Dissertations / Theses on the topic 'Biological interactions data'

Dans la première partie de cette thèse, nous avons étudié l'élasticité d'une molécule d'ADN simple brin à l'aide de pinces magnétiques. Les modèles de polymères idéaux ne rendent pas bien compte de l'élasticité de cette molécule, alors qu'ils décrivent très bien l'ADN double brin. Nous avons donc étudié expérimentalement l'élasticité d'une molécule simple brin dans différentes conditions salines, i.e. d'écrantage de charges, et dans des conditions modulant les interactions internes du polymère. En utilisant des conditions dénaturantes, nous avons pu séparer les effets des différentes interactions intramoléculaires et ainsi mieux caractériser leur importance respective pour décrire l'élasticité de la molécule. Il est ressorti de ces mesures qu'une description complète de l?ADN simple brin doit prendre en compte d'une part la formation de structures secondaires à basses forces, et d'autre part les effets de volume exclu: contrairement au double brin, le simple brin est tellement flexible que les répulsions électrostatiques dues aux groupements phosphates le long de la chaîne ne peuvent plus être négligées. Des simulations numériques prenant en compte ces deux effets sont en excellent accord avec nos observations expérimentales. Dans la seconde partie de cette thèse, nous avons étudié l'activité de deux hélicases à l'échelle de la molécule unique. Les hélicases sont des moteurs moléculaires qui catalysent la séparation des deux brins de la double hélice d?ADN, permettant ainsi l'accès aux bases individuelles formant le code génétique. Dans notre expérience, une unique molécule d'ADN double brin était immobilisée par pinces magnétiques et son extension mesurée avec une précision de 10 nm. Ceci nous a permis de suivre l'activité des hélicases, puisque celles-ci provoquent un changement de l'extension de la molécule lorsque le double brin est converti en simple brin. Cette méthode présente l'avantage de permettre l'observation en temps réel de l'activité d'une seule protéine. L'analyse statistique des données nous a permis d'accéder aux distributions complètes de vitesse et de processivité des enzymes. Nous avons ainsi caractérisé le comportement dynamique d?hélicases uniques (leur vitesse, leur processivité, leur coopérativité et leur pas élémentaire sur l'ADN). Le suivi en temps réel de l'activité des hélicases nous a permis d'observer une instabilité dans leur mode d'ouverture, et ainsi de rendre compte de mesures de vitesse obtenues en volume.

Le microscope à force atomique (AFM) est un outil privilégié pour sonder la matière à l'échelle nanométrique. Dans cette thèse, nous l'utilisons comme instrument de mesure de force. Nous montrons que la mesure des fluctuations thermiques des ressorts permet de déterminer précisément leur raideur à condition d'utiliser un modèle qui prend en compte la forme des modes et la méthode de détection. A l'aide de nouvelle méthodes d'analyse des courbes de rétraction, nous étudions la conformation de polymères et de copolymères adsorbés, ainsi que l'interaction spécifique entre un complexe du nickel (Ni-NTA) et l'acide aminé histidine. Nous mettons en évidence des comportements inattendus en présence de liens multiples et nous en proposons une interprétation basée sur un équilibre entre formations et ruptures des liaisons. Nous présentons des premiers résultats expérimentaux concernant la transition conformationnelle de la polylysine sous étirement.

Physical visualizations are artifacts that materialize abstract data. They take advantage of human natural abilities to interact with information in the physical world. These visualizations present an opportunity to be applied on new application domains. With the objective of discovering if physical visualizations can support remote monitoring of biological data, a technology probe is presented in the form of a reversed voodoo doll. This probe uses the natural affordance of an anthropomorphic figure to represent a person and reverses the concept of voodoo dolls in a playful way. The scenario of safety is selected for testing physical visualizations of bio-data. Two measurements from the human body, heart rate and motion are chosen as a light way to monitor remotely over a person’s conditions. During the study, a group of six participants were exposed to the technology probe and their interactions with it were observed. The study reports on the users’ interpretations of the data and uses given to the alternative modalities of the probe. The results suggest that the data mapping to the object’s body parts was effective for conveying meaning. Additionally, the results confirm that the use of multiple modalities in physical visualizations offers an opportunity to present information in situated contexts in the real world. The degree of physicality achieved by the reversed voodoo doll and the effects of the selected metaphors are discussed. In conclusion, it is argued that the responses and interpretations from the users indicate that the reversed voodoo doll served as a means in its own right to transmit information for monitoring of bio-data.<br>Fysiska visualiseringar är artefakter som materialiserar abstrakt data. Genom att använda sig av mänskliga naturliga förmågor interagerar de med information i den fysiska världen. Dessa visualiseringar skapar möjligheter för appliceringar inom nya tillämpningsområden. För att undersöka om fysiska visualiseringar kan stödja fjärrövervakning av biologisk data introducerades en sond i form av en omvänd voodoodocka. Med en människolik figur representerar denna sond en verklig person. På så sätt utnyttjar den naturliga associationer till mänskliga egenskaper och omvänder konceptet vodoodockor på ett lekfullt sätt. De fysiska visualiseringarna av biologisk data testas ur ett säkerhetsperspektiv. Två värden, hjärtfrekvens och rörelse, mäts från en människokropp för att göra det möjligt att övervaka en persons tillstånd på distans. Under studien observeras sex användare då de interagerar med sonden. Studien visar hur användarna tolkar sondens data och hur användningen varierar med avseende på sondens olika modaliteter. Resultaten från denna studie tyder på att datamappningen till sondens kroppsdelar effektivt ökade förståelsen. Dessutom bekräftar resultaten att användning av flera modaliteter i fysiska visualiseringar gör det möjligt att presentera information, anpassat till olika situationer i den verkliga världen. Till vilken grad voodoodockan ger en känsla av kroppslighet samt konsekvenser av de valda metaforerna diskuteras. I slutsatsen hävdas att användarnas svar och tolkningar tyder på att den omvända voodoodockan fungerade som ett medel för att övervaka biologisk data.

Microarray technology enables researchers to measure the expression levels of thousands of genes simultaneously to understand relationships between genes, extract pathways, and in general understand a diverse amount of biological processes such as diseases and cell cycles. While microarrays provide the great opportunity of revealing information about biological processes, it is a challenging task to mine the huge amount of information contained in the microarray datasets. Generally, since an accurate model for the data is missing, first a clustering algorithm is applied and then the resulting clusters are examined manually to find genes that are related with the biological process under inspection. We need automated methods for this analysis which can be used to eliminate unrelated genes from data and mine for biologically important genes. Here, we introduce a general methodology which makes use of traditional clustering algorithms and involves integration of the two main sources of biological information, Gene Ontology and interaction networks, with microarray data for eliminating unrelated information and find a clustering result containing only genes related with a given biological process. We applied our methodology successfully on a number of different cases and on different organisms. We assessed the results with Gene Set Enrichment Analysis method and showed that our final clusters are highly enriched. We also analyzed the results manually and found that most of the genes that are in the final clusters are actually related with the biological process under inspection.

Doutoramento em Ciências da Computação<br>O estudo em larga escala de proteínas e das suas eventuais interações tem sido alvo de bastante atenção pela comunidade científica. Os métodos de análise experimentais têm produzido uma quantidade imensa de dados, que têm sido armazenados em diferentes repositórios. A disponibilidade destes dados, muitos deles curados por especialistas, abre um leque de oportunidades de investigação. Dado que as técnicas experimentais de identificação de interações proteína- proteína (PPIs) são dispendiosas, demoradas e requerem análise de um perito, os métodos computacionais têm vindo a dar um contributo valioso neste domínio. Embora já existam alguns métodos computacionais para prever PPIs, estes apenas se focam na previsão de PPIs dentro da mesma espécie. Deste modo, estes métodos não podem ser aplicados diretamente na previsão de PPIs entre diferentes espécies. Estas interações estão na origem das doenças infecciosas, sendo essencial a sua identificação para prevenir e travar estados de doença. Esta tese apresenta novos modelos computacionais para prever PPIs entre diferentes espécies, para estimar o impacto destas interações no hospedeiro, e para prever interações entre medicamentos e os seus alvos proteicos. A inovação desta proposta advém do uso de técnicas de aprendizagem automática em combinação com análise de redes biológicas. Os resultados obtidos irão ser úteis para compreender as associações entre mecanismos biológicos e estados de doença, e para o desenvolvimento de técnicas de diagnóstico e terapia.<br>Proteomics and the study of protein-protein interactions (PPIs) have become a trending research topic in the past decade. Thanks to the high-throughput experimental methodologies, the amount of data generated and uploaded to heterogeneous data repositories is increasing exponentially, presenting several research opportunities. Since experimental protein interaction identification techniques are expensive, time consuming, and require expert analysis, computational methods will prove crucial to tackle this issue. Several efforts have already been made regarding this problem, resulting in models for predicting intra-species interactions. Nevertheless, these models cannot be directly applied to inter-species PPI prediction. Inter-species PPIs are responsible or the basis of colonization and infection by bacterial pathogens and thus, their identification is crucial to prevent and treat disease states. This thesis proposes new computational models to predict inter-species PPIs, the impact of such associations to the human host, and associations between drugs and bacterial targets. The innovation of this proposal comes from the use of machine learning techniques tuned to biological problems, combined with complex biological network analysis. The obtained results will offer the means to better understand the associations between biological mechanisms and disease states, and aid the development of new diagnostic and therapeutic tools.

Le Pacifique tropical ouest (120°E-160°W, 20°S-20°N) est une région complexe où coexistent deux écosystèmes aux frontières variables, et aux caractéristiques physiques et biologiques très différentes : la warm pool à l'ouest, écosystème oligotrophe limité par le nitrate, et la cold tongue à l'est, limitée par le fer. Nous utilisons les concentrations en chlorophylle SeaWiFS comme proxy pour la biomasse phytoplanctonique sur la période septembre 1997 à décembre 2004. Une analyse statistique nous permet de dégager les principaux modes spatiaux-temporels où se concentre la variabilité de la chlorophylle. Nous étudions ensuite successivement le cycle saisonnier, une manifestation de l'activité interannuelle et l'action des coups de vent d'ouest à l'échelle intrasaisonnière. Nous montrons ainsi que la variabilité des vents et des courants contrôle au premier ordre la biologie dans le Pacifique tropical ouest. Cette étude met également en lumière l'influence de la topographie sur la variabilité de la chlorophylle, bien au-delà des régions côtières.

L'océan est le plus grand réservoir d'énergie solaire de notre planète. La quantité de chaleur qu'il est capable de stocker est modulée par sa circulation complexe, opérant sur une vaste gamme d’échelles allant du centimètre à la dizaine de milliers de kilomètres. Cette thèse s'intéresse à deux types de processus océaniques: les tourbillons de mésoéchelle, d'une taille de 100 à 300 km, et les fronts de sous-mésoéchelle, d'une taille inférieure à 50 km. L'idée communément admise est que les mouvements agéostrophiques de sous-mésoéchelle sont principalement confinés à la couche de mélange océanique de surface et sont faibles dans l'océan intérieur. Cette vision classique de la dynamique océanique repose sur l'hypothèse que l'océan intérieur est en équilibre quasi-géostrophique, empêchant la formation de forts gradients de densité en profondeur. Cette thèse remet en question ce paradigme en se basant sur des observations CTD in situ à haute résolution collectées par des éléphants de mer instrumentés, des images satellite d’élévation de la surface de l’océan, et des sorties de modèle à haute résolution dans le Courant Circumpolaire Antarctique.Les résultats indiquent que les mouvements agéostrophiques sont (i) générés par le champ tourbillonnaire de mésoéchelle via des processus defrontogenèse, et (ii) ne sont pas limités à la couche de mélange de surface ; bien au contraire, ils pénètrent dans l'océan intérieur jusqu'à 1000 m deprofondeur. Ces fronts agéostrophiques de sous-mésoéchelle sont associés à d'importants flux de chaleur dirigés de l'intérieur de l'océan vers la surface, d'une amplitude comparable aux flux air-mer.Cet effet peut potentiellement altérer la capacité de stockage de chaleur de l'océan et devrait être le plus fort dans les zones tourbillonnaires telles que le Courant Circumpolaire Antarctique, le Kuroshio et le Gulf Stream, les trois courants clefs du système climatique. Il apparaît ainsi que les fronts agéostrophiques de sous-mésoéchelle représentent une voie importante, mais encore largement méconnue, pour le transport de chaleur, de nutriments et de gaz entre l'intérieur et la surface de l'océan, avec des répercussions potentiellement majeures pour les systèmes biogéochimique et climatique<br>The ocean is the largest solar energy collector on Earth. The amount of heat it can store is modulated by its complex circulation, which spans a broad range of spatial scales, from centimeters to thousands of kilometers. This dissertation investigates two types of physical processes: mesoscale eddies (100-300 km size) and submesoscale fronts (£ 50 km size). To date, ageostrophic submesoscale motions are thought to be mainly trapped within the ocean surface mixed layer, and to be weak in the ocean interior. This is because, in the classical paradigm, motions below the mixed layer are broadly assumed to be in quasigeostrophic balance, preventing the formation of strong buoyancy gradients at depth. This dissertation introduces a paradigm shift; based on a combination of high-resolution in situ CTD data collected by instrumented elephant seals, satellite observations of sea surface height, and high-resolution model outputs in the Antarctic Circumpolar Current, we show that ageostrophic motions (i) are generated by the backgound mesoscale eddy field via frontogenesis processes, and (ii) are not solely confined to the ocean surface mixed layer but, rather, can extend in the ocean interior down to depths of 1 000 m. Deepreaching ageostrophic fronts are shown to drive an anomalous upward heat transport from the ocean interior back to the surface that is larger than other contributions to vertical heat transport and of comparable magnitude to air-sea fluxes. This effect can potentially alter oceanic heat uptake and will be strongest in eddy-rich regions such as the Antarctic Circumpolar Current, the Kuroshio Extension, and the Gulf Stream, all of which are key players in the climate system. As such, ageostrophic fronts at submesoscale provide an important, yet unexplored, pathway for the transport of heat, chemical and biological tracers, between the ocean interior and the surface, with potential major implications for the biogeochemical and climate systems

La importancia de comprender los procesos biológicos ha estimulado el desarrollo de métodos para la detección de interacciones proteína-proteína. Esta tesis presenta PIANA (Protein Interactions And Network Analysis), un programa informático para la integración y el análisis de redes de interacción proteicas. Además, describimos un método que identifica motivos de interacción basándose en que las proteínas con parejas de interacción comunes tienden a interaccionar con esas parejas a través del mismo motivo de interacción. Encontramos que las proteínas altamente conectadas (i.e., hubs) con múltiples motivos tienen mayor probabilidad de ser esenciales para la viabilidad de la célula que los hubs con uno o dos motivos. Finalmente, presentamos un método que predice genes relacionados con cáncer mediante la integración de redes de interacción proteicas, datos de expresión diferenciada y propiedades estructurales, funcionales y evolutivas. El valor de predicción positiva es 71% con sensitividad del 1%, superando a otros métodos usados independientemente.<br>The importance of understanding cellular processes prompted the development of experimental approaches that detect protein-protein interactions. Here, we describe a software platform called PIANA (Protein Interactions And Network Analysis) that integrates interaction data from multiple sources and automates the analysis of protein interaction networks. Moreover, we describe a method that delineates interacting motifs by relying on the observation that proteins with common interaction partners tend to interact with these partners through the same interacting motif. We find that highly connected proteins (i.e., hubs) with multiple interacting motifs are more likely to be essential for cellular viability than hubs with one or two interacting motifs. Furthermore, we present a method that predicts cancer genes by integrating protein interaction networks, differential expression studies and structural, functional and evolutionary properties. For a sensitivity of 1%, the positive predictive value is 71%, which outperforms the use of any of the methods independently.

Over the last several decades, the emerging ‘integrated’ view of the cell has triumphed over the ‘one gene/one protein/one function’ paradigm. This is illustrated by the biologically opposite effects of key regulatory proteins in different cell types, in established versus primary cells, and in vitro versus in vivo situations. The persistent theme throughout this dissertation is the integration of a wide range of data sources for the purpose of understanding distinct cellular contexts. We first use circadian expression data from human epidermal stem cells to discover waves of transcripts expressed in tune with known clock genes and show that time-of-day dependent responses to proliferation/differentiation cues is important for skin homeostasis. We then combine this expression data with information on protein structures and complexes to describe how protein-complex assembly is temporally regulated during differentiation. Lastly, we show that human protein complexes are composed of a stable ‘core’ and a plastic ‘periphery’ whose tissue-specific expression allows protein complexes to function in a context-dependent manner.<br>En las últimas décadas, la emergente vista integrativa de la célula ha triunfado sobre el paradigma histórico: ‘un gene/una proteína/una función’. Esto es ilustrado por los efectos biológicos opuestos de proteínas regulatorias clave en cultivos celulares inmortalizados frente a primarios e in vitro frente a in vivo. El tema persistente en este disertación es la integración de un amplio set de datos para estudiar los distintos contextos celulares. En primer lugar, utilizamos los datos de expresión génica obtenidos de células madre epidérmicas para descubrir las ondas de transcripción expresadas en sintonía con los genes conocidos de los ritmos circadianos. En este estudio demostramos que las respuestas de las células madres a las señales de proliferación/diferenciación dependen de hora del día y el tiempo circadiano es importante para la homeostasis de la piel. Posteriormente, combinamos estos datos de expresión con la información estructural de proteínas y complejos proteicos para describir la regulación temporal de complejos durante el proceso de diferenciación. Por último, mostramos que los complejos de proteínas humanos están compuestos de un ‘núcleo’ estable y una 'periferia' plástica cuya expresión específica de tejido celular permite que los complejos de proteínas funcionen de una manera dependiente del contexto.

Climate change affects lake ecosystems in many ways by direct and indirect temperature impacts on hydrophysical structure, hydrology, chemical cycles and on biological interactions. The identification of these climate signals can be complicated and superimposed by other environmental changes, such as land use changes. The aim of this thesis was to seperate temperature effects from effects of management and other environmental influences and to understand the underlying complex processes causing significant changes of ecosystem states. This understanding is important for decisions of lake and reservoir managers to counteract unfavorable consequences of climate change. For the recent study, long-term data of meteorological, hydrophysical and biological variables (phytoplankton, crustacean zooplankton, fish) of the German drinking water reservoir Saidenbach were analysed. Based on this long-term data set, strong indicators for climate induced changes have been identified. In particular, increasing water temperatures since 1975, earlier break up of ice covers and an altered hydrophysical structure could be detected. Thereby, stratification stability increased and turbulent mixing decreased in summer. The water of the reservoir warmed more than the tributaries resulting in a trend to deeper entrainment of the inflows. As further indicators of climate change, an increased annual biomass of phytoplankton and species shifts in the phytoplankton community in spring and summer had been observed. During the spring mass development, the diatom Aulacoseira subarctica became dominant in recent years with warm winters and early ice-out. Its unusual spatial pattern with occurrences in aphotic depths could be explained by easier resuspension compared to other diatoms. By being resuspended first and establishing a high inoculum, A. subarctica profits from an earlier ice-out and earlier full circulation. In spite of a reduced nutrient loading to the epilimnion, in summer, the diatom Fragilaria crotonensis was displaced increasingly by cyanobacteria. This species shift could be explained well by the hydrophysical regime shift. Although, the annual total phytoplankton biomass increased since 1990, the crustacean zooplankton in Saidenbach reservoir did not seem to profit from improved food resources. To the contrary, Daphnia abundances reduced tremendously. We could show that the influcence of fish stocks were underestimated. The stocked silvercarp may have contributed up to 70 % of the total zooplanktivorous fish biomass which had a temperature and density dependent effect. The faster growth of Daphnia at higher temperatures could not compensate for the more actively grazing fish when stock of zooplankitvorous fish was too high. Still, temperature was identified as the most important factor that explained 29 % of the zooplankton phenology, while the second most important predictors were zooplanktivorous fish biomass and nutrient loading, explaining 18 % of the variance. The importance of submerged macrophytes in shallow lakes is well investigated. To increase also the understanding of their impact and their role during climate change on water quality in deep lakes, a model for stratified lakes that includes submerged macrophytes was developed. The simulations showed that macrophyte effects were mainly positive for water quality and macrophytes in deep lakes were able to potentially reduce summer phytoplankton, especially cyanobacteria by 50 % in 11 m deep and still by 15 % in 100 m deep oligotrophic lakes. Nutrient competition with phytoplankton contributed most to this macrophyte effect. In conclusion, for deep lake restoration the re-establishment of submerged macrophytes might be as important as for shallow lakes. The full lake model includes hydrophysical and ecological submodules and thus will allow further comprehensive climate simulations and the evaluation of the effectivity of adaptive strategies and scenarios for deep lakes and reservoirs.<br>Der Klimawandel beeinflusst Seeökosysteme vielfältig durch direkte und indirekte Temperatureffekte auf die hydrophysikalische Struktur, die Hydrologie, chemische Kreisläufe und biologische Interaktionen. Die Identifikation von Klimasignalen kann durch Landnutzungs- und weitere Umweltveränderungen überlagert werden. Ziel dieser Arbeit war es, Temperatureffekte von Effekten zu unterscheiden, die durch Gewässermanagement oder anderen Umweltveränderungen verursacht werden. Weiterhin sollten komplexe Prozesse verstanden werden, die zu signifikanten Veränderungen in Seeökosystemen führen. Dieses Verständnis ist für Talsperren- und Gewässermanager von besonderer Bedeutung, um ungewünschten Folgen des Klimawandels entgegenwirken zu können. Für die Studie wurden Langzeitdaten für meteorologische, hydrophysikalische und biologische Variablen (Phytoplankton, Crustaceen-Zooplankton, Fischbesatz) der Talsperre Saidenbach ausgewertet. Mehrere Indikatoren für die Auswirkungen des Klimawandels konnten basierend auf diesen Daten identifiziert werden. Diese gehören insbesondere eine Erhöhung der Wassertemperatur seit 1975, zeitigere Eisaufbrüche und eine veränderte Schichtungsstruktur. Dabei wurde im Sommer die Schichtungsstabilität höher und die Intensität der Durchmischung geringer. Das Wasser in der Talsperre erwärmte sich stärker als die Zuflüsse, wodurch diese sich zunehmend tiefer und unterhalb der Thermokline einschichten. Eine zunehmende jährliche Phytoplanktonbiomasse und Artenwechsel innerhalb der Planktongemeinschaft sind weitere Indikatoren für Klimafolgen. Die Kieselalge Aulacoseira subarctica erlangte in Jahren mit warmen Wintern und zeitigen Eisaufbrüchen eine Dominanz während der Frühjahrsentwicklung. Das ungewöhnliche Auftreten dieser Art in aphotischen Tiefen konnte durch eine leichtere Resuspension im Vergleich zu anderen Kieselalgen erklärt werden. Durch zeitige Resuspension gleich nach Eisaufbruch kann A. subarctica ein hohes Inokulum etablieren. Trotz reduzierter Nährstoffzufuhr ins Epilimnion wurde im Sommer die Kieselalge Fragilaria crotonensis vermehrt durch Cyanobakterien verdrängt, was jedoch gut mit den Änderungen der hydrophysikalischen Struktur erklärt werden kann. Obwohl seit 1990 insgesamt mehr Phytoplankton zur Verfügung steht konnte das Crustaceen- Zooplankton in der Talsperre Saidenbach nicht von diesen verbesserten Nahrungsbedingungen profitieren. Die Daphnia-Abundanzen waren seit 1990 stark verringert. Es konnte gezeigt werden, dass der Einfluss des Fischbesatzes unterschätzt wurde und die künstlich ins System eingebrachten Silberkarpfen zeitweise bis zu 70% der zooplanktivoren Fischbiomasse ausgemacht haben. Zoo- planktivore Fische haben einen temperatur- und dichteabhängigen Effekt auf das Zooplankton. Das schnellere Populationswachstum von Daphnia kann bei hohem Besatz mit zooplanktivoren Fischen nicht die erhöhte Fraßaktivität der Fische ausgleichen. Dennoch konnte Temperatur als der wichtigste Einflussfaktor auf die Phänologie des Zooplanktons identifiziert werden, gefolgt von zooplanktivorem Fisch und Nährstoffzufuhr. Die Wichtigkeit von submersen Makrophyten in Flachseen ist gut untersucht. Um den Einfluss von Makropyhten auf die Wasserqualität während des Klimawandels auch in tiefen Seen abschätzen zu können, wurde ein komplexes Seemodell entwickelt. Die Simulationen zeigen, dass sich Makrophyten hauptsächlich positiv auf die Wassergüte auswirken und zur Reduktion von Phytoplankton, insbesondere von Cyanobakterien im Sommer, beitragen. In einem 11 m tiefen See betrug die Reduktion 50 %, in 100 m tiefen oligotrophen Seen immer noch 15 %. Die Konkurrenz um Nährstoffe mit dem Phytoplankton war dabei die ursächliche Makrophyten-Plankton-Interaktion. Submerse Makrophyten könnten für die Restaurierung von tiefen Seen folglich genauso wichtig sein, wie für Flachseen. Das komplette Seemodell enthält hydrophysikalische und ökologische Module und ermöglicht damit weitere umfassende Simulationen zur Untersuchung der Auswirkungen des Klimawandels und zur Evaluation von Adaptionsstrategien für Seen und Talsperren.

Quantitative exploration of biological pathway networks must begin with a qualitative understanding of them. Often researchers aggregate and disseminate experimental data using regulatory diagrams with ad hoc notations leading to ambiguous interpretations of presented results. This thesis has two main aims. First, it develops software to allow researchers to aggregate pathway data diagrammatically using the Molecular Interaction Map (MIM) notation in order to gain a better qualitative understanding of biological systems. Secondly, it develops a quantitative biological model to study the effect of DNA damage on circadian rhythms. The second aim benefits from the first by making use of visual representations to identify potential system boundaries for the quantitative model. I focus first on software for the MIM notation - a notation to concisely visualize bioregulatory complexity and to reduce ambiguity for readers. The thesis provides a formalized MIM specification for software implementation along with a base layer of software components for the inclusion of the MIM notation in other software packages. It also provides an implementation of the specification as a user-friendly tool, PathVisio-MIM, for creating and editing MIM diagrams along with software to validate and overlay external data onto the diagrams. I focus secondly on the application of the MIM software to the quantitative exploration of the poorly understood role of SIRT1 and PARP1, two NAD+-dependent enzymes, in the regulation of circadian rhythms during DNA damage response. SIRT1 and PARP1 participate in the regulation of several key DNA damage-repair proteins and are the subjects of study as potential cancer therapeutic targets. In this part of the thesis, I present an ordinary differential equation (ODE) model that simulates the core circadian clock and the involvement of SIRT1 in both the positive and negative arms of circadian regulation. I then use this model is then used to predict a potential role for the competition for NAD+ supplies by SIRT1 and PARP1 leading to the observed behavior of primarily phase advancement of circadian oscillations during DNA damage response. The model further predicts a potential mechanism by which multiple forms of post-transcriptional modification may cooperate to produce a primarily phase advancement.

A raingauge network made of six stations was installed in the Hyblean region. Stations were located at different altitudes (from 5 m to 986 m a.s.l.) and along two directions (E-W and SW-NE). Rainwater samples were monthly collected for stable isotope measurements. Spatial distribution of rainwater isotope composition has confirmed the wet air masses move from South-East/South-West toward North. Water balance has highlighted that the annual volume of infiltrating waters is in the range of 1-1.5 *105 m3 Km-2. 82 well waters and 12 spring waters located within the Hyblean Plateau (South-Estern Sicily), were also collected from 1999 to 2001 during several surveys for chemical (major,minor and trace elements) analyses. Water chemistry allowed to identify two main aquifers: the first aquifer hosted within sedimentary rocks is characterized by earthalkaline bicarbonate waters, while the second aquifer, located within the volcanic deposits (mainly towards North- North-East) is characterized by groundwaters evolving from earthalkaline bicarbonate water-type towards a Na-HCO3-type. A slightly anomaly in water temperature (24-28°C) have been identified along the northern margin, while the lower Eh values have been recorded along the M.Lauro-Scicli and the Hyblean Malta Escarpment fault systems. Isotope composition of groundwaters has suggested the occurrence of evaporative processes during soil infiltration having a dD/d18O slope close to 4.5. Chemical and isotope composition of dissolved gases (d13CTDIC, d13CCH4, 3He/4He) have revealed, as expected, that deeply-derived gases rise along the main tectonic discontinuities. Chemical and isotope analyses of dissolved carbon have revealed the existence of two sampling sites (NA and FE samples) attesting the interaction between groundwaters and a consistent amount of deep inorganic carbon dioxide. He isotope ratios (from 0.81Ra to 6.19 Ra) have revealed the occurrence of mixing process, in different proportions, between crustal and mantle components. On the base of the obtained results, a clear picture of the groundwaters circulation within the Hyblean aquifers has been drawn. In framework of projecting of a geochemical network for the continuous monitoring of the local seismic activity the most suitable geochemical parameters and the sites of great interest have been identified.<br>- Unione Europea Fondo Sociale Europeo; - Ministero dell’Università e della Ricerca Scientifica e Tecnologica; - Università degli studi di Palermo<br>Published<br>open

Indiana University-Purdue University Indianapolis (IUPUI)<br>Carbon nanomaterials are widely produced and used in industry, medicine and scientific research. To examine the impact of exposure to nanoparticles on human health, the human airway epithelial cell line, Calu-3, was used to evaluate changes in the cellular proteome that could account for alterations in cellular function of airway epithelia after 24 h exposure to 10 μg/mL and 100 ng/mL of two common carbon nanoparticles, singleand multi-wall carbon nanotubes (SWCNT, MWCNT). After exposure to the nanoparticles, label-free quantitative mass spectrometry (LFQMS) was used to study differential protein expression. Ingenuity Pathway Analysis (IPA) was used to conduct a bioinformatics analysis of proteins identified by LFQMS. Interestingly, after exposure to a high concentration (10 μg/mL; 0.4 μg/cm2) of MWCNT or SWCNT, only 8 and 13 proteins, respectively, exhibited changes in abundance. In contrast, the abundance of hundreds of proteins was altered in response to a low concentration (100 ng/mL; 4 ng/cm2) of either CNT. Of the 281 and 282 proteins that were significantly altered in response to MWCNT or SWCNT, respectively, 231 proteins were the same. Bioinformatic analyses found that the proteins common to both kinds of nanotubes are associated with the cellular functions of cell death and survival, cell-to-cell signaling and interaction, cellular assembly and organization, cellular growth and proliferation, infectious disease, molecular transport and protein synthesis. The decrease in expression of the majority proteins suggests a general stress response to protect cells. The STRING database was used to analyze the various functional protein networks. Interestingly, some proteins like cadherin 1 (CDH1), signal transducer and activator of transcription 1 (STAT1), junction plakoglobin (JUP), and apoptosis-associated speck-like protein containing a CARD (PYCARD), appear in several functional categories and tend to be in the center of the networks. This central positioning suggests they may play important roles in multiple cellular functions and activities that are altered in response to carbon nanotube exposure. To examine the effect of nanotubes on the plasma membrane, we investigated the interaction of short purified MWCNT with model lipid membranes using a planar bilayer workstation. Bilayer lipid membranes were synthesized using neutral 1, 2-diphytanoylsn-glycero-3-phosphocholine (DPhPC) in 1 M KCl. The ion channel model protein, Gramicidin A (gA), was incorporated into the bilayers and used to measure the effect of MWCNT on ion transport. The opening and closing of ion channels, amplitude of current, and open probability and lifetime of ion channels were measured and analyzed by Clampfit. The presence of an intermediate concentration of MWCNT (2 μg/ml) could be related to a statistically significant decrease of the open probability and lifetime of gA channels. The proteomic studies revealed changes in response to CNT exposure. An analysis of the changes using multiple databases revealed alterations in pathways, which were consistent with the physiological changes that were observed in cultured cells exposed to very low concentrations of CNT. The physiological changes included the break down of the barrier function and the inhibition of the mucocillary clearance, both of which could increase the risk of CNT’s toxicity to human health. The biophysical studies indicate MWCNTs have an effect on single channel kinetics of Gramicidin A model cation channel. These changes are consistent with the inhibitory effect of nanoparticles on hormone stimulated transepithelial ion flux, but additional experiments will be necessary to substantiate this correlation.

Indiana University-Purdue University Indianapolis (IUPUI)<br>Proteins are nano-machines that work inside every living organism. Functional disruption of one or several proteins is the cause for many diseases. However, the functions for most proteins are yet to be annotated because inexpensive sequencing techniques dramatically speed up discovery of new protein sequences (265 million and counting) and experimental examinations of every protein in all its possible functional categories are simply impractical. Thus, it is necessary to develop computational function-prediction tools that complement and guide experimental studies. In this study, we developed a series of predictors for highly accurate prediction of proteins with DNA-binding, RNA-binding and carbohydrate-binding capability. These predictors are a template-based technique that combines sequence and structural information with predicted binding affinity. Both sequence and structure-based approaches were developed. Results indicate the importance of binding affinity prediction for improving sensitivity and precision of function prediction. Application of these methods to the human genome and structure genome targets demonstrated its usefulness in annotating proteins of unknown functions and discovering moon-lighting proteins with DNA,RNA, or carbohydrate binding function. In addition, we also investigated disruption of protein functions by naturally occurring genetic variations due to insertions and deletions (INDELS). We found that protein structures are the most critical features in recognising disease-causing non-frame shifting INDELs. The predictors for function predictions are available at http://sparks-lab.org/spot, and the predictor for classification of non-frame shifting INDELs is available at http://sparks-lab.org/ddig.

Indiana University-Purdue University Indianapolis (IUPUI)<br>There have been many endeavors to design humanoid robots that have human characteristics such as dexterity, autonomy and intelligence. Humanoid robots are intended to cooperate with humans and perform useful work that humans can perform. The main advantage of humanoid robots over other machines is that they are flexible and multi-purpose. In this thesis, a human-like robotic arm is designed and used in a task which is typically performed by humans, namely, catching a ball. The robotic arm was designed to closely resemble a human arm, based on anthropometric studies. A rigid multibody dynamics software was used to create a virtual model of the robotic arm, perform experiments, and collect data. The inverse kinematics of the robotic arm was solved using a Newton-Raphson numerical method with a numerically calculated Jacobian. The system was validated by testing its ability to find a kinematic solution for the catch position and successfully catch the ball within the robot's workspace. The tests were conducted by throwing the ball such that its path intersects different target points within the robot's workspace. The method used for determining the catch location consists of finding the intersection of the ball's trajectory with a virtual catch plane. The hand orientation was set so that the normal vector to the palm of the hand is parallel to the trajectory of the ball at the intersection point and a vector perpendicular to this normal vector remains in a constant orientation during the catch. It was found that this catch orientation approach was reliable within a 0.35 x 0.4 meter window in the robot's workspace. For all tests within this window, the robotic arm successfully caught and dropped the ball in a bin. Also, for the tests within this window, the maximum position and orientation (Euler angle) tracking errors were 13.6 mm and 4.3 degrees, respectively. The average position and orientation tracking errors were 3.5 mm and 0.3 degrees, respectively. The work presented in this study can be applied to humanoid robots in industrial assembly lines and hazardous environment recovery tasks, amongst other applications.