But for an important class of complex oxide materials, stretching doesn’t work so well; they’re as brittle as ceramic coffee cups and would break.

Scientists at the Department of Energy’s SLAC National Accelerator Laboratory and Stanford University have now found a way around this problem for a complex oxide known as LCMO. They created a super-thin, flexible membrane from the normally brittle material, used micromanipulators to stretch it on a tiny apparatus and glued it in place to preserve the stretch.

By applying gentle heat to melt the glue, they could release and stretch the same transparent membrane again and again and watch it flip from being an insulator to a conductor and back again. Stretching also changed its magnetic properties.

“We can really stretch and strain these things dramatically, by up to 8%,” said Harold Hwang, a professor at SLAC and Stanford and an investigator with the Stanford Institute for Materials and Energy Sciences (SIMES). “This opens a whole new world of possibilities that will have an impact beyond this particular study.”

The research team reported its findings in Science today.

New ways to float free and stretch

LCMO, or lanthanum calcium manganese oxide, is what’s known as a quantum material because its electrons behave in unconventional and often surprising ways. Scientists want to be able to control and fine-tune this behavior for a new generation of electronics with applications in power transmission, transportation, computing, sensors and detectors.

Thin films of quantum materials are generally grown on the surface of another material. Four years ago, Hwang’s group reported an easy way to detach those delicate layers so they could be studied in new ways.

One of the researchers who worked on that study, Seung Sae Hong, led this one as well. He used the new method to create and free small pieces of LCMO that were thinner than ever before — less than 20 nanometers thick. They were nearly transparent and surprisingly flexible.

Directly stretching such a small, fragile scrap would be difficult, but Hong got around that problem by putting it on a thin polymer film — kind of like a plastic bag from a grocery store — where it stuck of its own volition.

Then he clamped the polymer film on each of its four sides and used a micromanipulator to pull and stretch it — sometimes in one direction, sometimes in both directions at once. Once the LCMO was stretched, its polymer backing could be glued to another surface and taken to another instrument for examination with X-rays.

Flipping electronic states

“The experiments were quite tedious and difficult,” said Hong, who is now an assistant professor at the University of California, Davis. “We’d look at the film, warm it to soften the glue and relax the stretch, manipulate it in some other way, freeze it in place and look at it again.”

The researchers were able to directly measure the spacing between atoms and confirm that it increased with stretching. They also measured the electrical resistance of the LMCO and discovered that stretching flipped it from a metallic state that readily conducts electricity to an insulating state, which doesn’t. Applying a strong magnetic field changed the magnetic state of the material and also flipped it back into being a metal.

“As a scientific tool this is really exciting,” Hong said. “It opens opportunities for mechanically manipulating broad classes of materials in ways we couldn’t do before. And it gives us ideas for how we might design flexible materials for electronic devices, including sensors and detectors that measure very small changes.”

The paper appeared today in EBioMedicine, which is published by The Lancet, and is the first study to be published after critique from fellow scientists at outside institutions that describes a candidate vaccine for COVID-19. The researchers were able to act quickly because they had already laid the groundwork during earlier coronavirus epidemics.

“We had previous experience on SARS-CoV in 2003 and MERS-CoV in 2014. These two viruses, which are closely related to SARS-CoV-2, teach us that a particular protein, called a spike protein, is important for inducing immunity against the virus. We knew exactly where to fight this new virus,” said co-senior author Andrea Gambotto, M.D., associate professor of surgery at the Pitt School of Medicine. “That’s why it’s important to fund vaccine research. You never know where the next pandemic will come from.”

“Our ability to rapidly develop this vaccine was a result of scientists with expertise in diverse areas of research working together with a common goal,” said co-senior author Louis Falo, M.D., Ph.D., professor and chair of dermatology at Pitt’s School of Medicine and UPMC.

Compared to the experimental mRNA vaccine candidate that just entered clinical trials, the vaccine described in this paper — which the authors are calling PittCoVacc, short for Pittsburgh Coronavirus Vaccine — follows a more established approach, using lab-made pieces of viral protein to build immunity. It’s the same way the current flu shots work.

The researchers also used a novel approach to deliver the drug, called a microneedle array, to increase potency. This array is a fingertip-sized patch of 400 tiny needles that delivers the spike protein pieces into the skin, where the immune reaction is strongest. The patch goes on like a Band-Aid and then the needles — which are made entirely of sugar and the protein pieces — simply dissolve into the skin.

“We developed this to build on the original scratch method used to deliver the smallpox vaccine to the skin, but as a high-tech version that is more efficient and reproducible patient to patient,” Falo said. “And it’s actually pretty painless — it feels kind of like Velcro.”

The system also is highly scalable. The protein pieces are manufactured by a “cell factory” — layers upon layers of cultured cells engineered to express the SARS-CoV-2 spike protein — that can be stacked further to multiply yield. Purifying the protein also can be done at industrial scale. Mass-producing the microneedle array involves spinning down the protein-sugar mixture into a mold using a centrifuge. Once manufactured, the vaccine can sit at room temperature until it’s needed, eliminating the need for refrigeration during transport or storage.

“For most vaccines, you don’t need to address scalability to begin with,” Gambotto said. “But when you try to develop a vaccine quickly against a pandemic that’s the first requirement.”

When tested in mice, PittCoVacc generated a surge of antibodies against SARS-CoV-2 within two weeks of the microneedle prick.

Those animals haven’t been tracked long term yet, but the researchers point out that mice who got their MERS-CoV vaccine produced a sufficient level of antibodies to neutralize the virus for at least a year, and so far the antibody levels of the SARS-CoV-2 vaccinated animals seem to be following the same trend.

Importantly, the SARS-CoV-2 microneedle vaccine maintains its potency even after being thoroughly sterilized with gamma radiation — a key step toward making a product that’s suitable for use in humans.

The authors are now in the process of applying for an investigational new drug approval from the U.S. Food and Drug Administration in anticipation of starting a phase I human clinical trial in the next few months.

“Testing in patients would typically require at least a year and probably longer,” Falo said. “This particular situation is different from anything we’ve ever seen, so we don’t know how long the clinical development process will take. Recently announced revisions to the normal processes suggest we may be able to advance this faster.”

Additional authors on the study are Eun Kim, Geza Erdos, Ph.D., Shaohua Huang, Thomas Kenniston, Stephen Balmert, Ph.D., Cara Donahue Carey, Michael Epperly, Ph.D., William Klimstra, Ph.D., and Emrullah Korkmaz, Ph.D., all of Pitt; and Bart Haagmans, of Erasmus Medical Center.

Funding for this study was provided by National Institute of Allergy and Infectious Diseases grant R21-AI114264, National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01-AR074285, R01-AR071277 and R01-AR068249, and National Cancer Institute grant T32-CA175294.

It is World Autism Awareness Day, which this year, we observe during a time where the world faces a Covid-19 outbreak.

The outbreak does not make it easy for such a day to be fully acknowledged, and even giving adequate care to autistic persons and advocating fully, that they too have rights.

All that changes when tau misfolds. It becomes sticky and insoluble, aggregating and forming neurofibrillary tangles within neurons, disrupting their function and ultimately killing them. Worse, it probably can take relatively few misfolded tau proteins from one cell to turn its neighbors into malfunctioning, dying brain cells.

“This abnormal form of tau starts to spread from cell to cell,” said UC Santa Barbara neuroscientist Kenneth S. Kosik. “It’s reminiscent of a serious problem that’s known in biology, called prion diseases, such as mad cow disease.”

Importantly, unlike true prion diseases, which are spread by contact with infected tissue or bodily fluid, prion-like diseases such as frontotemporal dementia and other tauopathies aren’t contagious — they can’t be spread from person to person or by coming into contact with infected tissue. However, the replication is eerily familiar: A misfolded tau protein gets out of a cell and gets taken up by a normal neighboring cell. It then acts as a template in that cell, Kosik explained, which subsequently produces misfolded tau. Over and over again, the cells produce and secrete the toxic knockoff version of tau until whole regions of the brain are affected, which over time will rob a person of their cognitive and physical functions.

What if the spread could be contained? If caught early enough, controlling the proliferation of pathological tau could keep the neurodegenerative disease from progressing, and give the patient a shot at a normal life. But in order to do that, scientists first have to understand how the protein gets around.

In a paper published in the journal Nature, Kosik and his team have uncovered one such mechanism by which tau travels from neuron to neuron. Not only does it shed light on the extensively studied but rather poorly understood tau propagation in neurodegenerative disease, it hints at a way to control the spread of pathological tau.

“The discovery of a mechanism by which tau transits from cell to cell provides a clue that will open up a deep structural approach to the design molecules that can prevent tau spread,” said Kosik, who is the Harriman Professor of Neuroscience Research in UC Santa Barbara’s Department of Molecular, Cellular, and Developmental Biology.

The major player in this mechanism of uptake and spread, it turns out, is the low-density lipoprotein called LRP1 (low density lipoprotein receptor-related protein 1). It’s located on the brain cell membrane and is involved is several biological processes, among them helping the neuron take in cholesterol, which is used as part of cellular structure.

LRP1, the researchers discovered, takes up tau in neighboring cells after it escapes from a cell into the extra-cellular space. One of several low density lipoprotein receptors, LRP1 was singled out by process of elimination: By systematically inhibiting the expression of each of the members of this family via CRISPRi technology, and exposing them to tau, the researchers determined that genetic silencing of LRP1 effectively inhibited tau uptake.

“This protein is an interesting one in its own right because it’s a little bit like an extracellular trash can,” Kosik said. “It doesn’t just pick up tau; if there’s other rubbish out there, it also picks it up.”

But what about tau is LRP1 recognizing? Digging deeper, the scientists found that a stretch of the amino acid lysine on the tau protein acts as kind of the secret handshake that opens the doors to the neuron.

“So these are all clues,” Kosik said.

Stopping the Spread

“Since our cellular work showed that tau can interact with the cell-surface receptor LRP1 and that this causes tau’s endocytosis, our hypothesis was that if we reduce LRP1 expression in the mice we should reduce the ability for neighboring neurons to take up tau,” explained the study’s lead author, postdoctoral researcher Jennifer Rauch.

To back their in-vitro studies, the researchers injected tau into mice, some of which had their LRP1 genes downregulated by a LRP1 suppressor RNA. The tau proteins were bound by a small string of amino acids to a green fluorescent protein to help the scientists observe tau after it was injected.

“As soon as this construct is in a cell, the amino acid connector gets cut, and the fluorescent protein and tau separate from each other,” Kosik explained. What they found was that in the animals with normal LRP1, the tau had a tendency to spread; in the LRP1-suppressed mice, the protein stayed put, greatly reducing the likelihood that it would be taken up and replicated by other, normal neurons. “This is the first time we’ve seen the complete obliteration of tau spread,” he said.

“When we reduce LRP1 expression, we see reduced tau spread in the animals,” said Rauch, who has previously worked on the role of heparan sulphate proteoglycans on tau uptake. She pointed out a recent study that included Kosik and graduate student Juliana Acost-Uribe that described a patient with a severe genetic form of early-onset Alzheimers’s but was spared getting the disease due to a second mutation that appeared to prevent tau spread. The team is keen to learn how this patient’s second mutation might prevent tau spread possibly by interacting with LRP1.

“Next,” Rauch said, “we are focusing on trying to decipher the interface of the tau-LRP1 interaction and understand if this could be a drug-able target.”

“The earlier that COVID-19 is diagnosed and treated, the shorter the time to disease resolution and the lower the highest and last CT scores are,” concluded lead author Guoquan Huang of Wuhu Second People’s Hospital in China.

Assigning CT scores to 25 patients according to CT findings and lung involvement, Huang and colleagues recorded the time from symptom onset to diagnosis and treatment for each patient. Patients with COVID-19 were divided into two groups: (patients for whom this interval was ? 3 days) and group 2 (those for whom the interval was > 3 days).

Using a Lorentzian line-shape curve to show the variation tendency during treatment, the fitted tendency curves for group 1 and group 2 were significantly different. Peak points showed that the estimated highest CT score was 10 and 16 for each group, respectively, and the time to disease resolution was 6 and 13 days, respectively.

The Mann-Whitney test showed that the last CT scores were lower for group 1 than for group 2 (p = 0.025), although the chi-square test found no difference in age and sex between the groups. The time from symptom onset to diagnosis and treatment had a positive correlation with the time to disease resolution (r = 0.93; p = 0.000), as well as with the highest CT score (r = 0.83; p = 0.006).

“Sequential chest CT examinations enable qualitative investigation of alterations in COVID-19 infection during the course of treatment,” Huang explained.

Because previously proposed CT scoring criteria regarding lobe involvement gave no consideration to changes in CT features (i.e., the change from observation of GGO to a crazy-paving pattern and then consolidation), Huang et al. suggest that such a rubric is not sufficiently accurate to assess the progression of pneumonia.

“In the present study,” wrote Huang, “we propose a new version of CT scoring criteria that considers both lobe involvement and changes in CT findings, in an attempt to more comprehensively evaluate COVID-19 pneumonia on sequential chest CT examinations.”

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Much research has gone into the evolution of ancient hominins — human relatives and ancestors — but little is known about their growth and development. Most hominin fossils represent adult individuals, and remains of developmentally young hominins are rare. This has left a gap in our understanding of how our ancient relatives grew from young into adults, and how modern human growth patterns evolved.

In this study, Bolter and colleagues examined fossils from the Dinaledi Chamber of the Rising Star Cave System in South Africa. This site is famous for providing abundant remains of the hominin Homo naledi, including individuals ranging from infants to adult. These fossils date to the late Middle Pleistocene, between 335,000 and 226,000 years ago, possibly overlapping in time with the earliest members of our own species. The team identified a collection of arm and leg bones and a partial jaw as the remains of a single young individual designated DH7.

The bones and teeth of DH7 were not fully developed and display a mixture of maturity patterns seen in modern humans and earlier hominins. DH7 is estimated to be similar in its developmental stage to immature specimens of other fossil hominins between 8-11 years old at death. The authors note, however, that if Homo naledi had a slower growth rate like modern humans, DH7 might have been as old as 15. Further study is needed to assess how Homo naledi grew and where it fits into the evolution of human growth and development.

Bolter adds: The rare juvenile Homo naledi partial skeleton will shed light on whether this extinct species is more human-like in its development, or more primitive. The findings help reconstruct the selective pressures that shaped extended maturity in our own species.

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