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Summary: The brain is spatially organized and contains unique cell types, each performing diverse functions and exhibiting differential susceptibility to neurodegeneration. This is exemplified in Parkinson’s disease with the preferential loss of dopaminergic neurons of the substantia nigra pars compacta. Using a Parkinson’s transgenic model, we conducted a single-cell spatial transcriptomic and dopaminergic neuron translatomic analysis of young and old mouse brains. Through the high resolving capacity of single-cell spatial transcriptomics, we provide a deep characterization of the expression features of dopaminergic neurons and 27 other cell types within their spatial context, identifying markers of healthy and aging cells, spanning Parkinson’s relevant pathways. We integrate gene enrichment and genome-wide association study data to prioritize putative causative genes for disease investigation, identifying CASR as a regulator of dopaminergic calcium handling. These datasets represent the largest public resource for the investigation of spatial gene expression in brain cells in health, aging, and disease.

Summary: Variants at the GBA locus, encoding glucocerebrosidase, are the strongest common genetic risk factor for Parkinson’s disease (PD). To understand GBA-related disease mechanisms, we use a multi-part-enrichment proteomics and post-translational modification (PTM) workflow, identifying large numbers of dysregulated proteins and PTMs in heterozygous GBA-N370S PD patient induced pluripotent stem cell (iPSC) dopamine neurons. Alterations in glycosylation status show disturbances in the autophagy-lysosomal pathway, which concur with upstream perturbations in mammalian target of rapamycin (mTOR) activation in GBA-PD neurons. Several native and modified proteins encoded by PD-associated genes are dysregulated in GBA-PD neurons. Integrated pathway analysis reveals impaired neuritogenesis in GBA-PD neurons and identify tau as a key pathway mediator. Functional assays confirm neurite outgrowth deficits and identify impaired mitochondrial movement in GBA-PD neurons. Furthermore, pharmacological rescue of glucocerebrosidase activity in GBA-PD neurons improves the neurite outgrowth deficit. Overall, this study demonstrates the potential of PTMomics to elucidate neurodegeneration-associated pathways and potential drug targets in complex disease models.

Abstract Background Patients with SLE display marked clinical and immunlogical heterogeneity. The purpose of the study was to investigate patterns of serum cytokines in patients with active and stable systemic lupus erythematosus (SLE) and to determine how they relate to clinical phenotype. Methods Serum levels of 10 cytokines were measured retrospectively in a cohort of patients with SLE and in healthy controls using a high-sensitivity multiplex bead array. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG-2004) indices. Logistic regression models were used to determine the association between cytokine levels and active SLE. Principal component analysis (PCA) and cluster analysis was then used to identify subgroups of patients on the basis of cytokine levels. Results Serum chemokine (C-X-C motif) ligand 10 (CXCL10) and CXCL13 were significantly higher in patients with SLE compared to healthy controls. Two cytokines (pentraxin-related protein (PTX3) and CXCL10) were significantly higher in patients with active disease after adjustment for potential confounding factors. Measurement of four cytokines (CXCL10, IL-10, IL-21 and PTX3) significantly improved the performance of a model to identify patients with clinically active disease. Cluster analysis revealed that the patients formed 3 distinct groups, characterised by higher levels of interferon alpha (IFNα) and B lymphocyte stimulator (BLyS) (group 1), increased CXCL10 and CXCL13 (group 2) or low levels of cytokines (group 3). Group 2 had significantly lower serum complement and higher anti-double-stranded DNA antibodies and increased prevalence of inflammatory arthritis. Conclusions Multiplex analysis has identified a serum cytokine signature for active SLE. Within the SLE population distinct cytokine subgroups were identified, with differing clinical and immunological phenotypes that appeared stable over time. Assessment of cytokine profiles may reveal unique insights into disease heterogeneity.

This study explored the effects that the incorporation of nature of science (NoS) activities in the primary science classroom had on children's perceptions and understanding of science. We compared children's ideas in four classes by inviting them to talk, draw and write about what science meant to them: two of the classes were taught by "NoS" teachers who had completed an elective nature of science (NoS) course in the final year of their Bachelor of Education (B.Ed) degree. The "non-NoS" teachers who did not attend this course taught the other two classes. All four teachers had graduated from the same initial teacher education institution with similar teaching grades and all had carried out the same science methods course during their B.Ed programme. We found that children taught by the teachers who had been NoS-trained developed more elaborate notions of nature of science, as might be expected. More importantly, their reflections on science and their science lessons evidenced a more in-depth and sophisticated articulation of the scientific process in terms of scientists "trying their best" and "sometimes getting it wrong" as well as "getting different answers". Unlike children from non-NoS classes, those who had engaged in and reflected on NoS activities talked about their own science lessons in the sense of "doing science". These children also expressed more positive attitudes about their science lessons than those from non-NoS classes. We therefore suggest that there is "added value" in including NoS activities in the primary science curriculum in that they seem to help children make sense of science and the scientific process, which could lead to improved attitudes towards school science. We argue that as opposed to considering the relevance of school science only in terms of children's experience, relevance should include relevance to the world of science, and NoS activities can help children to link school science to science itself.

This article reports on the outcomes of a study that compared implicit and explicit teaching approaches on the development of contemporary conceptions of the nature of science (NoS). The sample comprised two groups of prospective primary teachers in the Republic of Ireland, all non-specialists in science. Research has shown that contemporary conceptions of NoS can be developed through implicit means--that is, by hands-on participation in scientific activities and by applying the process (scientific) skills in scientific inquiry. International research studies indicate that primary and secondary teachers, in general, do not hold contemporary (elaborate) conceptions of the NoS. This article reports on the outcomes of a comparative study that examined 148 prospective Irish primary teachers' conceptions of NoS. Seventy-four of these students were taught about aspects of NoS through explicit approaches during a science methodology course. The study compares the effectiveness of implicit and explicit approaches in the development of students' conceptions of NoS. The participants responded to the question "What is science?" before and after a science methodology course. Interestingly, analyses of the individual responses revealed that the students who had received explicit instruction (test group) in NoS had developed more insightful conceptions of NoS, contradicting research advocating implicit approaches. (Contains 3 tables, 2 figures, and 1 note.)

This article describes a four-year project undertaken to develop a set of performance tasks that could be used for assessing hands-on science in Irish primary schools. It begins by considering some of the literature on performance assessment and concludes with a discussion on the potential of the tasks to support teaching and learning in science. The main body of the article is structured to reflect the five phases of the research project itself. In phase one, science assessments used in a variety of educational systems in Australia, Canada, New Zealand, the United Kingdom and the United States were located and catalogued. In phase two, approximately 170 performance tasks were selected and adapted by the authors to suit the requirements of the Irish primary science curriculum. In phase three, a purposive convenience sample of teachers evaluated the extent to which the tasks (a subset of 67) were suitable for use at different grade levels. The teachers' feedback was used to amend tasks. In phase four, the researchers observed 11 different tasks being implemented in classrooms. The eleven teachers involved were interviewed about their experiences immediately afterwards. Again, based on the outcomes of this study, changes were made to the tasks. The fifth phase of the project, due to be completed in 2006, will involve the dissemination of 124 of the tasks to teachers via a booklet and a CD-ROM. Future prospects relating to other elements of the project such as Web-based resources, professional development courses and exemplars of performance are also discussed. (Contains 4 tables and 5 notes.)