These infections are usually treated with the drug fluconazole, which inhibits the synthesis of ergosterol in Candida. Ergosterol fulfils similar important functions in fungi as cholesterol in humans.

Candida albicans can, however, become resistant to this drug. Scientists have uncovered the main mechanisms of fluconazole resistance in recent years. The group of Professor Joachim Morschhäuser from the Institute for Molecular Infection Biology at Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has contributed important findings.

The fungus succeeds in becoming resistant with numerous mechanisms. For example, it uses pumps to transport the drug out of its cells. “Highly resistant Candida albicans, in which fluconazole therapy fails, usually use a combination of several of these mechanisms,” says Morschhäuser.

New combinations of resistance mechanisms

Normally Candida albicans reproduces asexually by cell division. Morschhäuser’s research group has now discovered that resistant fungal cells can quickly switch to sexual reproduction in the presence of fluconazole. In this case, the cells fuse and unite their genetic material. In the offspring cells, different resistance mechanisms are newly combined and the fungal population thus becomes even less sensitive to fluconazole.

“In our investigations, we found out that the cells that retained the advantageous resistance characteristics are selected and become dominant in the population when treated with fluconazole,” says first author Christina Popp. Fluconazole not only selects for resistance mutations, but can also lead to changes in the genome that make the normally asexual fungus “mating-competent,” thereby enabling the cells to combine individually acquired resistance mechanisms and produce highly resistant offspring.

Knowledge about the molecular mechanisms of drug resistance can be useful for the development of better and new drugs and help overcome resistance.

Morschhäuser assumes that the resistance mechanisms described here are only one example of how Candida albicans can change in its host. Next, his team wants to investigate whether other forms of adaptation can also contribute in a similar way to the successful establishment of the fungus in different host niches.

This research was funded by the German Research Foundation (DFG) and the Open Access Publication Programme of DFG and JMU.

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Materials provided by University of Würzburg. Original written by Corinna Russow/Robert Emmerich. Note: Content may be edited for style and length.

Moritz Lang and Mikhail Shkonikov from the Institute of Science and Technology Austria (IST Austria) have now discovered a new property of this mathematical model: by adding sand grains in a specific manner to the sandpile, they induce dynamics reminiscent of the emergence, movement, collision and disappearance of sand dunes in the Gobi or the Namib desert. Different to real-world sand dunes, however, the dunes in their work — which is published in the current issue of PNAS — are composed of self-similar fractal patterns, somewhat similar to the famous Mandelbrot set.

The rules of the “sandpile experiment” are fairly simple: The model essentially consist of a grid of quadratic fields, similar to a checkerboard, onto which sand grains are dropped randomly. Fields that end up with less than four grains of sand remain stable, but when more grains accumulate on a field, the field becomes unstable and “topples.” In such a “toppling,” four grains of sand are passed on to the four neighboring fields: one to the top, one to the bottom, one to the left, and one to the right. This might cause the neighboring fields to also become unstable and topple, which then in turn may cause the next neighbors to topple and so on — an “avalanche” emerges. Similar to real-world avalanches in the Alps, these “sandpile avalanches” have no characteristic size, and it is extremely challenging to predict if the next sand grain will cause a huge avalanche, or nothing at all.

While, due to the simplicity of these rules, the sandpile model is regularly used as an easy example in elementary programming courses, it nevertheless displays various mathematical and physical phenomena still unexplained today — despite more than 30 years of extensive research. Among the most fascinating of these phenomena is the appearance of fractal sandpile configurations. These fractal sandpiles are characterized by repetitive and self-similar patterns where the same shapes appear over and over again, but in smaller and smaller versions. The occurrence of these fractal patterns has yet evade any mathematical explanation. While the researchers at IST Austria could also not solve this mathematical riddle, they rendered this phenomenon even more mysterious by showing that these fractal patterns can seemingly continuously transform into one another: They were able to produce movies in which the fractal patterns display dynamics which are, depending on the background of the observer, either reminiscent of the movement of real-world sand dunes, or of “psychedelic movies” characteristic for the 70’ies.

Not solving a mathematical question but only making it appear to be even more mysterious might at first sight not seem to be the ideal outcome. However, the two scientists — Moritz Lang who is a postdoc in the research group of Professor Calin Guet, and Mikhail Shkonikov, a postdoc in the group of Professor Tamas Hausel — believe that their “psychedelic movies” might be the key to a better understanding of the sandpile model, and maybe also of many other physical, biological or even economical problems. “You could say that we have found universal coordinates for the sandpile,” say Mikhail Shkonikov, “essentially, we can give every sand dune in the desert a very specific identifier.” Moritz Lang, who is a theoretical biologist, adds: “the key to understand any physical or biological phenomenon is to understand its consequences. The more consequences we know, the harder it becomes to develop a scientific hypothesis which is in agreement with all those consequences. In that sense, knowing all possible sand dunes and how they move represents a lot of constraints, and we hope that, in the end, this will remove sufficient hay from the stack such that we can find the needle.”

The two researchers see many applications of their theoretical work to real-world problems like the prediction of earthquake magnitudes, the functioning of the human brain, physics, or even economics: “In all these fields, we find haystacks which look similar, very similar. Maybe it turns out that all haystacks are the same, and that there is only one needle to find.”

Moritz Lang finished his PhD at ETH Zürich in spring 2015 with a thesis entitled “Modular identification and analysis of biomolecular networks.” He joined IST Austria in August 2015. Mikhail Shkonikov obtained his PhD from the University of Geneva and joined IST Austria in 2017.

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Van der Kooi’s main research focus is the evolution of flower color, and the interaction between flower color and pollinators. This led him to investigate how petals produce their visual signals. He explains why the flowers of poppies (Papaver, Meconopsis and related species) are interesting: ‘The common poppy is an extreme case, it has very thin petals that nevertheless cause a very high scattering of light. Poppies also contain high concentrations of pigments.’

Jigsaw pieces

The researchers collected petals from different poppy species and studied their structures using different techniques. They discovered that the pigment was only present in the two outer cell layers and not in the middle layer. The pigmented cells had a fascinating shape, with many invaginations that made them look like complicated jigsaw pieces. ‘This creates many air-filled gaps between the cells, which cause the reflection of light on the cell/air boundary’, says Van der Kooi.

Furthermore, the petals contained huge amounts of pigment. ‘They are among the highest concentrations that I have ever measured in any flower.’ Indeed, the characteristic black markings at the center of some poppy flowers are caused by extreme concentrations of red pigment. Van der Kooi concludes that dense pigmentation together with strong scattering causes the striking poppy colors in the red parts of the petal.

Sexual mimicry

The new findings can be linked to previous work on poppy color evolution. Intriguingly, poppies in the Middle East reflect no ultraviolet light, while the same species in Europe do. This difference may be due to their preferred pollinators. ‘In Europe, poppies are pollinated mostly by bees, which cannot see red very well; however, they will pick up ultraviolet.’ In contrast, poppies in the Middle East are pollinated by beetles that do see red colors.

‘Moreover, previous studies have shown that the black spots at the heart of some poppies mimic the presence of a female beetle. This is a way for the flowers to attract male beetles. A case of sexual mimicry, as occurs in other plants such as orchids’, explains Van der Kooi.

Air gaps

The next question will be how these jigsaw-like cells and the air gaps that cause the efficient scattering have evolved. ‘These cell shapes are commonly present in leaves, so that might be a clue.’ Furthermore, results suggest that poppies evolved ultraviolet signals when they began growing in more northern regions. It makes the evolutionary history of these brightly colored flowers an interesting object of study.

The paper by Van der Kooi and Stavenga will be included in a special edition of the Journal of Comparative Physiology A, edited by Friedrich Barth (University of Vienna). This special edition, with the title “Insects and Flowers. New insights into an old partnership,” is due to appear in print late this spring. The paper has already been published online.

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“The biggest problem for brain repair is that neurons don’t regenerate after brain damage, because they don’t divide,” said Gong Chen, professor of biology and Verne M. Willaman Chair in Life Sciences at Penn State and leader of the research team. “In contrast, glial cells, which gather around damaged brain tissue, can proliferate after brain injury. I believe turning glial cells that are the neighbors of dead neurons into new neurons is the best way to restore lost neuronal functions.”

Chen’s team previously published research describing a sequence of nine small molecules that could directly convert human glial cells into neurons, but the large number of molecules and the specific sequence required for reprogramming the glial cells complicated the transition to a clinical treatment. In the current study, the team tested various numbers and combinations of molecules to identify a streamlined approach to the reprogramming of astrocytes, a type of glial cells, into neurons.

“We identified the most efficient chemical formula among the hundreds of drug combinations that we tested,” said Jiu-Chao Yin, a graduate student in biology at Pen State who identified the ideal combination of small molecules. “By using four molecules that modulate four critical signaling pathways in human astrocytes, we can efficiently turn human astrocytes — as many as 70 percent — into functional neurons.”

The resulting chemically converted neurons can survive more than seven months in a culture dish in the lab. They form robust neural networks and send chemical and electrical signals to each other, as normal neurons do inside the brain.

Using three of the small molecules instead of four also results in the conversion of astrocytes into neurons, but the conversion rate drops by about 20 percent. The team also tried using only one of the molecules, but this approach did not induce conversion.

Chen and his team had previously developed a gene therapy technology to convert astrocytes into functional neurons, but due to the excessive cost of gene therapy — which can cost a patient half a million dollars or more — the team has been pursuing more economical approaches to convert glial cells into neurons. The delivery system for gene therapies is also more complex, requiring the injection of viral particles into the human body, whereas the small molecules in the new method can be chemically synthesized and packaged into a pill.

“The most significant advantage of the new approach is that a pill containing small molecules could be distributed widely in the world, even reaching rural areas without advanced hospital systems,” said Chen. “My ultimate dream is to develop a simple drug delivery system, like a pill, that can help stroke and Alzheimer’s patients around the world to regenerate new neurons and restore their lost learning and memory capabilities.”

The researchers acknowledge that many technical issues still need to be resolved before a drug using small molecules could be created, including the specifics of drug packaging and delivery. They also plan to investigate potential side effects of this approach in future studies in order to develop the safest drug pills. Nonetheless, the research team is confident that this combination of molecules has promising implications for future drug therapies to treat individuals with neurological disorders.

“Our years of effort in discovering this simplified drug formula take us one step closer to reaching our dream,” said Chen.

In addition to Chen and Yin, other co-authors contributed to this work include Lei Zhang, Ning-Xin Ma, Yue Wang, Grace Lee, Xiao-Yi Hou, Zhuo-Fan Lei, Feng-Yu Zhang, Feng-Ping Dong and Gang-Yi Wu from Penn State. This work was supported by the National Institutes of Health (AG045656), the Alzheimer’s Association (ZEN-15-321972), and the Charles H. “Skip” Smith Endowment Fund at Penn State.

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