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Publication Metadata only 32 novel pathogenic sequence variants in 253 DMD/BMD patients from Turkey(Nature Publishing Group, 2018) Toksoy, G.; Aghayev, A.; Bagirova, G.; Tekce, H. Durmus; Avci, S.; Altunolu, U.; Parman, Y.; Oflazer, P.; Yapici, Z.; N/A; Kayserili, Hülya; Faculty Member; School of Medicine; 7945N/APublication Metadata only 3D printing of cytocompatible gelatin-cellulose-alginate blend hydrogels(Wiley-V C H Verlag Gmbh, 2020) Erkoc, Pelin; Uvak, Ileyna; Odeh, Yazan Nitham; Akdogan, Ozan; Odeh, Yazan Nitham; Akdogan, Ozan; N/A; Department of Chemistry; Department of Chemical and Biological Engineering; Nazeer, Muhammad Anwaar; Batool, Syeda Rubab; Kızılel, Seda; PhD Student; Researcher; Faculty Member; Department of Chemistry; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Sciences; College of Engineering; N/A; N/A; 283763D bioprinting of hydrogels has gained great attention due to its potential to manufacture intricate and customized scaffolds that provide favored conditions for cell proliferation. Nevertheless, plain natural hydrogels can be easily disintegrated, and their mechanical strengths are usually insufficient for printing process. Hence, composite hydrogels are developed for 3D printing. This study aims to develop a hydrogel ink for extrusion-based 3D printing which is entirely composed of natural polymers, gelatin, alginate, and cellulose. Physicochemical interactions between the components of the intertwined gelatin-cellulose-alginate network are studied via altering copolymer ratios. The structure of the materials and porosity are assessed using infrared spectroscopy, swelling, and degradation experiments. The utility of this approach is examined with two different crosslinking strategies using glutaraldehyde or CaCl2. Multilayer cylindrical structures are successfully 3D printed, and their porous structure is confirmed by scanning electron microscopy and Brunauer-Emmett-Teller surface area analyses. Moreover, cytocompatibility of the hydrogel scaffolds is confirmed on fibroblast cells. The developed material is completely natural, biocompatible, economical, and the method is facile. Thus, this study is important for the development of advanced functional 3D hydrogels that have considerable potential for biomedical devices and artificial tissues.Publication Metadata only A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude(Elsevier, 2020) Akyel, Yasemin Kübra; Yılmaz, Fatma; Öztürk, Nuri; Öztürk, Narin; Okyar, Alper; N/A; N/A; Department of Chemical and Biological Engineering; N/A; Department of Molecular Biology and Genetics; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Doruk, Yağmur Umay; Yarparvar, Darya; Gül, Şeref; Taşkın, Ali Cihan; Barış, İbrahim; Türkay, Metin; Kavaklı, İbrahim Halil; Master Student; PhD Student; Researcher; Other; Teaching Faculty; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; College of Sciences; College of Engineering; College of Engineering; N/A; N/A; N/A; 291296; 111629; 24956; 40319Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ?2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both in vivo and in vitro. Results from further experiments indicated that CLK8 enhances the amplitude of the cellular circadian rhythm by stabilizing the negative arm of the transcription/translation feedback loop without affecting period length. Our results reveal CLK8 as a tool for further studies of CLOCK's role in circadian rhythm amplitude regulation and as a potential candidate for therapeutic development to manage disorders associated with dampened circadian rhythms.Publication Metadata only A genome-wide functional screen identifies enhancer and protective genes for amyloid beta-peptide toxicity(Multidisciplinary Digital Publishing Institute (MDPI), 2023) Picon-Pages, Pol; Bosch-Morato, Monica; Subirana, Laia; Rubio-Moscardo, Francisca; Guivernau, Biuse; Fanlo-Ucar, Hugo; Herrera-Fernandez, Victor; Vicente, Ruben; Fernandez-Fernandez, Jose M.; Garcia-Ojalvo, Jordi; Oliva, Baldomero; Posas, Francesc; de Nadal, Eulalia; Munoz, Francisco J.; N/A; N/A; N/A; Department of Computer Engineering; Department of Computer Engineering; Zeylan, Melisa Ece; Şenyüz, Simge; Gürsoy, Attila; Keskin, Özlem; PhD Student; Master Student; Faculty Member; Faculty Member; Department of Computer Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; N/A; 8745; 26605Alzheimer's disease (AD) is known to be caused by amyloid beta-peptide (A beta) misfolded into beta-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in A beta toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing A beta(1-42). We identified 81 mammalian orthologue genes that enhance A beta(1-42) toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by A beta oligomers (oA beta). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oA beta(1-42), whereas SURF4 overexpression induced A beta(1-42) cytotoxicity. In summary, we identified new enhancer and protective activities for A beta toxicity and showed that SURF4 contributes to oA beta(1-42) neurotoxicity by decreasing SOCE activity.Publication Metadata only A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta(Oxford Univ Press, 2019) Guillemyn, Brecht; Demuynck, Lynn; Sips, Patrick; De Paepe, Anne; Syx, Delfien; Coucke, Paul J.; Malfait, Fransiska; Symoens, Sofie; N/A; Kayserili, Hülya; Faculty Member; School of Medicine; 7945The cyclic adenosine monophosphate responsive element binding protein 3-like 1 (CREB3L1) gene codes for the endoplasmic reticulum stress transducer old astrocyte specifically induced substance (OASIS), which has an important role in osteoblast differentiation during bone development. Deficiency of OASIS is linked to a severe form of autosomal recessive osteogenesis imperfecta (OI), but only few patients have been reported. We identified the first homozygous pathogenic missense variant [p.(Ala304Val)] in a patient with lethal OI, which is located within the highly conserved basic leucine zipper domain, four amino acids upstream of the DNA binding domain. In vitro structural modeling and luciferase assays demonstrate that this missense variant affects a critical residue in this functional domain, thereby decreasing the type I collagen transcriptional binding ability. In addition, overexpression of the mutant OASIS protein leads to decreased transcription of the SEC23A and SEC24D genes, which code for components of the coat protein complex type II (COPII), and aberrant OASIS signaling also results in decreased protein levels of SEC24D. Our findings therefore provide additional proof of the potential involvement of the COPII secretory complex in the context of bone-associated disease.Publication Metadata only A novel and promising multi-enzyme co-embedded organicinorganic hybrid nanoflower with enhanced stability and catalytic activity(Wiley, 2019) Gecili, Firdevs; Ozdemir, Nalan; N/A; Aydemir, Duygu; Ulusu, Nuriye Nuray; PhD Student; Faculty Member; Graduate School of Health Sciences; School of Medicine; N/A; 6807N/APublication Metadata only A platinum blue complex exerts its cytotoxic activity via DNA damage and induces apoptosis in cancer cells(Wiley, 2017) Adiguzel, Zelal; Ozalp-Yaman, Seniz; Celik, Gokalp; Salem, Safia; Cetin, Yuksel; Acilan, Ceyda; N/A; N/A; Önder, Tuğba Bağcı; Şenbabaoğlu, Filiz; Faculty Member; PhD Student; School of Medicine; Graduate School of Health Sciences; 184359; N/AHere, we describe the characteristics of a Pt-blue complex [Pt-4(2-atp)(8)(H2O)(OH)] (2-atp: 2-aminothiophenol) as a prodrug for its DNA-binding properties and its use in cancer therapy. The nature of the interaction between the Pt-blue complex and DNA was evaluated based on spectroscopic measurements, the electronic absorption spectra, thermal behavior, viscosity, fluorometric titration, and agarose gel electrophoresis. Our results suggested that the compound was able to partially intercalate DNA and appeared to induce both single- and double-stranded breaks (DBS) on DNA in vitro, but no DSBs in cells. The ability of the compound to induce DNA damage was dependent on reactive oxygen species (ROS) in vitro. There was also elevated formation of ROS and SOD expression in response to drug treatment in cell culture. The complex was found to be more cytotoxic to cancer cells in comparison with noncancer controls using WST-1 assay. The mean of cell death was determined to be apoptosis as assessed via biochemical, morphological, and molecular observations, including DNA condensation/fragmentation analysis, live cell imaging microscopy, TUNEL analyses, and increase in the levels of pro-apoptotic genes such as Bag3, Bak, Bik, Bmf, and Hrk. Hence, the Pt-blue complex under study grants premise for further studies.Publication Metadata only A small molecule identified through an in silico screen inhibits Aurora B–INCENP interaction(Wiley, 2016) N/A; N/A; N/A; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Ünsal, Esra; Harmanda, Büşra; Erman, Burak; Master Student; N/A; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; N/A; N/A; 179997; 105301Aurora B is a serine/threonine kinase that has a central role in the regulation of mitosis. The observation of Aurora B overexpression in cancer makes it a promising target to develop antitumoral inhibitors. We describe a new potential inhibitor that exclusively targets the interaction site of Aurora B and its activator INCENP. We performed a structure-based virtual screening and determined five potential candidates of 200000 compounds, which selectively bind to the Aurora BPublication Metadata only Advances in template-based protein docking by utilizing interfaces towards completing structural interactome(Current Biology Ltd, 2015) N/A; N/A; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; N/A; 26605; 8745The increase in the number of structurally determined protein complexes strengthens template-based docking (TBD) methods for modelling protein-protein interactions (PPIs). These methods utilize the known structures of protein complexes as templates to predict the quaternary structure of the target proteins. The templates may be partial or complete structures. Interface based (partial) methods have recently gained interest due in part to the observation that the interface regions are reusable. We describe how available template interfaces can be used to obtain the structural models of protein interactions. Despite the agreement that a majority of the protein complexes can be modelled using the available Protein Data Bank (PDB) structures, a handful of studies argue that we need more template proteins to increase the structural coverage of PPIs. We also discuss the performance of the interface TBD methods at large scale, and the significance of capturing multiple conformations for improving accuracy.Publication Metadata only An integrative analysis of transcriptomic response of ethanol tolerant strains to ethanol in Saccharomyces cerevisiae(Royal Soc Chemistry, 2016) Kasavi, Ceyda; Oner, Ebru Toksoy; Kirdar, Betul; N/A; Eraslan, Serpil; Researcher; School of Medicine; N/AThe accumulation of ethanol is one of the main environmental stresses that Saccharomyces cerevisiae cells are exposed to in industrial alcoholic beverage and bioethanol production processes. Despite the known impacts of ethanol, the molecular mechanisms underlying ethanol tolerance are still not fully understood. Novel gene targets leading to ethanol tolerance were previously identified via a network approach and the investigations of the deletions of these genes resulted in the improved ethanol tolerance of pmt7 Delta/pmt7 Delta and yhl042w Delta/yhl042w Delta strains. In the present study, an integrative system based approach was used to investigate the global transcriptional changes in these two ethanol tolerant strains in response to ethanol and hence to elucidate the mechanisms leading to the observed tolerant phenotypes. In addition to strain specific biological processes, a number of common and already reported biological processes were found to be affected in the reference and both ethanol tolerant strains. However, the integrative analysis of the transcriptome with the transcriptional regulatory network and the ethanol tolerance network revealed that each ethanol tolerant strain had a specific organization of the transcriptomic response. Transcription factors around which most important changes occur were determined and active subnetworks in response to ethanol and functional clusters were identified in all strains.