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Publication Open Access 3D spatial organization and network-guided comparison of mutation profiles in Glioblastoma reveals similarities across patients(Public Library of Science, 2019) Dinçer, Cansu; Kaya, Tuğba; Tunçbağ, Nurcan; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Engineering; 26605; 8745Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor. Molecular heterogeneity is a hallmark of GBM tumors that is a barrier in developing treatment strategies. In this study, we used the nonsynonymous mutations of GBM tumors deposited in The Cancer Genome Atlas (TCGA) and applied a systems level approach based on biophysical characteristics of mutations and their organization in patient-specific subnetworks to reduce inter-patient heterogeneity and to gain potential clinically relevant insights. Approximately 10% of the mutations are located in "patches" which are defined as the set of residues spatially in close proximity that are mutated across multiple patients. Grouping mutations as 3D patches reduces the heterogeneity across patients. There are multiple patches that are relatively small in oncogenes, whereas there are a small number of very large patches in tumor suppressors. Additionally, different patches in the same protein are often located at different domains that can mediate different functions. We stratified the patients into five groups based on their potentially affected pathways, revealed from the patient-specific subnetworks. These subnetworks were constructed by integrating mutation profiles of the patients with the interactome data. Network-guided clustering showed significant association between each group and patient survival (P-value = 0.0408). Also, each group carries a set of signature 3D mutation patches that affect predominant pathways. We integrated drug sensitivity data of GBM cell lines with the mutation patches and the patient groups to analyze the therapeutic outcome of these patches. We found that Pazopanib might be effective in Group 3 by targeting CSF1R. Additionally, inhibiting ATM that is a mediator of PTEN phosphorylation may be ineffective in Group 2. We believe that from mutations to networks and eventually to clinical and therapeutic data, this study provides a novel perspective in the network-guided precision medicine.Publication Open Access A cartridge based sensor array platform for multiple coagulation measurements from plasma(Royal Society of Chemistry (RSC), 2015) Bulut, Serpil; Yaralioglu, G. G.; Department of Electrical and Electronics Engineering; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Çakmak, Onur; Ermek, Erhan; Kılınç, Necmettin; Barış, İbrahim; Kavaklı, İbrahim Halil; Ürey, Hakan; PhD Student; Other; Researcher; Teaching Faculty; Faculty Member; Department of Electrical and Electronics Engineering; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; College of Sciences; N/A; 109991; N/A; 111629; 40319; 8579This paper proposes a MEMS-based sensor array enabling multiple clot-time tests for plasma in one disposable microfluidic cartridge. The versatile LoC (Lab-on-Chip) platform technology is demonstrated here for real-time coagulation tests (activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)). The system has a reader unit and a disposable cartridge. The reader has no electrical connections to the cartridge. This enables simple and low-cost cartridge designs and avoids reliability problems associated with electrical connections. The cartridge consists of microfluidic channels and MEMS microcantilevers placed in each channel. The microcantilevers are made of electroplated nickel. They are actuated remotely using an external electro-coil and the read-out is also conducted remotely using a laser. The phase difference between the cantilever oscillation and the coil drive is monitored in real time. During coagulation, the viscosity of the blood plasma increases resulting in a change in the phase read-out. The proposed assay was tested on human and control plasma samples for PT and aPTT measurements. PT and aPTT measurements from control plasma samples are comparable with the manufacturer's datasheet and the commercial reference device. The measurement system has an overall 7.28% and 6.33% CV for PT and aPTT, respectively. For further implementation, the microfluidic channels of the cartridge were functionalized for PT and aPTT tests by drying specific reagents in each channel. Since simultaneous PT and aPTT measurements are needed in order to properly evaluate the coagulation system, one of the most prominent features of the proposed assay is enabling parallel measurement of different coagulation parameters. Additionally, the design of the cartridge and the read-out system as well as the obtained reproducible results with 10 mu l of the plasma samples suggest an opportunity for a possible point-of-care application.Publication Open Access A comparative molecular dynamics study of methylation state specificity of JMJD2A(Public Library of Science, 2011) Bozfakioğlu S.; Uğurel, Elif; Sinan, M.; Department of Chemical and Biological Engineering; Keskin, Özlem; Erman, Burak; Gürsoy, Attila; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; College of Sciences; College of Engineering; 26605; 179997; N/AHistone modifications have great importance in epigenetic regulation. JMJD2A is a histone demethylase which is selective for di- and trimethyl forms of residues Lys9 and Lys36 of Histone 3 tail (H3K9 and H3K36). We present a molecular dynamics simulations of mono-, di- and trimethylated histone tails in complex with JMJD2A catalytic domain to gain insight into how JMJD2A discriminates between the methylation states of H3K9. The methyl groups are located at specific distances and orientations with respect to Fe(II) in methylammonium binding pocket. For the trimethyllysine the mechanism which provides the effectual orientation of methyl groups is the symmetry, whereas for the dimethyllysine case the determining factors are the interactions between methyllysine head and its environment and subsequently the restriction on angular motion. The occurrence frequency of methyl groups in a certain proximity of Fe(II) comes out as the explanation of the enzyme activity difference on di-and tri-methylated peptides. Energy analysis suggests that recognition is mostly driven by van der Waals and followed by Coulombic interactions in the enzyme-substrate interface. The number (mono, di or tri) and orientations of methyl groups and water molecules significantly affect the extent of van der Waals interaction strengths. Hydrogen bonding analysis suggests that the interaction between JMJD2A and its substrates mainly comes from main chain-side chain interactions. Binding free energy analysis points out Arg8 as an important residue forming an intra-substrate hydrogen bond with tri and dimethylated Lys9 of the H3 chain. Our study provides new insights into how JMJD2A discriminates between its substrates from both a structural and dynamical point of view.Publication Open Access A mixed-integer linear programming based training and feature selection method for artificial neural networks using piece-wise linear approximations(Elsevier, 2022) Şıldır, Hasan; Department of Chemical and Biological Engineering; Aydın, Erdal; Faculty Member; Department of Chemical and Biological Engineering; Koç University Tüpraş Energy Center (KUTEM) / Koç Üniversitesi Tüpraş Enerji Merkezi (KÜTEM); College of EngineeringArtificial Neural Networks (ANNs) may suffer from suboptimal training and test performance related issues not only because of the presence of high number of features with low statistical contributions but also due to their non-convex nature. This study develops piecewise-linear formulations for the efficient approximation of the non-convex activation and objective functions in artificial neural networks for optimal, global and simultaneous training and feature selection in regression problems. Such formulations include binary variables to account for the existence of the features and piecewise-linear approximations, which in turn, after one exact linearization step, calls for solving a mixed-integer linear programming problem with a global optimum guarantee because of convexity. Suggested formulation is implemented on two industrial case studies. Results show that efficient approximations are obtained through the usage of the method with only a few number of breakpoints. Significant feature space reduction is observed bringing about notable improvement in test accuracy.Publication Open Access A multi-state coarse grained modeling approach for an intrinsically disordered peptide(American Institute of Physics (AIP) Publishing, 2017) Department of Chemical and Biological Engineering; N/A; Sayar, Mehmet; Dalgıçdır, Cahit; Ramezanghorbani, Farhad; Faculty Member; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 109820; N/A; N/AMany proteins display a marginally stable tertiary structure, which can be altered via external stimuli. Since a majority of coarse grained (CG) models are aimed at structure prediction, their success for an intrinsically disordered peptide's conformational space with marginal stability and sensitivity to external stimuli cannot be taken for granted. In this study, by using the LK alpha 14 peptide as a test system, we demonstrate a bottom-up approach for constructing a multi-state CG model, which can capture the conformational behavior of this peptide in three distinct environments with a unique set of interaction parameters. LK alpha 14 is disordered in dilute solutions; however, it strictly adopts the alpha-helix conformation upon aggregation or when in contact with a hydrophobic/hydrophilic interface. Our bottom-up approach combines a generic base model, that is unbiased for any particular secondary structure, with nonbonded interactions which represent hydrogen bonds, electrostatics, and hydrophobic forces. We demonstrate that by using carefully designed all atom potential of mean force calculations from all three states of interest, one can get a balanced representation of the nonbonded interactions. Our CG model behaves intrinsically disordered in bulk water, folds into an alpha-helix in the presence of an interface or a neighboring peptide, and is stable as a tetrameric unit, successfully reproducing the all atom molecular dynamics simulations and experimental results.Publication Open Access A new class of porous materials for efficient CO2 separation: ionic liquid/graphene aerogel composites(Elsevier, 2021) Department of Chemical and Biological Engineering; N/A; Department of Chemistry; Zeeshan, Muhammad; Yalçın, Kaan; Keskin, Seda; Uzun, Alper; Öztuna, Feriha Eylül Saraç; Ünal, Uğur; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Chemistry; Koç University Tüpraş Energy Center (KUTEM) / Koç Üniversitesi Tüpraş Enerji Merkezi (KÜTEM); Koç University Surface Science and Technology Center (KUYTAM) / Koç Üniversitesi Yüzey Teknolojileri Araştırmaları Merkezi (KUYTAM); Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; N/A; 40548; 59917; N/A; 42079Here, we report a new post-synthesis modification strategy for functionalizing reduced graphene aerogels (rGAs) towards an exceptional CO2 separation performance. 1-N-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) was impregnated on a rGA, prepared by reducing GA at 700 degrees C, at various ionic liquid (IL) loadings of 5, 10, 30, and 50 wt%. The resulting composites were characterized in deep detail by X-ray photoelectron spectroscopy, X-ray diffraction, N-2 physical adsorption measurements, scanning electron microscopy, Fourier transform infrared and Raman spectroscopies, and thermogravimetric analysis. Results indicated the presence of interactions between the rGA surface and the anion of the IL, potentially improving the CO2 affinity. Volumetric gas adsorption measurements using these materials showed that the deposition of [BMIM][PF6] on rGA surface at an IL loading of 50 wt% boosts the CO2/CH4 selectivity by more than 20-times, exceeding an absolute value of 120, a remarkably higher CO2/CH4 selectivity compared to that of other functionalized materials under similar operating conditions. Tunability of both the IL structure and the surface characteristics of rGA offer a tremendous degree of flexibility for the rational design of these IL/rGA composites towards high performance in gas separation applications.Publication Open Access A novel hybrid material: an inorganic silica aerogel core encapsulated with a tunable organic alginate aerogel layer(Royal Society of Chemistry (RSC), 2014) Department of Chemical and Biological Engineering; Ülker, Zeynep; Erkey, Can; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 29633A novel layered material consisting of a silica aerogel core encapsulated by an alginate aerogel layer was developed. The components of the hybrid aerogel had the high surface area and high porosity of pure aerogels which should lead to development of new layered systems for a wide variety of applications.Publication Open Access A novel IL/MOF/polymer mixed matrix membrane having superior CO2/N2 selectivity(Elsevier, 2022) Department of Chemical and Biological Engineering; Habib, Nitasha; Durak, Özce; Zeeshan, Muhammad; Uzun, Alper; Keskin, Seda; PhD Student; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Koç University Tüpraş Energy Center (KUTEM) / Koç Üniversitesi Tüpraş Enerji Merkezi (KÜTEM); Koç University Surface Science and Technology Center (KUYTAM) / Koç Üniversitesi Yüzey Teknolojileri Araştırmaları Merkezi (KUYTAM); Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; N/A; 59917; 40548In this work, we synthesized an ionic liquid (IL)/metal organic framework (MOF) composite, 1-ethyl-3-methylimidazolium acetate/copper-1,3,5-benzenetricarboxylate ([EMIM][OAc]/CuBTC) and used it as a filler in a polymer, Pebax, to fabricate novel IL/MOF/polymer mixed matrix membranes (MMMs). CuBTC/Pebax and [EMIM][OAc]/CuBTC/Pebax MMMs having different filler loadings of 10, 15, and 20 wt.% were prepared by solution casting method and characterized using various techniques including X-ray diffraction (XRD), scanning electron microscopy (SEM), infrared spectroscopy (IR), and thermogravimetric analysis (TGA). Uniform dispersion of MOF and IL/MOF fillers in the MMMs was observed. Incorporation of IL/MOF composite into Pebax significantly improved CO2 permeability and CO2/N2 selectivity of the polymer by 2.5- and 5.5-times, respectively. Gas permeability measurements showed that the MMM having 15 wt.% IL/MOF loading exhibits significantly higher CO2 permeability of 335 Barrer and CO2/N2 selectivity of 176 than the Pebax membrane having CO2 permeability of 135 Barrer and CO2/N2 selectivity of 32. CO2/N2 selectivity of the [EMIM][OAc]/CuBTC/Pebax MMM with 15 wt.% [EMIM][OAc]/CuBTC filler loading was the highest among the selectivity values reported for other types of IL/MOF/polymer MMMs in the literature. All the CuBTC/Pebax MMMs and [EMIM][OAc]/CuBTC/Pebax MMMs that we fabricated in this work exceeded the Robeson's updated upper bound, showing the excellent potential of these novel membranes for CO2/N2 separation.Publication Open Access A novel method for PEGylation of chitosan nanoparticles through photopolymerization(Royal Society of Chemistry (RSC), 2019) Department of Chemical and Biological Engineering; Bozüyük, Uğur; Gökulu, İpek Simay; Doğan, Nihal Olcay; Kızılel, Seda; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; N/A; N/A; N/A; 28376An ultrafast and convenient method for PEGylation of chitosan nanoparticles has been established through a photopolymerization reaction between the acrylate groups of PEG and methacrylated-chitosan nanoparticles. The nanoparticle characteristics under physiological pH conditions were optimized through altered PEG chain length, concentration and duration of UV exposure. The method developed here has potential for clinical translation of chitosan nanoparticles. It also allows for the scalable and fast synthesis of nanoparticles with colloidal stability.Publication Open Access A promising catalyst for the dehydrogenation of perhydro-dibenzyltoluene: Pt/Al2O3 prepared by supercritical CO2 deposition(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Modisha, Phillimon; Garidzirai, Rudaviro; Rommel, Sarshad; Uzunlar, Erdal; Aindow, Mark; Bessarabov, Dmitri; Department of Chemical and Biological Engineering; Bozbağ, Selmi Erim; Erkey, Can; Güneş, Hande; Researcher; Faculty Member; Department of Chemical and Biological Engineering; Koç University Tüpraş Energy Center (KUTEM) / Koç Üniversitesi Tüpraş Enerji Merkezi (KÜTEM); College of Engineering; N/A; 29633; N/APt/Al2O3 catalysts prepared via supercritical deposition (SCD), with supercritical CO2, wet impregnation (WI) methods and a selected benchmark catalyst, were evaluated for the dehydrogenation of perhydro-dibenzyltoluene (H18-DBT) at 300 degrees C in a batch reactor. After ten dehydrogenation runs, the average performance of the catalyst prepared using SCD was the highest compared to the benchmark and WI-prepared catalysts. The pre-treatment of the catalysts with the product (dibenzyltoluene) indicated that the deactivation observed is mainly due to the adsorbed H0-DBT blocking the active sites for the reactant (H18-DBT). Furthermore, the SCD method afforded a catalyst with a higher dispersion of smaller sized Pt particles, thus improving catalytic performance towards the dehydrogenation of H18-DBT. The particle diameters of the SCD- and WI-prepared catalysts varied in the ranges of 0.6-2.2 nm and 0.8-3.4 nm and had average particle sizes of 1.1 nm and 1.7 nm, respectively. Energy dispersive X-ray spectroscopy analysis of the catalysts after ten dehydrogenation runs revealed the presence of carbon. In this study, improved catalyst performance led to the production of more liquid-based by-products and carbon material compared to catalysts with low catalytic performance.