PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.M A Di Biase, A Zalesky, G O'keefe, L Laskaris, B T Baune, C S Weickert, J Olver, P D McGorry, G P Amminger, B Nelson, A M Scott, I Hickie, R Banati, F Turkheimer, M Yaqub, I P Everall, C Pantelis and V Crople

The Art of Research: A Divergent/Convergent Framework and Opportunities for Science-Based Approaches

Applying science to the current art of producing engineering and research knowledge has proven difficult, in large part because of its seeming complexity. We posit that the microscopic processes underlying research are not so complex, but instead are iterative and interacting cycles of divergent (generation of ideas) and convergent (testing and selecting of ideas) thinking processes. This reductionist framework coherently organizes a wide range of previously disparate microscopic mechanisms which inhibit these processes. We give examples of such inhibitory mechanisms and discuss how deeper scientific understanding of these mechanisms might lead to dis-inhibitory interventions for individuals, networks and institutional levels

An Integrated Micro- and Macroarchitectural Analysis of the Drosophila Brain by Computer-Assisted Serial Section Electron Microscopy

A new software package allows for dense electron microscopy reconstructions of neuronal networks in the fruit fly brain, and reveals specific differences in microcircuits between insects and vertebrates

Community-based assessment of human rights in a complex humanitarian emergency: the Emergency Assistance Teams-Burma and Cyclone Nargis

<p>Abstract</p> <p>Introduction</p> <p>Cyclone Nargis hit Burma on May 2, 2008, killing over 138,000 and affecting at least 2.4 million people. The Burmese military junta, the State Peace and Development Council (SPDC), initially blocked international aid to storm victims, forcing community-based organizations such as the Emergency Assistance Teams-Burma (EAT) to fill the void, helping with cyclone relief and long-term reconstruction. Recognizing the need for independent monitoring of the human rights situation in cyclone-affected areas, particularly given censorship over storm relief coverage, EAT initiated such documentation efforts.</p> <p>Methods</p> <p>A human rights investigation was conducted to document selected human rights abuses that had initially been reported to volunteers providing relief services in cyclone affected areas. Using participatory research methods and qualitative, semi-structured interviews, EAT volunteers collected 103 testimonies from August 2008 to June 2009; 42 from relief workers and 61 from storm survivors.</p> <p>Results</p> <p>One year after the storm, basic necessities such as food, potable water, and shelter remained insufficient for many, a situation exacerbated by lack of support to help rebuild livelihoods and worsening household debt. This precluded many survivors from being able to access healthcare services, which were inadequate even before Cyclone Nargis. Aid efforts continued to be met with government restrictions and harassment, and relief workers continued to face threats and fear of arrest. Abuses, including land confiscation and misappropriation of aid, were reported during reconstruction, and tight government control over communication and information exchange continued.</p> <p>Conclusions</p> <p>Basic needs of many cyclone survivors in the Irrawaddy Delta remained unmet over a year following Cyclone Nargis. Official impediments to delivery of aid to storm survivors continued, including human rights abrogations experienced by civilians during reconstruction efforts. Such issues remain unaddressed in official assessments conducted in partnership with the SPDC. Private, community-based relief organizations like EAT are well positioned and able to independently assess human rights conditions in response to complex humanitarian emergencies such as Cyclone Nargis; efforts of this nature must be encouraged, particularly in settings where human rights abuses have been documented and censorship is widespread.</p

Prácticas docentes para creatividad en la universidad: estudio en Portugal y Brasil

Creativity is nowadays seen as an essential feature in higher education. Nevertheless, there is a discrepancy between the need for creativity and what higher education classrooms provide. This study assessed the perceptions of 1599 higher education students from two countries (1059 Brazilian and 540 Portuguese students), from two academic domains (Sciences and Technologies – Sc&T; Social Sciences, Arts, and Humanities – SScA&H), about the presence of creativity in their teachers’ instruction and evaluation practices. The study’s findings evidence interactive effects between the variables country and academic domain for most of the assessed factors: encouragement of new ideas, climate for the expression of ideas, and interest in students’ learning. Brazilian Sc&T students presented more negative perceptions of their classroom environments when compared to SScA&H students; Portuguese students showed opposite patterns of results. Some hypothetical explanations are discussed and future directions for research are presented.Criatividade é atualmente tomada como aspecto essencial na Educação Superior. Há, contudo, discrepância entre a necessidade de criatividade e o que a universidade proporciona. Este estudo avaliou percepções de 1599 alunos universitários de dois países (1059 brasileiros e 540 portugueses), de duas áreas curriculares (Ciências e Tecnologias – Sc&T; Ciências Sociais, Artes e Humanidades – SscA&H) sobre a presença de criatividade nas práticas docentes, instrucionais e avaliativas, de que são alvo. Os resultados mostraram efeitos interativos significativos entre as variáveis país e área curricular para a maioria dos fatores avaliados: encorajamento de novas ideias, clima para expressão de ideias e interesse pela aprendizagem dos alunos. Os estudantes brasileiros de Sc&T mostraram percepções mais negativas da sala de aula, comparados com os de SScA&H; os alunos portugueses obtiveram padrões opostos nos resultados. Algumas hipóteses explicativas são discutidas e são apresentadas orientações para pesquisa futura.La creatividad está actualmente considerada como aspecto esencial en la Educación Superior. Sin embargo, existe discrepancia entre la necesidad de creatividad y lo que la universidad ofrece. Este estudio evaluó percepciones de 1.599 estudiantes universitarios (1.059 de Brasil y 540 de Portugal) de dos áreas curriculares (Ciencia y Tecnología – Sc&T; Ciencias Sociales, Artes y Humanidades – SscA&T) acerca de la presencia de creatividad en las prácticas docentes, instructivas y evaluativas dirigidas a ellos. Los resultados mostraron efectos de interacción significativos entre las variables país y área curricular para la mayoría de los factores evaluados: fomento de nuevas ideas, entorno para la expresión de ideas e interés en el aprendizaje del estudiante. Los estudiantes brasileños de Sc&T mostraron percepciones más negativas de la clase en comparación con los de SSCA&H; los estudiantes portugueses obtuvieron patrones opuestos en los resultados. Algunas hipótesis explicativas se discuten y se presentan directrices para investigación futura.Thermo Scientificinfo:eu-repo/semantics/publishedVersio

A Model for Transgenerational Imprinting Variation in Complex Traits

Despite the fact that genetic imprinting, i.e., differential expression of the same allele due to its different parental origins, plays a pivotal role in controlling complex traits or diseases, the origin, action and transmission mode of imprinted genes have still remained largely unexplored. We present a new strategy for studying these properties of genetic imprinting with a two-stage reciprocal F mating design, initiated with two contrasting inbred lines. This strategy maps quantitative trait loci that are imprinted (i.e., iQTLs) based on their segregation and transmission across different generations. By incorporating the allelic configuration of an iQTL genotype into a mixture model framework, this strategy provides a path to trace the parental origin of alleles from previous generations. The imprinting effects of iQTLs and their interactions with other traditionally defined genetic effects, expressed in different generations, are estimated and tested by implementing the EM algorithm. The strategy was used to map iQTLs responsible for survival time with four reciprocal F populations and test whether and how the detected iQTLs inherit their imprinting effects into the next generation. The new strategy will provide a tool for quantifying the role of imprinting effects in the creation and maintenance of phenotypic diversity and elucidating a comprehensive picture of the genetic architecture of complex traits and diseases

Widespread white matter microstructural differences in schizophrenia across 4322 individuals:Results from the ENIGMA Schizophrenia DTI Working Group

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.Molecular Psychiatry advance online publication, 17 October 2017; doi:10.1038/mp.2017.170

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning)

Environmental chemical stressors as epigenome modifiers:a new horizon in assessment of toxicological effects

In eukaryotic cells, chromatin transformation from euchromatin into heterochromatin as a means of controlling gene expression and replication has been known as the ?accessibility hypothesis?. The interplay of epigenetic changes including histone modifications, DNA methylation, RNA interference (RNAi) and other functional epigenetic components are intricate. It is believed that these changes are well-programmed, inherited and can be modified by environmental contaminant stressors. Environmentally-driven epigenetic alterations during development, e.g. embryonic, foetal or neonatal stage, may influence disease susceptibility in adulthood. Therefore, understanding how epigenome modifications develop in response to environmental chemicals and, how epigenetic-xenobiotic interactions influence human health will shed new insights into gene-environment interactions in the epidemiology of several diseases including cancer. In this review, we consider studies of chemical modifiers including nutritional and xenobiotic effects on epigenetic components in vitro or in vivo. By examining the most-studied epigenome modifications and how their respective roles are interlinked, we highlight the central role of xenbiotic-modified epigenetic mechanisms. A major requirement will be to study and understand effects following environmentally-relevant exposures. We suggest that the study of epigenetic toxicology will open up new opportunities to devise strategies for the prevention or treatment of at-risk populations