For the past 50 years, scientists have used humanmade, synthetic and nucleoside analogues to create drug therapies for diseases that involve the cellular division and/or the viral reproduction of infected cells. These diseases include hepatitis, herpes simplex, HIV and cancer.

But, says Britton, “That process has been intensive and challenging, limiting and preventing the discovery of new drug therapies.”

Now, using the new process, scientists can create new nucleoside analogues months earlier than with the previous method, paving the way for quicker drug discoveries. A paper on this research was published today in the journal Science.

“The reduction in time and cost of synthesis will vary, depending on the individual nucleoside analogue, but we have examples where we cut a 20-plus step synthesis, which takes several months to complete at the very least, down to three or four steps, which would only take a week or so,” says Britton.

“This is clearly a critical factor when it comes to treating newly evolved viruses like SARS-CoV-2 (COVID-19).”

The team shortened the process by replacing naturally occurring carbohydrates typically used for synthesising these types of drugs.

“This entirely new approach builds in opportunities to diversify these drug scaffolds and should inspire new and unusual nucleoside analogue drug discoveries,” says Britton.

The team also replaced naturally derived chiral materials with achiral materials since they are generally cheaper and more versatile.

L.-C. Campeau, Merck’s head of process chemistry and discovery process chemistry says, “One of our priorities is identifying problems limiting the speed of drug discovery and development, especially regarding synthesizing custom nucleoside analogues. We are very excited to collaborate with Professor Britton in establishing new methods to access this therapeutically important class of molecules.”

Britton is also an investigator with GlycoNet, a Canada-wide network of researchers working to further our understanding of the biological roles of sugars.

The three-year project was funded by GlycoNet and Merck, patent pending.

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The deep sea, ocean depths below 650 feet (200 metres), constitutes more than 90% of the biosphere, harbors the most remote and extreme ecosystems on the planet, and supports biodiversity and ecosystem services of global importance. Interest in deep-seabed mining for copper, cobalt, zinc, manganese and other valuable metals has grown substantially in the last decade and mining activities are anticipated to begin soon.

“As a team of deep-sea ecologists, we became alarmed by the misconceptions present in the scientific literature that discuss the potential impacts of seabed mining,” said Smith. “We found underestimates of mining footprints and a poor understanding of the sensitivity and biodiversity of deep-sea ecosystems, and their potential to recover from mining impacts. All the authors felt it was imperative to dispel misconceptions and highlight what is known and unknown about deep seabed mining impacts.”

In addition to the impacts of mining on ecosystems in the water above extraction activities, as detailed in another UH-led study published last month, Smith and co-authors emphasize deep-seabed mining impacts on the seafloor, where habitats and communities will be permanently destroyed by mining.

“The bottom line is that many deep-sea ecosystems will be very sensitive to seafloor mining, are likely to be impacted over much larger scales than predicted by mining interests, and that local and regional biodiversity losses are likely, with the potential for species extinctions,” said Smith.

The scope of mining impacts from full scale mining, however, will not be well understood until a full-scale mining operation is conducted for years. The geographic scale and ecosystem sensitivities to mining disturbance occurring continuously for decades cannot be simulated or effectively studied at a smaller scale, according to the authors.

“All the simulations conducted so far do not come close to duplicating the spatial scale, intensity and duration of full-scale mining,” said Smith. “Further, the computer models use ecosystem sensitivities derived from shallow-water communities that experience orders of magnitude higher levels turbidity and sediment burial (mining-type perturbations) under natural conditions than the deep-sea communities targeted for mining.”

Much of the planned deep-seabed mining will be focused in the Pacific Ocean, near Hawai’i, and also near Pacific Island nations. Hawai’i and Pacific Island nations are likely to particularly suffer from any negative environmental impacts, but may benefit economically from deep-seabed mining, creating a need to understand the trade-offs of such mining.

“Polymetallic-nodule mining (as currently planned) may ultimately impact 500,000 square kilometers of deep seafloor in the Pacific, an area the size of Spain, yielding perhaps the largest environmental footprint of a single extractive activity by humans,” said Smith. “Addressing the misconceptions and knowledge gaps related to deep-sea mining is the first step towards effective management of deep-seabed mining.”

The researchers aim to work closely with regulators and society to help manage deep-seabed mining and emphasize the need to proceed slowly with seabed mining until impacts are fully appreciated.

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Materials provided by University of Hawaii at Manoa. Original written by Marcie Grabowski. Note: Content may be edited for style and length.

This research, published in the journal Cell Host & Microbe, shows that both Pseudomonas and Burkholderia use toxic weaponry, called Type VI Secretion Systems (T6SS), to compete with and establish dominance over each other. It’s possible that scientists could target, or mimic, this weaponry to defeat the bacteria before they cause irreparable harm to lungs of patients.

Scientists have wondered for a long time why Burkholderia does not infect infants and young children. First author and former Cotter Lab graduate student Andrew Perault, MPH, PhD, designed and conducted experiments to show that Pseudomonas bacteria isolated from infants and young children use their harpoon-like T6SS to fire toxins at, and kill, competitor bacteria, including Burkholderia.

“This may be one of the reasons Burkholderia does not take root in young patients,” Cotter said. “Andy showed that although Burkholderia also produce T6SSs, they cannot effectively compete with Pseudomonas isolates taken from young CF patients.”

However, as those Pseudomonas bacteria adapt to living in the lungs of CF patients, they lose their ability to produce T6SSs and to fight with Burkholderia. The Burkholderia, using their own T6SSs, are then able to kill the Pseudomonas and establish infection.

“We believe the findings of our study, at least in part, may explain why Burkholderia infections are limited to older CF patients,” Perault said. “It appears that as at least some strains of Pseudomonas evolve to persist in the CF lung, they also evolve to lose their T6SSs, and hence their competitive edge over Burkholderia, which are then free to colonize the respiratory tract.”

The scientists think the Burkholderia T6SS is an important factor promoting the ability of these pathogens to infect CF patients. Therefore, researchers could potentially develop therapeutics to target these secretion systems to prevent infections.

Moreover, assessing the T6SS potential of resident Pseudomonas populations within the CF respiratory tract may predict susceptibility of patients to potentially fatal Burkholderia infections.

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Instead, they found that Earth’s dynamic atmosphere is a wild card that plays a much bigger role than sea surface temperatures, yet defies predictability, in the wet and dry cycles that whipsaw the western states. The study, published Monday in Science Advances, is a detailed assessment of long-term drought variability.

The findings are significant for water management, agriculture, urban planning and natural resources protection. Recent droughts have claimed many lives and caused damaging crop losses, making drought forecasting a high priority. Meanwhile, the West faces rapid population growth at the same time that forecasts show dry times ahead due to global climate change.

“The main finding is not terribly hopeful for short-term drought prediction,” said Julien Emile-Geay, a study author and associate professor of Earth sciences at the USC Dornsife College of Letters, Arts and Sciences. “We found that, historically speaking, year-to-year droughts in the western United States were less predictable than previous studies have claimed.”

New study examines 1,000 years of droughts in the West and beyond

Emile-Geay and postdoctoral scholar Michael Erb, who is lead author from USC and now at Northern Arizona University, joined with other scientists at the University of Washington and Columbia University to produce the study.

The researchers set out to answer the question: What determines droughts in the West?

They examined North American droughts and global conditions spanning more than 1,000 years. Megadroughts, which lasted decades, and dry spells predate the Industrial Revolution, American expansion on the continent or European colonialism. For example, a megadrought in the late 13th century likely contributed to the dispersal of the Anasazi people.

The prevailing explanation is that the El Niño-Southern Oscillation plays a key role in these drought episodes. The oscillation is a two-sided coin based on water conditions in the eastern equatorial Pacific Ocean. El Niño conditions occur when sea temperatures in the region are warmer than normal and are associated with wet years in the American Southwest; La Niña conditions occur when water is cooler than normal and are associated with dry years in the Southwest.

But the scientists found that rule of thumb didn’t jibe well with all drought cycles of the past. While it’s true there’s a correlation between La Niña and drought, these ocean water conditions accounted for only about 13% of the variability, the study says.

“La Niña proved to not be the only game in town,” Emile-Geay said. “La Niña is part of the game, but not the biggest part.”

A notable example of this phenomenon occurred in 2015-16, an El Niño year when Southern California did not receive the increased precipitation that was predicted. Instead, the relief came unexpectedly the following year, a La Niña year that should have been drier than normal.

What other variables can lead to drought?

The scientists also examined other drought influencers, including water temperatures in the Atlantic Ocean and volcanic activity. While those phenomena can influence drought conditions, they are too weak or episodic to explain many droughts.

Instead, the study says droughts can originate in the atmosphere. The air around Earth is highly dynamic and influenced by more variables than the ocean alone.

“The atmosphere creates a lot of variations in moisture supply on its own, and it can cook up droughts all by itself, without being told what to do by the ocean,” Emile-Geay said.

But while the past is key to the future, it does not hold all the keys. In the future, research says carbon emissions will continue to trap heat and warm the surface, and the West will experience increasingly dry conditions as a result.

“Our study suggests that the atmosphere will continue to add a strongly unpredictable element to moisture conditions in the southwestern United States, on top of drying induced by global warming,” Emile-Geay said. “That is, the Southwest is headed for a drier future overall but with the atmosphere adding a wildcard that may, at times, make things better or worse for the people and ecosystems that depend on that water.”

The study integrates numerous sources of information spanning centuries to support the findings. The dataset, called the Last Millennium Reanalysis, aggregates climate models, modern temperature measurements and nearly 3,000 climate proxies, such as tree rings, corals, and ice cores. The reanalysis was developed by scientists at USC, the University of Washington and the University of Colorado, with the support of the National Oceanic and Atmospheric Administration. According to the NOAA, the reanalysis aimed to “transform the ways in which the climate community investigates low-frequency climate.”