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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 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 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.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 Comparison of the trifecta outcomes of robotic and open nephron-sparing surgeries performed in the robotic era of a single institution(SpringerOpen, 2015) Isik, Esin Ozturk; Mut, Tuna; Saglican, Yesim; Vural, Metin; Musaoğlu, Ahmet; N/A; N/A; Acar, Ömer; Onay, Aslıhan; Esen, Tarık; Faculty Member; Faculty Member; School of Medicine; 237530; N/A; 50536Purpose: In this study we aimed to report a comparative analysis between open and robotic nephron sparing surgeries (NSS) from a single institutional database. Methods: Patients who have undergone NSS during the robotic era of our institution were included in this study. Open (n = 74) and robotic (n = 59) groups were compared regarding trifecta outcome. Trifecta was defined as; warm ischemia time (WIT) <25 min, negative surgical margins and the absence of perioperative complications. Results: A total of 57 (77 %) and 45 (76 %) patients in the open and robotic groups, respectively achieved the trifecta outcome. Overall trifecta rate was 77 % (n = 102/133). The only statistically significant difference between trifecta positive and trifecta negative patients was the length of hospitalization (LOH). Except LOH; none of the tested parameters were shown to be predictive of trifecta outcome on univariate and multivariate analyses. Concerning trifecta positive patients; those in the open surgery group had larger tumors with a higher degree of morphometric complexity and were hospitalized for a longer period of time. Additionally, operative duration was significantly higher in the robotic group. Conclusions: In our cohort, no significant difference in achieving the trifecta outcome was reported after open and robotic NSS. Length of hospitalization was the only parameter that differed significantly between trifecta positive and trifecta negative patients. Surgical approach was not a significant predictor of simultaneous achievement of trifecta outcomes. Irrespective of the trifecta definition; larger and more complicated tumors were handled via open NSS.