Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

Music as Math Waves: Exploring Trigonometry Through Sound

Students studying transformations of trigonometric functions may learn formulas associated with period and frequency without developing an understanding of the concepts themselves. In this article, the authors present a task that uses arts integration in the form of sound waves to help students explore the relationship between period and frequency. Students are guided through a task of generating a ringtone for a smartphone that blends music, maths, and technology. Links to worksheets and a sample ringtone are provided to facilitate a teacher\u27s implementation of the task; suggestions and advice are included. Using the arts to teach traditional STEM topics, an initiative known as STEAM offers promising opportunities for students to apply creative elements to solve technical problems. Although the topic in this article is suitable for precalculus students, STEAM-based instruction is applicable across multiple grade levels

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E CONCLUSION: In LCH-ND patients, BRAFV600

Changes to the ACGME Common Program Requirements and Their Potential Impact on Emergency Medicine Core Faculty Protected Time

The Accreditation Council for Graduate Medical Education (ACGME), which regulates residency and fellowship training in the United States, recently revised the minimum standards for all training programs. These standards are codified and published as the Common Program Requirements (CPRs). Recent specific revisions, particularly removing the requirement ensuring protected time for core faculty, are poised to have a substantial impact on emergency medicine training programs. A group of representatives and relevant stakeholders from national emergency medicine organizations was convened to assess the potential effects of these changes on core faculty and the training of emergency physicians. We reviewed the literature and results of surveys conducted by emergency medicine organizations to examine the role of core faculty protected time. Faculty nonclinical activities contribute greatly to the academic missions of emergency medicine training programs. Protected time and reduced clinical hours allow core faculty to engage in education and research, which are two of the three core pillars of academic emergency medicine. Loss of core faculty protected time is expected to have detrimental impacts on training programs and on emergency medicine generally. We provide consensus recommendations regarding emergency medicine core faculty clinical work hour limitations to maintain protected time for educational activities and scholarship and preserve the quality of academic emergency medicine