Computationally Comparing Biological Networks and Reconstructing Their Evolution

Biological networks, such as protein-protein interaction, regulatory, or metabolic networks, provide information about biological function, beyond what can be gleaned from sequence alone. Unfortunately, most computational problems associated with these networks are NP-hard. In this dissertation, we develop algorithms to tackle numerous fundamental problems in the study of biological networks. First, we present a system for classifying the binding affinity of peptides to a diverse array of immunoglobulin antibodies. Computational approaches to this problem are integral to virtual screening and modern drug discovery. Our system is based on an ensemble of support vector machines and exhibits state-of-the-art performance. It placed 1st in the 2010 DREAM5 competition. Second, we investigate the problem of biological network alignment. Aligning the biological networks of different species allows for the discovery of shared structures and conserved pathways. We introduce an original procedure for network alignment based on a novel topological node signature. The pairwise global alignments of biological networks produced by our procedure, when evaluated under multiple metrics, are both more accurate and more robust to noise than those of previous work. Next, we explore the problem of ancestral network reconstruction. Knowing the state of ancestral networks allows us to examine how biological pathways have evolved, and how pathways in extant species have diverged from that of their common ancestor. We describe a novel framework for representing the evolutionary histories of biological networks and present efficient algorithms for reconstructing either a single parsimonious evolutionary history, or an ensemble of near-optimal histories. Under multiple models of network evolution, our approaches are effective at inferring the ancestral network interactions. Additionally, the ensemble approach is robust to noisy input, and can be used to impute missing interactions in experimental data. Finally, we introduce a framework, GrowCode, for learning network growth models. While previous work focuses on developing growth models manually, or on procedures for learning parameters for existing models, GrowCode learns fundamentally new growth models that match target networks in a flexible and user-defined way. We show that models learned by GrowCode produce networks whose target properties match those of real-world networks more closely than existing models

Saliency Guided Summarization of Molecular Dynamics Simulations

We present a novel method to measure saliency in molecular dynamics simulation data. This saliency measure is based on a multiscale center-surround mechanism, which is fast and efficient to compute. We explore the use of the saliency function to guide the selection of representative and anomalous timesteps for summarization of simulations. To this end, we also introduce a multiscale keyframe selection procedure which automatically provides keyframes representing the simulation at varying levels of coarseness. We compare our saliency guided keyframe approach against other methods, and show that it consistently selects superior keyframes as measured by their predictive power in reconstructing the simulation

Salient Frame Detection for Molecular Dynamics Simulations

Recent advances in sophisticated computational techniques have facilitated simulation of incrediblydetailed time-varying trajectories and in the process have generated vast quantities of simulation data. The current tools to analyze and comprehend large-scale time-varying data, however, lag far behind our ability to produce such simulation data. Saliency-based analysis can be applied to time-varying 3D datasets for the purpose of summarization, abstraction, and motion analysis. As the sizes of time-varying datasets continue to grow, it becomes more and more difficult to comprehend vast amounts of data and information in a short period of time. In this paper, we use eigenanalysis to generate orthogonal basis functions over sliding windows to characterize regions of unusual deviations and significant trends. Our results show that motion subspaces provide an effective technique for summarization of large molecular dynamics trajectories

Differences In Perceptions And Fast Food Eating Behaviours Between Indians Living In High- And Low-Income Neighbourhoods Of Chandigarh, India

Increased density of fast food restaurants is associated with increased prevalence of obesity in developed countries. However, less is known about this relationship in developing countries undergoing rapid urbanization and how differences in neighbourhood income affect the patronage of fast food outlets. The purpose of the study is to explore the differences in fast food preferences, perceptions, and patronage between Indians living in high- and low-income neighbourhoods.METHODS:This cross-sectional study recruited 204 men and women (35 to 65 years in age) from high- and low-income neighbourhoods who completed a questionnaire on fast food consumption. The questionnaire asked participants to define fast food and to provide reasons for and frequency of visits to fast food restaurants. The differences were analyzed using Chi square and t-tests for categorical and continuous variables, respectively.RESULTS:Participants from a high-income neighbourhood were more likely to perceive Western -style fast food as fast food, while people from the low-income neighbourhood were more likely to identify food sold by street vendors as fast food (p <0.001). Furthermore, compared to participants from the high-income neighbourhood, people from the low-income neighbourhood were more likely to report buying food from street vendors while less likely to dine out at both fast food and non-fast food restaurants (p<0.001). Although the high-income neighbourhood group was more likely to report enjoying eating at fast food restaurants than their low-income neighbourhood counterparts, there were no significant differences in the reasons for visiting fast food restaurants (convenience, price, social enjoyment, and quality of meals) between the two groups. Both groups preferred home cooked over restaurant meals, and they recognized that home cooked food was healthier.CONCLUSIONS:Overall, consumption of fast food was low. People from a high-income neighbourhood dined out more frequently and were more likely to perceive Western-style food as fast food compared to their counterparts from the low-income neighbourhood

Assembly, assessment and availability of de novo generated transcriptomes

De novo assembly of a complete transcriptome without the need for a guiding reference genome is attractive, particularly where the cost and complexity of generating a eukaryote genome is prohibitive. The transcriptome should not however be seen as just a quick and cheap alternative to building a complete genome. Transcriptomics allows the understanding and comparison of spatial and temporal samples within an organism and allows surveying of multiple individuals or closely related species. De novo assembly in theory allows the building of a complete transcriptome without any prior knowledge of the genome it also allows the discovery of alternate splice forms of coding RNAs and also non-coding RNAs, which are often missed by proteomic approaches or are incompletely annotated in genome studies. The limitations of the method are that generation of a truly complete assembly is unlikely and so we require some method for assessment of the quality and appropriateness of a generated transcriptome. Whilst no single consensus pipeline or tools is agreed as optimal, various algorithms and easy to use software do exist making transcriptome generation a more common approach. With this expansion of data, questions still exist relating to how do we make these datasets fully discoverable, comparable and most useful to understand complex biological systems

Assessing the energy potential of modernizing the European hydropower fleet

About 50% of all hydropower plants (HPPs) worldwide were originally commissioned more than 40 years ago, so that the advanced age of the fleet is a major concern across all continents, and especially in Europe. The retrofitting of HPPs can generate several benefits for production, flexibility, safety, management and environment. In this work, the benefits related to energy and flexibility were considered and quantified by conducting a large-scale assessment for the European Union and Europe, taking into account several retrofitting strategies: dam heightening, head loss reduction in waterways, increase of installed power in run-of-the-river and storage power plants, increase of annual inflow, increase of maximum efficiency and weighted efficiency of electro-mechanical equipment, start and stop improvement, digitalization and inflow forecast, floating photovoltaic and reservoir interconnection. For most of these strategies, an indicator of the additional capacity and/or annual production that could be obtained compared to the current conditions was calculated. Excluding site-specific strategies (e.g. installation of new parallel waterways, increase of withdrawals from existing intakes) the resulting compound value of the indicator is 10.2% for European Union and 12.2% for the whole Europe, plus 4-28.6 TWh achievable by interconnecting reservoirs. This suggests that the retrofitting of HPPs can generate significant benefits in terms of energy and flexibility, minimizing environmental impacts, and should be considered as an important element of both energy transition and water management policies

Norma DIN 476, su uso para desarrollar algunos temas de matemática de un programa de segundo año

Se presenta una propuesta de enseñanza, utilizando un material concreto que nos permite desarrollar algunos temas del programa de Matemática correspondiente al 2do año de la Escuela Industrial Superior de la ciudad de Santa Fe. La selección del material tiene que ver con una búsqueda de relaciones con otras asignaturas del mismo nivel (u otros) porque creemos que la enseñanza y aprendizaje de los contenidos de nuestra área tienen mejor recepción en los alumnos cuando se la contextualiza, cuando se evidencia su necesidad, valor o colaboración en otras áreas de estudio. El abordaje transdisciplinario requiere de mentes creativas, abiertas y capaces de resolver situaciones problemáticas específicas desde muchas perspectivas. Esto indica que el docente debe diseñar estrategias de enseñanza basadas en una concepción cognitiva del aprendizaje, favoreciendo el tratamiento de los contenidos disciplinares desde una perspectiva crítica y reflexiva; en la cual el joven pueda poner en juego sus propias capacidades y posibilidades para participar activamente del proceso y construir el conocimiento.Facultad de Humanidades y Ciencias de la Educació

An Intergenic Region Shared by At4g35985 and At4g35987 in Arabidopsis Thaliana is a Tissue Specific and Stress Inducible Bidirectional Promoter Analyzed in Transgenic Arabidopsis and Tobacco Plants

On chromosome 4 in the Arabidopsis genome, two neighboring genes (calmodulin methyl transferase At4g35987 and senescence associated gene At4g35985) are located in a head-to-head divergent orientation sharing a putative bidirectional promoter. This 1258 bp intergenic region contains a number of environmental stress responsive and tissue specific cis-regulatory elements. Transcript analysis of At4g35985 and At4g35987 genes by quantitative real time PCR showed tissue specific and stress inducible expression profiles. We tested the bidirectional promoter-function of the intergenic region shared by the divergent genes At4g35985 and At4g35987 using two reporter genes (GFP and GUS) in both orientations in transient tobacco protoplast and Agro-infiltration assays, as well as in stably transformed transgenic Arabidopsis and tobacco plants. In transient assays with GFP and GUS reporter genes the At4g35985 promoter (P85) showed stronger expression (about 3.5 fold) compared to the At4g35987 promoter (P87). The tissue specific as well as stress responsive functional nature of the bidirectional promoter was evaluated in independent transgenic Arabidopsis and tobacco lines. Expression of P85 activity was detected in the midrib of leaves, leaf trichomes, apical meristemic regions, throughout the root, lateral roots and flowers. The expression of P87 was observed in leaf-tip, hydathodes, apical meristem, root tips, emerging lateral root tips, root stele region and in floral tissues. The bidirectional promoter in both orientations shows differential up-regulation (2.5 to 3 fold) under salt stress. Use of such regulatory elements of bidirectional promoters showing spatial and stress inducible promoter-functions in heterologous system might be an important tool for plant biotechnology and gene stacking applications

Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases

HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5-specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains. Here we describe engineering a pair of zinc finger nucleases that, when introduced into human T cells, efficiently disrupt cxcr4 by cleavage and error-prone non-homologous DNA end-joining. The resulting cells proliferated normally and were resistant to infection by X4-tropic HIV-1 strains. CXCR4 could also be inactivated in ccr5Δ32 CD4+ T cells, and we show that such cells were resistant to all strains of HIV-1 tested. Loss of CXCR4 also provided protection from X4 HIV-1 in a humanized mouse model, though this protection was lost over time due to the emergence of R5-tropic viral mutants. These data suggest that CXCR4-specific ZFNs may prove useful in establishing resistance to CXCR4-tropic HIV for autologous transplant in HIV-infected individuals