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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease(BioMed Central, 2016) Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; N/A; Department of Molecular Biology and Genetics; Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; 214694; 110772Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.Publication Open Access A proximity mapping journey into the biology of the mammalian centrosome/cilium complex(Multidisciplinary Digital Publishing Institute (MDPI), 2020) Department of Molecular Biology and Genetics; Arslanhan, Melis Dilara; Gülensoy, Dila; Karalar, Elif Nur Fırat; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 206349The mammalian centrosome/cilium complex is composed of the centrosome, the primary cilium and the centriolar satellites, which together regulate cell polarity, signaling, proliferation and motility in cells and thereby development and homeostasis in organisms. Accordingly, deregulation of its structure and functions is implicated in various human diseases including cancer, developmental disorders and neurodegenerative diseases. To better understand these disease connections, the molecular underpinnings of the assembly, maintenance and dynamic adaptations of the centrosome/cilium complex need to be uncovered with exquisite detail. Application of proximity-based labeling methods to the centrosome/cilium complex generated spatial and temporal interaction maps for its components and provided key insights into these questions. In this review, we first describe the structure and cell cycle-linked regulation of the centrosome/cilium complex. Next, we explain the inherent biochemical and temporal limitations in probing the structure and function of the centrosome/cilium complex and describe how proximity-based labeling approaches have addressed them. Finally, we explore current insights into the knowledge we gained from the proximity mapping studies as it pertains to centrosome and cilium biogenesis and systematic characterization of the centrosome, cilium and centriolar satellite interactomes.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 ENKD1 is a centrosomal and ciliary microtubule-associated protein important for primary cilium content regulation(Wiley, 2022) Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Tiryaki, Fatmanur; Deretic, Jovana; Karalar, Elif Nur Fırat; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 206349Centrioles and cilia are conserved, microtubule-based structures critical for cell function and development. Their dysfunction causes cancer and developmental disorders. How microtubules are organized into ordered structures by microtubule-associated proteins (MAPs) and tubulin modifications is best understood during mitosis but is largely unexplored for the centrioles and the ciliary axoneme, which are composed of stable microtubules that maintain their length at a steady-state. In particular, we know little about the identity of the centriolar and ciliary MAPs and how they work together during the assembly and maintenance of the cilium and centriole. Here, we identified the Enkurin domain containing 1 (ENKD1) as a component of the centriole wall and the axoneme in mammalian cells and showed that it has extensive proximity interactions with these compartments and MAPs. Using in vitro and cellular assays, we found that ENKD1 is a new MAP that regulates microtubule organization and stability. Consistently, we observed an increase in tubulin polymerization and microtubule stability, as well as disrupted microtubule organization in ENKD1 overexpression. Cells depleted for ENKD1 were defective in ciliary length and content regulation and failed to respond to Hedgehog pathway activation. Together, our results advance our understanding of the functional and regulatory relationship between MAPs and the primary cilium.Publication Open Access Plasmon-coupled photocapacitor neuromodulators(American Chemical Society (ACS), 2020) Ülgüt, Burak; Çetin, Arif E.; N/A; N/A; Department of Molecular Biology and Genetics; Department of Electrical and Electronics Engineering; Department of Chemical and Biological Engineering; Melikov, Rustamzhon; Srivastava, Shashi Bhushan; Karatüm, Onuralp; Doğru-Yüksel, Itır Bakış; Jalali, Houman Bahmani; Sadeghi, Sadra; Dikbaş, Uğur Meriç; Kavaklı, İbrahim Halil; Nizamoğlu, Sedat; PhD Student; Researcher; PhD Student; PhD Student; Master Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Electrical and Electronics Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Sciences; College of Engineering; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 40319; 130295Efficient transduction of optical energy to bioelectrical stimuli is an important goal for effective communication with biological systems. For that, plasmonics has a significant potential via boosting the light-matter interactions. However, plasmonics has been primarily used for heat-induced cell stimulation due to membrane capacitance change (i.e., optocapacitance). Instead, here, we demonstrate that plasmonic coupling to photocapacitor biointerfaces improves safe and efficacious neuromodulating displacement charges for an average of 185% in the entire visible spectrum while maintaining the faradic currents below 1%. Hot-electron injection dominantly leads the enhancement of displacement current in the blue spectral window, and the nanoantenna effect is mainly responsible for the improvement in the red spectral region. The plasmonic photocapacitor facilitates wireless modulation of single cells at three orders of magnitude below the maximum retinal intensity levels, corresponding to one of the most sensitive optoelectronic neural interfaces. This study introduces a new way of using plasmonics for safe and effective photostimulation of neurons and paves the way toward ultrasensitive plasmon-assisted neurostimulation devices.Publication Open Access Generation of integration-free induced pluripotent stem cells from a patient with Familial Mediterranean Fever (FMF)(Elsevier, 2015) Gül, Ahmet; Department of Molecular Biology and Genetics; Fidan, Kerem; Kavaklıoğlu, Gülnihal; Ebrahimi, Ayyub A.; Özlü, Can; Ay, Nur Zeynep; Ruacan, Ayşe Arzu; Önder, Tamer Tevfik; Master Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; Graduate School of Sciences and Engineering; N/A; N/A; N/A; N/A; N/A; 38250; 42946Fibroblasts from a Familial Mediterranean Fever (FMF) patient were reprogrammed with episomal vectors by using the Neon Transfection System for the generation of integration-free induced pluripotent stem cells (iPSCs). The resulting iPSC line was characterized to determine the expression of pluripotency markers, proper differentiation into three germ layers, the presence of normal chromosomal structures as well as the lack of genomic integration. A homozygous missense mutation in the MEFV gene (p.Met694Val), which lead to typical FMF phenotype, was shown to be present in the generated iPSC line.Publication Open Access A bacteria-derived tail anchor localizes to peroxisomes in yeast and mammalian cells(Nature Publishing Group (NPG), 2018) Seferoğlu, Ayşe Bengisu; Department of Molecular Biology and Genetics; Dunn, Cory David; Keskin, Abdurrahman; Akdoğan, Emel; Lutfullahoglu-Bal, Guleycan; Department of Molecular Biology and Genetics; College of SciencesProkaryotes can provide new genetic information to eukaryotes by horizontal gene transfer (HGT), and such transfers are likely to have been particularly consequential in the era of eukaryogenesis. Since eukaryotes are highly compartmentalized, it is worthwhile to consider the mechanisms by which newly transferred proteins might reach diverse organellar destinations. Toward this goal, we have focused our attention upon the behavior of bacteria-derived tail anchors (TAs) expressed in the eukaryote Saccharomyces cerevisiae. In this study, we report that a predicted membrane-associated domain of the Escherichia coli YgiM protein is specifically trafficked to peroxisomes in budding yeast, can be found at a pre-peroxisomal compartment (PPC) upon disruption of peroxisomal biogenesis, and can functionally replace an endogenous, peroxisome-directed TA. Furthermore, the YgiM(TA) can localize to peroxisomes in mammalian cells. Since the YgiM(TA) plays no endogenous role in peroxisomal function or assembly, this domain is likely to serve as an excellent tool allowing further illumination of the mechanisms by which TAs can travel to peroxisomes. Moreover, our findings emphasize the ease with which bacteria-derived sequences might target to organelles in eukaryotic cells following HGT, and we discuss the importance of flexible recognition of organelle targeting information during and after eukaryogenesis.Publication Open Access Growth of non-English-language literature on biodiversity conservation(Wiley, 2022) Chowdhury, S.; Gonzalez, K.; Baek, S.Y.; Be?cik, M.; Bertolino, S.; Duijns S.; Han Y.; Jantke, K. Katayose, R.; Lin, M.M.; Nourani, E.; Ramos, D.L.; Rouyer, M.O.; Sidemo Holm, W.; Vozykova, S. Zamora-Gutierrez, V.; Amano T.; Department of Molecular Biology and Genetics; Aytekin, M. Çisel Kemahlı; Undergraduate Student; Faculty Member; Department of Molecular Biology and Genetics; College of SciencesEnglish is widely recognized as the language of science, and English-language publications (ELPs) are rapidly increasing. It is often assumed that the number of non-ELPs is decreasing. This assumption contributes to the underuse of non-ELPs in conservation science, practice, and policy, especially at the international level. However, the number of conservation articles published in different languages is poorly documented. Using local and international search systems, we searched for scientific articles on biodiversity conservation published from 1980 to 2018 in English and 15 non-English languages. We compared the growth rate in publications across languages. In 12 of the 15 non-English languages, published conservation articles significantly increased every year over the past 39 years, at a rate similar to English-language articles. The other three languages showed contrasting results, depending on the search system. Since the 1990s, conservation science articles in most languages increased exponentially. The variation in the number of non-English-language articles identified among the search systems differed markedly (e.g., for simplified Chinese, 11,148 articles returned with local search system and 803 with Scopus). Google Scholar and local literature search systems returned the most articles for 11 and 4 non-English languages, respectively. However, the proportion of peer-reviewed conservation articles published in non-English languages was highest in Scopus, followed by Web of Science and local search systems, and lowest in Google Scholar. About 20% of the sampled non-English-language articles provided no title or abstract in English; thus, in theory, they were undiscoverable with English keywords. Possible reasons for this include language barriers and the need to disseminate research in countries where English is not widely spoken. Given the known biases in statistical methods and study characteristics between English- and non-English-language studies, non-English-language articles will continue to play an important role in improving the understanding of biodiversity and its conservation.Publication Open Access Aurora kinase A proximity map reveals centriolar satellites as regulators of its ciliary function(Wiley, 2021) Rauniyar, N.; Yates, J. R. III; Department of Molecular Biology and Genetics; Karalar, Elif Nur Fırat; Arslanhan, Melis Dilara; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; Graduate School of Sciences and Engineering; 206349; N/AAurora kinase A (AURKA) is a conserved kinase that plays crucial roles in numerous cellular processes. Although AURKA overexpression is frequent in human cancers, its pleiotropic functions and multifaceted regulation present challenges in its therapeutic targeting. Key to overcoming these challenges is to identify and characterize the full range of AURKA interactors, which are often weak and transient. Previous proteomic studies were limited in monitoring dynamic and non-mitotic AURKA interactions. Here, we generate the proximity interactome of AURKA in asynchronous cells, which consists of 440 proteins involving multiple biological processes and cellular compartments. Importantly, AURKA has extensive proximate and physical interactions to centriolar satellites, key regulators of the primary cilium. Loss-of-function experiments identify satellites as negative regulators of AURKA activity, abundance, and localization in quiescent cells. Notably, loss of satellites activates AURKA at the basal body, decreases centrosomal IFT88 levels, and causes ciliogenesis defects. Collectively, our results provide a resource for dissecting spatiotemporal regulation of AURKA and uncover its proteostatic regulation by satellites as a new mechanism for its ciliary functions.Publication Open Access MicroRNA exocytosis by vesicle fusion in neuroendocrine cells(Frontiers, 2017) Department of Molecular Biology and Genetics; Park, Yongsoo; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; 240759MicroRNAs (miRNAs) are short non-coding RNAs that posttranscriptionally regulate gene expression inside the cell. Extracellular circulating miRNAs are also observed outside the cell, but their origin is poorly understood. Recently, miRNA has been shown to be exocytosed by vesicle fusion; this observation demonstrates that vesicle-free miRNAs are secreted from neuroendocrine cells, in a manner similar to hormone secretion. miRNAs are stored in large dense-core vesicles together with catecholamines, then released by vesicle fusion in response to stimulation; in this way, vesicle-free miRNA may regulate cell-to-cell communication including the regulation of gene expression and cellular signaling. Therefore, miRNA has been suggested to function as a hormone; i.e., a ribomone (ribonucleotide + hormone). This review focuses on the mechanisms by which vesicle-free miRNAs are secreted from neuroendocrine cells and will discuss potential functions of vesicle-free miRNAs and how vesicle-free miRNAs regulate cell-to-cell communication.