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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 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 new, structurally nonredundant, diverse data set of protein-protein interfaces and its implications(Wiley, 2004) Tsai, CJ; Wolfson, H; Nussinov, R; Department of Chemical and Biological Engineering; Keskin, Özlem; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 26605Here, we present a diverse, structurally nonredundant data set of two-chain protein–protein interfaces derived from the PDB. Using a sequence order-independent structural comparison algorithm and hierarchical clustering, 3799 interface clusters are obtained. These yield 103 clusters with at least five nonhomologous members. We divide the clusters into three types. In Type I clusters, the global structures of the chains from which the interfaces are derived are also similar. This cluster type is expected because, in general, related proteins associate in similar ways. In Type II, the interfaces are similar; however, remarkably, the overall structures and functions of the chains are different. The functional spectrum is broad, from enzymes/inhibitors to immunoglobulins and toxins. The fact that structurally different monomers associate in similar ways, suggests “good” binding architectures. This observation extends a paradigm in protein science: It has been well known that proteins with similar structures may have different functions. Here, we show that it extends to interfaces. In Type III clusters, only one side of the interface is similar across the cluster. This structurally nonredundant data set provides rich data for studies of protein–protein interactions and recognition, cellular networks and drug design. In particular, it may be useful in addressing the difficult question of what are the favorable ways for proteins to interact.Publication Metadata only Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder(Nature Publishing Group (NPG), 2015) Yuksel, C.; Du, F.; Ravichandran, C.; Goldbach, J. R.; Thida, T.; Lin, P.; Gelda, J.; O'Connor, L.; Sehovic, S.; Gruber, S.; Ongur, D.; Cohen, B. M.; Department of Psychology; Dora, Begüm; PhD Student; Department of Psychology; College of Social Sciences and Humanities; N/AConverging evidence suggests bioenergetic abnormalities in bipolar disorder (BD). In the brain, phosphocreatine (PCr) acts a reservoir of high-energy phosphate (HEP) bonds, and creatine kinases (CK) catalyze the transfer of HEP from adenosine triphosphate (ATP) to PCr and from PCr back to ATP, at times of increased need. This study examined the activity of this mechanism in BD by measuring the levels of HEP molecules during a stimulus paradigm that increased local energy demand. Twenty-three patients diagnosed with BD-I and 22 healthy controls (HC) were included. Levels of phosphorus metabolites were measured at baseline and during visual stimulation in the occipital lobe using P-31 magnetic resonance spectroscopy at 4T. Changes in metabolite levels showed different patterns between the groups. During stimulation, HC had significant reductions in PCr but not in ATP, as expected. In contrast, BD patients had significant reductions in ATP but not in PCr. In addition, PCr/ATP ratio was lower at baseline in patients, and there was a higher change in this measure during stimulation. This pattern suggests a disease-related failure to replenish ATP from PCr through CK enzyme catalysis during tissue activation. Further studies measuring the CK flux in BD are required to confirm and extend this finding.Publication Metadata only Architectures and functional coverage of protein-protein interfaces(Elsevier, 2008) Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; N/A; Department of Chemical and Biological Engineering; Tunçbağ, Nurcan; Gürsoy, Attila; Güney, Emre; Keskin, Özlem; Faculty Member; Faculty Member; Master Student; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; College of Engineering; 245513; 8745; N/A; 26605The diverse range of cellular functions is performed by a limited number of protein folds existing in nature. One may similarly expect that cellular functional diversity would be covered by a limited number of protein-protein interface architectures. Here, we present 8205 interface clusters, each representing a unique interface architecture. This data set of protein-protein interfaces is analyzed and compared with older data sets. We observe that the number of both biological and crystal interfaces increases significantly compared to the number of Protein Data Bank entries. Furthermore, we find that the number of distinct interface architectures grows at a much faster rate than the number of folds and is yet to level off. We further analyze the growth trend of the functional coverage by constructing functional interaction networks from interfaces. The functional coverage is also found to steadily increase. Interestingly, we also observe that despite the diversity of interface architectures, some are more favorable and frequently used, and of particular interest, are the ones that are also preferred in single chains.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 Open Access Bosonic helium droplets with cationic impurities: onset of electrostriction and snowball effects from quantum calculations(American Institute of Physics (AIP) Publishing, 2007) Coccia, E.; Bodo, E.; Marinetti, F.; Gianturco, F. A.; Yıldırım, E.; Yurtsever, M.; Department of Chemistry; Yurtsever, İsmail Ersin; Faculty Member; Department of Chemistry; College of Sciences; 7129Variational Monte Carlo and diffusion Monte Carlo calculations have been carried out for cations such as Li(+), Na(+), and K(+) as dopants of small helium clusters over a range of cluster sizes up to about 12 solvent atoms. The interaction has been modeled through a sum-of-potential picture that disregards higher order effects beyond atom-atom and atom-ion contributions. The latter were obtained from highly correlated ab initio calculations over a broad range of interatomic distances. This study focuses on two of the most striking features of the microsolvation in a quantum solvent of a cationic dopant: electrostriction and snowball effects. They are discussed here in detail and in relation with the nanoscopic properties of the interaction forces at play within a fully quantum picture of the cluster features.Publication Metadata only Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming(Nature Publishing Group (NPG), 2019) Cribbs, Adam P.; Philpott, Martin; Dunford, James E.; Ari, Sule; Oppermann, Udo; N/A; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Önder, Tamer Tevfik; Ebrahimi, Ayyub A.; Sevinç, Kenan; Sevinç, Gülben Gürhan; Uyulur, Fırat; Morova, Tunç; Göklemez, Sencer; Faculty Member; Researcher; PhD Student; PhD Student; Undergraduate Student; Master Student; Undergraduate Student; Department of Molecular Biology and Genetics; School of Medicine; School of Medicine; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; College of Sciences; Graduate School of Sciences and Engineering; School of Medicine; 42946; 381072; N/A; N/A; N/A; N/A; N/ASilencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.Publication Metadata only Clinical exome sequencing as a powerful tool for the diagnosis of complex phenotypes(Springer Nature, 2018) Altunoğlu, Umut; Bertoli-Avella, Aida; Rolfs, Arndt; Börklü Yücel, Esra; Eraslan, Serpil; Kayserili, Hülya; Other; Researcher; Faculty Member; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; N/A; N/A; 7945N/A