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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access Virulence determinants of colistin-resistant K. pneumoniae high-risk clones(Multidisciplinary Digital Publishing Institute (MDPI), 2021) Department of Industrial Engineering; Ergönül, Önder; Gönen, Mehmet; Can, Füsun; Doğan, Özlem; Vatansever, Cansel; Ataç, Nazlı; Albayrak, Özgür; Karahüseyinoğlu, Serçin; Şahin, Özgün Ekin; Kılıçoğlu, Bilge Kaan; Demiray, Atalay; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Undergraduate Student; Researcher; Faculty Member; Master Student; Department of Industrial Engineering; School of Medicine; Graduate School of Health Sciences; College of Engineering; 110398; 237468; 103165; 170418; N/A; N/A; N/A; 110772; N/A; N/A; N/AWe proposed the hypothesis that high-risk clones of colistin-resistant K. pneumoniae (ColR-Kp) possesses a high number of virulence factors and has enhanced survival capacity against the neutrophil activity. We studied virulence genes of ColR-Kp isolates and neutrophil response in 142 patients with invasive ColR-Kp infections. The ST101 and ST395 ColR-Kp infections had higher 30-day mortality (58%, p = 0.005 and 75%, p = 0.003). The presence of yersiniabactin biosynthesis gene (ybtS) and ferric uptake operon associated gene (kfu) were significantly higher in ST101 (99%, p <= 0.001) and ST395 (94%, p < 0.012). Being in ICU (OR: 7.9; CI: 1.43-55.98; p = 0.024), kfu (OR:27.0; CI: 5.67-179.65; p < 0.001) and ST101 (OR: 17.2; CI: 2.45-350.40; p = 0.01) were found to be predictors of 30-day mortality. Even the neutrophil uptake of kfu+-ybtS+ ColR-Kp was significantly higher than kfu--ybtS- ColR-Kp (phagocytosis rate: 78% vs. 65%, p < 0.001), and the kfu+-ybtS+ ColR-Kp survived more than kfu--ybtS- ColR-Kp (median survival index: 7.90 vs. 4.22; p = 0.001). The kfu+-ybtS+ ColR-Kp stimulated excessive NET formation. Iron uptake systems in high-risk clones of colistin-resistant K. pneumoniae enhance the success of survival against the neutrophil phagocytic defense and stimulate excessive NET formation. The drugs targeted to iron uptake systems would be a promising approach for the treatment of colistin-resistant high-risk clones of K. pneumoniae infections.Publication Open Access Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice(Nature Portfolio, 2022) Akyel, Yasemin Kübra; Korkmaz, Tuba; Selvi, Saba; Danış, İbrahim; İpek, Özgecan Savluğ; Aygenli, Fatih; Öztürk, Nuri; Öztürk, Narin; Ünal, Durişehvar Özer; Güzel, Mustafa; Okyar, Alper; N/A; Department of Chemical and Biological Engineering; Department of Industrial Engineering; Gül, Şeref; Gül, Zeynep Melis; Işın, Şafak; Özcan, Onur; Akarlar, Büşra; Taşkın, Ali Cihan; Türkay, Metin; Kavaklı, İbrahim Halil; Researcher; Other; Faculty Member; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Industrial Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Engineering; N/A; N/A; N/A; N/A; N/A; 291296; 105301; 24956; 40319Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53(-/-) mice by similar to 25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.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 Rapid molecular detection of gastrointestinal pathogens and its role in antimicrobial stewardship(American Society for Microbiology, 2018) Keske, Şiran; Palaoğlu, Erhan; N/A; Department of Industrial Engineering; Zabun, Burak; Aksoy, Kahraman; Can, Füsun; Ergönül, Önder; Faculty Member; Faculty Member; Department of Industrial Engineering; School of Medicine; N/A; N/A; N/A; 110398We aimed to detect the etiological agents of acute diarrhea by a molecular gastrointestinal pathogen test (MGPT) and to assess the impact of MGPT on antimicrobial stewardship programs (ASP). This is a prospective observational study and was conducted between 1 January 2015 and 30 June 2017. We included consequent patients who had acute diarrhea. At the end of 2015, we implemented ASP in acute diarrhea cases and compared the outcomes in the pre-ASP and post-ASP periods. An FDA-cleared multiplexed gastrointestinal PCR panel system, the BioFire FilmArray (Idaho Technology, Salt Lake City, UT), which detects 20 pathogens in stool, was used. In 499 out of 699 patients (71%), at least one pathogen was detected. Among 314 adults with positive MGPT, 101 (32%) enteropathogenic Escherichia coli (EPEC), 71 (23%) enteroaggregative E. coli (EAEC), 68 (22%) enterotoxigenic E. coli (ETEC), 55 (18%) Shiga toxin-producing E. coli (STEC) (17%) Norovirus, 48 (15%) Campylobacter, 21 (7%) Salmonella, and 20 (6%) Clostridium difficile strains were detected. Among 185 children, 55 (30%) EPEC, 37 (20%) C. difficile, 32 (17%) Norovirus, 29 (16%) EAEC, 22 (12%) STEC, 21 (11%) ETEC, 21 (11%) Campylobacter, 20 (11%) Salmonella, and 16 (5%) Rotavirus strains were detected. Inappropriate antibiotic use decreased in the post-ASP period compared with the pre-ASP period among inpatients (42.9% and 25.8%, respectively; P = 0.023). Using MGPT in clinical practice significantly decreased the unnecessary use of antibiotics. Detection of high rates of C. difficile in children and Salmonella spp., as well as relatively high rates of Campylobacter spp., which were hard to isolate by routine stool culture, were remarkable.Publication Open Access The role of AcrAB-TolC Efflux pumps on quinolone resistance of E-coli ST131(Springer, 2018) Kurt-Azap, O.; Dolapcı, I.; Yeşilkaya, A.; Can, F.; N/A; Department of Industrial Engineering; Ergönül, Önder; Ataç, Nazlı; Gönen, Mehmet; Faculty Member; Researcher; Faculty Member; Department of Industrial Engineering; School of Medicine; College of Engineering; 110398; N/A; 237468Escherichia coli ST131 is a cause for global concern because of its high multidrug resistance and several virulence factors. In this study, the contribution of acrAB-TolC efflux system of E. coli ST131 to fluoroquinolone resistance was evaluated. A total of nonrepetitive 111 ciprofloxacin-resistant E. coli isolates were included in the study. Multilocus sequence typing was used for genotyping. Expressions of acrA, acrB, and TolC efflux pump genes were measured by RT-PCR. Mutations in marA, gyrA, parC, and aac(6)-lb-cr positivity were studied by Sanger sequencing. Sixty-four (57.7%) of the isolates were classified as ST131, and 52 (81.3%) of the ST131 isolates belonged to H30-Rx subclone. In ST131, CTX-M 15 positivity (73%) and aac(6)-lb-cr carriage (75%) were significantly higher than those in non-ST131 (12.8% and 51%, respectively) (P<0.05). The ampicillin-sulbactam (83%) resistance was higher, and gentamicin resistance (20%) was lower in ST131 than that in non-ST131 (64% and 55%, respectively) (P=0.001 and P=0.0002). Numbers of the isolates with MDR or XDR profiles did not differ in both groups. Multiple in-dels (up to 16) were recorded in all quinolone-resistant isolates. However, marA gene was more overexpressed in ST131 compared to that in non-ST131 (median 5.98 vs. 3.99; P=0.0007). Belonging to H30-Rx subclone, isolation site, ciprofloxacin MIC values did not correlate with efflux pump expressions. In conclusion, the marA regulatory gene of AcrAB-TolC efflux pump system has a significant impact on quinolone resistance and progression to MDR profile in ST131 clone. Efflux pump inhibitors might be alternative drugs for the treatment of infections caused by E. coli ST131 if used synergistically in combination with antibiotics.Publication Open Access Customer mobility signatures and financial indicators as predictors in product recommendation(Public Library of Science, 2018) Bozkaya, Burçin; Department of Industrial Engineering; Ürküp, Çağan; Salman, Fatma Sibel; Department of Industrial Engineering; College of Engineering; Graduate School of Sciences and Engineering; N/A; 178838The rapid growth of mobile payment and geo-aware systems as well as the resulting emergence of Big Data present opportunities to explore individual consuming patterns across space and time. Here we analyze a one-year transaction dataset of a leading commercial bank to understand to what extent customer mobility behavior and financial indicators can predict the use of a target product, namely the Individual Consumer Loan product. After data preprocessing, we generate 13 datasets covering different time intervals and feature groups, and test combinations of 3 feature selection methods and 10 classification algorithms to determine, for each dataset, the best feature selection method and the most influential features, and the best classification algorithm. We observe the importance of spatio-temporal mobility features and financial features, in addition to demography, in predicting the use of this exemplary product with high accuracy (AUC = 0.942). Finally, we analyze the classification results and report on most interesting customer characteristics and product usage implications. Our findings can be used to potentially increase the success rates of product recommendation systems.Publication Open Access Sustainability in supply chain management: aggregate planning from sustainability perspective(Public Library of Science, 2016) Saraçoğlu, O.; Arslan, M.C.; Department of Industrial Engineering; Türkay, Metin; Saraçoğlu, Öztürk; Arslan, Mehmet Can; Faculty Member; Department of Industrial Engineering; College of Engineering; 24956; N/A; N/ASupply chain management that considers the flow of raw materials, products and information has become a focal issue in modern manufacturing and service systems. Supply chain management requires effective use of assets and information that has far reaching implications beyond satisfaction of customer demand, flow of goods, services or capital. Aggregate planning, a fundamental decision model in supply chain management, refers to the determination of production, inventory, capacity and labor usage levels in the medium term. Traditionally standard mathematical programming formulation is used to devise the aggregate plan so as to minimize the total cost of operations. However, this formulation is purely an economic model that does not include sustainability considerations. In this study, we revise the standard aggregate planning formulation to account for additional environmental and social criteria to incorporate triple bottom line consideration of sustainability. We show how these additional criteria can be appended to traditional cost accounting in order to address sustainability in aggregate planning. We analyze the revised models and interpret the results on a case study from real life that would be insightful for decision makers.Publication Open Access A prospective prediction tool for understanding Crimean-Congo haemorrhagic fever dynamics in Turkey(Elsevier, 2020) N/A; N/A; Department of Industrial Engineering; Ak, Çiğdem; Ergönül, Önder; Gönen, Mehmet; Faculty Member; Faculty Member; Department of Industrial Engineering; Graduate School of Sciences and Engineering; School of Medicine; College of Engineering; N/A; 110398; 237468Objectives: we aimed to develop a prospective prediction tool on Crimean-Congo haemorrhagic fever (CCHF) to identify geographic regions at risk. The tool could support public health decision-makers in implementation of an effective control strategy in a timely manner. Methods: we used monthly surveillance data between 2004 and 2015 to predict case counts between 2016 and 2017 prospectively. The Turkish nationwide surveillance data set collected by the Ministry of Health contained 10 411 confirmed CCHF cases. We collected potential explanatory covariates about climate, land use, and animal and human populations at risk to capture spatiotemporal transmission dynamics. We developed a structured Gaussian process algorithm and prospectively tested this tool predicting the future year's cases given past years' cases. Results: we predicted the annual cases in 2016 and 2017 as 438 and 341, whereas the observed cases were 432 and 343, respectively. Pearson's correlation coefficient and normalized root mean squared error values for 2016 and 2017 predictions were (0.83; 0.58) and (0.87; 0.52), respectively. The most important covariates were found to be the number of settlements with fewer than 25 000 inhabitants, latitude, longitude and potential evapotranspiration (evaporation and transpiration). Conclusions: main driving factors of CCHF dynamics were human population at risk in rural areas, geographical dependency and climate effect on ticks. Our model was able to prospectively predict the numbers of CCHF cases. Our proof-of-concept study also provided insight for understanding possible mechanisms of infectious diseases and found important directions for practice and policy to combat against emerging infectious diseases.Publication Open Access National case fatality rates of the COVID-19 pandemic(Elsevier, 2020) Tiemeier, H. W.; Petersen, Eskild; Petrosillo, Nicola; Department of Industrial Engineering; Ergönül, Önder; Akyol, Merve; Tanrıöver, Cem; Gönen, Mehmet; Faculty Member; Undergraduate Student; Faculty Member; Department of Industrial Engineering; School of Medicine; College of Engineering; 110398; N/A; N/A; 237468Objectives: the case fatality rate (CFR) of coronavirus disease 2019 (COVID-19) varies significantly between countries. We aimed to describe the associations between health indicators and the national CFRs of COVID-19. Methods: we identified for each country health indicators potentially associated with the national CFRs of COVID-19. We extracted data for 18 variables from international administrative data sources for 34 member countries of the Organization for Economic Cooperation and Development (OECD). We excluded the collinear variables and examined the 16 variables in multivariable analysis. A dynamic web-based model was developed to analyse and display the associations for the CFRs of COVID-19. We followed the Guideline for Accurate and Transparent Health Estimates Reporting (GATHER). Results: in multivariable analysis, the variables significantly associated with the increased CFRs were percentage of obesity in ages >18 years (β = 3.26; 95%CI = 1.20, 5.33; p 0.003), tuberculosis incidence (β = 3.15; 95%CI = 1.09, 5.22; p 0.004), duration (days) since first death due to COVID-19 (β = 2.89; 95%CI = 0.83, 4.96; p 0.008), and median age (β = 2.83; 95%CI = 0.76, 4.89; p 0.009). The COVID-19 test rate (β = –3.54; 95%CI = –5.60, –1.47; p 0.002), hospital bed density (β = –2.47; 95%CI = –4.54, –0.41; p 0.021), and rural population ratio (β = –2.19; 95%CI = –4.25, –0.13; p 0.039) decreased the CFR. Conclusions: the pandemic hits population-dense cities. Available hospital beds should be increased. Test capacity should be increased to enable more effective diagnostic tests. Older patients and patients with obesity and their caregivers should be warned about a potentially increased risk.Publication Open Access The seroprevalence of SARS-CoV-2 antibodies among health care workers before the era of vaccination: a systematic review and meta-analysis(Elsevier, 2021) Arribas, Jose Ramon; Pshenichnaya, Natalia; Petrosillo, Nicola; Department of Industrial Engineering; Kayı, İlker; Keske, Şiran; Karanfil, Özge; Gönen, Mehmet; Ergönül, Önder; Faculty Member; Faculty Member; Faculty Member; Department of Industrial Engineering; Koç Üniversitesi İş Bankası Enfeksiyon Hastalıkları Uygulama ve Araştırma Merkezi (EHAM) / Koç University İşbank Center for Infectious Diseases (KU-IS CID); School of Medicine; Graduate School of Health Sciences; College of Engineering; Koç University Hospital; 168599; N/A; 125555; 294019; 237468; 110398Background: the prevalence of SARS-CoV-2 infection among health care workers (HCWs) provides information about the spread of COVID-19 within health care facilities, and the risk groups. Objectives: We aimed to describe the rate of SARS-CoV-2 seroprevalence and its determinants among HCWs. Data sources: we used Web of Science, PubMed, Scopus, MEDLINE, EBSCOhost and Cochrane Library. Study eligibility criteria: we included the reports of SARS-CoV-2 seroprevalence with a sample size of minimum 1000 HCWs. Methods: the study was registered at the International Prospective Register of Systematic Reviews (PROSPERO, no. CRD42021230456). We used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The keywords were “COVID-19”, “SARS-CoV-2”, “Coronavirus”, “seroprevalence”, “health care workers” and “risk factors”. Results: in total 4329 reports were retrieved, duplications were removed; after filtering according to the title and abstract, 25 studies were selected. Risk of bias was assessed in 25 studies; it was low in 13 studies, medium in four studies, and high in eight studies. In meta-analysis using the random effect model, the weighted average of seroprevalence was calculated as 8% (95% CI 6–10%). The pooled seroprevalence rates of the selected variables that have a rate above the average were male HCWs with 9% (95% CI 7–11%); HCWs from ethnic minorities with 13% (95% CI 9–17%); high exposure 9% (95% CI 6–13%); exposure to the virus outside the health care setting 22% (95% CI 14–32%). Conclusions: our analysis indicates a SARS-CoV-2 seroprevalence rate of 8% among studies that included >1000 HCWs for the year 2020, before vaccinations started. The most common risk factors associated with higher seroprevalence rate were ethnicity, male gender and having a higher number of household contacts. Working as a frontline HCW was inconsistent in its association with higher seroprevalence.
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