Diseases caused by a combination of bacteria, viruses, fungi and parasites — also known as polymicrobial infections — are challenging to treat because scientists don’t fully understand how pathogens interact during infection and how these interactions impact the drugs used to treat them.

In a study published in the journal Infection and Immunity, researchers in the Molecular & Biomedical Sciences Department looked at two pathogens that often occur at similar sites, particularly in cystic fibrosis and mechanically ventilated patients: Candida albicans and Pseudomonas aeruginosa.

Candida is the fourth most common hospital-acquired pathogen, and is particularly difficult to treat. It is targeted by a number of antifungal agents, but some only slow it rather than kill it outright. Meanwhile, P. aeruginosa infects 90% of all adult cystic fibrosis patients. Combined, C. albicans and P. aeruginosa cause more serious disease in cystic fibrosis and ventilated patients.

The researchers investigated the effectiveness of an antifungal drug, fluconazole, in the test tube and during infection of the zebrafish with both pathogens. Fluconazole is known to slow fungal growth, but Candida can become tolerant to the drug and not only survive, but also develop tolerance that leads to failed therapy and, potentially, death.

What the study found was promising. The results showed that P. aeruginosa works with fluconazole to eliminate drug tolerance and clear the C. albicans infection in the culture and the zebrafish.

“Polymicrobial infections are challenging to treat not only because of the lack of understanding of how invading microorganisms interact but also because we don’t know how these interactions affect treatment efficacy. Our work demonstrates that polymicrobial interactions can indeed affect treatment efficacy and, most importantly, it highlights the importance of nutrient availability in the environment — such as iron in our study — and how it modulates treatment efficacy,” says Siham Hattab, lead author of the study who conducted the research as part of her Ph.D. in the Department of Molecular and Biomolecular Sciences.

What’s more, the bacteria also enhance the drug’s ability against a second pathogenic Candida species that tends to be more resistant to the drug.

The increased effectiveness of the drug suggests to the researchers that there is still much more to learn about how current drugs work when targeting these dangerous and complex polymicrobial infections. “We are really excited to have revealed that sometimes drugs against fungal infection can work even better in a more ‘real-world’ situation than in the test tube. There is still a lot to learn about how pathogens interact during infection, and it will be interesting to see how the bacteria manage to work with the drugs to target Candida,” says Robert Wheeler, associate professor of microbiology and senior author of the study.

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Materials provided by University of Maine. Note: Content may be edited for style and length.

Researchers from half a dozen universities investigated what the future might hold in terms of rainfall and soil moisture, two measurements of drought. The team, led by UC Santa Barbara’s Samantha Stevenson, found that many regions of the world will enter permanent dry or wet conditions in the coming decades, under modern definitions. The findings, published in the Proceedings of the National Academy of Sciences, reveal the importance of rethinking how we classify these events as well as how we respond to them.

“Essentially, we need to stop thinking about returning to normal as a thing that is possible,” said Stevenson, an assistant professor in the Bren School of Environmental Science & Management. This idea affects both how we define drought and pluvial (abnormally wet) events and how we adapt to a changing environment.

A drought is when conditions are drier than expected. But this concept becomes vague when the baseline itself is in flux. Stevenson suggests that, for some applications, it’s more productive to frame drought relative to this changing background state, rather than a region’s historical range of water availability.

To predict future precipitation and soil moisture levels, Stevenson and her colleagues turned to a new collection of climate models from different research institutions. Researchers had run each model many times with slightly different initial conditions, in what scientists call an “ensemble.” Since the climate is an inherently chaotic system, researchers use ensembles to account for some of this unpredictability.

The results show a world where certain regions are in permanent drought while others experience perennial pluvial for the rest of the 21^st century. The team calculated the year in which average soil moisture will exceed the threshold that defines either a megadrought or a megapluvial. “In other words, at what point do average conditions exceed what we would consider a megadrought if it happened now, [and never return to ‘normal’]” Stevenson said.

The western United States has already crossed this benchmark, and there are other places headed that way as well, including Australia, southern Africa and western Europe. “But, again, that’s if we use today’s definition of a drought,” Stevenson said.

The authors argue that we need to move away from fixed definitions toward a more nuanced account of drought and pluvial. “Our idea of normal is, in a sense, meaningless when ‘normal’ is continuously changing,” Stevenson added.

Climate models indicate that average soil moisture in many regions will continue to drop. That said, the team’s ensembles suggests that soil moisture will continue to experience drought-related variation similar to today, relative to the ever-drier baseline.

The fluctuation highlights the need to consider both long term changes and the usual ups and downs associated with historic droughts and pluvials. “The most important management challenge will be to adjust for the relentless declines in water availability, as this exceeds the expected impact of future megadroughts,” said co-author Julia Cole, a professor at the University of Michigan.

Precipitation patterns, on the other hand, will become much more extreme. Warm air holds more moisture than cold air. So as the atmosphere heats up, it’ll be able to suck more moisture from dry areas and dump more precipitation on wet regions.

“We wanted to consider both precipitation and soil moisture at the same time because that can be important for water management,” Stevenson said. For instance, we will need to adapt infrastructure to more arid conditions in the American West, but that infrastructure will also need to handle more intense rainfall.

“When we talk about being in a drought, the presumption is that eventually the drought will end, and conditions will return to normal,” Stevenson said. “But if we’re never returning to normal, then we need to adapt all of the ways that we manage water with the expectation that normal will continually be drier and drier every year.”

The discovery, published in the scientific journal Cell, results from a collaboration of scientists at the Max Planck Florida Institute for Neuroscience, HHMI’s Janelia Research Campus, the Allen Institute for Brain Science, and others. Led by co-first authors Dr. Hidehiko Inagaki and Dr. Susu Chen and senior author Dr. Karel Svoboda, the scientists set out to understand how cues in our environment can trigger planned movement.

“The brain is like an orchestra,” said Dr. Inagaki. “In a symphony, instruments play diverse tunes with different tempos and timbres. The collective of these sounds shapes a musical phrase. Similarly, neurons in the brain are active with diverse patterns and timing. The ensemble of neuronal activities mediates specific aspects of our behavior.”

For example, the motor cortex is a brain area that controls movement. Activity patterns in the motor cortex are dramatically different between the planning and execution phases of movement. The transition between these patterns is critical to trigger movement. Yet, the brain areas controlling this transition were unknown. “There must be brain areas acting as the conductor,” described Dr. Inagaki. “Such areas monitor environmental cues and orchestrate neuronal activities from one pattern to the other. The conductor ensures that plans are converted into action at the right time.”

To identify the neural circuit that serves as the conductor to initiate planned movement, the team simultaneously recorded the activity of hundreds of neurons while a mouse performed a cue-triggered movement task. In this task, mice were trained to lick to the right if whiskers were touched or to the left if whiskers were not touched. If the animals licked in the correct direction, they received a reward. However, there was a catch. The animals had to delay their movement until a tone, or “go cue,” was played. Only correct movements after the go cue would be rewarded. Therefore, mice maintain a plan of the direction they will lick until the go cue and execute the planned lick after.

The scientists then correlated complex neuronal activity patterns to relevant stages of the behavioral task. The researchers found brain activity occurring immediately after the go cue and during the switch between motor planning and execution. This brain activity arose from a circuit of neurons in the midbrain, thalamus, and cortex.

To test whether this circuit acted as a conductor, the team used optogenetics. This approach enabled the scientists to activate or inactivate this circuit using light. Activating this circuit during the planning phase of the behavioral task switched the mouse’s brain activity from motor planning to execution and caused the mouse to lick. On the other hand, turning off the circuit while playing the go cue suppressed the cued movement. The mice remained in a motor planning stage as if they had not received the go cue.

This work by Dr. Inagaki and his colleagues identified a neural circuit critical for triggering movement in response to environmental cues. Dr. Inagaki explains how their findings demonstrate generalizable features of behavioral control. “We have found a circuit that can change the activity of the motor cortex from motor planning to execution at the appropriate time. This gives us insight into how the brain orchestrates neuronal activity to produce complex behavior. Future work will focus on understanding how this circuit and others reorganize neuronal activity across many brain regions.”

In addition to these fundamental advances in understanding how the brain functions, this work has important clinical implications. In motor disorders, such as Parkinson’s disease, patients experience difficulty in self-initiated movement, including difficulty in walking. However, adding environmental cues to trigger movements, such as lines on the floor or auditory tones, can dramatically improve a patient’s mobility. This phenomenon, known as paradoxical kinesia, suggests that different mechanisms in the brain are recruited for self-initiated movement and cue-triggered movement. Discovering the brain networks involved in cue-triggered movements, which are relatively spared in Parkinson’s disease, may help to optimize treatment.

Global permafrost today contains a whopping 1,500 trillion grams of carbon. That’s twice as much as what’s stored in the atmosphere. Alpine permafrost, which is found closer to the equator at high elevations, isn’t as well studied as arctic permafrost but contains 85 trillion grams of carbon. When melted, it can release carbon dioxide and methane — greenhouse gases that influence global temperature.

Alpine permafrost is expected to melt at a faster rate than arctic permafrost under current global warming conditions, according to new research published in Nature Communications, and this may contribute even more to rising global temperatures.

“Atmospheric carbon dioxide concentrations today are similar, or maybe even higher, than the mid-Pliocene because of the burning of fossil fuels, and so scientists point at that time period as an analog for our current and near-future climate,” said paper co-author Carmala Garzione, dean of the University of Arizona College of Science. “We’re not feeling the full effects of the rise in atmospheric carbon dioxide yet because our Earth system takes time to adjust.”

“We wanted to estimate the stability of modern permafrost globally in a warmer-than-today climate scenario,” said Feng Cheng, the paper’s lead author and a professor at Peking University in China. Cheng formerly worked with Garzione as a postdoctoral fellow. “Our findings were very surprising and highlight the fact that we need to put more effort into monitoring the stability of the permafrost in the alpine region.”

The team used carbonate — a family of minerals — that formed in a Tibetan Plateau lake to estimate temperatures during the Pliocene period (5.3 to 2.6 million years ago) and the Pleistocene period (between 2.6 million and 11,700 years ago). When algae grows in lakes, it absorbs carbon dioxide from the water and, as a result, decreases lake acidity. That decrease drives the lake to form finely grained carbonate minerals that settle at the lake bottom. The atoms in that carbonate reflect the temperature at which the carbonate formed, and can be used like a time-traveling thermometer.

The Tibetan Plateau, which sits at an elevation over 15,400 feet, is the largest alpine permafrost region on Earth, but others can be found in the Mongolian Plateau in central Asia, the Canadian and American Rocky Mountains, the southern stretches of the Andes, and other mountain ranges worldwide at elevations where the air temperature is consistently below freezing.

The team also modeled the paleoclimate on Earth during the Pliocene. They found that not only was the average temperature of much of the Tibetan Plateau above freezing in the Pliocene, but the same was true for many of the alpine regions across the globe.

Ultimately, the modeling suggests that under current levels of atmospheric carbon dioxide, 20% of arctic permafrost land area and 60% of alpine permafrost land area will be lost in the future. High altitude alpine regions are more sensitive than high latitude arctic regions to warming under higher atmospheric carbon dioxide conditions.

“The Pliocene is an important period as an ancient analog for how Earth will adjust to the carbon dioxide that humans have already released to the atmosphere,” Garzione said. “We need better and broader studies of the vulnerability of alpine regions under global warming scenarios. There’s been a lot of focus on the stability of arctic permafrost, because it covers more land area and contains a huge reservoir of organic carbon trapped in permafrost, but we also need to be aware that alpine regions stand to lose more permafrost proportionally and are important in understanding of potential carbon release under global warming scenarios.”

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Materials provided by University of Arizona. Original written by Mikayla Mace Kelley. Note: Content may be edited for style and length.