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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 Metadata only A communication theoretical modeling of axonal propagation in hippocampal pyramidal neurons(IEEE-Inst Electrical Electronics Engineers Inc, 2017) N/A; N/A; Department of Electrical and Electronics Engineering; Ramezani, Hamideh; Akan, Özgür Barış; PhD Student; Faculty Member; Department of Electrical and Electronics Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 6647Understandingthe fundamentals of communication among neurons, known as neuro-spike communication, leads to reach bio-inspired nanoscale communication paradigms. In this paper, we focus on a part of neuro-spike communication, known as axonal transmission, and propose a realistic model for it. The shape of the spike during axonal transmission varies according to previously applied stimulations to the neuron, and these variations affect the amount of information communicated between neurons. Hence, to reach an accurate model for neuro-spike communication, the memory of axon and its effect on the axonal transmission should be considered, which are not studied in the existing literature. In this paper, we extract the important factors on the memory of axon and define memory states based on these factors. We also describe the transition among these states and the properties of axonal transmission in each of them. Finally, we demonstrate that the proposed model can follow changes in the axonal functionality properly by simulating the proposed model and reporting the root mean square error between simulation results and experimental data.Publication Open Access A compressed sensing framework for efficient dissection of neural circuits(Nature Publishing Group (NPG), 2019) Lee, Jeffrey B.; Yonar, Abdullah; Hallacy, Timothy; Shen, Ching-Han; Milloz, Josselin; Srinivasan, Jagan; Ramanathan, Sharad; Department of Physics; Kocabaş, Aşkın; Department of Physics; College of Sciences; 227753A fundamental question in neuroscience is how neural networks generate behavior. The lack of genetic tools and unique promoters to functionally manipulate specific neuronal subtypes makes it challenging to determine the roles of individual subtypes in behavior. We describe a compressed sensing-based framework in combination with non-specific genetic tools to infer candidate neurons controlling behaviors with fewer measurements than previously thought possible. We tested this framework by inferring interneuron subtypes regulating the speed of locomotion of the nematode Caenorhabditis elegans. We developed a real-time stabilization microscope for accurate long-term, high-magnification imaging and targeted perturbation of neural activity in freely moving animals to validate our inferences. We show that a circuit of three interconnected interneuron subtypes, RMG, AVB and SIA control different aspects of locomotion speed as the animal navigates its environment. Our work suggests that compressed sensing approaches can be used to identify key nodes in complex biological networks.Publication Metadata only A multitask multiple kernel learning formulation for discriminating early- and late-stage cancers(Oxford University Press (OUP), 2020) N/A; N/A; Department of Industrial Engineering; Rahimi, Arezou; Gönen, Mehmet; PhD Student; Faculty Member; Department of Industrial Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 237468Motivation: Genomic information is increasingly being used in diagnosis, prognosis and treatment of cancer. The severity of the disease is usually measured by the tumor stage. Therefore, identifying pathways playing an important role in progression of the disease stage is of great interest. Given that there are similarities in the underlying mechanisms of different cancers, in addition to the considerable correlation in the genomic data, there is a need for machine learning methods that can take these aspects of genomic data into account. Furthermore, using machine learning for studying multiple cancer cohorts together with a collection of molecular pathways creates an opportunity for knowledge extraction. Results: We studied the problem of discriminating early- and late-stage tumors of several cancers using genomic information while enforcing interpretability on the solutions. To this end, we developed a multitask multiple kernel learning (MTMKL) method with a co-clustering step based on a cutting-plane algorithm to identify the relationships between the input tasks and kernels. We tested our algorithm on 15 cancer cohorts and observed that, in most cases, MTMKL outperforms other algorithms (including random forests, support vector machine and single-task multiple kernel learning) in terms of predictive power. Using the aggregate results from multiple replications, we also derived similarity matrices between cancer cohorts, which are, in many cases, in agreement with available relationships reported in the relevant literature.Publication Metadata only A survey of available tools and web servers for analysis of protein-protein interactions and interfaces(Oxford University Press (OUP), 2009) Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; N/A; Department of Chemical and Biological Engineering; Keskin, Özlem; Gürsoy, Attila; Makinacı, Gözde Kar; Tunçbağ, Nurcan; Faculty Member; Faculty Member; PhD Student; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; College of Engineering; 26605; 8745; N/A; 245513The unanimous agreement that cellular processes are (largely) governed by interactions between proteins has led to enormous community efforts culminating in overwhelming information relating to these proteins; to the regulation of their interactions, to the way in which they interact and to the function which is determined by these interactions. These data have been organized in databases and servers. However, to make these really useful, it is essential not only to be aware of these, but in particular to have a working knowledge of which tools to use for a given problem; what are the tool advantages and drawbacks; and no less important how to combine these for a particular goal since usually it is not one tool, but some combination of tool-modules that is needed. This is the goal of this review.Publication Metadata only An approach to monitoring home-cage behavior in mice that facilitates data sharing(Nature Portfolio, 2018) Balzani, Edoardo; Falappa, Matteo; Tucci, Valter; Department of Psychology; Balcı, Fuat; Faculty Member; Department of Psychology; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Social Sciences and Humanities; 51269Genetically modified mice are used as models for a variety of human behavioral conditions. However, behavioral phenotyping can be a major bottleneck in mouse genetics because many of the classic protocols are too long and/or are vulnerable to unaccountable sources of variance, leading to inconsistent results between centers. We developed a home-cage approach using a Chora feeder that is controlled by-and sends data to-software. In this approach, mice are tested in the standard cages in which they are held for husbandry, which removes confounding variables such as the stress induced by out-of-cage testing. This system increases the throughput of data gathering from individual animals and facilitates data mining by offering new opportunities for multimodal data comparisons. In this protocol, we use a simple work-for-food testing strategy as an example application, but the approach can be adapted for other experiments looking at, e.g., attention, decision-making or memory. The spontaneous behavioral activity of mice in performing the behavioral task can be monitored 24 h a day for several days, providing an integrated assessment of the circadian profiles of different behaviors. We developed a Python-based open-source analytical platform (Phenopy) that is accessible to scientists with no programming background and can be used to design and control such experiments, as well as to collect and share data. This approach is suitable for large-scale studies involving multiple laboratories.Publication Metadata only Analysis of single amino acid variations in singlet hot spots of protein-protein interfaces(Oxford Univ Press, 2018) N/A; N/A; Department of Computer Engineering; Department of Chemical and Biological Engineering; Özdemir, E. Sıla; Gürsoy, Attila; Keskin, Özlem; PhD Student; Faculty Member; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 8745; 26605Motivation: Single amino acid variations (SAVs) in protein-protein interaction (PPI) sites play critical roles in diseases. PPI sites (interfaces) have a small subset of residues called hot spots that contribute significantly to the binding energy, and they may form clusters called hot regions. Singlet hot spots are the single amino acid hot spots outside of the hot regions. The distribution of SAVs on the interface residues may be related to their disease association. Results: We performed statistical and structural analyses of SAVs with literature curated experimental thermodynamics data, and demonstrated that SAVs which destabilize PPIs are more likely to be found in singlet hot spots rather than hot regions and energetically less important interface residues. In contrast, non-hot spot residues are significantly enriched in neutral SAVs, which do not affect PPI stability. Surprisingly, we observed that singlet hot spots tend to be enriched in disease-causing SAVs, while benign SAVs significantly occur in non-hot spot residues. Our work demonstrates that SAVs in singlet hot spot residues have significant effect on protein stability and function.Publication Metadata only Antitumor efficacy of ceranib-2 with nano-formulation of PEG and rosin esters(Humana Press Inc, 2021) Ben Taleb, Ali; Karakus, Selcan; Tan, Ezgi; Ilgar, Merve; Kutlu, Ozlem; Kutlu, Hatice Mehtap; Kilislioglu, Ayben; N/A; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248Ceranib-2 is a recently discovered, poorly water-soluble potent ceramidase inhibitor, with the ability to suppress cancer cell proliferation and delay tumor growth. However, its poor water solubility and weak cellular bioavailability hinder its use as a therapeutic agent for cancer. PEGylated rosin esters are an excellent platform as a natural polymer for drug delivery applications, especially for controlling drug release due to their degradability, biocompatibility, capability to improve solubility, and pharmacokinetics of potent drugs. In this study, stable aqueous amphiphilic submicron-sized PEG400-rosin ester-ceranib-2 (PREC-2) particles, ranging between 100 and 350 nm in a 1:1 mixture, were successfully synthesized by solvent evaporation mediated by sonication. Conclusion: Stable aqueous PEGylated rosin ester nanocarriers might present a significant solution to improve solubility, pharmacokinetic, and bioavailability of ceranib-2, and hold promises for use as an anticancer adjacent drug after further investigations.Publication Open Access Applications of augmented reality in ophthalmology [invited](Optical Society of America (OSA), 2021) Artal, Pablo; Department of Physics; Department of Electrical and Electronics Engineering; Aydındoğan, Güneş; Kavaklı, Koray; Ürey, Hakan; Şahin, Afsun; Faculty Member; Faculty Member; Department of Physics; Department of Electrical and Electronics Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; N/A; N/A; 8579; 171267Throughout the last decade, augmented reality (AR) head-mounted displays (HMDs) have gradually become a substantial part of modern life, with increasing applications ranging from gaming and driver assistance to medical training. Owing to the tremendous progress in miniaturized displays, cameras, and sensors, HMDs are now used for the diagnosis, treatment, and follow-up of several eye diseases. In this review, we discuss the current state-of-the-art as well as potential uses of AR in ophthalmology. This review includes the following topics: (i) underlying optical technologies, displays and trackers, holography, and adaptive optics; (ii) accommodation, 3D vision, and related problems such as presbyopia, amblyopia, strabismus, and refractive errors; (iii) AR technologies in lens and corneal disorders, in particular cataract and keratoconus; (iv) AR technologies in retinal disorders including age-related macular degeneration (AMD), glaucoma, color blindness, and vision simulators developed for other types of low-vision patients.