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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 Effect of reaction solvent on hydroxyapatite synthesis in sol-gel process(The Royal Society, 2017) Department of Chemistry; Nazeer, Muhammad Anwaar; Yılgör, Emel; Yağcı, Mustafa Barış; Ünal, Uğur; Yılgör, İskender; PhD Student; Researcher; Researcher; Faculty Member; Faculty Member; Department of Chemistry; Koç University Surface Science and Technology Center (KUYTAM) / Koç Üniversitesi Yüzey Teknolojileri Araştırmaları Merkezi (KUYTAM); College of Sciences; Graduate School of Sciences and Engineering; N/A; 40527; N/A; N/A; 24181Synthesis of hydroxyapatite (HA) through sol-gel process in different solvent systems is reported. Calcium nitrate tetrahydrate (CNTH) and diammonium hydrogen phosphate (DAHP) were used as calcium and phosphorus precursors, respectively. Three different synthesis reactions were carried out by changing the solvent media, while keeping all other process parameters constant. A measure of 0.5 M aqueous DAHP solution was used in all reactions while CNTH was dissolved in distilled water, tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) at a concentration of 0.5 M. Ammonia solution (28-30%) was used to maintain the pH of the reaction mixtures in the 10-12 range. All reactions were carried out at 40 +/- 2 degrees C for 4 h. Upon completion of the reactions, products were filtered, washed and calcined at 500 degrees C for 2 h. It was clearly demonstrated through various techniques that the dielectric constant and polarity of the solvent mixture strongly influence the chemical structure and morphological properties of calcium phosphate synthesized. Water-based reaction medium, with highest dielectric constant, mainly produced beta-calcium pyrophosphate (beta-CPF) with a minor amount of HA. DMF/water system yielded HA as the major phase with a very minor amount of beta-CPF. THF/water solvent system with the lowest dielectric constant resulted in the formation of pure HA.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 Modelling and analysis of the impact of correlated inter-event data on production control using Markovian arrival processes(Springer, 2019) Department of Business Administration; Department of Industrial Engineering; N/A; Tan, Barış; Dizbin, Nima Manafzadeh; Faculty Member; Department of Business Administration; Department of Industrial Engineering; College of Administrative Sciences and Economics; College of Engineering; Graduate School of Business; 28600; N/AEmpirical studies show that the inter-event times of a production system are correlated. However, most of the analytical studies for the analysis and control of production systems ignore correlation. In this study, we show that real-time data collected from a manufacturing system can be used to build a Markovian arrival processes (MAP) model that captures correlation in inter-event times. The obtained MAP model can then be used to control production in an effective way. We first present a comprehensive review on MAP modeling and MAP fitting methods applicable to manufacturing systems. Then we present results on the effectiveness of these fitting methods and discuss how the collected inter-event data can be used to represent the flow dynamics of a production system accurately. In order to study the impact of capturing the flow dynamics accurately on the performance of a production control system, we analyze a manufacturing system that is controlled by using a base-stock policy. We study the impact of correlation in inter-event times on the optimal base-stock level of the system numerically by employing the structural properties of the MAP. We show that ignoring correlated arrival or service process can lead to overestimation of the optimal base-stock level for negatively correlated processes, and underestimation for the positively correlated processes. We conclude that MAPs can be used to develop data-driven models and control manufacturing systems more effectively by using shop-floor inter-event data.Publication Open Access The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD(Nature Publishing Group (NPG), 2022) Günsel, Gizem Güneş; Conlon, Thomas M.; Jeridi, Aicha; Kim, Rinho; Ertuez, Zeynep; Lang, Niklas J.; Ansari, Meshal; Novikova, Mariia; Jiang, Dongsheng; Strunz, Maximilian; Gaianova, Mariia; Hollauer, Christine; Gabriel, Christina; Angelidis, Ilias; Doll, Sebastian; Pestoni, Jeanine C.; Edelmann, Stephanie L.; Kohlhepp, Marlene Sophia; Guillot, Adrien; Bassler, Kevin; Van Eeckhoutte, Hannelore P.; Kanashova, Tamara; Rodius, Sophie; Ballester-Lopez, Carolina; Robles, Carlos M. Genes; Smirnova, Natalia; Rehberg, Markus; Agarwal, Charu; Krikki, Ioanna; Piavaux, Benoit; Verleden, Stijn E.; Vanaudenaerde, Bart; Koenigshoff, Melanie; Dittmar, Gunnar; Bracke, Ken R.; Schultze, Joachim L.; Watz, Henrik; Eickelberg, Oliver; Stoeger, Tobias; Burgstaller, Gerald; Tacke, Frank; Heissmeyer, Vigo; Rinkevich, Yuval; Schiller, Herbert B.; Conrad, Marcus; Schneider, Robert; Kayalar, Özgecan; Konyalılar, Nur; Bayram, Hasan; Yıldırım, Ali Önder; Researcher; PhD Student; Faculty Member; Other; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; N/A; N/A; 4890; N/AExtravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-kappa B/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated. Chronic obstructive pulmonary disease is a progressive and incurable chronic condition that involves accumulation of inflammatory macrophages in the lung tissue. Authors here show in mouse models of lung disease that PRMT7, a protein arginine methyltransferase, is an important regulator of recruitment and the pro-inflammatory phenotype of macrophages.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 Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice(Nature Portfolio, 2022) Akyel, Yasemin Kübra; Korkmaz, Tuba; Selvi, Saba; Danış, İbrahim; İpek, Özgecan Savluğ; Aygenli, Fatih; Öztürk, Nuri; Öztürk, Narin; Ünal, Durişehvar Özer; Güzel, Mustafa; Okyar, Alper; N/A; Department of Chemical and Biological Engineering; Department of Industrial Engineering; Gül, Şeref; Gül, Zeynep Melis; Işın, Şafak; Özcan, Onur; Akarlar, Büşra; Taşkın, Ali Cihan; Türkay, Metin; Kavaklı, İbrahim Halil; Researcher; Other; Faculty Member; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Industrial Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Engineering; N/A; N/A; N/A; N/A; N/A; 291296; 105301; 24956; 40319Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53(-/-) mice by similar to 25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.Publication Open Access Cross-linguistic patterns in the acquisition of quantifiers(National Academy of Sciences, 2016) Katsos, Napoleon; Cummins, Chris; Ezeizabarrena, Maria-Jose; Gavarro, Anna; Kraljevic, Jelena Kuvac; Hrzica, Gordana; Grohmann, Kleanthes K.; Skordi, Athina; de Lopez, Kristine Jensen; Sundahl, Lone; van Hout, Angeliek; Hollebrandse, Bart; Overweg, Jessica; Faber, Myrthe; van Koert, Margreet; Smith, Nafsika; Vija, Maigi; Zupping, Sirli; Kunnari, Sari; Morisseau, Tiffany; Rusieshvili, Manana; Yatsushiro, Kazuko; Fengler, Anja; Varlokosta, Spyridoula; Konstantzou, Katerina; Farby, Shira; Guasti, Maria Teresa; Vernice, Mirta; Okabe, Reiko; Isobe, Miwa; Crosthwaite, Peter; Hong, Yoonjee; Balciuniene, Ingrida; Nizar, Yanti Marina Ahmad; Grech, Helen; Gatt, Daniela; Cheong, Win Nee; Asbjornsen, Arve; Torkildsen, Janne von Koss; Haman, Ewa; Miekisz, Aneta; Gagarina, Natalia; Puzanova, Julia; Andelkovic, Darinka; Savic, Maja; Josic, Smiljana; Slancova, Daniela; Kapalkova, Svetlana; Barberan, Tania; Hassan, Saima; Chan, Cecilia Yuet Hung; Okubo, Tomoya; van der Lely, Heather; Sauerland, Uli; Noveck, Ira; Department of Psychology; Özge, Duygu; Department of Psychology; College of Social Sciences and HumanitiesLearners of most languages are faced with the task of acquiring words to talk about number and quantity. Much is known about the order of acquisition of number words as well as the cognitive and perceptual systems and cultural practices that shape it. Substantially less is known about the acquisition of quantifiers. Here, we consider the extent to which systems and practices that support number word acquisition can be applied to quantifier acquisition and conclude that the two domains are largely distinct in this respect. Consequently, we hypothesize that the acquisition of quantifiers is constrained by a set of factors related to each quantifier's specific meaning. We investigate competence with the expressions for "all," "none," "some," "some. not," and "most" in 31 languages, representing 11 language types, by testing 768 5-y-old children and 536 adults. We found a cross-linguistically similar order of acquisition of quantifiers, explicable in terms of four factors relating to their meaning and use. In addition, exploratory analyses reveal that language-and learner-specific factors, such as negative concord and gender, are significant predictors of variation.