How educational innovations and attention to competencies in postgraduate medical education relate to preparedness for practice:The key role of the learning environment

Introduction Many training programmes in postgraduate medical education (PGME) have introduced competency frameworks, but the effects of this change on preparedness for practice are unknown. Therefore, we explored how elements of competency-based programmes in PGME (educational innovations, attention to competencies and learning environment) were related to perceived preparedness for practice among new consultants. Methods A questionnaire was distributed among 330 new consultants. Respondents rated how well their PGME training programme prepared them for practice, the extent to which educational innovations (portfolio, Mini-CEX) were implemented, and how much attention was paid to CanMEDS competencies during feedback and coaching, and they answered questions on the learning environment and general self-efficacy. Multiple regression and mediation analyses were used to analyze data. Results The response rate was 43 % (143/330). Controlling for self-efficacy and gender, the learning environment was the strongest predictor of preparedness for practice (B = 0.42, p < 0.001), followed by attention to competencies (B = 0.29, p < 0.01). Educational innovations were not directly related to preparedness for practice. The overall model explained 52 % of the variance in preparedness for practice. Attention to competencies mediated the relationship between educational innovations and preparedness for practice. This mediation became stronger at higher learning environment values. Conclusions The learning environment plays a key role in determining the degree to which competency-based PGME prepares trainees for independent practice

αTAT1 controls longitudinal spreading of acetylation marks from open microtubules extremities OPEN

International audienceAcetylation of the lysine 40 of α-tubulin (K40) is a post-translational modification occurring in the lumen of microtubules (MTs) and is controlled by the α-tubulin acetyl-transferase αTAT1. How αTAT1 accesses the lumen and acetylates α-tubulin there has been an open question. Here, we report that acetylation starts at open ends of MTs and progressively spreads longitudinally from there. We observed acetylation marks at the open ends of in vivo MTs re-growing after a Nocodazole block, and acetylated segments growing in length with time. Bias for MTs extremities was even more pronounced when using non-dynamic MTs extracted from HeLa cells. In contrast, K40 acetylation was mostly uniform along the length of MTs reconstituted from purified tubulin in vitro. Quantitative modelling of luminal diffusion of αTAT1 suggested that the uniform acetylation pattern observed in vitro is consistent with defects in the MT lattice providing lateral access to the lumen. Indeed, we observed that in vitro MTs are permeable to macromolecules along their shaft while cellular MTs are not. Our results demonstrate αTAT1 enters the lumen from open extremities and spreads K40 acetylation marks longitudinally along cellular MTs. This mode of tip-directed microtubule acetylation may allow for selective acetylation of subsets of microtubules. Results and Discussion Microtubules (MTs) are dynamic polymers composed of α β-tubulin dimers that assembled into hollow tubes. In most eukaryotic cells, MTs can undergo post-translational modifications (PTMs) that modify their properties and functions 1. Acetylation of the lysine 40 of α-tubulin (K40) is a common PTM that is catalysed by the α-tubulin acetyl-transferase α TAT1 and is associated with stable, long-lived MTs 2-4. Remarkably, K40 acetylation occurs in the lumen of MTs 5,6 and is the only such PTM that we know of ref. 1. Supporting this, Szyk et al. recently used in vitro approaches to demonstrate that α TAT1 enters into and diffuses within the MT lumen 7. However, Szyk et al. also suggested that fast diffusivity of α TAT1 leads to stochastic acetylation that occurs uniformly along the length of MTs. This was in marked contrast with earlier in vivo observations of discrete acetylated segments along MTs 8-10 progressively elongating with time 11. More recently, several groups have reported that the acetylated segments were predominately associated with the ends of MTs in vivo 3,12. Thus, reported observations in vivo do not match the proposed model of uniformly distributed acetylated K40 marks based on experiments performed with in vitro MTs 7. To understand how acetylated K40 marks spreading occurs in vivo, we first analyzed acetylation dynamics in HeLa cells. In order to synchronize acetylation events, HeLa cells were subjected to complete MT depolymeri-sation by a prolonged treatment with Nocodazole before being allowed to reassemble MTs after washing out th

Evidence for new C-terminally truncated variants of α- and β-tubulins

New C-terminally truncated α- and β-tubulin variants, both ending with an -EEEG sequence, are identified in vivo: αΔ3-tubulin, which has a specific neuronal distribution pattern (distinct from that of αΔ2-tubulin) and seems to be related to dynamic microtubules, and βΔ4-tubulin, corresponding to β2A/B-tubulin modified by truncation of four C-terminal residues, which is ubiquitously present in cells and tissues. Cellular α-tubulin can bear various carboxy-terminal sequences: full-length tubulin arising from gene neosynthesis is tyrosinated, and two truncated variants, corresponding to detyrosinated and Δ2 α‑tubulin, result from the sequential cleavage of one or two C-terminal residues, respectively. Here, by using a novel antibody named 3EG that is highly specific to the -EEEG C-terminal sequence, we demonstrate the occurrence in neuronal tissues of a new αΔ3‑tubulin variant corresponding to α1A/B‑tubulin deleted of its last three residues (EEY). αΔ3‑tubulin has a specific distribution pattern: its quantity in the brain is similar to that of αΔ2-tubulin around birth but is much lower in adult tissue. This truncated α1A/B-tubulin variant can be generated from αΔ2-tubulin by the deglutamylases CCP1, CCP4, CCP5, and CCP6 but not by CCP2 and CCP3. Moreover, using 3EG antibody, we identify a C‑terminally truncated β-tubulin form with the same -EEEG C-terminal sequence. Using mass spectrometry, we demonstrate that β2A/B-tubulin is modified by truncation of the four C-terminal residues (EDEA). We show that this newly identified βΔ4-tubulin is ubiquitously present in cells and tissues and that its level is constant throughout the cell cycle. These new C-terminally truncated α- and β-tubulin variants, both ending with -EEEG sequence, are expected to regulate microtubule physiology. Of interest, the αΔ3-tubulin seems to be related to dynamic microtubules, resembling tyrosinated-tubulin rather than the other truncated variants, and may have critical function(s) in neuronal development

Genetic diversity and demographic history of the leopard seal: A Southern Ocean top predator

Leopard seals (Hydrurga leptonyx) are top predators that can exert substantial top-down control of their Antarctic prey species. However, population trends and genetic diversity of leopard seals remain understudied, limiting our understanding of their ecological role. We investigated the genetic diversity, effective population size and demographic history of leopard seals to provide fundamental data that contextualizes their predatory influence on Antarctic ecosystems. Ninety leopard seals were sampled from the northern Antarctic Peninsula during the austral summers of 2008–2019 and a 405bp segment of the mitochondrial control region was sequenced for each individual. We uncovered moderate levels of nucleotide (π = 0.013) and haplotype (Hd = 0.96) diversity, and the effective population size was estimated at around 24,000 individuals (NE = 24,376; 95% CI: 16,876–33,126). Consistent with findings from other ice-breeding pinnipeds, Bayesian skyline analysis also revealed evidence for population expansion during the last glacial maximum, suggesting that historical population growth may have been boosted by an increase in the abundance of sea ice. Although leopard seals can be found in warmer, sub-Antarctic locations, the species’ core habitat is centered on the Antarctic, making it inherently vulnerable to the loss of sea ice habitat due to climate change. Therefore, detailed assessments of past and present leopard seal population trends are needed to inform policies for Antarctic ecosystems

Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxy­methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence

Proteasome Nuclear Import Mediated by Arc3 Can Influence Efficient DNA Damage Repair and Mitosis in Schizosaccharomyces Pombe

Proteasomes must efficiently remove their substrates throughout the cells in a timely manner as many of these proteins can be toxic. This study shows that proteasomes can do so efficiently because they are highly mobile. Furthermore this study uncovers that proteasome mobility requires functional Arc3, a subunit of the Arp2/3 complex

Role of Disorder in III-V Nanocrystal Emitters and Self Assembly of Charge Stabilized Colloids

I begin this dissertation with an overview of the colloidal nanomaterials field and highlight the versatility of colloidal methods for producing nanoscale soluble precursors to useful optoelectronic materials. The subsequent content is divided broadly between two aspects of colloidal nanomaterials science. In the first portion, Chapters 2 and 3, I discuss an in-depth study of the properties of InP quantum dot emitters with an emphasis on elucidating the barriers to achieving better performance and providing a path forward for future optimization. Chapter 2 covers an investigation into carrier dynamics in these materials by a range of spectroscopic techniques and presents evidence of defect coupled emission in passivated InP quantum dots. Chapter 3 continues to explore InP quantum dot emitters by following up on the hypothesis of defect coupled emission presented at the end of Chapter 2, and makes use of Raman spectroscopy, x-ray absorption fine structure spectroscopy and density functional theory calculations. Here, I aim to observe and account for classes of structural disorder in InP quantum dot emitters that can lead to defect coupled emission and persistently broad ensemble emission linewidths. In the latter portion of the document, Chapters 4 and 5, I turn the focus away from the properties of isolated colloidal particles and toward studying assembly of extended solids composed of colloidal nanomaterials. In particular, I examine the relation between surface chemistry and interparticle forces. I study the effect of this relationship on the morphology of aggregates grown from colloids that are electrostatically stabilized by compact inorganic ligands. In Chapter 4, I present a new method for growing ordered and maximally dense supercrystals of metal nanoparticles capped with inorganic ligands. Characterization of structural, optical, and electronic properties of these assemblies verifies strong electronic coupling and macroscopically metallic behavior. In Chapter 5, I investigate the mechanism of densification and ordering in these assemblies and find that an interaction between the high polarizability of the individual nanocrystal units and asymmetric electrolyte species in solution produces a crucial short-range repulsive potential. It is this repulsion that prevents particles from jamming and allows for the system to settle into the thermodynamically favored, ordered, and dense supercrystalline phase