Allosteric activation of MALT1 by its ubiquitin-binding Ig3 domain.

The catalytic activity of the protease MALT1 is required for adaptive immune responses and regulatory T (Treg)-cell development, while dysregulated MALT1 activity can lead to lymphoma. MALT1 activation requires its monoubiquitination on lysine 644 (K644) within the Ig3 domain, localized adjacent to the protease domain. The molecular requirements for MALT1 monoubiquitination and the mechanism by which monoubiquitination activates MALT1 had remained elusive. Here, we show that the Ig3 domain interacts directly with ubiquitin and that an intact Ig3-ubiquitin interaction surface is required for the conjugation of ubiquitin to K644. Moreover, by generating constitutively active MALT1 mutants that overcome the need for monoubiquitination, we reveal an allosteric communication between the ubiquitination site K644, the Ig3-protease interaction surface, and the active site of the protease domain. Finally, we show that MALT1 mutants that alter the Ig3-ubiquitin interface impact the biological response of T cells. Thus, ubiquitin binding by the Ig3 domain promotes MALT1 activation by an allosteric mechanism that is essential for its biological function.

Mediators of Change in Capnometry Guided Respiratory Intervention for Panic Disorder.

Capnometry guided respiratory interventions have shown promising results in the treatment of panic disorder, but mechanisms of change are not yet well-understood. The current study examined changes in end-tidal carbon dioxide (ETCO2), anxiety sensitivity, and perceived control as mediators of panic symptom change. Sixty-nine adults with panic disorder received 4 weeks of respiratory training, and panic symptom severity and potential mediators were assessed at Pre-treatment, Mid-treatment, Post-treatment, 2-month follow-up, and 12-month follow-up. Multilevel mediation analyses showed that changes in perceived control significantly mediated changes in panic disorder severity and that for individuals who were hypocapnic at pre-treatment, ETCO2 was a significant mediator of symptom outcome. Findings provide further evidence that changes in perceived control, and improvements in respiratory dysregulation for hypocapnic individuals specifically, underlie symptom improvement from capnometry guided respiratory intervention for panic disorder.

Predictive Relationship Between Parental Beliefs and Accommodation of Pediatric Anxiety.

Behavior performed by parents to assist a youth in avoiding or alleviating anxiety, known as accommodation, is ubiquitous among pediatric anxiety disorders and strongly related to poor treatment outcome. According to cognitive-behavioral theory, the beliefs parents hold regarding accommodation should predict parental accommodating behavior. Unfortunately, little is known about the beliefs parents hold regarding accommodation, as there exists no validated measure of this construct. First, the psychometric properties were examined for the Parental Accommodation Scale (PAS), a novel measure of parental accommodating behavior frequency (PAS-Behavior scale) and parental beliefs about accommodation (PAS-Belief scale). Second, the relationship between parental beliefs about accommodation and accommodation frequency was examined. Results provide preliminary evidence of the internal consistency and convergent validity of the PAS. Stronger positive beliefs about accommodation significantly predicted accommodation frequency, even after controlling for youth anxiety severity. Specifically, beliefs that accommodation prevents youth from losing behavioral and emotional control significantly predicted accommodation frequency. Therefore, efforts to decrease accommodation in clinical settings should involve correcting maladaptive parental beliefs about accommodation, with a particular emphasis on beliefs regarding the necessity of accommodation in preventing a youth from losing behavioral and emotional control.

A Multisite Benchmarking Trial of Capnometry Guided Respiratory Intervention for Panic Disorder in Naturalistic Treatment Settings.

Panic disorder (PD) is associated with hyperventilation. The efficacy of a brief respiratory feedback program for PD has been established. The aim of the present study was to expand these results by testing a similar program with more clinically representative patients and settings. Sixty-nine adults with PD received 4 weeks of Capnometry Guided Respiratory Intervention (CGRI) using Freespira, which provides feedback of end-tidal CO2 (PETCO2) and respiration rate (RR), in four non-academic clinical settings. This intervention is delivered via home use following initial training by a clinician and provides remote monitoring of client adherence and progress by the clinician. Outcomes were assessed post-treatment and at 2- and 12-month follow-up. CGRI was associated with an intent-to-treat response rate of 83% and a remission rate of 54%, and large decreases in panic severity. Similar decreases were found in functional impairment and in global illness severity. Gains were largely sustained at follow-up. PETCO2 moved from the slightly hypocapnic range to the normocapnic range. Benchmarking analyses against a previously-published controlled trial showed very similar outcomes, despite substantial differences in sample composition and treatment settings. The present study confirms prior clinical results and lends further support to the viability of CGRI in the treatment of PD.

Altered source memory retrieval is associated with pathological doubt in obsessive-compulsive disorder.

Individuals with obsessive-compulsive disorder (OCD) often complain of doubt related to memory. As neuropsychological research has demonstrated that individuals with OCD tend to focus on details and miss the larger context, the construct of source (contextual) memory may be particularly relevant to memory complaints in OCD. Memory for object versus contextual information relies on partially distinct regions within the prefrontal cortex, parietal and medial temporal lobe, and may be differentially impacted by OCD. In the present study, we sought to test the hypothesis that individuals with OCD exhibit impaired source memory retrieval using a novel memory paradigm - The Memory for Rooms Test (MFRT) - a four-room memory task in which participants walk through four rooms and attempt to encode and remember objects. Demographically matched individuals with OCD and healthy controls studied objects in the context of four rooms, and then completed a memory retrieval test while undergoing functional magnetic resonance imaging (fMRI). While no differences were observed in source memory accuracy, individuals with OCD exhibited greater task related activation in the posterior cingulate cortex (PCC) relative to healthy controls during correct source memory retrieval. During correct object recognition, individuals with OCD failed to recruit the dorsolateral prefrontal(DLPFC)/premotor, left mPFC, and right parietal regions to the same extent as healthy controls. Our results suggest abnormal recruitment of frontal-parietal and PCC regions during source verses object memory retrieval in OCD. Within the OCD group, activation in the PCC and the premotor/DLPFC was associated with greater pathological doubt. This finding is consistent with the observation that OCD patients often experience extreme doubt, even when memory performance is intact.

Solution structure of the SGTA dimerisation domain and investigation of its interactions with the ubiquitin-like domains of BAG6 and UBL4A.

BACKGROUND: The BAG6 complex resides in the cytosol and acts as a sorting point to target diverse hydrophobic protein substrates along their appropriate paths, including proteasomal degradation and ER membrane insertion. Composed of a trimeric complex of BAG6, TRC35 and UBL4A, the BAG6 complex is closely associated with SGTA, a co-chaperone from which it can obtain hydrophobic substrates. METHODOLOGY AND PRINCIPAL FINDINGS: SGTA consists of an N-terminal dimerisation domain (SGTA_NT), a central tetratricopeptide repeat (TPR) domain, and a glutamine rich region towards the C-terminus. Here we solve a solution structure of the SGTA dimerisation domain and use biophysical techniques to investigate its interaction with two different UBL domains from the BAG6 complex. The SGTA_NT structure is a dimer with a tight hydrophobic interface connecting two sets of four alpha helices. Using a combination of NMR chemical shift perturbation, isothermal titration calorimetry (ITC) and microscale thermophoresis (MST) experiments we have biochemically characterised the interactions of SGTA with components of the BAG6 complex, the ubiquitin-like domain (UBL) containing proteins UBL4A and BAG6. We demonstrate that the UBL domains from UBL4A and BAG6 directly compete for binding to SGTA at the same site. Using a combination of structural and interaction data we have implemented the HADDOCK protein-protein interaction docking tool to generate models of the SGTA-UBL complexes. SIGNIFICANCE: This atomic level information contributes to our understanding of the way in which hydrophobic proteins have their fate decided by the collaboration between SGTA and the BAG6 complex.

Musical obsessions: a comprehensive review of neglected clinical phenomena.

Intrusive musical imagery (IMI) consists of involuntarily recalled, short, looping fragments of melodies. Musical obsessions are distressing, impairing forms of IMI that merit investigation in their own right and, more generally, research into these phenomena may broaden our understanding of obsessive-compulsive disorder (OCD), which is phenomenologically and etiologically heterogeneous. We present the first comprehensive review of musical obsessions, based on the largest set of case descriptions ever assembled (N=96). Characteristics of musical obsessions are described and compared with normal IMI, musical hallucinations, and visual obsessional imagery. Assessment, differential diagnosis, comorbidity, etiologic hypotheses, and treatments are described. Musical obsessions may be under-diagnosed because they are not adequately assessed by current measures of OCD. Musical obsessions have been misdiagnosed as psychotic phenomena, which has led to ineffective treatment. Accurate diagnosis is important for appropriate treatment. Musical obsessions may respond to treatments that are not recommended for prototypic OCD symptoms.

Anterior cingulate cortex involvement in subclinical social anxiety.

We demonstrated differential activation in the anterior cingulate cortex (ACC) between subjects with high and low social anxiety in response to angry versus neutral faces. Activation in the ACC distinguished between facial expressions in the low, but not the high, anxious group. The ACC's role in threat processing is discussed.

The timing of exposure in clinic-based treatment for childhood anxiety disorders.

The present study examines treatment length and timing of exposure from two child anxiety disorders clinics. Data regarding symptoms and treatment characteristics for 28 youth were prospectively obtained through self, parent, and therapist report at each session. Information regarding length of treatment, timing of exposure initiation, and drop-out rates were compared with those obtained through efficacy and effectiveness trials of manualized treatment for anxious youth. Findings from the authors' clinical data revealed significantly shorter treatment duration with exposures implemented sooner than in the previous studies. Dropout rates were significantly higher than in the efficacy trial but comparable with the effectiveness trial. Outcome data from a subset of eight patients revealed large effect sizes. These findings suggest that effective treatment can be shorter and more focused on exposure than is often outlined in manuals and have important implications for outcome research and dissemination.

1H, 13C and 15N assignments of Sgt2 N-terminal dimerisation domain and its binding partner, Get5 Ubiquitin-like domain.

The first stage of the GET (guided entry of tail-anchored proteins) mechanism for tail-anchored (TA) membrane protein insertion is thought to occur when Sgt2 (small, glutamine-rich, tetratricopeptide repeat-containing protein 2) binds TA proteins upon their release from the ribosome. It sorts them and passes the majority over to a complex of Get5 and Get4 for transmission along the GET pathway and delivery to their membrane destination. Sgt2 is a 38 kDa protein consisting of three domains. The N-terminal domain effects tight dimerisation of the protein and is also the site for binding with the ubiquitin-like (UBL) domain of Get5. Here we have expressed and purified uniformly-(15)N/(13)C-labelled N-terminal Sgt2 (Sgt2_NT) and its binding partner, Get5 UBL domain (Get5_UBL) and assigned the backbone and side-chain resonances as a basis for structure solution of the individual components and, ultimately, the complex. This will provide detailed molecular insight into the early stages of the GET pathway.

The timing of exposure in clinic-based treatment for childhood anxiety disorders.

The present study examines treatment length and timing of exposure from two child anxiety disorders clinics. Data regarding symptoms and treatment characteristics for 28 youth were prospectively obtained through self, parent, and therapist report at each session. Information regarding length of treatment, timing of exposure initiation, and drop-out rates were compared with those obtained through efficacy and effectiveness trials of manualized treatment for anxious youth. Findings from the authors' clinical data revealed significantly shorter treatment duration with exposures implemented sooner than in the previous studies. Dropout rates were significantly higher than in the efficacy trial but comparable with the effectiveness trial. Outcome data from a subset of eight patients revealed large effect sizes. These findings suggest that effective treatment can be shorter and more focused on exposure than is often outlined in manuals and have important implications for outcome research and dissemination.

Psychoeducational groups for youth attention-deficit hyperactivity disorder: a family medicine pilot project.

Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioural disorder of youth and is estimated to affect ∼4% of school-age children. Although medication is the most common and efficacious treatment for ADHD, some experts believe that multimodal treatment strategies help children improve symptoms more than medicine alone. Psychoeducational strategies focus on educating youth and families about a given disorder. This study compared youth who participated with their parents in a five-session, one-hour psychoeducational group at a family medicine clinic and those who received customary treatment and were on a waiting list for the intervention. Findings of youth behaviour from parent and teacher perspectives were compared at the outset of the group and one month after group completion using the Vanderbilt scales. Results revealed that youth in both conditions improved over the two months of the study from the parent perspective in terms of all ADHD symptoms (e.g. inattention, hyperactivity/impulsivity) and in terms of school functioning. However, no gains were made in youth functioning or ADHD behaviour from the teacher perspective. Youth in the treatment group made modest gains in school performance from the parent perspective when compared with youth in the control condition. The results suggest that parents of ADHD youth should be involved in the treatment process to maximise the likelihood of improvement. Psychoeducational groups can be of modest benefit to help educate parents and youth regarding the challenges of ADHD management.

The relationship between obsessive beliefs and symptom dimensions in obsessive-compulsive disorder.

Research findings on the specific relationships between beliefs and OCD symptoms have been inconsistent, yet the existing studies vary in their approach to measuring the highly heterogeneous symptoms of this disorder. The Dimensional Obsessive-Compulsive Scale (DOCS) is a new measure that allows for the assessment of OCD symptom dimensions, rather than types of obsessions and compulsions per se. The present study examined the relationship between OCD symptom dimensions and dysfunctional (obsessive) beliefs believed to underlie these symptom dimensions using a large clinical sample of treatment-seeking adults with OCD. Results revealed that certain obsessive beliefs predicted certain OCD symptom dimensions in a manner consistent with cognitive-behavioral conceptual models. Specifically, contamination symptoms were predicted by responsibility/threat estimation beliefs, symmetry symptoms were predicted by perfectionism/certainty beliefs, unacceptable thoughts were predicted by importance/control of thoughts beliefs and symptoms related to being responsible for harm were predicted by responsibility/threat estimation beliefs. Implications for cognitive conceptualizations of OCD symptom dimensions are discussed.

Assessment of obsessive-compulsive symptom dimensions: development and evaluation of the Dimensional Obsessive-Compulsive Scale.

Although several measures of obsessive-compulsive (OC) symptoms exist, most are limited in that they are not consistent with the most recent empirical findings on the nature and dimensional structure of obsessions and compulsions. In the present research, the authors developed and evaluated a measure called the Dimensional Obsessive-Compulsive Scale (DOCS) to address limitations of existing OC symptom measures. The DOCS is a 20-item measure that assesses the four dimensions of OC symptoms most reliably replicated in previous structural research. Factorial validity of the DOCS was supported by exploratory and confirmatory factor analyses of 3 samples, including individuals with OC disorder, those with other anxiety disorders, and nonclinical individuals. Scores on the DOCS displayed good performance on indices of reliability and validity, as well as sensitivity to treatment and diagnostic sensitivity, and hold promise as a measure of OC symptoms in clinical and research settings.

An fMRI study examining effects of acute D-cycloserine during symptom provocation in spider phobia.

BACKGROUND: Exposure-based therapy for anxiety disorders is believed to operate on the basis of fear extinction. Studies have shown acute administration of D-cycloserine (DCS) enhances fear extinction in animals and facilitates exposure therapy in humans, but the neural mechanisms are not completely understood. To date, no study has examined neural effects of acute DCS in anxiety-disordered populations. METHODS: Two hours prior to functional magnetic resonance imaging scanning, 23 spider-phobic and 23 non-phobic participants were randomized to receive DCS 100 mg or placebo. During scanning, participants viewed spider, butterfly, and Gaussian-blurred baseline images in a block-design paradigm. Diagnostic and treatment groups were compared regarding differential activations to spider versus butterfly stimuli. RESULTS: In the phobic group, DCS enhanced prefrontal (PFC), dorsal anterior cingulate (ACC), and insula activations. For controls, DCS enhanced ventral ACC and caudate activations. There was a positive correlation between lateral PFC and amygdala activation for the placebo-phobic group. Reported distress during symptom provocation was correlated with amygdala activation in the placebo-phobic group and orbitofrontal cortex activation in the DCS-phobic group. CONCLUSIONS: Results suggest that during initial phobic symptom provocation DCS enhances activation in regions involved in cognitive control and interoceptive integration, including the PFC, ACC, and insular cortices for phobic participants.

Psychopathy is related to negative affectivity but not to anxiety sensitivity.

Although the hypothesis that psychopathic individuals are characterized by a reduced capacity for experiencing anxiety is central to many theories of psychopathy, most prior studies have examined anxiety and fear measures generally considered outdated in the literature. Moreover, prior findings are mixed, with several studies reporting no relationships between psychopathy and anxiety, and others suggesting negative relationships for the affective, interpersonal aspects of the disorder and positive relationships for the antisocial behavior dimension. To examine whether psychopathy dimensions are associated with contemporary measures of anxiety, the Anxiety Sensitivity Index and State Trait Anxiety Inventory-Trait scale were administered to 157 male inmates. Participants also completed the MMPI-derived Welsh Anxiety Scale (WAS), commonly used in psychopathy studies. Analyses provide no evidence for a negative relationship between psychopathy's affective, interpersonal factor and anxiety sensitivity after controlling for trait anxiety. Trait anxiety and WAS scores were positively associated with the antisocial behavior dimension of psychopathy. Findings do replicate prior relationships between the WAS and psychopathy, suggesting the WAS may measure aspects of negative affectivity that differ from anxiety.