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

Synthesis of quaternary aryl phosphonium salts: photoredox-mediated phosphine arylation

We report a synthesis method for the construction of quaternary aryl phoshonium salts at ambient temperature. The regiospecific reaction invovles the coupling of phosphines with aryl radicals derived from diaryliodonium salts under photoredox conditions

E,Z-Stereodivergent synthesis of N-tosyl α,β-dehydroamino esters via a Mukaiyama-Michael addition

The stereodivergent synthesis of N-tosyl α,β-dehydroamino esters via a Mukaiyama-Michael addition is reported. The reaction of silylketene acetals with N-tosylimines derived from β,γ-unsaturated α-keto esters in dichloromethane provided the corresponding (Z)-α,β-dehydroamino esters while the (E)-isomers were obtained when the reaction was carried out in the presence of 10 mol% copper(II) triflate

A widely employed germ cell marker is an ancient disordered protein with reproductive functions in diverse eukaryotes

The advent of sexual reproduction and the evolution of a dedicated germline in multicellular organisms are critical landmarks in eukaryotic evolution. We report an ancient family of GCNA (germ cell nuclear antigen) proteins that arose in the earliest eukaryotes, and feature a rapidly evolving intrinsically disordered region (IDR). Phylogenetic analysis reveals that GCNA proteins emerged before the major eukaryotic lineages diverged; GCNA predates the origin of a dedicated germline by a billion years. Gcna gene expression is enriched in reproductive cells across eukarya – either just prior to or during meiosis in single-celled eukaryotes, and in stem cells and germ cells of diverse multicellular animals. Studies of Gcna-mutant C. elegans and mice indicate that GCNA has functioned in reproduction for at least 600 million years. Homology to IDR-containing proteins implicated in DNA damage repair suggests that GCNA proteins may protect the genomic integrity of cells carrying a heritable genome.Life Sciences Research FoundationHoward Hughes Medical Institut

Stock markets and effective exchange rates in European countries: threshold cointegration findings

© 2015, Eurasia Business and Economics Society. The nexus between stock markets and exchange rates is examined in the case of eight European countries. The sample consists of four economies with national currencies and four that have adopted the euro. Thus, if differences between the two groups in the relationship governing the two markets exist, they will be unveiled. To this effect, a threshold cointegration methodology is adopted that allows for more reliable inferences to be drawn for both the short and long run nexus between the two markets. Monthly data is used covering the period 01/2000–12/2014. The findings reported herein offer support in favor of the portfolio approach thesis over the recent economic crisis period, but this finding is not the case for the entire sample. Bidirectional causality is found for Norway and the UK, pointing to a currency effect on stock markets. In view of the findings reported herein, policies aiming at reducing uncertainty in the stock markets can exert beneficial effects on currency markets

From complex questionnaire and interviewing data to intelligent Bayesian network models for medical decision support

OBJECTIVES: 1) To develop a rigorous and repeatable method for building effective Bayesian network (BN) models for medical decision support from complex, unstructured and incomplete patient questionnaires and interviews that inevitably contain examples of repetitive, redundant and contradictory responses; 2) To exploit expert knowledge in the BN development since further data acquisition is usually not possible; 3) To ensure the BN model can be used for interventional analysis; 4) To demonstrate why using data alone to learn the model structure and parameters is often unsatisfactory even when extensive data is available. METHOD: The method is based on applying a range of recent BN developments targeted at helping experts build BNs given limited data. While most of the components of the method are based on established work, its novelty is that it provides a rigorous consolidated and generalised framework that addresses the whole life-cycle of BN model development. The method is based on two original and recent validated BN models in forensic psychiatry, known as DSVM-MSS and DSVM-P. RESULTS: When employed with the same datasets, the DSVM-MSS demonstrated competitive to superior predictive performance (AUC scores 0.708 and 0.797) against the state-of-the-art (AUC scores ranging from 0.527 to 0.705), and the DSVM-P demonstrated superior predictive performance (cross-validated AUC score of 0.78) against the state-of-the-art (AUC scores ranging from 0.665 to 0.717). More importantly, the resulting models go beyond improving predictive accuracy and into usefulness for risk management purposes through intervention, and enhanced decision support in terms of answering complex clinical questions that are based on unobserved evidence. CONCLUSIONS: This development process is applicable to any application domain which involves large-scale decision analysis based on such complex information, rather than based on data with hard facts, and in conjunction with the incorporation of expert knowledge for decision support via intervention. The novelty extends to challenging the decision scientists to reason about building models based on what information is really required for inference, rather than based on what data is available and hence, forces decision scientists to use available data in a much smarter way

Childhood socioeconomic position and adult mental wellbeing:Evidence from four British birth cohort studies

There is much evidence showing that childhood socioeconomic position is associated with physical health in adulthood; however existing evidence on how early life disadvantage is associated with adult mental wellbeing is inconsistent. This paper investigated whether childhood socioeconomic position (SEP) is associated with adult mental wellbeing and to what extent any association is explained by adult SEP using harmonised data from four British birth cohort studies.The sample comprised 20,717 participants with mental wellbeing data in the Hertfordshire Cohort Study (HCS), the MRC National Survey of Health and Development (NSHD), the National Child Development Study (NCDS), and the British Cohort Study (BCS70). Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) scores at age 73 (HCS), 60-64 (NSHD), 50 (NCDS), or 42 (BCS70) were used. Harmonised socioeconomic position (Registrar General's Social Classification) was ascertained in childhood (age 10/11) and adulthood (age 42/43). Associations between childhood SEP, adult SEP, and wellbeing were tested using linear regression and multi-group structural equation models.More advantaged father's social class was associated with better adult mental wellbeing in the BCS70 and the NCDS. This association was independent of adult SEP in the BCS70 but fully mediated by adult SEP in the NCDS. There was no evidence of an association between father's social class and adult mental wellbeing in the HCS or the NSHD.Socioeconomic conditions in childhood are directly and indirectly, through adult socioeconomic pathways, associated with adult mental wellbeing, but findings from these harmonised data suggest this association may depend on cohort or age

The dark side of social movements: Social identity, non-conformity, and the lure of conspiracy theories

Social change does not always equal social progress--there is a dark side of social movements. We discuss conspiracy theory beliefs –beliefs that a powerful group of people are secretly working towards a malicious goal–as one contributor to destructive social movements. Research has linked conspiracy theory beliefs to anti-democratic attitudes, prejudice and non-normative political behavior. We propose a framework to understand the motivational processes behind conspiracy theories and associated social identities and collective action. We argue that conspiracy theories comprise at least two components – content and qualities— that appeal to people differently based on their motivations. Social identity motives draw people foremost to contents of conspiracy theories while uniqueness motives draw people to qualities of conspiracy theories