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The type VI secretion (T6S) system is a devastating quick-kill mechanism that has been found to exist in nearly a quarter of gram-negative bacteria, including Vibrio cholerae—the infectious agent that causes cholera—and Pseudomonas aeruginosa, a versatile pathogen that can cause sepsis and organ failure. New research from Princeton University and the University of Basel in Switzerland has revealed that T6S, once thought to be a microbial superweapon, can be thwarted if groups of targets are large enough when the assault begins. Although organisms on the outside of the cluster will perish, the protected interior cells can multiply quickly enough to replenish the group's numbers from the inside—even to the point where the number of targets spawning exceeds the number dying—and the attacking bacteria cannot take over. Reported in the journal PLOS Computational Biology, the findings—which combined computer simulations with observations of living bacteria—could provide insight into how cells withstand powerful aggressors, which scientists could use to develop treatments against pathogens. "Having T6S is not a 'Terminator' weapon, which is what it looked like initially and what a lot of people thought," explained first author David Borenstein, a postdoctoral research associate in Princeton's Lewis-Sigler Institute for Integrative Genomics. "We now think that the reason more bacteria don't have it is because it's not necessarily a good weapon." The researchers suggest that T6S may be only an occasional weapon used to eliminate specific targets under certain circumstances, which would help prevent the accidental killing of beneficial bacteria. The secretion system also is highly energy-intensive, Borenstein said. Thus, bacteria relying primarily on T6S would be laboring to constantly produce toxins. "There seem to be certain circumstances in which T6S is useful," Borenstein said. "It's not just turned on and fired willy-nilly in every direction. It's definitely something bacteria are choosing to use." In a new twist, the researchers found that the T6S system also has a potential role as a defensive weapon when cells with T6S attack other cells that also have it. While immune to their own secretion systems, the cells can kill each other. A computer simulation showed that when T6S-equipped bacteria attacked others, the organisms with the majority population won out. "If bacteria have T6S and an established population, it will be much easier for them to defend against an invading microbe, even if the attackers have it, too," Borenstein said. "The T6S system is a way to have a standby defense without producing defense toxins all the time and without inadvertently killing bacteria that might be beneficial in the meantime." The fusion of simulations and laboratory work are a notable feature of this work that could be used to better explore other biological systems and interactions, said Jeff Gore, an associate professor of physics at the Massachusetts Institute of Technology. The work illustrates that unique and potentially important ideas can spring from the interchange of computer modeling and experimentation, said Gore, who is familiar with the work but was not involved in it. "This paper represents a wonderful example of combining biologically motivated modeling with laboratory experiments," Gore said. "This is a powerful mode of inquiry that in my opinion could be used fruitfully to elucidate many other biological systems. In particular, more modeling should be motivated by surprising experimental results, and more quantitative experiments should be motivated by surprising theoretical predictions." Borenstein and co-author Ned Wingreen, Princeton's Howard A. Prior Professor of the Life Sciences and professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, first simulated the assault by cells with T6S on cells vulnerable to the secretion system. The target cells' resilience was surprising, Borenstein said. "The phenomenon we saw is similar to a herd of animals that cluster around each other when predators attack—the individuals on the outside are vulnerable, but the interior of the community is protected," Borenstein said. "But in this case, the prey animals on the inside rapidly reproduced during the assault. Once there were enough, it didn't matter how many predators there were anymore—they couldn't win." Co-authors Marek Basler, a professor of biology, and graduate student Peter Ringel, both at the University of Basel, tested the simulations in the laboratory on live bacteria by pitting V. cholerae against the bacteria Escherichia coli, which are vulnerable to T6S, and found the same results. A 2013 paper published in the journal Cell on which Basler was the first author inspired the current research. The simulations allowed the researchers to not only build upon their previous laboratory work, but also realize theories that would be difficult to physically carry out, Basler said. "Even before this collaboration, my group and others in the field made certain observations that we were explaining only intuitively," Basler said. "One beauty of these simulations is that one can vary parameters that are not so easy to vary experimentally, such as the killing rate or growth rate, and learn what would happen in a competition of bacteria strains under completely different conditions. "In many cases, the way we set up our competition assays in the lab is artificial; in nature you hardly see exponentially growing bacterial communities," he said. "But here we showed that the prey cells can win by outgrowing the competition even though they are constantly getting killed. I believe that in the future, we will discover more strategies about how prey cells deal with aggressors." Wingreen initiated the project after reading Basler's 2013 paper. That study showed that when P. aeruginosa attacked V. cholerae and the bacteria Acinetobacter baylyi—which also has the T6S system—they only resorted to using T6S when they detected that their targets also were using it. Wingreen began thinking that perhaps the use of T6S is selective and that there are costs and benefits bacteria consider, he said. He approached Borenstein, a software engineer, who had designed a simulation program called Nanoverse that predicts the outcomes of biological processes. "We quickly realized that the spatial structure of the competing strains are crucial to the outcome—there is a critical domain size above which sensitive colonies will survive," Wingreen said. "Real biology is always more complicated than our models, so to confirm that this simple idea actually held up in a real system, we initiated an experimental collaboration. [Basler and Ringel's] observations confirmed our main prediction—large colonies can survive an attack while small ones perish." The dynamic the researchers uncovered also could apply to other natural scenarios in which a vulnerable organism faces a powerful assailant, such as coral reefs struggling to resist algae, Wingreen said. Such an organism's resilience might depend on strengthening its pre-assault population and ensuring that it can maintain steady regeneration during the onslaught. Indeed, Gore said, the researchers show that considerations such as spatial structure can supersede principles otherwise presumed to be true. "Given that toxin-producing strains can kill toxin-sensitive strains, it is natural to assume that toxin production will always spread throughout a population," Gore said. "However, these researchers have demonstrated that the fate of toxin-production in a population depends critically on the size of the domains that each of these strains occupies. "The microbial world is full of examples of cells interacting in rich ways, either competitively or cooperatively," he said. "This work highlights that the range of that interaction can be very important." The paper, "Established microbial colonies can survive type VI secretion assault," was published by PLOS Computational Biology. Explore further: Deadly bacteria attack not only us, but each other as well, with remarkable precision More information: David Bruce Borenstein et al. Established Microbial Colonies Can Survive Type VI Secretion Assault, PLOS Computational Biology (2015). DOI: 10.1371/journal.pcbi.1004520

Human ancestors explored "Out of Africa" despite impaired nasal faculties. In humans inhaled air is conditioned poorly in the nasal cavity in comparison with primates, such as chimpanzees and macaques, according a recent study published in PLOS Computational Biology. Credit: Nishimura et al. In humans inhaled air is conditioned poorly in the nasal cavity in comparison with primates, such as chimpanzees and macaques, according a recent study published in PLOS Computational Biology. Unlike our protruding external nose, which has little effect on improving air conditioning performance, other hominins (including australopithecines) were endowed with flat nasal features and faculties to improve air conditioning. The study, produced by Dr Takeshi Nishimura from Kyoto University and colleagues, is the first investigation of nasal air conditioning in nonhuman hominoids based on computational fluid dynamics (CFD). The human nasal passage conditions inhaled air in terms of temperature and humidity to match the conditions required in the lung. Insufficient conditioning can damage the tissues in the respiratory system and impair respiratory performance, thereby undermining health and increasing the likelihood of death. Our ancestors, the genus Homo, diversified under the fluctuating climate of the Plio-Pleistocene, to be flat-faced with a short nasal cavity and a protruding external nose, as seen in modern humans. Anatomical variation in nasal region is believed to be evolutionarily sensitive to the ambient atmospheric conditions of a given habitat, but the nasal anatomy of early Homo was not sensitive to the ambient atmosphere conditions. The inhaled air can be fully conditioned subsequently in the pharyngeal cavity, which was lengthened in early Homo. This study highlights the importance of compensating human evolution, as well as adaptive evolution. The diversification of Pleistocene hominins is a major evolutionary event in terms of understanding human evolution. These linked changes in the nasal and pharyngeal regions would in part have contributed to how flat-faced Homo members must have survived fluctuations in climate, before they moved "Out of Africa" in the Early Pleistocene to explore the more severe climates and ecological environments of Eurasia. Explore further: Eastern Eurasian archaic humans featured a bi-level nasal floor as seen in Neandertals More information: Nishimura T, Mori F, Hanida S, Kumahata K, Ishikawa S, Samarat K, et al. (2016) Impaired Air Conditioning within the Nasal Cavity in Flat-Faced Homo. PLoS Comput Biol 12(3): e1004807.DOI: 10.1371/journal.pcbi.1004807

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Site: phys.org

Mathematically, coexistence means that a path through the interaction matrix, formed by all species in the food web, can be found. The figure visualizes an example interaction matrix, with white boxes connecting neighbor trophic levels contain non-zero elements. The path consists of using the combination of a given row and column only once, as shown by blue boxes. The connections to the nutrient source, shown by yellow, which feeds all species at the bottom layer, can - but need not - be used as a part of the path. In the given case, there are 4 basal species, e.g. plants, 5 plant eaters, and 2 top predators. Credit: Jan Härter, Niels Bohr Institutet We humans are affecting nature to a greater and greater degree and this is contributing to the reduction of biodiversity globally. To better assess the consequences requires a better understanding of the environmental conditions that the species in an ecosystem live under. A group of biophysicists from the Niels Bohr Institute have therefore analysed data and calculated how the species in an area affect each other and how an ecosystem can be in balance or out of balance. The results are published in the scientific journal, PLoS Computational Biology. In nature, animals move around and encroach into new areas where other animals have their habitat. Here they might be prey for some of the original animals and they can also be eaten themselves. They are all part of the food chain. This pattern of eating and being eaten can be in balance or it can lead to disturbances in the environment, for example when rabbits were introduced in Australia and the rabbits multiplied dramatically, as they had no natural enemies. But how do you know if an ecosystem is in balance? Can you even formulate it? Yes, a group of biophysicists from the Niels Bohr Institute has done it. The formula is called Lotka-Volterra and it is used to calculate the mutual influence, which is a key factor in a sustainable coexistence. "We have used data from biological observations and analysed the relationship between the different species and their place in the food chain. Some species eat plants, while others eat other animals. We can see that it is extremely important that there is a balance between who eats what and how many are hunting the same prey," explains Namiko Mitarai, Associate Professor of biophysics at the Niels Bohr Institute at the University of Copenhagen. She, along with Assistant Professor Jan Härter and Professor Kim Sneppen, both from the research group Biocomplexity at the Niels Bohr Institute, performed the comprehensive statistical calculations. Namiko Mitarai explains that they first used the classical calculations from the theories about ecosystems that say that two predators cannot exist simultaneously if they both live exclusively on the same prey. But in their analysis, they have modified the mutual competition by saying that the two competing predators might well exist side by side, if only they are prey for other predators. Predators may also be prey Whatever is eating grass is eaten by a carnivore, which is eaten by another carnivore and so on. If two species are chasing the same prey, it is important that the two species are also being hunted by other animals. Without it, one of the two species - say the one better at catching the pray, will eventually outcompete the other species because not enough pray is left for the other. But if the "better" species is also hunted by other animals, the "worse" species can have enough food to survive. Hence the "links" between species are very important. What they can also see is the combination of species in the different links of the food chain. As you can also see in the data from field studies, it turns out that these 'rules' that predators have to be prey for other predators means that there are far more species in the middle part of the food chain than at the bottom and the top. In addition, the research shows that animals that are both herbivores and carnivores - so-called omnivores, may have a special role in stabilising the food chain as they combine several nutrient chains. "In a larger perspective, our calculation method enables us to predict which types of invasive species can cause major changes and perhaps even the collapse of the ecosystem in a given area and the method could also be used to predict the later extinction of species due to the removal of native animals in the area," explains Namiko Mitarai.

Computer simulations show that skin cell ensembles on a micropatterned substrate simulating a wound can bridge gaps of up to about 200 micrometres. Credit: Philipp Albert Scientists from Heidelberg University have developed a novel mathematical model to explore cellular processes: with the corresponding software, they now are able to simulate how large collections of cells behave on given geometrical structures. The software supports the evaluation of microscope-based observations of cell behaviour on micropatterned substrates. One example is a model for wound healing in which skin cells are required to fill a gap. Other areas of application lie in high throughput screening for medicine when a decision needs to be taken automatically on whether a certain active substance changes cell behaviour. Prof. Dr. Ulrich Schwarz and Dr. Philipp Albert work both at the Institute for Theoretical Physics and at the Bioquant Centre of Heidelberg University. Their findings were recently published in PLOS Computational Biology. One of the most important foundations of the modern Life Sciences is being able to cultivate cells outside the body and to observe them with optical microscopes. In this way, cellular processes can be analysed in much more quantitative detail than in the body. However, at the same time a problem arises. "Anyone who has ever observed biological cells under a microscope knows how unpredictable their behaviour can be. When they are on a traditional culture dish they lack 'orientation', unlike in their natural environment in the body. That is why, regarding certain research issues, it is difficult to derive any regularities from their shape and movement," explains Prof. Schwarz. In order to learn more about the natural behaviour of cells, the researchers therefore resort to methods from materials science. The substrate for microscopic study is structured in such a way that it normalises cell behaviour. The Heidelberg physicists explain that with certain printing techniques, proteins are deposited on the substrate in geometrically well-defined areas. The cell behaviour can then be observed and evaluated with the usual microscopy techniques. The group of Ulrich Schwarz aims at describing in mathematical terms the behaviour of biological cells on micropatterned substrates. Such models should make it possible to quantitatively predict cell behaviour for a wide range of experimental setups. For that purpose, Philipp Albert has developed a complicated computer programme which considers the essential properties of individual cells and their interaction. It can also predict how large collections of cells behave on the given geometric structures. He explains: "Surprising new patterns often emerge from the interplay of several cells, such as streams, swirls and bridges. As in physical systems, e.g. fluids, the whole is here more than the sum of its parts. Our software package can calculate such behaviour very rapidly." Dr Albert's computer simulations show, for example, how skin cell ensembles can overcome gaps in a wound model up to about 200 micrometres. Another promising application of these advances is investigated by Dr. Holger Erfle and his research group at the BioQuant Centre, namely high throughput screening of cells. Robot-controlled equipment is used to carry out automatic pharmacological or genetic tests with many different active substances. They are, for example, designed to identify new medications against viruses or for cancer treatment. The new software now enables the scientists to predict what geometries are best suited for a certain cell type. The software can also show the significance of changes in cell behaviour observed under the microscope. Explore further: Movies of cell growth explain skin graft success and may help understand cancer More information: Philipp J. Albert et al. Dynamics of Cell Ensembles on Adhesive Micropatterns: Bridging the Gap between Single Cell Spreading and Collective Cell Migration, PLOS Computational Biology (2016). DOI: 10.1371/journal.pcbi.1004863

Signals in the brain can hint at whether a person undergoing anesthesia will slip under easily or fight the drug, a new study suggests. The results, published January 14 in PLOS Computational Biology, bring scientists closer to being able to tailor doses of the powerful drugs for specific patients. Drug doses are often given with a one-size-fits-all attitude, says bioengineer and neuroscientist Patrick Purdon of Massachusetts General Hospital and Harvard Medical School. But the new study finds clear differences in people’s brain responses to similar doses of an anesthetic drug, Purdon says. “To me, that’s the key and interesting point.” Cognitive neuroscientist Tristan Bekinschtein of the University of Cambridge and colleagues recruited 20 people to receive low doses of the general anesthetic propofol. The low dose wasn’t designed to knock people out, but to instead dial down their consciousness until they teetered on the edge of awareness — a point between being awake and alert and being drowsy and nonresponsive. While the drug was being delivered, participants repeatedly heard either a buzzing sound or a noise and were asked each time which they heard, an annoying question designed to gauge awareness. Of the 20 people, seven were sidelined by the propofol and they began to respond less. Thirteen other participants, however, kept right on responding, “fighting the drug,” Bekinschtein says. EEG measurements that tracked electrical activity in the brain revealed a brain signature that differed between these two groups. In people who resisted the propofol, a particular type of brain wave called an alpha oscillation appeared to be strong and efficient, with lots of connections between near and far brain areas, the team found. In contrast, people who succumbed easily to the drug had weaker, less efficient alpha wave behavior. This difference was present even before the drug was delivered, Bekinschtein says. At the beginning of the experiment, people already showed predictive alpha wave signatures. The results raise the prospect that a presurgical EEG measurement could pinpoint the lowest dose of drug that would still put a person under while reducing potential side effects. “It’s adding a layer of complexity,” Bekinschtein says. “But the beauty of this is that it’s a layer of complexity that we can measure before giving the drug.” EEG machines are widely available in clinical settings, and Bekinschtein and colleagues are trying to adapt their results to be useful to anesthesiologists. “It’s a very simple analysis to do” once the mathematical framework is in place, Bekinschtein says. He and others hope to design a way for physicians to enter a person’s raw EEG data and get an estimate of anesthesia susceptibility. Purdon cautions that the results are based on a limited number of people. “It’s a preliminary finding in that regard,” he says. And more work is needed to translate the results so that they can be applied to individual patients. Nonetheless, he says, the results “all really make sense.”

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