The lab of chemical and biomolecular engineer Xue Sherry Gao discovered a way to further tap the therapeutic potential of proteolysis targeting chimeras (PROTACs), small molecules that are used as effective tools for treating cancer, immune disorders, viral infections and neurodegenerative diseases.

Gao and collaborators reengineered the PROTAC molecular infrastructure and showed it can be used to achieve chemically induced dimerization (CID), a mechanism by which two proteins bind together only in the presence of a specific third molecule known as an inducer. The research is described in a study published in the Journal of the American Chemical Society.

“The novelty of this is the extent of control that combining these two mechanisms gives us over inducing gene activation at desired locations in the body and for desired durations,” Gao said.

“Small molecules can act as a switch to turn gene expression on and off,” she said. “Temporal control is a result of the fact that small molecules are metabolized by living organisms. What this means is that you can schedule for a certain gene to be expressed for a certain amount of time.

“In terms of spatial control, we can deliver the system only to the organ or site of the body where it is needed,” Gao continued. “You don’t need to have the medication go through your whole body and generate unnecessary and harmful toxicity.”

The CID mechanism is a key part of many biological processes, and over the past two decades scientists have devised a host of ways to engineer it to serve medical, research and even manufacturing needs. The development highlights the growing impact of synthetic biology, which takes an engineering approach to biological systems, repurposing their mechanisms to harness new resources.

Sirolimus, formerly known as rapamycin. is an example of a molecule that can act as an inducer and form CID systems with multiple cell pathways in the body. Discovered in 1972 in soil bacteria on Easter Island, the compound has been used as an antitumor and immunosuppressant drug. More recently, it was touted as a potential anti-aging drug after researchers discovered it could interfere with a cellular pathway that activates lysosomes, organelles responsible for cleaning up damaged cells.

“CID systems are attractive tools because they enable precise control over molecular interactions, which in turn can activate or inhibit biological outcomes, such as, for example insulin production in a diabetic patient or tumor growth in a cancer patient,” Gao said.

“Right now there are only a limited number of functional and efficient CID systems,” she added. “I wanted to address this unmet need. I saw PROTACs, which are already being used with good results as therapies, as an opportunity to expand the CID toolbox.”

PROTACs work by targeting specific proteins, such as those found in a tumor, causing them to disintegrate. One side of the molecule binds to a targeted harmful protein, another side flags down a specific enzyme that initiates protein degradation and a third element connects the two sides together.

“You can think of this mechanism as similar to a smart missile that relies on a sensor to track its target,” Gao said. “The vocabulary is suggestive in this sense, too, since the protein you want to destroy is called a ‘target protein,’ and the part of the PROTAC system that binds to the target protein is called a ‘warhead.’ We are hijacking this system to control gene expression instead.”

The advantage of PROTACs over other drugs is that they can be effective in small doses and do not lead to the development of drug resistance. There are over 1,600 PROTAC small molecules approved for cancer therapy, acting on more than 100 human protein targets.

“PROTACs are very efficient and act with great specificity against oncogenic proteins, which are proteins encoded by certain activated or dysregulated genes that have a potential to cause cancer,” Gao said. “We wanted to harness that efficiency and precision and put it to work in a new way. We redesigned PROTAC from a protein-degradation system to a gene-activation system.

“Ultimately, I hope this will prove useful in the context of treating real diseases,” she continued. “The ability to regulate when and where genes are activated in the body could help solve a wide range of medical problems. My main goal with this project is to have a small molecule-controlled gene expression system, including the CRISPR genome editors.”

Gao is Rice’s T.N. Law Assistant Professor of Chemical and Biomolecular Engineering and an assistant professor of bioengineering and chemistry. The study was developed in collaboration with the Zheng Sun lab at Baylor College of Medicine.

The National Science Foundation (2143626), the Robert A. Welch Foundation (C-1952), the National Institutes of Health (HL157714, HL153320, DK111436, AG069966, ES027544), the John S. Dunn Foundation, the Clifford Elder White Graham Endowed Research Fund, the Cardiovascular Research Institute at Baylor College of Medicine, the Dan L. Duncan Comprehensive Cancer Center (P30CA125123), the Specialized Programs of Research Excellence (P50CA126752), the Gulf Coast Center for Precision Environmental Health (P30ES030285) and the Texas Medical Center Digestive Diseases Center (P30DK056338) supported the research.

Today’s biggest quantum computers still only have a few hundred “qubits,” the quantum equivalents of digital bits.

Now, researchers at MIT have proposed a new approach to making qubits and controlling them to read and write data. The method, which is theoretical at this stage, is based on measuring and controlling the spins of atomic nuclei, using beams of light from two lasers of slightly different colors. The findings are described in a paper published in the journal Physical Review X, written by MIT doctoral student Haowei Xu, professors Ju Li and Paola Cappellaro, and four others.

Nuclear spins have long been recognized as potential building blocks for quantum-based information processing and communications systems, and so have photons, the elementary particles that are discreet packets, or “quanta,” of electromagnetic radiation. But coaxing these two quantum objects to work together was difficult because atomic nuclei and photons barely interact, and their natural frequencies differ by six to nine orders of magnitude.

In the new process developed by the MIT team, the difference in the frequency of an incoming laser beam matches the transition frequencies of the nuclear spin, nudging the nuclear spin to flip a certain way.

“We have found a novel, powerful way to interface nuclear spins with optical photons from lasers,” says Cappellaro, a professor of nuclear science and engineering. “This novel coupling mechanism enables their control and measurement, which now makes using nuclear spins as qubits a much more promising endeavor.”

The process is completely tunable, the researchers say. For example, one of the lasers could be tuned to match the frequencies of existing telecom systems, thus turning the nuclear spins into quantum repeaters to enable long-distance- quantum communication.

Previous attempts to use light to affect nuclear spins were indirect, coupling instead to electron spins surrounding that nucleus, which in turn would affect the nucleus though magnetic interactions. But this requires the existence of nearby unpaired electron spins and leads to additional noise on the nuclear spins. For the new approach, the researchers took advantage of the fact that many nuclei have an electric quadrupole, which leads to an electric nuclear quadrupolar interaction with the environment. This interaction can be affected by light in order to change the state of the nucleus itself.

“Nuclear spin is usually pretty weakly interacting,” says Li. “But by using the fact that some nuclei have an electric quadrupole, we can induce this second-order, nonlinear optical effect that directly couples to the nuclear spin, without any intermediate electron spins. This allows us to directly manipulate the nuclear spin.”

Among other things, this can allow the precise identification and even mapping of isotopes of materials, while Raman spectroscopy, a well-established method based on analogous physics, can identify the chemistry and structure of the material, but not isotopes. This capability could have many applications, the researchers say.

As for quantum memory, typical devices presently being used or considered for quantum computing have coherence times — meaning the amount of time that stored information can be reliably kept intact — that tend to be measured in tiny fractions of a second. But with the nuclear spin system, the quantum coherence times are measured in hours.

Since optical photons are used for long-distance communications through fiber-optic networks, the ability to directly couple these photons to quantum memory or sensing devices could provide significant benefits in new communications systems, the team says. In addition, the effect could be used to provide an efficient way of translating one set of wavelengths to another. “We are thinking of using nuclear spins for the transduction of microwave photons and optical photons,” Xu says, adding that this can provide greater fidelity for such translation than other methods.

So far, the work is theoretical, so the next step is to implement the concept in actual laboratory devices, probably first of all in a spectroscopic system. “This may be a good candidate for the proof-of-principle experiment,” Xu says. After that, they will tackle quantum devices such as memory or transduction effects, he says.

The team also included Changhao Li, Guoqing Wang, Hua Wang, Hao Tang, and Ariel Barr, all at MIT.

At the Aspen Center for Physics in Colorado, Vayrynen discussed this issue with a colleague from the Weizmann Institute of Science in Israel, Dr. Yuval Oreg, who helped circumvent the obstacle. The team used this new understanding of their calculations to propose a quantum device that could be tested experimentally to succinctly realize emergent particles such as the Fibonacci anyon. They have published their findings, “Multichannel topological Kondo effect,” in Physical Review Letters on February 10, 2023.

Condensed matter theory is a field of physics that studies, for example, the properties of electronic quantum systems, with applications to technologies such as superconductors, transistors, or quantum computing devices. One of the challenges in this field is understanding the quantum mechanical behavior of many electrons, also known as the “many-body problem.” It is a problem because it can only be theoretically modeled in very limited cases. However, even in those limited cases, rich emergent phenomena such as collective excitations or fractionally charged emergent “quasi”-particles are known to emerge. These phenomena are a result of the complex interactions between electrons and can lead to the development of new materials and technologies.

“In our paper, we propose a quantum device that is simple enough to be theoretically modeled and tested experimentally in the future, yet also complex enough to display non-trivial emergent particles,” says Vayrynen. “Our results indicate that the proposed device can realize an emergent particle called a Fibonacci anyon that can be used as a building block of a quantum computer. The device is therefore a promising candidate for the development of quantum computing technology.”

This discovery could be used in future quantum computers in a way that allows one to make them more resistant to decoherence, a.k.a. noise.

According to their publication, the team introduced a physically motivated N-channel generalization of a topological Kondo model. Starting from the simplest case N = 2, they conjecture a stable intermediate coupling fixed point and evaluate the resulting low-temperature impurity entropy. The impurity entropy indicates that an emergent Fibonacci anyon can be realized in the N = 2 model.

According to Li, “a Fibonacci anyon is an emergent particle with the property that as you add more particles to the system, the number of quantum states grows like the Fibonacci sequence, 1, 2, 3, 5, 8, etc. In our system, a small quantum device is connected to conduction electron leads which will overly screen the device and can result in an emergent Fibonacci anyon.”

The team also gives a number of predictions that could be experimentally tested in future quantum devices.

“We evaluate the zero-temperature impurity entropy and conductance to obtain experimentally observable signatures of our results. In the large-N limit we evaluate the full cross over function describing the temperature-dependent conductance,” says Vayrynen.

This research is the first in a series that the Purdue team of Li and Vayrynen will work on. They collaborated with a senior scientist from Max Planck Institute for Solid State Research in Germany, Dr. Elio König, and posted a related work, “Topological Symplectic Kondo Effect,” in a preprint arXiv (2210.16614) on October 20, 2022.

This research was based on work supported by the Quantum Science Center, a U.S. Department of Energy National Quantum Information Science Research Center headquartered at DOE’s Oak Ridge National Laboratory. Dr. Yong Chen, the Karl Lark-Horovitz Professor of Physics and Astronomy and Professor of Electrical and Computer Engineering, is on the QSC’s Governance Advisory Board, and Purdue is one of the center’s core partners.

To test their accuracy, models are programmed to simulate past climate to see if they agree with the geologic evidence. The model simulations can conflict with the evidence. How can we know which is correct?

A review article published today in Nature addresses this conflict between models and evidence, known as the Holocene global temperature conundrum. Lead author Darrell Kaufman, a Regents’ professor in the School of Earth and Sustainability, and University of Arizona postdoctoral researcher Ellie Broadman, a co-author who worked on this study while earning her Ph.D. at NAU, analyzed a broad swath of available data from the last 12,000 years to break down the conundrum. The study builds on work Kaufman did that was included in the latest major climate report by the Intergovernmental Panel on Climate Change (IPCC) and looks at whether the global average temperature 6,500 years ago was warmer, as indicated by proxy evidence from natural archives of past climate information, or colder, as simulated by models, in comparison to the late 19^th century, when the Industrial Revolution led to a significant increase in human-caused warming.

This comprehensive assessment concludes that the global average temperature about 6,500 years ago was likely warmer and was followed by a multi-millennial cooling trend that ended in the 1800s. But, they cautioned, uncertainty still exists despite recent studies that claimed to have resolved the conundrum.

“Quantifying the average temperature of the earth during the past, when some places were warming while others were cooling, is challenging, and more research is needed to firmly resolve the conundrum,” Kaufman said. “But tracing changes in global average temperature is important because it’s the same metric used to gauge the march of human-caused warming and to identify internationally negotiated targets to limit it. In particular, our review revealed how surprisingly little we know about slow-moving climate variability, including forces now set into motion by humans that will play out as sea level rises and permafrost thaws over coming millennia.”

What we know

We know more about the climate of the Holocene, which began after the last major ice age ended 12,000 years ago, than any other multi-millennial period. There are published studies from a variety of natural archives that store information about historical changes that occurred in the atmosphere, oceans, cryosphere and on land; studies that look at the forces that drove past climate changes, such as Earth’s orbit, solar irradiance, volcanic eruptions and greenhouse gases; and climate model simulations that translate those forces into changing global temperatures. All these types of studies were included in this review.

The challenge up to now has been that our two significant lines of evidence point in opposite directions. Paleo-environmental “proxy” data, which includes evidence from oceans, lakes, and other natural archives, point to a peak global average temperature about 6,500 years ago and then a global cooling trend until humans started burning fossil fuels. Climate models generally show global average temperatures increasing in the last 6,500 years.

If the proxy data are correct, that points to deficiencies in the models and specifically suggests that climate feedbacks that can amplify global warming are underrepresented. If the climate models are correct, then the tools for reconstructing paleotemperatures need to be sharpened.

We also know that, whether the numbers trend up or down, the change in global average temperature in the past 6,500 years has been gradual—probably less than 1 degree Celsius (1.8 degrees Fahrenheit). This is less than the warming already measured in the last 100 years, most of which humans have caused. However, because global temperature change of any magnitude is significant, especially in response to changing greenhouse gases, knowing whether temperatures were higher or lower 6,500 years ago is important to our knowledge of the climate system and improving forecasts of future climate.

What we don’t know

This study highlighted uncertainties in the climate models. If the authors’ preferred interpretation—that recent global warming was preceded by 6,500 years of global cooling—is correct, then scientists’ understanding of natural climate forcings and feedbacks, and how they are represented in models, needs improvement. If they’re incorrect, then scientists need to improve their understanding of the temperature signal in proxy records and further develop analytical tools to capture these trends on a global scale.

Attempting to resolve the Holocene global temperature conundrum has been a priority for climate scientists in the last decade; Broadman remembers reading the initial paper on this topic when she started her Ph.D. in 2016. All the studies since have added to the understanding of this issue, which gets scientists in the field closer to a comprehensive understanding. Recent studies on this topic have tried adjusting proxy data to account for their presumed weaknesses, inserting plausible forcings into climate models and blending proxy data with climate-model output, all arriving at different conclusions about the cause of the conundrum. This review takes a step back to revisit the issue with a comprehensive global-scale assessment, showing that we don’t yet know the solution to this conundrum.

Developing widely applicable methods of quantifying past temperature is a high priority for climate scientists already. For example, Kaufman’s lab is testing the use of chemical reactions involving amino acids preserved in lake sediment as a new method for studying past temperature changes. Combined with new radiocarbon dating technology from the Arizona Climate and Ecosystem lab at NAU, this technique could help determine whether global warming reversed a long-term cooling trend.

Why it matters

Broadman, whose work includes a focus on science communication, created the figures that accompany the research. This is a critical way of communicating hard-to-understand results to audiences—and in climate science, the audiences are diverse and include educators, policymakers, nonprofits and scientists throughout the world.

“One interesting takeaway is that our findings demonstrate the impact that regional changes can have on global average temperature. Environmental changes in some regions of the Earth, like declining Arctic sea ice or changing vegetation cover in what are now vast deserts, can cause feedbacks that influence the planet as a whole,” Broadman said. “With current global warming, we already see some regions changing very quickly. Our work highlights that some of those regional changes and feedbacks are really important to understand and capture in climate models.”

Additionally, Kaufman said, accurately reconstructing the details of past temperature change offers insights into climate’s response to various causes of both natural and anthropogenic climate change. The responses serve as benchmarks to test how well climate models simulate the Earth’s climate system.

“Climate models are the only source of detailed quantitative climate predictions, so their fidelity is critical for planning the most effective strategies to mitigate and adapt to climate change,” he said. “Our review suggests that climate models are underestimating important climate feedbacks that can amplify global warming.”

In a paper published in the Royal Society of Chemistry journal Environmental Science Processes & Impacts, the group showed how PFAS — chemicals that had been widely used in water, heat and stain-resistant products and have been linked to serious health problems — can leach out of fertilizer made from recycled waste with the help of microbial decomposition. The finding could help to explain how PFAS accumulates in the soil, crops and groundwater in farmland across the country.

“Because it is not currently possible to eliminate PFAS from the environment, it’s important to understand everything we can about how it is able to persist and accumulate so broadly in the natural world,” said co-author Asa Lewis, PhD, who led the research as a doctoral student at Drexel along with environmental engineers from Temple University. “Our work shows how microbial weathering fits into the PFAS dissemination pathway from biosolids.”

According to the Environmental Protection Agency, about half of all sewage waste in the U.S. — about 4.5 million metric tons — is treated and converted to a sludge, called biosolid waste. About half of that goes through further treatment to remove biological and chemical contaminants and is converted into a fertilizer product. For the last 50 years, this fertilizer has been used throughout the country on farmland, residential gardens and landscaping.

But research in the last year raised concerns about this widespread use when it revealed that PFAS can persist in biosolid fertilizer, despite the treatment process.

“We know that microbes exist in biosolid sludge even after the stabilization treatment process and given the role they play in the decomposition of organic compounds, such as fats, protein, and polysaccharide residuals in the biosolids, we wanted to examine how microbial weathering of these organic compounds can impact PFAS leaching potential from biosolids over time because it PFAS compounds are thought to stick to these compounds,” said Christopher Sales, PhD, an associate professor in the College of Engineering and a co-author of the study.

To do it, the team collected biosolid samples that had undergone one of three types of treatment — aerobic digestion, anaerobic digestion or composting — at wastewater recycling and reuse facilities. The content of each sample was tested to determine the initial level of organic matter, proteins and lipids and PFAS concentration in these different types of biosolids. These samples were then placed in an environmentally controlled chamber for three months to look for indicators of microbial activity, especially degradation of organics, lipids and proteins, and sought to see how this microbial activity affected how much PFAS would partition from the biosolids into water.

The researchers found that the samples with the highest level of microbial activity also demonstrated the highest level of PFAS partitioning — an indicator that this biosolid sludge would be more susceptible to PFAS leaching.

The results demonstrated this increase in PFAS partitioning over the three months, especially in the first 10 days of the experiment, is likely due to the microbes breaking down proteins and lipids in the biosolid, which allows the PFAS to spread, or partition, as water passes through.

“This work provides evidence that microbial weathering processes that lead to degradation of organic matter and biopolymers — as indicated by lipase activity, protease activity, and oxygen consumption rate, as well as changes in lipid, protein, and organic content — can impact PFAS partitioning and increase leaching potential in biosolids,” the authors wrote.

The team noted that the results likely implicate microbes in the process of PFAS leaching from biosolids after they are land-applied, but further research is needed to confirm how they are transported through the soils to surface waters, like rivers and lakes, groundwaters and how they bioaccumulate in crops and animals that might graze where biosolids are applied. In addition, the rate of biosolid weathering in nature might be much different than their lab study considering the role that rainfall, solar irradiation, and physical disturbances impact soil weathering would play outdoors.

The team contends that in order for agencies like the EPA to provide accurate guidance on PFAS risk and acceptable levels of contamination, understanding the path of “forever chemicals” is critical information.

“This research provides evidence that PFAS can leach from biosolids across different stabilization methods in wastewater treatment,” Lewis said. “And it provides more support that regulation or advanced treatment in wastewater treatment plants is needed to reduce impacts to the environment.”

And little had been known about how they did what they did when hunting by themselves — until now.

Thanks to researchers at NSU’s Guy Harvey Research Institute (GHRI) who designed a novel electronic tag package incorporating high-tech sensors and a video camera, we now have for the first time, a detailed view of exactly how these fish behave and hunt once they are on their own and out of view of the surface. This research was carried out offshore of one of the premier fishing locations in the world, Tropic Star Lodge, in southwest Panama.

“Most of the day they dive back and forth between the surface and the thermocline layer, where the water gets cold,” said Ryan Logan, the lead author of the study and a doctoral candidate and research associate at NSU’s GHRI. “The thermocline can concentrate prey that don’t want to enter the cold water, so it looks like the sailfish might be using this to its advantage.”

The new research study just published in Scientific Reports originally set out to determine how long it took the sailfish to recover after being released by a recreational fisher, the answer to which you can find in another study conducted by the authors. But after the fish had recovered, the video cameras continued to roll, picking up some never-before-seen footage of hunting behavior.

Sailfish are known for their distinctive large dorsal fins and elongated front-end bill, which gives them a built-in sword-like weapon for hunting. These open ocean wanderers can travel both by themselves, or in groups. Sailfish have been observed to hunt in groups on schooling fishes, using their bill in a slash, stun, and eat the baitfish sequence of actions.

This type of hunting by sailfish has been observed several times by wildlife photographers because it often occurs at the surface of the ocean, where it is easily accessible to human eyes.

However, when sailfish are not engaged in these cooperative group hunting events, they are thought to live a mostly solitary lifestyle. Sailfish have some other pretty unique features that separates them from many other groups of fish. For example, they can keep their eyes and brain warmer than the surrounding water, which gives them an advantage over their prey when hunting in colder or dimly lit water. But because of this, it’s assumed that they burn a lot of calories throughout the day, so one could assume that they must also need to eat in between those group hunting events, although this had never been documented.

While this new video footage provides a unique perspective on the daily lives of sailfish, researcher caution that most of isn’t that exciting — not exactly the kind of footage that makes it to Instagram or TikTok.

“Most of what you see in the videos is just a lot of blue water,” said Logan, describing the open ocean habitat of these fish. “But when I saw the sailfish start to swim really fast toward the surface, I knew something was up.”

The video shows a 100-pound sailfish ascending fast to the surface from nearly 200 feet deep, and vigorously chasing a small tuna once it reaches the surface. The sailfish makes several attempts to catch the little tuna, twisting and turning, speeding up and slowing down, often breaking the surface of the water during each attack. In the end, it looks like the sailfish got what it was after, returning to a normal, calm swimming behavior.

Logan said that these findings change what we know about the daily lives of sailfish.

“Because you can’t keep a sailfish in captivity, we know surprisingly little about their basic biology,” he said. “For instance, how much food do they need on a daily basis to survive?”

These are questions that this research is helping to answer. The team of researchers used the video footage, along with other swimming information collected by the high-resolution tag, to estimate how much energy the sailfish burned throughout the day, and how much energy it gained back by consuming the tuna, an energy-rich prey item.

“Based on our estimations, this sailfish needs roughly half of a tuna like this per day to meet energetic demands,” said Logan.

While this research took place in Panama, sport fishing is a huge business around the world, especially in the state NSU’s GHRI calls home — Florida. Recent numbers show that fishing is an $11.5 billion dollar industry in Florida, supporting approximately 100,000 jobs.

“This research improves our understanding of the hidden lives of these majestic, ecologically and economically very important fishes,” said Mahmood Shivji, Ph.D., a co-author of the study and Director of NSU’s GHRI. “Such knowledge is essential to help us better protect the health of these fish and their prey to have a sustainable sportfish industry for many years to come.”

Video: https://youtu.be/ouVnskumc2Y