Nationwide introduction of a new competency framework for undergraduate medical curricula: a collaborative approach.

Switzerland recently introduced PROFILES, a revised version of its national outcomes reference framework for the undergraduate medical curriculum. PROFILES is based on a set of competencies adapted from the CanMEDS framework and nine entrustable professional activities (EPAs) that students have to be able to perform autonomously in the context of a predefined list of clinical situations. The nationwide implementation of such a competency- and EPA-based approach to medical education is a complex process that represents an important change to the organisation of undergraduate training in the various medical schools. At the same time, the concepts underlying PROFILES also have to be reflected at the level of the Federal Licencing Examination (FLE) and the national accreditation process. The vice-deans for education mandated a Swiss Working Group for PROFILES Implementation (SWGPI) to elaborate a guide presenting the principles and best practices based on the current scientific literature, to ensure the coherence between the future developments of the medical curricula and the evolution of the FLE, and to propose a coordinated research agenda to evaluate the implementation process. On the basis of the literature and analysis of our national context, we determined the key elements important for a successful implementation. They can be grouped into several areas including curricular design and governance, the assessment system and entrustment process, faculty development and change management. We also identified two dimensions that will be of particular importance to create synergies and facilitate exchange between the medical schools: a systematic approach to curriculum mapping and the longitudinal integration of an e-portfolio to support the student learning process. The nationwide collaborative approach to define strategies and conditions for the implementation of a new reference framework has allowed to develop a shared understanding of the implications of PROFILES, to promote the establishment of Swiss mapping and e-portfolio communities, and to establish the conditions necessary for ensuring the continuous alignment of the FLE with the evolving medical curricula.

[PROFILES: typical portrait of the future Swiss doctors]. / PROFILES: portrait-type de nos futurs médecins !

In each professional practice, a greater or lesser part of the activity is devoted to teaching. Indeed, the transmission of the medical knowledge is an essential objective for the training of students and residents, but also an opportunity to adapt one's own practices to the current context, since fast changes are not necessarily easy to follow and assimilate. If the relationship with Medical school is rather straightforward in the university hospitals, it is not always the same for those who are more distant, but whose participation in teaching is desired, and clearly growing. In this way, it is therefore crucial that everyone is informed about recent changes to the undergraduated learning objectives (PROFILES) and the resulting needs for educational reforms for all Medical schools in Switzerland.

Dans chaque pratique professionnelle, une part plus ou moins grande de l'activité est dévolue à l'enseignement. En effet, la transmission de l'art médical représente un objectif essentiel pour la formation des étudiant·e·s et des jeunes collègues, mais aussi une opportunité pour adapter ses pratiques au contexte actuel, car les changements, rapides, ne sont pas forcément faciles à assimiler. Si, dans les hôpitaux universitaires, le contact avec les Facultés de médecine est plutôt aisé, il n'en va pas toujours de même pour ceux qui en sont plus distants, mais dont la participation à l'enseignement est souhaitée et croissante. En ce sens, il apparaît crucial que tou·te·s soient informé·e·s sur les modifications récentes des objectifs d'apprentissage prégradué (PROFILES) et sur les réformes qui en découlent pour les Facultés de médecine en Suisse.

[The informatics: a remarkable tool for teaching general internal medicine]. / L'informatique: un outil remarquable pour l'enseignement de la médecine interne générale!

INTERMED training implies a three week course, integrated in the "primary care module" for medical students in the first master year at the school of medicine in Lausanne. INTERMED uses an innovative teaching method based on repetitive sequences of e-learning-based individual learning followed by collaborative learning activities in teams, named Team-based learning (TBL). The e-learning takes place in a web-based virtual learning environment using a series of interactive multimedia virtual patients. By using INTERMED students go through a complete medical encounter applying clinical reasoning and choosing the diagnostic and therapeutic approach. INTERMED offers an authentic experience in an engaging and safe environment where errors are allowed and without consequences.

Synthesis and investigation of tryptophan-amphotericin B conjugates.

Anchors aweigh! The synthesis of tryptophan-amphotericin B conjugates (see figure) is described. The membrane-anchoring effect of tryptophane was thus combined with the pore-formation effect of amphotericin B leading to high channel activity in sterol-free liposomes.

Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease.

Eukaryotic cells use autophagy and the ubiquitin-proteasome system (UPS) as their major protein degradation pathways. Whereas the UPS is required for the rapid degradation of proteins when fast adaptation is needed, autophagy pathways selectively remove protein aggregates and damaged or excess organelles. However, little is known about the targets and mechanisms that provide specificity to this process. Here we show that mature ribosomes are rapidly degraded by autophagy upon nutrient starvation in Saccharomyces cerevisiae. Surprisingly, this degradation not only occurs by a non-selective mechanism, but also involves a novel type of selective autophagy, which we term 'ribophagy'. A genetic screen revealed that selective degradation of ribosomes requires catalytic activity of the Ubp3p/Bre5p ubiquitin protease. Although ubp3Delta and bre5Delta cells strongly accumulate 60S ribosomal particles upon starvation, they are proficient in starvation sensing and in general trafficking and autophagy pathways. Moreover, ubiquitination of several ribosomal subunits and/or ribosome-associated proteins was specifically enriched in ubp3Delta cells, suggesting that the regulation of ribophagy by ubiquitination may be direct. Interestingly, ubp3Delta cells are sensitive to rapamycin and nutrient starvation, implying that selective degradation of ribosomes is functionally important in vivo. Taken together, our results suggest a link between ubiquitination and the regulated degradation of mature ribosomes by autophagy.

The clathrin adaptor Gga2p is a phosphatidylinositol 4-phosphate effector at the Golgi exit.

Phosphatidylinositol 4-phosphate (PI(4)P) is a key regulator of membrane transport required for the formation of transport carriers from the trans-Golgi network (TGN). The molecular mechanisms of PI(4)P signaling in this process are still poorly understood. In a search for PI(4)P effector molecules, we performed a screen for synthetic lethals in a background of reduced PI(4)P and found the gene GGA2. Our analysis uncovered a PI(4)P-dependent recruitment of the clathrin adaptor Gga2p to the TGN during Golgi-to-endosome trafficking. Gga2p recruitment to liposomes is stimulated both by PI(4)P and the small GTPase Arf1p in its active conformation, implicating these two molecules in the recruitment of Gga2p to the TGN, which ultimately controls the formation of clathrin-coated vesicles. PI(4)P binding occurs through a phosphoinositide-binding signature within the N-terminal VHS domain of Gga2p resembling a motif found in other clathrin interacting proteins. These data provide an explanation for the TGN-specific membrane recruitment of Gga2p.

Annotating novel genes by integrating synthetic lethals and genomic information.

BACKGROUND: Large scale screening for synthetic lethality serves as a common tool in yeast genetics to systematically search for genes that play a role in specific biological processes. Often the amounts of data resulting from a single large scale screen far exceed the capacities of experimental characterization of every identified target. Thus, there is need for computational tools that select promising candidate genes in order to reduce the number of follow-up experiments to a manageable size. RESULTS: We analyze synthetic lethality data for arp1 and jnm1, two spindle migration genes, in order to identify novel members in this process. To this end, we use an unsupervised statistical method that integrates additional information from biological data sources, such as gene expression, phenotypic profiling, RNA degradation and sequence similarity. Different from existing methods that require large amounts of synthetic lethal data, our method merely relies on synthetic lethality information from two single screens. Using a Multivariate Gaussian Mixture Model, we determine the best subset of features that assign the target genes to two groups. The approach identifies a small group of genes as candidates involved in spindle migration. Experimental testing confirms the majority of our candidates and we present she1 (YBL031W) as a novel gene involved in spindle migration. We applied the statistical methodology also to TOR2 signaling as another example. CONCLUSION: We demonstrate the general use of Multivariate Gaussian Mixture Modeling for selecting candidate genes for experimental characterization from synthetic lethality data sets. For the given example, integration of different data sources contributes to the identification of genetic interaction partners of arp1 and jnm1 that play a role in the same biological process.

Selective requirement for SAGA in Hog1-mediated gene expression depending on the severity of the external osmostress conditions.

Regulation of gene expression by the Hog1 stress-activated protein kinase is essential for proper cell adaptation to osmostress. Hog1 coordinates an extensive transcriptional program through the modulation of transcription. To identify systematically novel components of the transcriptional machinery required for osmostress-mediated gene expression, we performed an exhaustive genome-wide genetic screening, searching for mutations that render cells osmosensitive at high osmolarity and that are associated with reduced expression of osmoresponsive genes. The SAGA and Mediator complexes were identified as putative novel regulators of osmostress-mediated transcription. Interestingly, whereas Mediator is essential for osmostress gene expression, the requirement for SAGA is different depending on the strength of the extracellular osmotic conditions. At mild osmolarity, SAGA mutants show only very slight defects on RNA polymerase II (Pol II) recruitment and gene expression, whereas at severe osmotic conditions, SAGA mutants show completely impaired RNA Pol II recruitment and transcription of osmoresponsive genes. Thus, our results define an essential role for Mediator in osmostress gene expression and a selective role for SAGA under severe osmostress. Our results indicate that the requirement for a transcriptional complex to regulate a promoter might be determined by the strength of the stimuli perceived by the cell through the regulation of interactions between transcriptional complexes.

A novel strategy for bioconjugation: synthesis and preliminary evaluation with amphotericin B.

A novel linker strategy is presented based on a double reductive amination of a dialdehyde to the amine of the amphotericin B mycosamine sugar and the biological activity of a series of conjugates is compared to the native amphotericin B.

The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics.

The soil nematodes Caenorhabditis briggsae and Caenorhabditis elegans diverged from a common ancestor roughly 100 million years ago and yet are almost indistinguishable by eye. They have the same chromosome number and genome sizes, and they occupy the same ecological niche. To explore the basis for this striking conservation of structure and function, we have sequenced the C. briggsae genome to a high-quality draft stage and compared it to the finished C. elegans sequence. We predict approximately 19,500 protein-coding genes in the C. briggsae genome, roughly the same as in C. elegans. Of these, 12,200 have clear C. elegans orthologs, a further 6,500 have one or more clearly detectable C. elegans homologs, and approximately 800 C. briggsae genes have no detectable matches in C. elegans. Almost all of the noncoding RNAs (ncRNAs) known are shared between the two species. The two genomes exhibit extensive colinearity, and the rate of divergence appears to be higher in the chromosomal arms than in the centers. Operons, a distinctive feature of C. elegans, are highly conserved in C. briggsae, with the arrangement of genes being preserved in 96% of cases. The difference in size between the C. briggsae (estimated at approximately 104 Mbp) and C. elegans (100.3 Mbp) genomes is almost entirely due to repetitive sequence, which accounts for 22.4% of the C. briggsae genome in contrast to 16.5% of the C. elegans genome. Few, if any, repeat families are shared, suggesting that most were acquired after the two species diverged or are undergoing rapid evolution. Coclustering the C. elegans and C. briggsae proteins reveals 2,169 protein families of two or more members. Most of these are shared between the two species, but some appear to be expanding or contracting, and there seem to be as many as several hundred novel C. briggsae gene families. The C. briggsae draft sequence will greatly improve the annotation of the C. elegans genome. Based on similarity to C. briggsae, we found strong evidence for 1,300 new C. elegans genes. In addition, comparisons of the two genomes will help to understand the evolutionary forces that mold nematode genomes.

Polarizing without a c(l)ue.

Most cells polarize in response to an asymmetric signal but some can spontaneously establish a discrete axis of polarity in the absence of a directional cue. Many mathematical models predict that locally acting positive feedback loops and globally acting negative regulators are required for pattern formation. Here, we summarize recent progress towards identifying some of the molecular components involved in these positive and negative feedback mechanisms. In addition, we describe the increasing evidence suggesting that the actin cytoskeleton is fundamentally important for the spontaneous symmetry breaking observed in a range of different organisms.

Systematic functional analysis of the Caenorhabditis elegans genome using RNAi.

A principal challenge currently facing biologists is how to connect the complete DNA sequence of an organism to its development and behaviour. Large-scale targeted-deletions have been successful in defining gene functions in the single-celled yeast Saccharomyces cerevisiae, but comparable analyses have yet to be performed in an animal. Here we describe the use of RNA interference to inhibit the function of approximately 86% of the 19,427 predicted genes of C. elegans. We identified mutant phenotypes for 1,722 genes, about two-thirds of which were not previously associated with a phenotype. We find that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles. Our resulting data set and reusable RNAi library of 16,757 bacterial clones will facilitate systematic analyses of the connections among gene sequence, chromosomal location and gene function in C. elegans.