Antibiotic chemotherapy against heterogeneous pathogen populations in complex host tissues

Antibiotic chemotherapy effectively cures many infections caused by susceptible bacterial pathogens. However, in some cases, even extended treatment duration does not completely eradicate the pathogenic bacteria from host tissues. A common model for underlying mechanisms assumes the stochastic formation of bacterial persisters similar to observations in laboratory cultures. However, alternative explanations related to the complexity of infected host tissues could also be relevant. We discuss several of these aspects and emphasize the need for integrated analysis as a basis for new control strategies

The effects of parasitism and body length on positioning within wild fish shoals

The influence of body length and parasitism on the positioning behaviour of individuals in wild fish shoals was investigated by a novel means of capturing entire shoals of the banded killifish (Fundulus diaphanus, Lesueur) using a grid-net that maintained the two-dimensional positions of individuals within shoals. Fish in the front section of a shoal were larger than those in the rear. Individuals parasitized by the digenean trematode (Crassiphiala bulboglossa, Haitsma) showed a tendency to occupy the front of shoals. Parasitized fish were also found more in peripheral positions than central ones in a significant number of shoals. Shoal geometry was affected by the overall parasite prevalence of shoal members; shoals with high parasite prevalence displayed increasingly phallanx-like shoal formations, whereas shoals with low prevalence were more elliptical. There was no relationship between body length and parasite abundance or prevalence in the fish population which suggests body length and parasite status are independent predictors of positioning behaviour. Solitary individuals found outside shoals were both more likely to be parasitized and had higher parasite abundance than individuals engaged in shoaling. Differences in the shoaling behaviour of parasitized and unparasitized fish are discussed in the context of the adaptive manipulation hypothesis

Plant-Derived Catechols Are Substrates of TonB-Dependent Transporters and Sensitize Pseudomonas aeruginosa to Siderophore-Drug Conjugates

Pseudomonas aeruginosa is an opportunistic pathogen responsible for acute and chronic infections in immunocompromised hosts. This organism is known to compete efficiently against coinfecting microorganisms, due in part to the secretion of antimicrobial molecules and the synthesis of siderophore molecules with high affinity for iron. P. aeruginosa possess a large repertoire of TonB-dependent transporters for the uptake of its own, as well as xenosiderophores released from other bacteria or fungi. Here, we show that P. aeruginosa is also capable of utilizing plant-derived polyphenols as an iron source. We found that exclusively plant-derived phenols containing a catechol group (i.e., chlorogenic acid, caffeic acid, quercetin, luteolin) induce the expression of the TonB-dependent transporters PiuA or PirA. This induction requires the two-component system PirR-PirS. Chlorogenic acid in its Fe(III)-loaded form was actively transported by PiuA and PirA and supported growth under iron-limiting conditions. Coincidentally, PiuA and PirA are also the main TonB transporters for the recently approved siderophore-drug conjugate cefiderocol. Surprisingly, quercetin supplementation increased the susceptibility of P. aeruginosa to siderophore-drug conjugates, due to induction of; piuA; and; pirA; expression mediated by the PirR-PirS two-component system. These findings suggest a potential novel therapeutic application for these biologically active dietary polyphenols.; IMPORTANCE; Iron is an essential element for living organisms. Most bacteria synthesize species-specific iron chelators, called siderophores, able to capture iron from their host or the environment. Pseudomonas aeruginosa, an opportunistic pathogen, produces two endogenous siderophores but is able to acquire iron also via xenosiderophores, produced by other bacteria or fungi, using a set of conserved TonB transporters. Here, we show that P. aeruginosa is also able to use plant metabolites, like quercetin and chlorogenic acid, as siderophores. These metabolites possess an iron-chelating catechol group and are recognized and transported by the TonB transporters PirA and PiuA. Since these transporters also promote the specific uptake of siderophore-drug conjugates, P. aeruginosa exposed to these plant catechols becomes hypersusceptible to this novel class of antibiotics. This unexpected finding suggests a potential therapeutic application for quercetin and chlorogenic acid, which were mainly investigated for their antioxidant and anti-inflammatory properties

Assessing Responses of \u3ci\u3eBetula papyrifera\u3c/i\u3e to Climate Variability in a Remnant Population along the Niobrara River Valley in Nebraska U.S. through Dendroecological and Remote Sensing Techniques

Remnant populations of Betula papyrifera have persisted in the Great Plains after the Wisconsin Glaciation along the Niobrara River Valley, Nebraska. Population health has declined in recent years, and has been hypothesized to be due to climate change. We used dendrochronological techniques to assess the response of B. papyrifera to microclimate (1950-2014), and satellite imagery [Landsat 5 TM (1985-2011) and MODIS (2000-2014)] derived NDVI as a proxy for population health. Growing-season streamflow and precipitation were positively correlated with raw and standardized tree-ring widths and basal area increment increase. Increasing winter and spring temperatures were unfavorable for tree growth while increasing summer temperatures were favorable in the absence of drought. The strongest predictor for standardized tree-rings was the Palmer Drought Severity Index, suggesting that B. papyrifera is highly responsive to a combination of temperature and water availability. The NDVI from vegetation community was positively correlated with standardized tree-ring growth, indicating the potential of these techniques to be used as a proxy for ex-situ monitoring of B. papyrifera. These results aid in forecasting the dynamics of the species in the face of climate variability and change in both remnant populations and across its current distribution in northern latitudes of North America

Crystal structure of an HD-GYP domain cyclic-di-GMP phosphodiesterase reveals an enzyme with a novel trinuclear catalytic iron centre

Bis-(3′,5′) cyclic di-guanylate (c-di-GMP) is a key bacterial second messenger that is implicated in the regulation of many crucial processes that include biofilm formation, motility and virulence. Cellular levels of c-di-GMP are controlled through synthesis by GGDEF domain diguanylate cyclases and degradation by two classes of phosphodiesterase with EAL or HD-GYP domains. Here, we have determined the structure of an enzymatically active HD-GYP domain protein from Persephonella marina (PmGH) alone, in complex with substrate (c-di-GMP) and final reaction product (GMP). The structures reveal a novel trinuclear iron binding site, which is implicated in catalysis and identify residues involved in recognition of c-di-GMP. This structure completes the picture of all domains involved in c-di-GMP metabolism and reveals that the HD-GYP family splits into two distinct subgroups containing bi- and trinuclear metal centres.</p

Single Dose Novel Salmonella Vaccine Enhances Resistance against Visceralizing L. major and L. donovani Infection in Susceptible BALB/c Mice

Visceral leishmaniasis is a major neglected tropical disease, with an estimated 500,000 new cases and more than 50,000 deaths attributable to this disease every year. Drug therapy is available but costly and resistance against several drug classes has evolved. Despite all efforts, no commercial, let alone affordable, vaccine is available to date. Thus, the development of cost effective, needle-independent vaccines is a high priority. Here, we have continued efforts to develop live vaccine carriers based on recombinant Salmonella. We used an in silico approach to select novel Leishmania parasite antigens from proteomic data sets, with selection criteria based on protein abundance, conservation across Leishmania species and low homology to host species. Five chosen antigens were differentially expressed on the surface or in the cytosol of Salmonella typhimurium SL3261. A two-step procedure was developed to select optimal Salmonella vaccine strains for each antigen, based on bacterial fitness and antigen expression levels. We show that vaccine strains of Salmonella expressing the novel Leishmania antigens LinJ08.1190 and LinJ23.0410 significantly reduced visceralisation of L. major and enhanced systemic resistance against L. donovani in susceptible BALB/c mice. The results show that Salmonella are valid vaccine carriers for inducing resistance against visceral leishmaniasis but that their use may not be suitable for all antigens

Computer simulation of leadership, consensus decision making and collective behaviour in humans

The aim of this study is to evaluate the reliability of a crowd simulation model developed by the authors by reproducing Dyer et al.’s experiments(published in Philosophical Transactions in 2009) on human leadership and consensus decision-­making in a computer-­based environment. The theoretical crowd model of the simulation environment is presented, and its results are compared and analysed against Dyer et al.’s original experiments. It is concluded that the results are 11 largely consistent with the experiments, which demonstrates the reliability of the crowd model. Furthermore, the simulation data also reveals several additional new findings, namely: 1) the phenomena of sacrificing accuracy to reach a quicker consensus decision found in ants colonies was also discovered in the simulation; 2) the ability of reaching consensus in groups has a direct impact on the time and accuracy of arriving at the target position; 3) the positions of the informed individuals or leaders in the crowd could have significant impact on the overall crowd movement; 4) the simulation also confirmed Dyer et al.’s anecdotal evidence of the proportion of the leadership in large crowds and its effect on crowd movement. The potential applications of these findings are highlighted in the final discussion of this paper

Prediction of Extracellular Proteases of the Human Pathogen Helicobacter pylori Reveals Proteolytic Activity of the Hp1018/19 Protein HtrA

Exported proteases of Helicobacter pylori (H. pylori) are potentially involved in pathogen-associated disorders leading to gastric inflammation and neoplasia. By comprehensive sequence screening of the H. pylori proteome for predicted secreted proteases, we retrieved several candidate genes. We detected caseinolytic activities of several such proteases, which are released independently from the H. pylori type IV secretion system encoded by the cag pathogenicity island (cagPAI). Among these, we found the predicted serine protease HtrA (Hp1019), which was previously identified in the bacterial secretome of H. pylori. Importantly, we further found that the H. pylori genes hp1018 and hp1019 represent a single gene likely coding for an exported protein. Here, we directly verified proteolytic activity of HtrA in vitro and identified the HtrA protease in zymograms by mass spectrometry. Overexpressed and purified HtrA exhibited pronounced proteolytic activity, which is inactivated after mutation of Ser205 to alanine in the predicted active center of HtrA. These data demonstrate that H. pylori secretes HtrA as an active protease, which might represent a novel candidate target for therapeutic intervention strategies

Some Causes of the Variable Shape of Flocks of Birds

Flocks of birds are highly variable in shape in all contexts (while travelling, avoiding predation, wheeling above the roost). Particularly amazing in this respect are the aerial displays of huge flocks of starlings (Sturnus vulgaris) above the sleeping site at dawn. The causes of this variability are hardly known, however. Here we hypothesise that variability of shape increases when there are larger local differences in movement behaviour in the flock. We investigate this hypothesis with the help of a model of the self-organisation of travelling groups, called StarDisplay, since such a model has also increased our understanding of what causes the oblong shape of schools of fish. The flocking patterns in the model prove to resemble those of real birds, in particular of starlings and rock doves. As to shape, we measure the relative proportions of the flock in several ways, which either depend on the direction of movement or do not. We confirm that flock shape is usually more variable when local differences in movement in the flock are larger. This happens when a) flock size is larger, b) interacting partners are fewer, c) the flock turnings are stronger, and d) individuals roll into the turn. In contrast to our expectations, when variability of speed in the flock is higher, flock shape and the positions of members in the flock are more static. We explain this and indicate the adaptive value of low variability of speed and spatial restriction of interaction and develop testable hypotheses