A. James Clark School of Engineering

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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.

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Author: search.filters.author.Markovic, Nikola

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    Nuclear envelope laminopathies: evidence for developmentally inappropriate chromatin-nuclear envelope interactions
    (Springer Nature, 2013-03-18) Perovanovic, Jelena; Jaiswal, Jyoti; Markovic, Nikola; Hoffman, Eric
    During terminal differentiation of cells, there is typically a transition of the nuclear envelope from the Lamin B protein to Lamin A/C proteins. This is commensurate with exit from the cell cycle, and maintenance of the transcriptional programs associated with the terminally differentiated cells. Dominant missense mutations in Lamin A/C cause a broad spectrum of human genetic disorders, where specific point mutations are associated with defects in specific organs or tissues. We have previously presented a model where Lamin A/C mutations disrupt developmentally appropriate interactions between chromatin and the nuclear envelope and lead to poor coordination of E2F cell cycle pathways and terminal differentiation pathways [1]. One of the phenotypes caused by Lamin A/C mutations is Emery Dreifuss Muscular Dystrophy (EDMD). An X-linked recessive phenocopy of EDMD is caused by loss of function of emerin – a binding partner to Lamin A/C at the nuclear envelope. Here, we tested the hypothesis that emerin plays a role in chromatin remodeling via stabilizing nuclear lamina-heterochromatin interactions necessary for appropriate and time dependent muscle differentiation. We used WT and emerin null mouse myogenic stem cells to study transcriptional and epigenetic changes during in vitro exit from the cell cycle and differentiation to the myogenic lineage. Specific cell cycle (E2F) and myogenic genes were analyzed by qPCR and ChlP-qPCR to determine mRNA timing and H3K9me3 enrichment on gene promoters. Nuclear lamina-chromatin colocalization was determined and quantified by confocal imaging and Matlab. Our results showed that TK1 and other cell cycle genes are inappropriately persistently expressed in emerin null cells during differentiation causing delayed exit from cell cycle. Transcripts marking commitment to the myogenic lineage (myogenin and Mef5A) showed delayed activation on both mRNA and protein level. Epigenetic imprints predicted observed deviations from transcriptional timing in emerin null cells, with persistent suppressive chromatin state on myog promoter upon myogenic induction and failure to appropriately establish repressive histone marks (H3K9me3) on Tk1 promoter (cell cycle). Finally, we showed that the early cell cycle exit and terminal differentiation of emerin null myoblasts were accompanied by decreased H3K9me3 staining at the nuclear periphery (lamin A/C immunostaining). Myogenic cells lacking emerin exhibit perturbations in terminal commitment to the myogenic lineage. Our transcriptional, chromatin remodeling and gene promoter accessibility data show that both exit from cell cycle and terminal commitment to myogenesis are disrupted due to inappropriate heterochromatin-nuclear lamina interactions in EMD myogenic cells.
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    Evasive Flow Capture
    (2013) Markovic, Nikola; Schonfeld, Paul; Civil Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The flow-capturing location-allocation problem (FCLAP) consists of locating facilities in order to maximize the number of flow-based customers that encounter at least one of these facilities along their predetermined travel paths. In FCLAP, it is assumed that if a facility is located along (or "close enough"' to) a predetermined path of a flow, the flow of customers is considered captured. However, existing models for FCLAP do not consider the likelihood that targeted users may exhibit non-cooperative behavior by changing their travel paths to avoid fixed facilities. Examples of facilities that targeted subjects may have an incentive to avoid include weigh-in-motion stations used to detect and fine overweight trucks, tollbooths, and security and safety checkpoints. The location of these facilities cannot be adequately determined with the existing flow-capturing models. This dissertation contributes to the literature on facility location by introducing a new type of flow capturing framework, called the "Evasive Flow Capturing Problem" (EFCP), in which targeted flows exhibit non-cooperative behavior by trying to avoid the facilities. The EFCP proposed herein generalizes the FCLAP and has relevant applications in transportation, revenue management, and security and safety management. This work formulates several variants of EFCP. In particular, three optimization models, deterministic, two-stage stochastic, and multi-stage stochastic, are developed to allocate facilities given different availability of information and planning policies. Several properties are proved and exploited to make the models computationally tractable. These results are crucial for solving optimally the instances of EFCP that include real-world road networks, which is demonstrated on case studies of Nevada and Vermont.
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    Scheduling under uncertainty for a Single-Hub Intermodal Freight System
    (2010) Markovic, Nikola; Schonfeld, Paul; Civil Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    This thesis addresses the optimization of an intermodal system with freight transfers at a single hub. It investigates the transportation processes and constraints that arise in a system's recovery after a major disruption during which backlogs have accumulated along the routes. When dealing with the backlogs, the system operator must coordinate the transportation processes and control the inflow of freight to the terminal in order to avoid overloading its storage facilities, which might reduce the throughput of the system. The coordination of transportation processes during the system's recovery can further improve the overall system performance by reducing the dwell time, increasing vehicle utilization and reducing late delivery penalties. This work focuses on the scheduling problem and develops an approach that would help the system operator reduce the overall system cost while taking into account the constraints arising in actual intermodal and intra-modal systems. Assuming that the schedule on some routes is exogenously determined and inflexible, we seek to optimize the schedules of vehicles on remaining routes. Models are developed that minimize the total cost of operating an intermodal system with freight transfers at one hub by optimizing the departure times of vehicles on the routes with flexible schedules. This model can be solved numerically without the approximations of alternative methods such as simulation. Moreover, it can be successfully applied to situations when statistical or queuing analyses are not applicable due to the small number of events (vehicle arrivals). We specifically analyze an intermodal system consisting of multiple feeder truck routes and multiple main airline routes. The specific example of two transportation modes was used to make the development and application of the model easier to understand. However, the mathematical model developed in this thesis is applicable to any other combination of transportation modes using discrete vehicles.