The role of miR-137 in schizophrenia

The genetic basis of schizophrenia is still largely unknown. Recent evidence suggests that a microRNA (miRNA), miR-137 may be involved. The first large schizophrenia genome wide association (GWAS) study, published in 2011, identified a variant within the host gene of this miRNA (MIR-137) as the top association. Since then, further evidence for the potential influence of this miRNA within the disorder has accumulated. These studies used a variety of methods from GWAS to neuroimaging. However, few studies have evaluated the mechanism for the association of the MIR-137 variant, nor how alterations in the miRNA may have downstream effects on its targets and the function of these targets within biological pathways. We hypothesized that the target genes of miR-137 are involved in schizophrenia relevant pathways, such as those affecting neuronal development and plasticity, and that the MIR-137 risk-associated variant may lead to altered regulation of such pathways. We predict that variants within the targets of the miRNA may further alter target regulation. Here we completed the following three aims to determine the potential impact of dysregulation by this miRNA in schizophrenia. 1) We characterized the targets of the miRNA and the pathways over-representing these genes. 2) We determined the schizophrenia-risk association of these targets within these target enriched pathways. 3) We evaluated the influence of variants within target genes of an enriched pathway and the previously associated miR-137 host gene variant on structural gray matter. Our results suggest that the targets of this miRNA are indeed involved in pathways relevant to neuronal development and plasticity and thus the development of schizophrenia. The target genes within these pathways contain variants associated with schizophrenia that may disrupt regulation by the miRNA. Variants within targets of the PKA signaling pathway coupled with the MIR-137 variant may influence the development of gray matter within the occipital, temporal, and parietal lobe. Overall, our studies further suggest that this miRNA is influential in schizophrenia and provide a map for future studies to determine the effects of dysregulation by miR-137 in the disorder

Medical student confidence to care for a dying patient and their family: a systematic review

Background: The General Medical Council expects medical graduates to care for dying patients with skill, clinical judgement and compassion. UK surveys continually demonstrate low confidence and increasing distress amongst junior doctors when providing care to the dying. Aim: This systematic review aims to determine what has been evidenced within worldwide literature regarding medical undergraduate confidence to care for dying patients. Design: A systematic electronic search was undertaken. Data extraction included measurements of baseline confidence, associated assessment tools, and details of applied educational interventions. Pre/post-intervention confidence comparisons were made. Factors influencing confidence levels were explored. The review was prospectively registered via PROSPERO (CRD42019119057). Data sources: MEDLINE, CINAHL, EMBASE, ISI Web of Science, ERIC, PsychINFO, British Education Index and Cochrane Review databases were accessed, with no restrictions on publication year. Eligible studies included the terms ‘medical student’, ‘confidence’, and ‘dying’, alongside appropriate MeSH headings. Study quality was assessed using the Mixed Methods Appraisal Tool. Results: Fifteen eligible studies were included, demonstrating a diversity of assessment tools. Student confidence was low in provision of symptom management, family support, and psycho-spiritual support to dying patients. Eight interventional studies demonstrated increased post-interventional confidence. Lack of undergraduate exposure to dying patients and lack of structure within undergraduate palliative care curricula were cited as factors responsible for low confidence. Conclusion: This review clarifies the objective documentation of medical undergraduate confidence to care for the dying. Identifying where teaching fails to prepare graduates for realities in clinical practice will help inform future undergraduate palliative care curriculum planning

Potential Impact of miR-137 and Its Targets in Schizophrenia

The significant impact of microRNAs (miRNAs) on disease pathology is becoming increas- ingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. Schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function

Guiding Future Practices: A Review of Parent and Family Services

Working with college students often includes working with their parents and families. Higher education institutions across the US have addressed this cultural shift with the creation of parent and family services. As research illustrates continued relationships between students and their parents, student affairs practitioners will need to address this need. This article is a call for student affairs professionals to be creative and proactive when focusing on the future needs of parents and families of college students. Innovations for parent and family services, including the use of technology and the need for collaboration between on-campus departments, are shared

Submillimetre observations of WISE-selected high-redshift, luminous, dusty galaxies

We present SCUBA-2 850um submillimetre (submm) observations of the fields of 10 dusty, luminous galaxies at z ~ 1.7 - 4.6, detected at 12um and/or 22um by the WISE all-sky survey, but faint or undetected at 3.4um and 4.6um; dubbed hot, dust-obscured galaxies (Hot DOGs). The six detected targets all have total infrared luminosities greater than 10^13 L_sun, with one greater than 10^14 L_sun. Their spectral energy distributions (SEDs) are very blue from mid-infrared to submm wavelengths and not well fitted by standard AGN SED templates, without adding extra dust extinction to fit the WISE 3.4um and 4.6um data. The SCUBA-2 850um observations confirm that the Hot DOGs have less cold and/or more warm dust emission than standard AGN templates, and limit an underlying extended spiral or ULIRG-type galaxy to contribute less than about 2% or 55% of the typical total Hot DOG IR luminosity, respectively. The two most distant and luminous targets have similar observed submm to mid-infrared ratios to the rest, and thus appear to have even hotter SEDs. The number of serendipitous submm galaxies (SMGs) detected in the 1.5-arcmin-radius SCUBA-2 850um maps indicates there is a significant over-density of serendipitous sources around Hot DOGs. These submm observations confirm that the WISE-selected ultra-luminous galaxies have very blue mid-infrared to submm SEDs, suggesting that they contain very powerful AGN, and are apparently located in unusual arcmin-scale overdensities of very luminous dusty galaxies.Comment: 12 pages, 8 figures, 3 tables, accepted for publication in MNRA

Santé et pauvreté: introduction de l'apprentissage transformateur dans les structures et les paradigmes de l’éducation médicale

Background: As a paradigm of education that emphasizes equity and social justice, transformative education aims to improve societal structures by inspiring learners to become agents of social change. In an attempt to contribute to transformative education, the University of Toronto MD program implemented a workshop on poverty and health that included tutors with lived experience of poverty. This research aimed to examine how tutors, as members of a group that faces structural oppression, understood their participation in the workshop. Methods: This research drew on qualitative case study methodology and interview data, using the concept of transformative education to direct data analysis and interpretation. Results: Our findings centred around two broad themes: misalignments between transformative learning and the structures of medical education; and unintended consequences of transformative education within the dominant paradigms of medical education. These misalignments and unintended consequences provided insight into how courses operating within the structures, hierarchies and paradigms of medical education may be limited in their potential to contribute to transformative education. Conclusions: To be truly transformative, medical education must be willing to try to modify structures that reinforce oppression rather than integrating marginalized persons into educational processes that maintain social inequity.Contexte : En tant que paradigme favorisant l’équité et la justice sociale, l’éducation axée sur la transformation vise à améliorer les structures sociétales en inspirant les apprenants à devenir des agents du changement social. Dans une visée d’éducation transformatrice, le programme de doctorat en médecine de l’Université de Toronto a mis en place un atelier sur le thème de la santé et la pauvreté auquel participaient des tuteurs ayant une expérience vécue de la pauvreté. Notre recherche visait à examiner comment les tuteurs, en tant que membres d’un groupe confronté à l’oppression structurelle, ont compris leur participation à l’atelier. Méthodes : Cette recherche qualitative s’est appuyée sur une méthodologie d’étude de cas et sur des données d’entrevue, en utilisant le concept d’éducation transformatrice comme prisme pour l’analyse et l’interprétation des données. Résultats : Nos résultats s’articulent autour de deux grands thèmes : les décalages entre l’apprentissage transformateur et les structures de l’éducation médicale, et les conséquences inattendues de l’éducation transformatrice au sein des paradigmes dominants de l’éducation médicale. Ces divergences et ces conséquences non voulues ont permis de constater que les cours qui sont ancrés dans les structures, les hiérarchies et les paradigmes contribueront peu à l’éducation transformatrice. Conclusions : Pour que l’éducation médicale soit véritablement transformatrice, il faut qu’il y ait une volonté de modifier les structures qui renforcent l’oppression plutôt que de faire entrer les personnes marginalisées dans des processus éducatifs qui perpétuent l’inégalité sociale.

Meta Gene Set Enrichment Analyses Link miR-137-regulated Pathways With Schizophrenia Risk

Background: A single nucleotide polymorphism (SNP) within MIR137, the host gene for miR-137, has been identified repeatedly as a risk factor for schizophrenia. Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function. Methods: In this study, we evaluated the schizophrenia risk of miR-137 target genes within these pathways. Gene set enrichment analysis of pathway-specific miR-137 targets was performed using the stage 1 (21,856 subjects) schizophrenia genome wide association study data from the Psychiatric Genomics Consortium and a small independent replication cohort (244 subjects) from the Mind Clinical Imaging Consortium and Northwestern University. Results: Gene sets of potential miR-137 targets were enriched with variants associated with schizophrenia risk, including target sets involved in axonal guidance signaling, Ephrin receptor signaling, long-term potentiation, PKA signaling, and Sertoli cell junction signaling. The schizophrenia-risk association of SNPs in PKA signaling targets was replicated in the second independent cohort. Conclusions: These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk. SNPs in targets and the miRNA host gene may collectively lead to dysregulation of target expression and aberrant functioning of such implicated pathways. Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases

Interferometric Follow-Up of WISE Hyper-Luminous Hot, Dust-Obscured Galaxies

WISE has discovered an extraordinary population of hyper-luminous dusty galaxies which are faint in the two bluer passbands ($3.4\, \mu$m and $4.6\, \mu$m) but are bright in the two redder passbands of WISE ($12\, \mu$m and $22\, \mu$m). We report on initial follow-up observations of three of these hot, dust-obscured galaxies, or Hot DOGs, using the CARMA and SMA interferometer arrays at submm/mm wavelengths. We report continuum detections at $\sim$ 1.3 mm of two sources (WISE J014946.17+235014.5 and WISE J223810.20+265319.7, hereafter W0149+2350 and W2238+2653, respectively), and upper limits to CO line emission at 3 mm in the observed frame for two sources (W0149+2350 and WISE J181417.29+341224.8, hereafter W1814+3412). The 1.3 mm continuum images have a resolution of 1-2 arcsec and are consistent with single point sources. We estimate the masses of cold dust are 2.0$\times 10^{8} M_{\odot}$ for W0149+2350 and 3.9$\times 10^{8} M_{\odot}$ for W2238+2653, comparable to cold dust masses of luminous quasars. We obtain 2$\sigma$ upper limits to the molecular gas masses traced by CO, which are 3.3$\times 10^{10} M_{\odot}$ and 2.3$\times 10^{10} M_{\odot}$ for W0149+2350 and W1814+3412, respectively. We also present high-resolution, near-IR imaging with WFC3 on the Hubble Space Telescope for W0149+2653 and with NIRC2 on Keck for W2238+2653. The near-IR images show morphological structure dominated by a single, centrally condensed source with effective radius less than 4 kpc. No signs of gravitational lensing are evident.Comment: 13 pages, 3 figures. ApJ in pres