG2 may help prevent the dead cell debris from spreading.

The researchers also demonstrated that if one type of glial cell missed the dead neuron for whatever reason, other types of cells would take over their role in the waste removal process – suggesting some sort of communication is occurring between the glial cells.

Another interesting finding from the research was that older mouse brains were less efficient at clearing out dead neural cells, even though the garbage removal cells seemed to be just as aware that a dying cell was there.

This is a good opportunity for future research, and could give experts insight into how older brains start to fail in various ways, as the garbage disposal service starts to slow down or even breaks.

New treatments might one day be developed that can take over this clearing process on the brain’s behalf – not just in elderly people, but also those who have suffered trauma to the head, for example.

“Cell death is very common in diseases of the brain,” says neurologist Eyiyemisi Damisah, from the Yale School of Medicine.

“Understanding the process might yield insights on how to address cell death in an injured brain from head trauma to stroke and other conditions.”

The research has been published in Science Advances.

https://www.sciencealert.com/for-the-first-time-scientists-capture-video-of-brains-clearing-out-dead-neurons


Microscopy image of a section through one brain hemisphere of a 101 day- old ARHGAP11B-transgenic marmoset fetus. Cell nuclei are visualized by DAPI (white). Arrows indicate a sulcus and a gyrus. Credit: Heide et al. / MPI-CBG

The expansion of the human brain during evolution, specifically of the neocortex, is linked to cognitive abilities such as reasoning and language. A certain gene called ARHGAP11B that is only found in humans triggers brain stem cells to form more stem cells, a prerequisite for a bigger brain. Past studies have shown that ARHGAP11B, when expressed in mice and ferrets to unphysiologically high levels, causes an expanded neocortex, but its relevance for primate evolution has been unclear.

Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, together with colleagues at the Central Institute for Experimental Animals (CIEA) in Kawasaki and the Keio University in Tokyo, both located in Japan, now show that this human-specific gene, when expressed to physiological levels, causes an enlarged neocortex in the common marmoset, a New World monkey. This suggests that the ARHGAP11B gene may have caused neocortex expansion during human evolution. The researchers published their findings in the journal Science.

The human neocortex, the evolutionarily youngest part of the cerebral cortex, is about three times bigger than that of the closest human relatives, chimpanzees, and its folding into wrinkles increased during evolution to fit inside the restricted space of the skull. A key question for scientists is how the human neocortex became so big. In a 2015 study, the research group of Wieland Huttner, a founding director of the MPI-CBG, found that under the influence of the human-specific gene ARHGAP11B, mouse embryos produced many more neural progenitor cells and could even undergo folding of their normally unfolded neocortex. The results suggested that the gene ARHGAP11B plays a key role in the evolutionary expansion of the human neocortex.

The rise of the human-specific gene

The human-specific gene ARHGAP11B arose through a partial duplication of the ubiquitous gene ARHGAP11A approximately five million years ago along the evolutionary lineage leading to Neanderthals, Denisovans, and present-day humans, and after this lineage had segregated from that leading to the chimpanzee. In a follow-up study in 2016, the research group of Wieland Huttner uncovered a surprising reason why the ARHGAP11B protein contains a sequence of 47 amino acids that is human-specific, not found in the ARHGAP11A protein, and essential for ARHGAP11B’s ability to increase brain stem cells.

Specifically, a single C-to-G base substitution found in the ARHGAP11B gene leads to the loss of 55 nucleotides from the ARHGAP11B messenger RNA, which causes a shift in the reading frame resulting in the human-specific, functionally critical 47 amino acid sequence. This base substitution probably happened much later than when this gene arose about 5 million years ago, anytime between 1.5 million and 500,000 years ago. Such point mutations are not rare, but in the case of ARHGAP11B its advantages of forming a bigger brain seem to have immediately influenced human evolution.


Wildtype (normal) and ARHGAP11B-transgenic fetal (101 days) marmoset brains. Yellow lines, boundaries of cerebral cortex; white lines, developing cerebellum; arrowheads, folds. Scale bars, 1 mm. Credit: Heide et al. / MPI-CBG

The gene’s effect in monkeys

However, it has been unclear until now if the human-specific gene ARHGAP11B would also cause an enlarged neocortex in non-human primates. To investigate this, the researchers in the group of Wieland Huttner teamed up with Erika Sasaki at the Central Institute for Experimental Animals (CIEA) in Kawasaki and Hideyuki Okano at the Keio University in Tokyo, both located in Japan, who had pioneered the development of a technology to generate transgenic non-human primates. The first author of the study, postdoc Michael Heide, traveled to Japan to work with the colleagues directly on-site.

They generated transgenic common marmosets, a New World monkey, that expressed the human-specific gene ARHGAP11B, which they normally do not have, in the developing neocortex. Japan has similarly high ethical standards and regulations regarding animal research and animal welfare as Germany does. The brains of 101-day-old common marmoset fetuses (50 days before the normal birth date) were obtained in Japan and exported to the MPI-CBG in Dresden for detailed analysis.

Michael Heide explains: “We found indeed that the neocortex of the common marmoset brain was enlarged and the brain surface folded. Its cortical plate was also thicker than normal. Furthermore, we could see increased numbers of basal radial glia progenitors in the outer subventricular zone and increased numbers of upper-layer neurons, the neuron type that increases in primate evolution.” The researchers had now functional evidence that ARHGAP11B causes an expansion of the primate neocortex.

Ethical consideration

Wieland Huttner, who led the study, adds: “We confined our analyses to marmoset fetuses, because we anticipated that the expression of this human-specific gene would affect the neocortex development in the marmoset. In light of potential unforeseeable consequences with regard to postnatal brain function, we considered it a prerequisite—and mandatory from an ethical point of view—to first determine the effects of ARHGAP11B on the development of fetal marmoset neocortex.”

The researchers conclude that these results suggest that the human-specific ARHGAP11B gene may have caused neocortex expansion in the course of human evolution.

More information: “Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset” Science (2020). science.sciencemag.org/cgi/doi … 1126/science.abb2401

https://medicalxpress.com/news/2020-06-human-brain-size-gene-triggers.html

by Ruth Williams

By activating a particular pattern of nerve endings in the brain’s olfactory bulb, researchers can make mice smell a non-existent odor, according to a paper published June 18 in Science. Manipulating these activity patterns reveals which aspects are important for odor recognition.

“This study is a beautiful example of the use of synthetic stimuli . . . to probe the workings of the brain in a way that is just not possible currently with natural stimuli,” neuroscientist Venkatesh Murthy of Harvard University who was not involved with the study writes in an email to The Scientist.

A fundamental goal of neuroscience is to understand how a stimulus—a sight, sound, taste, touch, or smell—is interpreted, or perceived, by the brain. While a large number of studies have shown the various ways in which such stimuli activate brain cells, very little is understood about what these activations actually contribute to perception.

In the case of smell, for example, it is well-known that odorous molecules traveling up the nose bind to receptors on cells that then transmit signals along their axons to bundles of nerve endings—glomeruli—in a brain area called the olfactory bulb. A single molecule can cause a whole array of different glomeruli to fire in quick succession, explains neurobiologist Kevin Franks of Duke University who also did not participate in the research. And because these activity patterns “have many different spatial and temporal features,” he says, “it is difficult to know which of those features is actually most relevant [for perception].”

To find out, neuroscientist Dmitry Rinberg of New York University and colleagues bypassed the nose entirely. “The clever part of their approach is to gain direct control of these neurons with light, rather than by sending odors up the animal’s nose,” Caltech neurobiologist Markus Meister, who was not involved in the work, writes in an email to The Scientist.

The team used mice genetically engineered to produce light-sensitive ion channels in their olfactory bulb cells. They then used precisely focused lasers to activate a specific pattern of glomeruli in the region of the bulb closest to the top of the animal’s head, through a surgically implanted window in the skull. The mice were trained to associate this activation pattern with a reward—water, delivered via a lick-tube. The same mice did not associate random activation patterns with the reward, suggesting they had learned to distinguish the reward-associated pattern, or synthetic smell, from others.

Although the activation patterns were not based on any particular odors, they were designed to be as life-like as possible. For example, the glomeruli were activated one after the other within the space of 300 milliseconds from the time at which the mouse sniffed—detected by a sensor. “But, I’ll be honest with you, I have no idea if it stinks [or] it is pleasant” for the mouse, Rinberg says.

Once the mice were thoroughly trained, the team made methodical alterations to the activity pattern—changing the order in which the glomeruli were activated, switching out individual activation sites for alternatives, and changing the timing of the activation relative to the sniff. They tried “hundreds of different combinations,” Rinberg says. He likened it to altering the notes in a tune. “If you change the notes, or the timing of the notes, does the song remain the same?” he asks. That is, would the mice still be able to recognize the induced scent?

From these experiments, a general picture emerged: alterations to the earliest-activated regions caused the most significant impairment to the animal’s ability to recognize the scent. “What they showed is that, even though an odor will [induce] a very complex pattern of activity, really it is just the earliest inputs, the first few glomeruli that are activated that are really important for perception,” says Franks.

Rinberg says he thinks these early glomeruli most likely represent the receptors to which an odorant binds most strongly.

With these insights into the importance of glomeruli firing times for scent recognition, “the obvious next question,” says Franks, is to go deeper into the brain to where the olfactory bulb neurons project and ask, “ How does the cortex make sense of this?”

E. Chong et al., “Manipulating synthetic optogenetic odors reveals the coding logic of olfactory perception,” Science, 368:eaba2357, 2020.

https://www.the-scientist.com/news-opinion/researchers-make-mice-smell-odors-that-arent-really-there-67643?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_medium=email&_hsmi=89854591&_hsenc=p2ANqtz–BMhsu532UL56qwtB0yErPYlgoFTIZWsNouvTV9pnT1ikTw6CvyIPyun3rPGdciV29we7ugRVWYc1uuBDh5CN_F-0FzA&utm_content=89854591&utm_source=hs_email


Oleh Hornykiewicz in his Vienna office in 2009 He helped identify low dopamine levels as a cause of Parkinson’s disease, a finding that led to an effective treatment.

Oleh Hornykiewicz, a Polish-born pharmacologist whose breakthrough research on Parkinson’s disease has spared millions of patients the tremors and other physical impairments it can cause, died on May 27 in Vienna. He was 93.

His death was confirmed by his longtime colleague, Professor Stephen J. Kish of the University of Toronto, where Professor Hornykiewicz (pronounced whor-nee-KEE-eh-vitch) taught from 1967 until his retirement in 1992.

Professor Hornykiewicz was among several scientists who were considered instrumental in first identifying a deficiency of the neurotransmitter dopamine as a cause of Parkinson’s disease, and then in perfecting its treatment with L-dopa, an amino acid found in fava beans.

The Nobel laureate Dr. Arvid Carlsson and his colleagues had earlier shown that dopamine played a role in motor function. Drawing on that research, Professor Hornykiewicz and his assistant, Herbert Ehringer, discovered in 1960 that the brains of patients who had died of Parkinson’s had very low levels of dopamine.

He persuaded another one of his collaborators, the neurologist Walther Birkmayer, to inject Parkinson’s patients with L-dopa, the precursor of dopamine, which could cross the barrier between blood vessels and the brain and be converted into dopamine by enzymes in the body, thus replenishing those depleted levels. The treatment alleviated symptoms of the disease, and patients who had been bedridden started walking.

The initial results of this research were published in 1961 and presented at a meeting of the Medical Society of Vienna. The “L-dopa Miracle,” as it was called, inspired Dr. Oliver Sacks’s memoir “Awakenings” (1973) and the fictionalized movie of the same name in 1990.
As a therapy for Parkinson’s, L-dopa was further refined by other scientists, including George C. Cotzias and Melvin D. Yahr. But it was Professor Hornykiewicz, defying colleagues who had argued that post-mortem brain studies were worthless, who is credited with the critical breakthroughs.

His findings spurred the establishment of human brain tissue banks, research into dopamine and treatments of other diseases caused by low levels of neurotransmitters.

“Today, it is generally agreed that the initiation of the treatment of Parkinson’s disease with L-dopa represented one of the triumphs of pharmacology of our time,” Professor Hornykiewicz wrote in “The History of Neuroscience in Autobiography, Volume IV” (2004). “This provided, apart from the benefit to the patients, a stimulus for analogous studies of many other brain disorders, both neurological and psychiatric.”

He received several distinguished awards, including the Wolf Prize in Medicine in 1979 and the Ludwig Wittgenstein Prize of the Austrian Research Foundation in 1993.

In 2000, when Dr. Carlsson, of Sweden, and others were awarded the Nobel Prize in Physiology or Medicine for discovering dopamine and “allowing for the development of drugs for the disease,” as the Nobel committee wrote, more than 200 scientists signed a petition protesting that the prize had not also been awarded to Professor Hornykiewicz.

Oleh Hornykiewicz was born on Nov. 17, 1926, in the village of Sychow, near Lviv, in what was then southeastern Poland and is now western Ukraine. His was a fourth-generation family of Eastern Orthodox Catholic priests. His father, Theophil Hornykiewicz, ministered to the village’s several dozen parishioners and taught religion; his mother, Anna (Sas-Jaworsky) Hornykiewicz, managed the affairs of the village’s 300-year-old wooden church.

When the Soviet Union invaded in 1939, the family fled to Austria, his mother’s ancestral home, with whatever belongings they could carry. Oleh knew no German but learned it by reading Hitler’s “Mein Kampf,” which was readily available in Vienna. He suffered from tuberculosis and, when the war ended, decided to follow his eldest brother and become a doctor.

He received his medical degree from the University of Vienna in 1951 and began his academic and research career in its pharmacology department. He held a British Council Research Scholarship at the University of Oxford from 1956 to 1958. Beginning in 1967, he headed the psychopharmacology department at the Clarke Institute of Psychiatry in Toronto (now the Center for Addiction and Mental Health), where he established the Human Brain Laboratory in 1978.

He was named a full professor of pharmacology and psychiatry at the University of Toronto in 1973 and, in 1976, appointed to head the newly-founded Institute of Biochemical Pharmacology of the University of Vienna. He held both posts concurrently.

He is survived by his daughter, Maria Hentosz; three sons, Nicholas, Stephen and Joseph; six grandchildren; and one great-grandchild. His wife, Christina (Prus-Jablonowski) Hornykiewicz, had died.

“He was a pharmacologist, biochemist and neurologist who wanted to find out how the brain works and how dopamine was involved,” Professor Kish said. “And he wanted to be known also as a philosopher.”

Despite being snubbed by the Nobel committee, Professor Hornykiewicz was philosophical about what he had accomplished and the degree to which it had been credited.

“I am surprised to see that I have achieved everything I could have wished for,” he wrote in 2004. “The support and recognition I received for my work, I have accepted with gratitude, as a charming reminder to do more and better.”

Professor Kish, who heads the Human Brain Laboratory at the University of Toronto’s Centre for Addiction and Mental Health, said L-dopa, or Levodopa, as it is also called, is today “the mainstay treatment for Parkinson’s disease — no drug is more efficacious.”

“Hornykiewicz,” he added, “reminds us that before L-dopa, persons with Parkinson’s disease were bedridden, crowding chronic hospital wards, and the doctors were powerless to do anything. His discovery changed all that —- it was a miracle.”

Oleh Hornykiewicz, Who Discovered Parkinson’s Treatment, Dies at 93


S. Inami et al., “Environmental light is required for maintenance of long-term memory in Drosophila,” J Neurosci, 40:1427–39, 2020.

by Diana Kwon

As Earth rotates around its axis, the organisms that inhabit its surface are exposed to daily cycles of darkness and light. In animals, light has a powerful influence on sleep, hormone release, and metabolism. Work by Takaomi Sakai, a neuroscientist at Tokyo Metropolitan University, and his team suggests that light may also be crucial for forming and maintaining long-term memories.

The puzzle of how memories persist in the brain has long been of interest to Sakai. Researchers had previously demonstrated, in both rodents and flies, that the production of new proteins is necessary for maintaining long-term memories, but Sakai wondered how this process persisted over several days given cells’ molecular turnover. Maybe, he thought, an environmental stimulus, such as the light-dark cycles, periodically triggered protein production to enable memory formation and storage.

Sakai and his colleagues conducted a series of experiments to see how constant darkness would affect the ability of Drosophila melanogaster to form long-term memories. Male flies exposed to light after interacting with an unreceptive female showed reduced courtship behaviors toward new female mates several days later, indicating they had remembered the initial rejection. Flies kept in constant darkness, however, continued their attempts to copulate.

The team then probed the molecular mechanisms of these behaviors and discovered a pathway by which light activates cAMP response element-binding protein (CREB)—a transcription factor previously identified as important for forming long-term memories—within certain neurons found in the mushroom bodies, the memory center in fly brains.

“The fact that light is essential for long-term memory maintenance is fundamentally interesting,” says Seth Tomchick, a neuroscientist at the Scripps Research Institute in Florida who wasn’t involved in the study. However, he adds, “more work will be necessary” to fully characterize the molecular mechanisms underlying these effects.

https://www.the-scientist.com/the-literature/lasting-memories-67441?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_source=hs_email&utm_medium=email&utm_content=87927085&_hsenc=p2ANqtz-_7gIn7Nu8ghtWiBtiy6oqTctJuYb31bx6bzhbcV3gVpx0-YoIVNtAhnXXNJT0GC496PAntAiSvYpxLdVAnvITlfOG96g&_hsmi=87927085

Astronauts’ brains increase in volume after long space flights, causing pressure to build up inside their heads. This may explain why some astronauts experience worsened vision after prolonged periods in space.

“This raises additional concerns for long-duration interplanetary travel, such as the future mission to Mars,” says Larry Kramer at the University of Texas Health Science Center at Houston, who led the study.

Kramer and his colleagues scanned the brains of 11 astronauts before they spent about six months on the International Space Station, and at six points over the year after they returned to Earth. They found that all the astronauts had increased brain volume – including white matter, grey matter and cerebrospinal fluid around the brain – after returning from space.

Under normal gravity, it is thought that fluid in the brain naturally moves downwards when we stand upright. But there is evidence that microgravity prevents this, resulting in accumulation of fluid in the brain and skull.

The astronauts’ brain volume increased by 2 per cent on average and the increases were still present one year after they returned to Earth, which could result in higher intracranial pressure, Kramer says. He suspects this might press on the optic nerve, potentially explaining the vision problems frequently reported by astronauts.

Kramer and his team also observed that part of the brain called the pituitary gland was deformed in six out of the 11 astronauts. These results add to a body of evidence suggesting that brain structure can be altered after space flight.

“This study is important because it provides data, for the first time in NASA astronauts, demonstrating the persistence of structural brain changes even up to one year following return to Earth,” says Donna Roberts at the Medical University of South Carolina.

“We are currently working on methods to counteract the changes we are observing in the brain using artificial gravity,” says Kramer. These methods to pull blood back towards the feet could include a human-sized centrifuge that would spin a person around at high speed, or a vacuum chamber around the lower half of the body.

“Hopefully one of these or other methods will be tested in microgravity and show efficacy,” he says.

Journal reference: Radiology, DOI: 10.1148/radiol.2020191413

Read more: https://www.newscientist.com/article/2240405-long-space-flights-can-increase-the-volume-of-astronauts-brains/#ixzz6Jh5CtujT

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by Emma Yasinski

Researchers at RIKEN and the University of Tokyo report the existence of a new class of proteins in Drosophila and human cell extracts that may serve as shields that protect other proteins from becoming damaged and causing disease. An excess of the proteins, known as Hero proteins, was associated with a 30 percent increase in the lifespan of Drosophila, according to the study, which was published last week (March 12) in PLOS Biology.

“The discovery of Hero proteins has far-reaching implications,” says Caitlin Davis, a chemist at Yale University who was not involved in the study, “and should be considered both at a basic science level in biochemistry assays and for applications as a potential stabilizer in protein-based pharmaceuticals.”

Nearly 10 years ago, Shintaro Iwasaki, then a graduate student studying biochemistry at the University of Tokyo, discovered a strangely heat-resistant protein in Drosophila that seemed to help stabilize another protein, Argonaute, in the face of high temperatures that would denature most proteins. Although he didn’t publish the work at the time, Iwasaki called the new type of protein a Heat-resistant obscure (Hero) protein—not because of their ability to rescue Argonaute from destruction, but because in Japan, the term “hero” means “weak or not rigid,” and Hero proteins don’t have stiff 3-D structures like other proteins do.
But recognition of a more widespread role for Hero proteins in protecting other molecules in the cell gives the name new meaning.

“It is generally assumed that proteins are folded into three-dimensional structures, which determine their functions,” says Kotaro Tsuboyama, a biochemist at the University of Tokyo and the lead author of the new study. But these 3-D structures are disrupted when the proteins are exposed to extreme conditions. When proteins are denatured, they lose the ability to function normally, and sometimes begin to aggregate, forming pathologic clumps that can lead to disease.

Hero proteins can survive these biologically challenging conditions. Heat-resistant proteins have been found in extremophiles—organisms known to live in extreme environments—but were thought to be rare in other organisms. In the new study, Tsuboyama and his team boiled lysates from Drosophila and human cell lines, identifying hundreds of Hero proteins that withstood the temperature.

The researchers selected six of these proteins and mixed them with “client” proteins—other functional proteins that on their own would be denatured by extreme conditions—before exposing them to high temperatures, drying, chemicals, and other harsh treatments. The Hero proteins prevented certain clients from losing their shape and function.

Next, the team tested the effects of Hero proteins in cellular models of two neurodegenerative disorders characterized by pathologic protein clumps: Huntington’s disease and amyotrophic lateral sclerosis (ALS). When the Hero proteins were present, there was a significant reduction in protein clumping in both models.

“This is an extremely important finding as it may pave new therapeutic and preventive strategies for neurodegenerative diseases, such as Alzheimer and Parkinson diseases,” Morteza Mahmoudi, who studies regenerative medicine at Michigan State University and was not involved in the research, writes in an email to The Scientist.

Lastly, the team genetically engineered Drosophila to produce an excess of Hero proteins. These flies lived up to 30 percent longer than their wildtype counterparts.

Not everyone is convinced that the Hero proteins play a major protective role. “Although they show these proteins help their proven targets remain folded/shielded etc, I don’t think there’s a broader application at all,” Nihal Korkmaz, who designs proteins at the University of Washington Institute of Protein Design and also did not participate in the study, tells The Scientist in an email. She adds that many proteins she works with can withstand high temperatures and the researchers “don’t mention at all if [Hero proteins] are found throughout the brain or in CSF [cerebrospinal fluid],” where they’d be able to protect against Huntington’s or ALS.

The authors emphasized that there is a lot left to learn about the proteins. Each Hero protein seems able to protect some client proteins, but not all of them. Moreover, amino acid sequences differ considerably between Hero proteins, making it difficult to predict their functions. The researchers write in the study that they hope future studies will help them identify which clients each Hero might work with.

Whatever discoveries future work might hold, Tsuboyama says, the scientific community’s reaction to the team’s new study has been consistent: “Almost everyone says that Hero proteins are interesting but mysterious.”

K. Tsuboyama et al., “A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation,” PLOS Biol, doi:10.1371/journal.pbio.3000632, 2020.

https://www.the-scientist.com/news-opinion/hero-proteins-may-shield-other-proteins-from-harm-67293?utm_campaign=TS_OTC_2020&utm_source=hs_email&utm_medium=email&utm_content=86341663&_hsenc=p2ANqtz–kkYtO3Wn5lK7HmDq3SWf1KLtul94Crlb2ELPzvFBQWGep0tFzWAy3UdVi_w7ml_E1bn1g9HU_2SVNp–jib-1JCCU_w&_hsmi=86341663


A patient is moved out of Gateway Care and Rehabilitation Center, a skilled nursing facility in Hayward, Calif., on Thursday.

People with severe COVID-19 may experience neurological symptoms, including confusion, delirium and muscle pain, and could be at higher risk for a stroke, a new study out of Wuhan, China has suggested.

Nearly 40 percent of people with the disease caused by the new coronavirus suffered brain-related complications, according to findings published Friday in JAMA Neurology.

Among those with serious infection as a result of the virus, nearly 6 percent experienced a stroke or stenosis, roughly 15 percent had dementia-like symptoms and roughly 20 percent reported severe muscle pain, researchers in China reported.

“This study indicates that neurological complications are relatively common in people who have COVID-19,” S. Andrew Josephson, professor and chair of the Department of Neurology at the University of California, San Francisco and editor-in-chief of JAMA Neurology, told UPI. Josephson also co-authored a related commentary on the study findings.

“However, the majority of those complications are are also relatively common in people with severe pneumonia and viral infections in hospital intensive care units,” he added.

That includes symptoms such as muscle pain and “confusion or difficulty thinking,” according to Josephson, although he emphasizes that if these neurological issues develop in people who know they have COVID-19 — or have symptoms of the disease and are among those at high risk for serious illness — they should be considered a “red flag like shortness of breath,” he said.

“Somebody who has COVID-19 and is at home and experiences difficulty thinking or confusion or anything that indicates a possible stroke, that is a sign they should come into the hospital for additional care,” Josephson continued. “But a symptom like muscle pain is common in viral infections. People don’t need to come into hospital with that.”

To date, nearly 1.7 million people worldwide have been infected with COVID-19, and nearly 100,000 have died from the disease. Although numbers vary by country and region, it is believed that approximately 20 percent of people infected by the new coronavirus become ill enough to require hospital care, and roughly 5 percent experience life-threatening symptoms, including pneumonia.

Those at highest risk for serious illness are believed to be the elderly, as are people with a history of diabetes, high blood pressure and heart disease. Of course these same people are also at increased risk for cerebrovascular diseases like stroke and stenosis, Josephson noted.

The new study looked at 214 patients with the disease at three Wuhan hospitals, all of whom were hospitalized between Jan. 16 and Feb. 19.

Of the 214 patients, who had mean age of 53, 87 were men and 126, or 59 percent, had severe infection based on respiratory status — with shortness of breath caused by a severe lower respiratory tract infection, like pneumonia.

As in prior studies, those with serious illness were older, had more underlying conditions — particularly high blood pressure — and had fewer typical symptoms of COVID-19, like fever and cough, when compared to patients with mild to moderate infection.

Additionally, 6 percent of patients experienced “taste impairment” and 5 percent had “smell impairment.” What causes people with the virus to experience these neurological complications remains unclear, according to Josephson. Because of the known heart-related complications associated with the virus, it’s possible they are the result of blood clots emanating from the heart, he added.

“As with all of the research coming out about the virus, this study shows we still have a lot more to learn,” Josephson said. “The bottom line is that people should be aware of these neurological symptoms, and seek medical attention if they need it.”

https://www.upi.com/Health_News/2020/04/10/40-of-people-with-severe-COVID-19-experience-neurological-complications/2491586526495/?ur3=1