Characterization of natural product inhibitors of quorum sensing reveals competitive inhibition of Pseudomonas aeruginosa RhlR by ortho-vanillin.

Quorum sensing (QS) is a cell-cell signaling system that enables bacteria to coordinate population density-dependent changes in behavior. This chemical communication pathway is mediated by diffusible N-acyl L-homoserine lactone signals and cytoplasmic signal-responsive LuxR-type receptors in Gram-negative bacteria. As many common pathogenic bacteria use QS to regulate virulence, there is significant interest in disrupting QS as a potential therapeutic strategy. Prior studies have implicated the natural products salicylic acid, cinnamaldehyde, and other related benzaldehyde derivatives as inhibitors of QS in the opportunistic pathogen Pseudomonas aeruginosa, yet we lack an understanding of the mechanisms by which these compounds function. Herein, we evaluate the activity of a set of benzaldehyde derivatives using heterologous reporters of the P. aeruginosa LasR and RhlR QS signal receptors. We find that most tested benzaldehyde derivatives can antagonize LasR or RhlR reporter activation at micromolar concentrations, although certain molecules also cause mild growth defects and nonspecific reporter antagonism. Notably, several compounds showed promising RhlR or LasR-specific inhibitory activities over a range of concentrations below that causing toxicity. ortho-Vanillin, a previously untested compound, was the most promising within this set. Competition experiments against the native ligands for LasR and RhlR revealed that ortho-vanillin can interact competitively with RhlR but not with LasR. Overall, these studies expand our understanding of benzaldehyde activities in the LasR and RhlR receptors and reveal potentially promising effects of ortho-vanillin as a small molecule QS modulator against RhlR. IMPORTANCE: Quorum sensing (QS) regulates many aspects of bacterial pathogenesis and has attracted much interest as a target for anti-virulence therapies over the past 30 years, for example, antagonists of the LasR and RhlR QS receptors in Pseudomonas aeruginosa. Potent and selective QS inhibitors remain relatively scarce. However, natural products have provided a bounty of chemical scaffolds with anti-QS activities, but their molecular mechanisms are poorly characterized. The current study serves to fill this void by examining the activity of an important and wide-spread class of natural product QS modulators, benzaldehydes, and related derivatives, in LasR and RhlR. We demonstrate that ortho-vanillin can act as a competitive inhibitor of RhlR, a receptor that has emerged and may supplant LasR in certain settings as a target for P. aeruginosa QS control. The results and insights provided herein will advance the design of chemical tools to study QS with improved activities and selectivities.

Characterization of natural product inhibitors of quorum sensing in Pseudomonas aeruginosa reveals competitive inhibition of RhlR by ortho-vanillin.

Quorum sensing (QS) is a cell-cell signaling system that enables bacteria to coordinate population density-dependent changes in behavior. This chemical communication pathway is mediated by diffusible N-acyl L-homoserine lactone signals and cytoplasmic signal-responsive LuxR-type receptors in Gram-negative bacteria. As many common pathogenic bacteria use QS to regulate virulence, there is significant interest in disrupting QS as a potential therapeutic strategy. Prior studies have implicated the natural products salicylic acid, cinnamaldehyde and other related benzaldehyde derivatives as inhibitors of QS in the opportunistic pathogen Pseudomonas aeruginosa, yet we lack an understanding of the mechanisms by which these compounds function. Herein, we evaluate the activity of a set of benzaldehyde derivatives using heterologous reporters of the P. aeruginosa LasR and RhlR QS signal receptors. We find that most tested benzaldehyde derivatives can antagonize LasR or RhlR reporter activation at micromolar concentrations, although certain molecules also caused mild growth defects and nonspecific reporter antagonism. Notably, several compounds showed promising RhlR or LasR specific inhibitory activities over a range of concentrations below that causing toxicity. Ortho-Vanillin, a previously untested compound, was the most promising within this set. Competition experiments against the native ligands for LasR and RhlR revealed that ortho-vanillin can interact competitively with RhlR but not with LasR. Overall, these studies expand our understanding of benzaldehyde activities in the LasR and RhlR receptors and reveal potentially promising effects of ortho-vanillin as a small molecule QS modulator against RhlR.

Conjoint behavioral consultation: implementing a tiered home-school partnership model to promote school readiness.

An ecological perspective to school readiness focuses on child and family readiness by enhancing the developmental contexts and relationships within which children reside (e.g., home environment, parent-child relationship, home-school relationships). The Getting Ready intervention is an ecological, relationally based, tiered intervention providing both universal and intensive services to children and families to promote child and family school readiness. Intensive level consultation services were provided via Conjoint Behavioral Consultation (CBC; Sheridan & Kratochwill, 1992 , 2008 ). The purpose of this article is to describe the implementation and effects of CBC within the Getting Ready intervention to promote child and family school readiness. Keys to successful implementation of the CBC intervention and issues needing further investigation are discussed.

Functional analysis and intervention for chronic rumination.

We conducted a functional analysis and treatment evaluation of chronic rumination in a 19-year-old man with intellectual disabilities. Outcomes of the functional analysis suggested that rumination was maintained by automatic reinforcement. Results of the intervention evaluation suggested that (a) noncontingent access to food after meals reduced rumination more effectively than did noncontingent access to inedible stimuli, (b) a particular type of food was associated with lower levels of rumination than other types of food, and (c) both presession and continuous access to food reduced levels of rumination more effectively than did fixed-time access to food.

Review of sports performance research with youth, collegiate, and elite athletes.

This brief review summarizes translational and intervention research in the area of sports performance. We describe studies with youth, collegiate, and elite athletes; identify recent trends; and propose recommendations for future research.

Family involvement for children with disruptive behaviors: the role of parenting stress and motivational beliefs.

Children with disruptive behaviors are at risk for adverse outcomes. Family involvement is a significant predictor of positive child behavior outcomes; however, little research has investigated parent psychological variables that influence family involvement for children with disruptive behaviors. This study investigated the role of parental motivational beliefs (i.e., role construction and efficacy) as a potential mechanism by which parenting stress impacts family involvement for families of children with disruptive behaviors. Results indicated that parent role construction mediated the relation between parenting stress and all aspects of family involvement examined (i.e., home-based involvement, school-based involvement, and home-school communication). Parent efficacy mediated the relation between parenting stress and home-based involvement only. Parents of children with disruptive behaviors reporting stress may experience negative beliefs about their role and efficacy to support their child's education, which may thereby negatively influence their actual involvement. Therefore, parent motivational beliefs may serve as an important point for intervention to support involvement of families of children with disruptive behavior.