Visualisation of bioinformatics datasets

Analysing the molecular polymorphism and interactions of DNA, RNA and proteins is of fundamental importance in biology. Predicting functions of polymorphic molecules is important in order to design more effective medicines. Analysing major histocompatibility complex (MHC) polymorphism is important for mate choice, epitope-based vaccine design and transplantation rejection etc. Most of the existing exploratory approaches cannot analyse these datasets because of the large number of molecules with a high number of descriptors per molecule. This thesis develops novel methods for data projection in order to explore high dimensional biological dataset by visualising them in a low-dimensional space. With increasing dimensionality, some existing data visualisation methods such as generative topographic mapping (GTM) become computationally intractable. We propose variants of these methods, where we use log-transformations at certain steps of expectation maximisation (EM) based parameter learning process, to make them tractable for high-dimensional datasets. We demonstrate these proposed variants both for synthetic and electrostatic potential dataset of MHC class-I. We also propose to extend a latent trait model (LTM), suitable for visualising high dimensional discrete data, to simultaneously estimate feature saliency as an integrated part of the parameter learning process of a visualisation model. This LTM variant not only gives better visualisation by modifying the project map based on feature relevance, but also helps users to assess the significance of each feature. Another problem which is not addressed much in the literature is the visualisation of mixed-type data. We propose to combine GTM and LTM in a principled way where appropriate noise models are used for each type of data in order to visualise mixed-type data in a single plot. We call this model a generalised GTM (GGTM). We also propose to extend GGTM model to estimate feature saliencies while training a visualisation model and this is called GGTM with feature saliency (GGTM-FS). We demonstrate effectiveness of these proposed models both for synthetic and real datasets. We evaluate visualisation quality using quality metrics such as distance distortion measure and rank based measures: trustworthiness, continuity, mean relative rank errors with respect to data space and latent space. In cases where the labels are known we also use quality metrics of KL divergence and nearest neighbour classifications error in order to determine the separation between classes. We demonstrate the efficacy of these proposed models both for synthetic and real biological datasets with a main focus on the MHC class-I dataset.

Parallel Class Intersection Matrices of Orthogonal Resolutions

This work was partially supported by the Bulgarian National Science Fund under Contract No MM 1405. Part of the results were announced at the Fifth International Workshop on Optimal Codes and Related Topics (OCRT), White Lagoon, June 2007, Bulgaria

Social and seasonal plasticity of the electric fish, Brachyhypopomus gauderio

The South American electric knifefish, Brachyhypopomus gauderio, uses weakly electric fields to see and communicate in the dark. Only one study to date has investigated natural behavior in this species during the breeding season; this study proposed that B. guarerio has an exploded lek polygyny breeding system. To test this hypothesis, artificial marshes simulating the native vegetation, temperature, and water conductivities of the South American subtropics were created to study seasonal variation in associative behavior of B. gauderio during the breeding and non-breeding seasons. Mark/recapture methods were used to keep track of individual fish and their dispersion inside the experimental designs. The experimental design proved to be extremely successful at eliciting reproduction. Differences were found in seasonal variations of social behaviors between adult and juvenile populations. Although no apparent sex. differences in movement patterns were found during the breeding season; a trend for male-male aversion was found, suggesting male-male avoidance as a possible strategy guiding aspects of social behaviors in this species. Further, movement may be a tactic for mate seeking as the individuals who moved the most during the breeding season obtained the most opposite sex interactions. These findings support the exploded lek polygyny model. Social interactions are subject to complex regulation by social, physiologic and ecological factors; the extent to which these associations are repeatable may provide novel insights on the evolution of sociality as it has been shaped by natural selection.

When does female multiple mating evolve to adjust inbreeding? : Effects of inbreeding depression, direct costs, mating constraints, and polyandry as a threshold trait

Ackowledgements: This work was funded by a European Research Council Starting Grant to JMR. All simulations were performed using the Maxwell computing cluster at the University of Aberdeen

Structural Basis of RNA Recognition by Mycobacterium tuberculosis MazF Homologues

The MazEF toxin-antitoxin (TA) system consists of the antitoxin MazE and the toxin MazF. MazF is a sequence-specific endoribonuclease that upon activation causes cellular growth arrest and increass the level of persisters. Moreover, MazF-induced cells are in a quasi-dormant state that cells remain metabolically active while stop dividing. The quasi-dormancy is similar to the nonreplicating state of M. tuberculosis during latent tuberculosis, thus suggesting the role of mazEF in M. tuberculosis dormancy and persistence. M. tuberculosis has nine mazEF TA modules, each with different RNA cleavage specificities and implicated in selective gene expression during stress conditions. To date only the Bacillus subtilis MazF-RNA complex structure has been determined. As M. tuberculosis MazF homologues recognize distinct RNA sequences, their molecular mechanisms of substrate specificity remain unclear. By taking advantage of X-ray crystallography, we have determined structures of two M. tuberculosis MazF-RNA complexes, MazF-mt1 (Rv2801c) and MazF-mt3 (Rv1991c) in complex with an uncleavable RNA substrate. These structures have provided the molecular basis of sequence-specific RNA recognition and cleavage by MazF toxins.

Both MazF-mt1-RNA and MazF-mt3-RNA complexes showed similar structural organization with one molecule of RNA bound to a MazF-mt1 or MazF-mt3 dimer and occupying the same pocket within the MazF dimer interface. Similar to B. subtilis MazF-RNA complex, MazF-mt1 and MazF-mt3 displayed a conserved active site architecture, where two highly conserved residues, Arg and Thr, form hydrogen bonds with the scissile phosphate group in the cleavage site of the bound RNA. The MazF-mt1-RNA complex also showed specific interactions with its three-base RNA recognition element. Compared with the B. subtilis MazF-RNA complex, our structures showed that residues involved in sequence-specific recognition of target RNA vary between the MazF homologues, therefore explaining the molecular basis for their different RNA recognition sequences. In addition, local conformational changes of the loops in the RNA binding site of MazF-mt1 appear to play a role in MazF targeting different RNA lengths and sequences. In contrast, the MazF-mt3-RNA complex is in a non-optimal RNA binding state with a symmetry-related MazF-mt3 molecule found to make interactions with the bound RNA in the crystal. The crystal-packing interactions were further examined by isothermal titration calorimetry (ITC) studies on selected MazF-mt3 mutants. Our attempts to utilize a MazF-mt3 mutant bearing mutations involved in crystal contacts all crystallized with few nucleotides, which are still found to interact with a symmetry mate. However, these different crystal forms revealed the conformational flexibility of loops in the RNA binding interface of MazF-mt3, suggesting their role in RNA binding and recognition, which will require further studies on additional MazF-mt3-RNA complex interactions.

In conclusion, the structures of the MazF-mt1-RNA and MazF-mt3-RNA complexes provide the first structural information on any M. tuberculosis MazF homologues. Supplemented with structure-guided mutational studies on MazF toxicity in vivo, this study has addressed the structural basis of different RNA cleavage specificities among MazF homologues. Our work will guide future studies on the function of other M. tuberculosis MazF and MazE-MazF homologues, and will help delineate their physiological roles in M. tuberculosis stress responses and pathogenesis.

Mechanisms of Cdc42 Polarization in Yeast

Polarization is important for the function and morphology of many different cell types. The keys regulators of polarity in eukaryotes are the Rho-family GTPases. In the budding yeast Saccharomyces cerevisiae, which must polarize in order to bud and to mate, the master regulator is the highly conserved Rho GTPase, Cdc42. During polarity establishment, active Cdc42 accumulates at a site on the plasma membrane characterizing the “front” of the cell where the bud will emerge. The orientation of polarization is guided by upstream cues that dictate the site of Cdc42 clustering. However, in the absence of upstream cues, yeast can still polarize in a random direction during symmetry breaking. Symmetry breaking suggests cells possess an autocatalytic polarization mechanism that can amplify stochastic fluctuations of polarity proteins through a positive feedback mechanism.

Two different positive feedback mechanisms have been proposed to polarize Cdc42 in budding yeast. One model posits that Cdc42 activation must be localized to a site at the plasma membrane. Another model posits that Cdc42 delivery must be localized to a particular site at the plasma membrane. Although both mechanisms could work in parallel to polarize Cdc42, it is unclear which mechanism is critical to polarity establishment. We directly tested the predictions of the two positive feedback models using genetics and live microscopy. We found that localized Cdc42 activation is necessary for polarity establishment.

While this explains how active Cdc42 localizes to a particular site at the plasma membrane, it does not address how Cdc42 concentrates at that site. Several different mechanisms have been proposed to concentrate Cdc42. The GDI can extract Cdc42 from membranes and selective mobilize GDP-Cdc42 in the cytoplasm. It was proposed that selectively mobilizing GDP-Cdc42 in combination with local activation could locally concentrate total Cdc42 at the polarity site. Although the GDI is important for rapid Cdc42 accumulation at the polarity site, it is not essential to Cdc42 concentration. It was proposed that delivery of Cdc42 by actin-mediated vesicle can act as a backup pathway to concentrate Cdc42. However, we found no evidence for an actin-dependent concentrating pathway. Live microscopy experiments reveal that prenylated proteins are not restricted to membranes, and can enter the cytoplasm. We found that the GDI-independent concentrating pathway still requires Cdc42 to exchange between the plasma membrane and the cytoplasm, which is supported by computational modeling. In the absence of the GDI, we found that Cdc42 GAP became essential for polarization. We propose that the GAP limits GTP-Cdc42 leak into the cytoplasm, which would be prohibitive to Cdc42 polarization.

The Genetics of Success: How Single-Nucleotide Polymorphisms Associated With Educational Attainment Relate to Life-Course Development.

A previous genome-wide association study (GWAS) of more than 100,000 individuals identified molecular-genetic predictors of educational attainment. We undertook in-depth life-course investigation of the polygenic score derived from this GWAS using the four-decade Dunedin Study (N = 918). There were five main findings. First, polygenic scores predicted adult economic outcomes even after accounting for educational attainments. Second, genes and environments were correlated: Children with higher polygenic scores were born into better-off homes. Third, children's polygenic scores predicted their adult outcomes even when analyses accounted for their social-class origins; social-mobility analysis showed that children with higher polygenic scores were more upwardly mobile than children with lower scores. Fourth, polygenic scores predicted behavior across the life course, from early acquisition of speech and reading skills through geographic mobility and mate choice and on to financial planning for retirement. Fifth, polygenic-score associations were mediated by psychological characteristics, including intelligence, self-control, and interpersonal skill. Effect sizes were small. Factors connecting DNA sequence with life outcomes may provide targets for interventions to promote population-wide positive development.

Mosaic image of the artificial light produced by Berlin on the night of September 11, 2010 observed from an altitude of 10,000 ft

Aerial observations of light pollution can fill an important gap between ground based surveys and nighttime satellite data. Terrestrially bound surveys are labor intensive and are generally limited to a small spatial extent, and while existing satellite data cover the whole world, they are limited to coarse resolution. This paper describes the production of a high resolution (1 m) mosaic image of the city of Berlin, Germany at night. The dataset is spatially analyzed to identify themajor sources of light pollution in the city based on urban land use data. An area-independent 'brightness factor' is introduced that allows direct comparison of the light emission from differently sized land use classes, and the percentage area with values above average brightness is calculated for each class. Using this methodology, lighting associated with streets has been found to be the dominant source of zenith directed light pollution (31.6%), although other land use classes have much higher average brightness. These results are compared with other urban light pollution quantification studies. The minimum resolution required for an analysis of this type is found to be near 10 m. Future applications of high resolution datasets such as this one could include: studies of the efficacy of light pollution mitigation measures, improved light pollution simulations, economic and energy use, the relationship between artificial light and ecological parameters (e.g. circadian rhythm, fitness, mate selection, species distributions, migration barriers and seasonal behavior), or the management of nightscapes. To encourage further scientific inquiry, the mosaic data is freely available at Pangaea.

Prudent female allocation by modular hermaphrodites: female investment is promoted by the opportunity to outcross in cyclostome bryozoans

Many sessile, suspension-feeding marine invertebrates mate by spermcasting: aquatic sperm are spawned and gathered by conspecific individuals to fertilize eggs that are generally retained during development. In two phylogenetically distant examples, a cheilostome bryozoan and an aplousobranch ascidian, the receipt of allosperm has previously been shown to alter sex allocation by triggering female investment in eggs and brooding. Here we report experiments demonstrating that two species of cyclostome bryozoan also show restrained female investment in the absence of mating opportunity. In Tubulipora plumosa, the production of female zooids and progeny is much reduced in reproductive isolation. In Filicrisia geniculata, development of distinctive female zooids (gonozooids) begins but halts in the absence of mating opportunity, and no completed gonozooids or progeny result. Reduced female investment in the absence of a mate thus occurs in at least two orders of Bryozoa, but significant differences in detail exist and the evolutionary history within the phylum of the mechanism(s) by which female investment is initiated might be complex. The broadening taxonomic spectrum of examples where female investment appears restrained until allosperm becomes available may signify a general adaptive strategy among outcrossing modular animals, analogous to similarly adaptive sex allocation typical of many flowering plants.

Prudent female allocation by modular hermaphrodites: female investment is promoted by the opportunity to outcross in cyclostome bryozoans

Many sessile, suspension-feeding marine invertebrates mate by spermcasting: aquatic sperm are spawned and gathered by conspecific individuals to fertilize eggs that are generally retained during development. In two phylogenetically distant examples, a cheilostome bryozoan and an aplousobranch ascidian, the receipt of allosperm has previously been shown to alter sex allocation by triggering female investment in eggs and brooding. Here we report experiments demonstrating that two species of cyclostome bryozoan also show restrained female investment in the absence of mating opportunity. In Tubulipora plumosa, the production of female zooids and progeny is much reduced in reproductive isolation. In Filicrisia geniculata, development of distinctive female zooids (gonozooids) begins but halts in the absence of mating opportunity, and no completed gonozooids or progeny result. Reduced female investment in the absence of a mate thus occurs in at least two orders of Bryozoa, but significant differences in detail exist and the evolutionary history within the phylum of the mechanism(s) by which female investment is initiated might be complex. The broadening taxonomic spectrum of examples where female investment appears restrained until allosperm becomes available may signify a general adaptive strategy among outcrossing modular animals, analogous to similarly adaptive sex allocation typical of many flowering plants.

“Niemand zeugt für den Zeugen”. Temporalidad y memoria en la poesía de Paul Celan

El artículo analiza cómo Paul Celan, utilizando recursos arreferenciales y antimiméticos propios de la poésie pure y la poesía absoluta, desarrolla un modelo poético en el que la temporalidad y la memoria son determinantes. En el nuevo modelo, el lenguaje no constituye una realidad autónoma e inmanente; antes bien, se concreta en una acción dialógica y remite a una realidad extralingüística. El mismo texto poético configura un espacio del recuerdo, se erige en un lugar de memoria que, a través de las sedimentaciones históricas que arrastra el lenguaje, da testimonio de lo ocurrido.

La presencia del "flâneur" en "Tetralogie der Erinnerung" de Dieter Forte

Reflejando la ciudad moderna, el flâneur se encuentra atrapado entre dos tiempos: el presente, que se transforma continuamente, y el pasado, que permanece en forma de vestigios materiales. Desde su aparición en la literatura, la trayectoria del flâneur va ligada a los principales cambios históricos, sociales y culturales, que se plasman en distintas texturas urbanas. En todas ellas ejerce una función de nexo entre la ciudad antigua y la nueva que se superpone. El objeto del presente artículo es analizar la evolución de esta figura histórico y literaria como punto de partida para interpretar la obra en prosa Tetralogie der Erinnerung (1992-2004) de Dieter Forte.

Sense making by middlemanagement

Aanleiding voor het onderzoek Deze scriptie sluit aan bij de afstudeerkring “effectieve verandermanagers”. Aanleiding voor dit onderzoek was de brede vraag “Wat onderscheidt een effectieve veranderingsmanager op het middenniveau in organisaties van een minder effectieve bij het implementeren van veranderingen?” Binnen deze brede vraag past de centrale vraagstelling in dit onderzoek: “Welke neerwaartse activiteiten oefenen middenmanagers uit in een sensemakingproces tijdens een verandering?“ Middenmanager Allereerst definiëren we het begrip ‘middenmanager’. De middenmanager bevindt zich op een kruispunt: In de verticale lijn tussen het topmanagement en de werkvloer, op de horizontale lijn tussen de diverse afdelingen (Nonaka,1994). Ten behoeve van mijn onderzoek sluit ik mij aan bij de positionering van Huy (2001). Hij plaatst de middenmanager 2 lagen onder de CEO en 1 laag boven lijnmedewerkers en professionals. In een veranderingsproces heeft de middenmanager verschillende rollen te vervullen. Deze verschillende rollen zijn, onder anderen, beschreven door Huy (2001) en Quinn (1998). Zij noemen: entrepreneur, communicator en therapeut, stimulator, mentor, innovator, bemiddelaar, producent, bestuurder, coördinator, controleur. De onderzoekers zijn het er over eens dat de middenmanager moet balanceren en doseren in de verschillende rollen om effectief te kunnen zijn in een veranderingsproces. Sensemakingproces Dit onderzoek probeert meer kennis te genereren over welke neerwaartse activiteiten middenmanagers uitoefenen gedurende een sensemakingproces tijdens een verandering. We definiëren het begrip ‘sensemakingproces’. Het sensemakingproces vindt plaats als mensen geconfronteerd worden met boodschappen of gebeurtenissen die nieuw zijn. Door met deze nieuwe informatie te kijken naar de bestaande werkelijkheid, is een bewustwording op gang geholpen die kan leiden tot verandering. Er is nog weinig onderzoek gedaan naar de activiteiten (wat doen middenmanagers op dagelijkse basis) van middenmanagers in sensemakingprocessen. Rouleau & Balogun (2007) hebben dat wel onderzocht en onderscheiden de volgende vier sensegivingactiviteiten: het uitrollen van netwerken; het distribueren van gedachten door het voeren van gesprekken; het identificeren van sociale en culturele systemen. Relevantie onderzoek De externe validiteit van het hierboven genoemde onderzoek van Rouleau & Balogun (2007) is echter beperkt, doordat deze is uitgevoerd onder een kleine populatie in Canada en het Verenigd Koninkrijk. Mijn onderzoek wil een bijdrage leveren aan de toename van de externe validiteit door te verifiëren of de neerwaartse activiteiten van de middenmanager die gevonden zijn in het onderzoek van Rouleau & Balogun (2007) middels een andere onderzoeksmethode en met een andere onderzoekspopulatie (de Nederlandse zorginstelling Tactus). Wat betreft de praktische relevantie kan gezegd worden dat mijn onderzoek meer inzicht geeft aan de middenmanagers in welke activiteiten zij uitvoeren of zouden kunnen uitvoeren. Zij kunnen zich bewust worden van hun mogelijkheden om invloed uit te oefenen op het sensemakingproces van hun medewerkers. Ik verwacht daarmee hun effectiviteit te vergroten. Centrale vraag en deelvragen Bij de centrale vraag kunnen de volgende deelvragen geformuleerd worden: 1. Wat is de rol van middenmanagers in een sensemakingproces tijdens een verandering? 2. Zijn de neerwaartse sensemakingactiviteiten van middenmanagers (uit de studie van Rouleau & Balogun, 2007) ook te identificeren zijn binnen één Nederlandse GGZ-stichting? 3. Zijn er andere neerwaartse sensemakingactiviteiten van middenmanagers te identificeren? Conceptuele model Het model dat de basis is voor de beantwoording van de tweede en derde deelvraag, is gebaseerd op de literatuur. In dit model worden de sensemakingactiviteiten van de middenmanager als een onafhankelijke variabele gezien die direct invloed heeft op het sensemakingproces binnen het team. Daarbij kunnen we enkele mediërende en modererende factoren onderscheiden. Als modererende factor noemen we, ten eerste, de mate waarin voor het teamlid het persoonlijke triggerpoint bereikt is. Hoe dichter genaderd, hoe meer kans op verandering bij dit teamlid (Kloosterboer, 2008). Ten tweede noemen we het sneeuwbaleffect van de positieve feedback (Kelman, 2005): hoe verder in het proces, hoe meer kans op verandering. Tenslotte noemen we als modererende factor het emotiemanagement van de middenmanager. Hoe meer de middenmanager in staat is de balans te vinden, hoe meer kans op verandering (Huy, 2002). Als mediërende factor kunnen we de horizontale sensegiving noemen, ofwel de sensegiving door peers (Balogun & Johnson, 2005). Deze sensegiving kan, los van de sensemakingactiviteiten van de manager een geheel eigen verandering op gang brengen. Het kan dus gezien worden als (een deel van) de verklaring voor het sensemakingproces binnen het team. Dit onderzoek beperkt zich tot het bestuderen van de sensemakingactiviteiten van de middenmanager en hun effect op het sensemakingproces binnen het team. In het onderzoek worden de modererende factoren en de mediërende factor dus niet meegenomen. Onderzoeksopzet Het onderzoek is opgesteld als multiple-case design, toetsend onderzoek. Toetsend, omdat de externe validering van de neerwaartse sensemakingactiviteiten van de middenmanager nog laag is. Het multiple-case design biedt de mogelijkheid om cases met elkaar te vergelijken en bredere steun te vinden voor de geformuleerde proposities. De voorgenomen bronnen waren een (één op één) interview met acht middenmanagers, een groepsinterview met meerdere medewerkers per middenmanager en documenten. De focus in alle interviews was de middenmanager en diens sensemakingactiviteiten. De opgevraagde en aangeleverde documenten zijn echter geen adequate bron van informatie gebleken. Resultaten De eerste deelvraag is beantwoord middels literatuurstudie. De onderzoekers zijn het er over eens dat de middenmanager moet balanceren en doseren in de verschillende rollen om effectief te kunnen zijn in een veranderingsproces. De tweede en derde deelvraag werden beantwoord middels een multiple-case design onderzoek. De resultaten uit dit onderzoek laten zien dat de neerwaartse sensemakingactiviteiten uit de studie van Rouleau & Balogun (2007), inderdaad gevonden werden binnen de genoemde GGZ-stichting. De hypothese is daarmee geverifieerd. De derde conclusie is dat er geen andere neerwaartse sensemakingactiviteiten van middenmanagers zijn geïdentificeerd. Door de verkregen informatie over de vier sensemakingactiviteiten van middenmanager terug te brengen naar handelingsniveau, is zichtbaar geworden dat er verschillen zijn tussen de middenmanagers. De handelingen in gezamenlijkheid leidden wel tot de vier sensemakingactiviteiten. Discussie De casestudie heeft geen nieuwe activiteiten aangetoond. Dat maakt de definiëring van het begrip steviger. Door de vier sensemakingactiviteiten (Rouleau & Balogun, 2007) op een derde niveau op te delen in kleinere eenheden, draagt deze casestudie tevens bij aan een nadere definiëring van het begrip ‘neerwaartse sensemakingactiviteiten van de middenmanager’. Door de verduidelijking van het begrip is kwantitatief onderzoek beter mogelijk, waardoor nu ook causale verbanden tussen de neerwaartse sensemakingactiviteiten van de middenmanager en de sensemaking bij de medewerkers gemaakt kunnen worden. Aanbevelingen In een vervolgonderzoek zou het conceptuele model deels of geheel onderzocht kunnen worden. Met een dergelijk onderzoek, of meerdere onderzoeken zou meer duidelijkheid kunnen komen over de mate van invloed van de mediërende factoren en modererende factor op de sensemaking. Aanbeveling voor verder onderzoek is om de onderzoeksmethode te variëren of uit te breiden met bijvoorbeeld participerende observatie. Dan zou waarneming kunnen plaatsvinden vanuit het perspectief van een betrokkene (Yin, 2003). Een andere methode om de activiteiten beter te inventariseren is het laten bijhouden door managers van hun sensemakingactiviteiten. Een bijkomende propositie die dit onderzoek oplevert, is dat de relatie tussen al dan niet hebben van onbewuste kennis en het beschikken over ervaring als leidinggevende niet gelegd kan worden. Deze propositie zou verder onderzocht kunnen worden.

Gedragsmatige en Emotionele Betrokkenheid in de Mbo Opleidingen Allround Operationeel Technicus en Koopvaardij Officier Alle Schepen Bij het Scheepvaart en Transport College

Rikhof, O. (2016).Gedragsmatige en Emotionele Betrokkenheid in de Mbo Opleidingen Allround Operationeel Technicus en Koopvaardij Officier Alle Schepen Bij het Scheepvaart en Transport College. Mei, 26, 2016, Heerlen, Nederland: Open Universiteit