Experiential avoidance as a functional dimensional approach to psychopathology: an empirical review

The construct of experiential avoidance has become more frequently used by clinical researchers. Experiential avoidance involves the unwillingness to remain in contact with private experiences such as painful thoughts and emotions and is often proposed to be critical to the development and maintenance of psychopathology. This review summarizes the empirical studies on experiential avoidance as a factor in the etiology of maladaptive behavior and its relationship to specific diagnostic categories. Although some of the current literature suggests that experiential avoidance may be implicated in various forms of psychopathology, a fundamental limitation of this research is the lack of theoretical integration and refinement with regard to operationalizing and assessing experiential avoidance. Future studies should attempt to understand the core processes involved in experiential avoidance better, and then clearly operationalize the construct and determine its incremental validity relative to other constructs.     

Posttraumatic stress symptoms in parents of children with acute burns

OBJECTIVE: To develop a model of risk factors for posttraumatic stress disorder (PTSD) symptoms in parents of children with burns. METHODS: Immediately following the burn and 3 months later, parents reported on their children's and their own psychological functioning and traumatic stress responses. RESULTS: Approximately 47% of the parents reported experiencing significant posttraumatic stress symptoms 3 months after the burn. Our model indicates three independent pathways to PTSD symptoms (i.e., parent-child conflict, parents' dissociation, and children's PTSD symptoms). Additionally, parents' anxiety predicted increased parent-child conflict, conflict with extended family and size of the burn predicted parents' dissociation, and size of the burn and children's dissociation predicted children's PTSD symptoms. CONCLUSIONS: This study suggests that many parents of children with burns suffer from posttraumatic stress symptoms. Interventions that target factors such as family conflict, children's symptoms, and parents' acute anxiety and dissociation may diminish the risk for PTSD.     

Child Stress Disorders Checklist: a measure of ASD and PTSD in children

OBJECTIVE: To assess the psychometric properties of the Child Stress Disorders Checklist (CSDC), a 36-item observer-report instrument that measures acute stress and posttraumatic symptoms in children. METHOD: The CSDC was administered to parents of 43 children with acute burns and 41 children who had experienced a traffic crash. This instrument was also administered to the burned children's primary nurse to estimate interrater reliability. The CSDC was completed again by parents of burned children, 2 days and 3 months later. Convergent validity was determined by correlating scores on the CSDC with scores on instruments of known validity for assessing posttraumatic stress disorder (PTSD) in children. Concurrent validity was determined through an examination of the relationship between CSDC scores and an index of trauma severity (percentage of body surface area burned). Discriminant validity was assessed by administering the Child Behavior Checklist (CBCL): it was hypothesized that PTSD symptoms would be more closely related to the PTSD scale of the CBCL than the Thought Problems scale of the CBCL. RESULTS: The CSDC has reliable and valid psychometric properties. CONCLUSIONS: The CSDC, an observer-report instrument of ASD and PTSD in children, has important utility in clinical and research settings.     

Pathways to PTSD, part I: Children with burns

OBJECTIVE: The goal of this study was to develop a model of risk factors for posttraumatic stress disorder (PTSD) in a group of acutely burned children. METHOD: Seventy-two children between the ages of 7 and 17 who were admitted to the hospital for an acute burn were eligible for study. Members of families who consented completed the Child PTSD Reaction Index, the Multidimensional Anxiety Scale for Children, and other self-report measures of psychopathology and environmental stress both during the hospitalization and 3 months following the burn. A path analytic strategy was used to build a model of risk factors for PTSD. RESULTS: Two pathways to PTSD were discerned: 1) from the size of the burn and level of pain following the burn to the child's level of acute separation anxiety, and then to PTSD, and 2) from the size of the burn to the child's level of acute dissociation following the burn, and then to PTSD. Together these pathways accounted for almost 60% of the variance in PTSD symptoms and constituted a model with excellent fit indices. CONCLUSIONS: These findings support a model of complex etiology for childhood PTSD in which two independent pathways may be mediated by different biobehavioral systems.     

The mindfulness-based relapse prevention adherence and competence scale: Development,interrater reliability,and validity

Abstract

The present study describes the development of the Mindfulness-Based Relapse Prevention Adherence and Competence Scale (MBRP-AC), a measure of treatment integrity for mindfulness-based relapse prevention (MBRP). MBRP is a newly developed treatment integrating core aspects of relapse prevention with mindfulness practices. The MBRP-AC was developed in the context of a randomized controlled trial (RCT) of MBRP efficacy and consists of two sections: Adherence (adherence to individual components of MBRP and discussion of key concepts) and Competence (ratings of therapist style/approach and performance). Audio recordings from 44 randomly selected group treatment sessions (50%) were rated by independent raters for therapist adherence and competence in the RCT. Findings evinced high interrater reliability for all treatment adherence and competence ratings, and adequate internal consistency for Therapist Style/Approach and Therapist Performance summary scales. Ratings on the MBRP-AC suggested that therapists in the recent RCT adhered to protocol, discussed key concepts in each session, and demonstrated the intended style and competence in treatment delivery. Finally, overall ratings on the Adherence section were positively related to changes in mindfulness over the course of the treatment.     

Chaperones Skp and SurA dynamically expand unfolded OmpX and synergistically disassemble oligomeric aggregates

Periplasmic chaperones 17-kilodalton protein (Skp) and survival factor A (SurA) are essential players in outer membrane protein (OMP) biogenesis. They prevent unfolded OMPs from misfolding during their passage through the periplasmic space and aid in the disassembly of OMP aggregates under cellular stress conditions. However, functionally important links between interaction mechanisms, structural dynamics, and energetics that underpin both Skp and SurA associations with OMPs have remained largely unresolved. Here, using single-molecule fluorescence spectroscopy, we dissect the conformational dynamics and thermodynamics of Skp and SurA binding to unfolded OmpX and explore their disaggregase activities. We show that both chaperones expand unfolded OmpX distinctly and induce microsecond chain reconfigurations in the client OMP structure. We further reveal that Skp and SurA bind their substrate in a fine-tuned thermodynamic process via enthalpy–entropy compensation. Finally, we observed synergistic activity of both chaperones in the disaggregation of oligomeric OmpX aggregates. Our findings provide an intimate view into the multifaceted functionalities of Skp and SurA and the fine-tuned balance between conformational flexibility and underlying energetics in aiding chaperone action during OMP biogenesis.

Molecular chaperones are key cellular components that play fundamental roles in maintaining cellular proteostasis (1, 2). Essential activities of chaperones include the assistance of de novo protein folding, the stabilization of nonnative proteins in folding competent or unfolded states, and the rescue of misfolded and aggregated proteins (3–5). Chaperones are an integral part of a wide range of protein quality-control systems, and their activities are intimately coupled to the biogenesis networks that aid the structural and functional maturation of proteins from their site of cellular synthesis to their target cellular compartments.One network where chaperone activity is of particular relevance is the biogenesis of outer membrane proteins (OMPs) (6, 7). OMPs are a diverse group of β-barrel membrane proteins found in the outer membrane of Gram-negative bacteria, mitochondria, and chloroplasts. They fulfill a plethora of functions in cell signaling, metabolism, and transport (8–10); are indispensable to the survival of bacteria (10, 11); and constitute important virulence factors and drug targets (12–14). The OMP biosynthesis pathway is highly complex and conserved across all kingdoms of life (15) and involves the coordinated action of a multicomponent protein machinery that aids in overcoming the many hurdles that these proteins have to surmount on their way to their target outer membrane (4, 7, 16).In Gram-negative bacteria, OMPs are translated in the cytoplasm, from where they are translocated across the inner bacterial membrane via the Sec machinery to the periplasmic space (17, 5). Within this aqueous compartment, OMPs are escorted to the outer membrane in an unfolded state (denoted as the uOMP state) with the aid of various chaperones that maintain the largely insoluble and aggregation-prone uOMP polypeptide chains in a protected, partially unfolded state (18, 19). At the outer membrane, uOMPs are transferred to the β-barrel assembly machinery (BAM), which facilitates their native folding and insertion into the membrane (20). Noteworthy, the periplasm is devoid of any known source of energy-providing molecules, such as adenosine triphosphate (ATP); hence, all chaperones as well as the entire folding machinery likely operate without the aid of external energy, following thermodynamic principles (21).Two chaperones which have been shown to be indispensable for the biogenesis of bacterial OMPs are the 17-kilodalton protein (Skp) (22) and survival factor A (SurA) (23). Skp and SurA, both located in the periplasm, exhibit antifolding activity (also known as holdase activity), whereby they sequester uOMP substrates to prevent aggregation until they reach the bacterial outer membrane (24–26). Their interaction with uOMPs is thermodynamically modulated due to the lack of energy-carrying molecules in the periplasm (27–29). Depletion studies of periplasmic chaperones identified SurA as an essential chaperone for OMP biogenesis, leading to a drastic decrease in OMP density in the outer membrane due to the loss of SurA (30). Skp depletion, on the other hand, led to an accumulation of misfolded OMPs and the activation of the cellular stress response (30), while OMP density in the outer membrane remained the same. Interestingly, recent studies suggest substrate selectivity among the two chaperones (31). Hence, it is of importance to understand the functional mechanisms underlying both Skp and SurA association with uOMPs.Structural studies of the eight β-stranded protein outer membrane protein X (OmpX) in the presence of Skp using NMR spectroscopy have found that unfolded OmpX (uOmpX) shows submillisecond backbone dynamics (32) in complex with Skp. For binding of SurA to unfolded outer membrane protein A (uOmpA), both fluid globular (32) and expanded states (31) have been proposed. Recent studies have located various interaction sites of SurA and uOmpX using cross-linking, suggesting that SurA-bound uOmpX populates multiple conformations (31, 33). Yet, long-range polypeptide chain dynamics and conformational heterogeneity of unfolded OMPs upon binding to chaperones remain elusive. In particular, it is unknown how SurA- and Skp-bound OMP dynamics and heterogeneities differ, given their differential roles in regulating protein folding in the periplasmic space. Dynamic aspects are hypothesized to be important for chaperone–uOMP interactions, particularly to fine-tune energetics of the binding reaction through a reduction of the entropic costs upon binding (28, 29, 34–37). Yet, the enthalpic and entropic changes that determine Skp–OMP or SurA–OMP interactions and affect the conformations of the denatured substrate proteins are largely undefined.In addition to the well-described holdase activities of Skp and SurA that protect OMPs from misfolding or aggregating, a recent study has suggested that Skp disaggregates oligomeric uOMP structures (38). While SurA has not been directly implicated as a disaggregase, modeling studies propose a synergistic interaction among these chaperones especially under conditions of stress (18, 39), thus raising the question of the role that both chaperones played in disassembling OMP aggregates.To gain insights into the multifaceted functionalities of Skp and SurA and their action mechanisms, we study here the conformational dynamics and thermodynamics of the eight β-stranded protein OmpX in the presence of the chaperones and explore their disaggregation activities. Using single-molecule Förster resonance energy transfer (smFRET), we resolve the heterogeneities, structural dynamics, and thermodynamics underlying the different states of uOmpX at near-native conditions. Strikingly, we find that both chaperones expand the unfolded polypeptide chain upon binding. The degree of expansion is concentration dependent for SurA, but not for Skp. Probing structural changes and chaperone interaction at different temperatures, we gain insights into the enthalpic and entropic contributions of complex formation and find that the interaction modes of both chaperones differ strongly and are dictated by entropy–enthalpy compensation. Finally, we use fluorescence correlation spectroscopy (FCS) to probe the disaggregation capabilities of Skp and SurA and find synergistic activity of both chaperones in the disassembly reaction of oligomeric OmpX aggregates. Our findings provide fundamental insights into the structural and energetic mechanisms underlying Skp and SurA chaperone–OMP interactions and their role in OMP biogenesis.