Macromolecular crowding modulates folding mechanism of alpha/beta protein apoflavodoxin

Protein dynamics in cells may be different from that in dilute solutions in vitro since the environment in cells is highly concentrated with other macromolecules. This volume exclusion due to macromolecular crowding is predicted to affect both equilibrium and kinetic processes involving protein conformational changes. To quantify macromolecular crowding effects on protein folding mechanisms, here we have investigated the folding energy landscape of an alpha/beta protein, apoflavodoxin, in the presence of inert macromolecular crowding agents using in silico and in vitro approaches. By coarse-grained molecular simulations and topology-based potential interactions, we probed the effects of increased volume fraction of crowding agents (phi_c) as well as of crowding agent geometry (sphere or spherocylinder) at high phi_c. Parallel kinetic folding experiments with purified Desulfovibro desulfuricans apoflavodoxin in vitro were performed in the presence of Ficoll (sphere) and Dextran (spherocylinder) synthetic crowding agents. In conclusion, we have identified in silico crowding conditions that best enhance protein stability and discovered that upon manipulation of the crowding conditions, folding routes experiencing topological frustrations can be either enhanced or relieved. The test-tube experiments confirmed that apoflavodoxin's time-resolved folding path is modulated by crowding agent geometry. We propose that macromolecular crowding effects may be a tool for manipulation of protein folding and function in living cells.Comment: to appear in Biophysical Journal (2009). to appear in Biophysical Journal (2009

Autistic Disorders and Schizophrenia: Related or Remote? An Anatomical Likelihood Estimation

Shared genetic and environmental risk factors have been identified for autistic spectrum disorders (ASD) and schizophrenia. Social interaction, communication, emotion processing, sensorimotor gating and executive function are disrupted in both, stimulating debate about whether these are related conditions. Brain imaging studies constitute an informative and expanding resource to determine whether brain structural phenotype of these disorders is distinct or overlapping. We aimed to synthesize existing datasets characterizing ASD and schizophrenia within a common framework, to quantify their structural similarities. In a novel modification of Anatomical Likelihood Estimation (ALE), 313 foci were extracted from 25 voxel-based studies comprising 660 participants (308 ASD, 352 first-episode schizophrenia) and 801 controls. The results revealed that, compared to controls, lower grey matter volumes within limbic-striato-thalamic circuitry were common to ASD and schizophrenia. Unique features of each disorder included lower grey matter volume in amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for autism. Thus, in terms of brain volumetrics, ASD and schizophrenia have a clear degree of overlap that may reflect shared etiological mechanisms. However, the distinctive neuroanatomy also mapped in each condition raises the question about how this is arrived in the context of common etiological pressures

Distinct patterns of grey matter abnormality in high-functioning autism and Asperger's syndrome

Background: Autism exists across a wide spectrum and there is considerable debate as to whether children with Asperger's syndrome, who have normal language milestones, should be considered to comprise a subgroup distinct other from high-functioning children with autism (HFA), who have a history of delayed language development. Magnetic resonance imaging (MRI) studies of autism are in disagreement. One possible reason is that the diagnosis of autism takes precedence over Asperger's syndrome and a distinction in language acquisition is rarely made. We therefore planned to examine a whole brain hypothesis that the patterns of grey matter differences in Asperger's syndrome and HFA can be distinguished. Methods: We used voxel-based computational morphometry to map grey matter volume differences in 33 children with either Asperger's syndrome or high-functioning autism compared to 55 typical developing control children balanced for age, IQ, gender, maternal language and ethnicity. Results: Children with HFA had significantly smaller grey matter volumes in subcortical, posterior cingulate and precuneus regions than the Asperger's group. Compared to controls, children with HFA had smaller grey matter volumes in predominantly fronto-pallidal regions, while children with Asperger's had less grey matter in mainly bilateral caudate and left thalamus. In addition we found a significant negative correlation between the size of a grey matter cluster around BA44 language area and the age of acquisition of phrase speech in the children with HFA. When the groups were combined we confirmed a mixed picture of smaller grey matter volumes in frontal, basal ganglia, temporal and parietal regions. Conclusions: Our study suggests that the underlying neurobiology in HFA and Asperger's syndrome is at least partly discrete. Future studies should therefore consider the history of language acquisition as a valuable tool to refine investigation of aetiological factors and management options in pervasive developmental disorders

Are Bipolar Disorder and Schizophrenia Neuroanatomically Distinct? An Anatomical Likelihood Meta-analysis

Objective: There is renewed debate on whether modern diagnostic classification should adopt a dichotomous or dimensional approach to schizophrenia and bipolar disorder. This study synthesizes data from voxel-based studies of schizophrenia and bipolar disorder to estimate the extent to which these conditions have a common neuroanatomical phenotype. Methods: A post-hoc meta-analytic estimation of the extent to which bipolar disorder, schizophrenia, or both conditions contribute to brain gray matter differences compared to controls was achieved using a novel application of the conventional anatomical likelihood estimation (ALE) method. 19 schizophrenia studies (651 patients and 693 controls) were matched as closely as possible to 19 bipolar studies (540 patients and 745 controls). Result: Substantial overlaps in the regions affected by schizophrenia and bipolar disorder included regions in prefrontal cortex, thalamus, left caudate, left medial temporal lobe, and right insula. Bipolar disorder and schizophrenia jointly contributed to clusters in the right hemisphere, but schizophrenia was almost exclusively associated with additional gray matter deficits (left insula and amygdala) in the left hemisphere. Limitation: The current meta-analytic method has a number of constraints. Importantly, only studies identifying differences between controls and patient groups could be included in this analysis. Conclusion: Bipolar disorder shares many of the same brain regions as schizophrenia. However, relative to neurotypical controls, lower gray matter volume in schizophrenia is more extensive and includes the amygdala. This fresh application of ALE accommodates multiple studies in a relatively unbiased comparison. Common biological mechanisms may explain the neuroanatomical overlap between these major disorders, but explaining why brain differences are more extensive in schizophrenia remains challenging

Self-concept clarity, social support, and compulsive internet use: a study of the US and the UAE

Compulsive Internet Use (CIU) has been mostly studied among adolescents, yet some studies reveal that this can be a problem for the adult population, too. The lack of agreement on diagnostic tools and cut-off points results in markedly different prevalence figures. Building on Charlton’s (2002) distinction between core CIU and positive engagement dimensions, the first objective was to confirm that prevalence figures including the core dimensions of CIU were lower than those including the engagement dimensions as well. Second, building on Davis’s (2001) diathesis-stress model, we tested the role that self-concept clarity (SCC) and social support play in predicting core CIU in US subjects (NUS = 268). Finally, we expected that, because self-concept clarity is mostly linked to well-being in Western countries, the association between this variable and core CIU would be weak in the Eastern culture sample (NUAE = 270). Our findings confirmed that prevalence figures were 20–40% lower when including the core dimensions only, and that SCC is a key predictor of CIU at low levels of social support in the US. We also confirmed that this is not the case in the UAE. Future research opportunities to advance this study were discussed

Discovering the structure and organization of a free Cantonese emotion-label word association graph to understand mental lexicons of emotions

Emotions are not necessarily universal across different languages and cultures. Mental lexicons of emotions depend strongly on contextual factors, such as language and culture. The Chinese language has unique linguistic properties that are different from other languages. As a main variant of Chinese, Cantonese has some emotional expressions that are only used by Cantonese speakers. Previous work on Chinese emotional vocabularies focused primarily on Mandarin. However, little is known about Cantonese emotion vocabularies. This is important since both language variants might have distinct emotional expressions, despite sharing the same writing system. To explore the structure and organization of Cantonese-label emotion words, we selected 79 highly representative emotion cue words from an ongoing large-scale Cantonese word association study (SWOW-HK). We aimed to identify the categories of these emotion words and non-emotion words that related to emotion concepts. Hierarchical cluster analysis was used to generate word clusters and investigate the underlying emotion dimensions. As the cluster quality was low in hierarchical clustering, we further constructed an emotion graph using a network approach to explore how emotions are organized in the Cantonese mental lexicon. With the support of emotion knowledge, the emotion graph defined more distinct emotion categories. The identified network communities covered basic emotions such as love, happiness, and sadness. Our results demonstrate that mental lexicon graphs constructed from free associations of Cantonese emotion-label words can reveal fine categories of emotions and their relevant concepts

The default mode network is disrupted in Parkinson's disease with visual hallucinations.

BACKGROUND: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinson's disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. METHODS: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. RESULTS: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. CONCLUSION: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher "connectivity" is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to "positive" symptom generation in PD.Contract grant sponsor: Research Grant Council of Hong Kong (General Research Fund awarded to Chua and McAlonan); Infrastructural support: National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and [Institute of Psychiatry] King's College London (McAlonan); Wellcome Trust; Contract grant number: 088324 (Rowe); National Institute for Health Research Cambridge Biomedical Research Centre (Suckling).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/hbm.2257

Examining the predictability of the Stratospheric Sudden Warming of January 2013 using multiple NWP systems

The first multi-model study to estimate the predictability of a boreal Sudden Stratospheric Warming (SSW) is performed using five NWP systems. During the 2012-2013 boreal winter, anomalous upward propagating planetary wave activity was observed towards the end of December, which followed by a rapid deceleration of the westerly circulation around 2 January 2013, and on 7 January 2013 the zonal mean zonal wind at 60°N and 10 hPa reversed to easterly. This stratospheric dynamical activity was followed by an equatorward shift of the tropospheric jet stream and by a high pressure anomaly over the North Atlantic, which resulted in severe cold conditions in the UK and Northern Europe. In most of the five models, the SSW event was predicted 10 days in advance. However, only some ensemble members in most of the models predicted weakening of westerly wind when the models were initialized 15 days in advance of the SSW. Further dynamical analysis of the SSW shows that this event was characterized by the anomalous planetary wave-1 amplification followed by the anomalous wave-2 amplification in the stratosphere, which resulted in a split vortex occurring between 6 January 2013 and 8 January 2013. The models have some success in reproducing wave-1 activity when initialized 15 days in advance, they but generally failed to produce the wave-2 activity during the final days of the event. Detailed analysis shows that models have reasonably good skill in forecasting tropospheric blocking features that stimulate wave-2 amplification in the troposphere, but they have limited skill in reproducing wave-2 amplification in the stratosphere

microRNA-seq of cartilage reveals an over-abundance of miR-140-3p which contains functional isomiRs

miR-140 is selectively expressed in cartilage. Deletion of the entire Mir140 locus in mice results in growth retardation and early-onset osteoarthritis-like pathology; however, the relative contribution of miR-140-5p or miR-140-3p to the phenotype remains to be determined. An unbiased small RNA sequencing approach identified miR-140-3p as significantly more abundant (>10-fold) than miR-140-5p in human cartilage. Analysis of these data identified multiple miR-140-3p isomiRs differing from the miRBase annotation at both the 5' and 3' end, with >99% having one of two seed sequences (5' bases 2-8). Canonical (miR-140-3p.2) and shifted (miR-140-3p.1) seed isomiRs were overexpressed in chondrocytes and transcriptomics performed to identify targets. miR-140-3p.1 and miR-140-3p.2 significantly down-regulated 694 and 238 genes, respectively, of which only 162 genes were commonly down-regulated. IsomiR targets were validated using 3'UTR luciferase assays. miR-140-3p.1 targets were enriched within up-regulated genes in rib chondrocytes of Mir140- null mice and within down-regulated genes during human chondrogenesis. Finally, through imputing the expression of miR-140 from the expression of the host gene WWP2 in 124 previously published data sets, an inverse correlation with miR-140-3p.1 predicted targets was identified. Together these data suggest the novel seed containing isomiR miR-140- 3p.1 is more functional than original consensus miR-140-3p seed containing isomiR

Validation of the Internet Gaming Disorder Scale – Short-Form (IGDS9-SF) in an Italian-speaking sample

Background and aims: The inclusion of Internet Gaming Disorder (IGD) in Section III of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders has increased the interest of researchers in the development of new standardized psychometric tools for the assessment of such a disorder. To date, the nine-item Internet Gaming Disorder Scale – Short-Form (IGDS9-SF) has only been validated in English, Portuguese, and Slovenian languages. Therefore, the aim of this investigation was to examine the psychometric properties of the IGDS9-SF in an Italian speaking sample. Methods: A total of 757 participants were recruited to the present study. Confirmatory factor analysis and multi-group analyses were applied to assess the construct validity. Reliability analyses comprised the average variance extracted, the standard error of measurement, and the factor determinacy coefficient. Convergent and criterion validities were established through the associations with other related constructs. The receiver operating characteristic curve analysis was used to determine an empirical cut-off point. Results: Findings confirmed the single factor structure of the instrument, its measurement invariance at the configural level, and the convergent and criterion validities. Satisfactory levels of reliability and a cut-off point of 21 were obtained. Discussion and conclusions: The present study provides validity evidence for the use of the Italian version of the IGDS9-SF and may foster research into gaming addiction in the Italian context