“The results of our research strongly indicate that bacteria in the gut regulate the fungal microbiota and keep it under control. When bacteria are disrupted by antibiotics, fungi, Candida in particular, have the chance to reproduce,” says PhD student Rebecka Ventin-Holmberg from the University of Helsinki.

A new key finding in the study was that the changes in the fungal gut microbiota, together with the bacterial microbiota, be part of the cause of the long-term adverse effects of antibiotics on human health.

Long-term changes in infant gut microbiota

Antibiotics are the most commonly prescribed drugs for infants. They cause changes in the gut microbiota at its most important developmental stage. These changes have also been found to be more long-term compared with those of adults.

“Antibiotics can have adverse effects on both the bacterial and the fungal microbiota, which can result in, for example, antibiotic-associated diarrhea,” Ventin-Holmberg says.

“In addition, antibiotics increase the risk of developing chronic inflammatory diseases, such as inflammatory bowel disease (IBD), and they have been found also to have a link to overweight,” she adds.

These long-term effects are thought to be caused, at least partly, by an imbalance in the gut microbiota.

In the gut, everything is connected

The recently published study involved infants with a respiratory syncytial virus (RSV) infection who had never previously received antibiotics. While some of the children were given antibiotics due to complications, others received no antibiotic therapy throughout the study.

“Investigating the effects of antibiotics is important for the development of techniques that can be used to avoid chronic inflammatory diseases and other disruptions to the gut microbiota in the future,” Ventin-Holmberg emphasises.

While the effect of antibiotics on bacterial microbiota has been previously investigated, studies on fungal microbiota have been scarce. The findings of this study indicate that fungal microbiota may also have a role in the long-term effects of imbalance in the gut microbiota.

“Consequently, future research should focus on all micro-organisms in the gut together to better understand their interconnections and to obtain a better overview of the microbiome as a whole,” Ventin-Holmberg notes.

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When stem cells divide, they have the remarkable ability to choose to self-renew — that is, make a copy of themselves — or mature into defined lineages. How a specific lineage identity is maintained every time a stem cell divides can now be better understood thanks to the work of a team led by biochemists at the University of California, Riverside.

The study led by Sihem Cheloufi and Jernej Murn, both assistant professors in the Department of Biochemistry, shows how a protein complex, called chromatin assembly factor-1, or CAF-1, controls genome organization to maintain lineage fidelity. The report appears today in Nature Communications.

Each time a cell divides, it has to create a replica of its genome — not only its DNA sequence but also how the DNA is packaged with proteins into chromatin. Chromatin is organized into genomic sites that are either open and easily accessible or more densely packed and less accessible (or closed).

“Identities of different cells rely heavily on the genome sites that are more open because only genes located in those regions can potentially become expressed and turned into proteins,” Cheloufi explained.

She added that to maintain cell identity during cell division, the locations of open and closed chromatin, or “chromatin organization,” must be faithfully passed onto the new replica of the genome, a task largely entrusted to CAF-1.

“To help CAF-1 secure correct chromatin organization during cell division, a host of transcription factors are attracted to open regions in a DNA sequence-specific manner to serve as bookmarks and recruit transcription machinery to correct lineage-specific genes, ensuring their expression,” she said. “We wondered about the extent to which CAF-1 is required to maintain cell-specific chromatin organization during cell division.”

The authors took as a study paradigm immature blood cells that can either self-renew or turn into neutrophils, which are non-dividing cells that present our body’s first line of defense against pathogens. Intriguingly, they found CAF-1 to be essential not only for maintaining the self-renewal of these immature blood cells, but for preserving their lineage identity. Even a moderate reduction of CAF-1 levels caused the cells to forget their identity and adopt a mixed lineage stage.

“Neutrophil stem cells missing CAF-1 become more plastic, co-expressing genes from different lineages, including those of red blood cells and platelets,” Cheloufi said. “This is very intriguing from a developmental biology perspective.”

At the molecular level, the team found that CAF-1 normally keeps specific genomic sites compacted and inaccessible to specific transcription factors, especially one called ELF1.

“By looking at chromatin organization, we found a whole slew of genomic sites that are aberrantly open and attract ELF1 as a result of CAF-1 loss,” Murn said. “Our study further points to a key role of ELF1 in defining the fate of several blood cell lineages.”

The UCR researchers used immature blood cells derived from mouse bone marrow and engineered for growth in tissue culture. They validated their findings in vivo using a mouse model in collaboration with Andrew Volk, a hematology expert at the Cincinnati Children’s Hospital Medical Center and a co-corresponding author on the study.

Next, Cheloufi and her colleagues would like to understand the mechanism by which CAF-1 preserves the chromatin state at specific sites and whether this process works differently across different cell types.

“Like a city, the genome has its landscape with specific landmarks,” Cheloufi said. “It would be interesting to know how precisely CAF-1 and other molecules sustain the genome’s ‘skyline.’ Solving this problem could also help us understand how the fate of cells could be manipulated in a predictive manner. Given the fundamental role of CAF-1 in packaging the genome during DNA replication, we expect it to act as a general gatekeeper of cellular identity. This would in principle apply to all dividing cells across numerous tissues, such as cells of the intestine, skin, bone marrow, and even the brain.”

Cheloufi, Murn, and Volk were joined in the study by several UCR students, including first author Reuben Franklin, Yiming Guo, Shiyang He, Meijuan Chen, Carmen Chiem; as well as numerous collaborators among them Russell Rockne at the City of Hope, Maria Ninova at UCR, and Dr. David Sykes and Ruslan Sadreyev at the Massachusetts General Hospital.

The study was supported by the Department of Defense, National Institutes of Health, City of Hope/UCR biomedical research initiative, and UC cancer research coordinating committee.

The title of the research paper is “Regulation of Chromatin Accessibility by the Histone Chaperone CAF-1 Sustains Lineage Fidelity.”

These hydrogels can generate voltages when touched, but scientists did not clearly understand how — until a team of researchers at UBC devised a unique experiment, published today in Science.

“How hydrogel sensors work is they produce voltages and currents in reaction to stimuli, such as pressure or touch — what we are calling a piezoionic effect. But we didn’t know exactly how these voltages are produced,” said the study’s lead author Yuta Dobashi, who started the work as part of his master’s in biomedical engineering at UBC.

Working under the supervision of UBC researcher Dr. John Madden, Dobashi devised hydrogel sensors containing salts with positive and negative ions of different sizes. He and collaborators in UBC’s physics and chemistry departments applied magnetic fields to track precisely how the ions moved when pressure was applied to the sensor.

“When pressure is applied to the gel, that pressure spreads out the ions in the liquid at different speeds, creating an electrical signal. Positive ions, which tend to be smaller, move faster than larger, negative ions. This results in an uneven ion distribution which creates an electric field, which is what makes a piezoionic sensor work.”

The researchers say this new knowledge confirms that hydrogels work in a similar way to how humans detect pressure, which is also through moving ions in response to pressure, inspiring potential new applications for ionic skins.

“The obvious application is creating sensors that interact directly with cells and the nervous system, since the voltages, currents and response times are like those across cell membranes,” says Dr. Madden, an electrical and computer engineering professor in UBC’s faculty of applied science. “When we connect our sensor to a nerve, it produces a signal in the nerve. The nerve, in turn, activates muscle contraction.”

“You can imagine a prosthetic arm covered in an ionic skin. The skin senses an object through touch or pressure, conveys that information through the nerves to the brain, and the brain then activates the motors required to lift or hold the object. With further development of the sensor skin and interfaces with nerves, this bionic interface is conceivable.”

Another application is a soft hydrogel sensor worn on the skin that can monitor a patient’s vital signs while being totally unobtrusive and generating its own power.

Dobashi, who’s currently completing his PhD work at the University of Toronto, is keen to continue working on ionic technologies after he graduates.

“We can imagine a future where jelly-like ‘iontronics’ are used for body implants. Artificial joints can be implanted, without fear of rejection inside the human body. Ionic devices can be used as part of artificial knee cartilage, adding a smart sensing element. A piezoionic gel implant might release drugs based on how much pressure it senses, for example.”

Dr. Madden added that the market for smart skins is estimated at $4.5 billion in 2019 and it continues to grow. “Smart skins can be integrated into clothing or placed directly on the skin, and ionic skins are one of the technologies that can further that growth.”

The research includes contributions from UBC chemistry PhD graduate Yael Petel and Carl Michal, UBC professor of physics, who used the interaction between strong magnetic fields and the nuclear spins of ions to track ion movements within the hydrogels. Cédric Plesse, Giao Nguyen and Frédéric Vidal at CY Cergy Paris University in France helped develop a new theory on how the charge and voltage are generated in the hydrogels.

This finding is unexpected because the plate tectonic regime of our planet progressively recycles crustal material via large-scale mantle convection at much smaller time scales. Therefore, it has been assumed that vestiges of early geological processes on Earth can only be found as analogues, on other terrestrial planets (Mercury, Venus, and Mars), asteroids, or the Moon. However, according to their study ‘Long-term preservation of Hadean protocrust in Earth’s mantle’, which has recently appeared in the Proceedings of the National Academy of Sciences (PNAS), magmatic rocks that erupted throughout Earth’s history can still carry signatures that provide detailed information about the nature of the first crust, its long-term preservation in a graveyard in the lower-most mantle, and its resurrection via younger volcanism.

For their study, the geologists investigated up to 3.55 billion years old rocks from southern Africa. The analysis of these rocks revealed small anomalies in the isotope composition of the element tungsten (W). The origin of these isotope anomalies, namely the relative abundance of ¹⁸²W, relates to geological processes that must have occurred immediately after the formation of the Earth more than 4.5 billion years ago.

Model calculations by the authors show that the observed ¹⁸²W isotope patterns are best explained by the recycling of Earth’s earliest crust into mantle material that ascends via plumes from the lower mantle to generate lavas erupting at Earth’s surface. Intriguingly, the study shows that similar isotope patterns can be observed in distinct types of modern volcanic rocks (ocean island basalts), which demonstrates that Earth’s earliest crust is still buried in the lowermost mantle.

‘We assume that the lower layers of the crust — or the roots of the primordial continents — became heavier than their surroundings due to a geological maturation process and therefore sank into the Earth’s underlying mantle. Similar to a lava lamp,’ geochemist Dr Jonas Tusch from the University of Cologne’s Institute of Geology and Mineralogy remarked. ‘This fascinating insight provides a geochemical fingerprint of the young Earth, allowing us to better understand how large continents formed over the history of our planet. It also explains how our current, oxygen-rich atmosphere evolved — setting the stage for the origin of complex life,’ Dr Elis Hoffmann of Freie Universität Berlin added.

The geochemical fingerprint of the early Earth can also be compared with findings about other planets obtained during space missions. For example, data from Mars missions and studies of Martian meteorites show that Mars still has a very old surface due to the lack of plate tectonics, and that its composition may correspond to that of the young Earth.

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