Energy Production in the Mitochondria Regulated by Microbes (Biology)

Energy production in the mitochondria was found to be regulated by microbes residing in the depths of the bowels

The last decade has witnessed a revolution in the study of the symbiotic relations between gut bacteria and their animal hosts, including humans, wherein these microbes were found to affect both health and disease. Yet, despite the immense progress that has been made, the mechanisms by which bowel-dwelling microbes engage with our bodily functions are not well understood. A recently published study conducted by scientists at the Weizmann Institute of Science has exposed a fundamental regulatory mechanism based on a tight relationship between gut bacteria and host energy production in a fruit fly model. These findings offer a unifying explanation for the diverse mechanistic impacts of gut bacteria and also account for the well-known trade-off between survival and reproduction.

Dr. Yulia Gnainsky. A semblance of cooperation between gut bacteria and their “primordial mothers” © Weizmann Institute of Science

Previous work by the group of Prof. Yoav Soen of the Biomolecular Sciences Department revealed a surprising connection between gut bacteria and oogenesis – the production or development of ova (egg cells) – in the ovaries. In the current study – led by Dr. Yulia Gnainsky in collaboration with Dr. Sergey Malitsky and Dr. Maxim Itkin from the Life Sciences Core Facilities Department – the researchers sought to understand exactly how gut bacteria wield their remote influence over the reproductive system. Recruiting the fruit fly to their cause, they found that this influence is mediated by bacterial-derived factors that regulate both the production of energy in the host body and the energy expenditure on various host functions. This includes regulation of the development and function of the reproductive system by circulating bacterial metabolites that are required for cellular respiration in the mitochondria.

Prof. Yoav Soen: “We uncovered a fundamental mechanism of bacterial regulation over mitochondrial activity throughout the host body”

The mitochondrion, popularly referred to as the cell’s “powerhouse,” is the eukaryotic organelle mediating the process of cellular respiration. Often found in hundreds or even thousands of copies in most of the body’s cells, mitochondria are our main source for the production of ATP – the primary energy currency of all organisms. ATP production in the mitochondria relies on key coenzymes, such as FAD. Coenzymes are commonly synthesized from vitamins that serve as precursor molecules. The precursor for the biosynthesis of FAD, for example, is vitamin B2 (riboflavin). However, much like humans and other animals, the fly cannot produce B-type vitamins on its own, so the provision of vitamins such as riboflavin has to be “outsourced” – to the diet or the gut microbiota (or both). B vitamins and other metabolic products of gut bacteria are absorbed in the intestine and subsequently distributed to numerous destinations throughout the body.

While the significance of bacterial vitamins is expected to increase when the host is malnourished, the researchers hypothesized that the bacterial supply of B vitamins can regulate the mitochondrial function in host cells under a range of standard nutritional conditions as well. To test their hypothesis, they removed all gut bacteria from female fruit flies – leaving them germ free – and noted a shortage of FAD, which led to reduced mitochondrial activity, lower ATP production and mild weight loss. Substantial attenuation of mitochondrial activity was observed in the ovaries, particularly in follicle cells of the developing egg chamber. To determine if the repressed oogenesis is caused by the attenuation of ovarian mitochondrial activity, the researchers inhibited the expression of certain mitochondrial genes in ovarian follicle cells, this time without eliminating the gut microbiota. They found that disrupting the mitochondrial function of these cells is enough to significantly impair oogenesis; in fact, this effect was similar to the one that was observed in germ-free flies. Moreover, recolonization of germ-free female flies with gut bacteria (or alternatively, supplementing their diets with riboflavin), restored the mitochondrial function in the follicle cells, elevated the ATP levels in the ovaries and the entire body and increased ova production. The causal relation between gut bacterial metabolism and host energy production was further supported by measurements of ATP levels and overall weight of male flies.

The bacterial-mitochondrial axis of regulation will most likely be found across different animal species 

“In our effort to elucidate the ‘remote’ influence of gut bacteria over the reproductive system, we uncovered a fundamental mechanism of bacterial regulation over mitochondrial activity throughout the host body,” Prof. Soen explains. “As previously observed time and again, the relative simplicity of the fruit fly model makes it particularly effective for discovering elementary processes that characterize all living beings, including humans. Since the basic mechanisms of energy production are highly evolutionarily conserved, we expect that this bacterial-mitochondrial axis of regulation will be found to apply to many other species as well.”

The findings of this study also offer a mechanistic explanation for the known trade-off between survival and reproduction. Various conditions of stress (including malnutrition) require reduced investment in the highly energy-consuming process of reproduction, so as to enable the body to cope with the stressor(s). The causal link between a shortage of type-B vitamins (and their derived coenzymes) and the predominant repression of mitochondrial activity in the ovary prioritizes the expenditure of energy on processes that ensure personal survival over reproduction. “Although we have only demonstrated this mechanistic reallocation of energy in germ-free flies, we expect it to apply in a broad range of scenarios,” says Dr. Gnainsky.

Taken together, these findings uncover an important bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction. The fact that the mitochondrion is a genetically distinct organelle that is thought to be derived from ancient bacteria forms an intriguing image of cooperation between gut bacteria and their “primordial mothers” – the mitochondria.

Science Numbers

The mitochondrion is a descendent of bacteria that merged through endosymbiosis with other unicellular microorganisms nearly 1.5 billion years ago.

Featured image: Ova in the early stages of their development in a segment of a fruit fly’s ovary. Green – inactive mitochondria; Yellow-red – active mitochondria © Weizmann Institute of Science

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Provided by Weizmann Institute of Science

Researchers Identify 64 Regions of the Genome That Increase Risk for Bipolar Disorder (Biology)

In the largest genetic study of bipolar disorder to date, researchers have identified 64 regions of the genome containing DNA variations that increase risk of bipolar disorder – more than double the number previously identified.

The research team also found overlap in the genetic bases of bipolar disorder and other psychiatric disorders. Furthermore, the study supports a role of sleep habits, alcohol, and substance usage in the development of bipolar disorder, although further research is needed to confirm these findings. The study results are published May 17 in Nature Genetics.

Bipolar disorder, a complex psychiatric disorder characterized by recurrent episodes of severely high and low mood, affects an estimated 40 to 50 million people worldwide. It typically begins in young adulthood, often takes a chronic course, and carries an increased risk of suicide, making it a major public health concern and cause of global disability.

To help elucidate the underlying biology of bipolar disorder, an international team of scientists from within the Psychiatric Genomics Consortium conducted a genome-wide association study. This means they scanned the DNA of lots of people, looking for genetic markers that were more common in those who had bipolar disorder. This involved scanning more than 7.5 million common variations in the DNA sequence of nearly 415,000 people, more than 40,000 of whom had bipolar disorder. The study identified 64 regions of the genome that contain DNA variations that increase risk of bipolar disorder.

“It is well-established that bipolar disorder has a substantial genetic basis and identifying DNA variations that increase risk can yield insights into the condition’s underlying biology,” says Niamh Mullins, PhD, Assistant Professor of Psychiatric Genomics at the Icahn School of Medicine at Mount Sinai and lead author of the paper. “Our study found DNA variations involved in brain cell communication and calcium signaling that increase risk of bipolar disorder.

The findings suggest that drugs, such as calcium channel blockers that are already used for the treatment of high blood pressure and other conditions of the circulatory system, could be investigated as potential treatments for bipolar disorder, yet it’s important to note that future research to directly assess whether these medications are effective is essential.”

The study also found overlap in the genetic basis of bipolar disorder and that of other psychiatric disorders and confirmed the existence of partially genetically distinct subtypes of the disorder. Specifically, they found that bipolar I disorder shows a strong genetic similarity with schizophrenia and bipolar II disorder is more genetically similar to major depression.

“This research would not have been possible without the collaborative efforts of scientists worldwide that enabled the study of hundreds of thousands of DNA sequences,” said Ole Andreassen, MD, PhD, Professor of Psychiatry, Institute of Clinical Medicine and Oslo University Hospital and senior author of the paper. “Through this work, we prioritized some specific genes and DNA variations which can now be followed up in laboratory experiments to better understand the biological mechanisms through which they act to increase risk of bipolar disorder.”

The biological insights gained from this research could ultimately lead to the development of new and improved treatments or precision medicine approaches to stratify patients at high genetic risk who may benefit from targeted treatment or intervention strategies. Understanding causal risk could aid clinical decision-making in the prevention or management of the illness. Future genetic studies in larger and more diverse populations are now needed to pinpoint the genes relevant to risk of bipolar disorder in other areas of the genome.

The Psychiatric Genomics Consortium (PGC) is an international consortium of scientists dedicated to studying the genetic basis of psychiatric disorders and includes over 800 researchers, from more than 150 institutions from over 40 countries.

Featured image: Niamh Mullins, PhD, Assistant Professor of Psychiatry and Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai © Mount Sinai Health System

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Reference: Mullins, N., Forstner, A.J., O’Connell, K.S. et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet (2021). https://doi.org/10.1038/s41588-021-00857-4

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Provided by Mount Sinai

Evolutionary Biologists Discover Mechanism That Enables Lizards to Breathe Underwater (Biology)

A team of evolutionary biologists from the University of Toronto has shown that Anolis lizards, or anoles, are able to breathe underwater with the aid of a bubble clinging to their snouts.

Anoles are a diverse group of lizards found throughout the tropical Americas. Some anoles are stream specialists, and these semi-aquatic species frequently dive underwater to avoid predators, where they can remain submerged for as long as 18 minutes.

“We found that semi-aquatic anoles exhale air into a bubble that clings to their skin,” says Chris Boccia, a recent Master of Science graduate from the Faculty of Arts & Science’s Department of Ecology & Evolutionary Biology (EEB). Boccia is lead author of a paper describing the finding published this week in Current Biology.

“The lizards then re-inhale the air,” says Boccia, “a maneuver we’ve termed ‘rebreathing’ after the scuba-diving technology.”

The researchers measured the oxygen (O2) content of the air in the bubbles and found that it decreased over time, confirming that rebreathed air is involved in respiration.

Rebreathing likely evolved because the ability to stay submerged longer increases the lizard’s chances of eluding predators.

The authors studied six species of semi-aquatic anoles and found that all possessed the rebreathing trait, despite most species being distantly related. While rebreathing has been studied extensively in aquatic arthropods like water beetles, it was not expected in lizards because of physiological differences between arthropods and vertebrates.

“Rebreathing had never been considered as a potential natural mechanism for underwater respiration in vertebrates,” says Luke Mahler, an assistant professor in EEB and Boccia’s thesis supervisor. “But our work shows that this is possible and that anoles have deployed this strategy repeatedly in species that use aquatic habitats.”

Mahler and co-author Richard Glor, from the University of Kansas, first observed anoles rebreathing in Haiti in 2009 but were unable to carry out further observations or experiments. Another co-author, Lindsey Swierk, from Binghamton University, State University of New York, described the same behaviour in a Costa Rican species in 2019. These early observations suggested that rebreathing was an adaptation for diving, but this idea had not been tested until now.

Boccia became interested in aquatic anoles after encountering one in Panama. He began his rebreathing investigations in Costa Rica in 2017 and continued the research in Colombia and Mexico.

As the authors point out, the rebreathing trait may have developed because anoles’ skin is hydrophobic — it repels water — a characteristic that likely evolved in anoles because it protects them from rain and parasites. Underwater, air bubbles cling to hydrophobic skin and the ability to exploit these bubbles for breathing developed as a result.

A submerged Anolis lizard with a rebreathing bubble on its snout. © Lindsey Swierk

While further work is required to understand how the process works in detail, Boccia, Mahler and their co-authors suggest different ways in which rebreathing may function.

In its simplest form, the air bubble on a lizard’s snout likely acts like a scuba tank, providing a submerged animal with a supply of air in addition to the air in its lungs. This is what aquatic arthropods like water beetles do to extend the time they can remain submerged.

The researchers also suggest that the rebreathing process may facilitate using air found in a lizard’s nasal passages, mouth and windpipe that would otherwise not be used by the lizard in breathing.

The bubble may also help rid waste carbon dioxide (CO2) from exhaled air through a process other researchers have already observed in aquatic arthropods. Those studies concluded that because CO2 is highly soluble in water and because the level of CO2 in the bubbles is higher than in the surrounding water, exhaled CO2 dissolves into the surrounding water rather than being rebreathed.

Finally, the authors speculate that the bubble may act as a gill and absorb oxygen from the water — again, something already observed in arthropods. Boccia and Mahler are planning further research to confirm if these rebreathing processes are occurring with anoles.

According to Mahler, “This work enriches our understanding of the creative and unexpected ways that organisms meet the challenges posed by their environments. That is valuable in its own right, but discoveries like this can also be valuable to humans as we seek solutions to our own challenging problems.”

“It’s too early to tell if lizard rebreathing will lead to any particular human innovations,” says Boccia, “But biomimicry of rebreathing may be an interesting proposition for several fields — including scuba-diving rebreathing technology, which motivated our naming of this phenomenon.”

Mahler’s participation in the research was supported by an NSERC Discovery Grant and a Harvard University Ken Miyata Field Research Award. Boccia’s participation was supported by an NSERC CGS M Grant, a National Geographic Young Explorer Grant and a Sigma Xi Grant in Aid of Research.

Featured image: Close-up of an Anolis lizard with a rebreathing bubble on its snout. © Lindsey Swierk

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Reference: Christopher K. Boccia, Lindsey Swierk, Fernando P. Ayala-Varela, “Repeated evolution of underwater rebreathing in diving Anolis lizards”, Current Biology, 2021. DOI: https://doi.org/10.1016/j.cub.2021.04.040

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Provided by University of Toronto

Research Reveals Ancient People Has More Diverse Gut Microorganisms (Biology)

UM researcher Meradeth Snow holds a vial containing ancient human DNA.

Only an anthropologist would treasure millennia-old human feces found in dry caves.

Just ask Dr. Meradeth Snow, a University of Montana researcher and co-chair of UM’s Department of Anthropology. She is part of an international team, led by the Harvard Medical School-affiliated Joslin Diabetes Center, that used human “paleofeces” to discover that ancient people had far different microorganisms living in their guts than we do in modern times.

Snow said studying the gut microbes found in the ancient fecal material may offer clues to combat diseases like diabetes that afflict people living in today’s industrialized societies.

“We need to have some specific microorganisms in the right ratios for our bodies to operate effectively,” Snow said. “It’s a symbiotic relationship. But when we study people today – anywhere on the planet – we know that their gut microbiomes have been influenced by our modern world, either through diet, chemicals, antibiotics or a host of other things. So understanding what the gut microbiome looked like before industrialization happened helps us understand what’s different in today’s guts.” 

This new research was published May 12 in the prestigious journal Nature. The article is titled “Reconstruction of ancient microbial genomes from the human gut.” Snow and UM graduate student Tre Blohm are among the 28 authors of the piece, who hail from institutions around the globe.

Snow said the feces they studied came from dry caves in Utah and northern Mexico. So what does the 1,000-year-old human excrement look like?

“The caves these paleofeces came from are known for their amazing preservation,” she said. “Things that would normally degrade over time look almost brand new. So the paleofeces looked like, well, feces that are very dried out.”

Snow and Blohm worked hands-on with the precious specimens, suiting up in a clean-room laboratory at UM to avoid contamination from the environment or any other microorganisms – not an easy task when the tiny creatures are literally in and on everything. They would carefully collect a small portion that allowed them to separate out the DNA from the rest of the material. Blohm then used the sequenced DNA to confirm the paleofeces came from ancient people.

The senior author of the Nature paper is Aleksandar Kostic of the Joslin Diabetes Center. In previous studies of children living in Finland and Russia, he and his partners revealed that kids living in industrialized areas – who are much more likely to develop Type 1 diabetes than those in non-industrialized areas – have very different gut microbiomes.

“We were able to identify specific microbes and microbial products that we believe hampered a proper immune education in early life,” Kostic said. “And this leads later on to higher incidents of not just Type 1 diabetes, but other autoimmune and allergic diseases.”

Kostic wanted to find a healthy human microbiome without the effects of modern industrialization, but he became convinced that couldn’t happen with any modern living people, pointing out that even tribes in the remote Amazon are contracting COVID-19.

So that’s when the researchers turned to samples collected from arid environments in the North American Southwest. The DNA from eight well-preserved ancient gut samples were compared with the DNA of 789 modern samples. Half the modern samples came from people eating diets where most food comes from grocery stores, and the remainder came from people consuming non-industrialized foods mostly grown in their own communities.

The differences between microbiome populations were striking. For instance, a bacterium known as Treponema succinifaciens wasn’t in a single “industrialized” population’s microbiome the team analyzed, but it was in every single one of the eight ancient microbiomes. But researchers found the ancient microbiomes did match up more closely with modern non-industrialized population’s microbiomes.

The scientists found that almost 40% of the ancient microbial species had never been seen before. Kostic speculated on what caused the high genetic variability:

“In ancient cultures, the foods you’re eating are very diverse and can support a more eclectic collection of microbes,” Kostic said. “But as you move toward industrialization and more of a grocery-store diet, you lose a lot of nutrients that help to support a more diverse microbiome.”

Moreover, the ancient microbial populations incorporated fewer genes related to antibiotic resistance. The ancient samples also featured lower numbers of genes that produce proteins that degrade the intestinal mucus layer, which then can produce inflammation that is linked with various diseases.

Snow and several coauthors and museum collection managers also led a project to ensure the inclusion of Indigenous perspectives in the research.

“This was a really vital part of the work that had to accompany this kind of research,” she said. “Initially, we sent out multiple letters and emails and called the tribal historic preservation officers of all the recognized tribes in the Southwest region. Then we met with anyone who was interested, doing short presentations and answering questions and following up with interested parties.

“The feedback we received was noteworthy, in that we needed to keep in mind that these paleofeces have to ties their ancestors, and we needed to be – and hopefully have been – as respectful as possible about them,” she said. “There is a long history of misuse of genetic data from Indigenous communities, and we strove to be mindful of this by meeting and speaking with as many people as possible to obtain their insights and perspectives. We hope that this will set a precedent for us as scientists and others working with genetic material from Indigenous communities past and present.”

Snow said the research overall revealed some fascinating things.

“The biggest finding is that the gut microbiome in the past was far more diverse than today – and this loss of diversity is something we are seeing in humans around the world,” she said. “It’s really important that we learn more about these little microorganisms and what they do for us in our symbiotic relationships.

“In the end, it could make us all healthier.”

Featured image: Dr. Meradeth Snow is part of an international team that used human “paleofeces” to discover that ancient people had far different microorganisms living in their guts than we do in modern times. © University of Montana

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Provided by University of Montana

How Do Simple Creatures Manage to Move to a Specific Place? (Biology)

Artificial intelligence and a physical model from TU Wien can now explain this.

How is it possible to move in the desired direction without a brain or nervous system? Single-celled organisms apparently manage this feat without any problems: for example, they can swim towards food with the help of small flagellar tails.

How these extremely simply built creatures manage to do this was not entirely clear until now. However, a research team at TU Wien (Vienna) has now been able to simulate this process on the computer: They calculated the physical interaction between a very simple model organism and its environment. This environment is a liquid with a non-uniform chemical composition, it contains food sources that are unevenly distributed.

The simulated organism was equipped with the ability to process information about food in its environment in a very simple way. With the help of a machine learning algorithm, the information processing of the virtual being was then modified and optimised in many evolutionary steps. The result was a computer organism that moves in its search for food in a very similar way to its biological counterparts.

Chemotaxis: Always going where the chemistry is right

“At first glance, it is surprising that such a simple model can solve such a difficult task,” says Andras Zöttl, who led the research project, which was carried out in the “Theory of Soft Matter” group (led by Gerhard Kahl) at the Institute of Theoretical Physics at TU Wien. “Bacteria can use receptors to determine in which direction, for example, the oxygen or nutrient concentration is increasing, and this information then triggers a movement into the desired direction. This is called chemotaxis.”

The behaviour of other, multicellular organisms can be explained by the interconnection of nerve cells. But a single-celled organism has no nerve cells – in this case, only extremely simple processing steps are possible within the cell. Until now, it was not clear how such a low degree of complexity could be sufficient to connect simple sensory impressions – for example from chemical sensors – with targeted motor activity.

“To be able to explain this, you need a realistic, physical model for the movement of these unicellular organisms,” says Andreas Zöttl. “We have chosen the simplest possible model that physically allows independent movement in a fluid in the first place. Our single-celled organism consists of three masses connected by simplified muscles. The question now arises: can these muscles be coordinated in such a way that the entire organism moves in the desired direction? And above all: can this process be realised in a simple way, or does it require complicated control?”

A small network of signals and commands

“Even if the unicellular organism does not have a network of nerve cells – the logical steps that link its ‘sensory impressions’ with its movement can be described mathematically in a similar way to a neuronal network,” says Benedikt Hartl, who used his expertise in artificial intelligence to implement the model on the computer. In the single-celled organism, too, there are logical connections between different elements of the cell. Chemical signals are triggered and ultimately lead to a certain movement of the organism.

“These elements and the way they influence each other were simulated on the computer and adjusted with a genetic algorithm: Generation after generation, the movement strategy of the virtual unicellular organisms was changed slightly,” reports Maximilian Hübl, who did many of the calculations on this topic as part of his Master’s thesis. Those unicellular organisms that succeeded best in directing their movement to where the desired chemicals were located were allowed to “reproduce”, while the less successful variants “died out”. In this way, after many generations, a control network emerged – very similar to biological evolution– that allows a virtual unicellular organism to convert chemical perceptions into targeted movement in an extremely simple way and with very basic circuits.

Random wobbling movement – but with a concrete goal

“You shouldn’t think of it as a highly developed animal that consciously perceives something and then runs towards it,” says Andreas Zöttl. “It’s more like a random wobbling movement. But one that ultimately leads in the right direction on average. And that’s exactly what you observe with single-celled organisms in nature.”

The computer simulations and algorithmic concepts recently published in the renowned journal PNAS prove that a minimal degree of complexity of the control network is indeed sufficient to implement relatively complex-looking movement patterns. If the physical conditions are correctly taken into account, then a remarkably simple internal machinery is sufficient to reproduce in the model exactly those movements that are known from nature.

Featured image: The single celled organism can detect, in which direction the concentration of nutrients is highest. © Tu Wien

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Original publication

B. Hartl et al., Microswimmers learning chemotaxis with genetic algorithms, PNAS, 2021 118 (19) e2019683118; https://doi.org/10.1073/pnas.2019683118. Link to paper

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Provided by Tu Wein

Scientists Confirm Bacteria’s Genetic ‘Swiss Army Knife’ is Key Driver of Antibiotic Resistance (Biology)

Antibiotic resistance is a huge challenge facing society globally, posing a threat not only to human health but in areas such as food security and the economy. The more we know about the mechanisms behind antibiotic resistance, the better we can respond to these threats. 

New research, published in eLife, by scientists at the University of Oxford and Universidad Complutense de Madrid has confirmed that one of those mechanisms – driven by a sophisticated genetic system known as an integron – plays a key role in accelerating resistance and gives bacteria an ‘incredible opportunity’ to evolve in response to antibiotic treatment.

The new study highlights both the danger posed by integrons and the need to develop tools to counter their influence – for example, new drugs given alongside antibiotics that could limit an integron’s ability to accelerate bacterial evolution.

Antibiotic resistance is one of the biggest threats to modern medicine. As resistance grows, it will become harder to treat common infections such as food poisoning or pneumonia, or even to perform minor surgeries

Lead author Dr Célia Souque, of Oxford’s Department of Zoology, said: ‘Antibiotic resistance is one of the biggest threats to modern medicine. As resistance grows, it will become harder to treat common infections such as food poisoning or pneumonia, or even to perform minor surgeries – and all parts of the world will be affected. We urgently need not only to develop new antibiotics, but to increase our understanding of how bacteria develop resistance to these treatments, with the aim of stifling the appearance of resistance in the first place.’

Integrons are genetic platforms found inside bacteria that allow bacteria to ‘shuffle’ antibiotic resistance genes carried within. This shuffling ability has been hypothesized to generate an important evolutionary advantage for bacteria, by allowing useful integron genes to be placed in more prominent positions, optimizing the levels of antibiotic resistance they provide.

To probe experimentally for the first time the role played in resistance by integrons, the researchers inserted a customised integron carrying several resistance genes into a bacterium called Pseudomonas aeruginosa, which can cause pneumonia and blood infections in humans.

Understanding the benefits that integrons provide to bacteria gives us insights into potential future treatment strategies to limit or counteract the evolution of antibiotic resistance

The scientists found that, when confronted with antibiotics, the P. aeruginosa bacteria with functioning integrons were able to survive longer than those without. Integron functionality was altered within the bacteria by retaining or removing integrase – the enzyme responsible for gene shuffling.

Dr Souque said: ‘Bacteria have multiple mechanisms to evolve resistance: they might mutate certain genes to dodge the effects of antibiotics, or acquire new genes that help produce antibiotic-destroying enzymes. But these mutations or novel genes often carry a cost, making the resistant bacteria less able to thrive than their non-resistant counterparts under normal conditions. Our results show that integrons give bacteria an incredible opportunity to evolve resistance “on demand”, while also using efficient gene shuffling to reduce the cost to the bacteria’s overall ability to thrive.’

Senior study author Professor Craig Maclean, also of Oxford’s Department of Zoology, added: ‘The integron is a remarkable genetic structure that is unique to bacteria – it provides them with a kind of Swiss army knife of antibiotic resistance genes that they can rapidly alter in response to our treatments.

‘Understanding the benefits that integrons provide to bacteria gives us insights into potential future treatment strategies to limit or counteract the evolution of antibiotic resistance. For example, antibiotics could be combined with molecules that inhibit integrase activity to reduce bacteria’s gene-shuffling ability and thus the evolution of higher levels of resistance.’

Read the full paper ‘Integron activity accelerates the evolution of antibiotic resistance’ in eLife: https://elifesciences.org/articles/62474

Read an accompanying commentary: https://elifesciences.org/articles/68070

Featured image: Microscopy image of two fluorescent strains of P. aeruginosa Credit: Sean Booth

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Provided by University of Oxford

New Species Discovered In Norway (Biology)

This brand new species of cuckoo wasp was discovered because of its own language.

Cuckoo wasps – also called emerald wasps – are some of the most beautiful insects we have, with colourful exteriors that shine like jewels. However, these beauties have also created a lot of headaches.

“Normally we distinguish insects from each other by their appearance, but cuckoo wasps are so similar to each other that it makes it difficult,” says Frode Ødegaard.

When a new species is described, it must be given a name, and Frode Ødegaard was lucky and got to name the newcomer. Photo: Jake Bryant

Ødegaard is an insect researcher at the NTNU University Museum and belongs to the European research group that has now described this recent contribution to species diversity. The new species is very rare, and is only a single specimen has been found on the Lista peninsula in Agder county in Norway.

For more than 200 years, insect researchers have struggled to sort cuckoo wasps into the right “species boxes,” and to determine which characteristics are variations within a species and which are species-specific differences.

Chemical language in insects

In the last 10 years, DNA barcoding has brought about a major breakthrough by making it possible to distinguish different species of cuckoo wasps from each other by looking at the differences in their genetic material.

“But it’s not always that easy, either. In this case, we had two cuckoo wasps with microscopic differences in appearance and very small differences in DNA,” Ødegaard says.

“The cuckoo wasp is an insect with above-average linguistic abilities.”

“The next step was to look at the language of each of the wasps to find out if they belonged to different species,” he says.

There are a total of over 2,500 described golden wasp species, with 40 recorded in Norway. Photo: Arnstein Staverløkk, NINA, CC BY3.0

Insects communicate with each other through pheromones – in other words, they have a chemical language. Very closely related species often have completely different languages to prevent them from interbreeding.

Linguistic parasite

The cuckoo wasp is an insect with above-average linguistic abilities. They are parasites, which means that they behave like cuckoos and lay their eggs in the nests of other bees and wasps. The larvae grow quickly and hatch before the host’s eggs. Then they eat the eggs, the larvae and the food supply that the host has arranged in the nest.

“When you live as a parasite, it’s important not to be discovered, and therefore the cuckoo wasp has also learned the language of its host,” says Ødegaard.

By conducting an ever-so-small language study, the researchers were able to discover that the two almost identical cuckoo wasps did indeed belong to different species. They use different hosts – and that means that they also speak completely different languages.

“The evolutionary development associated with sponging off another species happens very fast. That’s why you can have two species that are really similar genetically but still belong to different species,” says Ødegaard.

Honoured to name the new species

When a new species is described, it has to be given a name. Frode Ødegaard had the good fortune to receive the honour of naming the newcomer.

“A naming competition was announced among researchers in Europe who work with cuckoo wasps, and then the proposals that came in were voted on. It turned out my proposal actually got the most votes!” Ødegaard says.

“As mentioned, the new wasp is very similar to another species called Chrysis brevitarsis, so the new species was named Chrysis parabrevitarsis, which means ‘the one standing next to brevitarsis’.”

Ødegaard was also responsible for giving the species its slightly simpler Norwegian name of sporegullveps. He makes no secret of the fact that he found it great to be able to name a new species.

“In a way, you have to think from the perspective of eternity, because that species will always have that name. There’s something very fundamental about it.”

Conservation biologist and mass murderer

The picture at the top, as mentioned, shows the only known specimen of this cuckoo wasp. So it may seem both morally reprehensible and unnecessary that this one lone individual was stuck onto a needle.

“Even with today’s advanced methods, using live animals for studies like this isn’t possible, but collecting individual specimens fortunately has no impact on the population,” Ødegaard says.

“The insects have enormous reproductive potential, and the size and quality of the habitats are what determine the viability of the population, not whether any specimens are eaten by birds or collected by an insect researcher.”

He adds that the collected insects are absolutely crucial for researchers to be able to map and describe their diversity and thus take care of viable populations for posterity.

Featured image: The new species was discovered in the dunes on Lista in Farsund municipality. Photo: Arnstein Staverløkk

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Reference: Frode Ødegaard et al.: Cuticular Hydrocarbon Profile Analyses Help Clarify the Species Identity of Dry-Mounted Cuckoo Wasps (Hymenoptera: Chrysididae), Including Type Material, and Reveal Evidence for a Cryptic Species Insect Systematics and Diversity, Volume 5, Issue 1, January 2021, 3, https://doi.org/10.1093/isd/ixab002

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Provided by Norwegian Science tech

Origins of Life Could Have Started With DNA-like XNAs (Biology)

Nagoya University scientists in Japan have demonstrated how DNA-like molecules could have come together as a precursor to the origins of life. The findings, published in the journal Nature Communications, not only suggest how life might have begun, but also have implications for the development of artificial life and biotechnology applications.

“The RNA world is widely thought to be a stage in the origin of life,” says Nagoya University biomolecular engineer Keiji Murayama. “Before this stage, the pre-RNA world may have been based on molecules called xeno nucleic acids (XNAs). Unlike RNA, however, XNA replication probably didn’t require enzymes. We were able to synthesize an XNA without enzymes, strongly supporting the hypothesis that an XNA world might have existed before the RNA world.”

XNAs are formed of chains of linked nucleotides, similar to DNA and RNA but with a different sugar backbone. XNAs can carry genetic code very stably because the human body can’t break them down. Some researchers have reported that XNAs containing specific sequences can act as enzymes and bind to proteins. This makes XNAs exciting in the field of synthetic genetics, with potential biotechnology and molecular medicine applications.

Murayama and his colleagues showed that L-aTNA fragments could interlink on complementary L-aTNA, RNA and DNA templates without the need for enzymes. © Keiji Murayama

Murayama, Hiroyuki Asanuma and colleagues wanted to find out if conditions likely present on early Earth could have led to XNA chain formation. They synthesized fragments of acyclic (non-circular) L-threoninol nucleic acid (L-aTNA), a molecule that is thought to have existed before RNA came to be. They also made a longer L-aTNA with a nucleobase sequence that complemented the sequences of the fragments, similar to how DNA strands match up.

When placed together in a test tube under controlled temperature, the shorter L-aTNA fragments came together and linked up with each other on the longer L-aTNA template. Critically, this happened in the presence of a compound, called N-cyanoimidazole, and a metal ion, like manganese, both of which were possibly present in early Earth. The fragments interlinked when a phosphate at the end of one chemically attached to a hydroxyl group at the end of its neighbour, without the help of an enzyme.

“To the best of our knowledge, this is the first demonstration of template-driven, enzyme-free extension of acyclic XNA from a random fragment pool, generating phosphodiester bonding,” says Murayama.

The team also demonstrated that L-aTNA fragments could interlink on DNA and RNA templates. This suggests that genetic code could be transferred from DNA and RNA onto L-aTNA and vice versa.

“Our strategy is an attractive system for experimenting with the construction of artificial life and the development of highly functional biological tools composed of acyclic XNA,” says Murayama. “The data also indicate that L-aTNA could have been an RNA precursor.”

The team plans to continue their investigations to clarify whether L-aTNA could have been synthesized in early Earth ‘pre-life’ conditions and to examine their potential for developing advanced biological tools.

Featured image: Some scientists think that XNA evolved into RNA, which then evolved into DNA, forming the very beginnings of life. © Keiji Murayama

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Reference: Murayama, K., Okita, H., Kuriki, T. et al. Nonenzymatic polymerase-like template-directed synthesis of acyclic L-threoninol nucleic acid. Nat Commun 12, 804 (2021). https://www.nature.com/articles/s41467-021-21128-0 https://doi.org/10.1038/s41467-021-21128-0

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Provided by Nagoya University

Understanding How Cancer Can Relapse (Biology)

University of Missouri researchers discover a novel cell-to-cell communication network that helps tumors regrow following treatment.

In the fight against cancers, activating mutations in the RAS family of genes stand in the way of finding viable treatment options. Now, scientists at the University of Missouri and Yale University have discovered that one of these mutations — oncogenic RAS or RASV12 — is also responsible for the regrowth of cancer cells following genotoxic therapy treatment, or drugs that cause damage to a cancer cell’s DNA in order to eliminate it from the body.

“Most of our knowledge of how cells respond to DNA damage is mainly derived from studies looking at the single cell level,” said Yves Chabu, an assistant professor in the MU College of Arts and Science. “Therefore, we don’t know much about how tumor cells respond to DNA damage in the broader context of the tissue level, and what possible implications these responses might have on a tumor’s relapse following genotoxic therapies. To address this, we looked at how tissues containing patches of cells carrying oncogenic RAS mutations respond to DNA damage. We focused on oncogenic RAS because it is associated with cancers relapse and resistance to genotoxic therapies in humans. This approach has allowed us to identify novel cell-to-cell communication within the tissue that instructs tumor cells in tissues to regrow. It’s something we would not have identified if we were only looking at the single cell level.”

Genotoxic therapies eliminate cancer cells by causing DNA damage inside those cells. Cells normally will stop multiplying and attempt to repair this DNA damage in order to avoid elimination, but if the damage is too extensive the cell will abandon the repair process and trigger its own demise. Cells rely on a molecule called “p53” to execute these outcomes.

“We found that in oncogenic RAS tissues, cells elevate the levels of the p53 protein to varying degrees in response to DNA damage,” said Chabu, whose appointment is in the Division of Biological Sciences. “Further analyses revealed that cells with high p53 protein levels, or more extensive DNA damage, do not simply die in response to the DNA damage. Instead, they release a growth signal called interlukin-6 into the tumor environment. Interlinkin-6 instructs cells with low p53 levels, or cells with less DNA damage, to activate JAK/STAT, a growth-amplifying signal, and drive tumor regrowth after treatment. We essentially have a situation where cells that are vulnerable to the treatment are instructing the more robust cells to take over and grow.”

Chabu, who has been studying oncogenic RAS mutations for more than a decade, said their findings suggest that adding JAK/STAT inhibitors to genotoxic therapies will limit the ability of RAS tumors to regrow. He said another interesting aspect of their findings is that p53 is traditionally considered as a tumor suppressor protein.

“A loss of p53 activity, due to genetic mutation, causes cells to grow uncontrollably while accumulating even more DNA mutations,” Chabu said. “So, naturally one would think that having more p53 activity is a good thing because it prevents pre-cancerous cells from growing and forming cancers. Yet, here we find that too much of a normal, not mutated, p53 can signal the surrounding RAS tissues to overgrow.”

While scientists have been studying mutations in RAS genes for more than three decades, scientists today have a better understanding of how these mutant genes work. However, many of them still consider these mutations to be “undruggable” or resistant to therapeutic treatment, according to the National Cancer Institute.

The study, “Cooperation between oncogenic RAS and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance,” was published in Communications Biology, a journal published by Nature Research. The work was supported in part by the Howard Hughes Medical Institute and start-up funds from the University of Missouri. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Featured image: Yves Chabu © University of Missouri

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Provided by University of Missouri