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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6

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    PublicationOpen Access
    Multifunctional alginate-based hydrogel with reversible crosslinking for controlled therapeutics delivery
    (Elsevier, 2020) Ekinci, Duygu; N/A; Department of Chemical and Biological Engineering; Batool, Syeda Rubab; Nazeer, Muhammad Anwaar; Kızılel, Seda; Şahin, Afsun; PhD Student; Faculty Member; Faculty Member; 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; School of Medicine; N/A; N/A; 28376; 171267
    Glycan-based alginate hydrogels have great potential in creating new vehicles with responsive behavior and tunable properties for biomedicine. However, precise control and tunability in properties present major barrier for clinical translation of these materials. Here, we report the synthesis of pH responsive anthracene modified glycan-based hydrogels for selective release of therapeutic molecules. Hydrogels were crosslinked through simultaneous photopolymerization of vinyl groups and photodimerization of anthracene. Incorporation of anthracene into these gels leads to reversible control on crosslinking and transition between gel/sol states through dimerization/dedimerization of anthracene groups. Chemotherapeutic drug doxorubicin-loaded hydrogels were then tested in a cancer mimetic microenvironment where 85% of the drug was released from anthracene-conjugated hydrogels at pH 2 for 6 days. Control on gelation with anthracene incorporation was observed through alterations in modulus, where storage modulus was increased two-fold with anthracene conjugation during photopolymerization and photodimerization. Furthermore, cell survival analysis revealed that anthracene conjugation could selectively compromise cancer cell viability without inducing significant toxicity on healthy fibroblasts. This study combines light-induced control of crosslink density due to anthracene and pH-triggered therapeutics delivery with alginate. The approach would be applicable for systems where multiple control is required with high precision.
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    PublicationOpen Access
    HotRegion: a database of predicted hot spot clusters
    (Oxford University Press (OUP), 2012) N/A; Department of Computer Engineering; Department of Chemical and Biological Engineering; Çukuroğlu, Engin; Gürsoy, Attila; Keskin, Özlem; PhD Student; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 8745; 26605
    Hot spots are energetically important residues at protein interfaces and they are not randomly distributed across the interface but rather clustered. These clustered hot spots form hot regions. Hot regions are important for the stability of protein complexes, as well as providing specificity to binding sites. We propose a database called HotRegion, which provides the hot region information of the interfaces by using predicted hot spot residues, and structural properties of these interface residues such as pair potentials of interface residues, accessible surface area (ASA) and relative ASA values of interface residues of both monomer and complex forms of proteins. Also, the 3D visualization of the interface and interactions among hot spot residues are provided.
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    PublicationOpen Access
    Coagulation measurement from whole blood using vibrating optical fiber in a disposable cartridge
    (Society of Photo-optical Instrumentation Engineers (SPIE), 2017) Çivitci, Fehmi; Barış, İbrahim; Yaralıoğlu, Göksenin; Department of Electrical and Electronics Engineering; Yaras, Yusuf Samet; Gündüz, Ali Bars; Sağlam, Gökhan; Ölçer, Selim; Ürey, Hakan; Other; Faculty Member; Department of Electrical and Electronics Engineering; College of Engineering; N/A; N/A; N/A; N/A; 8579
    In clinics, blood coagulation time measurements are performed using mechanical measurements with blood plasma. Such measurements are challenging to do in a lab-on-a-chip (LoC) system using a small volume of whole blood. Existing LoC systems use indirect measurement principles employing optical or electrochemical methods. We developed an LoC system using mechanical measurements with a small volume of whole blood without requiring sample preparation. The measurement is performed in a microfluidic channel where two fibers are placed inline with a small gap in between. The first fiber operates near its mechanical resonance using remote magnetic actuation and immersed in the sample. The second fiber is a pick-up fiber acting as an optical sensor. The microfluidic channel is engineered innovatively such that the blood does not block the gap between the vibrating fiber and the pick-up fiber, resulting in high signal-to-noise ratio optical output. The control plasma test results matched well with the plasma manufacturer's datasheet. Activated-partial-thromboplastin-time tests were successfully performed also with human whole blood samples, and the method is proven to be effective. Simplicity of the cartridge design and cost of readily available materials enable a low-cost point-of-care device for blood coagulation measurements.
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    PublicationOpen Access
    Comprehensive research on past and future therapeutic strategies devoted to treatment of amyotrophic lateral sclerosis
    (Multidisciplinary Digital Publishing Institute (MDPI), 2022) Sever, Belgin; Sever, Hilal; Ocak, Firdevs; Yuluğ, Burak; Tateishi, Hiroshi; Tateishi, Takahisa; Otsuka, Masami; Mikako, Fujita; Department of Molecular Biology and Genetics; Başak, Ayşe Nazlı; Çiftçi, Halil İbrahim; Demirci, Hasan; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Sciences; 1512; N/A; 307350
    Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.
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    PublicationOpen 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/A
    IQ 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.
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    PublicationOpen Access
    Chronically radiation-exposed survivor glioblastoma cells display poor response to Chk1 inhibition under hypoxia
    (Multidisciplinary Digital Publishing Institute (MDPI), 2022) Department of Molecular Biology and Genetics; Değirmenci, Nareg Pınarbaşı; Sur, İlknur Erdem; Akçay, Vuslat; Bölükbaşı, Yasemin; Selek, Uğur; Solaroğlu, İhsan; Önder, Tuğba Bağcı; PhD Student; Faculty Member; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; College of Sciences; School of Medicine; Koç University Hospital; N/A; N/A; N/A; 216814; 27211; 102059; 184359
    Glioblastoma is the most malignant primary brain tumor, and a cornerstone in its treatment is radiotherapy. However, tumor cells surviving after irradiation indicates treatment failure; therefore, better understanding of the mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated clinically relevant irradiation-exposed models by applying fractionated radiotherapy over a long time and selecting irradiation-survivor (IR-Surv) glioblastoma cells. We examined the transcriptomic alterations, cell cycle and growth rate changes and responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Concomitantly, IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, and MGMT, and had better DNA repair capacity. IR-Surv cells displayed downregulation of hypoxic signature and lower induction of hypoxia target genes, compared to naive glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both naive and IR-Surv cells. However, IR-Surv cells' response to Chk1 inhibition markedly decreased under hypoxic conditions. Taken together, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both naive and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions.
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    PublicationOpen Access
    PRISM: a web server and repository for prediction of protein-protein interactions and modeling their 3D complexes
    (Oxford University Press (OUP), 2014) Nussinov, Ruth; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Başpınar, Alper; Çukuroğlu, Engin; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; 26605; 8745
    The PRISM web server enables fast and accurate prediction of protein-protein interactions (PPIs). The prediction algorithm is knowledge-based. It combines structural similarity and accounts for evolutionary conservation in the template interfaces. The predicted models are stored in its repository. Given two protein structures, PRISM will provide a structural model of their complex if a matching template interface is available. Users can download the complex structure, retrieve the interface residues and visualize the complex model.
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    PublicationOpen 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 Engineering
    Nanoscale 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.
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    PublicationOpen 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/A
    Human 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.
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    PublicationOpen Access
    CCRXP: exploring clusters of conserved residues in protein structures
    (Oxford University Press (OUP), 2010) Ahmad, Shandar; Mizuguchi, Kenji; Sarai, Akinori; Nussinov, Ruth; Department of Chemical and Biological Engineering; Keskin, Özlem; PhD Student; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; 26605
    Conserved residues forming tightly packed clusters have been shown to be energy hot spots in both protein-protein and protein-DNA complexes. A number of analyses on these clusters of conserved residues (CCRs) have been reported, all pointing to a crucial role that these clusters play in protein function, especially protein-protein and protein-DNA interactions. However, currently there is no publicly available tool to automatically detect such clusters. Here, we present a web server that takes a coordinate file in PDB format as input and automatically executes all the steps to identify CCRs in protein structures. In addition, it calculates the structural properties of each residue and of the CCRs. We also present statistics to show that CCRs, determined by these procedures, are significantly enriched in 'hot spots' in protein-protein and protein-RNA complexes, which supplements our more detailed similar results on protein-DNA complexes. We expect that CCRXP web server will be useful in studies of protein structures and their interactions and selecting mutagenesis targets.