Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D-1 receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia.

Cytokine pathway disruption in a mouse model of schizophrenia induced by Munc18-1a overexpression in the brain

Background: An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. Methods: Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. Results: Each cytokine evaluated (Interferon-gamma (IFN-gamma), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-alpha and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-kappa B)p65 levels were not different between the groups. Interleukin-1beta (IL-1 beta) and IL-6 levels were beneath detection limits. Conclusions: The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder.

Caracterización de las proteínas del complejo SNARE en esquizofrenia y su tratamiento

248 p.

The application of the statutory derivative action in Pt 2F.1A of the Corporations Act to companies in liquidation under Ch 5 : Well oiled machine or is Pt 2F.1A in need of a tune up?

The statutory derivative action was introduced in Australia in 2000. This right of action has been debated in the literature and introduced in a number of other jurisdictions as well. However, it is by no means clear that all issues have been resolved despite its operation in Australia for over 10 years. This article considers the application of Pt 2F.1A of the Corporations Act to companies in liquidation under Ch 5. It demonstrates that the application involves consideration of not only proper statutory interpretation but also policy matters around the role and the supervision by the court of a liquidator once a company has entered liquidation.

Director liability for uncommercial transactions : is s 588G(1A) impotent to provide liquidators the means to seek compensation for creditors?

In the 10 years since the addition of uncommercial transactions to the table of deemed “debts incurred” in s 588G(1A) of the Corporations Act, the sub-section has arguably achieved little. This article explains why this has been so, and what needs to be done to enable this aspect of Australia’s insolvent trading laws to operate effectively and as originally intended.

Association between endometriosis and the interleukin 1A (IL1A) locus

STUDY QUESTION Are single-nucleotide polymorphisms (SNPs) at the interleukin 1A (IL1A) gene locus associated with endometriosis risk? SUMMARY ANSWER We found evidence for strong association between IL1A SNPs and endometriosis risk. WHAT IS KNOWN ALREADY Genetic factors contribute substantially to the complex aetiology of endometriosis and the disease has an estimated heritability of ∼51%. We, and others, have conducted genome-wide association (GWA) studies for endometriosis, which identified a total of nine independent risk loci. Recently, two small Japanese studies reported eight SNPs (rs6542095, rs11677416, rs3783550, rs3783525, rs3783553, rs2856836, rs1304037 and rs17561) at the IL1A gene locus as suggestively associated with endometriosis risk. There is also evidence of a link between inflammation and endometriosis. STUDY DESIGN, SIZE, DURATION We sought to further investigate the eight IL1A SNPs for association with endometriosis using an independent sample of 3908 endometriosis cases and 8568 controls of European and Japanese ancestry. The study was conducted between October 2013 and July 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS By leveraging GWA data from our previous multi-ethnic GWA meta-analysis for endometriosis, we imputed variants in the IL1A region, using a recent 1000 Genomes reference panel. After combining summary statistics for the eight SNPs from our European and Japanese imputed data with the published results, a fixed-effect meta-analysis was performed. An additional meta-analysis restricted to endometriosis cases with moderate-to-severe (revised American Fertility Society stage 3 or 4) disease versus controls was also performed. MAIN RESULTS AND THE ROLE OF CHANCE All eight IL1A SNPs successfully replicated at P < 0.014 in the European imputed data with concordant direction and similar size to the effects reported in the original Japanese studies. Of these, three SNPs (rs6542095, rs3783550 and rs3783525) also showed association with endometriosis at a nominal P < 0.05 in our independent Japanese sample. Fixed-effect meta-analysis of the eight SNPs for moderate-to-severe endometriosis produced a genome-wide significant association for rs6542095 (odds ratio = 1.21; 95% confidence interval = 1.13–1.29; P = 3.43 × 10−8). LIMITATIONS, REASONS FOR CAUTION The meta-analysis for moderate-to-severe endometriosis included results of moderate-to-severe endometriosis cases from our European data sets and all endometriosis cases from the Japanese data sets, as disease stage information was not available for endometriosis cases in the Japanese data sets. WIDER IMPLICATIONS OF THE FINDINGS SNP rs6542095 is located ∼2.3 kb downstream of the IL1A gene and ∼6.9 kb upstream of cytoskeleton-associated protein 2-like (CKAP2L) gene. The IL1A gene encodes the IL1a protein, a member of the interleukin 1 cytokine family which is involved in various immune responses and inflammatory processes. These results provide important replication in an independent Japanese sample and, for the first time, association of the IL1A locus in endometriosis patients of European ancestry. SNPs within the IL1A locus may regulate other genes, but if IL1A is the target, our results provide supporting evidence for a link between inflammatory responses and the pathogenesis of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The research was funded by grants from the Australian National Health and Medical Research Council and Wellcome Trust. None of the authors has competing interests for the study.

Timing and broad-band spectroscopy of 1A 1118-61 with Suzaku

We present a timing and broad-band pulse-phase-resolved spectral analysis of the transient Be X-ray binary pulsar 1A 1118-61 observed during its outburst in 2009 January using Suzaku observations. The Suzaku observations were made twice, once at the peak of the outburst, and the other 13 d later at its declining phase. Pulse profiles from both observations exhibit strong energy dependence with several peaks at low energies and a single peak above similar to 10 keV. A weak, narrow peak is detected at the main dip of the pulse profiles from both observations in the energy bands below 3 keV, indicating the presence of a phase-dependent soft excess in the source continuum. The broad-band energy spectrum of the pulsar could be fitted well with a partial covering cut-off power-law model and a narrow iron fluorescence line. We also detect a broad cyclotron feature at similar to 50 keV from both observations which is a feature common for accretion-powered pulsars with high magnetic field strength. The pulse-phase-resolved spectral analysis shows an increase in the absorption column density of the partial covering component, as well as variation in the covering fraction at the dips of the pulse profiles, which naturally explains energy dependence of the same. The cyclotron line parameters also show significant variation with pulse phase with an similar to 10 keV variation in the cyclotron line energy and a variation in depth by a factor of 3. This can be explained either as the effect of different viewing angles of the dipole field at different pulse phases, or due to a more complex underlying magnetic field geometry.

Differential dynamics of the serotonin(1A) receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation

The serotonin(1A) receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin(1A) receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3s, to analyze the effect of cholesterol on the structure and dynamics of the serotonin(1A) receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin(1A) receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.

Taller Integrado 1A (Proyectos I, Dibujo Arquitectónico I, Análisis Constructivo I)

Nivel educativo: Grado. Duración (en horas): De 41 a 50 horas

Systematics of central heavy ion collisions in the 1A GeV regime

Using the large acceptance apparatus FOPI, we study central collisions in the reactions (energies in A GeV are given in parentheses): Ca-40 + Ca-40 (0.4, 0.6, 0.8, 1.0, 1.5, 1.93), Ni-58 + Ni-58 (0.15, 0.25, 0.4), Ru-96+Ru-96 (0.4, 1.0. 1.5), (96)zr+(96)zr 1.0, 1.5), Xe-129+CsI (0.15, 0.25, 0.4), Au-197 + Au-197 (0.09, 0.12, 0.15, 0.25, 0.4, 0.6, 0.8, 1.0, 1.2, 1.5). The observables include cluster multiplicities, longitudinal and transverse rapidity distributions and stopping, and radial flow. The data are compared to earlier data where possible and to transport model simulations. (C) 2010 Elsevier B.V. All rights reserved.

Dynamics of pion production in heavy-ion collisions around 1A GeV energies

Within the framework of the improved isospin-dependent quantum molecular dynamics model, the dynamics of pion emission in heavy-ion collisions in the region of 1A GeV energies as a probe of nuclear symmetry energy at suprasaturation densities is investigated systematically. The total pion multiplicities and the pi(-)/pi(+) yields are calculated for selected Skyrme parameters SkP, SLy6, Ska, and SIII and also for the cases of different stiffness of symmetry energy with the parameter SLy6. The influence of Coulomb potential, symmetry energy, and in-medium pion potential on the pion production is investigated and compared to each other by analyzing the distributions of transverse momentum and longitudinal rapidity and also the excitation functions of the total pion and the pi(-)/pi(+) ratio. The directed flow, elliptic flow, and polar-angle distributions are calculated for the cases of different collision centralities and also the various stiffnesses of the symmetry energies. A comparison of the calculations with the available experimental data is performed.

VD-1A型X射线衍射仪电流稳定器的故障排除

以故障实例详细地叙述了岛津VD-1A型X射线衍射仪电流稳定器系统的故障分析及排除方法。

VD-1A型X射线衍射仪信号检测系统故障检修一例

本文以故障实例详细介绍了岛津VD－IA型x社线1行射议信号检测系统一种典型故障的分析及排除方法。

VD-1A型X射线衍射仪冷却循环水系统故障分析及排除

介绍了岛津ＶＤ＿１Ａ型Ｘ射线衍射仪冷却循环水系统的故障分析及排除方法。