995 research outputs found

    Extensive in vivo resilience of persistent Salmonella

    Get PDF
    Chronic infections caused by persistent pathogens represent an important health problem. Here, we establish a simple practical mouse Salmonella infection model for identifying bacterial maintenance functions that are essential for persistency. In this model, a substantial fraction of Salmonella survived even several days of treatment with a potent fluoroquinolone antibiotic indicating stringency of the model. Evaluation of twelve metabolic defects revealed dramatically different requirements for Salmonella during persistency as compared to acute infections. Disrupted synthesis of unsaturated/cyclopropane fatty acids was the only defect that resulted in rapid Salmonella clearance suggesting that this pathway might contain suitable targets for antimicrobial chemotherapy of chronic infection

    Metzincin's canonical methionine is responsible for the structural integrity of the zinc-binding site

    Get PDF
    The metzincins constitute a subclan of metalloproteases possessing a HEXXHXXGXXH/D zinc-binding consensus sequence where the three histidines are zinc ligands and the glutamic acid is the catalytic base. A completely conserved methionine is located downstream of this motif. Families of the metzincin clan comprise, besides others, astacins, adamalysins proteases, matrix metallo-proteases, and serralysins. The latter are extracellular 50kDa proteases secreted by Gram-negative bacteria via a type I secretion system. While there is a large body of structural and biochemical information available, the function of the conserved methionine has not been convincingly clarified yet. Here, we present the crystal structures of a number of mutants of the serralysin member protease C with the conserved methionine being replaced by Ile, Ala, and His. Together with our former report on the leucine and cysteine mutants, we demonstrate here that replacement of the methionine side chain results in an increasing distortion of the zinc-binding geometry, especially pronounced in the χ2 angles of the first and third histidine of the consensus sequence. This is correlated with an increasing loss of proteolytic activity and a sharp increase of flexibility of large segments of the polypeptide chai

    cAMP activates adenylate and guanylate cyclase of Dictyostelium discoideum cells by binding to different classes of cell-surface receptors. A study with extracellular Ca2+

    Get PDF
    cAMP induces a transient increase of cAMP and cGMP levels in Dictyostelium discoideum cells. Fast binding experiments reveal three types of cAMP-binding site (S, H and L), which have different off-rates (t0.5, 0.7-15 s) and different affinities (Kd, 15-450 nM). A time- and cAMP-concentration-dependent transition of H- to L-sites occurs during the binding reaction. Extracellular Ca2+ had multiple effects on cAMP-binding sites. (i) The number of H + L-sites increased 2.5-fold, while the number of S-sites was not strongly affected. (ii) The Kd of the S-sites was reduced from 16 nM to 5 nM (iii) The conversion of H-sites to L-sites was inhibited up to 80%. The kinetics of the cAMP-induced cAMP accumulation was not strongly altered by Ca2+, but the amount of cAMP produced was inhibited up to 80%. The kinetics of the cAMP-induced cGMP accumulation was strongly altered; maximal levels were obtained sooner, and the Ka was reduced from 15 to 3.5 nM cAMP. Ca2+, Mg2+ and Mn2+ increased the number of binding sites, all with EC50 = 0.5 mM. The S-sites and the cGMP response were modified by equal Ca2+ concentrations and by higher concentrations of Mg2+ and Mn2+ (EC50 are respectively 0.4 mM, 2.5 mM and about 25 mM). The conversion of H- to L-sites and the cAMP response were specifically inhibited by Ca2+ with EC50 = 20 µM. It is concluded that cAMP activates guanylate cyclase through the S-sites; adenylate cyclase is activated by the H + L-sites, in which the appearance of the L-sites during the binding reaction represents the coupling of occupied surface cAMP receptors to adenylate cyclase.

    Immediate action is the best strategy when facing uncertain climate change

    Get PDF
    Mitigating the detrimental effects of climate change is a collective problem that requires global cooperation. However, achieving cooperation is difficult since benefits are obtained in the future. The so-called collective-risk game, devised to capture dangerous climate change, showed that catastrophic economic losses promote cooperation when individuals know the timing of a single climatic event. In reality, the impact and timing of climate change is not certain; moreover, recurrent events are possible. Thus, we devise a game where the risk of a collective loss can recur across multiple rounds. We find that wait and see behavior is successful only if players know when they need to contribute to avoid danger and if contributions can eliminate the risks. In all other cases, act quickly is more successful, especially under uncertainty and the possibility of repeated losses. Furthermore, we incorporate influential factors such as wealth inequality and heterogeneity in risks. Even under inequality individuals should contribute early, as long as contributions have the potential to decrease risk. Most importantly, we find that catastrophic scenarios are not necessary to induce such immediate collective action

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

    Get PDF
    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

    No Ground Truth at Sea – Developing High-Accuracy AI Decision-Support for Complex Environments

    Get PDF
    As AI decision-support systems are increasingly developed for applications outside of traditional organizational confinements, developers are confronted with new sources of complexity they need to address. However, we know little about how AI applications are developed for natural use domains with high environmental complexity, stemming from physical influences outside of the developers’ control. This study investigates what challenges emerge from such complexity and how developers mitigate them. Drawing upon a rich longitudinal single-case study on the development of AI decision-support for maritime navigation, findings show that achieving high output accuracy is complicated by the physical environment hindering training data creation. Further, developers chose to reduce the output accuracy and adapt the HMI design to successfully situate the AI application in an existing sociotechnical context. This study contributes to IS literature following recent calls for phenomenon-based examination of emerging challenges when extending the scope frontier of AI and provides practical recommendations for developing AI decision-support for complex environments

    Assessing Responses of \u3ci\u3eBetula papyrifera\u3c/i\u3e (Paper Birch) to Climate Variability in a Remnant Population Along the Niobrara River in Nebraska Through Dendroecological and Remote Sensing Techniques

    Get PDF
    Remnant populations of the boreal species Betula papyrifera, found along north-facing canyons and river banks of the Niobrara River Valley in north-central Nebraska, represent one of the southernmost distributions of the species in North America. Although, the species has persisted in the Great Plains after the Wisconsin Glaciation due to the local topography and microclimatic conditions, canopy dieback has been reported in recent years, which is believed to be attributed to temperature change. Therefore, the goals of this research are to: 1) use dendroecological techniques, or the study of tree rings to assess the responses B. papyrifera to intra- and inter-annual micro-environmental variability between 1950 and 2014, and identify the abiotic factor(s) which best describe the observed growth trends in this species; and 2) determine whether the use of satellite imagery from Landsat 5 TM (1985-2011) and MODIS (2000-2014) can serve as a proxy for assessing tree health by relating indices like the Normalized Difference Vegetation Index (NDVI) to tree rings characteristics. Results showed that growing-season streamflow and precipitation were positively and significantly correlated with raw tree ring widths, basal area increment increase, and standardized ring widths (p \u3c 0.05), while high late fall and spring precipitation and streamflow seemed to have a negative effects. The strongest predictor for standardized tree ring growth was the Palmer’s Drought Severity Index (PDSI), suggesting that B. papyrifera is highly responsive to a combination of temperature and water availability. GLMMs and Pearson R2 correlations indicated that increasing winter and spring temperatures were unfavorable for tree growth while increasing summer temperatures were favorable in the absence of drought. Maximum and accumumlated NDVI derived from satellite imagery showed potential of these techniques to be used as a proxy for ex-situ monitoring B. papyrifera performance through high Pearson’s R2 values (≥0.76) at the pixel level. Landsat 5 TM derived max-value NDVI correlations identified adjacent rangeland of moderate bison grazing on rough landscape - similar to those occupied by B. papyrifera – as a likely reliable proxy for predicting seasonal growth and performance the species. Results from this study have significant management implications and are critical to the development of biogeographical and ecophysiological predictive models aimed at forecasting the dynamics and performance of this species in the face of future climate variability, extremes, and change in both remnant populations and across its current habitat range in more northern latitudes. Advisor: Tala Awad
    corecore