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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access The after-hours circadian mutant has reduced phenotypic plasticity in behaviors at multiple timescales and in sleep homeostasis(Nature Publishing Group (NPG), 2017) Maggi, Silvia; Balzani, Edoardo; Lassi, Glenda; Garcia-Garcia, Celina; Plano, Andrea; Espinoza, Stefano; Mus, Liudmila; Tinarelli, Federico; Nolan, Patrick M.; Gainetdinov, Raul R.; Nieus, Thierry; Tucci, Valter; Department of Psychology; Balcı, Fuat; Faculty Member; Department of Psychology; College of Social Sciences and Humanities; 51269Circadian clock is known to adapt to environmental changes and can significantly influence cognitive and physiological functions. In this work, we report specific behavioral, cognitive, and sleep homeostatic defects in the after hours (Afh) circadian mouse mutant, which is characterized by lengthened circadian period. We found that the circadian timing irregularities in Afh mice resulted in higher interval timing uncertainty and suboptimal decisions due to incapability of processing probabilities. Our phenotypic observations further suggested that Afh mutants failed to exhibit the necessary phenotypic plasticity for adapting to temporal changes at multiple time scales (seconds-to-minutes to circadian). These behavioral effects of Afh mutation were complemented by the specific disruption of the Per/Cry circadian regulatory complex in brain regions that govern food anticipatory behaviors, sleep, and timing. We derive statistical predictions, which indicate that circadian clock and sleep are complementary processes in controlling behavioral/cognitive performance during 24 hrs. The results of this study have pivotal implications for understanding how the circadian clock modulates sleep and behavior.Publication Open Access Fabrication and microfluidic analysis of graphene-based molecular communication receiver for Internet of Nano Things (IoNT)(Springer Nature, 2021) Ramezani, Hamideh; Dinç, Ergin; Akhavan, Shahab; Department of Electrical and Electronics Engineering; Akan, Özgür Barış; Kuşcu, Murat; Faculty Member; Department of Electrical and Electronics Engineering; College of Engineering; 6647; 316349Bio-inspired molecular communications (MC), where molecules are used to transfer information, is the most promising technique to realise the Internet of Nano Things (IoNT), thanks to its inherent biocompatibility, energy-efficiency, and reliability in physiologically-relevant environments. Despite a substantial body of theoretical work concerning MC, the lack of practical micro/nanoscale MC devices and MC testbeds has led researchers to make overly simplifying assumptions about the implications of the channel conditions and the physical architectures of the practical transceivers in developing theoretical models and devising communication methods for MC. On the other hand, MC imposes unique challenges resulting from the highly complex, nonlinear, time-varying channel properties that cannot be always tackled by conventional information and communication tools and technologies (ICT). As a result, the reliability of the existing MC methods, which are mostly adopted from electromagnetic communications and not validated with practical testbeds, is highly questionable. As the first step to remove this discrepancy, in this study, we report on the fabrication of a nanoscale MC receiver based on graphene field-effect transistor biosensors. We perform its ICT characterisation in a custom-designed microfluidic MC system with the information encoded into the concentration of single-stranded DNA molecules. This experimental platform is the first practical implementation of a micro/nanoscale MC system with nanoscale MC receivers, and can serve as a testbed for developing realistic MC methods and IoNT applications.Publication Open Access Modeling convection-diffusion-reaction systems for microfluidic molecular communications with surface-based receivers in Internet of Bio-Nano Things(Public Library of Science, 2018) Department of Electrical and Electronics Engineering; Kuşcu, Murat; Akan, Özgür Barış; Faculty Member; Faculty Member; Department of Electrical and Electronics Engineering; College of Engineering; Graduate School of Sciences and EngineeringWe consider a microfluidic molecular communication (MC) system, where the concentration-encoded molecular messages are transported via fluid flow-induced convection and diffusion, and detected by a surface-based MC receiver with ligand receptors placed at the bottom of the microfluidic channel. The overall system is a convection-diffusion-reaction system that can only be solved by numerical methods, e.g., finite element analysis (FEA). However, analytical models are key for the information and communication technology (ICT), as they enable an optimisation framework to develop advanced communication techniques, such as optimum detection methods and reliable transmission schemes. In this direction, we develop an analytical model to approximate the expected time course of bound receptor concentration, i.e., the received signal used to decode the transmitted messages. The model obviates the need for computationally expensive numerical methods by capturing the nonlinearities caused by laminar flow resulting in parabolic velocity profile, and finite number of ligand receptors leading to receiver saturation. The model also captures the effects of reactive surface depletion layer resulting from the mass transport limitations and moving reaction boundary originated from the passage of finite-duration molecular concentration pulse over the receiver surface. Based on the proposed model, we derive closed form analytical expressions that approximate the received pulse width, pulse delay and pulse amplitude, which can be used to optimize the system from an ICT perspective. We evaluate the accuracy of the proposed model by comparing model-based analytical results to the numerical results obtained by solving the exact system model with COMSOL Multiphysics.Publication Open Access Increased srum uric acid over five years is a risk factor for developing fatty liver(Nature Publishing Group (NPG), 2017) Jensen, Thomas; Niwa, Koichiro; Hisatome, Ichiro; Andres-Hernando, Ana; Roncal-Jimenez, Carlos A.; Sato, Yuka; Garcia, Gabriela; Ohno, Minoru; Lanaspa, Miguel A.; Johnson, Richard J.; Kuwabara, Masanari; N/A; Kanbay, Mehmet; Faculty Member; School of Medicine; 110580The prevalence of fatty liver disease (FLD) is increasing. To clarify risk factors for developing FLD, we analyzed a database from healthy Japanese adults who had annual medical check-ups in 2004 and reexamined in 2009. We used the fatty liver index (FLI) to classify participants as FLD (FLI >= 60), borderline FLD (30 <= FLI < 60), and normal liver (FLI < 30). Subjects with hepatitis B or C virus infection and subjects with FLD at the baseline were excluded. The cumulative incidence of FLD from normal liver and from borderline FLD over five years were 0.65% (52/8,025) and 12.9% (244/1,888), respectively. After multiple adjustments, higher serum uric acid (SUA) (OR:1.92; 95% CI:1.40-2.63) and increased SUA change (OR:3.734; 95% CI:2.57-5.42) became risk factors for developing FLD from normal liver, as well as younger age and higher body mass index. The risk factors for developing FLD from borderline FLD were similar. Not only higher baseline SUA but also increased SUA change became independent risks for developing FLD.Publication Open Access A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels.(Nature Publishing Group (NPG), 2015) Kong, Bo; Wu, Weiwei; Valkovska, Nataliya; Jager, Carsten; Hong, Xin; Nitsche, Ulrich; Friess, Helmut; Esposito, Irene; Kleeff, Joerg; Michalski, Christoph W.; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689HNF1 homeoboxA(HNF1A)-mediated gene expression constitutes an essential component of the secretory pathway in the exocrine pancreas. Melanoma inhibitory activity 2 (MIA2), a protein facilitating protein secretion, is an HNF1A target. Protein secretion is precisely coordinated by the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) system. Here, we demonstrate that HNFA and MIA2 are expressed in a subset of human PDAC tissues and that HNF1A induced MIA2 in vitro. We identified a common germline variant of MIA2 (c.A617G:p.I141M) associated with a secretory defect of the MIA2 protein in PDAC cells. Patients carrying MIA2(I141M) survived longer after tumor resection but the survival benefit was restricted to those patients who received adjuvant chemotherapy. The MIA2(I141M) variant was associated with high expression of ER stress/UPR genes - in particular those of the ERN1/XBP arm - in human PDAC samples. Accordingly, PDAC cell lines expressing the MIA2(I141M) variant expressed high levels of ERN1 and were more sensitive to gemcitabine. These findings define an interaction between the common MIA2(I141M) variant and the ER stress/UPR system and specify a subgroup of PDAC patients who are more likely to benefit from adjuvant chemotherapy.Publication Open Access MerR and ChrR mediate blue light induced photo-oxidative stress response at the transcriptional level in Vibrio cholerae(Nature Publishing Group (NPG), 2017) Department of Chemical and Biological Engineering; Tardu, Mehmet; Bulut, Selma; Kavaklı, İbrahim Halil; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; N/A; N/A; 40319Blue light (BL) is a major environmental factor that affects the physiology, behavior, and infectivity of bacteria as it contributes to the generation of reactive oxygen species (ROS) while increasing photo-oxidative stress in cells. However, precise photo-oxidative response mechanism in non-phototrophic bacteria is yet to be elucidated. In this study, we investigated the effect of BL in Vibrio cholerae by using genetics and transcriptome profiling. Genome-wide analysis revealed that transcription of 6.3% of V. cholerae genes were regulated by BL. We further showed that BL enhances ROS production, which is generated through the oxidative phosphorylation. To understand signaling mechanisms, we generated several knockouts and analyzed their transcriptome under BL exposure. Studies with a double-knockout confirm an anti-sigma factor (ChrR) and putative metalloregulatory-like protein (MerR) are responsible for the genome-wide regulation to BL response in V. cholerae. Collectively, these results demonstrate that MerR-like proteins, in addition to ChrR, are required for V. cholerae to mount an appropriate response against photo-oxidative stress induced by BL. Outside its natural host, V. cholerae can survive for extended periods in natural aquatic environments. Therefore, the regulation of light response for V. cholerae may be a critical cellular process for its survival in these environments.Publication Open Access Prediction of optimal folding routes of proteins that satisfy the principle of lowest entropy loss: dynamic contact maps and optimal control(Public Library of Science, 2010) Department of Computer Engineering; Department of Chemical and Biological Engineering; Arkun, Yaman; Erman, Burak; Faculty Member; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; College of Engineering; 108526; 179997An optimization model is introduced in which proteins try to evade high energy regions of the folding landscape, and prefer low entropy loss routes during folding. We make use of the framework of optimal control whose convenient solution provides practical and useful insight into the sequence of events during folding. We assume that the native state is available. As the protein folds, it makes different set of contacts at different folding steps. The dynamic contact map is constructed from these contacts. The topology of the dynamic contact map changes during the course of folding and this information is utilized in the dynamic optimization model. The solution is obtained using the optimal control theory. We show that the optimal solution can be cast into the form of a Gaussian Network that governs the optimal folding dynamics. Simulation results on three examples (CI2, Sso7d and Villin) show that folding starts by the formation of local clusters. Non-local clusters generally require the formation of several local clusters. Non-local clusters form cooperatively and not sequentially. We also observe that the optimal controller prefers "zipping" or small loop closure steps during folding. The folding routes predicted by the proposed method bear strong resemblance to the results in the literature.Publication Open Access The architecture of the TIR domain signalosome in the toll-like receptor-4 signaling pathway(Nature Publishing Group (NPG), 2015) VanWaes, Carter; Chen, Zhong; Tsai, Chung-Jung; Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; 26605; 8745Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro-and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro-and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro-and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways.Publication Open Access Dynamics and control of the ERK signaling pathway: sensitivity, bistability, and oscillations(Public Library of Science, 2018) Department of Chemical and Biological Engineering; Arkun, Yaman; Yasemi, Mohammadreza; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 108526; N/ACell signaling is the process by which extracellular information is transmitted into the cell to perform useful biological functions. The ERK (extracellular-signal-regulated kinase) signaling controls several cellular processes such as cell growth, proliferation, differentiation and apoptosis. The ERK signaling pathway considered in this work starts with an extracellular stimulus and ends with activated (double phosphorylated) ERK which gets translocated into the nucleus. We model and analyze this complex pathway by decomposing it into three functional subsystems. The first subsystem spans the initial part of the pathway from the extracellular growth factor to the formation of the SOS complex, ShC-Grb2-SOS. The second subsystem includes the activation of Ras which is mediated by the SOS complex. This is followed by the MAPK subsystem (or the Raf-MEK-ERK pathway) which produces the double phosphorylated ERK upon being activated by Ras. Although separate models exist in the literature at the subsystems level, a comprehensive model for the complete system including the important regulatory feedback loops is missing. Our dynamic model combines the existing subsystem models and studies their steady-state and dynamic interactions under feedback. We establish conditions under which bistability and oscillations exist for this important pathway. In particular, we show how the negative and positive feedback loops affect the dynamic characteristics that determine the cellular outcome.Publication Open Access Archaeometric evidence for the earliest exploitation of lignite from the bronze age Eastern Mediterranean(Nature Publishing Group (NPG), 2021) Buckley, Stephen; Power, Robert C.; Andreadaki-Vlazaki, Maria; Akar, Murat; Becher, Julia; Belser, Matthias; Cafisso, Sara; Eisenmann, Stefanie; Fletcher, Joann; Francken, Michael; Hallager, Birgitta; Harvati, Katerina; Kataki, Efthymia; Maran, Joseph; Martin, Mario A. S.; McGeorge, Photini J. P.; Milevski, Ianir; Papadimitriou, Alkestis; Protopapadaki, Eftychia; Salazar-Garcia, Domingo C.; Schmidt-Schultz, Tyede; Schuenemann, Verena J.; Shafiq, Rula; Stuijts, Ingelise; Yegorov, Dmitry; Yener, K. Aslıhan; Schultz, Michael; Spiteri, Cynthianne; Stockhammer, Philipp W.; Ingman, Tara; Researcher; Koç University Research Center for Anatolian Civilizations (ANAMED) / Anadolu Medeniyetleri Araştırma Merkezi (ANAMED)This paper presents the earliest evidence for the exploitation of lignite (brown coal) in Europe and sheds new light on the use of combustion fuel sources in the 2nd millennium BCE Eastern Mediterranean. We applied Thermal Desorption/Pyrolysis-Gas Chromatography-Mass Spectrometry and Polarizing Microscopy to the dental calculus of 67 individuals and we identified clear evidence for combustion markers embedded within this calculus. In contrast to the scant evidence for combustion markers within the calculus samples from Egypt, all other individuals show the inhalation of smoke from fires burning wood identified as Pinaceae, in addition to hardwood, such as oak and olive, and/or dung. Importantly, individuals from the Palatial Period at the Mycenaean citadel of Tiryns and the Cretan harbour site of Chania also show the inhalation of fire-smoke from lignite, consistent with the chemical signature of sources in the northwestern Peloponnese and Western Crete respectively. This first evidence for lignite exploitation was likely connected to and at the same time enabled Late Bronze Age Aegean metal and pottery production, significantly by both male and female individuals.