Enzyme SSH1 Impairs Disposal Of Accumulating Cellular Garbage, Leading To Brain Cell Death (Medicine)

In a healthy brain, the multistep waste clearance process known as autophagy routinely removes and degrades damaged cell components – including malformed proteins like tau and toxic mitochondria. This cellular debris would otherwise pile up like uncollected trash to drive the death of brain cells (neurons), ultimately destroying cognitive abilities like thinking, remembering and reasoning in patients with Alzheimer’s and certain other neurodegenerative diseases.

David Kang, PhD, professor of molecular medicine at the University of South Florida Health (USF Health) Byrd Alzheimer’s Center, led the research team that discovered a defect early in the dynamic cellular waste clearance process known as autophagy. © USF Health

The protein p62, a selective autophagy cargo receptor, plays a major role in clearing misfolded tau proteins and dysfunctional mitochondria, the energy powerhouse in all cells including neurons. Through autophagy (meaning “self-eating” in Greek) old or broken cellular material is ultimately digested and recycled in lysosomes, membrane-bound structures that work like mini-waste management plants.

Now, neuroscientists at the University of South Florida Health (USF Health) Byrd Alzheimer’s Center report for the first time that the protein phosphatase Slingshot-1, or SSH1 for short, disrupts p62’s ability to function as an efficient “garbage collector” and thereby impairs the disposal of both damaged tau and mitochondria leaking toxins. In a preclinical study, the researchers showed that SSH1’s influence in halting p62-mediated protective clearance of tau was separate from SSH1’s role in activating cofilin, an enzyme that plays an essential part in worsening tau pathology.

Their findings were published Oct. 12 in Autophagy.

“Slingshot-1 is an important player in regulating the levels of tau and neurotoxic mitochondria, so it’s important to understand exactly what’s going wrong when they accumulate in the brain,” said the paper’s senior author David Kang, PhD, professor of molecular medicine at the USF Health Morsani College of Medicine, who holds the Fleming Endowed Chair in Alzheimer’s Disease and serves as the director of basic research at the Byrd Alzheimer’s Center. “This study provides more insight into a defect stemming from the p62 pathway, which will help us develop SSH1 inhibitors (drugs) to stop or slow Alzheimer’s disease and related neurodegenerative disorders.”

At the start of their study, Dr. Kang’s team, including first author and doctoral student Cenxiao (Catherine) Fang, MD, already knew that, in the case of clearing bad mitochondria (known as mitophagy), the enzyme TBK1 transiently adds phosphate to p62. Phosphate is specifically added at the site of amino acid 403 (SER403), which activates p62. However, no scientist had yet discovered what enzyme removes phosphate from p62, known as dephosphorylation.

Cenxiao (Catherine) Fang, MD, PhD, was the paper’s lead author. © USF Health

Tightly controlled phosphorylation is needed to strike a balance in p62 activation, an early step key in priming the cargo receptor’s ability to recognize and collect chunks of cellular waste labelled as “garbage” by a ubiquitin tag. Put simply, when autophagy works well, ubiquitinated tau and ubiquitinated mitochondria are selectively targeted for collection and then delivered for destruction and recycling by autophagosomes (the garbage trucks in this dynamic process). But, garbage collector p62 doesn’t touch the cell’s healthy (untagged) proteins and organelles.

In a series of gene deactivation and overexpression experiments using human cell lines, primary neurons, and a mouse model of tauopathy, Dr. Kang’s team discovered SSH1, acting specifically on SER403, as the first enzyme to remove this key phosphate off p62, causing p62 deactivation.

“When something shifts out of balance, like overactivation of Slingshot-1 by Alzheimer’s-related protein Aβ for example, then SSH1 starts to remove the phosphate off the garbage collector p62, essentially relaying the message ‘stop, don’t do your job.’ That leads to bad consequences like accumulation of damaged tau proteins and toxic mitochondria,” Dr. Kang said.

“If we can bring phosphorylation regulation back into balance through inhibitors that dampen overactive Slingshot-1, we can increase p62’s normal activity in removing the toxic garbage.”

This latest study builds upon previous USF Health research showing that Aβ-activated cofilin, which occurs through SSH1, essentially kicks tau from the microtubules providing structural support to neurons, thereby boosting the build-up of tau tangles inside dying nerve cells. In the displacement process, cofilin gets transported to mitochondria and damage to the energy-producing mitochondria ensues. Following up on that collateral cofilin-triggered damage, Dr. Kang’s team expected to find widespread mitophagy to remove the sick mitochondria.

“We got exactly the opposite result, which meant there was another mechanism affecting how Slingshot-1 regulated mitochondria,” Dr. Kang said, “and it turned out to encompass the key autophagy machinery of p62.”

The researchers also showed that two major and entirely separate signaling pathways implicated in tau pathology – one for p62 and another for cofilin – are regulated by the same enzyme, SSH1.

“In addition to the SSH1-cofilin activation pathway in promoting tau displacement from microtubules, this study highlights the divergent SSH1-p62 inhibitory pathway in impairing autophagic clearance of misfolded tau,” the study authors report.

References: Cenxiao Fang , Jung-A A. Woo , Tian Liu , Xingyu Zhao , Sara Cazzaro , Yan Yan, et al., “SSH1 impedes SQSTM1/p62 flux and MAPT/Tau clearance independent of CFL (cofilin) activation”, Journal Autophagy, 2020. https://doi.org/10.1080/15548627.2020.1816663

Provided by University Of South Florida

Scientists Report Role For Dopamine And Serotonin In Human Perception And Decision-Making (Medicine)

Scientists at Wake Forest School of Medicine have recorded real time changes in dopamine and serotonin levels in the human brain that are involved with perception and decision-making. These same neurochemicals also are critical to movement disorders and psychiatric conditions, including substance abuse and depression.

Their findings are published in the Oct. 12 edition of the journal Neuron.

“This study provides us a unique window into the human brain that has been inaccessible until now,” said principal investigator Kenneth T. Kishida, Ph.D., assistant professor of physiology and pharmacology and neurosurgery at Wake Forest School of Medicine, part of Wake Forest Baptist Health. “Almost everything we have known mechanistically about these neurochemicals was from work done in preclinical animal models, not from direct evidence from humans.”

Having a clearer understanding of how these brain chemicals actually work in people may lead to improved medications or treatments for disorders like Parkinson’s disease, substance use disorder or depression, Kishida said.

In this observational study, the neurotransmitters dopamine and serotonin were tracked in five patients using fast scan cyclic voltammetry, an electrochemical technique used to measure dopamine and serotonin, adapted for use in patients. Dopamine and serotonin are chemical messengers used by the nervous system to regulate countless functions and processes in the body.

Study participants – two with Parkinson’s and three with essential tremor – were patients at Wake Forest Baptist who were scheduled to receive a deep brain stimulating implant to treat their condition. Working closely with neurosurgeons, Stephen B. Tatter, M.D., and Adrian W. Laxton, M.D., Kishida’s team was able to piggyback on the standard surgical mapping process to insert a carbon fiber microelectrode deep into the brain to detect and record serotonin and dopamine released from neurons. The patients with essential tremor were important to the study because, unlike Parkinson’s disease which is caused by loss of dopamine-producing neurons, essential tremor is not believed to be caused by changes in dopamine or serotonin function.

While the patients were awake in the operating room, they performed decision-making tasks similar to playing a simple computer game. As they performed the tasks, measurements of dopamine and serotonin were taken in the striatum, the part of the brain that controls cognition, reward and coordinated movements.

Kishida described the game as a series of dots on a computer screen that moved through a “cross-hair” reference point positioned in the center of the screen. Patients had to decide which way the dots were moving. Sometimes the dots would move in the same direction and at other times the dots would move more chaotically making the decision harder.

The dots then disappeared and the patient had to choose which way the dots had moved – clockwise or counter clockwise – relative to a fixed point. This experimental design, created by Kishida’s collaborators and co-authors Dan Bang and Stephen M. Fleming, at University College London, allowed the team to tease apart different aspects of how the human brain decides what it has perceived.

This sequence was repeated 200 to 300 times per patient, varying how the dots moved and thus how difficult it was for the patient to decide what they saw. Occasionally, the patients had to indicate how confident they were in their choices.

The test was designed to track the patient’s ability to perceive the dots’ movement and the patient’s confidence in correctly identifying the direction of that movement as a way to determine how dopamine and serotonin actually behaved. The trials were randomized so that predictability from one test trial to the next would be minimized, Kishida said.

The findings showed that the more uncertain the patient was about the direction of the dots, the higher the serotonin levels became. When their certainty increased, serotonin levels decreased.

The study also revealed that, prior to the act of choosing, dopamine rose in anticipation of the choice and serotonin levels fell, and when both reached a certain level, the person made their choice. It’s as if dopamine acted like a gas pedal and serotonin acted like a brake and only when both systems were committed was the act of choice (a button press) allowed, Kishida said.

“This study sheds light on the role these neurochemicals play in learning, brain plasticity and how we perceive the environment,” Kishida said. “We now have more detailed insight into how our brains build what we perceive, use those perceptions to make decisions, and interpret the consequences of the choices we make. Dopamine and serotonin appear to be critical in all of these processes.

“Importantly, studies like this will help us and other scientists develop a better understanding of how drugs or medications like serotonin reuptake inhibitors affect cognition, decision-making, and impact psychiatric conditions like depression.”

Provided by Wake Forest Baptist Medical Center

Single Gene Disorders Not So Simple After All (Neuroscience)

Traditionally, geneticists divide disorders into “simple,” where a single gene mutation causes disease, or complex, where mutations in many genes contribute modest amounts. A new study suggests that the truth is somewhere in between.

For many years, scientists studying patient genomes have gained glimpses of genetic “burden” or additional genetic variation that contributes to the effect of disease-causing mutations and makes them more (or less) potent. In principle, this phenomenon can help explain why some people are severely affected by disease and some are not. However, the notion of genetic burden has been controversial, in large part because it has been harrowingly difficult to detect and understand its properties.

Now, scientists from the Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago have used a conglomerate of genetic and functional approaches to demonstrate the existence of burden in diseases thought to be caused by a single gene.

Published in Nature Genetics, their study focused on several hundred patients with Bardet-Biedl syndrome (BBS), a rare disorder affecting cognitive function, vision, renal function and body weight regulation. Critically, all of these patients had already been diagnosed genetically with BBS, in that they carried mutations in one of the 25 genes known for this disorder. In simple terms, their genetic diagnosis was finished, and they were considered “solved.” However, when the authors analyzed these patients for all known BBS genes, they found that they carried three times as many additional mutations in a pattern more reminiscent of the genetic architecture of complex traits, such as Alzheimer disease or type II diabetes. Moreover, the distribution pattern of these mutations was not random, but clustered around specific subsets of genes that encode two different protein complexes. These observations intimate that the effect of these additional genetic mutations was driven not only by their number, but also their position in a “disease network.”

The study also has implications about the types of genetics data can be returned to patients in the clinical setting.

“It is imperative that we broaden our search for answers beyond the single causal gene,” says senior author Nico Katsanis, PhD, Director of the Advanced Center for Translational and Genetic Medicine at the Manne Research Institute at Lurie Children’s. Dr. Katsanis also is Professor of Pediatrics and Cell and Molecular Biology at Northwestern University Feinberg School of Medicine. “We have always known that disease causality was not binary, but a continuum, but we lacked the proof and the tools to detect it. To me, this is not too different from the development of tools that increased the magnification of telescopes. Now we can see deeper, better, and start making predictions about diseases: why they happen, why the progress the way they do. The work also gives us multiple potential entry points for therapies: some disease-causing genes are difficult to target–but their neighbors might be amenable.”

Looking forward, the research team is currently applying these concepts to a host of other related disorders, paying close attention to network mutations that both exacerbate disease severity but also attenuate. “It has taken us 20 years to get here,” says Dr. Katsanis. “Now, I feel we have a new depth of resolution to understand the problem better.”

Provided by ANN & ROBERT H. LURIE CHILDREN’S HOSPITAL OF CHICAGO

The Making Of Memory B Cells And Long-Term Immune Responses (Biology)

Only B cells that express Bach2 and reduced mTORC1 activity can become memory B cells, the body’s first responder to re-infections.

The current COVID-19 climate has made vaccines, antibodies, and immune responses topics of everyday conversation. Now, it isn’t just immunologists who want to know how our bodies respond to re-infections months, years, or sometimes decades after an initial immune response. A new study by Tomohiro Kurosaki at Osaka University shows that this ability requires Bach2, a protein that regulates the expression of genes needed to instruct activated B cells under selection to become memory B cells.

B cell differentiation in GC. ©Osaka University

Like most biological processes, immune responses are complicated. They involve numerous types of cells and proteins, performing precise step-by-step processes. And of course, we don’t know all of them yet. For example, memory B cells are a type of white blood cell that are created in lymph nodes or spleens during an infection. They stick around for years and allow rapid and strong antibody-related responses to re-infection by the same virus or bacteria. In contrast, plasma cells are much more numerous and help during an initial infection by producing antibodies, although they too can exist for long periods of time in the body. Kurosaki and his team focused their research on understanding what causes activated B cells, called germinal center B cells, to become memory B cells, plasma cells, or to be recycled.

Scientists can identify different types of B cells by markers–certain proteins–that they express. On the basis of specific markers, the researchers identified a subset of B cells that they determined were prone to become memory B cells, which they called pro-memory B cells. They then examined mice lacking the protein Bach2, a transcription factor required for memory B cell production. These mice are known to be deficient in producing memory B cells. The researchers found that the lack of Bach2 was associated with fewer pro-memory B cells and increased expression of genes related to a protein complex called mTORC1.

Further testing showed the importance of mTORC1. “We ultimately found that mTORC1 signaling was less active in pro-memory B cells than in those that ended up being recycled,” says Kurosaki. Inhibiting mTORC1 activity (in other words, inducing a state of mTORC1 hypometabolism) in the Bach2 knockout mice rescued them, allowing the mice to produce memory B cells. Additionally, in wild-type mice, artificially reducing mTORC1 activity in B cells led to the production of more memory B cells than normal, while increasing its activity had the opposite effect. However, mTORC1 activity alone could not explain everything. Experiments showed that the unique combination of Bach2 expression and reduced mTORC1 activity is necessary to become memory B cells.

Understanding the process through which memory B cells are produced means that this process can be manipulated for our benefit. “Given the importance of memory B cells in protecting us against re-infection, being able to induce their production could be helpful for developing efficient vaccines that remain effective for years,” says Kurosaki.

References: Takeshi Inoue, Ryo Shinnakasu, Chie Kawai, Wataru Ise, Eiryo Kawakami, Nicolas Sax, Toshihiko Oki, Toshio Kitamura, Kazuo Yamashita, Hidehiro Fukuyama, Tomohiro Kurosaki; Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal. J Exp Med 4 January 2021; 218 (1): e20200866. doi: https://doi.org/10.1084/jem.20200866

Provided by Osaka University

Computational Approach To Optimise Culture Conditions Required For Cell Therapy (Medicine)

Collaboration by researchers in Singapore and Australia lead to first-of-its-kind computational biology algorithm that could enable more effective cellular therapies against major diseases.

The scientists used EpiMogrify, an innovative computational biology algorithm, to predict molecules needed to control the cell state and fate of cardiac muscle cells (left) and astrocytes (right). ©Joseph Chen, Monash University

Cellular therapy is a powerful strategy to produce patient-specific, personalised cells to treat many diseases, including heart disease and neurological disorders. But a major challenge for cell therapy applications is keeping cells alive and well in the lab.

That may soon change as researchers at Duke-NUS Medical School, Singapore, and Monash University, Australia have devised an algorithm that can predict what molecules are needed to keep cells healthy in laboratory cultures. They developed a computational approach called EpiMogrify, that can predict the molecules needed to signal stem cells to change into specific tissue cells, which can help accelerate treatments that require growing patient cells in the lab.

“Computational biology is rapidly becoming a key enabler in cell therapy, providing a way to short-circuit otherwise expensive and time-consuming discovery approaches with cleverly designed algorithms,” said Assistant Professor Owen Rackham, a computational biologist at Duke-NUS, and a senior and corresponding author of the study, published today in the journal Cell Systems.

In the laboratory, cells are often grown and maintained in cell cultures, formed of a substance, called a medium, which contains nutrients and other molecules. It has been an ongoing challenge to identify the necessary molecules to maintain high-quality cells in culture, as well as finding molecules that can induce stem cells to convert to other cell types.

The research team developed a computer model called EpiMogrify that successfully identified molecules to add to cell culture media to maintain healthy nerve cells, called astrocytes, and heart cells, called cardiomyocytes. They also used their model to successfully predict molecules that trigger stem cells to turn into astrocytes and cardiomyocytes.

“Research at Duke-NUS is paving the road for cell therapies and regenerative medicine to enter the clinic in Singapore and worldwide; this study leverages our expertise in computational and systems biology to facilitate the good manufacturing practice (GMP) production of high-quality cells for these much needed therapeutic applications,” said Associate Professor Enrico Petretto, who leads the Systems Genetics group at Duke-NUS, and is a senior and corresponding author of the study.

The researchers added existing information into their model about genes tagged with epigenetic markers whose presence indicates that a gene is important for cell identity. The model then determines which of these genes actually code for proteins necessary for a cell’s identity. Additionally, the model incorporates data about proteins that bind to cell receptors to influence their activities. Together, this information is used by the computer model to predict specific proteins that will influence different cells’ identities.

“This approach facilitates the identification of the optimum cell culture conditions for converting cells and also for growing the high-quality cells required for cell therapy applications,” said ARC Future Fellow Professor Jose Polo, from Monash University’s Biomedicine Discovery Institute and the Australian Research Medicine Institute, who is also a senior and corresponding author of the study.

©Uma kamaraj et al.

The team compared cultures using protein molecules predicted by EpiMogrify to a type of commonly used cell culture that uses a large amount of unknown or undefined complex molecules and chemicals. They found the EpiMogrify-predicted cultures worked as well or even surpassed their effectiveness.

The researchers have filed for a patent on their computational approach and the cell culture factors it predicted for maintaining and controlling cell fate. EpiMogrify’s predicted molecules are available for other researchers to explore on a public database: http://epimogrify.ddnetbio.com.

“We aim to continue to develop tools and technologies that can enable cell therapies and bring them to the clinic as efficiently and safely as possible,” said Asst Prof Rack

“The developed technology can identify cell culture conditions required to manipulate cell fate and this facilitates growing important cells in chemically-defined cultures for cell therapy applications,” added Dr Uma S. Kamaraj, lead author of the study and a graduate of Duke-NUS’ Integrated Biology and Medicine PhD Programme.

References: Uma S. Kamaraj, Joseph Chen, Khairunnisa Katwadi, Jose M. Polo, Enrico Petretto, Owen J.L. Rackham, “EpiMogrify Models H3K4me3 Data to Identify Signaling Molecules that Improve Cell Fate Control and Maintenance”, Cell Biology, 2020. DOI: https://dx.doi.org/10.1016/j.cels.2020.09.004

Provided by Duke-NUS Medical School

This Is The Reason Behind Jet Formation At The Tip Of Laser Optical Fiber (Physics)

When an optical fiber is immersed in liquid, a high temperature, high speed jet is discharged. Researchers expect this to be applied to medical treatment in the future. Now, a research team from Russia and Japan has explored this phenomenon further and revealed the reasons behind the jet formation.

The schematics of the jet formation mechanism. ©Junnosuke Okajima, Tohoku University

Lasers using a thin optical fiber and combined with an endoscope and catheter can be easily transported into deep areas of the body or inside blood vessels. Traditionally, affected areas or lesions are removed by generating heat inside the tissue through laser absorption – a process known as the photothermal effect.

Yet, hydrodynamical phenomena, such as microbubble formation or high-speed jet generation from the optical fiber, show immense medical promise.

The process of jet formation happens when the laser is irradiated to the water, causing the water to boil and a vapor bubble to form at the tip of the optical fiber. The vapor bubble grows until the laser energy absorbed in the liquid is consumed. Because of the surrounding cold liquid, condensation suddenly shrinks the vapor bubble.

The observation of water jets in experiments. ©Junnosuke Okajima, Tohoku University

Using a numerical simulation, Dr. Junosuke Okajima from Tohoku University’s Institute of Fluid Science, along with his colleagues in Russia, set out to clarify the jet formation mechanism. Their simulation investigated the relationship between the bubble deformation and the induced flow field.

When the bubble shrinks, the flow toward the tip of the optical fiber is formed. The flow deforms the bubble into the cylindrical shape. This deformation induces the collision of flow in a radial direction. This collision generates the jet forward. As a result of collision and jet formation, the vortex is formed at the tip of the deformed bubble and it grows larger.

The numerical simulation results of bubble deformation at the tip of optical fiber and the induced flow field. ©Roman Fursenko

“We found the jet velocity depends on the relationship between the size of the vapor bubble just before the shrinking and the fiber radius,” said Okajima. “We will continue to develop this study and try to find the optimum condition which maximizes the jet velocity and temperature, making further laser surgical techniques more effective and safer.”

References: Roman V. Fursenko, Junnosuke Okajima et al., “Mechanism of high velocity jet formation after a gas bubble collapse near the micro fiber immersed in a liquid”, International Journal of Heat and Mass Transfer, Volume 163, December 2020, 120420, doi: https://dx.doi.org/10.1016/j.ijheatmasstransfer.2020.120420

Provided by Tohoku University

Skeletal Muscle Development And Regeneration Mechanisms Vary By Gender (Biology)

Researchers at Kumamoto University, Japan generated mice lacking the estrogen receptor beta (ERβ) gene, both fiber-specific and muscle stem cell-specific, which resulted in abnormalities in the growth and regeneration of skeletal muscle in female mice. This was not observed in male mice that lacked the ERβ gene, suggesting that estrogen and its downstream signals may be a female-specific mechanism for muscle growth and regeneration.

• ERβ controls muscle growth in young female mice
• ERβ is essential for muscle regeneration in female mice
• Inactivation of ERβ causes an increase in apoptosis
• ERβ is required for satellite cell population expansion. ©Associate Professor Yusuke Ono.

In humans, skeletal muscle mass generally peaks in the 20s with a gradual decline beginning in the 30s, but it is possible to maintain muscle mass through strength training and a healthy lifestyle. Skeletal muscle can be damaged through excessive exercise or bruising, but it has the ability to regenerate. The muscle stem cells that surround muscle fibers are essential for this regeneration; they also play a part in increasing muscle size (hypertrophy). Muscle stem cell dysfunction is thought to be associated with various muscle weakness, such as age-related sarcopenia and muscular dystrophy. Although basic research on skeletal muscle has progressed rapidly in recent years, most studies were conducted on male animals and gender differences were given much consideration.

Estrogen is a female hormone that maintains the homeostasis of various tissues and organs. A decrease in estrogen levels due to amenorrhea, menopause, or other factors can lead to a disturbance in biological homeostasis. When estrogen binds to estrogen receptors (ERs) in cells, it is transferred into the nucleus and binds to genomic DNA to induce the expression of specific genes as transcription factors. There are two types of ERs, ERα and ERβ. While both ERα and ERβ have high binding capacity to estrogen, their tissue distribution is different, they do not have a common DNA-binding domain, and they may act as antagonists to each other, suggesting that they have different roles. Furthermore, estrogen’s effects on cells can be both ER-mediated and non-ER-mediated.

Increased type I collagen-positive areas indicate fibrosis of muscle tissue. Fibrosis is seen only in female scKO mice.
Left: Muscle stem cells with stained type I collagen (red), laminin (green), and nuclei (blue).
Right: Relative comparison of type I collagen-positive areas. ©Associate Professor Yusuke Ono

An epidemiological study of pre and postmenopausal women in their 50s indicated an association between decreased blood estrogen levels and muscle weakness. A research group at Kumamoto University previously showed that estrogen is important for skeletal muscle development and regeneration using an ovariectomized estrogen deficiency mouse model (Kitajima and Ono, J Endocrinol 2016). They also examined the effectiveness of nutritional interventions in estrogen-deficient conditions (Kitajima et al., Nutrients 2017). However, whether estrogen acts directly on the ER of muscle fibers and muscle stem cells to regulate skeletal muscle growth and regeneration, or whether it acts indirectly through other tissues and organs was unclear. In this study, the researchers generated mice with either myofiber-specific or muscle stem cell-specific ERβ gene deletion and analyzed the function of ERβ in skeletal muscle.

To clarify the role of ERβ in the growth of skeletal muscle, researchers generated mice (mKO) in which the action of the ERβ gene could be turned off in myofibers with the administration of the drug doxycycline. ERβ deficiency was induced at 6 weeks of age, and muscle fiber area and strength of the tibialis anterior muscle was measured at 10-12 weeks. Compared to control mice, both indices were reduced in female mKO mice but not in male mice. Since there was no change in the expression of muscle atrophy-related genes, this reduced growth of female mice was not thought to be due to an increase in muscle atrophy. Ovariectomy-induced estrogen deficiency is known to be associated with muscle quality changes, such as a relative increase in the proportion of fast-type fibers (Kitajima and Ono, J Endocrinol 2016), but no such qualitative changes were observed in mKO mice. It was therefore suggested that, while it may have a direct effect on myofiber growth via ERβ (as expressed in myofibers), estrogen may also regulate the quality of myofibers in a non-ERβ-mediated manner.

(Top) Proliferation of muscle stem cells around an isolated and cultured single muscle fiber.
(Bottom) Increased cell death, decreased expression of Niche-related genes and increased expression of cellular senescence-related genes in scKO mice. ©Associate Professor Yusuke Ono

To determine the function of ERβ in muscle stem cells, the researchers generated scKO mice in which the ERβ gene could be deleted in muscle stem cells with the administration of the drug tamoxifen. They then evaluated muscle regenerative capacity by locally inducing muscle damage. While muscle regeneration was efficient in control mice, the regenerated muscle tissue of female scKO mice showed thin regenerated muscle fibers, fibrosis caused by collagen deposition, and significantly reduced muscle regenerative capacity. Muscle regeneration in male scKO mice, however, was not impaired. Because impaired muscle regeneration in females was not exacerbated by ovariectomies that made them estrogen deficient, the researchers thus thought that estrogen regulates muscle regeneration via ERβ expressed by muscle stem cells.

To further investigate the cause of reduced muscle regenerative capacity, researchers isolated and cultured muscle stem cells for evaluation. ERβ in cells from scKO mice was evaluated in several experiments using siRNAs and inhibitors. ERβ was found to contribute to the promotion of muscle stem cell proliferation and the inhibition of cell death. Gene expression analysis (RNA-seq) of scKO muscle stem cells showed that the expression of “niche”-related genes, which are required for the maintenance of stem cell properties, was reduced in scKO muscle stem cells. Therefore, the researchers hypothesize that the inactivation of ERβ may have affected the proliferation and survival of muscle stem cells by inhibiting the formation of stem cell niches.

This study is thought to be the first to show that ERβ in genetic mouse models plays an important role in the growth and regeneration of skeletal muscle through its function in both muscle fibers and muscle stem cells. However, the role of ERβ in male mice has not yet been elucidated and remains to be addressed even though its expression in both male and female mice is comparable.

“Amenorrhea is induced in female athletes through rigorous training or excessive dieting and has become one of three major problems, together with low energy availability and osteoporosis, faced by female athletes worldwide,” said study leader Associate Professor Yusuke Ono. “Although the animal findings of this study cannot be directly applied to humans, they do suggest that decreased estrogen during amenorrhea may suppress ERβ activity in muscle fibers and muscle stem cells. For female athletes, this may lead to poor athletic performance and delayed recovery from injuries, and puts them at risk for adverse competitive conditions. Our plan is to continue investigating the pathogenesis of age-related sarcopenia and muscular dystrophy by targeting ERβ and its downstream signals with the goal of developing treatments.”

References: Seko, D., Fujita, R., Kitajima, Y., Nakamura, K., Imai, Y., & Ono, Y. (2020). Estrogen Receptor β Controls Muscle Growth and Regeneration in Young Female Mice. Stem Cell Reports. doi: http://dx.doi.org/10.1016/j.stemcr.2020.07.017

Provided by Kumamoto University

Mass Loss Driven Shape Evolution Model Unveils Formation Of Flattened ‘Snowman’ (486958) Arrokoth (Astronomy)

The small Kuiper Belt object (486958) Arrokoth, encountered by NASA’s New Horizons spacecraft on Jan 1 2019, is so far the most distant and most primitive object ever explored by a spacecraft. The discoveries from the mission have provided detailed information on the object’s shape, geology, color and composition, which help people to reshape the knowledge and understanding of planetesimal origin and planet formation.

Mass loss driven shape evolution of Arrokoth analogues. ©ZHANG Xuan from PMO

The revealed shape of Arrokoth, which is bilobed with highly flattened lobes both aligned to its equatorial plane, is regarded to be the biggest surprise of the flyby. The contact binary is believed to be merged gently by two separate bodies that formed close together and at low velocity, orbited each other. On the other hand, how the flattened lobes formed is still under investigation.

An international research team led by Assoc. Prof. ZHAO Yuhui from the Purple Mountain Observatory (PMO) of the Chinese Academy of Sciences has built and applied a mass-loss-driven shape evolution model (MONET) and suggested that the current flattened shape of Arrokoth could be of evolutionary origin due to volatile outgassing in a timescale of about 1-100 Myr, which provides a natural explanation for the flattening shape of the body.

The study was published in Nature Astronomy on Oct. 5.

A Science publication led by Dr. Will Grundy from Lowell Observatory suggested an early sublimation history of Arrokoth. During the formation of the solar system, the region where Arrrokoth locates could have been a distinct environment in the cold, dust-shaded midplane of the outer nebula. The low temperatures enabled volatile such as CO and CH4 freeze onto dust grains and compose planetesimals. When the nebular dust cleared after Arrokoth’s formation, solar illumination would have raised its temperature and hence rapidly driven off the condensed CO and CH4.

Will the sublimation induced mass loss process change the shape of the body, and how?

The researchers from the PMO and Max Planck Institute for Solar System Research in Germany, started to investigate this topic in 2018, not specifically for (486958) Arrokoth, but for all the small icy bodies in our Solar System. It took three years to develop the numerical tools (MONET model), analyze the observational data from space missions, such as the Rosetta mission of ESA, and investigate how solar driven mass loss shape the global structure as well as local topography of small bodies.

Their research suggested that even weak solar driven mass loss rates play an important role in shape evolution of a small icy bodies when sustained over long periods, and the evolved shape highly depends on the configuration of the body’s orbit and spin states.

Starting from the merger of a spherical planetesimal and an oblate one, the flattening of Arrokoth’s shape is a natural outcome due to a favourable combination of its large obliquity, small eccentricity and mass-loss rate variation with solar flux, resulting in nearly symmetric erosion between north and south hemispheres.

Due to the orientation of Arrokoth, both polar regions experience continuous solar illumination during polar days (with strong mass loss), while the equatorial regions are dominated by diurnal variations year round. Therefore, the polar regions reach higher peak temperatures than the equator and experience more sublimation than the equatorial regions, and hence lead to the flattening.

The flattening process most likely occurred early in the evolution history of the body, and could proceed rather quickly, in a timescale of about 1-100 Myr, during the presence of super volatile ices in the near subsurface layers.

In addition, the researchers self-consistently demonstrated that the induced torques would play a negligible role in the planetestimal’s spin state change during the mass loss phase.

This study suggested that sublimation mass loss could be a ubiquitous process and dominant in shaping the structure of Kuiper Belt Objects (KBOs), granted that there were no catastrophic collision reshaping the body in their later history. Furthermore, while cold classical KBOs reserve their shape sculptured by early outgassing, the structure of Centaurs and Jupiter Family Comets (JFCs) would be further modified by the same scenario once they enter their current orbit configuration from the Kuiper Belt, under sublimation of different volatile species.

References: Zhao, Y., Rezac, L., Skorov, Y. et al. Sublimation as an effective mechanism for flattened lobes of (486958) Arrokoth. Nat Astron (2020). https://doi.org/10.1038/s41550-020-01218-7 link:

Provided by Chinese Academy Of Science is Hedquarters

Surface Waves Can Help Nanostructured Devices Keep Their Cool (Physics)

The continuing progress in miniaturization of silicon microelectronic and photonic devices is causing cooling of the device structures to become increasingly challenging. Conventional heat transport in bulk materials is dominated by acoustic phonons, which are quasiparticles that represent the material’s lattice vibrations, similar to the way that photons represent light waves. Unfortunately, this type of cooling is reaching its limits in these tiny structures.

A research team led by the Institute of Industrial Science, the University of Tokyo finds that hybrid surface waves called surface phonon-polaritons can conduct heat away from nanoscale material structures. ©Institute of Industrial Science, the University of Tokyo

However, surface effects become dominant as the materials in nanostructured devices become thinner, which means that surface waves may provide the thermal transport solution required. Surface phonon-polaritons (SPhPs) – hybrid waves composed of surface electromagnetic waves and optical phonons that propagate along the surfaces of dielectric membranes – have shown particular promise, and a team led by researchers from the Institute of Industrial Science, the University of Tokyo has now demonstrated and verified the thermal conductivity enhancements provided by these waves.

“We generated SPhPs on silicon nitride membranes with various thicknesses and measured the thermal conductivities of these membranes over wide temperature ranges,” says lead author of the study Yunhui Wu. “This allowed us to establish the specific contributions of the SPhPs to the improved thermal conductivity observed in the thinner membranes.”

The team observed that the thermal conductivity of membranes with thicknesses of 50 nm or less actually doubled when the temperature increased from 300 K to 800 K (approximately 27°C to 527°C). In contrast, the conductivity of a 200-nm-thick membrane decreased over the same temperature range because the acoustic phonons still dominated at that thickness.

“Measurements showed that the dielectric function of silicon nitride did not change greatly over the experimental temperature range, which meant that the observed thermal enhancements could be attributed to the action of the SPhPs,” explains the Institute of Industrial Science’s Masahiro Nomura, senior author of the study. “The SPhP propagation length along the membrane interface increases when the membrane thickness decreases, which allows SPhPs to conduct much more thermal energy than acoustic phonons when using these very thin membranes.”

The new cooling channel provided by the SPhPs can thus compensate for the reduced phonon thermal conductivity that occurs in nanostructured materials. SPhPs are thus expected to find applications in thermal management of silicon-based microelectronic and photonic devices.

References: Y. Wu, J. Ordonez-Miranda, S. Gluchko, R. Anufriev, D. De Sousa Meneses, L. Del Campo, S. Volz, M. Nomura, “Enhanced thermal conduction by surface phonon-polaritons”, Science Advances 30 Sep 2020:, Vol. 6, no. 40, eabb4461 DOI: 10.1126/sciadv.abb4461

Provided by Institute of Industrial Sciences, University Of Tokyo