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Publication Metadata only 3D printed styrax liquidus (liquidambar orientalis miller)-loaded poly (l-lactic acid)/chitosan based wound dressing material: fabrication, characterization, and biocompatibility results(Elsevier, 2023) Cakmak, Hanife Yuksel; Ege, Hasan; Yilmaz, Senanur; Agturk, Gokhan; Enguven, Gozde; Sarmis, Abdurrahman; Cakmak, Zeren; Gunduz, Oguzhan; Ege, Zeynep Ruya; Yöntem, Fulya Dal; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of MedicineThe medicinal plant of Styrax liquidus (ST) (sweet gum balsam) which extracted from Liquidambar orientalis Mill tree, was loaded into the 3D printed polylactic acid (PLA)/chitosan (CS) based 3D printed scaffolds to investigate its wound healing and closure effect, in this study. The morphological and chemical properties of the ST loaded 3D printed scaffolds with different concentrations (1 %, 2 %, and 3 % wt) were investigated by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FT-IR), respectively. In addition, the me-chanical and thermal properties of the materials were investigated by Tensile test and Differential Scanning Calorimetry (DSC), respectively. The antimicrobial activities of the ST loaded 3D printed scaffolds and their incubation media in the PBS (pH 7.4, at 37 degrees C for 24 h) were investigated on two Gram-positive and two Gram -negative standard pathogenic bacteria with the agar disc diffusion method. The colorimetric MTT assay was used to determine the cell viability of human fibroblast cells (CCD-1072Sk) incubated with free ST, ST loaded, and unloaded 3D printed scaffolds. The 1 % and 2 % (wt) ST loaded PLA/CS/ST 3D printed scaffolds showed an increase in the cell number. Annexin V/PI double stain assay was performed to test whether early or late apoptosis was induced in the PLA/CS/1 % ST and PLA/CS/2 % ST loaded groups and the results were consistent with the MTT assay. Furthermore, a wound healing assay was carried out to investigate the effect of ST loaded 3D printed scaffolds on wound healing in CCD-1072Sk cells. The highest wound closure compared to the control group was observed on cells treated with PLA/CS/1 % ST for 72 h. According to the results, novel biocompatible ST loaded 3D printed scaffolds with antimicrobial effect can be used as wound healing material for potential tissue engineering applications.Publication Metadata only Author correction: combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma(Nature Research, 2024) Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Heßmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT.; Koç University HospitalIn the originally published version of this article, there were errors in the histological sections depicted in Supplementary Figs. 4 and 10. Specifically: In Supplementary Fig. 4, the image of the Ki67 immunohistochemistry (IHC) for the Gemcitabine+JQ1 group was incorrect In Supplementary Fig. 10, the pSTAT3 image for the IHC for the JQ1 group was incorrect In Supplementary Fig. 10, Ki67 and MYC IHC images for JQ1 and JQ1+SAHA were swapped In Supplementary Fig. 4, the image of the Ki67 immunohistochemistry (IHC) for the Gemcitabine+JQ1 group was incorrect In Supplementary Fig. 10, the pSTAT3 image for the IHC for the JQ1 group was incorrect In Supplementary Fig. 10, Ki67 and MYC IHC images for JQ1 and JQ1+SAHA were swapped The original data were available and these errors have been corrected in the Supplementary Information accompanying this notice. Additionally, the authors wish to clarify that the Sirius Red staining for the control and JQ1 groups were identical in both Supplementary Figs. 4 and 10 because the control mice (JQ1 only or control treatment) were shared between experiments. To avoid confusion, the sections depicting Sirius Red staining for the control and JQ1 groups in Supplementary Fig. 4 were replaced with alternative sections from the same respective samplesPublication Metadata only Shared proteins and pathways of cardiovascular and cognitive diseases: relation to vascular cognitive impairment(Amer Chemical Soc, 2024) Picon-Pages, Pol; Garcia-Elias, Anna; Tajes, Marta; Munoz, Francisco J.; Oliva, Baldomero; Garcia-Ojalvo, Jordi; Barbu, Eduard; Vicente, Raul; Nattel, Stanley; Ois, Angel; Puig-Pijoan, Albert; Department of Chemical and Biological Engineering;Department of Computer Engineering; Zeylan, Melisa Ece; Şenyüz, Simge; Keskin, Özlem; Gürsoy, Attila; Graduate School of Sciences and Engineering; College of EngineeringOne of the primary goals of systems medicine is the detection of putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular cognitive impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular cognitive genes and proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.Publication Metadata only Navigating centriolar satellites: the role of PCM1 in cellular and organismal processes(WILEY, 2024) Department of Molecular Biology and Genetics; Begar, Efe; Seyrek, Ece; Karalar, Elif Nur Fırat; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of SciencesCentriolar satellites are ubiquitous membrane-less organelles that play critical roles in numerous cellular and organismal processes. They were initially discovered through electron microscopy as cytoplasmic granules surrounding centrosomes in vertebrate cells. These structures remained enigmatic until the identification of pericentriolar material 1 protein (PCM1) as their molecular marker, which has enabled their in-depth characterization. Recently, centriolar satellites have come into the spotlight due to their links to developmental and neurodegenerative disorders. This review presents a comprehensive summary of the major advances in centriolar satellite biology, with a focus on studies that investigated their biology associated with the essential scaffolding protein PCM1. We begin by exploring the molecular, cellular, and biochemical properties of centriolar satellites, laying the groundwork for a deeper understanding of their functions and mechanisms at both cellular and organismal levels. We then examine the implications of their dysregulation in various diseases, particularly highlighting their emerging roles in neurodegenerative and developmental disorders, as revealed by organismal models of PCM1. We conclude by discussing the current state of knowledge and posing questions about the adaptable nature of these organelles, thereby setting the stage for future research.Publication Metadata only SETD3 regulates endoderm differentiation of mouse embryonic stem cells through canonical Wnt signaling pathway(Wiley, 2024) Alganatay, Ceren; Balbasi, Emre; Sezginmert, Dersu; Cizmecioglu, Nihal Terzi; Department of Chemical and Biological Engineering; Tunçbağ, Nurcan; Department of Chemical and Biological Engineering; College of EngineeringWith self-renewal and pluripotency features, embryonic stem cells (ESCs) provide an invaluable tool to investigate early cell fate decisions. Pluripotency exit and lineage commitment depend on precise regulation of gene expression that requires coordination between transcription (TF) and chromatin factors in response to various signaling pathways. SET domain-containing 3 (SETD3 Delta) is a methyltransferase that can modify histones in the nucleus and actin in the cytoplasm. Through an shRNA screen, we previously identified SETD3 as an important factor in the meso/endodermal lineage commitment of mouse ESCs (mESC). In this study, we identified SETD3-dependent transcriptomic changes during endoderm differentiation of mESCs using time-course RNA-seq analysis. We found that SETD3 is involved in the timely activation of the endoderm-related gene network. The canonical Wnt signaling pathway was one of the markedly altered signaling pathways in the absence of SETD3. The assessment of Wnt transcriptional activity revealed a significant reduction in Setd3-deleted (setd3 increment ) mESCs coincident with a decrease in the nuclear pool of the key TF beta-catenin level, though no change was observed in its mRNA or total protein level. Furthermore, a proximity ligation assay (PLA) found an interaction between SETD3 and beta-catenin. We were able to rescue the differentiation defect by stably re-expressing SETD3 or activating the canonical Wnt signaling pathway by changing mESC culture conditions. Our results suggest that alterations in the canonical Wnt pathway activity and subcellular localization of beta-catenin might contribute to the endoderm differentiation defect of setd3 Delta increment mESCs.Publication Metadata only Tracking data highlight the importance of human-induced mortality for large migratory birds at a flyway scale(Elsevier Ltd, 2024) Serratosa, Juan; Oppel, Steffen; Rotics, Shay; Santangeli, Andrea; Butchart, Stuart H.M.; Cano-Alonso, Luis S.; Tellería, Jose Luis; Kemp, Ryno; Nicholas, Aaron; Kalvāns, Aigars; Galarza, Aitor; Franco, Aldina M.A.; Andreotti, Alessandro; Kirschel, Alexander N.G.; Ngari, Alex; Soutullo, Alvaro; Bermejo-Bermejo, Ana; Botha, Andre J.; Ferri, Andrea; Evangelidis, Angelos; Cenerini, Anna; Stamenov, Anton; Hernández-Matías, Antonio; Aradis, Arianna; Grozdanov, Atanas P.; Rodríguez, Beneharo; Cerecedo-Iglesias, Catuxa; Kassara, Christina; Barboutis, Christos; Bracebridge, Claire; García-Ripollés, Clara; Kendall, Corinne J.; Denac, Damijan; Schabo, Dana G.; Barber, David R.; Popov, Dimitar V.; Dobrev, Dobromir D.; Mallia, Egidio; Kmetova-Biro, Elena; Álvarez, Ernesto; Buechley, Evan R.; Bragin, Evgeny A.; Cordischi, Fabrizio; Zengeya, Fadzai M.; Monti, Flavio; Mougeot, Francois; Tate, Gareth; Stoyanov, Georgi; Dell'Omo, Giacomo; Lucia, Giuseppe; Gradev, Gradimir; Ceccolini, Guido; Friedemann, Guilad; Bauer, Hans-Günther; Kolberg, Holger; Peshev, Hristo; Catry, Inês; Øien, Ingar J.; Alanís, Isidoro Carbonell; Literák, Ivan; Pokrovsky, Ivan; Ojaste, Ivar; Østnes, Jan E.; de la Puente, Javier; Real, Joan; Guilherme, João L.; González, José C.; Fernández-García, José M.; Gil, Juan Antonio; Terraube, Julien; Poprach, Karel; Aghababyan, Karen; Klein, Katharina; Bildstein, Keith L.; Wolter, Kerri; Janssens, Kjell; Kittelberger, Kyle D.; Thompson, Lindy J.; AlJahdhami, Mansoor H.; Galán, Manuel; Tobolka, Marcin; Posillico, Mario; Cipollone, Mario; Gschweng, Marion; Strazds, Māris; Boorman, Mark; Zvidzai, Mark; Acácio, Marta; Romero, Marta; Wikelski, Martin; Schmidt, Matthias; Sarà, Maurizio; McGrady, Michael J.; Dagys, Mindaugas; Mackenzie, Monique L.; Al Taq, Muna; Mgumba, Msafiri P.; Virani, Munir Z.; Kassinis, Nicolaos I.; Borgianni, Nicolò; Thie, Nikki; Tsiopelas, Nikos; Anglister, Nili; Farwig, Nina; Sapir, Nir; Kleven, Oddmund; Krone, Oliver; Duriez, Olivier; Spiegel, Orr; Al Nouri, Osama; López-López, Pascual; Byholm, Patrik; Kamath, Pauline L.; Mirski, Paweł; Palatitz, Peter; Serroni, Pietro; Raab, Rainer; Buij, Ralph; Žydelis, Ramūnas; Nathan, Ran; Bowie, Rauri C.K.; Tsiakiris, Rigas; Hatfield, Richard Stratton; Harel, Roi; Kroglund, Rolf T.; Efrat, Ron; Limiñana, Ruben; Javed, Salim; Marinković, Saša P.; Rösner, Sascha; Pekarsky, Sasha; Kapila, Shiv R.; Marin, Simeon A.; Krejčí, Šimon; Giokas, Sinos; Tumanyan, Siranush; Turjeman, Sondra; Krüger, Sonja C.; Ewing, Steven R.; Stoychev, Stoycho; Nikolov, Stoyan C.; Qaneer, Tareq E.; Spatz, Theresa; Hadjikyriakou, Thomas G.; Mueller, Thomas; Katzner, Todd E.; Aarvak, Tomas; Veselovský, Tomáš; Nygård, Torgeir; Mellone, Ugo; Väli, Ülo; Sellis, Urmas; Urios, Vicente; Nemček, Vladimír; Arkumarev, Volen; Getz, Wayne M.; Fiedler, Wolfgang; Van den Bossche, Willem; Lehnardt, Yael; Jones, Victoria R.; Department of Molecular Biology and Genetics; Şekercioğlu, Çağan Hakkı; Department of Molecular Biology and Genetics; College of SciencesHuman-induced direct mortality affects huge numbers of birds each year, threatening hundreds of species worldwide. Tracking technologies can be an important tool to investigate temporal and spatial patterns of bird mortality as well as their drivers. We compiled 1704 mortality records from tracking studies across the African-Eurasian flyway for 45 species, including raptors, storks, and cranes, covering the period from 2003 to 2021. Our results show a higher frequency of human-induced causes of mortality than natural causes across taxonomic groups, geographical areas, and age classes. Moreover, we found that the frequency of human-induced mortality remained stable over the study period. From the human-induced mortality events with a known cause (n = 637), three main causes were identified: electrocution (40.5 %), illegal killing (21.7 %), and poisoning (16.3 %). Additionally, combined energy infrastructure-related mortality (i.e., electrocution, power line collision, and wind-farm collision) represented 49 % of all human-induced mortality events. Using a random forest model, the main predictors of human-induced mortality were found to be taxonomic group, geographic location (latitude and longitude), and human footprint index value at the location of mortality. Despite conservation efforts, human drivers of bird mortality in the African-Eurasian flyway do not appear to have declined over the last 15 years for the studied group of species. Results suggest that stronger conservation actions to address these threats across the flyway can reduce their impacts on species. In particular, projected future development of energy infrastructure is a representative example where application of planning, operation, and mitigation measures can enhance bird conservation. © 2024 The US Geological Survey, The Author(s)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 Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase(Nature Publishing Group (NPG), 2018) Ruess, Dietrich A.; Heynen, Guus J.; Ciecielski, Katrin J.; Ai, Jiaoyu; Berninger, Alexandra; Kabacaoglu, Derya; Goerguelue, Kivanc; Dantes, Zahra; Woermann, Sonja M.; Diakopoulos, Kalliope N.; Karpathaki, Angeliki F.; Kowalska, Marlena; Kaya-Aksoy, Ezgi; Song, Liang; van der Laan, Eveline A. Zeeuw; Lopez-Alberca, Maria P.; Nazare, Marc; Reichert, Maximilian; Saur, Dieter; Hopt, Ulrich T.; Sainz, Bruno, Jr.; Birchmeier, Walter; Schmid, Roland M.; Lesina, Marina; Alguel, Hana; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors(1). Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways(1-7). Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro(8). Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.Publication Metadata only Hot spots in protein-protein interfaces: towards drug discovery(Elsevier, 2014) N/A; N/A; Department of Computer Engineering; Department of Chemical and Biological Engineering; Çukuroğlu, Engin; Engin, Hatice Billur; Gürsoy, Attila; Keskin, Özlem; PhD Student; PhD Student; Faculty Member; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; N/A; College of Engineering; College of Engineering; N/A; N/A; 8745; 26605Identification of drug-like small molecules that alter protein-protein interactions might be a key step in drug discovery. However, it is very challenging to find such molecules that target interface regions in protein complexes. Recent findings indicate that such molecules usually target specifically energetically favored residues (hot spots) in protein protein interfaces. These residues contribute to the stability of protein-protein complexes. Computational prediction of hot spots on bound and unbound structures might be useful to find druggable sites on target interfaces. We review the recent advances in computational hot spot prediction methods in the first part of the review and then provide examples on how hot spots might be crucial in drug design. (C) 2014 Published by Elsevier Ltd.Publication Metadata only Structures and anticancer activity of chlorido platinum(II) saccharinate complexes with mono- and dialkylphenylphosphines(Elsevier Science Inc, 2019) İçsel, Ceyda; Yılmaz, Veysel T.; Aygün, Muhittin; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; N/A; N/Acis-[PtCl(sac)(PPh2Me)(2)] (1), cis-[PtCl(sac)(PPhMe2)(2)] (2), trans-[PtCl(sac)(PPh2Et)(2)] (3) and trans- [PtCl(sac) (PPhEt2)(2)] (4) complexes (sac = saccharinate) were synthesized and characterized by elemental analysis and spectroscopic methods. The structures of 2-4 were determined by X-ray single-crystal diffraction. The interaction of the complexes with DNA was studied various biochemical, biophysical and molecular docking methods. Only the cis-configured complexes (1 and 2) showed nuclease activity and their binding affinity towards DNA was considerably higher than those of their trans-congeners (3 and 4). The chlorido ligand in the cis-configured complexes underwent aquation, making them more reactive towards DNA. Furthermore, 1 and 2 exhibited anticancer potency on breast (MCF-7) and colon (HCT116) cancer cells similar to cisplatin, whereas 3 and 4 were biologicallly inactive. Mechanistic studies on MCF-7 cells showed that higher nuclear uptake, cell cycle arrest at the S phase, dramatically increased DNA double-strand breaks, apoptosis induction, elevated levels of reactive oxygen species (ROS) and high mitochondrial membrane depolarization greatly contribute to the anticancer potency of 1 and 2.