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

Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively

Evaluation of behavioural and antioxidant activity of Cytisus scoparius Link in rats exposed to chronic unpredictable mild stress

<p>Abstract</p> <p>Background</p> <p>Various human diseases have oxidative stress as one of their component. Many herbs have been reported to exhibit properties that combat oxidative stress through their active constituents such as flavonoids, tannins, phenolic compounds etc. <it>Cytisus scoparius </it>(CS) Link, (Family: Leguminosae), also called <it>Sarothamnus scoparius</it>, has been shown in <it>invitro </it>experiments to be endowed with anti-diabetic, hypnotic and sedative and antioxidant activity. Therefore this study was carried out to evaluate CS for its anxiolytic, antidepressant and anti-oxidant activity in stressed rats.</p> <p>Methods</p> <p>60% methanolic extract of CS was quantified for phenolic content by Folin-Ciocalteau's method. Chronic unpredictable mild stress (CMS) was employed to induce stress in rats. CS (125 and 250 mg/kg, p.o) and diazepam (DZM) (2 mg/kg, p.o) was administered during the 21 day stress exposure period. Anxiolytic and antidepressant activities of CS were assessed in open field exploratory and behavioural despair paradigms, respectively. Plasma glucose and total lipids; endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT); non-enzymic-ascorbic acid and thiobarbituric acid reactive substances (TBARS) levels were measured in brain, kidneys and adrenals using standard protocols to assess the effect of CS.</p> <p>Results</p> <p>Total phenolic content of CS was found to be 8.54 ± 0.16% w/w. CMS produced anxiogenic and depressive behaviour in experimental rats with metabolic disturbance. Significant decrease in SOD, CAT levels and increase in lipid peroxidation level was observed in stressed rats. CS administration for 21 days during stress exposure significantly increased the ambulatory behaviour and decreased the freezing time in open field behaviour. In behavioural despair test no significant alteration in the immobility period was observed. CS also improved SOD, CAT, and ascorbic acid level and controlled the lipid peroxidation in different tissues.</p> <p>Conclusion</p> <p>CS possesses anti-stress and moderate anxiolytic activity which may be due, in part, to its antioxidant effect that might warrant further studies.</p

A nonlinear updating algorithm captures suboptimal inference in the presence of signal-dependent noise

Bayesian models have advanced the idea that humans combine prior beliefs and sensory observations to optimize behavior. How the brain implements Bayes-optimal inference, however, remains poorly understood. Simple behavioral tasks suggest that the brain can flexibly represent probability distributions. An alternative view is that the brain relies on simple algorithms that can implement Bayes-optimal behavior only when the computational demands are low. To distinguish between these alternatives, we devised a task in which Bayes-optimal performance could not be matched by simple algorithms. We asked subjects to estimate and reproduce a time interval by combining prior information with one or two sequential measurements. In the domain of time, measurement noise increases with duration. This property takes the integration of multiple measurements beyond the reach of simple algorithms. We found that subjects were able to update their estimates using the second measurement but their performance was suboptimal, suggesting that they were unable to update full probability distributions. Instead, subjects’ behavior was consistent with an algorithm that predicts upcoming sensory signals, and applies a nonlinear function to errors in prediction to update estimates. These results indicate that the inference strategies employed by humans may deviate from Bayes-optimal integration when the computational demands are high

Germline Transgenic Pigs by Sleeping Beauty Transposition in Porcine Zygotes and Targeted Integration in the Pig Genome

Genetic engineering can expand the utility of pigs for modeling human diseases, and for developing advanced therapeutic approaches. However, the inefficient production of transgenic pigs represents a technological bottleneck. Here, we assessed the hyperactive Sleeping Beauty (SB100X) transposon system for enzyme-catalyzed transgene integration into the embryonic porcine genome. The components of the transposon vector system were microinjected as circular plasmids into the cytoplasm of porcine zygotes, resulting in high frequencies of transgenic fetuses and piglets. The transgenic animals showed normal development and persistent reporter gene expression for >12 months. Molecular hallmarks of transposition were confirmed by analysis of 25 genomic insertion sites. We demonstrate germ-line transmission, segregation of individual transposons, and continued, copy number-dependent transgene expression in F1-offspring. In addition, we demonstrate target-selected gene insertion into transposon-tagged genomic loci by Cre-loxP-based cassette exchange in somatic cells followed by nuclear transfer. Transposase-catalyzed transgenesis in a large mammalian species expands the arsenal of transgenic technologies for use in domestic animals and will facilitate the development of large animal models for human diseases

Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility

Review and analysis of fire and explosion accidents in maritime transportation

The globally expanding shipping industry has several hazards such as collision, capsizing, foundering, grounding, stranding, fire, and explosion. Accidents are often caused by more than one contributing factor through complex interaction. It is crucial to identify root causes and their interactions to prevent and understand such accidents. This study presents a detailed review and analysis of fire and explosion accidents that occurred in the maritimetransportation industry during 1990–2015. The underlying causes of fire and explosion accidents are identified and analysed. This study also reviewed potential preventative measures to prevent such accidents. Additionally, this study compares properties of alternative fuels and analyses their effectiveness in mitigating fire and explosionhazards. It is observed that Cryogenic Natural Gas (CrNG), Liquefied Natural Gas (LNG) and methanol have properties more suitable than traditional fuels in mitigating fire risk and appropriate management of their hazards could make them a safer option to traditional fuels. However, for commercial use at this stage, there exist several uncertainties due to inadequate studies, and technological immaturity. This study provides an insight into fire and explosion accident causation and prevention, including the prospect of using alternative fuels for mitigating fire and explosion risks in maritime transportation