Publications with Fulltext
Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access Investigation of hydrodynamic behavior of alginate aerogel particles in a laboratory scale Wurster fluidized bed(Multidisciplinary Digital Publishing Institute (MDPI), 2019) Department of Chemical and Biological Engineering; Erkey, Can; Akgün, Işık Sena; Faculty Member; Researcher; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; 29633; N/AThe effects of design and operating parameters on the superficial velocity at the onset of circulatory motion and the residence time of alginate aerogel particles in a laboratory scale Wurster fluidized bed were investigated. Several sets of experiments were conducted by varying Wurster tube diameter, Wurster tube length, batch volume and partition gap height. The superficial velocities for Wurster tube with 10 cm diameter were lower than the tube with 8 cm diameter. Superficial velocities increased with increasing batch volume and partition gap height. Moreover, increasing batch volume and partition gap height led to a decrease in the particle residence time in the Wurster tube. The results showed that there is an upper limit for each parameter in order to obtain a circulatory motion of the particles. It was found that the partition gap height should be 2 cm for proper particle circulation. Maximum batch volume for the tube with 10 cm diameter was found as 500 mL whereas maximum batch volume was 250 mL for the tube with 8 cm diameter. The fluidization behavior of the aerogel particles investigated in this study could be described by the general fluidization diagrams in the literature.Publication Open Access An information theoretical analysis of human insulin-glucose system toward the internet of bio-nano things(Institute of Electrical and Electronics Engineers (IEEE), 2017) Department of Electrical and Electronics Engineering; Abbasi, Naveed Ahmed; Akan, Özgür Barış; Faculty Member; Department of Electrical and Electronics Engineering; Graduate School of Sciences and EngineeringMolecular communication is an important tool to understand biological communications with many promising applications in Internet of Bio-Nano Things (IoBNT). The insulin-glucose system is of key significance among the major intra-body nanonetworks, since it fulfills metabolic requirements of the body. The study of biological networks from information and communication theoretical (ICT) perspective is necessary for their introduction in the IoBNT framework. Therefore, the objective of this paper is to provide and analyze for the first time in the literature, a simple molecular communication model of the human insulin-glucose system from ICT perspective. The data rate, channel capacity, and the group propagation delay are analyzed for a two-cell network between a pancreatic beta cell and a muscle cell that are connected through a capillary. The results point out a correlation between an increase in insulin resistance and a decrease in the data rate and channel capacity, an increase in the insulin transmission rate, and an increase in the propagation delay. We also propose applications for the introduction of the system in the IoBNT framework. Multi-cell insulin glucose system models may be based on this simple model to help in the investigation, diagnosis, and treatment of insulin resistance by means of novel IoBNT applications.Publication Open Access Rabenosyn separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder(Oxford University Press (OUP), 2022) Paul, Franziska; Ng, Calista; Mohamad Sahari, Umar Bin; Nafissi, Shahriar; Nilipoor, Yalda; Tavasoli, Ali Reza; Bonnard, Carine; Wong, Pui-Mun; Estiar, Mehrdad A.; Majoie, Charles B.; Lee, Hane; Nelson, Stanley F.; Gan-Or, Ziv; Rouleau, Guy A.; Van Veldhoven, Paul P.; Massie, Rami; Hennekam, Raoul C.; Kariminejad, Ariana; Reversade, Bruno; Nabavizadeh, Nasrinsadat; Altunoğlu, Umut; Faculty Member; Researcher; Faculty Member; School of Medicine; N/A; N/A; 126174Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.Publication Open Access Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2(American Society for Biochemistry and Molecular Biology (ASBMB), 2018) Jang, Hyunbum; Li, Zhigang; Sacks, David B.; Nussinov, Ruth; Department of Computer Engineering; Department of Chemical and Biological Engineering; Gürsoy, Attila; Keskin, Özlem; Özdemir, E. Sıla; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 8745; 26605; N/AIQ motif-containing GTPase-activating proteins (IQGAPs) are scaffolding proteins playing central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 and Rac1, in their GTP-bound active forms, interact with all three human IQGAPs. The IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite their high sequence identity, Cdc42 and Rac1 differ in their interactions with IQGAP. Two Cdc42 molecules can bind to the Ex-domain and the RasGAP site of the GTPase-activating protein (GAP)related domain (GRD) of IQGAP and promote IQGAP dimerization. Only one Rac1 molecule might bind to the RasGAP site of GRD and may not facilitate the dimerization, and the exact mechanism of Cdc42 and Rac1 binding to IQGAP is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, and Western blotting, we unraveled the detailed mechanisms of Cdc42 and Rac1 interactions with IQGAP2. We observed that Cdc42 binding to the Ex-domain of GRD of IQGAP2 (GRD2) releases the Ex-domain at the C-terminal region of GRD2, facilitating IQGAP2 dimerization. Cdc42 binding to the Ex-domain promoted allosteric changes in the RasGAP site, providing a binding site for the second Cdc42 in the RasGAP site. Of note, the Cdc42 "insert loop" was important for the interaction of the first Cdc42 with the Ex-domain. By contrast, differences in Rac1 insert-loop sequence and structure precluded its interaction with the Ex-domain. Rac1 could bind only to the RasGAP site of apo-GRD2 and could not facilitate IQGAP2 dimerization. Our detailed mechanistic insights help decipher how Cdc42 can stimulate actin polymerization in metastasis.Publication Open Access FRET-based nanoscale point-to-point and broadcast communications with multi-exciton transmission and channel routing(Institute of Electrical and Electronics Engineers (IEEE), 2014) Kuşcu, Murat; Akan, Özgür Barış; Faculty Member; Faculty Member; College of EngineeringNanoscale communication based on Forster Resonance Energy Transfer (FRET) enables nanoscale single molecular devices to communicate with each other utilizing excitons generated on fluorescentmolecules as information carriers. Based on the point-to-point single-exciton FRET-based nanocommunication model, we investigate the multiple-exciton case for point-to-point and broadcast communications following an information theoretical approach and conducting simulations through Monte Carlo approach. We demonstrate that the multi-exciton transmission significantly improves the channel reliability and the range of the communication up to tens of nanometers for immobile nanonodes providing high data transmission rates. Furthermore, our analyses indicate that multi-exciton transmission enables broadcasting of information from a transmitter nanonode to many receiver nanonodes pointing out the potential of FRET-based communication to extend over nanonetworks. In this study, we also propose electrically and chemically controllable routing mechanisms exploiting the strong dependence of FRET rate on spectral and spatial characteristics of fluorescent molecules. We show that the proposed routing mechanisms enable the remote control of information flow in FRET-based nanonetworks. The high transmission rates obtained by multi-exciton scheme for point-to-point and broadcast communications, as well as the routing opportunities make FRET-based communication promising for future molecular computers.Publication Open Access The secondary pocket of cryptochrome 2 is important for the regulation of its stability and localization(Elsevier, 2022) Gül, Şeref; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Kavaklı, İbrahim Halil; Barış, İbrahim; Özcan, Onur; Faculty Member; Teaching Faculty; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 40319; 111629; N/A; N/A; N/AHuman clock-gene variations contribute to the phenotypic differences observed in various behavioral and physiological processes, such as diurnal preference, sleep, metabolism, mood regulation, addiction, and fertility. However, little is known about the possible effects of identified variations at the molecular level. In this study, we performed a functional characterization at the cellular level of rare cryptochrome 2 (CRY2) missense variations that were identified from the Ensembl database. Our structural studies revealed that three variations (p.Pro123Leu, p.Asp406His, and p.Ser410Ile) are located at the rim of the secondary pocket of CRY2. We show that these variants were unable to repress CLOCK (circadian locomotor output cycles kaput)/BMAL1 (brain and muscle ARNT-like-1)-driven transcription in a cell-based reporter assay and had reduced affinity to CLOCK-BMAL1. Furthermore, our biochemical studies indicated that the variants were less stable than the WT CRY2, which could be rescued in the presence of period 2 (PER2), another core clock protein. Finally, we found that these variants were unable to properly localize to the nucleus and thereby were unable to rescue the circadian rhythm in a Cry1(-/-)Cry2(-/-) double KO mouse embryonic fibroblast cell line. Collectively, our data suggest that the rim of the secondary pocket of CRY2 plays a significant role in its nuclear localization independently of PER2 and in the intact circadian rhythm at the cellular level.Publication Open Access Cyclophilin40 isomerase activity is regulated by a temperature-dependent allosteric interaction with Hsp90(Portland Press, 2015) Blackburn, Elizabeth A.; Wear, Martin A.; Landre, Vivian; Narayan, Vikram; Ning, Jia; Ball, Kathryn L.; Walkinshaw, Malcolm D.; Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997Cyclophilin 40 (Cyp40) comprises an N-terminal cyclophilin domain with peptidyl-prolyl isomerase (PPIase) activity and a C-terminal tetratricopeptide repeat (TPR) domain that binds to the C-terminal -EEVD sequence common to both heat shock protein 70 (Hsp70) and Hsp90. We show in the present study that binding of peptides containing the MEEVD motif reduces the PPIase activity by similar to 30%. CD and fluorescence assays show that the TPR domain is less stable than the cyclophilin domain and is stabilized by peptide binding. Isothermal titration calorimetry (ITC) shows that the affinity for the -MEEVD peptide is temperature sensitive in the physiological temperature range. Results from these biophysical studies fit with the MD simulations of the apo and holo (peptide-bound) structures which show a significant reduction in root mean square (RMS) fluctuation in both TPR and cyclophilin domains when -MEEVD is bound. The MD simulations of the apo-protein also highlight strong anti-correlated motions between residues around the PPIase-active site and a band of residues running across four of the seven helices in the TPR domain. Peptide binding leads to a distortion in the shape of the active site and a significant reduction in these strongly anti-correlated motions, providing an explanation for the allosteric effect of ligand binding and loss of PPIase activity. Together the experimental and MD results suggest that on heat shock, dissociation of Cyp40 from complexes mediated by the TPR domain leads to an increased pool of free Cyp40 capable of acting as an isomerase/chaperone in conditions of cellular stress.Publication Open Access Bidirectional optical neuromodulation using capacitive charge-transfer(The Optical Society (OSA) Publishing, 2020) Department of Electrical and Electronics Engineering; N/A; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Melikov, Rustamzhon; Srivastava, Shashi Bhushan; Karatüm, Onuralp; Nizamoğlu, Sedat; Doğru-Yüksel, Itır Bakış; Dikbaş, Uğur Meriç; Kavaklı, İbrahim Halil; PhD Student; Researcher; PhD Student; Faculty Member; Master Student; Faculty Member; Department of Electrical and Electronics Engineering; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; N/A; N/A; 130295; N/A; N/A; 40319Artificial control of neural activity allows for understanding complex neural networks and improving therapy of neurological disorders. Here, we demonstrate that utilization of photovoltaic biointerfaces combined with light waveform shaping can generate safe capacitive currents for bidirectional modulation of neurons. The differential photoresponse of the biointerface due to double layer capacitance facilitates the direction control of capacitive currents depending on the slope of light intensity. Moreover, the strength of capacitive currents is controlled by changing the rise and fall time slope of light intensity. This approach allows for high-level control of the hyperpolarization and depolarization of membrane potential at single-cell level. Our results pave the way toward advanced bioelectronic functionalities for wireless and safe control of neural activity.Publication Open Access Impact of Di(2-ethylhexyl) phthalate administration on various trace elements in rat serum(Wiley, 2017) Karabulut, G.; Barlas, N.; Ulusu, Nuriye Nuray; Faculty Member; School of Medicine; Koç University Hospital; N/A; 6807Publication Open Access Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome(Oxford University Press (OUP), 2022) Motta, Marialetizia; Solman, Maja; Bonnard, Adeline; Kuechler, Alma; Pantaleoni, Francesca; Priolo, Manuela; Chandramouli, Balasubramanian; Coppola, Simona; Pizzi, Simone; Zara, Erika; Ferilli, Marco; Onesimo, Roberta; Leoni, Chiara; Brinkmann, Julia; Vial, Yoann; Kamphausen, Susanne B.; Thomas-Teinturier, Cecile; Guimier, Anne; Cordeddu, Viviana; Mazzanti, Laura; Zampino, Giuseppe; Chillemi, Giovanni; Zenker, Martin; Cave, Helene; Hertog, Jeroen; Tartaglia, Marco; Kayserili, Hülya; Undergraduate Student; PhD Student; School of Medicine; Koç University Hospital; 7945We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A?>?G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A?>?G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease.