Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis

Cystic fibrosis (CF) is the most common inherited lethal disease in Caucasians which results in multiorgan dysfunction. However, 85% of the deaths are due to pulmonary infections. Infection by Burkholderia cenocepacia (B. cepacia) is a particularly lethal threat to CF patients because it causes severe and persistent lung inflammation and is resistant to nearly all available antibiotics. In CFTR Delta F508 (Delta F508) mouse macrophages, B. cepacia persists in vacuoles that do not fuse with the lysosomes and mediates increased production of IL-1 beta. It is believed that intracellular bacterial survival contributes to the persistence of the bacterium. Here we show for the first time that in wild-type but not in Delta F508 macrophages, many B. cepacia reside in autophagosomes that fuse with lysosomes at later stages of infection. Accordingly, association and intracellular survival of B. cepacia are higher in CFTR-Delta F508 macrophages than in WT macrophages. An autophagosome is a compartment that engulfs nonfunctional organelles and parts of the cytoplasm then delivers them to the lysosome for degradation to produce nutrients during periods of starvation or stress. Furthermore, we show that B. cepacia downregulates autophagy genes in WT and Delta F508 macrophages. However, autophagy dysfunction is more pronounced in Delta F508 macrophages since they already have compromised autophagy activity. We demonstrate that the autophagy-stimulating agent, rapamycin markedly decreases B. cepacia infection in vitro by enhancing the clearance of B. cepacia via induced autophagy. In vivo, rapamycin decreases bacterial burden in the lungs of CF mice and drastically reduces signs of lung inflammation. Together, our studies reveal that if efficiently activated, autophagy can control B. cepacia infection and ameliorate the associated inflammation. Therefore, autophagy is a novel target for new drug development for CF patients to control B. cepacia infection and accompanying inflammation.

A two-tier model of polymyxin B resistance in Burkholderia cenocepacia

P>Burkholderia cenocepacia is an environmental bacterium causing serious human opportunistic infections and is extremely resistant to multiple antibiotics including antimicrobial peptides, such as polymyxin B (PmB). Extreme antibiotic resistance is attributed to outer membrane impermeability ('intrinsic' resistance). Previous work showed that production of full-length lipopolysaccharide (LPS) prevents surface binding of PmB. We hypothesized that two tiers of resistance mechanisms rendering different thresholds of PmB resistance exist in B. cenocepacia. To test this notion, candidate genes were mutated in two isogenic strains expressing full-length LPS or truncated LPS devoid of heptose ('heptoseless LPS') respectively. We uncovered various proteins required for PmB resistance only in the strain with heptoseless LPS. These proteins are not involved in preventing PmB binding to whole cells or permeabilization of the outer membrane. Our results support a two-tier model of PmB resistance in B. cenocepacia. One tier sets a very high threshold mediated by the LPS and the outer membrane permeability barrier. The second tier sets a lower threshold that may play a role in PmB resistance only when outer membrane permeability is compromised. This model may be of general applicability to understanding the high antimicrobial peptide resistance of environmental opportunistic pathogens.

From imagery to intention: A dual route model of imagined contact effects

Imagined intergroup contact (Crisp & R. Turner, 2009) is a new indirect contact strategy for promoting tolerance and more positive intergroup relations. In this chapter, we review existing research on imagined contact and propose two routes-cognitive and affective-through which it can exert a positive influence on contact-related attitudes and intentions. We first review research that has established the beneficial impacts of imagined contact on intergroup attitudes via reduced intergroup anxiety, supporting its efficacy as an intervention where there exists little or no opportunity for direct contact. We then review more recent research showing that imagined contact not only improves attitudes, but can also enhance intentions to engage in future contact. These studies suggest that contact imagery provides a behavioural script that forms the cognitive basis for subsequent judgements about future contact intentions. Collectively, the findings from this research programme support the idea that imagined contact can complement more direct forms of contact-providing a way of initially encouraging an interest in engaging positively with outgroups before introducing face-to-face encounters. We discuss the implications of these findings for future theory and research, and how they can inform prejudice-reduction interventions seeking to capitalise on the beneficial effects of mental imagery.

Characteristics of offenders:The HEXACO model of personality as a framework for studying offenders' personality

What are the personality differences between individuals who commit crime and those who refrain from crime? The HEXACO model of personality combines facets of honesty and humility with those of emotionality, extraversion, conscientiousness, agreeableness, and openness to experience within a unifying framework of personality. We applied the HEXACO model to examine differences in personality between offenders and nonoffenders. Criminal offenders differed from nonoffenders on five of the six dimensions of personality proposed by the HEXACO model. Compared to nonoffenders, offenders exhibited stronger tendencies toward greed and unfairness, but were also more anxious and fearful. Conversely, the offenders scored lower than nonoffenders on a number of facets of sociability, liveliness, and social boldness. The present findings indicate that offenders may in part be characterized by increased negative emotions but decreased sociability and liveliness. The HEXACO model of personality provides a valuable tool for studying this unique and important population. © 2012 Copyright Taylor and Francis Group, LLC.

A defeasible reasoning model of inductive concept learning from examples and communication

This paper introduces a logical model of inductive generalization, and specifically of the machine learning task of inductive concept learning (ICL). We argue that some inductive processes, like ICL, can be seen as a form of defeasible reasoning. We define a consequence relation characterizing which hypotheses can be induced from given sets of examples, and study its properties, showing they correspond to a rather well-behaved non-monotonic logic. We will also show that with the addition of a preference relation on inductive theories we can characterize the inductive bias of ICL algorithms. The second part of the paper shows how this logical characterization of inductive generalization can be integrated with another form of non-monotonic reasoning (argumentation), to define a model of multiagent ICL. This integration allows two or more agents to learn, in a consistent way, both from induction and from arguments used in the communication between them. We show that the inductive theories achieved by multiagent induction plus argumentation are sound, i.e. they are precisely the same as the inductive theories built by a single agent with all data. © 2012 Elsevier B.V.