ABTRAJ on-site tracking prediction program

Computer program, ABTRAJ, provides Deep Space Network tracking stations with the capability of generating spacecraft predictions with on-site computers. The program is comprised of two major sections - the main prediction portion and a trajectory subroutine which spans the desired predict interval with spacecraft ephemeris data written on magnetic tapes

Varying chiral ratio of Pinic acid enantiomers above the Amazon rainforest

Chiral chemodiversity plays a crucial role in biochemical processes such as insect and plant communication. However, the vast majority of organic aerosol studies do not distinguish between enantiomeric compounds in the particle phase. Here we report chirally specified measurements of secondary organic aerosol (SOA) at the Amazon Tall Tower Observatory (ATTO) at different altitudes during three measurement campaigns at different seasons. Analysis of filter samples by liquid chromatography coupled to mass spectrometry (LC-MS) has shown that the chiral ratio of pinic acid (C9H14O4) varies with increasing height above the canopy. A similar trend was recently observed for the gas-phase precursor α-pinene, but more pronounced. Nevertheless, the measurements indicate that neither the oxidation of (+/−)-α-pinene nor the incorporation of the products into the particulate phase proceeds with stereo preference and that the chiral information of the precursor molecule is merely transferred to the low-volatility product. The observation of the weaker height gradient of the present enantiomers in the particle phase at the observation site can be explained by the significant differences in the atmospheric lifetimes of reactant and product. Therefore, it is suggested that the chiral ratio of pinic acid is mainly determined by large-scale emission processes of the two precursors, while meteorological, chemical, or physicochemical processes do not play a particular role. Characteristic emissions of the chiral aerosol precursors from different forest ecosystems, in some cases even with contributions from forest related fauna, could thus provide large-scale information on the different contributions to biogenic secondary aerosols via the analytics of the chiral particle-bound degradation products

Unraveling implementation context: the Basel Approach for coNtextual ANAlysis (BANANA) in implementation science and its application in the SMILe project

Designing intervention and implementation strategies with careful consideration of context is essential for successful implementation science projects. Although the importance of context has been emphasized and methodology for its analysis is emerging, researchers have little guidance on how to plan, perform, and report contextual analysis. Therefore, our aim was to describe the Basel Approach for coNtextual ANAlysis (BANANA) and to demonstrate its application on an ongoing multi-site, multiphase implementation science project to develop/adapt, implement, and evaluate an integrated care model in allogeneic SteM cell transplantatIon facILitated by eHealth (the SMILe project).; BANANA builds on guidance for assessing context by Stange and Glasgow (Contextual factors: the importance of considering and reporting on context in research on the patient-centered medical home, 2013). Based on a literature review, BANANA was developed in ten discussion sessions with implementation science experts and a medical anthropologist to guide the SMILe project's contextual analysis. BANANA's theoretical basis is the Context and Implementation of Complex Interventions (CICI) framework. Working from an ecological perspective, CICI acknowledges contextual dynamics and distinguishes between context and setting (the implementation's physical location).; BANANA entails six components: (1) choose a theory, model, or framework (TMF) to guide the contextual analysis; (2) use empirical evidence derived from primary and/or secondary data to identify relevant contextual factors; (3) involve stakeholders throughout contextual analysis; (4) choose a study design to assess context; (5) determine contextual factors' relevance to implementation strategies/outcomes and intervention co-design; and (6) report findings of contextual analysis following appropriate reporting guidelines. Partly run simultaneously, the first three components form a basis both for the identification of relevant contextual factors and for the next components of the BANANA approach.; Understanding of context is indispensable for a successful implementation science project. BANANA provides much-needed methodological guidance for contextual analysis. In subsequent phases, it helps researchers apply the results to intervention development/adaption and choices of contextually tailored implementation strategies. For future implementation science projects, BANANA's principles will guide researchers first to gather relevant information on their target context, then to inform all subsequent phases of their implementation science project to strengthen every part of their work and fulfill their implementation goals

Theory-driven development of a medication adherence intervention delivered by eHealth and transplant team in allogeneic stem cell transplantation: the SMILe implementation science project

Medication adherence to immunosuppressants in allogeneic stem cell transplantation (alloSCT) is essential to achieve favorable clinical outcomes (e.g. control of Graft-versus-Host Disease). Over 600 apps supporting medication adherence exist, yet they lack successful implementation and sustainable use likely because of lack of end-user involvement and theoretical underpinnings in their development and insufficient attention to implementation methods to support their use in real-life settings. Medication adherence has three phases: initiation, implementation and persistence. We report the theory-driven development of an intervention module to support medication adherence (implementation and persistence phase) in alloSCT outpatients as a first step for future digitization and implementation in clinical setting within the SMILe project (Development, implementation and testing of an integrated care model in allogeneic SteM cell transplantatIon faciLitated by eHealth).; We applied Michie's Behavior Change Wheel (BCW) and the Capability-Opportunity-Motivation and Behavior (COM-B) model using three suggested stages followed by one stage added by our team regarding preparation for digitization of the intervention: (I) Defining the problem in behavioral terms; (II) Identifying intervention options; (III) Identifying content and implementation options; (IV) SMILe Care Model Prototype Development. Scientific evidence, data from a contextual analysis and patients'/caregivers' and clinical experts' inputs were compiled to work through these steps.; (I) Correct immunosuppressant taking and timing were defined as target behaviors. The intervention's focus was determined within the COM-B dimensions Capability (lack of knowledge, lack of routine), Opportunity (lack of cues, interruptions in daily routine) and Motivation (lack of problem solving, trivialization). (II) Five intervention functions were chosen, i.e. education, training, modelling, persuasion and enablement. (III) Twenty-four behavior change techniques were selected, e.g., goal setting, action planning and problem solving. (IV) Finally, seventeen user stories were developed to guide the SMILeApp's software development process.; Our example on the theory-driven development of an intervention module in alloSCT delivered by eHealth and transplant team using a rigorous 3 + 1-stage approach based on BCW, COM-B and agile software development techniques, can be used as methodological guidance for other eHealth intervention developers. Our approach has the potential to enhance successful implementation and sustained use of eHealth solutions in real-life settings

Anthrax Lethal Factor Cleavage of Nlrp1 Is Required for Activation of the Inflammasome

NOD-like receptor (NLR) proteins (Nlrps) are cytosolic sensors responsible for detection of pathogen and danger-associated molecular patterns through unknown mechanisms. Their activation in response to a wide range of intracellular danger signals leads to formation of the inflammasome, caspase-1 activation, rapid programmed cell death (pyroptosis) and maturation of IL-1β and IL-18. Anthrax lethal toxin (LT) induces the caspase-1-dependent pyroptosis of mouse and rat macrophages isolated from certain inbred rodent strains through activation of the NOD-like receptor (NLR) Nlrp1 inflammasome. Here we show that LT cleaves rat Nlrp1 and this cleavage is required for toxin-induced inflammasome activation, IL-1 β release, and macrophage pyroptosis. These results identify both a previously unrecognized mechanism of activation of an NLR and a new, physiologically relevant protein substrate of LT

Role of N-Terminal Amino Acids in the Potency of Anthrax Lethal Factor

Anthrax lethal factor (LF) is a Zn+2-dependent metalloprotease that cleaves several MAPK kinases and is responsible for the lethality of anthrax lethal toxin (LT). We observed that a recombinant LF (LF-HMA) which differs from wild type LF (LF-A) by the addition of two residues (His-Met) to the native Ala (A) terminus as a result of cloning manipulations has 3-fold lower potency toward cultured cells and experimental animals. We hypothesized that the “N-end rule”, which relates the half-life of proteins in cells to the identity of their N-terminal residue, might be operative in the case of LF, so that the N-terminal residue of LF would determine the cytosolic stability and thereby the potency of LF. Mutational studies that replaced the native N-terminal residue of LF with known N-end rule stabilizing or destabilizing residues confirmed that the N-terminal residue plays a significant role in determining the potency of LT for cultured cells and experimental animals. The fact that a commercially-available LF preparation (LF-HMA) that is widely used in basic research studies and for evaluation of vaccines and therapeutics is 3-fold less potent than native LF (LF-A) should be considered when comparing published studies and in the design of future experiments

Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome

Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes. Here, we show non-haemolytic enterotoxin (NHE) from the neglected human foodborne pathogen Bacillus cereus is an activator of the NLRP3 inflammasome and pyroptosis. NHE is a non-redundant toxin to haemolysin BL (HBL) despite having a similar mechanism of action. Via a putative transmembrane region, subunit C of NHE initiates binding to the plasma membrane, leading to the recruitment of subunit B and subunit A, thus forming a tripartite lytic pore that is permissive to efflux of potassium. NHE mediates killing of cells from multiple lineages and hosts, highlighting a versatile functional repertoire in different host species. These data indicate that NHE and HBL operate synergistically to induce inflammation and show that multiple virulence factors from the same pathogen with conserved function and mechanism of action can be exploited for sensing by a single inflammasome

Varying chiral ratio of pinic acid enantiomers above the Amazon rainforest

Chiral chemodiversity plays a crucial role in biochemical processes such as insect and plant communication. However, the vast majority of organic aerosol studies do not distinguish between enantiomeric compounds in the particle phase. Here we report chirally specified measurements of secondary organic aerosol (SOA) at the Amazon Tall Tower Observatory (ATTO) at different altitudes during three measurement campaigns at different seasons. Analysis of filter samples by liquid chromatography coupled to mass spectrometry (LC-MS) has shown that the chiral ratio of pinic acid (C9H14O4) varies with increasing height above the canopy. A similar trend was recently observed for the gas-phase precursor α-pinene but more pronounced. Nevertheless, the measurements indicate that neither the oxidation of (+/−)-α-pinene nor the incorporation of the products into the particulate phase proceeds with stereo preference and that the chiral information of the precursor molecule is merely transferred to the low-volatility product. The observation of the weaker height gradient of the present enantiomers in the particle phase at the observation site can be explained by the significant differences in the atmospheric lifetimes of reactant and product. Therefore, it is suggested that the chiral ratio of pinic acid is mainly determined by large-scale emission processes of the two precursors, while meteorological, chemical, or physicochemical processes do not play a particular role. Characteristic emissions of the chiral aerosol precursors from different forest ecosystems, in some cases even with contributions from forest-related fauna, could thus provide large-scale information on the different contributions to biogenic secondary aerosols via the analytics of the chiral particle-bound degradation products.</p

Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin

Background:Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way.Methodology/Principal Findings:Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the μM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro.Conclusions/Significance:These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax. © 2013 Beitzinger et al

Evidence against a Human Cell-Specific Role for LRP6 in Anthrax Toxin Entry

The role of the cellular protein LRP6 in anthrax toxin entry is controversial. Previous studies showed that LRP6 was important for efficient intoxication of human M2182 prostate carcinoma cells but other studies performed with cells from gene-knockout mice demonstrated no role for either LRP6 or the related LRP5 protein in anthrax toxin entry. One possible explanation for this discrepancy is that LRP6 may be important for anthrax toxin entry into human, but not mouse, cells. To test this idea we have investigated the effect of knocking down LRP6 or LRP5 expression with siRNAs in human HeLa cells. We show here that efficient knockdown of either LRP6, LRP5, or both proteins has no influence on the kinetics of anthrax lethal toxin entry or MEK1 substrate cleavage in these cells. These data argue against a human-specific role for LRP6 in anthrax toxin entry and suggest instead that involvement of this protein may be restricted to certain cell types independently of their species of origin