In their study, which initially published in an unedited version on March 28, 2024, in Nature, the chemists showed that their new methods can be used to perform two modifications — called dehydrogenations and lactonizations — on a broad class of inexpensive starting compounds. The reactions require only a simple copper-based catalyst, whereas related reactions typically require much more cumbersome and expensive methods — though this specific type of reaction was previously inaccessible by any organic synthesis method.

“This new two-mode approach could be particularly useful for late-stage modifications and diversifications of natural products and drug molecules,” says study senior author Jin-Quan Yu, PhD, Frank and Bertha Hupp Professor of Chemistry and Bristol Myers Squibb Endowed Chair in Chemistry at Scripps Research.

The study’s first authors were postdoctoral research associate Shupeng Zhou, PhD, and doctoral student Annabel Zhang, PhD, both of the Yu lab during the study.

The initial goal of the research was to find a new and better method for what chemists call carbon-hydrogen (CH) activation, in which a hydrogen atom on the carbon backbone of an organic compound is detached and replaced with something else — a valuable tool for drug synthesis.

In this case, the Yu lab — which has a history of innovations in CH activation chemistry — sought a better way to do CH activations that replace the hydrogen with an oxygen atom. This is a common transformation in the construction or modification of biologically active molecules, though chemists haven’t had laboratory methods for doing it that are as simple, direct and broadly useful as they would like.

Yu and his team looked to nature for inspiration, in particular to cytochrome P450 enzymes, which are found in most living organisms, and help clear potentially toxic molecules in the human liver. Cytochrome P450 enzymes perform oxygen-for-hydrogen reactions very efficiently. Some of these enzymes have the additional ability to catalyze a different hydrogen-removal process called dehydrogenation, which can be used to strip hydrogens from two carbons simultaneously, allowing other atoms — or clusters of atoms — to replace them. The chemists set themselves the ambitious goal of finding a general organic synthesis method for doing either the oxygenation or dehydrogenation reaction, as these versatile “bimodal” enzymes do in living cells.

After months of experimentation, Yu’s team found that, through chemical transformations similar to those done by the bimodal cytochrome P450 enzymes, they could efficiently make compounds called unsaturated primary amides — a class that includes many drug molecules — by dehydrogenating inexpensive starting compounds called methoxyamides. For the catalyst, they needed only copper fluoride — also inexpensive and easy to use.

As the chemists explored the breadth of their new dehydrogenation method using different specific starting compounds, they observed trace amounts of a type of molecule called a lactone, indicating that an oxygenation reaction had occurred. Ultimately, they were able to determine the reaction conditions that favored this oxygenation or “lactonization” over the dehydrogenation. In other words, like the bimodal enzymes that had inspired them, they were able to control whether their approach led down one reaction path or the other.

The team demonstrated the remarkable versatility of this set of reactions by using it to modify — via dehydrogenation or lactonization, or both — a wide variety of starting compounds, including the neurological drug valproic acid and the cholesterol-lowering drug gemfibrozil. (Modifications of existing complex molecules to create potentially better variants are a common drug discovery and optimization technique.)

Yu and his group are currently developing a similar approach for making and modifying lactone- and amide-related compounds called lactams, which include some antibiotics.

“We’ve already had a lot of interest in this new approach from pharma industry chemists,” Yu says.

“Copper-catalyzed dehydrogenation or lactonization of C(sp3)−H bonds” was co-authored by Shupeng Zhou, Zi-Jun Zhang and Jin-Quan Yu.

Support for the research was provided by the National Institutes of Health (2R01GM084019).

Scientists have performed a new, more sensitive measurement of beta decay properties to hunt for a theorized feature of the weak nuclear force not currently included in the Standard Model. The weak nuclear force drives the process of nuclear beta decay. In beta decay, a proton or neutron in a nucleus emits a beta particle (an electron or its anti-particle, a positron) and a neutrino. The properties of the beta decays of the radioactive mirror nuclei lithium-8 and boron-8 are in perfect agreement with the predictions of the Standard Model. This effort combines state-of-the-art experimental and theoretical methods and paves the way for future advances in the study of the weak nuclear force.

A team of nuclear scientists from Lawrence Livermore National Laboratory, Argonne National Laboratory, and Louisiana State University precisely measured the beta-decay properties of the “mirror” nuclei lithium-8 and boron-8 to better understand the weak nuclear force. Mirror nuclei have the same total number of protons and neutrons, but the numbers of each particle are reversed. Mirror nuclei provide an opportunity to study the weak nuclear force with increased sensitivity. The predicted signature of many of the sought-after new effects would give rise to opposite contributions in the two different nuclei. This would allow scientists to compare the lithium-8 and boron-8 results to isolate the contributions to the decay from each nucleus.

By studying both these nuclei with the Beta-decay Paul Trap, a device that holds clouds of ions in vacuum, the researchers determined the energies and directions of the emitted beta particle and two alpha particles with high precision. This approach allowed the researchers to reconstruct the full decay properties, including the contribution from the unseen neutrino. The Standard Model (SM) predicts the distribution of emission angles for the beta particle and neutrino, and any observed difference would reveal new aspects of the weak nuclear force. The team was looking for differences smaller than 1%, which required a thorough understanding of the apparatus and detection system, paired with a newly developed first-principle approach using “Symmetry-Adapted No-Core Shell Model theory” to account for a number of small effects that arise from the complicated environment of the nucleus. The results were the highest precision of their kind and confirmed the SM prediction with increased confidence.

“The goal of this innovative insole technology is to mitigate the risk of diabetic foot ulcers by addressing one of their most significant causes: skin and soft tissue breakdown due to repetitive stress on the foot during walking,” said Muthu B.J. Wijesundara, principal research scientist at The University of Texas at Arlington Research Institute (UTARI).

Affecting about 39 million people in the U.S., diabetes can damage the small blood vessels that supply blood to the nerves, leading to poor circulation and foot sores, also called ulcers. About one-third of people with diabetes develop foot ulcers during their lifetime. In the U.S., more than 160,000 lower extremity amputations are performed annually due to complications from diabetic foot ulcers, costing the American health system about $30 billion a year. Those who have foot ulcers often die at younger ages than those without ulcers.

“Although many shoe insoles have been created over the years to try to alleviate the problem of foot ulcers, studies have shown that their success in preventing them is marginal,” Wijesundara said. “We took the research a step further by creating a pressure-alternating shoe insole that works by cyclically relieving pressure from different areas of the foot, thereby providing periods of rest to the soft tissues and improving blood flow. This approach aims to maintain the health of the skin and tissues, thereby reducing the risk of diabetic foot ulcers.”

In an article in the peer-reviewed International Journal of Lower Extremity Wounds, Wijesundara and UTA colleagues Veysel Erel, Aida Nasirian and Yixin Gu, along with Larry Lavery of UT Southwestern Medical Center, described their innovative insole technology. After this successful pilot project, the next step for the research team will be refining the technology to make it more accessible for users with varying weights and shoe sizes.

“Considering the impact of foot ulcers, it’s exciting that we may be able to make a real difference in the lives of so many people,” Wijesundara said.

This work was supported by a $229,480 grant from the National Institute of Aging of the National Institutes of Health, grant number 7R21AG061471.

But a study by University of Rhode Island researchers has found direct evidence of a species — the American woodcock, a migratory shorebird from eastern and central North America — that overlaps periods of migration and reproduction, a rare breeding strategy known as “itinerant breeding.” Their work, backed by collaborators across the East Coast, was published today in the biological sciences journal Proceedings of the Royal Society B.

“I think this is a very exciting moment for bird researchers,” said Colby Slezak, a URI Ph.D. student in biological and environmental sciences who led the study. “It’s interesting to see that these distinct periods in a bird’s annual cycle are not so cut and dried. We often think of migration, breeding, fall migration and wintering as separate events. But woodcock are combining two of these into one period, which is interesting because both are so energetically expensive.”

“Each year the period of migration is distinct from the period of breeding in the vast majority of migratory birds, presumably because doing so at the same time is simply too costly,” said Scott McWilliams, URI professor in natural resources science and principal investigator on the study. “This paper provides the best documented case of a migratory bird that is an itinerant breeder. Such itinerant breeding is exceptionally rare, and documenting exceptions often proves the rules of nature.”

The American woodcock — also called a timberdoodle, bogsucker, night partridge, and Labrador twister, among many more — is a migratory shorebird that occurs throughout eastern and central North America but its populations have been declining over the past half century. The species is known for its long, needlelike bill that can extract earthworms from deep in the ground and the males’ elaborate mating dance and “peent” call to attract females, Slezak said.

While there are about a dozen bird species in the world believed to be itinerant breeders, the study is the first to show direct evidence of the rare strategy. “They’ve suspected other species of being itinerant breeders, but this is the first time we’ve had detailed GPS-tracking data and on-the-ground verification of nests to confirm that this was happening.” said Slezak, of Broadalbin, New York.

To do that, the study benefitted from the work of scores of biologists from federal, state and non-governmental agencies along the American woodcock’s flyway, from the southern U.S. into Canada, who tagged more than 350 females with GPS transmitters between 2019 and 2022. That initiative was part of the University of Maine’s Eastern Woodcock Migration Research Cooperative.

Slezak, whose work on the study was part of his dissertation research, organized and analyzed the tracking data and alerted collaborators along the bird’s range to verify possible nesting locations. URI graduate students Liam Corcoran, Megan Gray and Shannon Wesson also worked on other aspects of the woodcock project, all part of a collaborative research program with biologists from the Rhode Island Department of Environmental Management Division of Fish & Wildlife.

“I was looking for really short movement patterns during the breeding season to find suspected nests,” Slezak said. “Relying on all of these collaborators from across the East Coast, I would reach out to them to tell them there was a suspected nest. They would travel out to the sites, sometimes quite far. It was amazing that we got the buy-in that we did.”

Based on GPS tracking of more than 200 females, the URI study found that more than 80% of the tagged females nested more than once during migration — some up to six times. During northward migration, females traveled an average of 800 kilometers between first and second nests, and shorter distances between subsequent nests, the study said. During 2021-22, URI researchers oversaw onsite verification of 26 nests from 22 females. Four females nested more than once, three of which migrated a substantial distance northward after their first nest attempt, the study said.

“There are many records of woodcock males singing along their migration routes, which has always been a mystery because it’s energetically expensive,” said Slezak. “With this new data on females, we’re seeing that females are also nesting in the south early, moving north and nesting as they go. So, these males are probably getting breeding opportunities along the way.”

While migration and reproduction take a lot of energy, American woodcock reduce the cost in other ways, Slezak said. They have shorter migration distances than other species and have the flexibility of using various young-forest habitats. Also, females are larger than males and their eggs are small relative to the size of the females.

“A lot of birds probably can’t do it because they don’t have these lower reproductive costs that woodcock have evolved to do,” he said.

Another evolutionary driver of itinerant breeding in woodcock could be predation. While they use a variety of habitats — wetlands, young forests with different tree types — they often nest near edges of open fields, leaving them prone to numerous predators.

“We think most of these post-nesting migratory movements are in response to predation events,” he said. “They’re sitting on the nest and something comes and eats the eggs. The female takes off and keeps migrating north before trying to nest again. What we don’t know is: if the female has a successful nest, does she stop nesting the rest of the year?”

Despite steady declines in woodcock populations and their preferred young forest habitat over the last half century, the study offers a glimmer of hope for woodcock, and other itinerant breeders facing the challenges of ongoing human development and climate change.

“Itinerant breeders may be more flexible in their response to environmental change because they are willing to breed in a wide variety of places,” said Slezak. “So as long as some suitable habitat remains, the consequences may be less.”