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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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Publication 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 Quantification of interactions among circadian clock proteins via surface plasmon resonance(Wiley, 2014) N/A; N/A; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Kepsütlü, Burcu; Kızılel, Rıza; Kızılel, Seda; Master Student; Researcher; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 114475; 28376Circadian clock is an internal time keeping system recurring 24h daily rhythm in physiology and behavior of organisms. Circadian clock contains transcription and translation feedback loop involving CLOCK/NPaS2, BMaL1, Cry1/2, and Per1/2. in common, heterodimer of CLOCK/NPaS2 and BMaL1 binds to EBOX element in the promoter of Per and Cry genes in order to activate their transcription. CRY and PER making heterodimeric complexes enter the nucleus in order to inhibit their own BMaL1-CLOCK-activated transcription. the aim of this study was to investigate and quantify real-time binding affinities of clock proteins among each other on and off DNa modes using surface plasmon resonance. the pairwise interaction coefficients among clock proteins, As well as interaction of PER2, CRY2, and PER2:CRY2 proteins with BMaL1:CLOCK complex in the presence and absence of EBOX motif have been investigated via analysis of surface plasmon resonance data with pseudo first-order reaction kinetics approximation and via nonlinear regression curve fitting. the results indicated that CRY2 and PER2, BMaL1, and CLOCK proteins form complexes in vitro and that PER2, CRY2 and PER2:CRY2 complex have similar affinities toward BMaL1:CLOCK complex. CRY2 protein had the highest affinity toward EBOX complex, whereas PER2 and CRY2:PER2 complexes displayed low affinity toward EBOX complex. the quantification of the interaction between clock proteins is critical to understand the operation mechanism of the biological clock and to address the behavioral and physiological disorders, and it will be useful for the design of new drugs toward clock-related diseases.Publication Metadata only Design, semi-synthesis and examination of new gypsogenin derivatives against leukemia via Abl tyrosine kinase inhibition and apoptosis induction(Elsevier, 2022) Ulusoy, Nafia Gökçe; Emirdağ, Safiye; Sözer, Ece; Radwan, Mohamed O.; Aksel, Mehran; Özmen, Ali; Yayli, Nurettin; Karayıldırım, Tamer; Alankuş, Özgen; Tateishi, Hiroshi; Otsuka, Masami; Fujita, Mikako; Sever, Belgin; Bölükbaşı, Serap Şahin; Department of Molecular Biology and Genetics; Çiftçi, Halil İbrahim; Researcher; Department of Molecular Biology and Genetics; N/A; College of Sciences; N/A; N/AChronic myelogenous leukemia (CML) is characterized by Philadelphia translocation arising from Bcr-Abl fusion gene, which encodes abnormal oncoprotein showing tyrosine kinase (TK) function. Certain mutations in kinase domain, off-target effects and resistance problems of current TK inhibitors require the discovery of novel Abl TK inhibitors. For this purpose, herein, we synthesized new gypsogenin derivatives (6a-l) and evaluated their anticancer effects towards CML cells along with healthy cell line and different leukemic cells. Among these compounds, compound 6l was found as the most active anti-leukemic agent against K562 CML cells compared to imatinib exerting less cytotoxicity towards PBMCs (healthy). This compound also revealed significant anti -leukemic effects against Jurkat cell line. Besides, compound 6l enhanced apoptosis in CML cells with 52.4 % when compared with imatinib (61.8 %) and inhibited Abl TK significantly with an IC50 value of 13.04 +/- 2.48 mu M in a large panel of kinases accentuating Abl TK-mediated apoptosis of compound 6l in CML cells. Molecular docking outcomes showed that compound 6l formed mainly crucial interactions in the ATP-binding cleft of Abl TK similar to that of imatinib. Ultimately, in silico pharmacokinetic evaluation of compound 6l indicated that this compound was endowed with anti-leukemic drug candidate features.Publication Metadata only Machine learning-enabled optimization of extrusion-based 3D printing(Academic Press Inc Elsevier Science, 2022) N/A; Department of Media and Visual Arts; Department of Mechanical Engineering; Dabbagh, Sajjad Rahmani; Özcan, Oğuzhan; Taşoğlu, Savaş; PhD Stud; ent; Faculty Member; Faculty Member; Department of Media and Visual Arts; Department of Mechanical Engineering; Research Center for Creative Industries (KUAR) / KU Arçelik Yaratıcı Endüstriler Uygulama ve Araştırma Merkezi (KUAR); Graduate School of Sciences and Engineering; College of Social Sciences and Humanities; College of Engineering; N/A; 12532; 291971Machine learning (ML) and three-dimensional (3D) printing are among the fastest-growing branches of science. While ML can enable computers to independently learn from available data to make decisions with minimal human intervention, 3D printing has opened up an avenue for modern, multi-material, manufacture of complex 3D structures with a rapid turn-around ability for users with limited manufacturing experience. However, the determination of optimum printing parameters is still a challenge, increasing pre-printing process time and material wastage. Here, we present the first integration of ML and 3D printing through an easy-to-use graphical user interface (GUI) for printing parameter optimization. Unlike the widely held orthogonal design used in most of the 3D printing research, we, for the first time, used nine different computer-aided design (CAD) images and in order to enable ML algorithms to distinguish the difference between designs, we devised a self-designed method to calculate the "complexity index" of CAD designs. In addition, for the first time, the similarity of the print outcomes and CAD images are measured using four different self-designed labeling methods (both manually and automatically) to figure out the best labeling method for ML purposes. Subsequently, we trained eight ML algorithms on 224 datapoints to identify the best ML model for 3D printing applications. The "gradient boosting regression" model yields the best prediction performance with an R-2 score of 0.954. The ML-embedded GUI developed in this study enables users (either skilled or unskilled in 3D printing and/or ML) to simply upload a design (desired to print) to the GUI along with desired printing temperature and pressure to obtain the approximate similarity in the case of actual 3D printing of the uploaded design. This ultimately can prevent error-and-trial steps prior to printing which in return can speed up overall design-to-end-product time with less material waste and more cost-efficiency.Publication Metadata only Chitosan-anthracene hydrogels as controlled stiffening networks(Elsevier, 2021) N/A; N/A; N/A; N/A; Department of Chemical and Biological Engineering; Batool, Syeda Rubab; Nazeer, Muhammad Anwaar; Yıldız, Erdost; Şahin, Afsun; Kızılel, Seda; PhD Student; PhD Student; 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; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; School of Medicine; College of Engineering; N/A; N/A; N/A; 171267; 28376In this study, we report the synthesis of single and dual-crosslinked anthracene-functional chitosan-based hydrogels in the absence of toxic initiators. Single crosslinking was achieved through dimerization of anthracene, whereas dual-crosslinked hydrogel was formed through dimerization of anthracene and free radical photopolymerization of methacrylated-chitosan in the presence of non-toxic initiator riboflavin, a well-known vitamin B2. Both single and dual-crosslinked hydrogels were found to be elastic, as was determined through rheological analysis. We observed that the dual-crosslinked hydrogels exhibited higher Young's modulus than the single-crosslinked hydrogels, where the modulus for single and dual-crosslinked hydrogels were measured as 9.2 +/- 1.0 kPa and 26 +/- 2.8 kPa, respectively resulting in significantly high volume of cells in dual-crosslinked hydrogel (2.2 x 107 mu m3) compared to single-crosslinked (4.9 x 106 mu m3). Furthermore, we investigated the cytotoxicity of both hydrogels towards 3T3-J2 fibroblast cells through CellTiter-Glo assay. Finally, immunofluorescence staining was carried out to evaluate the impact of hydrogel modulus on cell morphology. This study comprehensively presents functionalization of chitosan with anthracene, uses nontoxic initiator riboflavin, modulates the degree of crosslinking through dimerization of anthracene and free radical photopolymerization, and further modulates cell behavior through the alterations of hydrogel properties.Publication Metadata only Dependence of erythrocyte deformability on mechanical stress and oxygenation(Federation amer Soc Exp Biol, 2017) N/A; N/A; N/A; Department of Physics; N/A; Yalçın, Özlem; Uğurel, Elif; Sağlam, Gökay; Erten, Ahmet Can; Aksu, Ali Cenk; Faculty Member; Researcher; Undergraduate Student; Teaching Faculty; PhD Student; Department of Physics; School of Medicine; School of Medicine; School of Medicine; College of Engineering; Graduate School of Health Sciences; 218440; N/A; N/A; N/A; N/AMechanical properties of erythrocytes are known to be affected by their oxygenation status. Several studies suggested that cytoskeletal rearrangements are carried out in an oxygen dependent manner. The structure of the cytoskeleton determines the mechanical properties of erythrocyte membrane. However, oxygen-dependent mechanical characteristics of erythrocyte are poorly studied whether oxygenated state could alter erythrocyte deformability. In this study, we investigated shear stress induced improvements in erythrocyte deformability through their oxygenation status. Venous blood was collected from male, healthy volunteers (n=10) between 25–50 ages. An informed written consent was obtained from each subject participated in the study according to Declaration of Helsinki. The hematocrit of blood samples adjusted to 0.4 l/l with autologous plasma. Whole blood samples were diluted with polyvinylpyrrolidone (PVP) solution (Mechatronics, Hoorn, Netherlands) with a dilution ratio of 1/200. Blood samples were equilibrated with either ambient air or nitrogen gas for at least 10 minutes at room temperature. Erythrocyte deformability was measured by a laser-assisted optical rotational cell analyzer (LORRCA MaxSis, Mechatronics, Netherlands) applying shear stresses (SS) ranging between 0.3 to 50 Pa. Then, a constant SS of 5, 10 and 20 Pa were applied continuously for 300 seconds and erythrocyte deformability was measured immediately afterwards. Maximal erythrocyte elongation index (EImax) and the SS required for one-half of this maximal deformation (SS1/2) were calculated by using the linear Lineweaver-Burke (LB) model. Deoxygenation of blood samples significantly decreased SS1/2 values both before and after SS applications (p < 0.001). EImax was significantly increased in deoxygenated blood before applying 5 Pa SS (p < 0.05). However, there were no significant differences after continuous SS in oxygenated and deoxygenated blood. Deoxygenation significantly decreased SS1/2/EImax values both before and after SS applications (p < 0.01). SS1/2/EImax values in both oxygenated and deoxygenated blood were significantly decreased after 5 and 10 Pa continuous SS applications although they were not significantly decreased after applying 20 Pa SS. Our study showed for the first time that erythrocyte deformability is improved in deoxygenated conditions in contrast to results presented in previous studies. This deformability improvement may control blood flow and consequently erythrocyte distribution within hypoxic tissues. Our study also demonstrated the relationship of oxygenation-deoxygenation shifts and magnitude of shear stress on erythrocyte deformability.Publication Metadata only Analysis and network representation of hotspots in protein interfaces using minimum cut trees(Wiley, 2010) Department of Chemical and Biological Engineering; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Tunçbağ, Nurcan; Salman, Fatma Sibel; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; College of Engineering; College of Engineering; College of Engineering; College of Engineering; 245513; 178838; 26605; 8745We propose a novel approach to analyze and visualize residue contact networks of protein interfaces by graph-based algorithms using a minimum cut tree (mincut tree). Edges in the network are weighted according to an energy function derived from knowledge-based potentials. The mincut tree, which is constructed from the weighted residue network, simplifies and summarizes the complex structure of the contact network by an efficient and informative representation. This representation offers a comprehensible view of critical residues and facilitates the inspection of their organization. We observed, on a nonredundant data set of 38 protein complexes with experimental hotspots that the highest degree node in the mincut tree usually corresponds to an experimental hotspot. Further, hotspots are found in a few paths in the mincut tree. In addition, we examine the organization of hotspots (hot regions) using an iterative clustering algorithm on two different case studies. We find that distinct hot regions are located on specific sites of the mincut tree and some critical residues hold these clusters together. Clustering of the interface residues provides information about the relation of hot regions with each other. Our new approach is useful at the molecular level for both identification of critical paths in the protein interfaces and extraction of hot regions by clustering of the interface residues.