Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7148
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Article Citation - Scopus: 4Quasi-Supervised Strategies for Compound-Protein Interaction Prediction(John Wiley and Sons Inc, 2022) Çakı, O.; Karaçalı, B.In-silico compound-protein interaction prediction addresses prioritization of drug candidates for experimental biochemical validation because the wet-lab experiments are time-consuming, laborious and costly. Most machine learning methods proposed to that end approach this problem with supervised learning strategies in which known interactions are labeled as positive and the rest are labeled as negative. However, treating all unknown interactions as negative instances may lead to inaccuracies in real practice since some of the unknown interactions are bound to be positive interactions waiting to be identified as such. In this study, we propose to address this problem using the Quasi-Supervised Learning (QSL) algorithm. In this framework, potential interactions are predicted by estimating the overlap between a true positive dataset of compound-protein pairs with known interactions and an unknown dataset of all the remaining compound-protein pairs. The potential interactions are then identified as those in the unknown dataset that overlap with the interacting pairs in the true positive dataset in terms of the associated similarity structure. We also address the class-imbalance problem by modifying the conventional cost function of the QSL algorithm. Experimental results on GPCR and Nuclear Receptor datasets show that the proposed method can identify actual interactions from all possible combinations. © 2021 Wiley-VCH GmbH.Review Citation - WoS: 116Citation - Scopus: 125Salivary Biomarkers: Novel Noninvasive Tools To Diagnose Chronic Inflammation(Springer, 2023) Dongiovanni, Paola; Meroni, Marica; Casati, Sara; Goldoni, Riccardo; Thomaz, Douglas Vieira; Kehr, Nermin Seda; Galimberti, DanielaSeveral chronic disorders including type 2 diabetes (T2D), obesity, heart disease and cancer are preceded by a state of chronic low-grade inflammation. Biomarkers for the early assessment of chronic disorders encompass acute phase proteins (APP), cytokines and chemokines, pro-inflammatory enzymes, lipids and oxidative stress mediators. These substances enter saliva through the blood flow and, in some cases, there is a close relation between their salivary and serum concentration. Saliva can be easily collected and stored with non-invasive and cost-saving procedures, and it is emerging the concept to use it for the detection of inflammatory biomarkers. To this purpose, the present review aims to discuss the advantages and challenges of using standard and cutting-edge techniques to discover salivary biomarkers which may be used in diagnosis/therapy of several chronic diseases with inflammatory consequences with the pursuit to possibly replace conventional paths with detectable soluble mediators in saliva. Specifically, the review describes the procedures used for saliva collection, the standard approaches for the measurement of salivary biomarkers and the novel methodological strategies such as biosensors to improve the quality of care for chronically affected patients.Article Citation - WoS: 7Citation - Scopus: 7Novel Regulation Mechanism of Adrenal Cortisol and Dhea Biosynthesis Via the Endogen Erad Inhibitor Small Vcp-Interacting Protein(Nature Publishing Group, 2022) İlhan, Recep; Üner, Göklem; Yılmaz, Sinem; Atalay Sahar, Esra; Çaylı, Sevil; Erzurumlu, Yalçın; Gözen, Oğuz; Ballar Kırmızıbayrak, PetekEndoplasmic reticulum-associated degradation (ERAD) is a well-characterized mechanism of protein quality control by removal of misfolded or unfolded proteins. The tight regulation of ERAD is critical for protein homeostasis as well as lipid metabolism. Although the mechanism is complex, all ERAD branches converge on p97/VCP, a key protein in the retrotranslocation step. The multifunctionality of p97/VCP relies on its multiple binding partners, one of which is the endogenous ERAD inhibitor, SVIP (small VCP-interacting protein). As SVIP is a promising target for the regulation of ERAD, we aimed to assess its novel physiological roles. We revealed that SVIP is highly expressed in the rat adrenal gland, especially in the cortex region, at a consistently high level during postnatal development, unlike the gradual increase in expression seen in developing nerves. Steroidogenic stimulators caused a decrease in SVIP mRNA expression and increase in SVIP protein degradation in human adrenocortical H295R cells. Interestingly, silencing of SVIP diminished cortisol secretion along with downregulation of steroidogenic enzymes and proteins involved in cholesterol uptake and cholesterol biosynthesis. A certain degree of SVIP overexpression mainly increased the biosynthesis of cortisol as well as DHEA by enhancing the expression of key steroidogenic proteins, whereas exaggerated overexpression led to apoptosis, phosphorylation of eIF2α, and diminished adrenal steroid hormone biosynthesis. In conclusion, SVIP is a novel regulator of adrenal cortisol and DHEA biosynthesis, suggesting that alterations in SVIP expression levels may be involved in the deregulation of steroidogenic stimulator signaling and abnormal adrenal hormone secretion.Article Citation - WoS: 58Citation - Scopus: 86Intrinsic Surface-Drying Properties of Bioadhesive Proteins(John Wiley and Sons Inc., 2014) Akdoğan, Yaşar; Wei, Wei; Huang, Kuo-Ying; Kageyama, Yoshiyuki; Danner, Eric W.; Miller, Dusty R.; Martinez Rodriguez, Nadine R.; Waite, J. Herbert; Han, SongiSessile marine mussels must "dry" underwater surfaces before adhering to them. Synthetic adhesives have yet to overcome this fundamental challenge. Previous studies of bioinspired adhesion have largely been performed under applied compressive forces, but such studies are poor predictors of the ability of an adhesive to spontaneously penetrate surface hydration layers. In a force-free approach to measuring molecular-level interaction through surface-water diffusivity, different mussel foot proteins were found to have different abilities to evict hydration layers from surfaces - a necessary step for adsorption and adhesion. It was anticipated that DOPA would mediate dehydration owing to its efficacy in bioinspired wet adhesion. Instead, hydrophobic side chains were found to be a critical component for protein-surface intimacy. This direct measurement of interfacial water dynamics during force-free adsorptive interactions at solid surfaces offers guidance for the engineering of wet adhesives and coatings. Home and dry underwater: Repulsive hydration forces hinder wet adhesion in the absence of applied external forces. The direct measurement of hydration-water dynamics by NMR relaxometry at 10 GHz revealed that the most hydrophobic mussel adhesive protein, and not the most enriched with 3,4-dihydroxyphenylalanine, effectively dries the surface and overcomes repulsive hydration forces to adsorb spontaneously to surfaces in preparation for adhesion.Article Citation - WoS: 7Citation - Scopus: 9Automatic Identification of Highly Conserved Family Regions and Relationships in Genome Wide Datasets Including Remote Protein Sequences(Public Library of Science, 2013) Doğan, Tunca; Karaçalı, BilgeIdentifying shared sequence segments along amino acid sequences generally requires a collection of closely related proteins, most often curated manually from the sequence datasets to suit the purpose at hand. Currently developed statistical methods are strained, however, when the collection contains remote sequences with poor alignment to the rest, or sequences containing multiple domains. In this paper, we propose a completely unsupervised and automated method to identify the shared sequence segments observed in a diverse collection of protein sequences including those present in a smaller fraction of the sequences in the collection, using a combination of sequence alignment, residue conservation scoring and graph-theoretical approaches. Since shared sequence fragments often imply conserved functional or structural attributes, the method produces a table of associations between the sequences and the identified conserved regions that can reveal previously unknown protein families as well as new members to existing ones. We evaluated the biological relevance of the method by clustering the proteins in gold standard datasets and assessing the clustering performance in comparison with previous methods from the literature. We have then applied the proposed method to a genome wide dataset of 17793 human proteins and generated a global association map to each of the 4753 identified conserved regions. Investigations on the major conserved regions revealed that they corresponded strongly to annotated structural domains. This suggests that the method can be useful in predicting novel domains on protein sequences.Article Citation - WoS: 49Citation - Scopus: 495-Fluorouracil Signaling Through a Calcium-Calmodulin Pathway Is Required for P53 Activation and Apoptosis in Colon Carcinoma Cells(Nature Publishing Group, 2013) Can, G.; Akpınar, B.; Baran, Yusuf; Zhivotovsky, B.; Olsson, M.5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2+) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2+ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2+ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FU-induced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 -/- cells confirmed the importance of a Ca 2+ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes. © 2013 Macmillan Publishers Limited.Article Citation - WoS: 55Citation - Scopus: 61Insight Into Serum Protein Interactions With Functionalized Magnetic Nanoparticles in Biological Media(American Chemical Society, 2012) Wiogo, Hilda T. R.; Lim, May; Bulmuş, Volga; Gutie´rrez, Lucía; Woodward, Robert C.; Amal, RoseSurface modification with linear polymethacrylic acid (20 kDa), linear and branched polyethylenimine (25 kDa), and branched oligoethylenimine (800 Da) is commonly used to improve the function of magnetite nanoparticles (MNPs) in many biomedical applications. These polymers were shown herein to have different adsorption capacity and anticipated conformations on the surface of MNPs due to differences in their functional groups, architectures, and molecular weight. This in turn affects the interaction of MNPs surfaces with biological serum proteins (fetal bovine serum). MNPs coated with 25 kDa branched polyethylenimine were found to attract the highest amount of serum protein while MNPs coated with 20 kDa linear polymethacrylic acid adsorbed the least. The type and amount of protein adsorbed, and the surface conformation of the polymer was shown to affect the size stability of the MNPs in a model biological media (RPMI-1640). A moderate reduction in r 2 relaxivity was also observed for MNPs suspended in RPMI-1640 containing serum protein compared to the same particles suspended in water. However, the relaxivities following protein adsorption are still relatively high making the use of these polymer-coated MNPs as Magnetic Resonance Imaging (MRI) contrast agents feasible. This work shows that through judicious selection of functionalization polymers and elucidation of the factors governing the stabilization mechanism, the design of nanoparticles for applications in biologically relevant conditions can be improved. © 2012 American Chemical Society.Article Citation - WoS: 17Citation - Scopus: 19Effect of Thioredoxin Deletion and P53 Cysteine Replacement on Human P53 Activity in Wild-Type and Thioredoxin Reductase Null Yeast(American Chemical Society, 2009) Stoner, Christopher S.; Pearson, George D.; Koç, Ahmet; Merwin, Jason R.; Lopez, Nathan I.; Merrill, Gary FredericReporter gene transactivation by human p53 is inhibited in budding yeast lacking the TRR1 gene encoding thioredoxin reductase. To investigate the role of thioredoxin in controlling p53 activity, the level of reporter gene transactivation by p53 was determined in yeast lacking the TRX1 and TRX2 genes encoding cytosolic thioredoxin. Surprisingly, p53 activity was unimpaired in yeast lacking thioredoxin. Subsequent analyses showed that thioredoxin deletion suppressed the inhibitory effect of thioredoxin reductase deletion, suggesting that accumulation of oxidized thioredoxin in mutant yeast was necessary for p53 inhibition. Purified human thioredoxin and p53 interacted in vitro (K d = 0.9 μM thioredoxin). To test the idea that dithio-disulfide exchange reactions between p53 and thioredoxin were responsible for p53 inhibition in mutant yeast, each p53 cysteine was changed to serine, and the effect of the substitution on p53 activity in TRR1 and Δtrr1 yeast was determined. Substitutions at Zn-coordinating cysteines C176, C238, or C242 resulted in p53 inactivation. Unexpectedly, substitution at cysteine C275 also inactivated p53, which was the first evidence for a non-zinc-coordinating cysteine being essential for p53 function. Cysteine substitutions at six positions (C124, C135, C141, C182, C229, and C277) neither inactivated p53 nor relieved the requirement for thioredoxin reductase. Furthermore, no tested combination of these six cysteine substitutions relieved thioredoxin reductase dependence. The results suggested that p53 dependence on thioredoxin reductase either was indirect, perhaps mediated by an upstream activator of p53, or was due to oxidation of one or more of the four essential cysteines.Article Citation - WoS: 90Citation - Scopus: 93Purification and Characterization of Three Members of the Photolyase/Cryptochrome Family Blue-Light Photoreceptors From Vibrio Cholerae(American Society for Biochemistry and Molecular Biology, 2003) Worthington, Erin N.; Kavaklı, İ. Halil; Berrocal-Tito, Gloria M.; Bondo, Bruce; Sancar, AzizThe sequence of Vibrio cholerae genome revealed three genes belonging to the photolyase/cryptochrome blue-light photoreceptor family. The proteins encoded by the three genes were purified and characterized. All three proteins contain folate and flavin cofactors and have absorption peaks in the range of 350-500 nm. Only one of the three, VcPhr, is a photolyase specific for cyclobutane pyrimidine dimers. The other two are cryptochromes and were designated VcCry1 and VcCry2, respectively. Mutation of phr abolishes photoreactivation of UV-induced killing, whereas mutations in cry1 and cry2 do not affect photorepair activity. VcCry1 exhibits some unique features. Of all cryptochromes characterized to date, it is the only one that contains stoichiometric amounts of both chromophores and retains its flavin cofactor in the two-electron reduced FADH2 form. In addition, VcCry1 exhibits RNA binding activity and copurifies with an RNA of 60-70 nucleotides in length.