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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access TRMU-related transient liver failure of infancy presents with microcephaly and neurodevelopmental delay(Nature Publishing Group (NPG), 2019) N/A; N/A; Azaklı, Hülya; Börklü Yücel, Esra; Arıkan, Çiğdem; Armutlu, Ayşe; Eraslan, Serpil; Kayserili, Hülya; PhD Student; Faculty Member; Teaching Faculty; Researcher; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; N/A; 7945Publication Open Access Investigation of hydrodynamic behavior of alginate aerogel particles in a laboratory scale Wurster fluidized bed(Multidisciplinary Digital Publishing Institute (MDPI), 2019) Department of Chemical and Biological Engineering; Erkey, Can; Akgün, Işık Sena; Faculty Member; Researcher; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; 29633; N/AThe effects of design and operating parameters on the superficial velocity at the onset of circulatory motion and the residence time of alginate aerogel particles in a laboratory scale Wurster fluidized bed were investigated. Several sets of experiments were conducted by varying Wurster tube diameter, Wurster tube length, batch volume and partition gap height. The superficial velocities for Wurster tube with 10 cm diameter were lower than the tube with 8 cm diameter. Superficial velocities increased with increasing batch volume and partition gap height. Moreover, increasing batch volume and partition gap height led to a decrease in the particle residence time in the Wurster tube. The results showed that there is an upper limit for each parameter in order to obtain a circulatory motion of the particles. It was found that the partition gap height should be 2 cm for proper particle circulation. Maximum batch volume for the tube with 10 cm diameter was found as 500 mL whereas maximum batch volume was 250 mL for the tube with 8 cm diameter. The fluidization behavior of the aerogel particles investigated in this study could be described by the general fluidization diagrams in the literature.Publication Open Access In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials(Taylor _ Francis, 2020) Asar, Sinan; Okyar, Alper; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; 111629; 40319Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.Publication Open Access European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death(Nature Publishing Group (NPG), 2019) Fellmann, Florence; van El, Carla G.; Charron, Philippe; Michaud, Katarzyna; Howard, Heidi C.; Boers, Sarah N.; Clarke, Angus J.; Duguet, Anne-Marie; Forzano, Francesca; Kauferstein, Silke; Lucassen, Anneke; Mendes, Alvaro; Patch, Christine; Radojkovic, Dragica; Rial-Sebbag, Emmanuelle; Sheppard, Mary N.; Tasse, Anne-Marie; Temel, Şehime G.; Sajantila, Antti; Basso, Cristina; Wilde, Arthur A. M.; Cornel, Martina C.; Benjamin, Caroline; Borry, Pascal; Clarke, Angus; Cordier, Christophe; Cornel, Martina; European Society of Human Genetics; European Council of Legal Medicine; European Society of Cardiology working group; European Reference Network for rare, low prevalence and complex diseases of the heart (ERN GUARD-Heart); Association for European Cardiovascular Pathology; N/A; Kayserili, Hülya; Faculty Member; School of Medicine; 7945Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.Publication Open Access Rabenosyn separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder(Oxford University Press (OUP), 2022) Paul, Franziska; Ng, Calista; Mohamad Sahari, Umar Bin; Nafissi, Shahriar; Nilipoor, Yalda; Tavasoli, Ali Reza; Bonnard, Carine; Wong, Pui-Mun; Estiar, Mehrdad A.; Majoie, Charles B.; Lee, Hane; Nelson, Stanley F.; Gan-Or, Ziv; Rouleau, Guy A.; Van Veldhoven, Paul P.; Massie, Rami; Hennekam, Raoul C.; Kariminejad, Ariana; Reversade, Bruno; Nabavizadeh, Nasrinsadat; Altunoğlu, Umut; Faculty Member; Researcher; Faculty Member; School of Medicine; N/A; N/A; 126174Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.Publication Open Access Molecular phylogeny, morphology, and distribution of Polygordius (Polychaeta: Polygordiidae) in the Atlantic and Mediterranean(Elsevier, 2018) Fiege, Dieter; Struck, Torsten; Department of Molecular Biology and Genetics; Balcı, Patricia A. Ramey; Researcher; Department of Molecular Biology and Genetics; College of SciencesLow morphological diversity among interstitial taxa makes it difficult to delimit species and their geographic boundaries based solely on morphology and molecular data often reveal cryptic species. Polygordius (Annelida, Polygordiidae) have low morphological diversity, but are unusual among interstitial species in their comparatively large size due to their elongated form, high fecundity, and potential for long-distance dispersal via a planktotrophic larval stage. Polygordius species collected from 14 localities in the Northwest Atlantic, Mediterranean Sea, and Southwest Atlantic including several of the respective type localities were analysed. This study presents the first phylogeny of the genus Polygordius and combines molecular data, sequences of COI, 16S and ITS1/2 genes, and morphological data for a systematic re-evaluation focusing on Atlantic species, with an emphasis on populations from European waters. Phylogenetic analyses recovered six valid species (P. appendiculatus, P. lacteus, P. neapolitanus, P. triestinus, P. jouinae, and P. eschaturus) and their distinctness is confirmed by haplotype network analyses. Thus, molecular data supported the validity of the previously recognized morphospecies and no new species were present. P. erythrophthalmus and P. villoti are invalid species being synonymous with P. lacteus. Subtle differences in head and pygidial morphology and larval type (endolarva vs. exolarva), were useful characters for discrimination. Yet seemingly significant variation in characters among individuals in some species was not diagnostic (e.g., number of pygidial cirri). Highly similar species based on adult morphology were shown to be sister taxa occurring in allopatry. Present day distribution patterns of species are summarized in light of this study.Publication Open Access An efficient framework to identify key miRNA-mRNA regulatory modules in cancer(Oxford University Press (OUP), 2020) N/A; Department of Industrial Engineering; Mokhtaridoost, Milad; Gönen, Mehmet; Faculty Member; Department of Industrial Engineering; Graduate School of Sciences and Engineering; College of Engineering; School of MedicineMotivation: micro-RNAs (miRNAs) are known as the important components of RNA silencing and post-transcriptional gene regulation, and they interact with messenger RNAs (mRNAs) either by degradation or by translational repression. miRNA alterations have a significant impact on the formation and progression of human cancers. Accordingly, it is important to establish computational methods with high predictive performance to identify cancer-specific miRNA-mRNA regulatory modules. Results: we presented a two-step framework to model miRNA-mRNA relationships and identify cancer-specific modules between miRNAs and mRNAs from their matched expression profiles of more than 9000 primary tumors. We first estimated the regulatory matrix between miRNA and mRNA expression profiles by solving multiple linear programming problems. We then formulated a unified regularized factor regression (RFR) model that simultaneously estimates the effective number of modules (i.e. latent factors) and extracts modules by decomposing regulatory matrix into two low-rank matrices. Our RFR model groups correlated miRNAs together and correlated mRNAs together, and also controls sparsity levels of both matrices. These attributes lead to interpretable results with high predictive performance. We applied our method on a very comprehensive data collection by including 32 TCGA cancer types. To find the biological relevance of our approach, we performed functional gene set enrichment and survival analyses. A large portion of the identified modules are significantly enriched in Hallmark, PID and KEGG pathways/gene sets. To validate the identified modules, we also performed literature validation as well as validation using experimentally supportedmiRTarBase database.Publication Open Access PRISM-EM: template interface-based modelling of multi-protein complexes guided by cryo-electron microscopy density maps (corrigendum)(International Union of Crystallography, 2018) Nussinov, Ruth; Department of Chemical and Biological Engineering; Kuzu, Güray; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; N/A; 26605; 8745A revised Table 6 and Supporting Information are provided for the article by Kuzu et al. [(2016 ), Acta Cryst. D72, 1137-1148].Publication Open Access PRISM: protein interactions by structural matching(Oxford University Press (OUP), 2005) Nussinov, Ruth; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Öğmen, Utkan; Keskin, Özlem; Aytuna, Ali Selim; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605; N/A; 8745Prism (https://gordion.hpc.eng.ku.edu.tr/prism) is a website for protein interface analysis and prediction of putative protein-protein interactions. It is composed of a database holding protein interface structures derived from the Protein Data Bank (PDB). The server also includes summary information about related proteins and an interactive protein interface viewer. A list of putative protein-protein interactions obtained by running our prediction algorithm can also be accessed. These results are applied to a set of protein structures obtained from the PDB at the time of algorithm execution (January 2004). Users can browse through the non-redundant dataset of representative interfaces on which the prediction algorithm depends, retrieve the list of similar structures to these interfaces or see the results of interaction predictions for a particular protein. Another service provided is interactive prediction. This is done by running the algorithm for user input structures.Publication Open Access Cyclophilin40 isomerase activity is regulated by a temperature-dependent allosteric interaction with Hsp90(Portland Press, 2015) Blackburn, Elizabeth A.; Wear, Martin A.; Landre, Vivian; Narayan, Vikram; Ning, Jia; Ball, Kathryn L.; Walkinshaw, Malcolm D.; Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997Cyclophilin 40 (Cyp40) comprises an N-terminal cyclophilin domain with peptidyl-prolyl isomerase (PPIase) activity and a C-terminal tetratricopeptide repeat (TPR) domain that binds to the C-terminal -EEVD sequence common to both heat shock protein 70 (Hsp70) and Hsp90. We show in the present study that binding of peptides containing the MEEVD motif reduces the PPIase activity by similar to 30%. CD and fluorescence assays show that the TPR domain is less stable than the cyclophilin domain and is stabilized by peptide binding. Isothermal titration calorimetry (ITC) shows that the affinity for the -MEEVD peptide is temperature sensitive in the physiological temperature range. Results from these biophysical studies fit with the MD simulations of the apo and holo (peptide-bound) structures which show a significant reduction in root mean square (RMS) fluctuation in both TPR and cyclophilin domains when -MEEVD is bound. The MD simulations of the apo-protein also highlight strong anti-correlated motions between residues around the PPIase-active site and a band of residues running across four of the seven helices in the TPR domain. Peptide binding leads to a distortion in the shape of the active site and a significant reduction in these strongly anti-correlated motions, providing an explanation for the allosteric effect of ligand binding and loss of PPIase activity. Together the experimental and MD results suggest that on heat shock, dissociation of Cyp40 from complexes mediated by the TPR domain leads to an increased pool of free Cyp40 capable of acting as an isomerase/chaperone in conditions of cellular stress.