Higher-order topological insulators, or HOTIs, have attracted attention for their ability to conduct electricity along one-dimensional lines on their surfaces, but this property is quite difficult to experimentally distinguish from other effects. By instead studying the interiors of these materials from a different perspective, a team of physicists has identified a surface signature that is unique to HOTIs that can determine how light reflects from their surfaces. As the team reports in the journal Nature Communications, this property could be used to experimentally confirm the existence of such topological states in real materials.

“The bulk or interior properties of HOTIs and other topological insulators have been discounted for a long time, but it turns out that a lot of interesting things are going on there as well,” said Barry Bradlyn, a physics professor at the University of Illinois Urbana-Champaign and a project co-lead. “When we looked at the surfaces through a more careful lens, they immediately stood out as far from trivial or featureless.”

For a long time, topological insulators have been noted for their ability to carry electrical currents on their surfaces while having insulating interiors. HOTIs, though, would restrict electrical conduction to a one-dimensional edge, or “hinge,” rather than the entire two-dimensional surface.

“Charles Kane, who discovered topological insulators, introduced a good analogy,” said Benjamin Wieder, a faculty member at the Institut de Physique Théorique, Université Paris-Saclay and project co-lead. “We can think of standard topological insulators as Hershey’s Kisses™. A conducting metal foil wrapped around an insulator that doesn’t conduct electricity, the chocolate in this case, is a pretty good way to understand them. With HOTIs, though, it’s as though someone took the foil and crumpled it into a thin ring encircling the chocolate.”

While surface conducting states have been observed in standard topological insulators, resolving the hinge in HOTIs has proven to be exceptionally difficult. Bradlyn explained that this property can only exist in material samples that have an unusually high degree of symmetry, meaning that their crystal structures must be unrealistically perfect.

Instead, Bradlyn and his collaborators turned their attention from the hinge state to the interior, where the electrons tend to “delocalize” from individual atoms and spread through the entire material. Unlike past studies that treat all electrons the same, the researchers considered differences in spin — a property of electrons that allows them to behave as miniature magnets.

“When we divided the interior electrons into their two possible spin states, up and down, we saw that each state leaves a unique surface signature,” said Kuan-Sen Lin, a physics graduate student at the U. of I. and the study’s lead author. “Even though the surface of a HOTI seems uninteresting, when you look at what each spin is separately doing on the surface, an unmistakable new behavior emerges that we hope will soon be measured in experiment.”

Because electrons with different spins behave as magnets, they respond differently when electric voltage is applied to the material, causing the two spin states to accumulate on opposite sides. This accumulation can be detected by taking advantage of the magneto-optic Kerr effect, in which the polarization, or orientation of the light, changes when it reflects from the surface of a magnet. In the case of HOTIs, the researchers calculated the polarization change from each spin state, and they found it to be exactly half the change that would result from an ordinary insulator.

“In the Kiss analogy, we might expect that, because the foil has been crumpled, the chocolate is in direct contact with the air,” said Gregory Fiete, a physics professor at Northeastern University and a corresponding author on the study. “With the spin-dependent surface behaviors we found, we can say that there is in fact a transparent layer that keeps the chocolate separate from the rest of the supermarket.”

By building on first-principles calculations with the specialized theoretical toolkit the researchers developed for this study, they identified the metal bismuth bromide as a very strong candidate for observing this effect. They are currently working with U. of I. physics professor Fahad Mahmood and U. of I. materials science & engineering professor Daniel Shoemaker to design and perform the experiments proposed in this study.

“The properties of HOTIs that we identified here would be very useful in quantum computing and spintronic devices, but we need to see them in experiment first,” Bradlyn said. Wieder added, “We hope that our work shows that the insides and surfaces of topological materials still host many mysterious and advantageous features if you know how to look for them.”

The article, “Spin-Resolved Topology and Partial Axion Angles in Three-Dimensional Insulators,” is available online.

The first principles calculations on bismuth bromide were performed by Zhaopeng Guo and Zhijun Wang of the Chinese Academy of Sciences

Additional computational support was provided by Jeremey Blackburn of Binghamton University.

Giandomenico Palumbo of the Dublin Institute for Advanced Studies and Yoonseok Hwang of the U. of I. also contributed to this work.

Support was provided by the Center for Quantum Sensing and Quantum Materials, an Energy Frontier Research Center of the U.S. Department of Energy, Office of Science, Basic Energy Sciences; the European Union and European Research Council’s Horizon Europe Research and Innovation Program; the National Science Foundation; the Alfred P. Sloan Foundation; the Air Force Office of Scientific Research; the Office of Naval Research; the National Natural Science Foundation of China; and the Strategic Priority Research Program of the Chinese Academy of Sciences.

One major challenge to this therapeutic approach is to accurately quantify tumor kinases in human biopsy samples. Many kinases are not abundantly present and are therefore more difficult to measure accurately. Although currently there are methods to quantify small amounts of kinases, measuring multiple kinases concurrently is cumbersome and impractical in a clinical setting where rapid data return is critical. It is crucial to develop methodologies to enrich kinases present in clinical samples, an important step toward effective personalized medicine.

In a study published in Clinical Proteomics, researchers at Baylor College of Medicine and collaborating institutions report the development of a kinase inhibitor pulldown assay (KiP) that can optimally enrich and quantify the small amounts of kinases present in biopsy samples in combination with mass-spectrometry techniques.

The researchers established the coverage and quantitative fidelity of the assay for kinases in a single-shot approach, optimized a 100-kinase targeted panel and determined the effectiveness of KiP in subtyping breast cancer patient-derived animal models and two breast cancer patient sample cohorts.

“Our study represents a convergence of advanced technologies, redefining basic medical research and paving the way for future clinical applications,” said first author Dr. Alexander Saltzman, senior bioinformatics analyst at the Mass Spectrometry Proteomics Core at Baylor.

“This paper emphasizes that new methods in protein mass spectrometry hold great promise for better definition of the individual druggable landscape present in each cancer and should be more widely used for research and, ultimately, clinical care,” said co-corresponding author Dr. Matthew Ellis, faculty at Baylor’s Lester and Sue Smith Breast Center.

“This methodology’s approach to identifying key kinases in cancer may even extend beyond these enzymes and into other low-abundance and biologically relevant targets,” said co-corresponding author Dr. Beom-Jun Kim, currently an associate director at AstraZeneca and an assistant professor at Baylor at the time of research.

Doug W. Chan, Matthew V. Holt, Junkai Wang, Eric J. Jaehnig, Meenakshi Anurag, Purba Singh and Anna Malovannayaalso contributed to this work. The authors are affiliated with Baylor College of Medicine, the Lester and Sue Smith Breast Center and/or the Dan L Duncan Comprehensive Cancer Center.

This work was supported by CPTAC PTRC grant National Cancer Institute’s Specialized Programs of Research Excellence (SPORE) (U01 CA214125) and a CPTAC PGDAC Award (U24 CA210954). Ellis received support from a CPRIT Established Investigator Award (RR140033) and from Ralph and Lisa Eads. Ellis also is a McNair Medical Institute Scholar. The BCM Mass Spectrometry Proteomics Core is supported in part by a Dan L Duncan Comprehensive Cancer Center Award (P30 CA125123), CPRIT Core Facility Awards (RP170005 and RP210227) and an NIH High-End Instrumentation Award (S10 OD026804).

The study, conducted by researchers at Georgetown University Medical Center in collaboration with Trinity College Dublin, Ireland, is reported January 16, 2024, in the Journal of Neuroscience.

Importantly for diagnostic and treatment purposes, the researchers found that the memory loss attributed to head injury was not a permanent pathological event driven by a neurodegenerative disease. Indeed, the researchers could reverse the amnesia to allow the mice to recall the lost memory, potentially allowing cognitive impairment caused by head impact to be clinically reversed.

The Georgetown investigators had previously found that the brain adapts to repeated head impacts by changing the way the synapses in the brain operate. This can cause trouble in forming new memories and remembering existing memories. In their new study, investigators were able to trigger mice to remember memories that had been forgotten due to head impacts.

“Our research gives us hope that we can design treatments to return the head-impact brain to its normal condition and recover cognitive function in humans that have poor memory caused by repeated head impacts,” says the study’s senior investigator, Mark Burns, PhD, a professor and Vice-Chair in Georgetown’s Department of Neuroscience and director of the Laboratory for Brain Injury and Dementia.

In the new study, the scientists gave two groups of mice a new memory by training them in a test they had never seen before. One group was exposed to a high frequency of mild head impacts for one week (similar to contact sport exposure in people) and one group were controls that didn’t receive the impacts. The impacted mice were unable to recall the new memory a week later.

“Most research in this area has been in human brains with chronic traumatic encephalopathy (CTE), which is a degenerative brain disease found in people with a history of repetitive head impact,” said Burns. “By contrast, our goal was to understand how the brain changes in response to the low-level head impacts that many young football players regularly experience.”

Researchers have found that, on average, college football players receive 21 head impacts per week with defensive ends receiving 41 head impacts per week. The number of head impacts to mice in this study were designed to mimic a week of exposure for a college football player, and each single head impact by itself was extraordinarily mild.

Using genetically modified mice allowed the researchers to see the neurons involved in learning new memories, and they found that these memory neurons (the “memory engram”) were equally present in both the control mice and the experimental mice.

To understand the physiology underlying these memory changes, the study’s first author, Daniel P. Chapman, Ph.D., said, “We are good at associating memories with places, and that’s because being in a place, or seeing a photo of a place, causes a reactivation of our memory engrams. This is why we examined the engram neurons to look for the specific signature of an activated neuron. When the mice see the room where they first learned the memory, the control mice are able to activate their memory engram, but the head impact mice were not. This is what was causing the amnesia.”

The researchers were able to reverse the amnesia to allow the mice to remember the lost memory using lasers to activate the engram cells. “We used an invasive technique to reverse memory loss in our mice, and unfortunately this is not translatable to humans,” Burns adds. “We are currently studying a number of non-invasive techniques to try to communicate to the brain that it is no longer in danger, and to open a window of plasticity that can reset the brain to its former state.”

In addition to Burns and Chapman the authors include Stefano Vicini at Georgetown University and Sarah D. Power and Tomás J. Ryan at Trinity College Dublin, Ireland.

This work was supported by the Mouse Behavior Core in the Georgetown University Neuroscience Department and by the National Institutes of Health (NIH) / National Institute of Neurological Disorders and Stroke (NINDS) grants R01NS107370 & R01NS121316. NINDS also supported F30 NS122281 and the Neural Injury and Plasticity Training Grant housed in the Center for Neural Injury and Recovery at Georgetown University (T32NS041218). Seed funding is from the CTE Research Fund at Georgetown.

The authors report having no personal financial interests related to the study.