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Publication Metadata only Anomalies in the transcriptional regulatory network of the Yeast Saccharomyces cerevisiae(Elsevier, 2010) N/A; Department of Physics; Tuğrul, Murat; Kabakçıoğlu, Alkan; N/A; Faculty Member; Department of Physics; Graduate School of Sciences and Engineering; College of Sciences; N/A; 49854We investigate the structural and dynamical properties of the transcriptional regulatory network of the Yeast Saccharomyces cerevisiae and compare it with two "unbiased" ensembles: one obtained by reshuffling the edges and the other generated by mimicking the transcriptional regulation mechanism within the cell. Both ensembles reproduce the degree distributions (the first-by construction-exactly and the second approximately), degree-degree correlations and the k-core structure observed in Yeast. An exceptionally large dynamically relevant core network found in Yeast in comparison with the second ensemble points to a strong bias towards a collective organization which is achieved by subtle modifications in the network's degree distributions. We use a Boolean model of regulatory dynamics with various classes of update functions to represent in vivo regulatory interactions. We find that the Yeast's core network has a qualitatively different behavior, accommodating on average multiple attractors unlike typical members of both reference ensembles which converge to a single dominant attractor. Finally, we investigate the robustness of the networks and find that the stability depends strongly on the used function class. The robustness measure is squeezed into a narrower band around the order-chaos boundary when Boolean inputs are required to be nonredundant on each node. However, the difference between the reference models and the Yeast's core is marginal, suggesting that the dynamically stable network elements are located mostly on the peripherals of the regulatory network. Consistently, the statistically significant three-node motifs in the dynamical core of Yeast turn out to be different from and less stable than those found in the full transcriptional regulatory network.Publication Metadata only Bud14 function is crucial for spindle pole body size maintenance(TUBITAK, 2024) Department of Molecular Biology and Genetics; Girgin, Sevilay Münire; Çaydaşı, Ayşe Koca; Department of Molecular Biology and Genetics; College of Sciences; Graduate School of Sciences and EngineeringBackground/aim: Spindle pole bodies (SPB), the functional equivalent of centrosomes in yeast, duplicate through generation of a new SPB next to the old one. However, SPBs are dynamic structures that can grow and exchange, and mechanisms that regulate SPB size remain largely unknown. This study aims to elucidate the role of Bud14 in SPB size maintenance in Saccharomyces cerevisiae. Materials and methods: We employed quantitative fluorescence microscopy to assess the relative and absolute amounts of SPB structural proteins at SPBs of wildtype cells and in cells lacking BUD14 (bud14∆). Quantifications were performed using asynchronous cell cultures, as well as cultures synchronously progressing through the cell cycle and upon different cell cycle arrests. We also utilized mutants that allow the separation of Bud14 functions. Results: Our results indicate that higher levels of SPB inner, outer, and central plaque proteins are present at the SPBs of bud14∆ cells compared to wildtype cells during anaphase, as well as during nocodazole-induced M-phase arrest. However, during α-factor mediated G1 arrest, inner and outer plaque proteins responded differently to the absence of BUD14. A Bud14 mutant that cannot interact with the Protein Phosphatase 1 (Glc7) phenocopied bud14∆ in terms of SPB-bound levels of the inner plaque protein Spc110, whereas disruption of Bud14-Kel1-Kel2 complex did not alter Spc110 levels at SPBs. In cells synchronously released from α-factor arrest, lack of Bud14-Glc7 caused increase of Spc110 at the SPBs at early stages of the cell cycle. Conclusion: We identified Bud14 as a critical protein for SPB size maintenance. The interaction of Bud14 with Glc7, but not with the Kelch proteins, is indispensable for restricting levels of Spc110 incorporated into the SPBs. © TÜBİTAK.Publication Metadata only Coculture model of blood-brain barrier on electrospun nanofibers(TUBITAKScientific and Technical Research Council Turkey, 2020) Bayir, Ece; Dogan, Sule; Öztürk, Şükrü; Sendemir, Aylin; N/A; Özyurt, Mustafa Görkem; PhD Student; Graduate School of Sciences and Engineering; School of Medicine; N/AThe blood-brain barrier (BBB) is a control mechanism that limits the diffusion of many substances to the central nervous system (CNS). In this study, we designed an in-vitro 3-dimensional BBB system to obtain a fast and reliable model to mimic drug delivery characteristics of the CNS. A support membrane of polycaprolactone nanofiber surfaces was prepared using electrospinning. After confirming the fiber morphology and size, endothelial cells (HUVEC) and glial cells were cultured on either side of this membrane. The model's similarity to in vivo physiology was tested with a home-designed transmembrane resistance (TR) device, with positive and negative control molecules. Finally, 2 doses of methotrexate (MTX), a chemotherapy agent, were applied to the model, and its permeability through the model was determined indirectly by a vitality test on the MCF-7 cell line. Nicotine, the positive control, completed its penetration through the model almost instantly, while albumin, the negative control, was blocked significantly even after 2 days. MTX reached a deadly threshold 24 h after application. The TR value of the model was promising, being around 260 ohm.cm2. The provided model proposes a disposable and reliable tool for investigating drug permeability through the BBB and has the potential to reduce the number of animal experiments.Publication Metadata only Comparison of two intraoperative examination methods for the diagnosis of sentinel lymph node metastasis in clinically early stage endometrial cancer: a Turkish Gynecologic Oncology Group Study (TRSGO-SLN-003)(Elsevier, 2021) Taskin, Salih; Varli, Bulut; Altin, Duygu; Takmaz, Ozguc; Ersoz, Cevriye Cansiz; Turan, Hasan; Zeren, Handan; Havare, Semiha Battal; Karabuk, Emine; Naki, Murat; Gungor, Mete; Kose, Faruk; Ortac, Firat; Arvas, Macit; Ayhan, Ali; N/A; Vatansever, Doğan; Taşkıran, Çağatay; Bulutay, Pınar; Faculty Member; Faculty Member; Teaching Faculty; School of Medicine; School of Medicine; School of Medicine; 193687; 134190; 133565Objective: This study evaluated diagnostic accuracy of intraoperative sentinel lymph node (SLN) frozen section examination and scrape cytology as a possible solution for management of SLN positive patients. Study Design: Clinically early-stage endometrial cancer patients who underwent SLN algorithm and intraoperative SLN examination were analyzed. Findings were compared with final pathology results and diagnostic accuracy of frozen section and scrape cytology were evaluated. Results: Of the 208 eligible patients, 100 patients (48 %) had frozen section examination and 108 (52 %) had scrape cytology of the SLN. Intraoperative examination and final pathology were negative for metastasis in 187/208 (90 %) cases. The rest 21 cases had metastatic SLNs according to final pathology. 12 of 21 (57 %) metastases were classified as macrometastasis. Intraoperative examination of SLNs correctly identified 13 cases (true positive) and missed 8 cases (false negative). Five of 8 false negative cases had micrometastasis or isolated tumor cells. Considering identification of macrometastasis, sensitivity and negative predictive value were 85.71 % and 98.94 %, respectively, for the frozen section and 60.00 % and 98.15 %, respectively, for the scrape cytology. Conclusion: Frozen section examination of SLN has higher sensitivity in detecting macrometastasis compared to scrape cytology and it could help the surgeon in decision for further lymphadenectomy intraoperatively.Publication Open Access Crosstalk between autophagy and DNA repair systems(TÜBİTAK, 2021) Demirbağ Sarıkaya, Sinem; Çakır, Hatice; Gözüaçık, Devrim; Akkoç, Yunus; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248; N/AAutophagy and DNA repair are two essential biological mechanisms that maintain cellular homeostasis. Impairment of these mechanisms was associated with several pathologies such as premature aging, neurodegenerative diseases, and cancer. Intrinsic or extrinsic stress stimuli (e.g., reactive oxygen species or ionizing radiation) cause DNA damage. As a biological stress response, autophagy is activated following insults that threaten DNA integrity. Hence, in collaboration with DNA damage repair and response mechanisms, autophagy contributes to the maintenance of genomic stability and integrity. Yet, connections and interactions between these two systems are not fully understood. In this review article, current status of the associations and crosstalk between autophagy and DNA repair systems is documented and discussed.Publication Metadata only dentification of potential inhibitors of human methionine aminopeptidase (type II) for cancer therapy: Structure-based virtual screening, ADMET prediction and molecular dynamics studies(Elsevier Sci Ltd, 2020) Weako, Jackson; Uba, Abdullahi İbrahim; Yelekçi, Kemal; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; College of Engineering; 26605; 8745Methionine Aminopeptidases MetAPs are divalent-cofactor dependent enzymes that are responsible for the cleavage of the initiator Methionine from the nascent polypeptides. MetAPs are classified into two isoforms: namely, MetAP1 and MetAP2. Several studies have revealed that MetAP2 is upregulated in various cancers, and its inhibition has shown to suppress abnormal or excessive blood vessel formation and tumor growth in model organisms. Clinical studies show that the natural product fumagillin, and its analogs are potential inhibitors of MetAP2. However, due to their poor pharmacokinetic properties and neurotoxicities in clinical studies, their further developments have received a great setback. Here, we apply structure-based virtual screening and molecular dynamics methods to identify a new class of potential inhibitors for MetAP2. We screened Otava's Chemical Library, which consists of about 3 200 000 tangible-chemical compounds, and meticulously selected the top 10 of these compounds based on their inhibitory potentials against MetAP2. The top hit compounds subjected to ADMET predictor using 3 independent ADMET prediction programs, were found to be drug-like. To examine the stability of ligand binding mode, and efficacy, the unbound form of MetAP2, its complexes with fumagillin, spiroepoxytriazole, and the best promising compounds compound-3369841 and compound-3368818 were submitted to 100 ns molecular dynamics simulation. Like fumagillin, spiroepoxytriazole, and both compound-3369841 and compound-3368818 showed stable binding mode over time during the simulations. Taken together, these uninherited-fumagillin compounds may serve as new class of inhibitors or provide scaffolds for further optimization towards the design of more potent MetAP2 inhibitors -development of such inhibitors would be essential strategy against various cancer types.Publication Metadata only Does the magnetic field of a magnetic stirrer in an optical aggregometer affect concurrent platelet aggregation?(2013) Sağdilek, Engin; Çelebi, Gürbüz; Department of Physics; Sebik, Oğuz; Researcher; Department of Physics; College of Sciences; N/APlatelets are subjected to extremely low frequency electromagnetic fields during standard aggregometry measurements owing to the use of a magnetic stir bar in the instrument. This study evaluates the effects of this magnetic field exposure on platelet aggregation by comparing the results obtained in a modified aggregometer. Blood samples from healthy volunteers were anticoagulated using citrate or heparin. Platelet-rich plasma (PRP) samples were prepared. A mechanical stirring device was attached to the aggregometer instead of the magnetic stir bar system. The PRP samples were stirred using a stirring rod tip that did not produce any magnetic fields in one channel of the aggregometer; in the other channel, a stirring rod carrying a small magnet at its tip was used. As a result, a magnetic field in the extremely low frequency range and in the amplitude range of 1.9–65 mT was applied to the platelets assigned to the channel where the magnetic stirring rod tip was used. Aggregation was induced using adenosine diphosphate (ADP), collagen, or epinephrine. The slopes, maximum aggregation values, and areas under the aggregation curves were compared between the magnetic and neutral stirring rod tip groups. For samples stirred with the magnetic stirring rod tip, a significant decrease was observed in 12 of the 14 parameters evaluated for aggregations induced with ADP or collagen compared to the neutral stirring rod tip, regardless of the method used for anticoagulation. This observation indicates that the magnetic stir bars used in standard aggregometry may significantly alter aggregation parameters and platelets may be possible targets of electromagnetic fields.Publication Metadata only Exploring the candidate terminal glycan profile in neural regeneration of the sea urchin paracentrotus lividus, using lectin blotting and mass spectrometry(Univ Chicago Press) Sahar, Umut; Deveci, Remziye; N/A; Demir, Ramiz; PHD. Student; Graduate School of Health Sciences; N/AGlycans are expressed as conjugates of glycoproteins, glycolipids, and proteoglycans. The huge diversity of glycans on glycoconjugates contributes to many biological processes, from glycan-based molecular recognition to developmental events, such as regeneration in the nervous system. Echinoderms, which have a close phylogenetic relationship with chordates, are an important group of marine invertebrates for body regeneration. Although many major roles of glycans on glycoconjugates are known, their role in the glycosylation profile of the nervous system in sea urchins is poorly understood. In this study, we aimed to determine the terminal glycan profile by lectin blotting and to quantify sialic acids by the capillary liquid chromatography electrospray ionization tandem mass spectrometry system in the nervous tissue of the sea urchin Paracentrotus lividus. We determined the N-acetyl-D-glucosamine, mannose, and sialic acids (mainly alpha 2,3 linked) by lectin blotting and five types of sialic acids (N-glycolylneuraminic acid, N-acetylneuraminic acid, 9-O-acetyl-N-alycolylneuraminic acid, 5-N-acetyl-9-O-acetyl-N-acetylneuraminic acid, and di-O-acetylated-N-alycolylneuraminic acid) by capillary liquid chromatography electrospray ionization tandem mass spectrometry. This potential first description of the terminal glycan profile in the nervous system of the sea urchin is expected to help us understand its role in nervous system development and regeneration.Publication Metadata only Expression analyses of soluble starch synthase and starch branching enzyme isoforms in stem and leaf tissues under different photoperiods in lentil (Lens culinaris Medik.)(Springer, 2022) Gerçek, Yusuf Can; Boztaş, Kadir; Aydın, Cihan; Morgil, Hande; Öz, Gül Cevahir; Tulum, Işıl; Department of Molecular Biology and Genetics; Barış, İbrahim; Teaching Faculty; Department of Molecular Biology and Genetics; College of Sciences; 111629The metabolism of starch is sensitive to changes in light and plants respond to different light regimes by adjusting their carbon metabolism and regulating enzymes that participate in starch biosynthesis. Although there are several studies showing the influence of the circadian clock mechanism on starch biosynthesis on model plants, there is still limited information on how the circadian regulation of carbon assimilation and utilization works on crop plants and long-day plants. In our previous study, we examined lentil (Lens culinaris Medik.), a long-day crop plant, and determined the influence of circadian control on starch metabolism by investigating the transcriptional regulation of large (LS) and small (SS) subunits of ADP glucose pyrophosphorylase (AGPase). However, the regulation mechanism of the enzymes responsible for the formation of the starch granule remains unclear. In this study, the transcriptional regulation of soluble starch synthase isoforms I and III (SSSI and SSSIII) and starch branching enzyme isoforms I and II (SBEI and SBEII) were examined in sink and source tissues under different photoperiods in lentils by quantitative real time PCR (qPCR). The results showed that the temporal distribution of gene expression was altered when isoforms for both enzymes from the stem and leaf tissues were compared for different photoperiod regimes, exhibiting a rhythmic period of 4-6 h with maximal expression times and levels altered due to the shifting photoperiod. These results were in agreement with our previous observations on lentil AGPase supporting the circadian control of carbohydrate metabolism.Publication Open Access In silico drug repositioning against human NRP1 to block SARS-CoV-2 host entry(TÜBİTAK, 2021) Department of Chemical and Biological Engineering; Gül, Şeref; Researcher; Department of Chemical and Biological Engineering; Graduate School of Sciences and EngineeringDespite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing approach that bypasses a costly and long-time demanding drug discovery process is an effective way in search of finding drugs for the COVID-19 treatment. Recent studies showed that SARS-CoV-2 uses neuropilin-1 (NRP1) for host entry. Here we took advantage of structural information of the NRP1 in complex with C-terminal of spike (S) protein of SARSCoV-2 to identify drugs that may inhibit NRP1 and S protein interaction. U.S. Food and Drug Administration (FDA) approved drugs were screened using docking simulations. Among top drugs, well-tolerated drugs were selected for further analysis. Molecular dynamics (MD) simulations of drugs-NRP1 complexes were run for 100 ns to assess the persistency of binding. MM/GBSA calculations from MD simulations showed that eltrombopag, glimepiride, sitagliptin, dutasteride, and ergotamine stably and strongly bind to NRP1. In silico Alanine scanning analysis revealed that Tyr(297), Trp(301), and Tyr(353) amino acids of NRP1 are critical for drug binding. Validating the effect of drugs analyzed in this paper by experimental studies and clinical trials will expedite the drug discovery process for COVID-19.