The DISOPRED server for the prediction of protein disorder

Dynamically disordered regions appear to be relatively abundant in eukaryotic proteomes. The DISOPRED server allows users to submit a protein sequence, and returns a probability estimate of each residue in the sequence being disordered. The results are sent in both plain text and graphical formats, and the server can also supply predictions of secondary structure to provide further structural information.

Prediction and functional analysis of native disorder in proteins from the Three Kingdoms of Life

An automatic method for recognizing natively disordered regions from amino acid sequence is described and benchmarked against predictors that were assessed at the latest critical assessment of techniques for protein structure prediction (CASP) experiment. The method attains a Wilcoxon score of 90.0, which represents a statistically significant improvement on the methods evaluated on the same targets at CASP. The classifier, DISOPRED2, was used to estimate the frequency of native disorder in several representative genomes from the three kingdoms of life. Putative, long (>30 residue) disordered segments are found to occur in 2.0% of archaean, 4.2% of eubacterial and 33.0% of eukaryotic proteins. The function of proteins with long predicted regions of disorder was investigated using the gene ontology annotations supplied with the Saccharomyces genome database. The analysis of the yeast proteome suggests that proteins containing disorder are often located in the cell nucleus and are involved in the regulation of transcription and cell signalling. The results also indicate that native disorder is associated with the molecular functions of kinase activity and nucleic acid binding.

An experimental manipulation of responsibility in children: a test of the inflated responsibility model of obsessive-compulsive disorder

The objective of this study was to investigate whether Salkovskis (1985) inflated responsibility model of obsessive-compulsive disorder (OCD) applied to children. In an experimental design, 81 children aged 9– 12 years were randomly allocated to three conditions: an inflated responsibility group, a moderate responsibility group, and a reduced responsibility group. In all groups children were asked to sort sweets according to whether or not they contained nuts. At baseline the groups did not differ on children’s self reported anxiety, depression, obsessive-compulsive symptoms or on inflated responsibility beliefs. The experimental manipulation successfully changed children’s perceptions of responsibility. During the sorting task time taken to complete the task, checking behaviours, hesitations, and anxiety were recorded. There was a significant effect of responsibility level on the behavioural variables of time taken, hesitations and check; as perceived responsibility increased children took longer to complete the task and checked and hesitated more often. There was no between-group difference in children’s self reported state anxiety. The results offer preliminary support for the link between inflated responsibility and increased checking behaviours in children and add to the small but growing literature suggesting that cognitive models of OCD may apply to children.

Local orientational disorder in peptide fibrils probed by a combination of residue-specific 13C-18O labelling, polarised infrared spectroscopy and molecular combing

A novel combination of site-specific isotope labelling, polarised infrared spectroscopy and molecular combing reveal local orientational ordering in the fibril-forming peptide YTIAALLSPYSGGRADS. Use of 13C-18O labelled alanine residues demonstrates that the Nterminal end of the peptide is incorporated into the cross-beta structure, while the C-terminal end shows orientational disorder

The time course of implicit affective picture processing: an eye movement study

Consistent with a negativity bias account, neuroscientific and behavioral evidence demonstrates modulation of even early sensory processes by unpleasant, potentially threat-relevant information. The aim of this research is to assess the extent to which pleasant and unpleasant visual stimuli presented extrafoveally capture attention and impact eye movement control. We report an experiment examining deviations in saccade metrics in the presence of emotional image distractors that are close to a nonemotional target. We additionally manipulate the saccade latency to test when the emotional distractor has its biggest impact on oculomotor control. The results demonstrate that saccade landing position was pulled toward unpleasant distractors, and that this pull was due to the quick saccade responses. Overall, these findings support a negativity bias account of early attentional control and call for the need to consider the time course of motivated attention when affect is implicit

Mental contamination in obsessive–compulsive disorder

It was recently proposed that feelings of contamination can arise in the absence of physical contact with a contaminant. Currently, there are limited data regarding this construct of ‘mental contamination’ although it is hypothesised to be relevant to obsessive compulsive disorder(OCD) where compulsive washing in response to contamination fear is a common presentation (Rachman,2006). This research examined the presence of mental contamination in OCD. Participants (N=177) with obsessive compulsive symptoms completed questionnaires to assess mental contamination, OCD symptoms and thought-action fusion (TAF). Findings indicated that 46% of participants experienced mental contamination, and severity was associated with severity of OCD symptoms and TAF. Mental contamination in the absence of contact contamination was reported by 10.2% of participants. Similar findings were reported in a sub-sample of participants who had received a formal diagnosis of OCD (N=54). These findings suggest that mental contamination is a distinct construct that overlaps with, but is separate from, contact contamination, and provide preliminary empirical support for the construct.

Whole-brain functional connectivity during emotional word classification in medication-free Major Depressive Disorder: abnormal salience circuitry and relations to positive emotionality

Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n=25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject’s connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic-cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.

Are informed citizens more trusting? Transparency of performance data and trust towards a British police force

In Britain, substantial cuts in police budgets alongside controversial handling of incidents such as politically sensitive enquiries, public disorder and relations with the media have recently triggered much debate about public knowledge and trust in the police. To date, however, little academic research has investigated how knowledge of police performance impacts citizens’ trust. We address this long-standing lacuna by exploring citizens’ trust before and after exposure to real performance data in the context of a British police force. The results reveal that being informed of performance data affects citizens’ trust significantly. Furthermore, direction and degree of change in trust are related to variations across the different elements of the reported performance criteria. Interestingly, the volatility of citizens’ trust is related to initial performance perceptions (such that citizens with low initial perceptions of police performance react more significantly to evidence of both good and bad performance than citizens with high initial perceptions), and citizens’ intentions to support the police do not always correlate with their cognitive and affective trust towards the police. In discussing our findings, we explore the implications of how being transparent with performance data can both hinder and be helpful in developing citizens’ trust towards a public organisation such as the police. From our study, we pose a number of ethical challenges that practitioners face when deciding what data to highlight, to whom, and for what purpose.

The role of temperament and family environment in the development of anxiety disorder: two-year follow-up

Objective Behavioural inhibition (BI) in early childhood is associated with increased risk for anxiety. The present research examines BI alongside family environment factors, specifically maternal negativity and overinvolvement, maternal anxiety and mother-child attachment, with a view to providing a broader understanding of the development of child anxiety. Method Participants were 202 children classified at age 4 as either behaviourally inhibited (N=102) or uninhibited (N=100). Family environment, BI and child anxiety were assessed at baseline and child anxiety and BI were assessed again two-years later when participants were aged 6 years. Results After controlling for baseline anxiety, inhibited participants were significantly more likely to meet criteria for a diagnosis of social phobia and generalized anxiety disorder at follow-up. Path analysis suggested that maternal anxiety significantly affected child anxiety over time, even after controlling for the effects of BI and baseline anxiety. No significant paths from parenting or attachment to child anxiety were found. Maternal overinvolvement was significantly associated with BI at follow-up. Conclusions At age 4, BI, maternal anxiety and child anxiety represent risk factors for anxiety at age 6. Furthermore, overinvolved parenting increases risk for BI at age 6, which may then lead to the development of anxiety in later childhood.

Psychopathology in Williams Syndrome: the effect of individual differences across the life span

The present research aimed to comprehensively explore psychopathology in Williams syndrome (WS) across the lifespan and evaluate the relationship between psychopathology and age category (child or adult), gender and cognitive ability. The parents of 50 participants with WS, aged 6-50 years, were interviewed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS-PL). The prevalence of a wide range of Axis I DSM-IV disorders was assessed. In addition to high rates of anxiety and Attention Deficit Hyperactivity Disorder (ADHD) (38% and 20% respectively), 14% of our sample met criteria for a depressive disorder and 42% of participants were not experiencing any significant psychopathological difficulties. There was some evidence for different patterns of psychopathology between children and adults with WS and between males and females. These relationships were largely in keeping with those found in the typically developing population, thus supporting the validity of applying theory and treatment approaches for psychopathology in the typically developing population to WS.

Resting state cortico-thalamic-striatal connectivity predicts pesponse to dorsomedial prefrontal rTMS in major depressive disorder

Despite its high toll on society, there has been little recent improvement in treatment efficacy for Major Depressive Disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting state functional connectivity predicted response to treatment with rapid transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased sgACC-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Randomized controlled trial of parent-enhanced CBT compared with individual CBT for obsessive-compulsive disorder in young people

Objective: Obsessive-compulsive disorder (OCD) in young people can be effectively treated with Cognitive Behavior Therapy (CBT). Practice guidelines in the United Kingdom recommend that CBT be delivered with parental or family involvement; however, there is no evidence from randomized trials that this enhances effectiveness. The aim of this trial was to assess if CBT with high parental involvement was more effective than CBT with low parental involvement (individual CBT) in reducing symptoms of OCD. Method: Fifty young people ages 12–17 years with OCD were randomly allocated to individual CBT or parent-enhanced CBT. In parent-enhanced CBT parents attended all treatment sessions; in individual CBT, parents attended only Sessions 1, 7, and the final session. Participants received up to 14 sessions of CBT. Data were analyzed using intent-to-treat and per-protocol methods. The primary outcome measure was the Children’s Yale-Brown Obsessive Compulsion Scale (Scahill et al., 1997). Results: Both forms of CBT significantly reduced symptoms of OCD and anxiety. Change in OCD symptoms was maintained at 6 months. Per-protocol analysis suggested that parent-enhanced CBT may be associated with significantly larger reductions in anxiety symptoms. Conclusions: High and low parental involvement in CBT for OCD in young people were both effective, and there was no evidence that 1 method of delivery was superior on the primary outcome measure. However, this study was small. Future trials should be adequately powered and examine interactions with the age of the young person and comorbid anxiety disorders.

Expression of the Rap1 guanine nucleotide exchange factor, MR-GEF, is altered in individuals with bipolar disorder

In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission.

Substitutional and orientational disorder in organic crystals: a symmetry-adapted ensemble model

Modelling of disorder in organic crystals is highly desirable since it would allow thermodynamic stabilities and other disorder-sensitive properties to be estimated for such systems. Two disordered organic molecular systems are modeled using a symmetry-adapted ensemble approach, in which the disordered system is treated as an ensemble of the configurations of a supercell with respect to substitution of one disorder component for another. Computation time is kept manageable by performing calculations only on the symmetrically inequivalent configurations. Calculations are presented on a substitutionally disordered system, the dichloro/dibromobenzene solid solution, and on an orientationally disordered system, eniluracil, and the resultant free energies, disorder patterns, and system properties are discussed. The results are found to be in agreement with experiment following manual removal of physically implausible configurations from ensemble averages, highlighting the dangers of a completely automated approach to organic crystal thermodynamics which ignores the barriers to equilibration once the crystal has been formed.

Examining vulnerability to involuntary memories in schizophrenia comorbid with post-traumatic stress disorder

The current study explored whether individuals diagnosed with schizophrenia and a high level of PTSD symptoms experience more frequent neutral intrusive memories than individuals diagnosed with schizophrenia with low level PTSD symptoms. Results supported a vulnerability to neutral intrusive memories within the comorbid group, which did not seem to be related to psychotic symptom severity. It is possible that a subgroup of psychotic individuals’ process information in a manner that make them susceptible to frequent intrusive memories, characteristic of a PTSD presentation. A longitudinal study is required to specify the development of this vulnerability so as to inform future interventions.