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BACKGROUND: Infantile hemangiomas (IHs) of the anogenital region remain poorly characterized. OBJECTIVE: To examine the distribution, ulceration rate, and associated congenital anomalies of anogenital IHs. METHODS: Retrospective study at 8 tertiary referral centers. RESULTS: A total of 435 infants with an IH of the anogenital region were enrolled (of which, 319 [73%] were girls). Congenital anomalies were present in 6.4% (n = 28) of infants with an anogenital IH. Segmental or partial segmental anogenital IHs ulcerated in 72% (n = 99 of 138) of infants, whereas 45% (n = 133 of 297) of focal anogenital IHs experienced ulceration (P < .001). In a multivariable logistic regression analysis, segmental or partial segmental morphology (adjusted odds ratio [aOR], 2.70; 95% CI, 1.60-4.64), mixed type (aOR, 3.44; 95% CI, 2.01-6.07), and perianal (aOR, 3.01; 95% CI, 1.53-6.12) and buttocks location (aOR, 2.08; 95% CI, 1.17-3.76) had increased odds of ulceration. Segmental or partial segmental IHs of the genitalia were confined to distinct anatomic territories and were predominantly distributed unilaterally, with a linear demarcation at the perineal raphe. LIMITATIONS: Possible selection bias, given recruitment at tertiary referral centers. CONCLUSION: This study improves our understanding of high-risk features of anogenital IHs and demonstrates that genital segmental or partial segmental IHs develop within distinct anatomic territories.
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Phenomenon: Given the growing number of medical science educators, an examination of institutions' promotion criteria related to educational excellence and scholarship is timely. This study investigates the extent to which medical schools' promotion criteria align with published standards for documenting and evaluating educational activities. Approach: This document analysis systematically analyzed promotion and tenure (P&T) guidelines from U.S. medical schools. Criteria and promotion expectations (related to context, quantity, quality, and engagement) were explored across five educational domains including: (i) teaching, (ii) curriculum/program development, (iii) mentoring/advising, (iv) educational leadership/administration, and (v) educational measurement and evaluation, in addition to research/scholarship and service. After independent review and data extraction, paired researchers compared findings and reached consensus on all discrepancies prior to final data submission. Descriptive statistics assessed the frequency of referenced promotion criteria. Findings: Promotion-related documents were retrieved from 120 (of 185) allopathic and osteopathic U.S. medical schools. Less than half of schools (43%; 52 of 120) documented a well-defined education-related pathway for advancement in academic rank. Across five education-specific domains, only 24% (12 of 50) of the investigated criteria were referenced by at least half of the schools. The least represented domain within P&T documents was "Educational Measurement and Evaluation." P&T documents for 47% of schools were rated as "below average" or "very vague" in their clarity/specificity. Insights: Less than 10% of U.S. medical schools have thoroughly embraced published recommendations for documenting and evaluating educational excellence. This raises concern for medical educators who may be evaluated for promotion based on vague or incomplete promotion criteria. With greater awareness of how educational excellence is currently documented and how promotion criteria can be improved, education-focused faculty can better recognize gaps in their own documentation practices, and more schools may be encouraged to embrace change and align with published recommendations.
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Movilidad Laboral , Docentes Médicos/normas , Facultades de Medicina , Becas , Humanos , Liderazgo , Encuestas y Cuestionarios , Estados UnidosRESUMEN
BACKGROUND: The primary cilium is an extension of the cell membrane that encloses a microtubule-based axoneme. Primary cilia are essential for transmission of environmental cues that determine cell fate. Disruption of primary cilia function is the molecular basis of numerous developmental disorders. Despite their biological importance, the mechanisms governing their assembly and disassembly are just beginning to be understood. Cilia growth and disassembly are essential events when cells exit and reenter into the cell cycle. The kinases never in mitosis-kinase 2 (Nek2) and Aurora A (AurA) act to depolymerize cilia when cells reenter the cell cycle from G0. RESULTS: Coexpression of either kinase with its kinase dead companion [AurA with kinase dead Nek2 (Nek2 KD) or Nek2 with kinase dead AurA (AurA KD)] had different effects on cilia depending on whether cilia are growing or shortening. AurA and Nek2 are individually able to shorten cilia when cilia are growing but both are required when cilia are being absorbed. The depolymerizing activity of each kinase is increased when coexpressed with the kinase dead version of the other kinase but only when cilia are assembling. Additionally, the two kinases act additively when cilia are assembling but not disassembling. Inhibition of AurA increases cilia number while inhibition of Nek2 significantly stimulates cilia length. The complex functional relationship between the two kinases reflects their physical interaction. Further, we identify a role for a PP1 binding protein, PPP1R42, in inhibiting Nek2 and increasing ciliation of ARPE-19 cells. CONCLUSION: We have uncovered a novel functional interaction between Nek2 and AurA that is dependent on the growth state of cilia. This differential interdependence reflects opposing regulation when cilia are growing or shortening. In addition to interaction between the kinases to regulate ciliation, the PP1 binding protein PPP1R42 directly inhibits Nek2 independent of PP1 indicating another level of regulation of this kinase. In summary, we demonstrate a complex interplay between Nek2 and AurA kinases in regulation of ciliation in ARPE-19 cells.
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Aurora Quinasa A/metabolismo , Cilios/enzimología , Proteínas de Microtúbulos/metabolismo , Quinasas Relacionadas con NIMA/metabolismo , Receptores de Neuropéptido Y/agonistas , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Azepinas/farmacología , Línea Celular , Cilios/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/enzimología , Células Epiteliales/metabolismo , Humanos , Quinasas Relacionadas con NIMA/genética , Unión Proteica/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacologíaRESUMEN
BACKGROUND: The centrosome is the primary site for microtubule nucleation in cells and orchestrates reorganisation of the microtubule cytoskeleton during the cell cycle. The activities of the centrosome must be closely aligned with progression of the cell cycle; misregulation of centrosome separation and duplication is a hallmark of cancer. In a subset of cells, including the developing spermatid, the centrosome becomes specialised to form the basal body thereby supporting growth of the axoneme in morphogenesis of cilia and flagella, structures critical for signalling and motility. Mammalian spermatogenesis is an excellent model system to investigate the transformations in cellular architecture that accompany these changes including formation of the flagellum. We have previously identified a leucine-rich repeat protein (PPP1R42) that contains a protein phosphatase-1 binding site and translocates from the apical nucleus to the centrosome at the base of the flagellum during spermiogenesis. In this manuscript, we examine localisation and function of PPP1R42 in a ciliated epithelial cell model as a first step in understanding the role of this protein in centrosome function and flagellar formation. RESULTS: We demonstrate that PPP1R42 localises to the basal body in ARPE-19 retinal epithelial cells. Co-localisation and co-immunoprecipitation experiments further show that PPP1R42 interacts with γ-tubulin. Inhibition of PPP1R42 with small interfering RNAs causes accumulation of centrosomes indicating premature centrosome separation. Importantly, the activity of two signalling molecules that regulate centrosome separation, PP1 phosphatase and NEK2 kinase, changes when PPP1R42 is inhibited: PP1 activity is reduced with a corresponding increase in NEK2 activity. CONCLUSIONS: We have identified a role for the PP1-binding protein, PPP1R42, in centrosome separation in ciliated ARPE-19 cells. Our finding that inhibition of PPP1R42 expression increases the number of centrosomes per cell is consistent with our model that PPP1R42 is a positive regulator of PP1. PPP1R42 depletion reduces the activity of PP1 leading to activation of NEK2, the kinase responsible for phosphorylation of centrosomal linker proteins promoting centrosome separation. This work identifies a new molecule localised to the centrosome and basal body with a role in the complex signalling network responsible for controlling centrosome activities.
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Centrosoma/metabolismo , Células Epiteliales/metabolismo , Proteína Fosfatasa 1/metabolismo , Proteínas/metabolismo , Retina/metabolismo , Línea Celular , Centrosoma/enzimología , Cilios/enzimología , Cilios/metabolismo , Células Epiteliales/enzimología , Humanos , Proteínas Repetidas Ricas en Leucina , Unión Proteica , Proteína Fosfatasa 1/genética , Transporte de Proteínas , Proteínas/genética , Retina/enzimología , Tubulina (Proteína)/metabolismoRESUMEN
ABSTRACT: There are many variations of anatomy courses taught in accredited physician assistant (PA) programs in the United States. Course directors and program leadership must choose how to effectively deliver content within their program constraints. Our anatomy course has faced challenges related to instructional time for didactic and laboratory sessions, course length, curricular placement and alignment, assessments, and faculty availability. These challenges are not specific to anatomy courses in PA curricula but exist in anatomy courses in various health care programs. In this article, we present major solutions to challenges in didactic delivery, laboratory sessions, course content, and assessments over a 5-year period. Through modifications and problem-solving, we identified the following 4 lessons learned during this process: course alignment to clinical relevance, intentional content delivery for different pedagogical approaches, structured laboratory sessions with appropriate staffing, and an appropriate weighting for assessments. These lessons and solutions will be useful to other anatomy and disciplines-based course directors facing similar challenges.
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OBJECTIVES: The objective of this study is to better understand the medical student experience with prework to determine what factors influence their motivation to complete prework. INTRODUCTION: Medical education has been shifting to more active learning-type sessions such as flipped classrooms but these activities are unsuccessful when students do not complete the associated prework. The literature is lacking on why students do not complete prework and what would motivate them to do so. This qualitative study aims to answer those questions through the view of expectancy-value motivation theory. METHODS: Thirteen preclinical medical students participated in a semistructured basic interview study investigating their experience with prework. Interview transcripts were coded, and codes were clustered and analyzed for themes. RESULTS: Students develop particular routines they find successful for their studies. They explain how time in their schedules and the amount of time prework takes to complete plays a role in their study environment which must be favorable in order to complete prework. Students view video prework more favorably compared to reading assignments. Students note how the opinions of their peers influence their decision to complete prework. Each of these factors influences student motivation to complete prework. CONCLUSION: This study finds that motivation to complete prework is influenced by the environment, format, and use of prework, student interest and prior knowledge, and peer influence. The combination of these factors determines whether a student believes they are capable of completing prework and if they find it valuable. In order to increase motivation to complete prework, faculty should consider how to address these factors in a way that students are able to fit prework into their study routines. This study provides the first step in understanding the medical student experience with prework and suggests directions for future studies to maximize student motivation to complete prework.
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In this chapter, we describe the procedure for generating genetically modified Caenorhabditis elegans using microinjection via the Cas9-mediated Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) editing technique. Specifically, we describe the detailed method of performing CRISPR editing by microinjection using the Cloning-free Co-CRISPR method described by the Seydoux lab. This microinjection protocol can also be used for CRISPR editing with protocols from other labs as well as for a variety of other editing techniques including Mos1-mediated single-copy transgene insertions (MosSCI), transcriptional activator-like nucleases (TALENs), and zinc-finger nucleases (ZFNs). Further, this microinjection protocol can also be used for injecting plasmid DNA to generate heritable extrachromosomal arrays for gene expression and mosaic analysis, performing RNAi by injection and delivering RNA, dyes or other molecules into the C. elegans germline.