Healthcare AI: A Revised Quebec Framework for Nursing Education

Artificial Intelligence Health Technologies (AIHT) are taking their place in the practice of nursing. However, the curricula have not evolved to include competencies required of nursing graduates to incorporate their impact on theory and practice. This project was born of an identified need by nurse educators to articulate new competencies grounded in the literature and expert knowledge. Based on extensive literature reviews and an iterative process of expert validation, this paper provides recommendations for five new competencies that will be needed for nurses to use AIHT responsibly, ethically, and intelligently in the best interests of patient care. The methodology started with a literature review, then expert validation, leading to the development of the proposed competency framework, and finally validation with experts in Artificial Intelligence (AI) and healthcare. The first two competencies proposed address the underlying theory needed for effective practice: 1) Students will be able to apply knowledge of informatics and digital health technology to the practice of nursing, and 2) Students will be able to apply their knowledge of AIHT and their inherent benefits and limitations. The subsequent three competencies address application in practice: 3) Students will be able to use AIHT safely and effectively within their nursing practice, 4) Students will be able to participate in the development of AIHT guidelines considering ethical, social, and legal implications, and 5) Students will be able to engage in the development of AIHT training to support continuing nurse education. Clear statements, achievement contexts, elements, and performance criteria are provided for all levels of post-secondary education in Quebec including RN, BScN, and graduate-level programs. The proposed framework would also be of interest to nurse educators across Canada and internationally. Résumé Les technologies de l’intelligence artificielle en santé (TIAS) prennent leur place dans la pratique infirmière. Cependant, les programmes d’études n’ont pas évolué pour inclure les compétences requises des diplômées et diplômés en sciences infirmières afin d’intégrer leur impact sur la théorie et la pratique. Ce projet est né d’un besoin cerné par des professeures et enseignantes infirmières d’articuler de nouvelles compétences fondées sur la littérature et sur les connaissances d’experts. Basé sur des analyses approfondies des écrits et sur un processus itératif de validation par des experts, cet article fournit des recommandations pour cinq nouvelles compétences qui seront nécessaires aux infirmières et infirmiers pour utiliser les technologies de l’intelligence artificielle en santé de manière responsable, éthique et intelligente dans l’intérêt supérieur des soins aux patients. L’approche méthodologique a commencé par une revue de la littérature, puis une validation par des experts, conduisant à l’élaboration du référentiel de compétences proposé, et enfin une validation auprès d’experts en intelligence artificielle (IA) et en santé. Les deux premières compétences proposées portent sur la théorie sous-jacente nécessaire à une pratique efficace : 1) Les étudiantes et étudiants seront en mesure d’appliquer leurs connaissances en informatique et en technologie numérique de la santé à la pratique infirmière, et 2) Les étudiantes et étudiants seront en mesure d’appliquer leurs connaissances des technologies de l’intelligence artificielle en santé ainsi que de leurs avantages et limites inhérents. Les trois compétences suivantes concernent l’application dans la pratique : 3) Les étudiantes et étudiants seront en mesure d’utiliser les technologies de l’intelligence artificielle en santé de manière sûre et efficace dans leur pratique infirmière, 4) Les étudiantes et étudiants seront en mesure de participer à l’élaboration des lignes directrices des technologies d’intelligence artificielle en santé en tenant compte des implications éthiques, sociales et juridiques, et 5) Les étudiantes et étudiants seront en mesure de s’engager dans l’élaboration de la formation en matière de technologies d’intelligence artificielle en santé pour soutenir la formation continue des infirmières et infirmiers. Des énoncés clairs, des contextes de réussite, des éléments et des critères de rendement sont fournis pour tous les niveaux d’études postsecondaires au Québec, y compris les programmes techniques pour les infirmières et infirmiers, de baccalauréat en sciences infirmières et d’études supérieures. Le référentiel proposé pourrait intéresser également les formatrices et formateurs en sciences infirmières ailleurs au Canada et à l’international

Single molecule, long-read Apoer2 sequencing identifies conserved and species-specific splicing patterns

Apolipoprotein E receptor 2 (Apoer2) is a synaptic receptor in the brain that binds disease-relevant ligand Apolipoprotein E (Apoe) and is highly alternatively spliced. We examined alternative splicing (AS) of conserved Apoer2 exons across vertebrate species and identified gain of exons in mammals encoding functional domains such as the cytoplasmic and furin inserts, and loss of an exon in primates encoding the eighth LDLa repeat, likely altering receptor surface levels and ligand-binding specificity. We utilized single molecule, long-read RNA sequencing to profile full-length Apoer2 isoforms and identified 68 and 48 unique full-length Apoer2 transcripts in the mouse and human cerebral cortex, respectively. Furthermore, we identified two exons encoding protein functional domains, the third EGF-precursor like repeat and glycosylation domain, that are tandemly skipped specifically in mouse. Our study provides new insight into Apoer2 isoform complexity in the vertebrate brain and highlights species-specific differences in splicing decisions that support functional diversity.Published versio

Human APOER2 isoforms have differential cleavage events and synaptic properties

Human APOER2 is a type I transmembrane protein with a large extracellular domain (ECD) and a short cytoplasmic tail. APOER2-ECD contains several ligand binding domains (LBD) that are organized into exons with aligning phase junctions, which allows for in-frame exon cassette splicing events. We have identified 25 human APOER2 isoforms from cerebral cortex using gene-specific APOER2 primers, where the majority are exon-skipping events within the N-terminal LBD regions in comparison to 6 identified in the heart. APOER2 undergoes proteolytic cleavage in response to ligand binding that releases a C-terminal fragment (CTF) and transcriptionally active intracellular domain (ICD). We therefore tested whether the diversity of human brain-specific APOER2 variants affects APOER2 cleavage. We found exclusion of different ligand binding repeats from splicing generated different amounts of CTFs compared to full-length APOER2 (APOER2-FL). Specifically, APOER2 isoforms lacking exons 5-8 (Δex5-8) and lacking exons 4-6 (Δex4-6) generated the highest and lowest amounts of CTF generation respectively in response to APOE peptide compared to APOER2-FL. The differential CTF generation of APOER2 Δex5-8 and Δex4-6 coincides with the proteolytic release of the ICD which mediates transcriptional activation facilitated by the Mint1 adaptor protein. Functionally, we demonstrated loss of mouse Apoer2 decreased miniature event frequency in excitatory synapses suggesting that Apoer2 is required for spontaneous neurotransmitter release in mature neurons. Lentiviral rescue with human APOER2-FL or Δex4-6 isoform in Apoer2 knockout neurons fully restored the miniature event frequency but not Δex5-8 isoform. These results suggest that human APOER2 isoforms have differential cleavage events and synaptic properties.R01 AG059762 - NIA NIH HHSFirst author draf

Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice

10.1038/srep03754Scientific Reports4

ApoER2: functional tuning through splicing

Alternative splicing occurs in over 95% of protein-coding genes and contributes to the diversity of the human proteome. Apolipoprotein E receptor 2 (apoER2) is a critical modulator of neuronal development and synaptic plasticity in the brain and is enriched in cassette exon splicing events, in which functional exons are excluded from the final transcript. These alternative splicing events affect apoER2 function, as individual apoER2 exons tend to encode distinct protein functional domains. Although several apoER2 splice variants have been characterized, much work remains to understand how apoER2 splicing events modulate distinct apoER2 activities, including ligand binding specificity, synapse formation and plasticity. Additionally, little is known about how apoER2 splicing events are regulated. Often, alternative splicing events are regulated through the combinatorial action of RNA-binding proteins and other epigenetic mechanisms, however, the regulatory pathways corresponding to each specific exon are unknown in most cases. In this mini-review, we describe the structure of apoER2, highlight the unique functions of known isoforms, discuss what is currently known about the regulation of apoER2 splicing by RNA-binding proteins and pose new questions that will further our understanding of apoER2 splicing complexity.R01 AG059762 - NIA NIH HHSPublished versio

The Pafah1b Complex Interacts with the Reelin Receptor VLDLR

Reelin is an extracellular protein that directs the organization of cortical structures of the brain through the activation of two receptors, the very low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (ApoER2), and the phosphorylation of Disabled-1 (Dab1). Lis1, the product of the Pafah1b1 gene, is a component of the brain platelet-activating factor acetylhydrolase 1b (Pafah1b) complex, and binds to phosphorylated Dab1 in response to Reelin. Here we investigated the involvement of the whole Pafah1b complex in Reelin signaling and cortical layer formation and found that catalytic subunits of the Pafah1b complex, Pafah1b2 and Pafah1b3, specifically bind to the NPxYL sequence of VLDLR, but not to ApoER2. Compound Pafah1b1(+/−);Apoer2(−/−) mutant mice exhibit a reeler-like phenotype in the forebrain consisting of the inversion of cortical layers and hippocampal disorganization, whereas double Pafah1b1(+/−);Vldlr(−/−) mutants do not. These results suggest that a cross-talk between the Pafah1b complex and Reelin occurs downstream of the VLDLR receptor

Fueling the fire–a pan-cancer analysis of MYC-regulated lipid metabolism

The oncogene MYC and its product c-Myc are responsible for a multitude of changes in cancerous cells that trigger cell growth, proliferation and metastasis. The efforts to understand the multifaceted role of MYC in malignancies have highlighted metabolic reprogramming as a prominent function of this transcription factor, with effects across glycolysis, protein and lipid metabolism, mitochondrial respiration and energy storage. In particular, the role of MYC in lipid metabolism has been the focus of several studies in the past two decades, elucidating how the balance of lipid production and breakdown aids in tumor proliferation. Here, we provide a comprehensive summary of how modulation of MYC alters fatty acid synthesis and degradation, the metabolism of compound lipids, and the consequences for other metabolic pathways. The observed effects are highly cell type-specific, highlighting the MYC network’s ability to harness the existing cellular signaling pathways and specific tumor microenvironment to promote tumor growth and metastasis

The Reelin Receptors Apoer2 and Vldlr Coordinate the Patterning of Purkinje Cell Topography in the Developing Mouse Cerebellum

The adult cerebellar cortex is comprised of reproducible arrays of transverse zones and parasagittal stripes of Purkinje cells. Adult stripes are created through the perinatal rostrocaudal dispersion of embryonic Purkinje cell clusters, triggered by signaling through the Reelin pathway. Reelin is secreted by neurons in the external granular layer and deep cerebellar nuclei and binds to two high affinity extracellular receptors on Purkinje cells-the Very low density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (Apoer2). In mice null for either Reelin or double null for Vldlr and Apoer2, Purkinje cell clusters fail to disperse. Here we report that animals null for either Vldlr or Apoer2 individually, exhibit specific and parasagittally-restricted Purkinje cell ectopias. For example, in mice lacking Apoer2 function immunostaining reveals ectopic Purkinje cells that are largely restricted to the zebrin II-immunonegative population of the anterior vermis. In contrast, mice null for Vldlr have a much larger population of ectopic Purkinje cells that includes members from both the zebrin II-immunonegative and -immunopositive phenotypes. HSP25 immunoreactivity reveals that in Vldlr null animals a large portion of zebrin II-immunopositive ectopic cells are probably destined to become stripes in the central zone (lobules VI–VII). A small population of ectopic zebrin II-immunonegative Purkinje cells is also observed in animals heterozygous for both receptors (Apoer2+/−: Vldlr+/−), but no ectopia is present in mice heterozygous for either receptor alone. These results indicate that Apoer2 and Vldlr coordinate the dispersal of distinct, but overlapping subsets of Purkinje cells in the developing cerebellum