The Virtual Insect Brain protocol: creating and comparing standardized neuroanatomy

BACKGROUND: In the fly Drosophila melanogaster, new genetic, physiological, molecular and behavioral techniques for the functional analysis of the brain are rapidly accumulating. These diverse investigations on the function of the insect brain use gene expression patterns that can be visualized and provide the means for manipulating groups of neurons as a common ground. To take advantage of these patterns one needs to know their typical anatomy. RESULTS: This paper describes the Virtual Insect Brain (VIB) protocol, a script suite for the quantitative assessment, comparison, and presentation of neuroanatomical data. It is based on the 3D-reconstruction and visualization software Amira, version 3.x (Mercury Inc.) [1]. Besides its backbone, a standardization procedure which aligns individual 3D images (series of virtual sections obtained by confocal microscopy) to a common coordinate system and computes average intensities for each voxel (volume pixel) the VIB protocol provides an elaborate data management system for data administration. The VIB protocol facilitates direct comparison of gene expression patterns and describes their interindividual variability. It provides volumetry of brain regions and helps to characterize the phenotypes of brain structure mutants. Using the VIB protocol does not require any programming skills since all operations are carried out at an intuitively usable graphical user interface. Although the VIB protocol has been developed for the standardization of Drosophila neuroanatomy, the program structure can be used for the standardization of other 3D structures as well. CONCLUSION: Standardizing brains and gene expression patterns is a new approach to biological shape and its variability. The VIB protocol provides a first set of tools supporting this endeavor in Drosophila. The script suite is freely available at [2

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

CR1 Knops blood group alleles are not associated with severe malaria in the Gambia

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia

Importance The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis. Objectives To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class. Design, Setting, and Participants This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016. Main Outcomes and Measures Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning). Results The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10−3 min−1; P = .002) and the schizophrenia group (mean [SD], 12.94 [0.79] × 10−3 min−1; P = .04) compared with controls (mean [SD], 12.16 [0.92] × 10−3 min−1). There was no significant difference in striatal Kicer between the bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Kicer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity. Conclusions and Relevance These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia

Reflections on the labyrinth: Investigating Black and Minority Ethnic leaders’ career experiences

Black and Minority Ethnic (BME) employees appear to experience more difficulty reaching senior leadership positions than their white counterparts. Using Eagly and Carli’s (2007) metaphor of the labyrinth our aim was to give voice to black and minority ethnic managers who have successfully achieved senior management roles, and compare their leadership journeys with those of matched white managers. This paper used semi-structured interviews and attribution theory to examine how 20 black and minority ethnic and 20 white senior managers, from a UK government department made sense of significant career incidents in their leadership journeys. Template analysis was used to identify facilitators and barriers of career progression from causal explanations of these incidents. Although BME and white managers identified four common themes (visibility, networks, development, and line manager support), they differed in how they made sense of formal and informal organisational processes to achieve career progression. The findings are used to theorise about the individual and organisational factors that contribute to the leadership journeys of minority ethnic employees

Antiferromagnetic spintronics

Antiferromagnetic materials are magnetic inside, however, the direction of their ordered microscopic moments alternates between individual atomic sites. The resulting zero net magnetic moment makes magnetism in antiferromagnets invisible on the outside. It also implies that if information was stored in antiferromagnetic moments it would be insensitive to disturbing external magnetic fields, and the antiferromagnetic element would not affect magnetically its neighbors no matter how densely the elements were arranged in a device. The intrinsic high frequencies of antiferromagnetic dynamics represent another property that makes antiferromagnets distinct from ferromagnets. The outstanding question is how to efficiently manipulate and detect the magnetic state of an antiferromagnet. In this article we give an overview of recent works addressing this question. We also review studies looking at merits of antiferromagnetic spintronics from a more general perspective of spin-ransport, magnetization dynamics, and materials research, and give a brief outlook of future research and applications of antiferromagnetic spintronics.Comment: 13 pages, 7 figure

First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence

Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of ‘crossover’ to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen ‘within’ and ‘between’ groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity ‘within’ and ‘between’ groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer