The study was conducted by the group of Prof. Dan Peer, a pioneer in the use of RNA molecules for therapy and vaccines, world expert in nanomedicine, and a senior faculty member at TAU's Shmunis School of Biomedicine and Cancer Research, Department of Materials Sciences and Engineering at the Fleischman Faculty of Engineering, Jan Koum Center for Nanoscience and Nanotechnology, and Cancer Biology Research Center. The group, led by Neubauer doctoral student Shahd Qassem together with Dr. Gonna Somu Naidu, a postdoctoral fellow who collaborated with researchers from F. Hoffman La-Roche (Roche) pharmaceutical company in Switzerland. The article was published in Nature Communications.

Overcoming Previous Limitations of LNA

Prof. Peer explains: “Our study focused on unique RNA molecules called LNA. Unlike most RNA molecules, LNA molecules are very stable and do not break down easily. Consequently, until about 10 years ago, they were thought to have great potential as genetic drugs. However, experiments in laboratory animals, as well as clinical trials in humans (in chronic liver inflammation), showed that very large amounts of LNA are needed to achieve therapeutic efficacy. Moreover, administered by injection as a free drug, this high dosage proved very costly and caused severe side effects when spreading throughout the body. As a result, the effort to develop LNA-based drugs was abandoned. In our study we sought to test a new, better targeted and more effective approach.”

Prof. Dan Peer

Targeted Delivery With Lipid Nanoparticles

The researchers used a method previously developed at Prof. Peer’s lab for other RNA molecules (such as siRNA, mRNA, circRNA), now applying it to LNA: they encapsulated the molecules in lipid nanoparticles (LNPs) that serve as targeted drug carriers, delivering their therapeutic payload directly to the relevant organ in the body. Specifically, they chose an LNA molecule known to silence the TNFα gene, which plays a significant role in inflammatory bowel diseases. Screening a lipid library developed in Prof. Peer’s lab over the past 13 years, they identified the most suitable lipid molecules and encapsulated the LNA molecules in them. The resulted LNPs were injected into mice in a model of chronic bowel diseases such as colitis.

The findings were highly encouraging: the dosage required to achieve the desired therapeutic effect was 30 times lower compared to past studies – in which LNA molecules were administered as a free drug without lipid encapsulation. At the current dosage, delivered precisely to the correct site, the drug proved highly effective in treating the disease, without causing any side effects.

Prof. Peer: “Our study paves the way to developing new LNA-based drugs for inflammatory bowel diseases, as well as a wide range of other diseases – including rare genetic disorders, vascular and heart diseases, and neurological diseases such as Parkinson’s and Huntington’s. So far, we have demonstrated that the new method is effective in chronic bowel inflammation in mice. We hope to proceed to clinical trials in humans in the near future.”

Researchers from Tel Aviv University and Tel Aviv Sourasky Medical Center (“Ichilov”) have measured subjects' memory without asking whether they remembered something or not - -simply by tracking their eye movements as they watched animation videos. The study demonstrated that people actually remember more than they report. Moreover, this method can be used to measure memory in subjects who cannot speak— including infants, patients with brain injuries, and even animals.

The groundbreaking study was led by Dr. Flavio Jean Schmidig, Daniel Yamin, Dr. Omer Sharon, and Prof. Yuval Nir from the Sagol School of Neuroscience, the Gray Faculty of Medical and Health Sciences, and the Fleischman Faculty of Engineering at Tel Aviv University, as well as the Sagol Brain Institute at the Tel Aviv Sourasky Medical Center (“Ichilov”). The paper was published in Communications Psychology.

Beyond Traditional Memory Tests

"Memory is usually tested through direct questioning, with subjects verbally reporting whether they remember a certain event," explains Dr. Flavio Schmidig, currently completing his postdoctoral research in Prof. Yuval Nir’s lab at TAU. "For example, a subject might be shown a picture and asked if they remember having seen it before. However, this type of testing cannot be performed on animals, infants, patients with advanced Alzheimer’s, or people with head injuries who cannot speak. In this study we wanted to test memory in a more natural way, without asking people to remember."

"Gaze Memory" Illustration by Ana Yael

Inside the Experiment

In the study, 145 healthy subjects watched specially created animation videos that included a surprising event -  for example, a mouse suddenly jumping out of the corner of the frame. Tracking the subjects' eye movements  across two separate viewings of the same films, the researchers found that during the second viewing, subjects shifted their gaze toward the area where the surprising event was about to occur. A comparison of eye movement data with verbal memory reports indicated that gaze direction was in fact a more accurate measure.  In some cases, subjects said they did not remember the mouse, yet their gaze indicated that they did.

"The study proves that tracking eye movements can be an excellent alternative to verbal questions such as 'Do you remember this?'," says Daniel Yamin. "In a series of experiments, we demonstrated that gaze direction is a very sensitive gage of memory. Even when subjects said they didn’t remember, their gaze direction showed they did. This means that sometimes people remember, but can't say that they remember. By using AI machine learning techniques, it is possible to infer automatically, from just a few seconds of eye tracking, whether someone has seen a video before and formed a memory of it."

"When I ask you if you remember," adds Dr. Sharon, "you might give any of several answers: yes, no, not sure, etc. But when you look to the left of the frame due to a vague memory that something is about to happen there, finer nuances can be discerned. Now we have a tool for testing to what extent memory is present. Our new method is also more natural than traditional memory tests."

Looking Ahead

"The results of this study are especially relevant when verbal reports on memory cannot be obtained," adds Prof. Yuval Nir, the study's supervisor. "We believe that in the future this new method may be used for measuring memory functions in infants, Alzheimer's patients, and people with brain injury whose speech ability has been impaired. Gaze direction can be simply detected by the camera of a laptop or smartphone as the subject views a video - with no need for large, sophisticated equipment. The method has the potential for identifying memories even in situations that have so far been out of reach for us as scientists and clinicians."

“Existing 3D printers produce rough 3D structures that aren’t optically uniform and thus can’t be used for high-performance optics,” said research team leader Prof. Tal Carmon from the School of Electrical Engineering, Fleischman Faculty of Engineering, at Tel Aviv University in Israel. “Mimicking the way a pinecone’s scales bend outward to release seeds, our laser-induced technique triggers precise bending in ultra-thin glass sheets and can be used to create highly transparent, ultra-smooth 3D microphotonic devices for a variety of applications.”

In Optica, Optica Publishing Group’s journal for high-impact research, the researchers reported that the new laser-induced folding method can create 3-mm-long structures just 0.5 microns thick — about 1/200th the width of a human hair — setting a record length-to-thickness ratio of 3D structures. They also created helix shapes as well as concave and convex mirrors with surfaces so smooth — less than a nanometer of variation — that light reflects off them without distortion.

“Similar to how large 3D printers can fabricate almost any household item, photonic origami could enable a variety of tiny optical devices,” said Carmon. “For example, it can be used to generate micro-zoom lenses that could replace the five separate cameras used in most smartphones or to fabricate microphotonic components that use light instead of electricity — helping drive the shift toward faster, more efficient alternatives to traditional electronics in our computers.”

Structures made with photonic origami

Folded by accident

The new method was discovered by chance when Carmon asked graduate student Manya Malhotra to pinpoint where an invisible laser was hitting the glass by increasing the power until the spot glowed. Instead of glowing, the glass folded — revealing a simple and unexpected way to achieve glass folding. Malhotra then became the pioneering expert in photonic origami.

The glass folds because, as one side is heated with a laser, the glass liquifies and surface tension becomes stronger than gravity. As the surface tension increases, the glass is pulled into a fold precisely where the laser hits.

To apply this discovery, lab engineer Ronen Ben Daniel fabricated a thin layer of silica glass on a silicon chip and then shaped it into the required two-dimensional form. Before bending the glass, the researchers used etching to undercut the silicon beneath the glass sheet while leaving a small support region to hold it in place. Using CO2 laser pulses, they showed that thin glass sheets on a silicon chip could be folded in less than a millisecond, with a speed of 2 m/s and acceleration exceeding 2000 m/s2.

“It was exciting to see the folding silica under the microscope,” said Carmon. “The level of control we had over 3D microphotonic architecture came as a pleasant surprise — especially given that it was achieved with a simple setup involving just a single laser beam focused on the desired fold.”

Folding glass bar

Creating microscopic structures

Using the new photonic origami approach, the researchers were able to bend sheets of glass up to 10 microns thick into shapes ranging from a 90-degree knee to helices. They were able to do this with fine control, down to 0.1 microradians.

They also used the new approach to create an extremely lightweight and precise table structure containing a concave cavity mirror, a type of mirror that focuses light. This structure was inspired by a theoretical paper by P.K. Lam from the Australian National University that proposed exploring potential deviations from Newtonian gravity at very small scales using optically levitated cavity mirrors that might be possible to fabricate using photonic origami.

To make the tiny table light enough, the researchers began with a glass sheet just 1/20 the thickness of a human hair (5 microns). They patterned the sheet much like a child’s foldable paper table toy and used their photonic origami technique to fold it into a 3D table after fabricating a concave mirror at the base of the table.

According to the researchers, this ultra-light, compact table could, in principle, be optically levitated and used to explore possible deviations from Newtonian gravity. These types of experiments could provide insights into astronomical mysteries associated with dark matter —the only area in physics where experimental observations consistently defy current theoretical predictions.

“High-performance, 3D microphotonics had not been previously demonstrated,” said Carmon. “This new technique brings silica photonics — using glass to guide and control light — into the third dimension, opening up entirely new possibilities for high-performance, integrated optical devices.”

About Optica

Optica is an open-access journal dedicated to the rapid dissemination of high-impact peer-reviewed research across the entire spectrum of optics and photonics. Published monthly by Optica Publishing Group, the Journal provides a forum for pioneering research to be swiftly accessed by the international community, whether that research is theoretical or experimental, fundamental or applied. Optica maintains a distinguished editorial board of more than 60 associate editors from around the world and is overseen by Editor-in-Chief Prem Kumar, Northwestern University, USA. For more information, visit Optica.

About Optica Publishing Group

Optica Publishing Group is a division of the society, Optica, Advancing Optics and Photonics Worldwide. It publishes the largest collection of peer-reviewed and most-cited content in optics and photonics, including 18 prestigious journals, the society’s flagship member magazine, and papers and videos from more than 835 conferences. With over 400,000 journal articles, conference papers and videos to search, discover and access, our publications portfolio represents the full range of research in the field from around the globe.