19 research outputs found
Annotating novel genes by integrating synthetic lethals and genomic information
<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>We analyze synthetic lethality data for <it>arp1 </it>and <it>jnm1</it>, 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 <it>she1 </it>(YBL031W) as a novel gene involved in spindle migration. We applied the statistical methodology also to TOR2 signaling as another example.</p> <p>Conclusion</p> <p>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 <it>arp1 </it>and <it>jnm1 </it>that play a role in the same biological process.</p
Non-perturbative dynamics of hot non-Abelian gauge fields: beyond leading log approximation
Many aspects of high-temperature gauge theories, such as the electroweak
baryon number violation rate, color conductivity, and the hard gluon damping
rate, have previously been understood only at leading logarithmic order (that
is, neglecting effects suppressed only by an inverse logarithm of the gauge
coupling). We discuss how to systematically go beyond leading logarithmic order
in the analysis of physical quantities. Specifically, we extend to
next-to-leading-log order (NLLO) the simple leading-log effective theory due to
Bodeker that describes non-perturbative color physics in hot non-Abelian
plasmas. A suitable scaling analysis is used to show that no new operators
enter the effective theory at next-to-leading-log order. However, a NLLO
calculation of the color conductivity is required, and we report the resulting
value. Our NLLO result for the color conductivity can be trivially combined
with previous numerical work by G. Moore to yield a NLLO result for the hot
electroweak baryon number violation rate.Comment: 20 pages, 1 figur
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
Individual Video Training iVT and Annotating Academic Videos AAV: two complementing technologies
Individual Video Training iVT and Annotating Academic Videos AAV: two complementing technologies
1. Recording communication skills training sessions and reviewing them by oneself, with peers, and with tutors has become standard in medical education. Increasing numbers of students paired with restrictions of financial and human resources create a big obstacle to this important teaching method.
2. Everybody who wants to increase efficiency and effectiveness of communication training can get new ideas from our technical solution.
3. Our goal was to increase the effectiveness of communication skills training by supporting self, peer and tutor assessment over the Internet. Two technologies of SWITCH, the national foundation to support IT solutions for Swiss universities, came handy for our project. The first is the authentication and authorization infrastructure providing all Swiss students with a nationwide single login. The second is SWITCHcast which allows automated recording, upload and publication of videos in the Internet. Students start the recording system by entering their single login. This automatically links the video with their password. Within a few hours, they find their video password protected on the Internet. They now can give access to peers and tutors.
Additionally, an annotation interface was developed. This software has free text as well as checklist annotations capabilities. Tutors as well as students can create checklists. Tutor’s checklists are not editable by students. Annotations are linked to tracks. Tracks can be private or public. Public means visible to all who have access to the video. Annotation data can be exported for statistical evaluation.
4. The system was well received by students and tutors. Big numbers of videos were processed simultaneously without any problems.
5. iVT http://www.switch.ch/aaa/projects/detail/UNIBE.7
AAV http://www.switch.ch/aaa/projects/detail/ETHZ.
Coordinating a nation-wide introduction of a new competency framework for the Swiss undergraduate medical curricula: development of a common implementation guide
Background: In 2018, Switzerland introduced a new version of its nation-wide framework of reference for the undergraduate medical curriculum named PROFILES. It is based on the 7 CanMeds roles, 9 EPAs and 265 situations as starting points; but in contrast to previous editions it does not list diagnoses or disciplines.To accompany the implementation process the medical faculties created a joint, national working group.Summary of Work: Delegates of the medical schools and the federal licensing exam met regularly over one year. The resulting implementation guide, basedon a thorough review of the current literature, describes contextualized strategies to support the implementation of the different elements of PROFILES. This non-binding approach respects the autonomy of each Swiss medical school, allowing them to adapt the implementation process to their specific context and challenges.Summary of Results:The PROFILES implementation guide covers four main chapters: Curriculum organisation:the transition from a content-oriented to a competency-based teaching program needs an integrated curriculum, active teaching formats and a longitudinal clinical exposure. Assessment:the introduction of EPAs along the CanMeds roles requires a ‘program ofassessment’ combining different assessment strategies, rather than a collection of isolated assessment events. Faculty development:such a profound change can only be achieved if faculty members are trained and informed, and eventually adhere to the new educational orientations. Strategies of implementation:the last chapter emphasizes the importance of developing a change management approach to support a successful implementation of PROFILES.Discussion and Conclusions:The framework of reference for the undergraduate medical curriculum in Switzerland has recently undergone an in-depth update. A collaborative work with delegates from all medical schools resulted in an implementation guide with strategies to address the challenging shift to a competency-oriented curriculum based on CanMeds and EPAs.Take-home Messages: A nation-wide, collaborative approach to define strategies and conditions for the implementation of a new framework of reference has the potential to lead to a clearer appreciation of the challenges and an increased effort towards using common processes and tools to modify the current undergraduate medical curricula
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
Asymmetric segregation on spindle poles of the Schizosaccharomyces pombe septum-inducing protein kinase Cdc7p
Schizosaccharomyces pombe divides by means of a centrally placed division septum. The initiation of septation must be tightly coordinated with events in mitosis, as premature formation of the septum can lethally cut the undivided nucleus. The Spg1p GTPase and the Cdc7p kinase, with which it interacts, play a central role in signaling the initiation of septum formation. Loss-of-function mutations in either gene prevent septation, whereas inappropriate activation of Spg1p can induce septum formation from G(1) or G(2) interphase cells. Increased expression of either gene leads to multiple rounds of septation without cell cleavage, emphasizing the need for precise cell cycle regulation of their activity. To understand the mechanisms underlying this regulation, we have investigated whether these key initiators of septum formation are controlled by changes in their activity and/or location during mitosis and cytokinesis. We demonstrate that Spg1p localizes to the spindle pole body in interphase and to both spindle poles during mitosis. In contrast, Cdc7p shows no discrete localization during interphase, but early in mitosis it associates with both spindle pole bodies and, as the spindle extends, is seen on only one pole of the spindle during anaphase B. Spg1p activity is required for localization of Cdc7p in vivo but not for its kinase activity in vitro. Staining with an antiserum that recognizes preferentially GDP–Spg1p indicates that activated GTP–Spg1p predominates during mitosis when Cdc7p is associated with the spindle pole body. Furthermore, staining with this antibody shows that asymmetric distribution of Cdc7p may be mediated by inactivation of Spg1p on one spindle pole. Deregulated septation in mutant cells correlates with segregation of Cdc7p to both spindle poles
Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease
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 ∼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.R.S.K. was supported by a Howard Hughes Medical Institute Predoctoral Fellowship; A.G.F. by a US Army Breast Cancer Research Fellowship; Y.D., R.D., M.G., D.P.W. and P.Z. by the Wellcome Trust; G.P. by the Canadian Institute of Health Research and the Wellcome Trust; A.K. by the European Molecular Biology Laboratory; N.L.B. by the European Molecular Biology Organization; S.M. by the Centro de Investigacion del Cancer; M.S. by a Swiss National Science Foundation fellowship and J.A. by a Wellcome Trust Senior Research Fellowship.Peer Reviewe