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Blocking immune system pathway may stop COVID-19 infection, prevent severe organ damage

Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health While the world waits eagerly for a safe…

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Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

While the world waits eagerly for a safe and effective vaccine to prevent infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus behind the COVID-19 pandemic, researchers also are focusing on better understanding how SARS-CoV-2 attacks the body in the search for other means of stopping its devastating impact. The key to one possibility — blocking a protein that enables the virus to turn the immune system against healthy cells — has been identified in a recent study by a team of Johns Hopkins Medicine researchers.

Based on their findings, the researchers believe that inhibiting the protein, known as factor D, also will curtail the potentially deadly inflammatory reactions that many patients have to the virus.

Making the discovery even more exciting is that there may already be drugs in development and testing for other diseases that can do the required blocking.

The study is published in the Sept. 2, 2020, issue of the journal Blood.

Scientists already know that spike proteins on the surface of the SARS-CoV-2 virus — making the pathogen look like the spiny ball from a medieval mace — are the means by which it attaches to cells targeted for infection. To do this, the spikes first grab hold of heparan sulfate, a large, complex sugar molecule found on the surface of cells in the lungs, blood vessels and smooth muscle making up most organs. Facilitated by its initial binding with heparan sulfate, SARS-CoV-2 then uses another cell-surface component, the protein known as angiotensin-converting enzyme 2 (ACE2), as its doorway into the attacked cell.

The Johns Hopkins Medicine team discovered that when SARS-CoV-2 ties up heparan sulfate, it prevents factor H from using the sugar molecule to bind with cells. Factor H’s normal function is to regulate the chemical signals that trigger inflammation and keep the immune system from harming healthy cells. Without this protection, cells in the lungs, heart, kidneys and other organs can be destroyed by the defense mechanism nature intended to safeguard them.

“Previous research has suggested that along with tying up heparan sulfate, SARS-CoV-2 activates a cascading series of biological reactions — what we call the alternative pathway of complement, or APC — that can lead to inflammation and cell destruction if misdirected by the immune system at healthy organs,” says study senior author Robert Brodsky, M.D., director of the hematology division at the Johns Hopkins University School of Medicine. “The goal of our study was to discover how the virus activates this pathway and to find a way to inhibit it before the damage happens.”

The APC is one of three chain reaction processes involving the splitting and combining of more than 20 different proteins — known as complement proteins — that usually gets activated when bacteria or viruses invade the body. The end product of this complement cascade, a structure called membrane attack complex (MAC), forms on the surface of the invader and causes its destruction, either by creating holes in bacterial membranes or disrupting a virus’ outer envelope. However, MACs also can arise on the membranes of healthy cells. Fortunately, humans have a number of complement proteins, including factor H, that regulate the APC, keep it in check and therefore, protect normal cells from damage by MACs.

In a series of experiments, Brodsky and his colleagues used normal human blood serum and three subunits of the SARS-CoV-2 spike protein to discover exactly how the virus activates the APC, hijacks the immune system and endangers normal cells. They discovered that two of the subunits, called S1 and S2, are the components that bind the virus to heparan sulfate — setting off the APC cascade and blocking factor H from connecting with the sugar — and in turn, disabling the complement regulation by which factor H deters a misdirected immune response.

In turn, the researchers say, the resulting immune system response to chemicals released by the lysing of killed cells could be responsible for the organ damage and failures seen in severe cases of COVID-19.

Most notably, Brodsky says, the research team found by blocking another complement protein, known as factor D, which works immediately upstream in the pathway from factor H, they were able to stop the destructive chain of events triggered by SARS-CoV-2.

“When we added a small molecule that inhibits the function of factor D, the APC wasn’t activated by the virus spike proteins,” Brodsky says. “We believe that when the SARS-CoV-2 spike proteins bind to heparan sulfate, it triggers an increase in the complement-mediated killing of normal cells because factor H, a key regulator of the APC, can’t do its job.”

To better understand what happens, Brodsky says think of the APC like a car in motion.

“If the brakes are disabled, the gas pedal can be floored without restraint, very likely leading to a crash and destruction,” he explains. “The viral spike proteins disable the biological brakes, factor H, enabling the gas pedal, factor D, to accelerate the immune system and cause cell, tissue and organ devastation. Inhibit factor D, and the brakes can be reapplied and the immune system reset.”

Brodsky adds that cell death and organ damage from a misdirected APC associated with factor H suppression is already known to occur in several complement-related human diseases, including age-related macular degeneration, a leading cause of vision loss for people age 50 and older; and atypical hemolytic uremic syndrome (aHUS), a rare disease that causes clots to block blood flow to the kidneys.

Brodsky and his colleagues hope that their work will encourage more study into the potential use against COVID-19 of complement-inhibiting drugs already in the pipeline for other diseases.

“There are a number of these drugs that will be FDA-approved and in clinical practice within the next two years,” Brodsky says. “Perhaps one or more of these could be teamed with vaccines to help control the spread of COVID-19 and avoid future viral pandemics.”

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Along with Brodsky, the other members of the Johns Hopkins Medicine research team are lead author Jia Yu; Xuan Yuan; Hang Chen; Shruti Chaturvedi, M.B.B.S.; and Evan Braunstein, M.D., Ph.D.

The study was supported by National Heart, Lung and Blood Institute grant R01 HL133113.

https://www.hopkinsmedicine.org/news/newsroom/news-releases/blocking-immune-system-pathway-may-stop-covid-19-infection-prevent-severe-organ-damage

Source: https://bioengineer.org/blocking-immune-system-pathway-may-stop-covid-19-infection-prevent-severe-organ-damage/

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NYU Abu Dhabi researchers design simulator to help stop the spread of ‘fake news’

The new game, Fakey, emulates a social media feed and teaches users to recognize credible contentCredit: Courtesy of NYU Abu

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The new game, Fakey, emulates a social media feed and teaches users to recognize credible content

Abu Dhabi, UAE, April 27, 2021: As people around the world increasingly get their news from social media, online misinformation has emerged as an area of great concern. To improve news literacy and reduce the spread of misinformation, NYUAD Center for Cybersecurity researcher and lead author Nicholas Micallef is part of a team that designed Fakey, a game that emulates a social media news feed and prompts players to use available signals to recognize and scrutinize suspicious content and focus on credible information. Players can share, like, or fact-check individual articles.

In a new study, Fakey: A Game Intervention to Improve News Literacy on Social Media published in the ACM Digital Library, Micallef and his colleagues Mihai Avram, Filippo Menczer, and Sameer Patil from the Luddy School of Informatics, Computing, and Engineering, Indiana University, present the analysis of interactions with Fakey, which was released to the general public as a web and mobile app with data procured after 19 months of use. Interviews were conducted to verify player understanding of the game elements. The researchers found that the more players interacted with articles in the game, the better their skills at spotting credible content became. However, playing the game did not affect players’ ability to recognize questionable content. Further research will help determine how much gameplay would be necessary to be able to distinguish between legitimate and questionable content.

Games like Fakey, which was designed and developed by researchers at Indiana University, could be offered as a tool to social media users. For example, social media platforms could conduct regular exercises (akin to ‘phishing drills’ used in organizations for employee security training) wherein users practice identifying questionable articles. Or, the researchers say, such games could be integrated into media literacy curricula in schools. “The impact of misinformation could be substantially reduced if people were given tools to help them recognize and ignore such content,” said Micallef. “The principles and mechanisms used by Fakey can inform the design of social media functionality in a way that empowers people to distinguish between credible and fake content in their news feeds and increase their digital literacy.”

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About NYU Abu Dhabi

NYU Abu Dhabi is the first comprehensive liberal arts and science campus in the Middle East to be operated abroad by a major American research university. NYU Abu Dhabi has integrated a highly-selective liberal arts, engineering, and science curriculum with a world center for advanced research and scholarship enabling its students to succeed in an increasingly interdependent world and advance cooperation and progress on humanity’s shared challenges. NYU Abu Dhabi’s high-achieving students have come from more than 115 nations and speak over 115 languages. Together, NYU’s campuses in New York, Abu Dhabi, and Shanghai form the backbone of a unique global university, giving faculty and students opportunities to experience varied learning environments and immersion in other cultures at one or more of the numerous study-abroad sites NYU maintains on six continents.

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Source: https://bioengineer.org/nyu-abu-dhabi-researchers-design-simulator-to-help-stop-the-spread-of-fake-news/

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The science of sound, vibration to better diagnose, treat brain diseases

Multidisciplinary researchers uncover new ways to use ultrasound energy to image and treat hard-to-reach areas of brainCredit: Allison Carter, Georgia

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Multidisciplinary researchers uncover new ways to use ultrasound energy to image and treat hard-to-reach areas of brain

A team of engineering researchers at the Georgia Institute of Technology hopes to uncover new ways to diagnose and treat brain ailments, from tumors and stroke to Parkinson’s disease, leveraging vibrations and ultrasound waves.

The five-year, $2 million National Science Foundation (NSF) project initiated in 2019 already has resulted in several published journal articles that offer promising new methods to focus ultrasound waves through the skull, which could lead to broader use of ultrasound imaging — considered safer and less expensive than magnetic resonance imaging (MRI) technology.

Specifically, the team is researching a broad range of frequencies, spanning low frequency vibrations (audio frequency range) and moderate frequency guided waves (100 kHz to 1 MHz) to high frequencies employed in brain imaging and therapy (in the MHz range).

“We’re coming up with a unique framework that incorporates different research perspectives to address how you use sound and vibration to treat and diagnose brain diseases,” explained Costas Arvanitis, an assistant professor in Georgia Tech’s George W. Woodruff School of Mechanical Engineering and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “Each researcher is bringing their own expertise to explore how vibrations and waves across a range of frequencies could either extract information from the brain or focus energy on the brain.”

Accessing the Brain Is a Tough Challenge

While it is possible to treat some tumors and other brain diseases non-invasively if they are near the center of the brain, many other conditions are harder to access, the researchers say.

“The center part of the brain is most accessible; however, even if you are able to target the part of the brain away from the center, you still have to go through the skull,” Arvanitis said.

He added that moving just 1 millimeter in the brain constitutes “a huge distance” from a diagnostic perspective. The science community widely acknowledges the brain’s complexity, each part associated with a different function and brain cells differing from one to the other.

According to Brooks Lindsey, a biomedical engineering assistant professor at Georgia Tech and Emory, there is a reason why brain imaging or therapy works well in some people but not in others.

“It depends on the individual patient’s skull characteristics,” he said, noting that some people have slightly more trabecular bone ? the spongy, porous part of the bone ? that makes it more difficult to treat.

Using ultrasound waves, the researchers are tackling the challenge on multiple levels. Lindsey’s lab uses ultrasound imaging to assess skull properties for effective imaging and therapy. He said his team conducted the first investigation that uses ultrasound imaging to measure the effects of bone microstructure — specifically, the degree of porosity in the inner, trabecular bone layer of the skull.

“By understanding transmission of acoustic waves through microstructure in an individual’s skull, non-invasive ultrasound imaging of the brain and delivery of therapy could be possible in a greater number of people,” he said, explaining one potential application would be to image blood flow in the brain following a stroke.

Refocusing Ultrasound Beams on the Fly

Arvanitis’ lab recently found a new way to focus ultrasound through the skull and into the brain, which is “100-fold faster than any other method,” Arvanitis said. His team’s work in adaptive focusing techniques would allow clinicians to adjust the ultrasound on the fly to focus it better.

“Current systems rely a lot on MRIs, which are big, bulky, and extremely expensive,” he said. “This method lets you adapt and refocus the beam. In the future this could allow us to design less costly, simpler systems, which would make the technology available to a wider population, as well as be able to treat different parts of the brain.”

Using ‘Guided Waves’ to Access Periphery Brain Areas

Another research cohort, led by Alper Erturk, Woodruff Professor of Mechanical Engineering at Georgia Tech, and former Georgia Tech colleague Massimo Ruzzene, Slade Professor of Mechanical Engineering at the University of Colorado Boulder, performs high-fidelity modeling of skull bone mechanics along with vibration-based elastic parameter identification. They also leverage guided ultrasonic waves in the skull to expand the treatment envelope in the brain. Erturk and Ruzzene are mechanical engineers by background, which makes their exploration of vibrations and guided waves in difficult-to-reach brain areas especially fascinating.

Erturk noted that guided waves are used in other applications such as aerospace and civil structures for damage detection. “Accurate modeling of the complex bone geometry and microstructure, combined with rigorous experiments for parameter identification, is crucial for a fundamental understanding to expand the accessible region of the brain,” he said.

Ruzzene compared the brain and skull to the Earth’s core and crust, with the cranial guided waves acting as an earthquake. Just as geophysicists use earthquake data on the Earth’s surface to understand the Earth’s core, so are Erturk and Ruzzene using the guided waves to generate tiny, high frequency “earthquakes” on the external surface of the skull to characterize what comprises the cranial bone.

Trying to access the brain periphery via conventional ultrasound poses added risks from the skull heating up. Fortunately, advances such as cranial leaky Lamb waves increasingly are recognized for transmitting wave energy to that region of the brain.

These cranial guided waves could complement focused ultrasound applications to monitor changes in the cranial bone marrow from health disorders, or to efficiently transmit acoustic signals through the skull barrier, which could help access metastases and treat neurological conditions in currently inaccessible regions of the brain.

Ultimately, the four researchers hope their work will make full brain imaging feasible while stimulating new medical imaging and therapy techniques. In addition to transforming diagnosis and treatment of brain diseases, the techniques could better detect traumas and skull-related defects, map the brain function, and enable neurostimulation. Researchers also see the potential for uncovering ultrasound-based blood-brain barrier openings for drug delivery for managing and treating diseases such as Alzheimer’s.

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With this comprehensive research of the skull-brain system, and by understanding the fundamentals of transcranial ultrasound, the team hopes to make it more available to even more diseases and target many parts of the brain.

This work is funded by the National Science Foundation (CMMI Award 1933158 “Coupling Skull-Brain Vibroacoustics and Ultrasound Toward Enhanced Imaging, Diagnosis, and Therapy”).

CITATIONS: C. Sugino, M. Ruzzene, and A. Erturk, “Experimental and Computational Investigation of Guided Waves in a Human Skull.” (Ultrasound in Medicine and Biology, 2021) https://doi.org/10.1016/j.ultrasmedbio.2020.11.019

M. Mazzotti, E. Kohtanen, A. Erturk, and M. Ruzzene, “Radiation Characteristics of Cranial Leaky Lamb Waves.” (IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, 2021) https://doi.org/10.1109/TUFFC.2021.3057309

S. Schoen, C. Arvanitis, “Heterogeneous Angular Spectrum Method for Trans-Skull Imaging and Focusing.” (IEEE Xplore, 2020) https://ieeexplore.ieee.org/document/8902167

B. Jing, C. Arvanitis, B. Lindsey, “Effect of Incidence Angle and Wave Mode Conversion on Transcranial Ultrafast Doppler Imaging.” (IEEE Xplore, 2020) https://ieeexplore.ieee.org/document/9251477

The Georgia Institute of Technology, or Georgia Tech, is a top 10 public research university developing leaders who advance technology and improve the human condition.

The Institute offers business, computing, design, engineering, liberal arts, and sciences degrees. Its nearly 40,000 students, representing 50 states and 149 countries, study at the main campus in Atlanta, at campuses in France and China, and through distance and online learning.

As a leading technological university, Georgia Tech is an engine of economic development for Georgia, the Southeast, and the nation, conducting more than $1 billion in research annually for government, industry, and society.

https://rh.gatech.edu/news/646931/science-sound-vibration-better-diagnose-treat-brain-diseases

Source: https://bioengineer.org/the-science-of-sound-vibration-to-better-diagnose-treat-brain-diseases/

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Nontoxic, flexible energy converters could power wearable devices

Nontoxic, nanotube-based thermoelectric generation converts uneven heat distribution from wearables to electrical energy for their next cycle of operation.Credit: Injung

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Nontoxic, nanotube-based thermoelectric generation converts uneven heat distribution from wearables to electrical energy for their next cycle of operation.

WASHINGTON, April 27, 2021 — A wide variety of portable and wearable electronics have become a large part of our daily lives, so a group of Stanford University researchers wondered if these could be powered by harvesting electricity from the waste heat that exists all around us.

Further inspiration came from a desire to ultimately fabricate energy converting devices from the same materials as the active devices themselves, so they can blend in as an integral part of the total system. Today, many biomedical nanodevices’ power supplies come from several types of batteries that must be separated from the active portion of the systems, which is not ideal.

In Applied Physics Letters, from AIP Publishing, the researchers report the design and fabrication of single-wall carbon nanotube thermoelectric devices on flexible polyimide substrates as a basis for wearable energy converters.

“Carbon nanotubes are one-dimensional materials, known for good thermoelectric properties, which mean developing a voltage across them in a temperature gradient,” said Eric Pop, a professor of electrical engineering and materials science. “The challenge is that carbon nanotubes also have high thermal conductivity, meaning it’s difficult to maintain a thermal gradient across them, and they have been hard to assemble them into thermoelectric generators at low cost.”

The group uses printed carbon nanotube networks to tackle both challenges.

“For example, carbon nanotube spaghetti networks have much lower thermal conductivity than carbon nanotubes taken alone, due to the presence of junctions in the networks, which block heat flow,” Pop said. “Also, direct printing such carbon nanotube networks can significantly reduce their cost when they are scaled up.”

Thermoelectric devices generate electric power locally “by reusing waste heat from personal devices, appliances, vehicles, commercial and industrial processes, computer servers, time-varying solar illumination, and even the human body,” said Hye Ryoung Lee, lead author and a research scientist.

“To eliminate hindrances to large-scale application of thermoelectric materials — toxicity, materials scarcity, mechanical brittleness — carbon nanotubes offer an excellent alternative to other commonly used materials,” Lee said.

The group’s approach demonstrates a path to using carbon nanotubes with printable electrodes on flexible polymer substrates in a process anticipated to be economical for large-volume manufacturing. It is also “greener” than other processes, because water is used as the solvent and additional dopants are avoided.

Flexible and wearable energy harvesters can be embedded into fabrics or clothes or placed on unusual shapes and form factors.

“In contrast, traditional thermoelectrics that rely on bismuth telluride are brittle and stiff, with limited applications,” Pop said. “Carbon-based thermoelectrics are also more environmentally friendly than those based on rare or toxic materials like bismuth and tellurium.”

The most important concept in the group’s work is to “recycle energy as much as we can, converting uneven heat distribution to electrical energy for use for the next cycle of operation, which we demonstrated by using nontoxic nanotube-based thermoelectric generation,” said Yoshio Nishi, a professor of electrical engineering. “This concept is in full alliance with the world’s goal of reducing our total energy consumption.”

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The article “Carbon nanotube thermoelectric devices by direct printing: Towards wearable energy converters” is authored by Hye Ryoung Lee, Naoki Furukawa, Antonio J. Ricco, Eric Pop, Yi Cui, and Yoshio Nishi. The article will appear in Applied Physics Letters on April 27 (DOI: 10.1063/5.0042349). After that date, it can be accessed at https://aip.scitation.org/doi/10.1063/5.0042349.

ABOUT THE JOURNAL

Applied Physics Letters features rapid reports on significant discoveries in applied physics. The journal covers new experimental and theoretical research on applications of physics phenomena related to all branches of science, engineering, and modern technology. See https://aip.scitation.org/journal/apl.

In Applied Physics Letters, from AIP Publishing, the researchers report the design and fabrication of single-wall carbon nanotube thermoelectric devices on flexible polyimide substrates as a basis for wearable energy converters.

Source: https://bioengineer.org/nontoxic-flexible-energy-converters-could-power-wearable-devices/

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