ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

© 2015 Springer-Verlag Berlin Heidelberg.Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Results: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2∈=∈0.68, p∈=∈0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. Conclusions: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials

A possible method for non-Hermitian and non-PTPT-symmetric Hamiltonian systems

A possible method to investigate non-Hermitian Hamiltonians is suggested through finding a Hermitian operator $\eta_+$ and defining the annihilation and creation operators to be $\eta_+$-pseudo-Hermitian adjoint to each other. The operator $\eta_+$ represents the $\eta_+$-pseudo-Hermiticity of Hamiltonians. As an example, a non-Hermitian and non-$PT$-symmetric Hamiltonian with imaginary linear coordinate and linear momentum terms is constructed and analyzed in detail. The operator $\eta_+$ is found, based on which, a real spectrum and a positive-definite inner product, together with the probability explanation of wave functions, the orthogonality of eigenstates, and the unitarity of time evolution, are obtained for the non-Hermitian and non-$PT$-symmetric Hamiltonian. Moreover, this Hamiltonian turns out to be coupled when it is extended to the canonical noncommutative space with noncommutative spatial coordinate operators and noncommutative momentum operators as well. Our method is applicable to the coupled Hamiltonian. Then the first and second order noncommutative corrections of energy levels are calculated, and in particular the reality of energy spectra, the positive-definiteness of inner products, and the related properties (the probability explanation of wave functions, the orthogonality of eigenstates, and the unitarity of time evolution) are found not to be altered by the noncommutativity.Comment: 15 pages, no figures; v2: clarifications added; v3: 16 pages, 1 figure, clarifications made clearer; v4: 19 pages, the main context is completely rewritten; v5: 25 pages, title slightly changed, clarifications added, the final version to appear in PLOS ON

The Views of Mental Health Manager Towards the Use of a Family Work Model for Psychosis in Guangzhou, China

Family Interventions in Psychosis (FIP) have been promoted internationally but have been criticised for being based on western cultural models. This paper reports on a focus group study with 10 Integrated Mental Health Service Managers in Guangzhou, China using thematic analysis. Managers believed FIP might benefit families but identified potential difficulties due to (a) families avoiding services due to the ‘shame’ of mental illness (b) unrealistic expectations of services amongst families (c) deferral to ‘key decision-makers’ within families when discussing family issues with workers. The findings indicate that FIP work should focus on interaction between carers in the first instance with service users being introduced into sessions at a later date and that more attention needs to be given by the research community to how FIP may be adapted to cultural norms within China

Synthesis of titanate nanostructures using amorphous precursor material and their adsorption/photocatalytic properties

This paper reports on a new and swift hydrothermal chemical route to prepare titanate nanostructures (TNS) avoiding the use of crystalline TiO2 as starting material. The synthesis approach uses a commercial solution of TiCl3 as titanium source to prepare an amorphous precursor, circumventing the use of hazardous chemical compounds. The influence of the reaction temperature and dwell autoclave time on the structure and morphology of the synthesised materials was studied. Homogeneous titanate nanotubes with a high length/diameter aspect ratio were synthesised at 160^{\circ}C and 24 h. A band gap of 3.06\pm0.03 eV was determined for the TNS samples prepared in these experimental conditions. This value is red shifted by 0.14 eV compared to the band gap value usually reported for the TiO2 anatase. Moreover, such samples show better adsorption capacity and photocatalytic performance on the dye rhodamine 6G (R6G) photodegradation process than TiO2 nanoparticles. A 98% reduction of the R6G concentration was achieved after 45 minutes of irradiation of a 10 ppm dye aqueous solution and 1 g/L of TNS catalyst.Comment: 29 pages, 10 figures, accepted for publication in Journal of Materials Scienc

Probabilistic Team Semantics

Team semantics is a semantical framework for the study of dependence and independence concepts ubiquitous in many areas such as databases and statistics. In recent works team semantics has been generalised to accommodate also multisets and probabilistic dependencies. In this article we study a variant of probabilistic team semantics and relate this framework to a Tarskian two-sorted logic. We also show that very simple quantifier-free formulae of our logic give rise to backslashmathrm NP NP -hard model checking problems.Peer reviewe

Conscious monitoring and control (reinvestment) in surgical performance under pressure.

Research on intraoperative stressors has focused on external factors without considering individual differences in the ability to cope with stress. One individual difference that is implicated in adverse effects of stress on performance is "reinvestment," the propensity for conscious monitoring and control of movements. The aim of this study was to examine the impact of reinvestment on laparoscopic performance under time pressure

Swordtail Fry Attend to Chemical and Visual Cues in Detecting Predators and Conspecifics

Predation pressure and energy requirements present particularly salient opposing selective pressures on young fish. Thus, fry are expected to possess sophisticated means of detecting predators and resources. Here we tested the hypotheses that fry of the swordtail fish Xiphophorus birchmanni use chemical and visual cues in detection of predators and conspecifics. To test these hypotheses we presented young (<7 day-old) fry with combinations of visual and chemical stimuli from adult conspecifics and predators. We found that exposure to predator odors resulted in shoal tightening similar to that observed when fry were presented with visual cues alone. In trials with conspecific stimuli, fry were particularly attracted to adult conspecifics when presented simultaneous visual and chemical stimuli compared to the visual stimulus alone. These results show that fry attend to the odors of adult conspecifics, whose presence in a particular area may signal the location of resources as well as an absence of predators. This is one of the first studies to show that such young fish use chemical and visual cues in predator detection and in interactions with conspecifics. Previous research in X. birchmanni has shown that anthropogenic alteration of the chemical environment disrupts intraspecific chemical communication among adults; we suggest that because fry use the same chemosensory pathways to detect predators and conspecifics, alteration of the chemical environment may critically disrupt predator and resource detection

p150 ADAR1 isoform involved in maintenance of HeLa cell proliferation

BACKGROUND: RNA-specific adenosine deaminase ADAR1 is ubiquitously expressed in a variety of mammalian cells and tissues. Although its physiological importance in non-nervous tissues has been confirmed by analysis of null mutation phenotypes, few endogenous editing substrates have been identified in numerous peripheral tissues and biological function of ADAR1 has not been fully understood. METHODS: A conditional site-specific, ribozyme-based gene knock-down strategy was utilized to study the function of full-length isoform of ADAR1 (p150 protein) in HeLa cell. Double-stable HeLa cell lines were developed by transfecting HeLa Tet-On cells with a pTRE-derived plasmid that can express a hammerhead ribozyme against mRNA of p150 ADAR1 isoform under induction condition. Semi-quantitative RT-PCR and Western blotting were performed to measure the expression of p150 in selected cell clones. Cell proliferation was evaluated by means of MTT assay and growth curve analysis. Cellular morphological changes were observed under light microscope. Flow Cytometry was used for cell cycle analysis. Growth rate of cell transplants in BALB/c nude mice was also investigated. RESULTS: Both HeLa cell proliferation in vitro and the growth rate of transplanted HeLa cell-derived tumors in nude mice in vivo were significantly inhibited due to reduced expression of ADAR1 p150. Additionally, cell cycle analysis showed that cell progression from G1 phase to S phase was retarded in the ADAR1 p150 suppressed cells. CONCLUSION: Our results suggest that normal expression and functioning of p150 ADAR1 is essential for the maintenance of proper cell growth. The mechanisms underlying ADAR1's action might include both editing of currently unknown double-stranded RNAs and interacting with other cellular dsRNA-related processes

Admixture Mapping Scans Identify a Locus Affecting Retinal Vascular Caliber in Hypertensive African Americans: the Atherosclerosis Risk in Communities (ARIC) Study

Retinal vascular caliber provides information about the structure and health of the microvascular system and is associated with cardiovascular and cerebrovascular diseases. Compared to European Americans, African Americans tend to have wider retinal arteriolar and venular caliber, even after controlling for cardiovascular risk factors. This has suggested the hypothesis that differences in genetic background may contribute to racial/ethnic differences in retinal vascular caliber. Using 1,365 ancestry-informative SNPs, we estimated the percentage of African ancestry (PAA) and conducted genome-wide admixture mapping scans in 1,737 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) representing summary measures of retinal arteriolar and venular caliber, respectively, were measured from retinal photographs. PAA was significantly correlated with CRVE (ρ = 0.071, P = 0.003), but not CRAE (ρ = 0.032, P = 0.182). Using admixture mapping, we did not detect significant admixture association with either CRAE (genome-wide score = −0.73) or CRVE (genome-wide score = −0.69). An a priori subgroup analysis among hypertensive individuals detected a genome-wide significant association of CRVE with greater African ancestry at chromosome 6p21.1 (genome-wide score = 2.31, locus-specific LOD = 5.47). Each additional copy of an African ancestral allele at the 6p21.1 peak was associated with an average increase in CRVE of 6.14 µm in the hypertensives, but had no significant effects in the non-hypertensives (P for heterogeneity <0.001). Further mapping in the 6p21.1 region may uncover novel genetic variants affecting retinal vascular caliber and further insights into the interaction between genetic effects of the microvascular system and hypertension

Structural Basis for GTP-Dependent Dimerization of Hydrogenase Maturation Factor HypB

Maturation of [NiFe]-hydrogenase requires the insertion of iron, cyanide and carbon monoxide, followed by nickel, to the catalytic core of the enzyme. Hydrogenase maturation factor HypB is a metal-binding GTPase that is essential for the nickel delivery to the hydrogenase. Here we report the crystal structure of Archeoglobus fulgidus HypB (AfHypB) in apo-form. We showed that AfHypB recognizes guanine nucleotide using Asp-194 on the G5 loop despite having a non-canonical NKxA G4-motif. Structural comparison with the GTPγS-bound Methanocaldococcus jannaschii HypB identifies conformational changes in the switch I region, which bring an invariant Asp-72 to form an intermolecular salt-bridge with another invariant residue Lys-148 upon GTP binding. Substitution of K148A abolished GTP-dependent dimerization of AfHypB, but had no significant effect on the guanine nucleotide binding and on the intrinsic GTPase activity. In vivo complementation study in Escherichia coli showed that the invariant lysine residue is required for in vivo maturation of hydrogenase. Taken together, our results suggest that GTP-dependent dimerization of HypB is essential for hydrogenase maturation. It is likely that a nickel ion is loaded to an extra metal binding site at the dimeric interface of GTP-bound HypB and transferred to the hydrogenase upon GTP hydrolysis