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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access Comprehensive research on past and future therapeutic strategies devoted to treatment of amyotrophic lateral sclerosis(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Sever, Belgin; Sever, Hilal; Ocak, Firdevs; Yuluğ, Burak; Tateishi, Hiroshi; Tateishi, Takahisa; Otsuka, Masami; Mikako, Fujita; Department of Molecular Biology and Genetics; Başak, Ayşe Nazlı; Çiftçi, Halil İbrahim; Demirci, Hasan; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Sciences; 1512; N/A; 307350Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.Publication Open Access Biocompatible quantum funnels for neural photostimulation(American Chemical Society (ACS), 2019) N/A; Department of Chemical and Biological Engineering; N/A; Department of Electrical and Electronics Engineering; Department of Molecular Biology and Genetics; N/A; Jalali, Houman Bahmani; Doğru-Yüksel, Itır Bakış; Eren, Güncem Özgün; Nizamoğlu, Sedat; Karatüm, Onuralp; Melikov, Rustamzhon; Dikbaş, Uğur Meriç; Kavaklı, İbrahim Halil; Sadeghi, Sadra; Yıldız, Erdost; Ergün, Çağla; Şahin, Afsun; PhD Student; Faculty Member; PhD Student; Master Student; Faculty Member; PhD Student; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Department of Electrical and Electronics Engineering; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; School of Medicine; N/A; N/A; N/A; 130295; N/A; N/A; N/A; 40319; N/A; N/A; N/A; 171267Neural photostimulation has high potential to understand the working principles of complex neural networks and develop novel therapeutic methods for neurological disorders. A key issue in the light-induced cell stimulation is the efficient conversion of light to bioelectrical stimuli. In photosynthetic systems developed in millions of years by nature, the absorbed energy by the photoabsorbers is transported via nonradiative energy transfer to the reaction centers. Inspired by these systems, neural interfaces based on biocompatible quantum funnels are developed that direct the photogenerated charge carriers toward the bionanojunction for effective photostimulation. Funnels are constructed with indium-based rainbow quantum dots that are assembled in a graded energy profile. Implementation of a quantum funnel enhances the generated photoelectrochemical current 215% per unit absorbance in comparison with ungraded energy profile in a wireless and free-standing mode and facilitates optical neuromodulation of a single cell. This study indicates that the control of charge transport at nanoscale can lead to unconventional and effective neural interfaces.Publication Open Access Chronically radiation-exposed survivor glioblastoma cells display poor response to Chk1 inhibition under hypoxia(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Department of Molecular Biology and Genetics; Değirmenci, Nareg Pınarbaşı; Sur, İlknur Erdem; Akçay, Vuslat; Bölükbaşı, Yasemin; Selek, Uğur; Solaroğlu, İhsan; Önder, Tuğba Bağcı; PhD Student; Faculty Member; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; College of Sciences; School of Medicine; Koç University Hospital; N/A; N/A; N/A; 216814; 27211; 102059; 184359Glioblastoma is the most malignant primary brain tumor, and a cornerstone in its treatment is radiotherapy. However, tumor cells surviving after irradiation indicates treatment failure; therefore, better understanding of the mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated clinically relevant irradiation-exposed models by applying fractionated radiotherapy over a long time and selecting irradiation-survivor (IR-Surv) glioblastoma cells. We examined the transcriptomic alterations, cell cycle and growth rate changes and responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Concomitantly, IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, and MGMT, and had better DNA repair capacity. IR-Surv cells displayed downregulation of hypoxic signature and lower induction of hypoxia target genes, compared to naive glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both naive and IR-Surv cells. However, IR-Surv cells' response to Chk1 inhibition markedly decreased under hypoxic conditions. Taken together, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both naive and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions.Publication Open Access A new series of indeno[1,2-c]pyrazoles as EGFR TK inhibitors for NSCLC therapy(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Özdemir, A.; Sever, B.; Tateishi, H.; Otsuka, M.; Fujita, M.; Altıntop, M.D.; Department of Molecular Biology and Genetics; Çiftçi, Halil İbrahim; Department of Molecular Biology and Genetics; College of SciencesNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC.Publication Open Access Normal mode analysis of KRas4B reveals partner specific dynamics(American Chemical Society (ACS), 2021) Jang, Hyunbum; Nussinov, Ruth; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Computer Engineering; Tunçbağ, Nurcan; Gürsoy, Attila; Keskin, Özlem; Eren, Meryem; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Computer Engineering; School of Medicine; College of Engineering; Graduate School of Sciences and Engineering; 245513; 8745; 26605; N/ARas GTPase interacts with its regulators and downstream effectors for its critical function in cellular signaling. Targeting the disrupted mechanisms in Ras-related human cancers requires understanding the distinct dynamics of these protein-protein interactions. We performed normal mode analysis (NMA) of KRas4B in wild-type or mutant monomeric and neurofibromin-1 (NF1), Son of Sevenless 1 (SOS1) or Raf-1 bound dimeric conformational states to reveal partner-specific dynamics of the protein. Gaussian network model (GNM) analysis showed that the known KRas4B lobes further partition into subdomains upon binding to its partners. Furthermore, KRas4B interactions with different partners suppress the flexibility in not only their binding sites but also distant residues in the allosteric lobe in a partner-specific way. The conformational changes can be driven by intrinsic residue fluctuations of the open state KRas4B-GDP, as we illustrated with anisotropic network model (ANM) analysis. The allosteric paths connecting the nucleotide binding residues to the allosteric site at alpha 3-L7 portray differences in the inactive and active states. These findings help in understanding the partner-specific KRas4B dynamics, which could be utilized for therapeutic targeting.Publication Open Access Intersubunit coupling enables fast CO2-fixation by reductive carboxylases(American Chemical Society (ACS), 2022) Rao, Y.; Stoffel, G.M.; Vögeli, B.; Schell, K.; Gomez, A.; Batyuk, A.; Gati, C.; Sierra, R.G.; Hunter, M.S.; Dao, E.H.; Ciftci, H.I.; Hayes, B.; Poitevin, F.; Li, P.-N.; Kaur, M.; Tono, K.; Saez, D.A.; Deutsch, S.; Yoshikuni, Y.; Grubmüller, H.; Erb, T.J.; Vöhringer-Martinez, E.; Wakatsuki, S.; Department of Molecular Biology and Genetics; Demirci, Hasan; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; 307350Enoyl-CoA carboxylases/reductases (ECRs) are some of the most efficient CO2-fixing enzymes described to date. However, the molecular mechanisms underlying the extraordinary catalytic activity of ECRs on the level of the protein assembly remain elusive. Here we used a combination of ambient-temperature X-ray free electron laser (XFEL) and cryogenic synchrotron experiments to study the structural organization of the ECR from Kitasatospora setae. The K. setae ECR is a homotetramer that differentiates into a pair of dimers of open- and dosed-form subunits in the catalytically active state. Using molecular dynamics simulations and structure-based mutagenesis, we show that catalysis is synchronized in the K. setae ECR across the pair of dimers. This conformational coupling of catalytic domains is conferred by individual amino acids to achieve high CO2-fixation rates. Our results provide unprecedented insights into the dynamic organization and synchronized inter- and intrasubunit communications of this remarkably efficient CO2-fixing enzyme during catalysis.Publication Open Access An advanced workflow for single-particle imaging with the limited data at an X-ray free-electron laser(International Union of Crystallography, 2020) Assalauova, Dameli; Kim, Young Yong; Bobkov, Sergey; Khubbutdinov, Ruslan; Rose, Max; Alvarez, Roberto; Andreasson, Jakob; Balaur, Eugeniu; Contreras, Alice; Gelisio, Luca; Hajdu, Janos; Hunter, Mark S.; Kurta, Ruslan P.; Li, Haoyuan; McFadden, Matthew; Nazari, Reza; Schwander, Peter; Teslyuk, Anton; Walter, Peter; Xavier, P. Lourdu; Yoon, Chun Hong; Zaare, Sahba; Ilyin, Viacheslav A.; Kirian, Richard A.; Hogue, Brenda G.; Aquila, Andrew; Vartanyants, Ivan A.; Department of Molecular Biology and Genetics; Demirci, Hasan; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; 307350An improved analysis for single-particle imaging (SPI) experiments, using the limited data, is presented here. Results are based on a study of bacteriophage PR772 performed at the Atomic, Molecular and Optical Science instrument at the Linac Coherent Light Source as part of the SPI initiative. Existing methods were modified to cope with the shortcomings of the experimental data: inaccessibility of information from half of the detector and a small fraction of single hits. The general SPI analysis workflow was upgraded with the expectation-maximization based classification of diffraction patterns and mode decomposition on the final virus-structure determination step. The presented processing pipeline allowed us to determine the 3D structure of bacteriophage PR772 without symmetry constraints with a spatial resolution of 6.9 nm. The obtained resolution was limited by the scattering intensity during the experiment and the relatively small number of single hits.