Antimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence in Enterococcus faecalis.

Bacteria have developed several evolutionary strategies to protect their cell membranes (CMs) from the attack of antibiotics and antimicrobial peptides (AMPs) produced by the innate immune system, including remodeling of phospholipid content and localization. Multidrug-resistant Enterococcus faecalis, an opportunistic human pathogen, evolves resistance to the lipopeptide daptomycin and AMPs by diverting the antibiotic away from critical septal targets using CM anionic phospholipid redistribution. The LiaFSR stress response system regulates this CM remodeling via the LiaR response regulator by a previously unknown mechanism. Here, we characterize a LiaR-regulated protein, LiaX, that senses daptomycin or AMPs and triggers protective CM remodeling. LiaX is surface exposed, and in daptomycin-resistant clinical strains, both LiaX and the N-terminal domain alone are released into the extracellular milieu. The N-terminal domain of LiaX binds daptomycin and AMPs (such as human LL-37) and functions as an extracellular sentinel that activates the cell envelope stress response. The C-terminal domain of LiaX plays a role in inhibiting the LiaFSR system, and when this domain is absent, it leads to activation of anionic phospholipid redistribution. Strains that exhibit LiaX-mediated CM remodeling and AMP resistance show enhanced virulence in the Caenorhabditis elegans model, an effect that is abolished in animals lacking an innate immune pathway crucial for producing AMPs. In conclusion, we report a mechanism of antibiotic and AMP resistance that couples bacterial stress sensing to major changes in CM architecture, ultimately also affecting host-pathogen interactions

EUD-MARS: End-User Development of Model-Driven Adaptive Robotics Software Systems

Empowering end-users to program robots is becoming more significant. Introducing software engineering principles into end-user programming could improve the quality of the developed software applications. For example, model-driven development improves technology independence and adaptive systems act upon changes in their context of use. However, end-users need to apply such principles in a non-daunting manner and without incurring a steep learning curve. This paper presents EUD-MARS that aims to provide end-users with a simple approach for developing model-driven adaptive robotics software. End-users include people like hobbyists and students who are not professional programmers but are interested in programming robots. EUD-MARS supports robots like hobby drones and educational humanoids that are available for end-users. It offers a tool for software developers and another one for end-users. We evaluated EUD-MARS from three perspectives. First, we used EUD-MARS to program different types of robots and assessed its visual programming language against existing design principles. Second, we asked software developers to use EUD-MARS to configure robots and obtained their feedback on strengths and points for improvement. Third, we observed how end-users explain and develop EUD-MARS programs, and obtained their feedback mainly on understandability, ease of programming, and desirability. These evaluations yielded positive indications of EUD-MARS

Spatial and temporal uplift history of South America from calibrated drainage analysis

A multidisciplinary approach is used to analyze the Cenozoic uplift history of South America. Residual depth anomalies of oceanic crust abutting this continent help to determine the pattern of present-day dynamic topography. Admittance analysis and crustal thickness measurements indicate that the elastic thickness of the Borborema and Altiplano regions is ≤₁₀ km with evidence for sub-plate support at longer wavelengths. A drainage inventory of 1827 river profiles is assembled and used to investigate landscape development. Linear inverse modeling enables river profiles to be fitted as a function of the spatial and temporal history of regional uplift. Erosional parameters are calibrated using observations from the Borborema Plateau and tested against continent-wide stratigraphic and thermochronologic constraints. Our results predict that two phases of regional uplift of the Altiplano plateau occurred in Neogene times. Regional uplift of the southern Patagonian Andes also appears to have occurred in Early Miocene times. The consistency between observed and predicted histories for the Borborema, Altiplano, and Patagonian plateaux implies that drainage networks record coherent signals that are amenable to simple modeling strategies. Finally, the predicted pattern of incision across the Amazon catchment constrains solid sedimentary flux at the Foz do Amazonas. Observed and calculated flux estimates match, suggesting that erosion and deposition were triggered by regional Andean uplift during Miocene times

Paul L. Fackler

This paper develops a general modeling framework and some alternative methods for solving nonlinear rational expectations models. In addition, a user-friendly interface that implements the approach is presented. Although much of the discussion builds on previous work, the resulting synthesis should be of use to practitioner

Clostridium difficile

AbstractCovalent attachment of surface proteins to the cell wall of Gram-positive bacteria requires a sortase-mediated transpeptidation reaction. In almost all Gram-positive bacteria, the housekeeping sortase, sortase A, recognizes the canonical recognition sequence LPXTG (X=any amino acid). The human pathogen Clostridium difficile carries a single putative sortase gene (cd2718) but neither transpeptidation activity nor specificity of CD2718 has been investigated. We produced recombinant CD2718 and examined its transpeptidation activity in vitro using synthetic peptides and MALDI-ToF(-ToF) MS analysis. We demonstrate that CD2718 has sortase activity with specificity for a (S/P)PXTG motif and can accommodate diaminopimelic acid as a substrate for transpeptidation