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Item The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium inaugural meeting report(BMC, 2016-01-01) Chernomoretz, Ariel; Stolovitzky, Gustavo; Labaj, Pawel P.; Graf, Alexandra B.; Darling, Aaron; Burke, Catherine; Noushmehr, Houtan; Moraes, Milton Ozorio; Dias-Neto, Emmanuel; Guo, Yongli; Xie, Zhi; Lee, Patrick; Shi, Leming; Ruiz-Perez, Carlos A.; Mercedes Zambrano, Maria; Siam, Rania; Ouf, Amged; Richard, Hugues; Lafontaine, Ingrid; Wieler, Lothar H.; Semmler, Torsten; Ahmed, Niyaz; Prithi-viraj, Bharath; Nedunuri, Narasimha; Mehr, Shaadi; Banihashemi, Kambiz; Lista, Florigio; Anselmo, Anna; Suzuki, Haruo; Kuroda, Makoto; Yamashita, Riu; Sato, Yukoto; Kaminuma, Eli; Alpuche Aranda, Celia M.; Martinez, Jesus; Dada, Christopher; Dybwad, Marius; Oliveira, Manuela; Schuster, Stephan; Siwo, Geoffrey H.; Jang, Soojin; Seo, Sung Chul; Hwang, Sung Ho; Ossowski, Stephan; Bezdan, Daniela; Chaker, Salama; Chatziefthimiou, Aspassia D.; Udekwu, Klas; Liungdahl, Per; Sezerman, Ugur; Meydan, Cem; Elhaik, Eran; Gonnet, Gaston; Schriml, Lynn M.; Mongodin, Emmanuel; Huttenhower, Curtis; Gilbert, Jack; Mason, Christopher E.; Eisen, Jonathan; Hirschberg, David; Hernandez, Mark; Consortium, MetaSU.B. IntThe Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium is a novel, interdisciplinary initiative comprised of experts across many fields, including genomics, data analysis, engineering, public health, and architecture. The ultimate goal of the MetaSUB Consortium is to improve city utilization and planning through the detection, measurement, and design of metagenomics within urban environments. Although continual measures occur for temperature, air pressure, weather, and human activity, including longitudinal, cross-kingdom ecosystem dynamics can alter and improve the design of cities. The MetaSUB Consortium is aiding these efforts by developing and testing metagenomic methods and standards, including optimized methods for sample collection, DNA/RNA isolation, taxa characterization, and data visualization. The data produced by the consortium can aid city planners, public health officials, and architectural designers. In addition, the study will continue to lead to the discovery of new species, global maps of antimicrobial resistance (AMR) markers, and novel biosynthetic gene clusters (BGCs). Finally, we note that engineered metagenomic ecosystems can help enable more responsive, safer, and quantified cities.Item In silico analyses and global transcriptional profiling reveal novel putative targets for Pea3 transcription factor related to its function in neurons(PUBLIC LIBRARY SCIENCE, 2017-01-01) Kandemir, Basak; Dag, Ugur; Gungor, Burcu Bakir; Durasi, Ilknur Melis; Erdogan, Burcu; Sahin, Eray; Sezerman, Ugur; Kurnaz, Isil AksanPea3 transcription factor belongs to the PEA3 subfamily within the ETS domain transcription factor superfamily, and has been largely studied in relation to its role in breast cancer metastasis. Nonetheless, Pea3 plays a role not only in breast tumor, but also in other tissues with branching morphogenesis, including kidneys, blood vasculature, bronchi and the developing nervous system. Identification of Pea3 target promoters in these systems are important for a thorough understanding of how Pea3 functions. Present study particularly focuses on the identification of novel neuronal targets of Pea3 in a combinatorial approach, through curation, computational analysis and microarray studies in a neuronal model system, SH-SY5Y neuroblastoma cells. We not only show that quite a number of genes in cancer, immune system and cell cycle pathways, among many others, are either up- or down-regulated by Pea3, but also identify novel targets including ephrins and ephrin receptors, semaphorins, cell adhesion molecules, as well as metalloproteases such as kallikreins, to be among potential target promoters in neuronal systems. Our overall results indicate that rather than early stages of neurite extension and axonal guidance, Pea3 is more involved in target identification and synaptic maturation.Item Investigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation(NATURE PORTFOLIO, 2022-01-01) Everest, Elif; Ahangari, Mohammad; Uygunoglu, Ugur; Tutuncu, Melih; Bulbul, Alper; Saip, Sabahattin; Duman, Taskin; Sezerman, Ugur; Reich, Daniel S.; Riley, Brien P.; Siva, Aksel; Turanli, Eda TahirMany multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identifiedItem Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells(ELSEVIER, 2021-01-01) Le, Hillary H.; Cinaroglu, Suleyman S.; Manalo, Elise C.; Ors, Aysegul; Gomes, Michelle M.; Sahbaz, Burcin Duan; Bonic, Karla; Marmolejo, Carlos A. Origel; Quentel, Arnaud; Plaut, Justin S.; Kawashima, Taryn E.; Ozdemir, E. Sila; Malhotra V, Sanjay; Ahiska, Yavuz; Sezerman, Ugur; Akcapinar, Gunseli Bayram; Saldivar, Joshua C.; Timucin, Emel; Fischer, Jared M.Background: Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to develop a senolytic that acts not only on ageing cells but also senescent cancer cells to prevent cancer recurrence or progression. Methods: We used molecular modelling to develop a series of rationally designed peptides to mimic and target FOXO4 disrupting the FOXO4-TP53 interaction and releasing TP53 to induce apoptosis. We then tested these peptides as senolytic agents for the elimination of senescent cells both in cell culture and in vivo. Findings: Here we show that these peptides can act as senolytics for eliminating senescent human cancer cells both in cell culture and in orthotopic mouse models. We then further characterized one peptide, ES2, showing that it disrupts FOXO4-TP53 foci, activates TP53 mediated apoptosis and preferentially binds FOXO4 compared to TP53. Next, we show that intratumoural delivery of ES2 plus a BRAF inhibitor results in a significant increase in apoptosis and a survival advantage in mouse models of melanoma. Finally, we show that repeated systemic delivery of ES2 to older mice results in reduced senescent cell numbers in the liver with minimal toxicity. Interpretation: Taken together, our results reveal that peptides can be generated to specifically target and eliminate FOXO4+ senescent cancer cells, which has implications for eradicating residual disease and as a combination therapy for frontline treatment of cancer. Funding: This work was supported by the Cancer Early Detection Advanced Research Center at Oregon Health \& Science University. (C) 2021 The Authors. Published by Elsevier B.V.Item Comparison of endometrial prostanoid profiles in three infertile subgroups: the missing part of receptivity?(ELSEVIER SCIENCE INC, 2020-01-01) Keles, Irem Demiral; Ulgen, Ege; Erkan, Melike Belkiz; Celik, Saliha Esin; Aydin, Yasemin; Onem, Ayse Nur; Kandemir, Hulya; Arslanoglu, Tugce; Apak, Mustafa Resat; Sezerman, Ugur; Yeh, John; Buyru, Faruk; Bastu, ErcanObjective: To study the prostanoid profile of the endometria of patients with recurrent implantation failure (RIF), unexplained infertility (UIF), and recurrent miscarriages (RM), and to compare them with the endometria of healthy fertile controls. Design: Prospective cohort study. Setting: University hospital. Patient(s): Fifteen patients with RIF, 18 patients with UIF, 16 patients with RM, and 23 fertile controls were recruited. Intervention(s): Endometrial samples were taken during the window of implantation. After tissue homogenization and extraction, analysis with ultra-performance liquid chromatography diode array detector electrospray ionisation tandemmass spectrometrywas performed. Main Outcome Measures: Concentrations of prostaglandin (PG) D1, PGE1, PGF1 alpha, 6-ketoPGF1 alpha GD2, PGE2, PGF2 alpha, 15-deoxy-Delta 12,14-PGJ2, PGD3, PGE3, PGF3 alpha, thromboxane B2, 13,14-dihydro-PGE1, 13,14-dihydro-PGF1 alpha, 13,14-dihydro-PGF2 alpha, 13,14dihydro-15-keto-PGE1, 13,14-dihydro-15-keto-PGE2, and 13,14-dihydro-15-keto-PGF2 alpha were assessed. Result(s): Comparison of the endometria of patients with UIF and the controls showed no statistically significant differences. When the endometria of patients with RIF were compared with the controls, thromboxane B2 (TXB2) was found significantly higher (843.1 pg/mg vs. 133.5 pg/mg). When the endometria of patients with RM were compared with controls, 13,14-dihydro-15-keto PGF2 alpha and TXB2 were found significantly higher (3907.30 pg/mg vs. 17.80 pg/mg and 858.7 pg/mg vs. 133.5 pg/mg respectively). Conclusion(s): We identified increased endometrial presence of TXB2 in patients with RM and RIF, and 13,14-dihydro-15-keto PGF2 alpha in patients with RM. Although common ground is observed for RM and RIF, prostanoids, on the other hand, might make their own contribution to endometrial receptivity as important as genes and proteins. Attempts to normalize the prostaglandin profile of the endometrium via enzymatic activity can open new therapeutic options. (C) 2019 by American Society for Reproductive Medicine.Item Investigation of base excision repair gene variants in late-onset Alzheimer's disease(PUBLIC LIBRARY SCIENCE, 2019-01-01) Ertuzun, Tugce; Semerci, Asli; Cakir, Mehmet Emin; Ekmekcioglu, Aysegul; Gok, Mehmet Oguz; Soltys, Daniela T.; de Souza-Pinto, Nadja C.; Sezerman, Ugur; Muftuoglu, MeltemBase excision repair (BER) defects and concomitant oxidative DNA damage accumulation play a role in the etiology and progression of late-onset Alzheimer's disease (LOAD). However, it is not known whether genetic variant(s) of specific BER genes contribute to reduced BER activity in LOAD patients and whether they are associated with risk, development and/or progression of LOAD. Therefore, we performed targeted next generation sequencing for three BER genes, uracil glycosylase (UNG), endonuclease VIII-like DNA glycosylase 1 (NEIL1) and polymerase beta (POL beta) including promoter, exonic and intronic regions in peripheral blood samples and postmortem brain tissues (temporal cortex, TC and cerebellum, CE) from LOAD patients, high-pathology control and cognitively normal age-matched controls. In addition, the known LOAD risk factor, APOE was included in this study to test whether any BER gene variants associate with APOE variants, particularly APOE epsilon 4. We show that UNG carry five significant variants (rs1610925, rs2268406, rs80001089, rs1018782 and rs1018783) in blood samples of Turkish LOAD patients compared to age-matched controls and one of them (UNG rs80001089) is also significant in TC from Brazilian LOAD patients (p<0.05). The significant variants present only in CE and TC from LOAD are UNG rs2569987 and POL beta rs1012381950, respectively. There is also significant epistatic relationship (p = 0.0410) between UNG rs80001089 and NEIL1 rs7182283 in TC from LOAD subjects. Our results suggest that significant BER gene variants may be associated with the risk of LOAD in non-APOE epsilon 4 carriers. On the other hand, there are no significant UNG, NEIL1 and POL beta variants that could affect their protein level and function, suggesting that there may be other factors such as post-transcriptional or-translational modifications responsible for the reduced activities and protein levels of these genes in LOAD pathogenesis. Further studies with increased sample size are needed to confirm the relationship between BER variants and LOAD risk.Item Multiplex-PCR-Based Screening and Computational Modeling of Virulence Factors and T-Cell Mediated Immunity in Helicobacter pylori Infections for Accurate Clinical Diagnosis(PUBLIC LIBRARY SCIENCE, 2015-01-01) Oktem-Okullu, Sinem; Tiftikci, Arzu; Saruc, Murat; Cicek, Bahattin; Vardareli, Eser; Tozun, Nurdan; Kocagoz, Tanil; Sezerman, Ugur; Yavuz, Ahmet Sinan; Sayi-Yazgan, AycaThe outcome of H. pylori infection is closely related with bacteria's virulence factors and host immune response. The association between T cells and H. pylori infection has been identified, but the effects of the nine major H. pylori specific virulence factorsItem Differential gene expression analysis of human cumulus cells(KOREAN SOC REPRODUCTIVE MEDICINE, 2019-01-01) Demiray, Sirin Bakti; Goker, Ege Nazan Tavmergen; Tavmergen, Erol; Yilmaz, Ozlem; Calimlioglu, Nilufer; Soykam, Huseyin Okan; Oktem, Gulperi; Sezerman, UgurObjective: This study was performed to explore the possibility that each oocyte and its surrounding cumulus cells might have different genetic expression patterns that could affect human reproduction. Methods: Differential gene expression analysis was performed for 10 clusters of cumulus cells obtained from 10 cumulus-oocyte complexes from 10 patients. Same procedures related to oocyte maturation, microinjection, and microarray analyses were performed for each group of cumulus cells. Two differential gene expression analyses were performed: one for the outcome of clinical pregnancy and one for the outcome of live birth. Results: Significant genes resulting from these analyses were selected and the top 20 affected pathways in each group were analyzed. Circadian entrainment is determined to be the most affected pathway for clinical pregnancy, and proteoglycans in cancer pathway is the most affected pathway for live birth. Circadian entrainment is also amongst the 12 pathways that are found to be in top 20 affected pathways for both outcomes, and has both lowest p-value and highest number of times found count. Conclusion: Although further confirmatory studies are necessary, findings of this study suggest that these pathways, especially circadian entrainment in cumulus cells, may be essential for embryo development and pregnancy.Item Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity(WILEY, 2020-01-01) Altinoz, Meric A.; Ucal, Yasemin; Yilmaz, Muazzez C.; Kiris, Irem; Ozisik, Ozan; Sezerman, Ugur; Ozpinar, Aysel; Elmaci, IlhanWhile pregnancy may accelerate glioblastoma multiforme (GBM) growth, parity and progesterone (P4) containing treatments (ie, hormone replacement therapy) reduce the risk of GBM development. In parallel, low and high doses of P4 exert stimulating and inhibitory actions on GBM growth, respectively. The mechanisms behind the high-dose P4-suppression of GBM growth is unknown. In the present study, we assessed the changes in growth and proteomic profiles when high-dose P4 (100 and 300 mu M) was administered in human U87 and A172 GBM cell lines. The xCELLigence system was used to examine cell growth when different concentrations of P4 (20, 50, 100, and 300 mu M) was administered. The protein profiles were determined by two-dimensional gel electrophoresis in both cell lines when 100 and 300 mu M P4 were administered. Finally, the pathways enriched by the differentially expressed proteins were assessed using bioinformatic tools. Increasing doses of P4 blocked the growth of both GBM cells. We identified 26 and 51 differentially expressed proteins (fc > 2) in A172 and U87 cell lines treated with P4, respectively. Only the pro-tumorigenic mitochondrial ornithine aminotransferase and anti-apoptotic mitochondrial 60 kDa heat shock protein were downregulated in A172 cell line and U87 cell line when treated with P4, respectively. Detoxification of reactive oxygen species, cellular response to stress, glucose metabolism, and immunity-related proteins were altered in P4-treated GBM cell lines. The paradox on the effect of low and high doses of P4 on GBM growth is gaining attention. The mechanism related to the high dose of P4 on GBM growth can be explained by the alterations in detoxification mechanisms, stress, and immune response and glucose metabolism. P4 suppresses GBM growth and as it is nontoxic in comparison to classical chemotherapeutics, it can be used as a new strategy in GBM treatment in the future.Item Base-excess chloride(PUBLIC LIBRARY SCIENCE, 2021-01-01) Gucyetmez, Bulent; Tuzuner, Filiz; Atalan, Hakan Korkut; Sezerman, Ugur; Gucyetmez, Kaan; Telci, LutfiTo practically determine the effect of chloride (Cl) on the acid-base status, four approaches are currently used: accepted ranges of serum Cl values