Microbial strategies to exploit host cells. Meeting on spatial and temporal dynamics of the endomembrane system.

Meeting on Spatial and Temporal Dynamics of the Endomembrane Syste

Testing Strategies and Methodologies for the Max Launch Abort System

The National Aeronautics and Space Administration (NASA) Engineering and Safety Center (NESC) was tasked to develop an alternate, tower-less launch abort system (LAS) as risk mitigation for the Orion Project. The successful pad abort flight demonstration test in July 2009 of the "Max" launch abort system (MLAS) provided data critical to the design of future LASs, while demonstrating the Agency s ability to rapidly design, build and fly full-scale hardware at minimal cost in a "virtual" work environment. Limited funding and an aggressive schedule presented a challenge for testing of the complex MLAS system. The successful pad abort flight demonstration test was attributed to the project s systems engineering and integration process, which included: a concise definition of, and an adherence to, flight test objectives; a solid operational concept; well defined performance requirements, and a test program tailored to reducing the highest flight test risks. The testing ranged from wind tunnel validation of computational fluid dynamic simulations to component ground tests of the highest risk subsystems. This paper provides an overview of the testing/risk management approach and methodologies used to understand and reduce the areas of highest risk - resulting in a successful flight demonstration test

Mode of Inoculation of the Lyme Disease Agent Borrelia burgdorferi Influences Infection and Immune Responses in Inbred Strains of Mice

Mice were infected with Borrelia burgdorferi by infection via Ixodes ricinus and experimental inoculation to determine whether transmission rates of spirochetes and antibody responses are influenced. Mice infected by the natural route were substantially more infective for ticks; two- to sixfold more tick larvae were positive for B. burgdorferi than those fed on experimentally inoculated mice. In natural infection, spirochetemia may be greater or spirochetes may be more accessible for transmission. Thus, this form of xenodiagnosis could be used to determine levels of spirochetes in the vertebrate host. Similar levels of antibody were present in all mice; however, those infected by the natural route lacked antibodies to outer surface proteins (Osp) A and B. The small antigen dose given through a tick bite may not have been sufficient to induce rapid OspA or OspB antibodies, thereby allowing the later development of higher levels of spirochetemi

Generalized Nash Equilibrium and Market Coupling in the European Power System

Market Coupling'' is currently seen as the most advanced market design in the restructuring of the European electricity market. Market coupling, by construction, introduces what is generally referred to as an incomplete market: it leaves several constraints out of the market and hence avoids pricing them. This may or may not have important consequences in practice depending on the case on hand. QuasiVariational Inequality problems. We apply one of these methods to a subproblem of market coupling namely the coordination of counter-trading. This problem is an illustration of a more general question encountered for instance in hierarchical planning in production management. We first discuss the economic interpretation of the Quasi-Variational Inequality problem. We then apply the algorithmic approach to a set of stylized case studies in order to illustrate the impact of different organizations of counter-trading. The paper emphazises the structuring of the problem. A companion paper considers the full problem of market coupling and counter-trading and presents a more extensive numerical analysis

Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide.

Mycobacterium tuberculosis is a facultative intracellular pathogen that inhibits phagosome maturation in macrophages thereby securing survival and growth. Mycobacteria reside in an early endocytic compartment of near-neutral pH where they upregulate production of complex glycolipids such as trehalose dimycolate. Here, we report that trehalose dimycolate coated onto beads increased the bead retention in early phagosomes, i.e. at a similar stage as viable mycobacteria. Thus, a single mycobacterial lipid sufficed to divert phagosome maturation and likely contributes to mycobacterial survival in macrophages. Previous studies showed that activated macrophages promote maturation of mycobacterial phagosomes and eliminate mycobacteria through bactericidal effectors including nitric oxide generated by inducible nitric-oxide synthase. We show that deceleration of bead phagosome maturation by trehalose dimycolate was abolished in immune-activated wild type, but not in activated nitric-oxide synthase-deficient macrophages, nor when hydroxyl groups of trehalose dimycolate were chemically modified by reactive nitrogen intermediates. Thus, specific host defence effectors of activated macrophages directly target a specific virulence function of mycobacteria

Transport of Lipophilic Anti-Tuberculosis Drug Benzothiazone-043 in Ca3_{3}(PO4_{4})2_{2} Nanocontainers

1,3‐Benzothiazin‐4‐one‐043 (BTZ043) is a novel anti‐mycobacterial agent for tuberculosis (TB) therapy with highly hydrophobic properties. In order to enhance local drug concentrations by improved administration and delivery to the site of the mycobacterial infection, we suggest BTZ043/Toc@Ca(ds)$_{2}$@Ca$_{3}$(PO$_{4}$)$_{2}$ nanocontainers made via a microemulsion approach for drug delivery (Toc: tocopherol; ds: dodecylsulfate). Based on our concept, the surfactant of the microemulsion itself is used to stabilize the droplet phase by interaction with Ca$^{2+}$, followed by the formation of an inorganic Ca$_{3}$(PO$_{4}$)$_{2}$ sphere wall in one‐pot reaction. Tocopherol (vitamin E) was used as biocompatible droplet phase of the microemulsion to dissolve the highly lipophilic BTZ043. According to electron microscopy and electron spectroscopy, the resulting BTZ043/Toc@Ca(ds)$_{2}$@Ca$_{3}$(PO$_{4}$)$_{2}$ nanocontainers exhibit an outer diameter of 28±8 nm and a sphere wall of 4±1 nm. The inner cavity, 18±7 nm in diameter, is loaded with BTZ043 with a concentration of 30.5 μg/mL. First in vitro tests with murine bone marrow derived macrophages infected with Mycobacterium tuberculosis show promising antibiotic activity of the BTZ043/Toc@Ca(ds)$_{2}$@Ca$_{3}$(PO$_{4}$)$_{2}$ nanocontainers

Amikacin@SiO2_{2} core@shell nanocarriers to treat pulmonal bacterial infections

AMC@SiO$_{2}$ core@shell nanocarriers (AMC: amikacin) are realized and contain an exceptionally high drug load of 0.8 mg mg$^{-1}$ (i.e. 80% AMC of total nanocarrier mass). They are prepared via a solvent–antisolvent approach with AMC nanoparticles formed in a first step, which are then covered and stabilised by a thin silica shell in a one-pot synthesis. In total, the core@shell nanocarriers exhibit a mean diameter of 240 nm with an inner AMC core of 200 nm and an outer silica shell of 20 nm. Subsequent to synthesis, the nanocarriers can be stored in frozen dimethylsulfoxide (DMSO) and applied directly after warming to room temperature with particle contents of 5 mg mL$^{-1}$. Size, structure, and composition of the AMC@SiO$_{2}$ core@shell nanocarriers are evidenced by electron microscopy (SEM, TEM), spectroscopic methods (EDXS, FT-IR, UV-Vis), as well as X-ray powder diffraction and elemental analysis. As proof-of-concept, the AMC release and the activity of the novel nanocarriers are tested against two relevant, difficult-to-treat and notoriously multidrug resistant, bacterial pathogens: Mycobacterium tuberculosis (M.tb.) and Mycobacterium abscessus (M.abs.). Colloidal stability, storage stability, high drug load, and activity of the AMC@SiO$_{2}$ core@shell nanocarriers are promising for, e.g., aerosol-type pulmonal application

New challenges in studying nutrition-disease interactions in the developing world.

Latest estimates indicate that nutritional deficiencies account for 3 million child deaths each year in less-developed countries. Targeted nutritional interventions could therefore save millions of lives. However, such interventions require careful optimization to maximize benefit and avoid harm. Progress toward designing effective life-saving interventions is currently hampered by some serious gaps in our understanding of nutrient metabolism in humans. In this Personal Perspective, we highlight some of these gaps and make some proposals as to how improved research methods and technologies can be brought to bear on the problems of undernourished children in the developing world