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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6

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    PublicationOpen 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; 40319
    Cryptochromes 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.
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    PublicationOpen 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 Medicine
    Motivation: 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.
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    PublicationOpen Access
    Modeling and analysis of an auction-based logistics market
    (Elsevier, 2008) Ağralı, Semra; Department of Business Administration; Department of Industrial Engineering; Tan, Barış; Karaesmen, Fikri; Faculty Member; Faculty Member; Department of Business Administration; Department of Industrial Engineering; College of Administrative Sciences and Economics; College of Engineering; 28600; 3579
    We consider a logistics spot market where the transportation orders from a number of firms are matched with two types of carriers through a reverse auction. In the spot market, local carriers compete with in-transit carriers that have lower costs. In order to analyze the effects of implementing a logistics spot market on these three parties: firms, local carriers, and in-transit carriers and also the effects of various system parameters, we develop a two-stage stochastic model. We first model the auction in a static setting and determine the expected auction price based on the number of carriers engaging in the auction and their cost distributions. We then develop a continuous-time Markov chain model to evaluate the performance of the system in a dynamic setting with random arrivals and possible abandonment of orders and carriers. By combining these two models, we evaluate the performance measures such as the expected auction price, price paid to the carriers, distribution of orders between local and in-transit carriers, and expected number of carriers and orders waiting at the logistics center in the long run. We present analytical and computational results related to the performance of the system and discuss operation of such a logistics spot market in Turkey.
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    PublicationOpen 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; 110398
    We 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.
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    PublicationOpen Access
    Design of balanced energy savings performance contracts
    (Taylor _ Francis, 2020) Department of Business Administration; Department of Industrial Engineering; Tan, Barış; Faculty Member; Department of Business Administration; Department of Industrial Engineering; College of Administrative Sciences and Economics; College of Engineering; 28600
    Energy savings performance contracts between the energy users and the energy service companies (ESCO) are used to finance energy efficiency investments by using the future energy savings that will result from these investments. We present an analytical model to characterise the energy savings performance contracts and discuss how the risks of estimating the energy savings affect the energy user and the service provider. This characterisation allows determination of the contract parameters for a balanced contract with the information about the energy savings that are expected from the planned energy-efficiency investments. Since it is difficult to get the statistical information about the energy savings before investing in an energy-efficiency project, we develop a distribution-free contract that sets the guaranteed energy savings level based on the mean and the standard deviation of the energy savings and the profit-sharing ratio between the ESCO and the energy user. We show that a simple distribution-free balanced contract performs satisfactorily when the distribution of the energy savings is not known and its mean and the standard deviation are estimated with error. Our analytical results show that the energy savings contracts with the right parameters can mitigate the risks related to realisation of the anticipated energy savings.
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    PublicationOpen Access
    A multi-criteria decision analysis to include environmental, social, and cultural issues in the sustainable aggregate production plans
    (Elsevier, 2019) Department of Industrial Engineering; Türkay, Metin; Rasmi, Seyyed Amir Babak; Kazan, Cem; Faculty Member; PhD Student; Department of Industrial Engineering; Graduate School of Sciences and Engineering; 24956; N/A; N/A
    Aggregate production planning (APP) that is an important concept of supply chain management (SCM), is one of the tools to determine production rates, inventory levels, and workforce requirements for fulfilling customer demands in a multi-period setting. Traditional APP models employ a single objective function to optimize monetary issues only. In this paper, we present a multi-objective APP model to analyze economic, social, environmental, and cultural pillars inclusively; moreover, each pillar includes several sub-pillars in the model. The resulting model includes an accurate representation of the problem with binary and continuous variables under sustainability considerations. We illustrate the effectiveness of the model in an appliance manufacturer and solve the problem using an exact solution method for multi-objective mixed-integer linear programs (MOMILP). We find a large number of the non-dominated (ND) points in the objective function space and analyze their trade-offs systematically. We show how this framework supports multiple criteria decision making process in the APP problems in the presence of sustainability considerations. Our approach provides a comprehensive analysis of the ND points of sustainable APP (SAPP) problems, and hence, the trade-offs of objective functions are insightful to the decision makers.
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    PublicationOpen Access
    Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
    (Nature Publishing Group (NPG), 2019) Menden, Michael P.; Wang, Dennis; Mason, Mike J.; Szalai, Bence; Bulusu, Krishna C.; Guan, Yuanfang; Yu, Thomas; Kang, Jaewoo; Jeon, Minji; Wolfinger, Russ; Nguyen, Tin; Zaslavskiy, Mikhail; Jang, In Sock; Ghazoui, Zara; Ahsen, Mehmet Eren; Vogel, Robert; Neto, Elias Chaibub; Norman, Thea; Tang, Eric K. Y.; Garnett, Mathew J.; Di Veroli, Giovanni Y.; Fawell, Stephen; Stolovitzky, Gustavo; Guinney, Justin; Dry, Jonathan R.; Saez-Rodriguez, Julio; Abante, Jordi; Abecassis, Barbara Schmitz; Aben, Nanne; Aghamirzaie, Delasa; Aittokallio, Tero; Akhtari, Farida S.; Al-lazikani, Bissan; Alam, Tanvir; Allam, Amin; Allen, Chad; de Almeida, Mariana Pelicano; Altarawy, Doaa; Alves, Vinicius; Amadoz, Alicia; Anchang, Benedict; Antolin, Albert A.; Ash, Jeremy R.; Romeo Aznar, Victoria; Ba-alawi, Wail; Bagheri, Moeen; Bajic, Vladimir; Ball, Gordon; Ballester, Pedro J.; Baptista, Delora; Bare, Christopher; Bateson, Mathilde; Bender, Andreas; Bertrand, Denis; Wijayawardena, Bhagya; Boroevich, Keith A.; Bosdriesz, Evert; Bougouffa, Salim; Bounova, Gergana; Brouwer, Thomas; Bryant, Barbara; Calaza, Manuel; Calderone, Alberto; Calza, Stefano; Capuzzi, Stephen; Carbonell-Caballero, Jose; Carlin, Daniel; Carter, Hannah; Castagnoli, Luisa; Celebi, Remzi; Cesareni, Gianni; Chang, Hyeokyoon; Chen, Guocai; Chen, Haoran; Chen, Huiyuan; Cheng, Lijun; Chernomoretz, Ariel; Chicco, Davide; Cho, Kwang-Hyun; Cho, Sunghwan; Choi, Daeseon; Choi, Jaejoon; Choi, Kwanghun; Choi, Minsoo; De Cock, Martine; Coker, Elizabeth; Cortes-Ciriano, Isidro; Cserzo, Miklos; Cubuk, Cankut; Curtis, Christina; Van Daele, Dries; Dang, Cuong C.; Dijkstra, Tjeerd; Dopazo, Joaquin; Draghici, Sorin; Drosou, Anastasios; Dumontier, Michel; Ehrhart, Friederike; Eid, Fatma-Elzahraa; ElHefnawi, Mahmoud; Elmarakeby, Haitham; van Engelen, Bo; Engin, Hatice Billur; de Esch, Iwan; Evelo, Chris; Falcao, Andre O.; Farag, Sherif; Fernandez-Lozano, Carlos; Fisch, Kathleen; Flobak, Asmund; Fornari, Chiara; Foroushani, Amir B. K.; Fotso, Donatien Chedom; Fourches, Denis; Friend, Stephen; Frigessi, Arnoldo; Gao, Feng; Gao, Xiaoting; Gerold, Jeffrey M.; Gestraud, Pierre; Ghosh, Samik; Gillberg, Jussi; Godoy-Lorite, Antonia; Godynyuk, Lizzy; Godzik, Adam; Goldenberg, Anna; Gomez-Cabrero, David; de Graaf, Chris; Gray, Harry; Grechkin, Maxim; Guimera, Roger; Guney, Emre; Haibe-Kains, Benjamin; Han, Younghyun; Hase, Takeshi; He, Di; He, Liye; Heath, Lenwood S.; Hellton, Kristoffer H.; Helmer-Citterich, Manuela; Hidalgo, Marta R.; Hidru, Daniel; Hill, Steven M.; Hochreiter, Sepp; Hong, Seungpyo; Hovig, Eivind; Hsueh, Ya-Chih; Hu, Zhiyuan; Huang, Justin K.; Huang, R. Stephanie; Hunyady, Laszlo; Hwang, Jinseub; Hwang, Tae Hyun; Hwang, Woochang; Hwang, Yongdeuk; Isayev, Olexandr; Walk, Oliver Bear Don't; Jack, John; Jahandideh, Samad; Ji, Jiadong; Jo, Yousang; Kamola, Piotr J.; Kanev, Georgi K.; Karacosta, Loukia; Karimi, Mostafa; Kaski, Samuel; Kazanov, Marat; Khamis, Abdullah M.; Khan, Suleiman Ali; Kiani, Narsis A.; Kim, Allen; Kim, Jinhan; Kim, Juntae; Kim, Kiseong; Kim, Kyung; Kim, Sunkyu; Kim, Yongsoo; Kim, Yunseong; Kirk, Paul D. W.; Kitano, Hiroaki; Klambauer, Gunter; Knowles, David; Ko, Melissa; Kohn-Luque, Alvaro; Kooistra, Albert J.; Kuenemann, Melaine A.; Kuiper, Martin; Kurz, Christoph; Kwon, Mijin; van Laarhoven, Twan; Laegreid, Astrid; Lederer, Simone; Lee, Heewon; Lee, Jeon; Lee, Yun Woo; Leppaho, Eemeli; Lewis, Richard; Li, Jing; Li, Lang; Liley, James; Lim, Weng Khong; Lin, Chieh; Liu, Yiyi; Lopez, Yosvany; Low, Joshua; Lysenko, Artem; Machado, Daniel; Madhukar, Neel; De Maeyer, Dries; Malpartida, Ana Belen; Mamitsuka, Hiroshi; Marabita, Francesco; Marchal, Kathleen; Marttinen, Pekka; Mason, Daniel; Mazaheri, Alireza; Mehmood, Arfa; Mehreen, Ali; Michaut, Magali; Miller, Ryan A.; Mitsopoulos, Costas; Modos, Dezso; Van Moerbeke, Marijke; Moo, Keagan; Motsinger-Reif, Alison; Movva, Rajiv; Muraru, Sebastian; Muratov, Eugene; Mushthofa, Mushthofa; Nagarajan, Niranjan; Nakken, Sigve; Nath, Aritro; Neuvial, Pierre; Newton, Richard; Ning, Zheng; De Niz, Carlos; Oliva, Baldo; Olsen, Catharina; Palmeri, Antonio; Panesar, Bhawan; Papadopoulos, Stavros; Park, Jaesub; Park, Seonyeong; Park, Sungjoon; Pawitan, Yudi; Peluso, Daniele; Pendyala, Sriram; Peng, Jian; Perfetto, Livia; Pirro, Stefano; Plevritis, Sylvia; Politi, Regina; Poon, Hoifung; Porta, Eduard; Prellner, Isak; Preuer, Kristina; Angel Pujana, Miguel; Ramnarine, Ricardo; Reid, John E.; Reyal, Fabien; Richardson, Sylvia; Ricketts, Camir; Rieswijk, Linda; Rocha, Miguel; Rodriguez-Gonzalvez, Carmen; Roell, Kyle; Rotroff, Daniel; de Ruiter, Julian R.; Rukawa, Ploy; Sadacca, Benjamin; Safikhani, Zhaleh; Safitri, Fita; Sales-Pardo, Marta; Sauer, Sebastian; Schlichting, Moritz; Seoane, Jose A.; Serra, Jordi; Shang, Ming-Mei; Sharma, Alok; Sharma, Hari; Shen, Yang; Shiga, Motoki; Shin, Moonshik; Shkedy, Ziv; Shopsowitz, Kevin; Sinai, Sam; Skola, Dylan; Smirnov, Petr; Soerensen, Izel Fourie; Soerensen, Peter; Song, Je-Hoon; Song, Sang Ok; Soufan, Othman; Spitzmueller, Andreas; Steipe, Boris; Suphavilai, Chayaporn; Tamayo, Sergio Pulido; Tamborero, David; Tang, Jing; Tanoli, Zia-ur-Rehman; Tarres-Deulofeu, Marc; Tegner, Jesper; Thommesen, Liv; Tonekaboni, Seyed Ali Madani; Tran, Hong; De Troyer, Ewoud; Truong, Amy; Tsunoda, Tatsuhiko; Turu, Gabor; Tzeng, Guang-Yo; Verbeke, Lieven; Videla, Santiago; Vis, Daniel; Voronkov, Andrey; Votis, Konstantinos; Wang, Ashley; Wang, Hong-Qiang Horace; Wang, Po-Wei; Wang, Sheng; Wang, Wei; Wang, Xiaochen; Wang, Xin; Wennerberg, Krister; Wernisch, Lorenz; Wessels, Lodewyk; van Westen, Gerard J. P.; Westerman, Bart A.; White, Simon Richard; Willighagen, Egon; Wurdinger, Tom; Xie, Lei; Xie, Shuilian; Xu, Hua; Yadav, Bhagwan; Yau, Christopher; Yeerna, Huwate; Yin, Jia Wei; Yu, Michael; Yu, MinHwan; Yun, So Jeong; Zakharov, Alexey; Zamichos, Alexandros; Zanin, Massimiliano; Zeng, Li; Zenil, Hector; Zhang, Frederick; Zhang, Pengyue; Zhang, Wei; Zhao, Hongyu; Zhao, Lan; Zheng, Wenjin; Zoufir, Azedine; Zucknick, Manuela; Department of Industrial Engineering; Gönen, Mehmet; Faculty Member; Department of Industrial Engineering; College of Engineering; 237468
    The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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    PublicationOpen Access
    Routing multiple work teams to minimize latency in post-disaster road network restoration
    (Elsevier, 2021) Ajam, M.; Akbari V.; Department of Industrial Engineering; Salman, Fatma Sibel; Faculty Member; Department of Industrial Engineering; College of Engineering; 178838
    After a disaster, often roads are damaged and blocked, hindering accessibility for relief efforts. It is essential to dispatch work teams to restore the blocked roads by clearance or repair operations. With the goal of enabling access between critical locations in the disaster area in shortest time, we propose algorithms that determine the schedule and routes of multiple work teams. We minimize the total latency of reaching the critical locations, where the latency of a location is defined as the time it takes from the start of the operation until its first visit by one of the work teams. Coordination among the teams is needed since some blocked edges might be opened by a certain team and utilized by other teams later on. First, we develop an exact mathematical model that handles the coordination requirement. After observing the intractability of this formulation, we introduce two heuristic methods and a lower bounding procedure. In the first method, we develop a mathematical model based on a novel multi-level network representation that yields solutions with disjoint paths. Given that it does not coordinate the teams, we present a matheuristic based on a cluster-first-route-second approach embedded into a local search algorithm together with an additional coordination step to obtain alternative solutions with higher quality and in a shorter time. We test our heuristics on data sets coming from a real network from the literature (180 instances) and randomly generated ones (640 instances) and observe the superiority of the solutions obtained by incorporation of coordination.
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    PublicationOpen 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; 237468
    Objectives: 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.
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    PublicationOpen Access
    Agricultural planning of annual plants under demand, maturation, harvest, and yield risk
    (Elsevier, 2012) Department of Industrial Engineering; Tan, Barış; Faculty Member; Department of Industrial Engineering; College of Engineering; College of Administrative Sciences and Economics; N/A; 28600
    In this study we present a planning methodology for a firm whose objective is to match the random supply of annual premium fruits and vegetables from a number of contracted farms and the random demand from the retailers during the planning period. The supply uncertainty is due to the uncertainty of the maturation time, harvest time, and yield. The demand uncertainty is the uncertainty of weekly demand from the retailers. We provide a planning methodology to determine the farm areas and the seeding times for annual plants that survive for only one growing season in such a way that the expected total profit is maximized. Both the single period and the multi period cases are analyzed depending on the type of the plant. The performance of the solution methodology is evaluated by using numerical experiments. These experiments show that the proposed methodology matches random supply and random demand in a very effective way and improves the expected profit substantially compared to the planning approaches where the uncertainties are not taken into consideration. (c) 2012 Elsevier B.V. All rights reserved.