The present meta-analysis synthesizes the emerging literature on the relationship of Big Five personality traits to autism spectrum disorder. Studies were included if they (1) either (a) measured ...autism spectrum disorder characteristics using a metric that yielded a single score quantification of the magnitude of autism spectrum disorder characteristics and/or (b) studied individuals with an autism spectrum disorder diagnosis compared to individuals without an autism spectrum disorder diagnosis and (2) measured Big Five traits in the same sample or samples. Fourteen reviewed studies include both correlational analyses and group comparisons. Eighteen effect sizes per Big Five trait were used to calculate two overall effect sizes per trait. Meta-analytic effects were calculated using random effects models. Twelve effects (per trait) from nine studies reporting correlations yielded a negative association between each Big Five personality trait and autism spectrum disorder characteristics (Fisher’s z ranged from –.21 (conscientiousness) to –.50 (extraversion)). Six group contrasts (per trait) from six studies comparing individuals diagnosed with autism spectrum disorder to neurotypical individuals were also substantial (Hedges’ g ranged from –.88 (conscientiousness) to −1.42 (extraversion)). The potential impact of personality on important life outcomes and new directions for future research on personality in autism spectrum disorder are discussed in light of results.
Mechanical Properties of Nanoscopic Lipid Domains Nickels, Jonathan D; Cheng, Xiaolin; Mostofian, Barmak ...
Journal of the American Chemical Society,
12/2015, Letnik:
137, Številka:
50
Journal Article
Recenzirano
Odprti dostop
The lipid raft hypothesis presents insights into how the cell membrane organizes proteins and lipids to accomplish its many vital functions. Yet basic questions remain about the physical mechanisms ...that lead to the formation, stability, and size of lipid rafts. As a result, much interest has been generated in the study of systems that contain similar lateral heterogeneities, or domains. In the current work we present an experimental approach that is capable of isolating the bending moduli of lipid domains. This is accomplished using neutron scattering and its unique sensitivity to the isotopes of hydrogen. Combining contrast matching approaches with inelastic neutron scattering, we isolate the bending modulus of ∼13 nm diameter domains residing in 60 nm unilamellar vesicles, whose lipid composition mimics the mammalian plasma membrane outer leaflet. Importantly, the bending modulus of the nanoscopic domains differs from the modulus of the continuous phase surrounding them. From additional structural measurements and all-atom simulations, we also determine that nanoscopic domains are in-register across the bilayer leaflets. Taken together, these results inform a number of theoretical models of domain/raft formation and highlight the fact that mismatches in bending modulus must be accounted for when explaining the emergence of lateral heterogeneities in lipid systems and biological membranes.
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. ...Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the
FUS
gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies.
Particle design via spherical agglomeration is a size enlargement technique used in various bulk and fine chemical industries, with recent interest extending into pharmaceuticals, in which an ...immiscible bridging liquid is added to agglomerate crystals prior to deliquoring. Spherical agglomeration has the potential to dramatically simplify downstream processing, and improves the handling of difficult, needle-shaped crystals. This review consolidates the understanding of the controlling process parameters, identifies the rate processes that control agglomerate attributes, and examines the modelling approaches taken in the literature to optimise the design of such systems. The most important controlling parameters are solvent system composition (requiring knowledge of the ternary phase diagram) and bridging liquid to solid ratio (BSR). Agglomerate size is a highly non-linear function of BSR with many literature systems showing qualitatively similar behaviour. However, there is no method to predict the optimum BSR. Other important process parameters are temperature, constituent particle properties, agitation rate and batch/residence time. Each parameter can have significant effects on the final agglomerate properties including agglomerate size, porosity, strength and dissolution profile.
The rate processes in spherical agglomeration are analogous to those in wet granulation. A general classification of rate processes is proposed in this review including nucleation by distribution or immersion, consolidation, coalescence, layered growth and breakage. While many papers give proof of concept examples of spherical agglomeration for specific systems, only a few have focused explicitly on mechanistic understanding. There is significant scope for further work to quantify the effect of both process parameters and formulation properties on these rate processes. Recent developments in on-line monitoring using process analytical technologies (PAT) should enable these studies.
Using the mechanistic understanding, population balance models can be developed to include kernels for each of the relevant rate processes. Such models should be powerful tools of process optimisation and model driven design with reduced experiments at all scales.
Rate processes occurring during spherical agglomeration. Display omitted
•A critical review of spherical agglomeration•Understanding of controlling parameters summarised•Identification and classification of key rate processes•Current state of modelling approaches described•A frame work for future research identified
Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, ...behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4-9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4-9 months.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Limited reference values exist for visceral adipose tissue (VAT) mass measured by DXA. The objectives of this study were to provide reference values for DXA-derived VAT mass and compare the ...association with anthropometry measures. The study cohort comprised 677 men and 738 women aged 18-65 years from Western Australia. Whole-body scans using a GE Lunar iDXA and anthropometry measures were collected. Reference percentile data were stratified by sex and age. Correlation analysis compared DXA-derived and anthropometry variables. Specificity, sensitivity, and Youden's Index were used to evaluate the ability of anthropometric thresholds to predict individuals with high VAT. In men, waist circumference (WC), waist-hip ratio, and waist-height ratio (WHtR) had 'high' correlations with VAT mass. In women, only WHtR was 'highly' correlated with VAT mass. Overweight thresholds for WC, along with a body mass index of 25.0 kg/m
in women, had the highest combination of sensitivity and specificity when using anthropometry measures to identify individuals with high VAT mass. We provide the first reference data sets for DXA-derived VAT mass among Western Australians. Excessive VAT mass may be identified in men using the overweight WC threshold and in women using both the overweight BMI and WC thresholds.
High density lipoprotein (HDL) is the major atheroprotective particle in plasma. Recent studies demonstrate that myeloperoxidase (MPO) binds to HDL in vivo, selectively targeting apolipoprotein A1 ...(apoA1) of HDL for oxidative modification and concurrent loss in cholesterol efflux and lecithin cholesterol acyl transferase activating activities, generating a “dysfunctional HDL” particle. We now show that (patho)physiologically relevant levels of MPO-catalyzed oxidation result in loss of non-cholesterol efflux activities of HDL including anti-apoptotic and anti-inflammatory functions. One mechanism responsible is shown to involve the loss of modified HDL binding to the HDL receptor, scavenger receptor B1, and concurrent acquisition of saturable and specific binding to a novel unknown receptor independent of scavenger receptors CD36 and SR-A1. HDL modification by MPO is further shown to confer pro-inflammatory gain of function activities as monitored by NF-κB activation and surface vascular cell adhesion molecule levels on aortic endothelial cells exposed to MPO-oxidized HDL. The loss of non-cholesterol efflux activities and the gain of pro-inflammatory functions requires modification of the entire particle and can be recapitulated by oxidation of reconstituted HDL particles comprised of apoA1 and nonoxidizable phosphatidylcholine species. Multiple site-directed mutagenesis studies of apoA1 suggest that the pro-inflammatory activity of MPO-modified HDL does not involve methionine, tyrosine, or tryptophan, oxidant-sensitive residues previously mapped as sites of apoA1 oxidation within human atheroma. Thus, MPO-catalyzed oxidation of HDL results not only in the loss of classic atheroprotective reverse cholesterol transport activities of the lipoprotein but also both the loss of non-cholesterol efflux related activities and the gain of pro-inflammatory functions.
Multiple eukaryotic ribosomal proteins (RPs) are co-opted for extraribosomal “moonlighting” activities, but paradoxically, RPs exhibit rapid turnover when not ribosome-bound. In one illustrative case ...of a functional extraribosomal RP, interferon (IFN)-γ induces ribosome release of L13a and assembly into the IFN-gamma-activated inhibitor of translation (GAIT) complex for translational control of a subset of inflammation-related proteins. Here we show GAPDH functions as a chaperone, shielding newly released L13a from proteasomal degradation. However, GAPDH protective activity is lost following cell treatment with oxidatively modified low density lipoprotein and IFN-γ. These agonists stimulate S-nitrosylation at Cys247 of GAPDH, which fails to interact with L13a, causing proteasomal degradation of essentially the entire cell complement of L13a and defective translational control. Evolution of extraribosomal RP activities might require coevolution of protective chaperones, and pathological disruption of either protein, or their interaction, presents an alternative mechanism of diseases due to RP defects, and targets for therapeutic intervention.
Display omitted
► GAPDH acts as a shield, protecting free ribosomal protein L13a from degradation ► Condition-dependent degradation of an extraribosomal ribosomal protein ► S-Nitrosylation of GAPDH at Cys247 suppresses its protective activity ► Degradation of unprotected L13a inactivates GAIT system and induces VEGF-A expression
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