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Item Open Access Algorithms for effective querying of compound graph-based pathway databases(BioMed Central Ltd., 2009-11-16) Doğrusöz, Uğur; Çetintaş, Ahmet; Demir, Emek; Babur, ÖzgünBackground: Graph-based pathway ontologies and databases are widely used to represent data about cellular processes. This representation makes it possible to programmatically integrate cellular networks and to investigate them using the well-understood concepts of graph theory in order to predict their structural and dynamic properties. An extension of this graph representation, namely hierarchically structured or compound graphs, in which a member of a biological network may recursively contain a sub-network of a somehow logically similar group of biological objects, provides many additional benefits for analysis of biological pathways, including reduction of complexity by decomposition into distinct components or modules. In this regard, it is essential to effectively query such integrated large compound networks to extract the sub-networks of interest with the help of efficient algorithms and software tools. Results: Towards this goal, we developed a querying framework, along with a number of graph-theoretic algorithms from simple neighborhood queries to shortest paths to feedback loops, that is applicable to all sorts of graph-based pathway databases, from PPIs (protein-protein interactions) to metabolic and signaling pathways. The framework is unique in that it can account for compound or nested structures and ubiquitous entities present in the pathway data. In addition, the queries may be related to each other through "AND" and "OR" operators, and can be recursively organized into a tree, in which the result of one query might be a source and/or target for another, to form more complex queries. The algorithms were implemented within the querying component of a new version of the software tool PATIKAweb (Pathway Analysis Tool for Integration and Knowledge Acquisition) and have proven useful for answering a number of biologically significant questions for large graph-based pathway databases. Conclusion: The PATIKA Project Web site is http://www.patika.org. PATIKAweb version 2.1 is available at http://web.patika.org. © 2009 Dogrusoz et al; licensee BioMed Central Ltd.Item Open Access Biological properties of extracellular vesicles and their physiological functions(Taylor & Francis, 2015) Yáñez-Mó, M.; Siljander, P. R. M.; Andreu, Z.; Zavec, A. B.; Borràs, F. E.; Buzas, E. I.; Buzas, K.; Casal, E.; Cappello, F.; Carvalho, J.; Colás, E.; Cordeiro-Da, S. A.; Fais, S.; Falcon-Perez, J. M.; Ghobrial, I. M.; Giebel, B.; Gimona, M.; Graner, M.; Gursel, I.; Gursel, M.; Heegaard, N. H. H.; Hendrix, A.; Kierulf, P.; Kokubun, K.; Kosanovic, M.; Kralj-Iglic, V.; Krämer-Albers, E. M.; Laitinen, S.; Lässer, C.; Lener, T.; Ligeti, E.; Line, A.; Lipps, G.; Llorente, A.; Lötvall, J.; Manček-Keber, M.; Marcilla, A.; Mittelbrunn, M.; Nazarenko, I.; Nolte-'t Hoen, E. N. M.; Nyman, T. A.; O'Driscoll, L.; Olivan, M.; Oliveira, C.; Pállinger, E.; Del Portillo, H. A.; Reventós, J.; Rigau, M.; Rohde, E.; Sammar, M.; Sánchez-Madrid, F.; Santarém, N.; Schallmoser, K.; Ostenfeld, M. S.; Stoorvogel, W.; Stukelj, R.; Grein V. D. S.G.; Helena,ü V. M.; Wauben, M. H. M.; De Wever, O.In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells.While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.Item Open Access ChiBE: interactive visualization and manipulation of BioPAX pathway models(Oxford University Press, 2010-02-01) Babur, Özgün; Doğrusöz, Uğur; Demir, Emek; Sander, C.SUMMARY: Representing models of cellular processes or pathways in a graphically rich form facilitates interpretation of biological observations and generation of new hypotheses. Solving biological problems using large pathway datasets requires software that can combine data mapping, querying and visualization as well as providing access to diverse data resources on the Internet. ChiBE is an open source software application that features user-friendly multi-view display, navigation and manipulation of pathway models in BioPAX format. Pathway views are rendered in a feature-rich format, and may be laid out and edited with state-of-the-art visualization methods, including compound or nested structures for visualizing cellular compartments and molecular complexes. Users can easily query and visualize pathways through an integrated Pathway Commons query tool and analyze molecular profiles in pathway context. AVAILABILITY: http://www.bilkent.edu.tr/%7Ebcbi/chibe.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.Item Open Access Engineering sensorial delay to control phototaxis and emergent collective behaviors(American Physical Society, 2016-01) Mijalkov, M.; McDaniel, A.; Wehr, J.; Volpe, G.Collective motions emerging from the interaction of autonomous mobile individuals play a key role in many phenomena, from the growth of bacterial colonies to the coordination of robotic swarms. For these collective behaviors to take hold, the individuals must be able to emit, sense, and react to signals. When dealing with simple organisms and robots, these signals are necessarily very elementary; e.g., a cell might signal its presence by releasing chemicals and a robot by shining light. An additional challenge arises because the motion of the individuals is often noisy; e.g., the orientation of cells can be altered by Brownian motion and that of robots by an uneven terrain. Therefore, the emphasis is on achieving complex and tunable behaviors fromsimple autonomous agents communicating with each other in robust ways. Here, we show that the delay between sensing and reacting to a signal can determine the individual and collective long-term behavior of autonomous agents whose motion is intrinsically noisy. We experimentally demonstrate that the collective behavior of a group of phototactic robots capable of emitting a radially decaying light field can be tuned from segregation to aggregation and clustering by controlling the delay with which they change their propulsion speed in response to the light intensity they measure. We track this transition to the underlying dynamics of this system, in particular, to the ratio between the robots' sensorial delay time and the characteristic time of the robots' random reorientation. Supported by numerics, we discuss how the same mechanism can be applied to control active agents, e.g., airborne drones, moving in a three-dimensional space. Given the simplicity of this mechanism, the engineering of sensorial delay provides a potentially powerful tool to engineer and dynamically tune the behavior of large ensembles of autonomous mobile agents; furthermore, this mechanism might already be at work within living organisms such as chemotactic cells.Item Open Access Genetic education and the challenge of genomic medicine development of core competences to support preparation of health professionals in Europe(Nature Publishing Group, 2010) Skirton, H.; Lewis, C.; Kent, A.; Domenico, A. C.; Bloch-Zupan, A.; Cornel, M.; DeLozier, C.; Farndon, P.; Goetz, P.; Hongson, S.; Houge, G.; Hulten, M.; Kosztolanyi, G.; Kucinskas, V.; Ozcelik, T.; Serqueiros, J.; Soller, M.; Tranebjaerg, L.The use of genetics and genomics within a wide range of health-care settings requires health professionals to develop expertise to practise appropriately. There is a need for a common minimum standard of competence in genetics for health professionals in Europe but because of differences in professional education and regulation between European countries, setting curricula may not be practical. Core competences are used as a basis for health professional education in many fields and settings. An Expert Group working under the auspices of the EuroGentest project and European Society of Human Genetics Education Committee agreed that a pragmatic solution to the need to establish common standards for education and practice in genetic health care was to agree to a set of core competences that could apply across Europe. These were agreed through an exhaustive process of consultation with relevant health professionals and patient groups. Sets of competences for practitioners working in primary, secondary and tertiary care have been agreed and were approved by the European Society of Human Genetics. The competences provide an appropriate framework for genetics education of health professionals across national boundaries, and the suggested learning outcomes are available to guide development of curricula that are appropriate to the national context, educational system and health-care setting of the professional involved. Collaboration between individuals from many European countries and professions has resulted in an adaptable framework for both pre-registration and continuing professional education. This competence framework has the potential to improve the quality of genetic health care for patients globally.Item Open Access Integrating biological pathways and genomic profiles with ChiBE 2(BioMed Central Ltd., 2014) Babur, O.; Dogrusoz, U.; Çakır, M.; Aksoy, B. A.; Schultz, N.; Sander, C.; Demir, E.Background: Dynamic visual exploration of detailed pathway information can help researchers digest and interpret complex mechanisms and genomic datasets.Results: ChiBE is a free, open-source software tool for visualizing, querying, and analyzing human biological pathways in BioPAX format. The recently released version 2 can search for neighborhoods, paths between molecules, and common regulators/targets of molecules, on large integrated cellular networks in the Pathway Commons database as well as in local BioPAX models. Resulting networks can be automatically laid out for visualization using a graphically rich, process-centric notation. Profiling data from the cBioPortal for Cancer Genomics and expression data from the Gene Expression Omnibus can be overlaid on these networks.Conclusions: ChiBE's new capabilities are organized around a genomics-oriented workflow and offer a unique comprehensive pathway analysis solution for genomics researchers. The software is freely available at http://code.google.com/p/chibe. © 2014 Babur et al.; licensee BioMed Central Ltd.Item Open Access Is Romeo dead? On the persistence of organisms(Springer Netherlands, 2018) Tzinman, R.According to a prominent view of organism persistence (“vitalicism”), organisms cease to exist at death. According to a rival view (“somaticism”), organisms can continue to exist as dead organisms. Most of the arguments in favor of the latter view rely on linguistic and common sense intuitions. I propose a new argument for somaticism by appealing to two other sources that have thus far not figured in the debate: the concept of naturalness, and biological descriptions of organisms, in particular in ethology and ecology. I show that if we hone in on the relevant notion of naturalness, we can show that organisms can (and often do) continue to instantiate the natural property being an organism after death.Item Open Access Kronecker-based infinite level-dependent QBD processes(Applied Probability Trust, 2012) Dayar, T.; Orhan, M. C.Markovian systems with multiple interacting subsystems under the influence of a control unit are considered. The state spaces of the subsystems are countably infinite, whereas that of the control unit is finite. A recent infinite level-dependent quasi-birth-and-death model for such systems is extended by facilitating the automatic representation and generation of the nonzero blocks in its underlying infinitesimal generator matrix with sums of Kronecker products. Experiments are performed on systems of stochastic chemical kinetics having two or more countably infinite state space subsystems. Results indicate that, even though more memory is consumed, there are many cases where a matrix-analytic solution coupled with Lyapunov theory yields a faster and more accurate steady-state measure compared to that obtained with simulation. © Applied Probability Trust 2012.Item Open Access Kronecker-based infinite level-dependent QBDS : matrix analytic solution versus simulation(Bilkent University, 2011) Orhan, Muhsin CanMarkovian systems with multiple interacting subsystems under the influence of a control unit are considered. The state spaces of the subsystems are countably in- finite, whereas that of the control unit is finite. A recent infinite level-dependent quasi-birth-and-death (LDQBD) model for such systems is extended by facilitating the automatic representation and generation of the nonzero blocks in its underlying infinitesimal generator matrix with sums of Kronecker products. Experiments are performed on systems of stochastic chemical kinetics having two or more countably infinite state space subsystems. Results indicate that, albeit more memory consuming, there are many cases where a matrix analytic solution coupled with Lyapunov theory yields a faster and more accurate steady-state measure compared to that obtained with simulation.Item Open Access Methods and tools for visualization and management of SBGN process description maps(Bilkent University, 2014) Sarı, MecitGraphs are commonly used to model relational information in many areas such as relational databases, software engineering, biological and social networks. In visualization of graphs, automatic layout, interactive editing and complexity management of crowded graphs are essential for effective utilization of underlying information. Advances in graphical user interfaces have given rise and value to interactive editing and diagramming techniques in graph visualization. As the size of the information to be visualized vastly increased, it became harder to analyze such networks, making use of relational information needed to be acquired. To overcome this problem, sophisticated and domain-specific complexity management techniques should be provided. The Systems Biology Graphical Notation (SBGN) has been developed over a number of years by biochemists and computer scientists to standardize visual representation of biochemical and cellular processes. SBGN introduces a concrete, detailed set of symbols for scientists to represent network of interactions, in a way that is not open to more than one interpretation. It also describes the manner, in which such graphical information should be interpreted. The SBGN Process Description (PD) language shows how entities are influenced by processes, which are represented by several reaction types in a biological pathway. It can be used to show all the molecular interactions taking place in a network of biochemical entities, with the same entity appearing multiple times in the same diagram. We developed methods and tools to effectively visualize and manage SBGNPD diagrams. Specifically, we introduced new algorithms for proper management of complexity of large SBGN-PD diagrams. These algorithms strive to keep SBGN-PD diagrams intact as complexity management takes places. In addition, we provided software components and web-based tools that implement these methods. These tools use state-of-the-art web technologies and libraries.Item Open Access Moral mechanisms(2012) Davenport, D.Moral philosophies are arguably all anthropocentric and so fundamentally concerned with biological mechanisms. Computationalism, on the other hand, sees biology as just one possible implementation medium. Can non-human, non-biological agents be moral' This paper looks at the nature of morals, at what is necessary for a mechanism to make moral decisions, and at the impact biology might have on the process. It concludes that moral behaviour is concerned solely with social well-being, independent of the nature of the individual agents that comprise the group. While biology certainly affects human moral reasoning, it in no way restricts the development of artificial moral agents. The consequences of sophisticated artifical mechanisms living with natural human ones is also explored. While the prospects for peaceful coexistence are not particularly good, it is the realisation that humans no longer occupy a privileged place in the world, that is likely to be the most disconcerting. Computationalism implies we are mechanisms; probably the most immoral of moral mechanisms.Item Open Access Polymer-free nanofibers from vanillin/cyclodextrin inclusion complexes: high thermal stability, enhanced solubility and antioxidant property(Royal Society of Chemistry, 2016) Celebioglu A.; Kayaci-Senirmak, F.; Ipek, S.; Durgun, Engin; Uyar, TamerVanillin/cyclodextrin inclusion complex nanofibers (vanillin/CD-IC NFs) were successfully obtained from three modified CD types (HPβCD, HPγCD and MβCD) in three different solvent systems (water, DMF and DMAc) via an electrospinning technique without using a carrier polymeric matrix. Vanillin/CD-IC NFs with uniform and bead-free fiber morphology were successfully produced and their free-standing nanofibrous webs were obtained. The polymer-free CD/vanillin-IC-NFs allow us to accomplish a much higher vanillin loading (∼12%, w/w) when compared to electrospun polymeric nanofibers containing CD/vanillin-IC (∼5%, w/w). Vanillin has a volatile nature yet, after electrospinning, a significant amount of vanillin was preserved due to complex formation depending on the CD types. Maximum preservation of vanillin was observed for vanillin/MβCD-IC NFs which is up to ∼85% w/w, besides, a considerable amount of vanillin (∼75% w/w) was also preserved for vanillin/HPβCD-IC NFs and vanillin/HPγCD-IC NFs. Phase solubility studies suggested a 1:1 molar complexation tendency between guest vanillin and host CD molecules. Molecular modelling studies and experimental findings revealed that vanillin:CD complexation was strongest for MβCD when compared to HPβCD and HPγCD in vanillin/CD-IC NFs. For vanillin/CD-IC NFs, water solubility and the antioxidant property of vanillin was improved significantly owing to inclusion complexation. In brief, polymer-free vanillin/CD-IC NFs are capable of incorporating a much higher loading of vanillin and effectively preserve volatile vanillin. Hence, encapsulation of volatile active agents such as flavor, fragrance and essential oils in electrospun polymer-free CD-IC NFs may have potential for food related applications by integrating the particularly large surface area of NFs with the non-toxic nature of CD and inclusion complexation benefits, such as high temperature stability, improved water solubility and an enhanced antioxidant property, etc.Item Open Access A privacy-preserving solution for compressed storage and selective retrieval of genomic data(Cold Spring Harbor Laboratory Press, 2016) Huang Z.; Ayday, E.; Lin, H.; Aiyar, R. S.; Molyneaux, A.; Xu, Z.; Fellay, J.; Steinmetz, L. M.; Hubaux, Jean-PierreIn clinical genomics, the continuous evolution of bioinformatic algorithms and sequencing platforms makes it beneficial to store patients' complete aligned genomic data in addition to variant calls relative to a reference sequence. Due to the large size of human genome sequence data files (varying from 30 GB to 200 GB depending on coverage), two major challenges facing genomics laboratories are the costs of storage and the efficiency of the initial data processing. In addition, privacy of genomic data is becoming an increasingly serious concern, yet no standard data storage solutions exist that enable compression, encryption, and selective retrieval. Here we present a privacy-preserving solution named SECRAM (Selective retrieval on Encrypted and Compressed Reference-oriented Alignment Map) for the secure storage of compressed aligned genomic data. Our solution enables selective retrieval of encrypted data and improves the efficiency of downstream analysis (e.g., variant calling). Compared withBAM, thede factostandard for storing aligned genomic data, SECRAM uses 18%less storage. Compared with CRAM, one of the most compressed nonencrypted formats (using 34% less storage than BAM), SECRAM maintains efficient compression and downstream data processing, while allowing for unprecedented levels of security in genomic data storage. Compared with previous work, the distinguishing features of SECRAM are that (1) it is position-based insteadofread-based,and(2)itallowsrandomqueryingofasubregionfromaBAM-likefileinanencryptedform.Ourmethod thus offers a space-saving, privacy-preserving, and effective solution for the storage of clinical genomic data.Item Restricted Prof. Dr. Ali Demirsoy’un çalışmaları ve Türkiye’de biyolojinin gelişimine katkıları(Bilkent University, 2020) Kılınç, Ece; Kumdakçı, Bilge Zehra; Türkçapar, Mehmet Berk; Ekin, Yiğit; Eren, ArdaProf. Dr. Ali Demirsoy özellikle evrim alanında Türkiye’de aktif araştırmalarını sürdüren ve geniş kitlelere hitap edebilen sayılı isimlerden biridir. Bu araştırma yazısında Ali Demirsoy’un proje makalelerinden, katıldığı söyleşilerden, röportajlardan, kitaplardan, mesleğiyle ilgili yayınlardan, dokümanlardan ve eski öğrencilerinden alınan bilgilerden yola çıkılarak hayatı ve Türk bilim dünyasına katkıları anlatılmıştır. İlk olarak Prof. Dr. Ali Demirsoy’un hayatına dair bir araştırma yapılmış, daha sonra araştırmanın odak noktası genişletilerek kendisinin biyoloji bilimine katkılarından, ana akım medya tarafından sıkça gündeme getirilen evrim ve özellikle Türkiye’de evrimin gelişmemesi üzerine fikirlerinden, son olarak da Türkiye’nin bilimsel araştırmalardaki yetersizliği ve güncel problemleri üzerine görüşlerine değinilmiştir.Item Open Access Software support for SBGN maps: SBGN-ML and LibSBGN(Oxford University Press, 2012) Iersel, Martijn P. van; Villéger, A. C.; Czauderna, T.; Boyd, S. E.; Bergmann, F. T.; Luna, A.; Demir, E.; Sorokin, A.; Dogrusoz, U.; Matsuoka, Y.; Funahashi, A.; Aladjem, M. I.; Mi, H.; Moodie, S. L.; Kitano, H.; Le novère, N.; Schreiber, F.Motivation: LibSBGN is a software library for reading, writing and manipulating Systems Biology Graphical Notation (SBGN) maps stored using the recently developed SBGN-ML file format. The library (available in C++ and Java) makes it easy for developers to add SBGN support to their tools, whereas the file format facilitates the exchange of maps between compatible software applications. The library also supports validation of maps, which simplifies the task of ensuring compliance with the detailed SBGN specifications. With this effort we hope to increase the adoption of SBGN in bioinformatics tools, ultimately enabling more researchers to visualize biological knowledge in a precise and unambiguous manner. © The Author(s) 2012. Published by Oxford University Press.Item Open Access Software tools for visual analysis of cancer genomics data in the context of pathways(Bilkent University, 2016-08) Bahçeci, İstemi RahmanInformation visualization is concerned with effective visual presentation of abstract information, which reinforces human cognition. Graphs are structures that are well suited to represent relational information. Graph visualization is vital since the underlying relational information of the graph provides fine analysis and comprehension opportunities. Biological pathway visualization is one of the most popular areas, where graph visualization is highly favored. Interactive analysis and visualization of cancer related pathways in the context of genomic data, such as those available through the TCGA project, might reveal valuable information for scientists about disease conditions and potential causes. As the size and complexity of such cancer pathways and associated genomic data increase, exchangeable in-silico representations and their effective, enhanced visualizations, and complexity management become crucial for effective analysis of such data to potentially discover cause-effect relations. In this thesis, we designed and implemented software solutions to visualize cancer genomics data in the context of networks from simple gene interaction networks to process description diagrams within the cBioPortal for Cancer Genomics (cBioPortal). cBioPortal is a popular web portal, getting about 60.000 visits globally per month, providing visualization, analysis and download of largescale cancer genomics data sets. The network view in cBioPortal presents neighborhood of genes of interest. The alteration data is overlaid on the network with numerous ways to filter and manage complexity of the network (e.g. by alteration percentage or by type or source of the interactions). Upon demand, the user can obtain a more detailed, mechanistic view of the interactions among gene pairs, from Pathway Commons database with a live query using the SBGN process description notation. Finally, we also developed a new pathway visualization component, specifically for cancer pathways, using a uniform notation found in TCGA cancer publications. This tool also facilitates curation of pathways from scratch with support for collaborative editing.Item Open Access The systems biology graphical notation(Nature Publishing Group, 2009-08) Le Novère, N.; Hucka, M.; Mi, H.; Moodie, S.; Schreiber, F.; Sorokin, A.; Demir, Emek; Wegner, K.; Aladjem, M. I.; Wimalaratne, S. M.; Bergman, F. T.; Gauges, R.; Ghazal, P.; Kawaji, H.; Li, L.; Matsuoka, Y.; Villéger, A.; Boyd, S. E.; Calzone, L.; Courtot, M.; Doğrusöz, Uğur; Freeman, T. C.; Funahashi, A.; Ghosh, S.; Jouraku, A.; Kim, S.; Kolpakov, F.; Luna, A.; Sahle, S.; Schmidt, E.; Watterson, S.; Wu, G.; Goryanin, I.; Kell, D. B.; Sander, C.; Sauro, H.; Snoep, J. L.; Kohn, K.; Kitano, H.Circuit diagrams and Unified Modeling Language diagrams are just two examples of standard visual languages that help accelerate work by promoting regularity, removing ambiguity and enabling software tool support for communication of complex information. Ironically, despite having one of the highest ratios of graphical to textual information, biology still lacks standard graphical notations. The recent deluge of biological knowledge makes addressing this deficit a pressing concern. Toward this goal, we present the Systems Biology Graphical Notation (SBGN), a visual language developed by a community of biochemists, modelers and computer scientists. SBGN consists of three complementary languages: process diagram, entity relationship diagram and activity flow diagram. Together they enable scientists to represent networks of biochemical interactions in a standard, unambiguous way. We believe that SBGN will foster efficient and accurate representation, visualization, storage, exchange and reuse of information on all kinds of biological knowledge, from gene regulation, to metabolism, to cellular signaling. © 2009 Nature America, Inc.Item Open Access Time-delay estimation in multiple-input single-output systems(IEEE, 2010) Koçak, Fatih; Gezici, SinanIn this paper, the time-delay estimation problem is studied for multiple-input single-output (MISO) systems. First, a theoretical analysis is carried out by deriving the Cramer-Rao lower bound (CRLB) for time-delay estimation in a MISO system. Then, the maximum likelihood (ML) estimator for the time-delay parameter is obtained, which results in a complex optimization problem in general. In order to provide a solution of the ML estimator with low computational complexity, ML estimation based on a genetic global optimization algorithm, namely, differential evolution (DE), is proposed. Simulation studies for various fading scenarios are performed to investigate the performance of the proposed algorithm. ©2010 IEEE.