David Nesbitt

JILA Postdoctoral Researcher Vít Svoboda is Awarded a 2023 JUNIOR STAR project by the Czech Science Foundation

Steven Burrows — Mon, 06 Nov 2023 22:08:50 +0000

JILA Postdoctoral Researcher Vít Svoboda is Awarded a 2023 JUNIOR STAR project by the Czech Science Foundation Steven Burrows Mon, 11/06/2023 - 15:08

Catherine Klauss / JILA Science Communicator

JILA postdoctoral researcher Vit Svoboda

Every year, the Czech Science Foundation (GCAR) funds several JUNIOR STAR projects focused on new research areas and building powerful collaborative teams. These projects are awarded to early-career scientists coming to the Czech Republic from other countries or with significant international experience. Each project is awarded CZK 25 million over the following five years.

This year, JILA postdoctoral researcher Vít Svoboda is one of the 17 awardees in the 2023 JUNIOR STAR cohort. The title of his JUNIOR STAR project: “Probing Chiral Dynamics on Femtosecond Timescales,” will dive into using time-resolved photoelectron spectroscopy to study the physics of chiral molecules during chemical transformations. Congratulations!

Off

Traditional

White

A New “Spin” on Ergodicity Breaking

Steven Burrows — Thu, 17 Aug 2023 17:26:35 +0000

A New “Spin” on Ergodicity Breaking Steven Burrows Thu, 08/17/2023 - 11:26

Kenna Hughes-Castleberry / JILA Science Communicator

The researchers studied the C60 molecule, also known as a bucky ball, to look at breaking its ergodicity. Image credit: Steven Burrows / JILA

In a recent Science paper, researchers led by JILA and NIST Fellow Jun Ye, along with collaborators JILA and NIST Fellow David Nesbitt, scientists from the University of Nevada, Reno, and Harvard University, observed novel ergodicity-breaking in C60, a highly symmetric molecule composed of 60 carbon atoms arranged on the vertices of a “soccer ball” pattern (with 20 hexagon faces and 12 pentagon faces). Their results revealed ergodicity breaking in the rotations of C60. Remarkably, they found that this ergodicity breaking occurs without symmetry breaking and can even turn on and off as the molecule spins faster and faster. Understanding ergodicity breaking can help scientists design better-optimized materials for energy and heat transfer.

Many everyday systems exhibit “ergodicity” such as heat spreading across a frying pan and smoke filling a room. In other words, matter or energy spreads evenly over time to all system parts as energy conservation allows. On the other hand, understanding how systems can violate (or “break”) ergodicity, such as magnets or superconductors, helps scientists understand and engineer other exotic states of matter.

In many cases, ergodicity breaking is tied to what physicists call “symmetry breaking.” For example, the internal magnetic moments of atoms in a magnet all point in one direction, either “up” or “down.” Despite possessing the same energy, these two distinct configurations are separated by an energy barrier. The “symmetry breaking” refers to the system assuming a configuration with lower symmetry than the physical laws governing its behavior would allow, such as all magnetic moments pointing “down” as the default state. At the same time, since the magnet has permanently settled into just one of two equal-energy configurations, it has also broken ergodicity.

Symmetry breaking: magnets and footballs

To understand rotational ergodicity breaking, postdoctoral researcher and lead author, Lee Liu explained: "Consider a football thrown in a tight clockwise spiral. You would never see the football spontaneously flip 180 degrees end-over-end in mid-flight! [figure 1B] This would require it to overcome an energy barrier. So a spiraling football maintains its end-to-end orientation in free flight, thereby breaking ergodicity and symmetry much like a magnet does.”

However, unlike footballs, isolated molecules must obey the rules of quantum mechanics. Specifically, the two ends of an ethylene molecule (a quantum analog of a football) are indistinguishable (figure 1C). Thus, reorienting a spinning ethylene molecule 180 degrees end-over-end also entails overcoming an energy barrier; the initial and final states are indistinguishable. The molecule does not have two distinct end-to-end orientations to choose from, and symmetry and ergodicity are restored, meaning that the molecule’s ground state is a combination, or the superposition, of both the final and initial states.

Infrared spectroscopy of C60

To probe the rotational dynamics of the C60 molecule, the researchers turned to a technique pioneered by the Ye group in 2016: combining buffer gas cooling with sensitive cavity-enhanced infrared spectroscopy. Using this technique, the researchers measured the infrared spectrum of C60 with 1000-fold higher sensitivity than previously achieved. It involved shining laser light on C60 molecules and “listening” to the frequencies of light they absorb. “Just like the sound of an instrument can tell you about its physical properties, molecular resonant frequencies, encoded in its infrared spectrum, can tell us about the structure and rotation dynamics of the molecule,” said Liu. Rather than physically rotating the molecule faster and faster, the researchers probed a gas-phase sample of many C60 molecules in which some rotated rapidly and some slowly. The resulting infrared spectrum contained snapshots of the molecule at various rotation speeds. “Stitching of these traces together generated the complete spectrum, unraveling the full picture of the ergodicity evolution (or breaking) of the molecule,” elaborated Dina Rosenberg, a fellow postdoctoral researcher in Ye’s group.

Through this process, the researchers uncovered an astonishing behavior of C60: spinning it at 2.3 GHz (billion rotations per second) makes it ergodic. This ergodic phase persists until 3.2 GHz when the molecule breaks ergodicity. As the molecule spins faster, it reverts back to being ergodic at 4.5 GHz. This peculiar switching behavior surprised the researchers, as ergodicity transitions typically occur only once the energy increases and in one direction. Curious, the team dove further into the spectrum to understand where this behavior originated.

Ergodicity breaking—Quantum Football, Frisbee, and Soccer

By analyzing the infrared spectrum, the researchers could infer deformations of the molecule induced by its rotation. As Liu elaborated: “Just like drag race car’s tires bulge more when rotated at a faster rate, the rotation rate of C60 dictates its structural deformation. The infrared spectra imply that two possibilities occur when the C60 rotation rate hits 2.3 GHz: It can flatten out into a frisbee shape or elongate into a football shape. The former occurs if it is rotating about a pentagon, and the latter if it is rotating about a hexagon (figure 1D). When C60 reaches 3.2 GHz, hexagonal and pentagonal rotations result in football-like deformation (figure 1E). At 4.5 GHz, hexagonal rotation generates a frisbee-like deformation while pentagonal rotation generates a football-like deformation.” As it turns out, the peculiar ergodicity transitions of C60 could be attributed entirely to this sequence of deformations induced by the molecule’s rotation.

Breaking Ergodicity But Not Symmetry

In the gas phase, C60 molecules collide so infrequently that they behave as if they were isolated, meaning that the indistinguishability of each carbon atom in C60 becomes important. Therefore, spinning the molecule about any pentagon is equivalent to spinning it about any other pentagon (see the red Xs in Figure 1D). Likewise, spinning the molecule about any hexagon is equivalent to spinning it about any other hexagon (see the blue Xs in Figure 1D). Just as in ethylene, the quantum indistinguishability of C60‘s carbon atoms restores the symmetry of the pentagonal and hexagonal rotational sectors. Nevertheless, the researchers’ data showed that the molecule’s rotation axis never switched between sectors.

The data showed two reasons for this rotational isolation around a single axis. At rotation rates below 3.2 and above 4.5 GHz, the pentagonal and hexagonal rotational sectors are isolated due to energy conservation. “It takes more energy to spin a football than a frisbee [due to its moment of inertia],” said Liu. In this range, the C60 molecules are ergodic as the pentagonal and hexagonal sectors explore all possible states in distinct energy ranges, just as in the case of ethylene. This corresponds to the fact that red and blue crosses in the energy surface of Figure 1D exist at different energy values.

At rotation rates between 3.2 and 4.5 GHz, pentagonal and hexagonal sectors exist in the same energy range. “This is because spinning a hexagonal and a pentagonal football can take the same amount of energy,” said Liu. “Nevertheless, C60 still fails to switch between the two rotational sectors because of an energy barrier—the same barrier that prevents a football from flipping end-over-end mid-flight. In this regime, therefore, C60 has broken ergodicity without breaking symmetry. This mechanism of ergodicity breaking without symmetry breaking, which can be understood simply in terms of deformations of a spinning molecule, was a total surprise to us,” said Liu. These results reveal a rare example of ergodicity breaking without symmetry breaking, giving further insight into the quantum dynamics of the system.

As the researchers surmise, many other molecular species await detailed investigation using the team’s new technique. “Molecules will likely harbor many more surprises, and we’re excited to discover them.”

In a recent Science paper, researchers led by JILA and NIST Fellow Jun Ye, along with collaborators JILA and NIST Fellow David Nesbitt, scientists from the University of Nevada, Reno, and Harvard University, observed novel ergodicity-breaking in C60, a highly symmetric molecule composed of 60 carbon atoms arranged on the vertices of a “soccer ball” pattern (with 20 hexagon faces and 12 pentagon faces). Their results revealed ergodicity breaking in the rotations of C60. Remarkably, they found that this ergodicity breaking occurs without symmetry breaking and can even turn on and off as the molecule spins faster and faster. Understanding ergodicity breaking can help scientists design better-optimized materials for energy and heat transfer.

Off

Traditional

White

Going for Gold: New Advancements in Hot Carrier Science

Steven Burrows — Wed, 16 Aug 2023 17:28:57 +0000

Going for Gold: New Advancements in Hot Carrier Science Steven Burrows Wed, 08/16/2023 - 11:28

Kenna Hughes-Castleberry / JILA Science Communicator

An artistic representation of a "hot carrier" gold nanoparticle. Image credit: Steven Burrows / JILA

In a new ACS Nano paper, JILA and NIST Fellow David Nesbitt, along with former graduate student Jacob Pettine and other collaborators, developed a new method for measuring the dynamics of specific particles known as “hot carriers,” as a function of both time and energy, unveiling detailed information that can be used to improve collection efficiencies.

Within nanoscience, gold nanoparticles have emerged as fascinating building blocks for numerous applications, ranging from catalysis and sensing to biomedicine. Among their remarkable properties is the ability to generate large numbers of “hot carriers” upon light absorption. Hot carriers refer to highly energetic charge carriers, such as electrons, which bounce around inside the gold nanoparticles. If the kinetic energy stored in these hot carriers could be fully collected, it would lead to significant efficiency boosts and new capabilities in photovoltaics, photochemical catalysis, nanophotonics, and nanoelectronics.

Hot carriers can be collected for energy harvesting in several applications, such as solar cells. However, how to achieve technologically useful collection efficiencies in systems incorporating nanoscale metals remains unclear. “Whereas solar cells can exhibit energy collection efficiencies over 30%, many gold nanoparticle studies show less than 1% efficiencies,” explained former JILA graduate student Jacob Pettine, now a Director's Postdoctoral Fellow at Los Alamos National Laboratory. “But, if we can boost these underlying collection efficiencies, then nanoparticles have the added bonus of operating across a broader range of the solar spectrum than silicon. There is room for growth; in some cases, hot electron extraction from these nanoparticles has even exceeded 10%. The challenge is understanding what exactly is happening at these tiny length scales and very fast time scales.”

As Good As Gold: A Study of Metals

Gold has played a significant role in human history, captivating civilizations for centuries due to its inherent beauty, rarity, and versatility. “Gold is an amazing material,” Nesbitt elaborated. “In macroscopically large ‘chunks,’ gold behaves in a way that is essentially chemically inert.” However, at a nanoscale, gold behaves differently. “At the nanoscopic level, ‘small’ clusters of gold (say 10–10,000 atoms) can exhibit exceptionally high chemical reactivity, for example, in developing catalysts for oxidation/reduction of CO (carbon monoxide) to/from CO2,” added Nesbitt. “Of even greater interest, these small gold clusters are extremely good at absorbing visible solar light, with many orders of magnitude higher absorption per unit area than the ‘blackest’ materials like carbon soot. That’s ‘ironic’ for a metal like gold, which we typically think of as highly reflective and not absorbing!”

Thanks to their ability to absorb sunlight, the gold nanoparticles can be filled to the energetic “brim” with hot carriers. Pettine, the study’s lead author, and Nesbitt wanted to study the hot carrier dynamics and needed a method to track the energy decay of these hot carriers throughout their short lifetimes. “When you come in with a photon, and that light gets absorbed inside of these particles, the question becomes, how does the electron’s energy decay after being excited?” Nesbitt stated. “How does this energy spill out? Does it simply instantaneously heat up the gold atoms (which is not terribly useful) or keep the energy in hot electron currents bouncing around inside a gold cluster?” To answer these questions, Pettine and Nesbitt realized they would have to develop a novel procedure to dive deeper into these nanomaterials.

Nanoscale Games of Darts

In their experimental setup, Pettine and Nesbitt combined two laser beams to excite, and then detect, the hot carriers. According to Pettine, “The system we built up in the Nesbitt Lab has allowed us to perform time-resolved studies on single nanoparticles. This is a totally unique capability, which we use with a technique called photoemission spectroscopy to resolve how fast the electrons decay or jump down from a higher to lower energy level, as a function of excitation energy.” Photoemission spectroscopy has a rich historical legacy within physics. “It is based on the photoelectric effect,” Pettine added. “The idea for our study is to kick electrons out of the system, detect them, and reconstruct what they were doing in the nanoparticle.”

To capture and measure the hot carrier dynamics, the researchers first excited their gold nanoparticles with a red laser, transforming them into hot carriers. Then, a blue laser probed the system and ejected the cluster of hot carriers out of the nanoparticles. Using a series of copper plates at various voltages as a lens for these electrons, the researchers could focus them onto a detector. Similar to a game of darts, the electron “splatter” on this detector could then be used to measure their energy dynamics. “The general idea is that you're taking a snapshot of the system,” Pettine elaborated. “The idea is to come in and knock it out of equilibrium with the first pulse, then we come in with a second pulse and see what the electrons are up to. We can do several things with this second pulse, like measure the absorption or reflectivity of the nanoparticle, but in our case, we can use it to kick out electrons so we can see how fast they move and in what direction.”

From their new method, Pettine and Nesbitt found some unexpected results. “Our findings help us shed light on a few more basic ideas,” said Pettine. “Amazingly, we still don't fully understand the dynamics in simple metals like gold when you shine a light on them. In fact, our recent work, including this paper, teaches us a few new things about gold in general. In nanoscale gold, whereas you might expect the surface to play a huge role due to the huge surface-to-volume ratio, we find that it plays almost no role! So, everything we're looking at really comes from the bulk of the material, and by studying these nanoparticles, we can actually get a remarkably accurate view of what likely happens in macroscopic bulk metal, like a chunk of gold.”

In a new ACS Nano paper, JILA and NIST Fellow David Nesbitt, along with former graduate student Jacob Pettine and other collaborators, developed a new method for measuring the dynamics of specific particles known as “hot carriers,” as a function of both time and energy, unveiling detailed information that can be used to improve collection efficiencies.

Off

Traditional

White

Looking at a Cellular Switch

Steven Burrows — Tue, 23 May 2023 17:56:28 +0000

Looking at a Cellular Switch Steven Burrows Tue, 05/23/2023 - 11:56

Kenna Hughes-Castleberry / JILA Science Communicator

An artistic rendering of the bacterium's riboswitch and its interactions with three different potential ligands. Image credit: Steven Burrows / JILA

Although one might think it would be simple, the genetics of bacteria can be rather complicated. A bacterium’s genes use a set of regulatory proteins and other molecules to monitor and change genetic expressions within the organism. One such mechanism is the riboswitch, a small piece of RNA that can turn a gene “on” or “off.” In order to “flip” this genetic switch, a riboswitch must bind to a specific ion or molecule, called a ligand, at a special riboswitch site called the aptamer. The ligand either activates the riboswitch (allowing it to regulate gene expression) or inactivates it until the ligand unbinds and leaves the aptamer. Understanding the relationship between ligands and aptamers can have big implications for many fields, including healthcare. “Understanding riboswitches and gene expression can help us develop better antimicrobial drugs,” explained JILA graduate student Andrea Marton Menendez. “The more we know about how to attack bacteria, the better, and if we can just target one small interaction that prevents or abets a gene from being translated or transcribed, we may have an easier way to treat bacterial infections.”

To better understand the dynamics of aptamer and ligand binding, Marton Menendez, along with JILA and NIST Fellow David Nesbitt, looked at the lysine (an amino acid) riboswitch in Bacillus subtilis, a common type of bacterium present in environments ranging from cow stomachs to deep sea hydrothermal vents. With this model organism, the researchers studied how different secondary ligands, like, potassium, cesium, and sodium, affect riboswitch activation, or its physical folding. The results have been published in the Journal of Physical Chemistry B.

Pairing Up Molecules

“We know that cells are complicated; living systems are really complicated,” Marton Menendez stated. “There's a lot going on in them. But when we're trying to study complicated processes, such as how exactly does DNA or RNA fold? we tend to simplify a lot. So, we usually end up reducing the system down to the simplest DNA/RNA structure we want to study and a few necessary salts.” With this idea in mind, Marton Menendez and Nesbitt analyzed their bacterial system using single molecule FRET (fluorescence resonance energy transfer) microscopy. This type of microscopy uses pairs of fluorescent dye molecules to tag specific nucleic acid positions, for this study in particular, a larger RNA riboswitch, allowing researchers to study binding, folding, and unfolding in real time

For this particular riboswitch to work, lysine first binds to the aptamer, which causes the aptamer to fold around lysine. However, in the x-ray crystallography images of the riboswitch, a potassium ion was also bound in the aptamer. According to Marton Menendez: “You can take crystal structures of these pieces of RNA and analyze their content. If the something shows up in the crystal structure, like the potassium ion, it is likely to have been very tightly bound in the riboswitch, because it means that it stayed there a long time. This tells us that potassium can play a ligand-like role for our riboswitch.”

Besides studying potassium as a potential ligand, the researchers also found that when potassium was bound to the riboswitch, it changed how the riboswitch interacted with lysine, the primary ligand. “We looked at how the riboswitch functions with respect to lysine and potassium because they affect each other,” Marton Menendez said, “mainly potassium can tweak some of the lysine’s binding abilities. That's interesting because we think of riboswitches as extremely specific and working only with one specific target molecule.” Instead, in the B. subtilis system, this riboswitch interacts with both lysine and potassium, cooperatively, with the presence of one species enhancing the impact of the other.

A Complex Bacterial Evolution

The idea of RNA regulating its own gene expression suggests that the history of bacterial genetic evolution is more complicated than expected. “If you are an early bacterium, how do you regulate your own genes?” Marton Menendez explained. “"There is a hypothesis that the ancient world had only RNA, no proteins or DNA. So RNA alone was responsible for gene storage and regulation. Riboswitches are an example of how RNA can perform these regulatory functions without protein assistance.” As proteins and more complicated organisms emerged, it is easy to expect these genetic systems to evolve to being more complicated, with a larger number of genes and corresponding regulatory proteins. However, results like Marton Menendez’s and Nesbitt’s suggest that there is more in the bacteria’s genes than meets the eye.

With a more complicated relationship between ligands and aptamers, Marton and Nesbitt were interested to see if this relationship could be found in other bacteria, not just B. subtilis. “There's also a version of a lysine riboswitch that exists in bacteria that live in habitats that are at 80 degrees Celsius, near hydrothermal vents on the sea floor,” elaborated Marton Menendez. “We are preparing a paper comparing how regulation by the lysine riboswitches differs between the two bacteria.”

More Complicated and Cooperative Ligand Relationships

Curious about the flexibility in ligand binding to their aptamer, Marton Menendez and Nesbitt decided to see just how versatile the aptamer could be. “We were also interested to see if potassium ion could then be swapped out for something similar,” Marton Menendez added. “The reason the riboswitch goes for lysine might have something to do with the fact that you've got potassium in the system. But, if you have something that's bigger or smaller than potassium, the riboswitch may have higher or lower binding affinity to lysine.” This experiment suggested an additional project looking at how closely connected the potassium and lysine were as ligands, and also to see if the aptamer would bind to other potential ligand-cation combinations of different sizes. Cations are small positive molecules that organic systems use to regulate different molecular processes.

As Marton Menendez said: “We studied the size effects of ions binding to the riboswitch. The riboswitch typically binds lysine with potassium, so we tested cesium and sodium ions [common molecules within the bacterium] instead of potassium. However, it seems that cesium might be too big and sodium too small to allow lysine to bind properly.” Analyzing the data, the researchers found that the aptamer was quite specific with respect to choice of cation preferentially binding to potassium and lysine as the “perfect Goldilocks combination of sizes.” Most importantly, this finding suggests that riboswitch activity can be regulated with vastly more flexibility by responding cooperatively to more than a single ligand species concentration at a time. This cooperativity is a trick that Nature has long exploited for increasing functionality of proteins (e.g., oxygen bonding to hemoglobin in red blood cells), so it would seem an entirely plausible strategy for nucleic acids as well.

Off

Traditional

White

JILA Breathalyzer Research Highlighted in Scientific American

Steven Burrows — Fri, 12 May 2023 17:24:15 +0000

JILA Breathalyzer Research Highlighted in Scientific American Steven Burrows Fri, 05/12/2023 - 11:24

Kenna Hughes-Castleberry / JILA Science Communicator

A versatile tool called an optical frequency comb can detect the signatures of diseases like COVID-19 in exhaled breath. Credit: Jasmina81/Getty Images

JILA and NIST Fellows David Nesbitt's and Jun Ye's recent results in their breathalyzer study have been highlighted in a new article in Scientific American. Using frequency combs, a particular type of laser array, scientists could detect specific molecules in the breath, including diseases like COVID-19. This research suggests huge implications for the future of disease diagnosis and prevention. “We are training our frequency comb nose using machine learning, and once it’s trained, it becomes an electronic dog—with much greater sensitivity,” Ye says in the article.

Read the full article here.

JILA and NIST Fellows David Nesbitt's and Jun Ye's recent results in their breathalyzer study have been highlighted in a new article in Scientific American. Using frequency combs, a particular type of laser array, scientists could detect specific molecules in the breath, including diseases like COVID-19. This research suggests huge implications for the future of disease diagnosis and prevention.

Off

Traditional

White

JILA and NIST Fellows Jun Ye's and David Nesbitt's Frequency Comb Breathalyzer Apparatus Highlighted in SPIE Photonics West Show Daily

Steven Burrows — Wed, 19 Apr 2023 17:36:01 +0000

JILA and NIST Fellows Jun Ye's and David Nesbitt's Frequency Comb Breathalyzer Apparatus Highlighted in SPIE Photonics West Show Daily Steven Burrows Wed, 04/19/2023 - 11:36

Kenna Hughes-Castleberry / JILA Science Communicator

Image of Ye's and Nesbitt's Frequency Comb Breathalyzer setup

JILA and NIST Fellows Jun Ye and David Nesbitt, along with their respective teams, have recently been highlighted in the latest issue of the SPIE Photonics West Show Daily, a publication from SPIE. This highlight focuses on the recent advancements in the frequency comb breathalyzer apparatus that the researchers have built and tested, which looks at diagnosing COVID-19 and other diseases. For this highlight, Qizhong Liang, a graduate student in the Ye group, was interviewed.

You can read the full highlight here (found on pages 24-26).

This research was also highlighted in Spectroscopy Europe World, which the full article here can be found at the hyperlink.

Off

Traditional

White

Using Frequency Comb Lasers as a Breathalyzer for COVID-19

Steven Burrows — Thu, 06 Apr 2023 18:07:01 +0000

Using Frequency Comb Lasers as a Breathalyzer for COVID-19 Steven Burrows Thu, 04/06/2023 - 12:07

Rebecca Jacobson / NIST Public Outreach Coordinator

JILA and NIST Fellows Jun Ye and David Nesbitt have developed a new breathalyzer method for COVID-19 diagnoses using a frequency comb laser. Image credit: NIST

JILA researchers have upgraded a breathalyzer based on Nobel Prize-winning frequency-comb technology and combined it with machine learning to detect SARS-CoV-2 infection in 170 volunteer subjects with excellent accuracy. Their achievement represents the first real-world test of the technology’s capability to diagnose disease in exhaled human breath.

Frequency comb technology has the potential to non-invasively diagnose more health conditions than other breath analysis techniques while also being faster and potentially more accurate than some other medical tests. Frequency combs act as rulers for precisely measuring different colors of light, including the infrared light absorbed by biomolecules in a person’s breath.

Human breath contains more than 1,000 different trace molecules, many of which are correlated with specific health conditions. JILA’s frequency comb breathalyzer identifies chemical signatures of molecules based on exact colors and amounts of infrared light absorbed by a sample of exhaled breath.

Back in 2008, Jun Ye and colleagues at JILA demonstrated the world’s first frequency comb breathalyzer, which measured the absorption of light in the near-infrared part of the optical spectrum. In 2021 they achieved a thousandfold improvement in detection sensitivity by extending the technique to the mid-infrared spectral region, where molecules absorb light much more strongly. This enables some breath molecules to be identified at the parts-per-trillion level where those with the lowest concentrations tend to be present.

The added benefit to this study was the use of machine learning. Machine learning — a form of artificial intelligence (AI) — processes and analyzes a massive, complex mélange of data from all the breath samples as measured by 14,836 comb “teeth,” each representing a different color or frequency to create a predictive model to diagnose disease.

“Molecules increase or decrease in their concentrations when associated with specific health conditions. Machine learning analyzes this information, identifies patterns and develops reliable criteria we can use to predict a diagnosis,” said Qizhong Liang, a graduate student in the Jun Ye group, who is lead author of a new paper presenting the findings.

JILA is jointly operated by the National Institute of Standards and Technology (NIST) and the University of Colorado Boulder (��Ҵ�ý�ƽ��). The research was conducted on breath samples collected from 170 ��Ҵ�ý�ƽ�� students and staff from May 2021 to January 2022. Approximately half of the volunteers tested positive for COVID-19 with standard PCR tests. The other half of the subjects tested negative. The young study group had a median age of 23 years old, and all were above 18 years old. The general campus population was more than 90% vaccinated.

“I do think that this comb technique is superior to anything out there,” NIST/JILA Fellow Jun Ye said. “The basic point is not just the detection sensitivity, but the fact that we can generate a far greater amount of data, or breath markers, really establishing a whole new field of ‘comb breathomics’ with the help of AI. With a database, we can then use it to search and study many other physiological conditions for human beings and to help advance the future of healthcare.”

The JILA comb breathalyzer method demonstrated excellent accuracy for detecting COVID by using machine learning algorithms on absorption patterns to predict SARS-CoV-2 infection. H₂O (water), HDO (semi-heavy water), H₂CO (formaldehyde), NH₃ (ammonia), CH₃OH (methanol), and NO₂ (nitrogen dioxide) were identified as discriminating molecules for detection of SARS-CoV-2 infection.

The team measured the accuracy of their results by creating a data graph comparing their predictions of COVID-19 against the PCR test results (which, it should be noted, have high but not perfect accuracy). On the graph, they computed a quantity known as the “area under the curve” (AUC). An AUC of 1, for example, would be expected for perfectly discriminating between ambient air and exhaled breath. An AUC of 0.5 would be expected for making random guesses on whether the individuals were born on odd or even months. The researchers measured an AUC of 0.849 for their COVID-19 predictions. An AUC of 0.8 or greater for medical diagnostic data is considered “excellent” accuracy.

In the future, the researchers could further increase the accuracy by expanding the spectral coverage, analyzing the patterns with more powerful AI techniques, and measuring and analyzing additional molecules, which could include the SARS-CoV-2 virus itself. Researchers would need to build a database of the specific IR colors absorbed by the virus (its spectral “fingerprint”) to potentially measure viral concentrations in the breath.

The researchers also identified significant differences in breath samples based on tobacco use and a variety of gastrointestinal symptoms such as lactose intolerance. This suggests broader capability of the technique for diagnosing different sets of diseases.

The research was published in the Journal of Breath Research, the official Journal of the International Association for Breath Research.

The researchers plan further studies to try to diagnose other conditions such as chronic obstructive pulmonary disease, the third leading cause of death worldwide according to the World Health Organization. The researchers have also recently boosted the comb breathalyzer’s diagnostic power by expanding the spectral coverage to detect additional molecules. They plan to employ additional AI approaches such as deep learning to improve its disease-detection abilities. Efforts are already under way to miniaturize and simplify the technology to make it portable and easy to use in hospitals and other care settings.

Ye said there is interest from the medical community in seeing the comb breathalyzer developed further and commercialized. Approval by the U.S. Food and Drug Administration (FDA) would be needed before the technology could be used in medical settings.

The most prevalent analytical technique in breath research now is gas chromatography combined with mass spectrometry, which can detect hundreds of exhaled molecules but works slowly, typically requiring tens of minutes. Its use of chemical process also unavoidably alters breath components and presents analytical challenges to identify breath profiles accurately. Frequency comb technology measures breath molecules in a non-destructive and real time manner and can promote a more accurate and repeatable determination of exhaled breath contents.

The research is supported by the Air Force Office of Scientific Research, the Department of Energy, the National Science Foundation, and NIST.

Off

Traditional

White

When Breath Becomes Data

Steven Burrows — Tue, 05 Oct 2021 18:26:51 +0000

When Breath Becomes Data Steven Burrows Tue, 10/05/2021 - 12:26

Kenna Hughes-Castleberry / JILA Science Communicator

Model of frequency comb filtering breath molecules. Image credit: Steven Burrows / JILA

There are many ways to diagnose health conditions. One of the most common methods is blood testing. This sort of test can look for hundreds of different kinds of molecules in the body to determine if an individual has any diseases or underlying conditions. Not everyone is a fan of needles, however, which makes blood tests a big deal for some people. Another method of diagnosis is breath analysis. In this process, an individual's breath is measured for different molecules as indicators of certain health conditions. Breath analysis has been fast progressing in recent years and is continuing to gain more and more research interest. It is, however, experimentally challenging due to the extremely low concentrations of molecules present in each breath, limited number of detectable molecular species, and the long data-analysis time required. Now, a JILA-based collaboration between the labs of NIST Fellows Jun Ye and David Nesbitt has resulted in a more robust and precise breath-testing apparatus. In combining a special type of laser with a mirrored cavity, the team of researchers was able to precisely measure four molecules in human breath at unprecedented sensitivity levels, with the promise of measuring many more types of molecules. The team published their findings in the Proceedings of the National Academy of Sciences (PNAS).

Mirrors and Lasers

In order to make an effective breath-testing apparatus, the team of researchers needed a way to "code" the different molecules found in breath into usable data. They did this through a "fingerprinting" process. Using a laser known as a frequency comb, the team could shine over 10,000 different colors of infrared light at the breath sample. According to first author Qizhong Liang, the variation in color was important: "Molecules absorb infrared light in a selective manner. They give different absorption strengths to light at different optical frequencies. How the absorption pattern looks is governed by the molecular rotational and vibrational properties." Since each molecule in the breath absorbed light at a different frequency, this "fingerprinted" each molecule, associating it with a unique absorption pattern, making it easier for the researchers to measure and analyze the data. Liang added that "measuring the optical absorption signals over a broad spectral range, one can simultaneously determine what molecular species are present." As many other devices take tens of minutes, or could only test one molecule species at a time, this new apparatus increased the number of analyzed molecules in breath-testing significantly by analyzing breath in real-time–a reduction in analysis time and presumably, cost.

The implementation of the frequency comb was essential for the apparatus to work. The colors within this special type of laser are evenly spaced in frequency, making them easier to fine-tune than other lasers. In order for the frequency comb to work properly, it has to be coupled to the mirrored cavity by matching the cavity's resonance–a specific frequency that corresponds to the longitudinal mode of that cavity. Depending on the size and shape of the cavity, the resonance may vary. Matching the cavity resonance frequency to the laser frequency helped the team to better measure molecules. "By controlling and matching the light frequency to a specific cavity resonance frequency, one can measure ultrasensitive molecular absorption signals over a broad frequency range in a simultaneous manner," Liang explained. "In our experiment, we can measure absorption signals at 15,000 isolated optical frequencies in just three minutes. This allows us to detect multiple molecular species in a highly time-efficient manner." The increased efficiency made the apparatus capable of measuring and analyzing data in almost real-time.

In building their effective apparatus, the researchers realized that some molecules in breath had very weak light absorption. To boost this absorption, the team built a cavity with a pair of high-reflectivity mirrors. The mirrors enhanced the interaction length between the laser light and breath molecules by a factor of several thousand in order to make the absorption stronger in just one breath. The mirrored cavity increased the sensitivity of the apparatus, furthering its precision.

Testing the Breath: Bananas...and Booze?

After the apparatus was constructed, the researchers needed to test its effectiveness. They decided to look at methanol as a target molecule. In order to see possible changes in methanol levels, they had a test subject consume foods and drinks in an effort to change the methanol levels in their breath. "We actually started with alcohol, because there are some literature reviews in the past that suggest some change in the methanol levels of breath," Liang grinned. "This sounds like a fun experiment because your test subject gets the opportunity to drink alcohol. We tried brandy, whisky and soju, a South Korean wine. It turns out none of these alcohols actually gave some obvious change in molecular concentrations." Though drinking alcohol in the name of science would have been a rather whimsical endeavor, the team ultimately had to abandon the idea.
Instead, they turned to fruit, and found that collecting data in 15-minute intervals, while their test subject ate ripe bananas, resulted in a gradual increase of methanol concentration in the breath. Liang found the entire process to be: "…very impressive. We could monitor several other molecules simultaneously, like methane and partially-deuterated water. We could confirm their concentrations did not change over the time after the banana consumption."

COVID-19 Ready

After seeing success in their apparatus, the team of researchers is shifting their focus towards diagnosing COVID-19 in people. According to postdoctoral researcher Jutta Toscano: "We are currently conducting a campus-wide study to understand how much the molecules present in people's breath can tell us about the state of their health, including the presence of various conditions that could be affecting them, such as COVID-19, diabetes, and asthma, among others." Having a less invasive method to diagnose COVI9-19 will not only make it easier to contain the virus, but can also be a cheaper and faster option for the government in the long run. Toscano found that: "Collaborating and learning from people in other fields of research (from engineering to physiology) has been a very exciting part of this project. Building bridges across disciplines and sharing expertise to reach a common scientific goal is both fulfilling and formative." Such collaborations as this can result in timely and beneficial real-world applications, like the breath-analyzer apparatus, which may change the way COVID-19 infections are analyzed and treated.

Breath analysis has been fast progressing in recent years and is continuing to gain more and more research interest. It is, however, experimentally challenging due to the extremely low concentrations of molecules present in each breath, limited number of detectable molecular species, and the long data-analysis time required. Now, a JILA-based collaboration between the labs of NIST Fellows Jun Ye and David Nesbitt has resulted in a more robust and precise breath-testing apparatus. In combining a special type of laser with a mirrored cavity, the team of researchers was able to precisely measure four molecules in human breath at unprecedented sensitivity levels, with the promise of measuring many more types of molecules.

Off

Traditional

White

Overcoming Camera Blur

Steven Burrows — Tue, 10 Aug 2021 18:49:11 +0000

Overcoming Camera Blur Steven Burrows Tue, 08/10/2021 - 12:49

Kenna Hughes-Castleberry / JILA Science Communicator

Model of DNA Folding and motion blur. Image credit: Steven Burrows / JILA

The basic question of how strands of nucleic acids (DNA and RNA) fold and hybridize has been studied thoroughly by biophysicists around the globe. In particular, there can be unexpected challenges in obtaining accurate kinetic data when studying the physics of how DNA and RNA fold and unfold at the single molecule level. One problem comes from temporal camera blur, as the cameras used to capture signal photons emitted by these molecules do so in a finite time window that can blur the image and thereby skew the kinetic data In a paper published in the Journal of Physical Chemistry B, JILA Fellow David Nesbitt, and first author, and graduate student, David Nicholson, propose an extremely simple yet broadly effective way to overcome this camera blur. According to Nicholson: "We wanted to measure the speed of nucleic acid folding, but to our dismay, we encountered a systematic bias that comes up when you do these kinetic measurements if you're not careful. Specifically, you get into trouble if the DNA is folding as quickly as the camera is recording images. So, we started thinking, how can we come up with a way to fix this problem?" In looking at their data, Nicholson and Nesbitt realized that they could reduce this systematic error and extend the domain of kinetic study in a surprisingly simple way by shining a light on the problem, in particular, a strobe light.

Why Throwing Data Away is Beneficial... Sometimes

Nicholson and Nesbitt realized that they could reduce the camera blur by shining pulsed, rather than continuous, laser light onto the molecules, reducing the time fraction of observation (i.e., duty cycle), but making their total error due to camera blur significantly lower. Nesbitt explained: "This was entirely David Nicholson’s idea, for which I simply gave him a little encouragement to pursue. The key idea is really like a stroboscope in a crowded night club or disco. Basically, we're flashing light onto the molecular 'dance' in a short time window faster than the camera frame rate. This of course requires us to throw away information between pulses, but at the same time, provides much better kinetic information from each pulse." The data thrown away can be accounted for by a mathematical correction, resulting in kinetics that are accurate even up to the camera frame acquisition rate, an order of magnitude in improvement. Nesbitt clarified the fix in more technical terms: “The method reduces the error because normal analysis of blurred objects has a built-in mathematical bias that tends to make kinetic analysis of these actions appear systematically slower.” Nicholson and Nesbitt had just found a simple solution for their problem in a stroboscope.

A stroboscope is a fancy word for a strobe light. Stroboscopic imaging, a process wherein an objects movement is represented by short light samples, has been used for many decades, though not in single-molecule kinetic measurements. "Actually, we thought for sure someone would have already published this concept long ago," Nicholson commented, "but after digging through the literature, it turns out there was still a lot of confusion about how to deal with single-molecule camera blur. So, we said, 'OK, this seems like something researchers could find useful.’" With regard to the simplicity of such a method, both Nicholson and Nesbitt initially wondered if this approach was even worth publishing at all. "Once you appreciate the basic idea behind the method, it seems so completely simple, and frankly, a bit obvious! We wondered,' is this really new and worth publishing?' But in fact, it's exactly those sorts of discoveries that belong in the literature because everyone can so easily implement it." The fact that this simple method had not already been published made Nicholson and Nesbitt more interested in making their method public for everyone to use. As Nicholson noted, this method would be inexpensive for researchers to implement, and they would see an immediate improvement in their range of measurement by as much as an order of magnitude. The team hoped that their method could save researchers time and effort when it came to fixing kinetic measurement bandwidth problems associated with camera blur. They also realized that this method would help save researchers valuable time when it came to data analysis and to extending their kinetic measurements up to the camera frame acquisition rate limit. Said Nesbitt: "I think comparing our stroboscopic method to a flash on a camera is helpful. We're taking images with this method to get rid of motion blur. It's allowing us to see our DNA molecules more crisply."

Spreading the Word

Nesbitt and Nicholson look forward to seeing their work implemented by other researchers, "The wonderful corollary is that, as camera technologies get better and faster, David Nicholson’s method should improve right along with them," Nesbitt explained. The benefits of this new method are not only cost-effective and easy to use, but clearly can adapt as the technology itself improves in the coming years.

Off

Traditional

White

Guiding Electrons With Gold Nanostars

Steven Burrows — Fri, 13 Mar 2020 17:40:46 +0000

Guiding Electrons With Gold Nanostars Steven Burrows Fri, 03/13/2020 - 11:40

Rebecca Jacobson / JILA Science Communicator

The Nesbitt Lab has learned how to use optics and gold nanostars to steer nanoscale electric currents. Image credit: Steven Burrows / JILA

In nearly 80 years, computers have shrunk from electronic behemoths that filled 50-by-30-foot rooms to smartphones that fit in the palm of your hand.

That’s largely because transistors have shrunk down to the nanoscale—ten to a hundred billionths of a meter, which is a thousand times smaller than the width of a human hair. Those transistors control current in computer chips; they store the binary 1s and 0s your computer uses to process information. But recently scientists have run into a problem.

“We’re getting about as small as we can go. Recently we’ve been approaching the limit where transistors can’t get much smaller because you’re nearing the few-atom regime,” said Jake Pettine, a graduate student in the Nesbitt Lab at JILA.

But, if computers can’t get much smaller, why not make them faster? Today’s computers operate at a few gigahertz, with electrons moving around as fast as they can through the transistors, Pettine pointed out. At a few gigahertz, a computer goes through a cycle a few billion times a second.

“That’s pretty fast, but visible light is about a hundred thousand times faster,” he said. “So, one way to go faster, instead of controlling those electrons with typical electronic means, is to control them with light.”

“You can process information on a much faster timescale, as opposed to just having slow, lumbering voltages coming in from wires,” said JILA Fellow David Nesbitt.

To do that, you need to use light to steer electric currents in nanoscale circuits. Pettine and the Nesbitt Lab may have found a means of guiding that light using gold nanostars. Their findings were published recently in Nature Communications.

The golden touch

Gold is a key to the nanostar’s usefulness. The first thing you notice about gold is its brilliant shine, Nesbitt said, and that effect only gets stronger as the particles get smaller.

“It’s the material that provides a terrific hook to bring photons into it…Gold has these marvelous properties that allow it to have exceptionally strong interactions with light in the visible [spectrum], where many ultrafast lasers operate. As you shrink [gold] down to the nanoscale, it interacts more strongly per volume.”

Scientists have exploited this unique characteristic since the days of alchemy. Tiny particles of gold were embedded in glass to create red stained glass for medieval cathedrals. When white sunlight hits the particles in the glass, the gold absorbs blue light and transmits deep ruby red light.

Unlike light through a stained-glass window, Pettine and Nesbitt need to draw light into the gold nanostars and concentrate it at specific “hot spots.” That’s where the nanostars’ shapes come in handy.

A star is born

The gold nanostars in the Nesbitt Lab are shaped like toy jacks or caltrops, with pointy arms protruding from their small center. With a specialized “recipe”, the lab’s collaborator at Northwestern University grow the nanostars like crystals in a cave to reach the right size and shapes.

No two stars are exactly alike, with different arms of different lengths pointing in various directions. Those arms act like antennas, drawing in light from the laser, Nesbitt explained.

“Think of the nanostar just as being an old-style television antenna…pointing in different directions and able to bring in different stations as a result,” Nesbitt said. “The stations that these nanostars are communicating with are different colors of laser light.”

The electrons at the tips of these antennas are able to “tune in” to the energy coming from the laser light. But now, they need some direction.

Steering on the Fermi sea

There are millions of free-floating electrons inside the gold nanostars, collectively known as the Fermi sea. Hit the electron sea with light and it creates waves. Without direction, the electrons will just bob up and down in place, like a cork on the ocean.

That’s why the asymmetric antenna-like arms of the nanostars are so important. Electric fields collect near their sharp points, Nesbitt pointed out. As electrons slosh along the elongated arms, they pile up at the sharp tips and create a hot spot.

The electrons stream off this hot spot in a process called photoemission, or the photoelectric effect.

“When electrons build up at these really sharp tips, they can shoot out in a certain direction…If the electrons were just going back and forth, the electrons have energy but we can’t do much with it. Once you actually kick them off in a certain direction, that’s when you get useful current,” Pettine explained.

Pettine found that by changing the polarization and/or color of the laser, he could change which tips the current flowed through, and how many electrons spilled out.

“This is where the steering idea comes in,” Pettine added. “For instance, we change the angle of the light—the polarization of the light—and we see that as we do that, the angle of the emitted electrons changes.”

In this study, Pettine and his group created a detailed map to show exactly which light colors/polarizations couple to any particular tip. This kind of control is promising as a step toward new computers and technologies using electron beams, such as electron microscopy or electron diffraction.

“Part of this paper is showing that we can do this experimentally, and the other part is introducing a full model that we can then apply to other nanoscale systems…So, the nanostars are just a good prototypical system to illustrate these behaviors,” Pettine said.

You can read the full study in Nature Communications. This research was supported by the Air Force, the National Science Foundation’s Physics Frontier Center Grant, and a National Science Foundation Graduate Research Fellowship.

Computer chips can’t get much smaller, but they can get faster. That means moving electrons around more quickly. To speed up computers and possibly enable other technologies, scientists want to use light to drive electric currents. The Nesbitt Lab studied gold nanostars and found a way to optically control currents at the nanoscale.

Off

Traditional

White