The gene, called TSC2, codes for tuberin, a protein that acts to inhibit cell growth and proliferation. When mutations occur in TSC2, resulting in a lack of tuberin in cells, the cells enlarge and multiply, leading to the formation of tumors.

To restore the function of TSC2 and tuberin in a mouse model of tuberous sclerosis complex, researchers developed a form of gene therapy using an adeno-associated virus vector carrying the DNA that codes for a condensed form of tuberin (which fits within the vector’s carrying capacity) and functions like the normal full-length tuberin protein. Mice with tuberous sclerosis complex had a shortened life span of about 58 days on average, and they showed signs of brain abnormalities consistent with those that are often seen in patients with the disease. When the mice were injected intravenously with the gene therapy treatment, however, their average survival was extended to 462 days, and their brains showed reduced signs of damage.

“Current treatments for tuberous sclerosis complex include surgery and/or lifelong treatment with drugs that cause immune suppression and potentially compromise early brain development. Therefore, there is a clear need to identify other therapeutic approaches for this disease,” says co-lead author Shilpa Prabhakar, an investigator in the MGH departments of Neurology and Radiology. “Adeno-associated virus vectors have been used widely in clinical trials for many hereditary diseases with little to no toxicity, long-term action in nondividing cells, and improvement in symptoms,” adds Prabhakar. She notes that benefits can be seen after a single injection, and some forms of the viral vector can efficiently enter the brain and peripheral organs after intravenous injection.

The U.S. Food and Drug Administration has approved a limited number of gene therapy products for use in humans, and the results from this study suggest that clinical trials are warranted to test the strategy’s potential in patients with tuberous sclerosis complex.

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That’s according to an international study published Jan. 8 in The Lancet Respiratory Medicine, led by researchers at Vanderbilt University Medical Center in coordination with researchers in Spain.

The study, which is far the largest of its kind to date, tracks the incidence of delirium and coma in 2,088 COVID-19 patients admitted before April 28, 2020, to 69 adult intensive care units across 14 countries.

ICU delirium is associated with higher medical costs and greater risk of death and long-term ICU-related dementia. Seminal studies at VUMC over the past two decades have spurred widespread interest in ICU delirium research, and the resulting body of evidence has come to inform critical care guidelines endorsed by medical societies in several countries. These guidelines include well calibrated pain management with prompt discontinuation of analgesics and sedatives, daily spontaneous awakening trials, daily spontaneous breathing trials, delirium assessments throughout the day, early mobility and exercise, and family engagement.

Some 82% of patients in this observational study were comatose for a median of 10 days, and 55% were delirious for a median of three days. Acute brain dysfunction (coma or delirium) lasted for a median of 12 days.

“This is double what is seen in non-COVID ICU patients,” said VUMC’s Brenda Pun, DNP, RN, co-first author on the study with Rafael Badenes MD, PhD, of the University of Valencia in Spain. The authors cite a previous large, multi-site ICU study, also led by VUMC, where acute brain dysfunction lasted a median of five days, including four days of coma and one day of delirium.

The authors note that COVID-19 disease processes could predispose patient to a higher burden of acute brain dysfunction. But they also note that a number of patient care factors, some of which are related to pressures posed on health care by the pandemic, also appear to have played a significant role.

The study appears to show a reversion to outmoded critical care practices, including deep sedation, widespread use of benzodiazepine infusions (benzodiazepine is a nervous system depressant), immobilization, and isolation from families. The authors find that, where COVID-19 is concerned, there has been an apparent widespread abandonment of newer clinical protocols that are proven to help ward off the acute brain dysfunction that stalks many critically ill patients.

“It is clear in our findings that many ICUs reverted to sedation practices that are not in line with best practice guidelines,” Pun said, “and we’re left to speculate on the causes. Many of the hospitals in our sample reported shortages of ICU providers informed about best practices. There were concerns about sedative shortages, and early reports of COVID-19 suggested that the lung dysfunction seen required unique management techniques including deep sedation. In the process, key preventive measures against acute brain dysfunction went somewhat by the boards.”

Using electronic health records, investigators were able to closely examine patient characteristics, care practices and findings from clinical assessments. Some 88% of patients tracked in the study were invasively mechanical ventilated at some point during hospitalization, 67% on the day of ICU admission. Patients receiving benzodiazepine sedative infusions were at 59% higher risk of developing delirium. Patients who received family visitation (in-person or virtual) were at 30% lower risk of delirium.

“There’s no reason to think that, since the close of our study, the situation for these patients has changed,” said one of the study’s senior authors, Pratik Pandharipande, MD, MSCI, professor of Anesthesiology.

“These prolonged periods of acute brain dysfunction are largely avoidable. Our study sounds an alarm: as we enter the second and third waves of COVID-19, ICU teams need above all to return to lighter levels of sedation for these patients, frequent awakening and breathing trials, mobilization and safe in-person or virtual visitation.”

Pandharipande is co-director, with the study’s other senior author, Wesley Ely, MD, MPH, of the Critical Illness, Brain Dysfunction, and Survivorship Center. Pun is director of data quality with the center. Other VUMC investigators on the study include Onur Orun, MS, Wencong Chen, PhD, Rameela Raman, PhD, Beata-Gabriela Simpson, MPH, Stephanie Wilson-Linville, BSN, Nathan Brummel, MD, and Timothy Girard, MD.

“Our goal is to make a single-shot vaccine that does not require a cold-chain for storage or transport. If we’re successful at doing it well, it should be cheap too,” said Kim, who is the Virginia and D. K. Ludwig Professor of Biochemistry. “The target population for our vaccine is low- and middle-income countries.”

Their vaccine, detailed in a paper published Jan. 5 in ACS Central Science, contains nanoparticles studded with the same proteins that comprise the virus’s distinctive surface spikes. In addition to being the reason why these are called coronaviruses — corona is Latin for “crown” — these spikes facilitate infection by fusing to a host cell and creating a passageway for the viral genome to enter and hijack the cell’s machinery to produce more viruses. The spikes can also be used as antigens, which means their presence in the body is what can trigger an immune response.

Nanoparticle vaccines balance the effectiveness of viral-based vaccines with the safety and ease-of-production of subunit vaccines. Vaccines that use viruses to deliver the antigen are often more effective than vaccines that contain only isolated parts of a virus. However, they can take longer to produce, need to be refrigerated and are more likely to cause side effects. Nucleic acid vaccines — like the Pfizer and Moderna mRNA vaccines that have recently been authorized for emergency use by the FDA — are even faster to produce than nanoparticle vaccines but they are expensive to manufacture and may require multiple doses. Initial tests in mice suggest that the Stanford nanoparticle vaccine could produce COVID-19 immunity after just one dose.

The researchers are also hopeful that it could be stored at room temperature and are investigating whether it could be shipped and stored in a freeze-dried, powder form. By comparison, the vaccines that are farthest along in development in the United States all need to be stored at cold temperatures, ranging from approximately 8 to -70 degrees Celsius (46 to -94 degrees Fahrenheit).

“This is really early stage and there is still lots of work to be done,” said Abigail Powell, a former postdoctoral scholar in the Kim lab and lead author of the paper. “But we think it is a solid starting point for what could be a single-dose vaccine regimen that doesn’t rely on using a virus to generate protective antibodies following vaccination.”

The researchers are continuing to improve and fine-tune their vaccine candidate, with the intention of moving it closer to initial clinical trials in humans.

Spikes and nanoparticles

The spike protein from SARS-CoV-2 is quite large, so scientists often formulate abridged versions that are simpler to make and easier to use. After closely examining the spike, Kim and his team chose to remove a section near the bottom.

To complete their vaccine, they combined this shortened spike with nanoparticles of ferritin — an iron-containing protein — which has been previously tested in humans. Before the pandemic, Powell had been working with these nanoparticles to develop an Ebola vaccine. Together with scientists at the SLAC National Accelerator Laboratory, the researchers used cryo-electron microscopy to get a 3D image of the spike ferritin nanoparticles in order to confirm that they had the proper structure.

For the mouse tests, the researchers compared their shortened spike nanoparticles to four other potentially useful variations: nanoparticles with full spikes, full spikes or partial spikes without nanoparticles, and a vaccine containing just the section of the spike that binds to cells during infection. Testing the effectiveness of these vaccines against actual SARS-CoV-2 virus would have required the work to be done in a Biosafety Level 3 lab, so the researchers instead used a safer pseudo-coronavirus that was modified to carry SARS-CoV-2’s spikes.

The researchers determined the potential effectiveness of each vaccine by monitoring levels of neutralizing antibodies. Antibodies are blood proteins produced in response to antigens; neutralizing antibodies are the specific subset of antibodies that actually act to prevent the virus from invading a host cell.

After a single dose, the two nanoparticle vaccine candidates both resulted in neutralizing antibody levels at least twice as high as those seen in people who have had COVID-19, and the shortened spike nanoparticle vaccine produced a significantly higher neutralizing response than the binding spike or the full spike (non-nanoparticle) vaccines. After a second dose, mice that had received the shortened spike nanoparticle vaccine had the highest levels of neutralizing antibodies.

Looking back at this project, Powell estimates that the time from inception to the first mouse studies was about four weeks. “Everybody had a lot of time and energy to devote to the same scientific problem,” she said. “It is a very unique scenario. I don’t really expect I’ll ever encounter that in my career again.”

“What’s happened in the past year is really fantastic, in terms of science coming to the fore and being able to produce multiple different vaccines that look like they’re showing efficacy against this virus,” said Kim, who is senior author of the paper. “It normally takes a decade to make a vaccine, if you’re even successful. This is unprecedented.”

Vaccine access

Although the team’s new vaccine is intended specifically for populations that may have more difficulty accessing other SARS-CoV-2 vaccines, it is possible, given the rapid progress of other vaccine candidates, that it will not be needed to address the current pandemic. In that case, the researchers are prepared to pivot again and pursue a more universal coronavirus vaccine to immunize against SARS-CoV-1, MERS, SARS-CoV-2 and future coronaviruses that are not yet known.

“Vaccines are one of the most profound achievements of biomedical research. They are an incredibly cost-effective way to protect people against disease and save lives,” said Kim. “This coronavirus vaccine is part of work we’re already doing — developing vaccines that are historically difficult or impossible to develop, like an HIV vaccine — and I’m glad that we’re in a situation where we could potentially bring something to bear if the world needs it.”

Additional Stanford co-authors include Kaiming Zhang, research scientist in bioengineering; Mrinmoy Sanyal, research scientist in biochemistry; Shaogeng Tang, postdoctoral fellow in biochemistry; Payton Weidenbacher, graduate student in chemistry; Shanshan Li, postdoctoral researchers in bioengineering; Tho Pham, clinical assistant professor in pathology at Stanford Medicine (also affiliated with the Stanford Blood Center in Palo Alto); and Wah Chiu, the Wallenberg-Bienenstock Professor at Stanford and the SLAC National Accelerator Laboratory, and professor of bioengineering and of microbiology and immunology. A researcher from Chan Zuckerberg Biohub is also a co-author. Kim is a member of Stanford Bio-X, the Maternal & Child Health Research Institute (MCHRI) and the Wu Tsai Neurosciences Institute, and a faculty fellow of Stanford ChEM-H. He is also affiliated with the Chan Zuckerberg Biohub. Chiu is a member of Stanford Bio-X and the Wu Tsai Neurosciences Institute, and a faculty fellow of Stanford ChEM-H.

This work was funded by MCHRI, the Damon Runyon Cancer Research Foundation, the National Institutes of Health, the Virginia and D. K. Ludwig Fund for Cancer Research and Chan Zuckerberg Biohub.

The “ground effect” is most widely understood on airport runways. During take-off, air squeezes between the airplane and ground, which builds pressure and a force that boosts performance. Gemmell’s experiments have shown that jellyfish can use their two vortex rings in place of the ground. The vortex rings resist each other, creating a “virtual wall” that provides a similar boost in performance compared to animals that swim near the bottom. Never before has it been proven that an animal can create this phenomenon away from a solid boundary.

“The fact that these simple animals have figured out how to achieve a ‘ground effect’ type boost in open water, away from any solid surfaces, has the potential to open up a range of new possibilities for engineered vehicles to take advantage of this phenomenon,” Gemmell said.

In the study published in Proceedings of the Royal Society B, Gemmell captured the motion by recording the movements of eight jellyfish swimming in a glass filming vessel using a high-speed digital camera at 1,000 frames per second. He and his colleagues witnessed jellyfish that were in motion had a 41% increase in maximum swimming speed and a 61% increase in cumulative distance traveled per swimming cycle compared to those starting from rest.

Unlike locomotion by propellers, jellyfish do not produce cavitation bubbles and are silent, allowing them to move quietly through the water. The high efficiency of swimming also helps them store energy for growth and reproduction. Several research groups use jellyfish as a model for developing underwater vehicles that can be equipped with sensors that monitor the ocean without disruption. These new findings may enhance development of these technologies and further understanding of the ocean.

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Researchers said their centimeter-sized device provides the feeling of fullness by stimulating the endings of the vagus nerve with light. Unlike other devices that require a power cord, their device is wireless and can be controlled externally from a remote radio frequency source.

“We wanted to create a device that not only requires minimal surgery for implantation but also allows us to stimulate specific nerve endings in the stomach,” said Dr. Sung II Park, assistant professor in the Department of Electrical and Computer Engineering. “Our device has the potential to do both of these things in the harsh gastric conditions, which, in the future, can be hugely beneficial to people needing dramatic weight-loss surgeries.”

Further details about their device are published in the January issue of Nature Communications.

Obesity is a global epidemic. Furthermore, its associated health problems have a significant economic impact on the U.S. health care system, costing $147 billion a year. Additionally, obesity puts people at risk for chronic diseases such as diabetes, heart disease and even some cancers. For those with a body mass index greater than 35 or who have at least two obesity-related conditions, surgery offers a path for patients to not only lose the excess weight but maintain their weight over the long term.

In recent years, the vagus nerve has received much attention as a target for treating obesity since it provides sensory information about fullness from the stomach lining to the brain. Although there are medical devices that can stimulate the vagus nerve endings and consequently help in curbing hunger, these devices are similar in design to a pacemaker, that is, wires connected to a current source provide electrical jolts to activate the tips of the nerve.

However, Park said wireless technology, as well as the application of advanced genetic and optical tools, have the potential to make nerve stimulation devices less cumbersome and more comfortable for the patient.

“Despite the clinical benefit of having a wireless system, no device, as of yet, has the capability to do chronic and durable cell-type specific manipulation of neuron activity inside of any other organ other than the brain,” he said.

To address this gap, Park and his team first used genetic tools to express genes that respond to light into specific vagus nerve endings in vivo. Then, they designed a tiny, paddle-shaped device and inserted micro LEDs near the tip of its flexible shaft, which was fastened to the stomach. In the head of the device, called the harvester, they housed microchips needed for the device to wirelessly communicate with an external radio frequency source. The harvester was also equipped to produce tiny currents to power the LEDs. When the radio frequency source was switched on, the researchers showed that the light from the LEDs was effective at suppressing hunger.

The researchers said they were surprised to uncover that the biological machinery coordinating hunger suppression in their experiments was different from conventional wisdom. In other words, it is widely accepted that when the stomach is full, it expands and the information about stretch is conveyed to the brain by mechanoreceptors on the vagus nerve.

“Our findings suggest that stimulating the non-stretch receptors, the ones that respond to chemicals in the food, could also give the feeling of satiety even when the stomach was not distended,” said Park.

Looking ahead, he said that the current device could also be used to manipulate nerve endings throughout the gastrointestinal tract and other organs, like the intestine, with little or no modifications.

“Wireless optogenetics and identifying peripheral neural pathways that control appetite and other behaviors are all of great interest to researchers in both the applied and basic fields of study in electronics, material science and neuroscience,” said Park. “Our novel tool now enables interrogation of neuronal function in the peripheral nervous systems in a way that was impossible with existing approaches.”

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Magnetars are a type of neutron star, an incredibly dense object mainly made up of tightly packed neutron, which forms from the collapsed core of a massive star during a supernova.

What sets magnetars apart from other neutron stars is that they also have the most powerful known magnetic fields in the universe. For context, the strength of our planet’s magnetic field has a value of about one Gauss, while a refrigerator magnet measures about 100 Gauss. Magnetars, on the other hand, have magnetic fields of about a million billion Gauss. If a magnetar was located a sixth of the way to the Moon (about 40,000 miles), it would wipe the data from all of the credit cards on Earth.

On March 12, 2020, astronomers detected a new magnetar with NASA’s Neil Gehrels Swift Telescope. This is only the 31st known magnetar, out of the approximately 3,000 known neutron stars.

After follow-up observations, researchers determined that this object, dubbed J1818.0-1607, was special for other reasons. First, it may be the youngest known magnetar, with an age estimated to be about 500 years old. This is based on how quickly the rotation rate is slowing and the assumption that it was born spinning much faster. Secondly, it also spins faster than any previously discovered magnetar, rotating once around every 1.4 seconds.

Chandra’s observations of J1818.0-1607 obtained less than a month after the discovery with Swift gave astronomers the first high-resolution view of this object in X-rays. The Chandra data revealed a point source where the magnetar was located, which is surrounded by diffuse X-ray emission, likely caused by X-rays reflecting off dust located in its vicinity. (Some of this diffuse X-ray emission may also be from winds blowing away from the neutron star.)

Harsha Blumer of West Virginia University and Samar Safi-Harb of the University of Manitoba in Canada recently published results from the Chandra observations of J1818.0-1607 in The Astrophysical Journal Letters.

This composite image contains a wide field of view in the infrared from two NASA missions, the Spitzer Space Telescope and the Wide-Field Infrared Survey Explorer (WISE), taken before the magnetar’s discovery. X-rays from Chandra show the magnetar in purple. The magnetar is located close to the plane of the Milky Way galaxy at a distance of about 21,000 light-years from Earth.

Other astronomers have also observed J1818.0-1607 with radio telescopes, such as the NSF’s Karl Jansky Very Large Array (VLA), and determined that it gives off radio waves. This implies that it also has properties similar to that of a typical “rotation-powered pulsar,” a type of neutron star that gives off beams of radiation that are detected as repeating pulses of emission as it rotates and slows down. Only five magnetars including this one have been recorded to also act like pulsars, constituting less than 0.2% of the known neutron star population.

The Chandra observations may also provide support for this general idea. Safi-Harb and Blumer studied how efficiently J1818.0-1607 is converting energy from its decreasing rate of spin into X-rays. They concluded this efficiency is lower than that typically found for magnetars, and likely within the range found for other rotation-powered pulsars.

The explosion that created a magnetar of this age would be expected to have left behind a detectable debris field. To search for this supernova remnant, Safi-Harb and Blumer looked at the X-rays from Chandra, infrared data from Spitzer, and the radio data from the VLA. Based on the Spitzer and VLA data they found possible evidence for a remnant, but at a relatively large distance away from the magnetar. In order to cover this distance the magnetar would need to have traveled at speeds far exceeding those of the fastest known neutron stars, even assuming it is much older than expected, which would allow more travel time.

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

For more Chandra images, multimedia and related materials, visit: http://www.nasa.gov/chandra

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A team of neuroscientists of TU Dresden headed by Prof Dr Katharina von Kriegstein presents new findings that show that not only the cerebral cortex, but the entire auditory pathway, represents sounds according to prior expectations.

For their study, the team used functional magnetic resonance imaging (fMRI) to measure brain responses of 19 participants while they were listening to sequences of sounds. The participants were instructed to find which of the sounds in the sequence deviated from the others. Then, the participants’ expectations were manipulated so that they would expect the deviant sound in certain positions of the sequences. The neuroscientists examined the responses elicited by the deviant sounds in the two principal nuclei of the subcortical pathway responsible for auditory processing: the inferior colliculus and the medial geniculate body. Although participants recognised the deviant faster when it was placed on positions where they expected it, the subcortical nuclei encoded the sounds only when they were placed in unexpected positions.

These results can be best interpreted in the context of predictive coding, a general theory of sensory processing that describes perception as a process of hypothesis testing. Predictive coding assumes that the brain is constantly generating predictions about how the physical world will look, sound, feel, and smell like in the next instant, and that neurons in charge of processing our senses save resources by representing only the differences between these predictions and the actual physical world.

Dr Alejandro Tabas, first author of the publication, states on the findings: “Our subjective beliefs on the physical world have a decisive role on how we perceive reality. Decades of research in neuroscience had already shown that the cerebral cortex, the part of the brain that is most developed in humans and apes, scans the sensory world by testing these beliefs against the actual sensory information. We have now shown that this process also dominates the most primitive and evolutionary conserved parts of the brain. All that we perceive might be deeply contaminated by our subjective beliefs on the physical world.”

These new results open up new ways for neuroscientists studying sensory processing in humans towards the subcortical pathways. Perhaps due to the axiomatic belief that subjectivity is inherently human, and the fact that the cerebral cortex is the major point of divergence between the human and other mammal’s brains, little attention has been paid before to the role that subjective beliefs could have on subcortical sensory representations.

Given the importance that predictions have on daily life, impairments on how expectations are transmitted to the subcortical pathway could have profound repercussion in cognition. Developmental dyslexia, the most wide-spread learning disorder, has already been linked to altered responses in subcortical auditory pathway and to difficulties on exploiting stimulus regularities in auditory perception. The new results could provide with a unified explanation of why individuals with dyslexia have difficulties in the perception of speech, and provide clinical neuroscientists with a new set of hypotheses on the origin of other neural disorders related to sensory processing.

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