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1
Golovin, Sergey. "Representation of replacement rules in the form of a matrix." Journal of Quality in Maintenance Engineering 22, no. 2 (May 9, 2016): 164–79. http://dx.doi.org/10.1108/jqme-06-2015-0022.
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Purpose – The purpose of this paper is to represent replacement policies (rules) in the form of a matrix. Visualization of replacement rules is useful for maintenance records. Matrix representation is more effective than the verbal description usually provided, as it allows better understanding of the specifics of the different replacement rules without careful research of their mathematical models. Design/methodology/approach – This approach employs mathematical models to investigate the simple conditions (requirements) for replacement of system component with illustrative examples. When comparing the different replacement rules a cost structure is applied to takes into account the nature and technology of disassembly assembly actions for the repair unit. Findings – Representation of replacement rules in the matrix form is useful when describing planned replacement models, opportunity replacement models, group replacement models and others, as well as computer modeling of the renewal process. Forming simple conditions for the replacement of system components ensures the total average repair cost is minimized. These conditions can be applied in the early stages of creating a maintenance program for the machine. Practical implications – Replacement matrices can be specified in a technical manual for maintenance of machines to achieve reliable operation and to reduce repair costs. Replacement matrices can be put into practical use for maintenance records and may be included in the maintenance procedures library of CMMSs. Developed in the paper, the replacement matrix, the conditions for replacement of system components and the cost structure will help engineers to make decisions at the time of repair for assembly units. Originality/value – Proposed in the paper is a new approach to the visualization of the replacement rules and cost structure which simplifies the analysis of options for repair actions. The proposed technique contributes to the record of maintenance actions and the decision making process for replacement.
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Cardeal, Gonçalo, Kristina Höse, Inês Ribeiro, and Uwe Götze. "Sustainable Business Models–Canvas for Sustainability, Evaluation Method, and Their Application to Additive Manufacturing in Aircraft Maintenance." Sustainability 12, no. 21 (November 3, 2020): 9130. http://dx.doi.org/10.3390/su12219130.
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The topic of sustainable business models is growing in literature and in the industry, driving companies to search for opportunities to improve their impact on the three pillars of sustainability—profit, people, and planet (economic, social, and environmental). However, the process of developing sustainable business models is often complex, due to conflicting objectives from the three dimensions of sustainability. This paper presents a procedure model that supports the design and assessment of business models with a sustainable perspective, by integrating a new business model canvas for sustainability (BMCS) and an evaluation method to assess it. A comprehensive assessment is proposed, performed in a life cycle perspective. The proposed model is applied and validated with a real case study, based on a new business model for an aircraft maintenance, repair, and overhaul company. The case is based on shifting from traditional maintenance, repair, and overhaul activities to adopting additive manufacturing as an activity that allows manufacturing optimized spare parts with benefits for the costumer. The results show the application of the procedure model on a specific case study, as well as the potential of additive manufacturing as a driver for more sustainable business models in the aircraft maintenance sector.
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Capodieci, Antonio, Antonio Caricato, Antonio Paolo Carlucci, Antonio Ficarella, Luca Mainetti, and Cristian Vergallo. "Using different machine learning approaches to evaluate performance on spare parts request for aircraft engines." E3S Web of Conferences 197 (2020): 11014. http://dx.doi.org/10.1051/e3sconf/202019711014.
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The Aircraft uptime is getting increasingly important as the transport solutions become more complex and the transport industry seeks new ways of being competitive. To reach this objective, traditional Fleet Management systems are gradually extended with new features to improve reliability and then provide better maintenance planning. Main goal of this work is the development of iterative algorithms based on Artificial Intelligence to define the engine removal plan and its maintenance work, optimizing engine availability at the customer and maintenance costs, as well as obtaining a procurement plan of integrated parts with planning of interventions and implementation of a maintenance strategy. In order to reach this goal, Machine Learning has been applied on a workshop dataset with the aim to optimize warehouse spare parts number, costs and lead-time. This dataset consists of the repair history of a specific engine type, from several years and several fleets, and contains information like repair claim, engine working time, forensic evidences and general information about processed spare parts. Using these data as input, several Machine Learning models have been built in order to predict the repair state of each spare part for a better warehouse handling. A multi-label classification approach has been used in order to build and train, for each spare part, a Machine Learning model that predicts the part repair state as a multiclass classifier does. Mainly, each classifier is requested to predict the repair state (classified as “Efficient”, “Repaired” or “Replaced”) of the corresponding part, starting from two variables: the repairing claim and the engine working time. Then, global results have been evaluated using the Confusion Matrix, from which Accuracy, Precision, Recall and F1-Score metrics are retrieved, in order to analyse the cost of incorrect prediction. These metrics are calculated for each spare part related model on test sets and, then, a final single performance value is obtained by averaging results. In this way, three Machine Learning models (Naïve Bayes, Logistic Regression and Random Forest classifiers) are applied and results are compared. Naïve Bayes and Logistic Regression, that are fully probabilistic methods, have best global performances with an accuracy value of almost 80%, making the models being correct most of the times.
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Romanov, Vladimir S., and Valery G. Goldshtein. "To the question of damage, maintenance and repairs of submersible electric equipment for oil production." Vestnik of Samara State Technical University. Technical Sciences Series 28, no. 2 (July 27, 2020): 111–23. http://dx.doi.org/10.14498/tech.2020.2.8.
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In optimizing and managing the life cycles of submersible electrical equipment (SEE) for oil production, an integrated approach to the organization of maintenance and repairs (MRO) is advisable based on the development of a more advanced strategy for carrying out repair cycles. It is stated that the maintenance and repair strategies adopted by the oil industry do not fully ensure operational efficiency, which leads to an increase in premature equipment failures, a reduction in turnaround times and, as a result, losses for oil companies. The advantages and disadvantages of approaches to organizing the operation of SEE on the operating time and the actual state in the planning, implementation of maintenance and repair, as well as the feasibility of their complex application are evaluated. It is proposed to use statistical models to make an informed decision on determining the composition and period of MRO, forecasting the boundary states of sets in general and specific SEE electrical installations. At a given operating time, it is possible to determine the basic laws of the appearance of defects and the mean time between failures (MTBF) of the elements, as well as the fleet of equipment of oil-producing enterprises as a whole. The results obtained are the rationale for a set of recommendations to improve operational efficiency and optimize life cycle management of submersible electrical equipment for oil production.
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Islam, Md Shafiqul, Shayla Sharmin, and Jebunnesa Islam. "Multiple repair scenario of life cycle cost of RCC girder bridge using Markov chain model." Challenge Journal of Concrete Research Letters 10, no. 4 (December 21, 2019): 75. http://dx.doi.org/10.20528/cjcrl.2019.04.001.
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At present, many road authorities in the world face challenges in condition monitoring diagnosis of distress and forecasting deterioration, strengthening and convalescence of aging bridge structures. The accurate prediction of the future condition is crucial for optimizing the maintenance activities. It is very tough to predict the actual performance scenario or actual in–situ structures without carrying out inspection. Limited availability of detailed inspection data is considered as one of the major drawbacks in developing deterioration models. In State Based Markov deterioration (SNMD) modelling, the main job is to estimate transition probability matrixes (TPMs). In this paper, Markov Chain Monte Carlo (MCMC) is used to estimate TPMs. In Markov Chain Model, future conditions depend on only present bridge inspection data. Multiple repair options are adopted in order to optimize life cycle cost. Repairs are needed when the critical chloride concentration exceeds 0.2. Three distinct types of cost corresponding to each repair option is considered. The objective of this paper is to minimize the life cycle cost considering appropriate repair timings of mixed repair methods. Variation of life cycle cost of five different concretes (stronger to weaker) using three different repair option is shown in this paper. For specific normalized condition of concrete’s failure probability (0.3) and specific type of concrete, variation of life cycle cost using multiple repair options is also shown in this paper.
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Tomasova, Kristyna, Michal Kroupa, Asta Forsti, Pavel Vodicka, and Ludmila Vodickova. "Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer." Mutagenesis 35, no. 3 (February 21, 2020): 261–71. http://dx.doi.org/10.1093/mutage/geaa005.
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Abstract Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.
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Prizeman, Oriel. "Maintenance of shared spaces: courtyards of Tbilisi." Journal of Cultural Heritage Management and Sustainable Development 6, no. 3 (November 21, 2016): 316–29. http://dx.doi.org/10.1108/jchmsd-11-2015-0043.
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Purpose The courtyard dwellings of Tbilisi form a critical part of the city’s architectural identity. However, the multiple occupation of these buildings is blamed for confounding their prospects for repair and consequent valorisation as a World Heritage Site. Models for the shared ownership of residential blocks have been adapted globally. Some have established communal sources for rehabilitation and maintenance applicable to historic buildings. The purpose of this paper is to assess the relevance of such precedents to the complex and urgent context of Tbilisi’s threatened architectural heritage. Design/methodology/approach The paper uses existing literature and data to establish a hypothesis in support of adopting a collaborative approach for the maintenance and rehabilitation of shared buildings in a challenging and specific context. Using socio-economic data to characterise the occupants of such buildings and current critical sources, the paper investigates how existing collective communities can be empowered to capitalise from their unique social frameworks. Findings It finds evidence to support theoretical claims that there is scope for co-operative networks to flourish there. Research limitations/implications The paper is limited to a desktop analysis and relies upon available data and literature to draw its conclusions. Originality/value This paper addresses a critical problem in the formulation of conservation plans for Old Tbilisi, it tests the relevance of global exemplars for community repair programmes by reference to existing data for the care of the predominantly domestic architecture of Old Tbilisi at a time of rapid change.
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Ovchar, R. F. "Analysis of effectiveness of process operational and technological reliability of agricultural mashines." Naukovij žurnal «Tehnìka ta energetika» 11, no. 4 (September 10, 2020): 143–52. http://dx.doi.org/10.31548/machenergy2020.04.143.
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The analysis suggests that to solve the contradiction between the need of ensuring the required level of serviceability of combine harvesters and capabilities of existing system and repair management of the technical state of combine harvesters at the present stage, there is a need to improve the subsystem recovery combine harvesters subject to the requirements of readiness to perform tasks on purpose and financial capacity for its maintenance. Analysis of scientific literature showed that today the unsolved problem of search and introduction of effective methods and repair combine harvesters are: development of mathematical models of the process and repair, which would allow comparative assessment of technical and economic efficiency of different modes, and repair objects combine harvesters, alternative strategies for their repair, with the aim of improving the quality of control of technical condition of the vessel in conditions of limited funding. Consideration of the process of technical maintenance of combine harvesters as a set of stages and repair objects combine harvesters allows to identify possible directions of improving the system restore. The analysis allowed to determine four basic options for its organization and to make a qualitative assessment of the benefits and disadvantages of each of these options. Reduced operating costs in the operation of combine harvesters, along with other measures of organizational and technical nature require greater automation of control of technical condition. Automation of technical state control of combine harvesters developed in the following areas: embedded systems control, on-board automated control systems, specialized control systems and universal control systems dismantled equipment. A large share of false failures in equipment, violation of industrial relations in the repair network on-board equipment, the shortage of maintenance fund requires implementation and operation. Most fully able to examine the efficiency of the process of operation of complex technical systems using analytical models. Existing approaches to the assessment of the recovery system can be classified also according to the used indicators of effectiveness: the number of constructive variables of units that are replaced (restored) for a predetermined period of operation of the control object, repair cost of the constituent elements of the functional system for a specific period at different depths of the control and completeness of the recovery, the downtime of the test object within a certain period, for comprehensive reliability, such as coefficient of readiness, coefficient of technical use.
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Amadei, Bernard. "Agent-Based and System Dynamics Modeling of Water Field Services." Challenges 11, no. 2 (July 20, 2020): 13. http://dx.doi.org/10.3390/challe11020013.
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This paper explores the applicability of the agent-based (AB) and system dynamics (SD) methods to model a case study of the management of water field services. Water borehole sites are distributed over an area and serve the water needs of a population. The equipment at all borehole sites is managed by a single water utility that has adopted specific repair, replacement, and maintenance rules and policies. The water utility employs several service crews initially stationed at a single central location. The crews respond to specific operation and maintenance requests. Two software modeling tools (AnyLogic and STELLA) are used to explore the benefits and limitations of the AB and SD methods to simulate the dynamic being considered. The strength of the AB method resides in its ability to capture in a disaggregated way the mobility of the individual service crews and the performance of the equipment (working, repaired, replaced, or maintained) at each borehole site. The SD method cannot capture the service crew dynamics explicitly and can only model the average state of the equipment at the borehole sites. Their differences aside, both methods offer policymakers the opportunity to make strategic, tactical, and logistical decisions supported by integrated computational models.
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Ninou, Anna Huguet, Jemina Lehto, Dimitrios Chioureas, Hannah Stigsdotter, Korbinian Schelzig, Emma Åkerlund, Greta Gudoityte, et al. "PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair." Cancers 13, no. 14 (July 18, 2021): 3604. http://dx.doi.org/10.3390/cancers13143604.
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Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments.
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Dickson, Kristie-Ann, Tao Xie, Christian Evenhuis, Yue Ma, and Deborah J. Marsh. "PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer." International Journal of Molecular Sciences 22, no. 16 (August 7, 2021): 8506. http://dx.doi.org/10.3390/ijms22168506.
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Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.
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Hafez, Marwan, Khaled Ksaibati, and Rebecca A. Atadero. "Applying Large-Scale Optimization to Evaluate Pavement Maintenance Alternatives for Low-Volume Roads using Genetic Algorithms." Transportation Research Record: Journal of the Transportation Research Board 2672, no. 52 (June 11, 2018): 205–15. http://dx.doi.org/10.1177/0361198118781147.
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Over the last decade, significant progress has been made to customize the maintenance policies of low-volume roads (LVRs) to local needs and available resources. Low-cost treatments and surface repairs are extensively employed to reduce annual maintenance costs. Colorado Department of Transportation (CDOT) uses chip seals and thin overlays as the available treatment options applied to LVRs. However, the effectiveness of these treatments differs depending on the existing condition of pavements. Some surface treatments and light rehabilitations provide only short-term effectiveness. Multi-year optimization techniques can support decision makers with a set of optimal maintenance activities to achieve specific pavement performance targets. This study applies large-scale optimization to compare the current CDOT maintenance policy with an alternative strategy recommended for low-volume paved roads in Colorado. Genetic algorithms were applied in the optimization models because they are capable of resolving the computational complexity of optimization problems in a timely fashion. The optimized maintenance alternatives were comprehensively investigated for a LVR network in Colorado over a specific planning horizon. The specific optimization constraints and limitations prevailing in LVRs are addressed and introduced in the problem formulation of the optimization process. The results of both performance and cost analysis emphasize the effectiveness of the proposed maintenance strategy compared with the existing one. The alternative policy provides much more benefit-cost saving while preserving the overall pavement performance of the network. This approach is expected to be efficient to quantify the mid- and long-term financial impact of different treatment policies applied to LVRs within modest resources.
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dos Santos, Luís Gustavo. "EMBRAER Perspective on the Challenges for the Introduction of Scheduled SHM (S-SHM) Applications into Commercial Aviation Maintenance Programs." Key Engineering Materials 558 (June 2013): 323–30. http://dx.doi.org/10.4028/www.scientific.net/kem.558.323.
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This paper presents an overview of the challenges an original equipment manufacturer (OEM) such EMBRAER may face to introduce scheduled structural health monitoring (S-SHM) applications in the maintenance programs of its commercial aviation aircraft models. S-SHM solutions have the potential to reduce aircraft operators direct maintenance costs and fleet downtime while keeping aircraft airworthiness at a minimum maintenance downtime and costs. As part of new approach in terms of scheduled maintenance practices, the replacement or complementation of traditional structural inspections tasks by new maintenance procedures taking credit of SHM technologies must be done in ways that meet the expectations and requirements of Regulatory Authorities, OEMs and airlines maintenance and engineering departments related to topics such as: safety, continued airworthiness, cost/benefits ratio, S-SHM systems built-in redundancies and reliability to support higher fleet availability, as well as necessary mechanics qualification. Besides the efforts for validation, verification, qualification and certification of such systems to deliver the expected effectiveness levels to verify structural integrity and withstanding the operational conditions to which it will be exposed, an OEM intended to offer their customers with the benefits of S-SHM solutions will be required initially to revise its policy and procedures handbooks (PPH) to adopt the new S-SHM Air Transport Associations Maintenance Steering Group 3 (MSG-3) Methodology guidelines. This will alter in different ways the current Maintenance Review Board processes conducted by each OEM to develop and revise the minimum scheduled maintenance program for a given commercial aircraft type certificate. The contents of the Maintenance Review Board Reports (MRB) will need to be revised in order to clearly indicate the scope and frequencies of each approved S-SHM task, and how they will replace, complement and/or be an alternative means of compliance of the more traditional maintenance tasks types such as general and detailed visual inspections (GVI and DET, respectively). Additionally, the Airplane Maintenance Manuals (AMM) will need to be revised to include specific S-SHM procedures on how to perform the intended inspection, how to proceed when degradation is detected in the monitored structures and how to repair such systems in case of failures.
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Xavier-Elsas, Pedro, Bruno M. Vieira, Daniela Masid-de-Brito, Monica G. Barradas, and Maria I. C. Gaspar-Elsas. "The Need to Consider Context in the Evaluation of Anti-infectious and Immunomodulatory Effects of Vitamin A and its Derivatives." Current Drug Targets 20, no. 8 (May 10, 2019): 871–78. http://dx.doi.org/10.2174/1389450120666181217095323.
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Vitamin A and its derivatives (retinoids) act as potent regulators in many aspects of mammalian reproduction, development, repair, and maintenance of differentiated tissue functioning. Unlike other vitamins, Vitamin A and retinoids, which have hormonal actions, present significant toxicity, which plays roles in clinically relevant situations, such as hypervitaminosis A and retinoic acid ("differentiation") syndrome. Although clinical presentation is conspicuous in states of insufficient or excessive Vitamin A and retinoid concentration, equally relevant effects on host resistance to specific infectious agents, and in the general maintenance of immune homeostasis, may go unnoticed, because their expression requires either pathogen exposure or the presence of inflammatory co-morbidities. There is a vast literature on the roles played by retinoids in the maintenance of a tolerogenic, noninflammatory environment in the gut mucosa, which is considered by many investigators representative of a general role played by retinoids as anti-inflammatory hormones elsewhere. However, in the gut mucosa itself, as well as in the bone marrow and inflammatory sites, context determines whether one observes an anti-inflammatory or proinflammatory action of retinoids. Both interactions between specialized cell populations, and interactions between retinoids and other classes of mediators/regulators, such as cytokines and glucocorticoid hormones, must be considered as important factors contributing to this overall context. We review evidence from recent studies on mucosal immunity, granulocyte biology and respiratory allergy models, highlighting the relevance of these variables as well as their possible contributions to the observed outcomes.
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Khoroshko, Leonid L., and Pavel M. Kuznetsov. "Digitalization of Agricultural Machinery Rehabilitation." Engineering Technologies and Systems 30, no. 4 (December 30, 2020): 711–22. http://dx.doi.org/10.15507/2658-4123.030.202004.711-722.
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Introduction. The aim of the study is to develop the basic principles for digitalization of the processes of providing the diagnostics and repair of agricultural machinery. Materials and Methods. The specifics of agricultural machinery functioning are work in worst-on-worst operating conditions, such as significant abrasive contamination (soil particles, dust and other substances), operation in the conditions of exposure to natural climatic conditions, intensive use during the work shift and other factors that result in a regular need for testing and repairing. These factors significantly extend the time of maintenance and repair works. The study of the information environment for planning the distribution of agricultural machinery by repair enterprises has showed that the methods of this activity are not sufficiently developed. The authors propose a solution to the problem of rational distribution of agricultural machinery for repair and rehabilitation. Results. This article describes the main principles for developing structural relationships of databases used to find rational solutions for organizing repair and rehabilitation of agricultural machinery. Due to the fact that the solution of such a problem is time-consuming and is carried out under conditions that dynamically change over time, a mathematical model for the production environment of repair organizations is proposed, which is implemented by means of computer technology. The requirements for models describing the state of the production system of repair organizations are defined. A model of a generalized production system is proposed. Discussion and Conclusion. The model developed by the authors allows increasing the automation level of processes of distributing agricultural machinery by repair enterprises. The implementation of a new approach to planning repair works and distributing repairable agricultural machinery by repair enterprises will increase the efficiency of repair works, improve their quality parameters, reduce time, and optimize the structure of technological equipment of repair enterprises.
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Saygin, Caner, Andrew Wiechert, Vinay S. Rao, Ravi Alluri, Elizabeth Connor, Praveena S. Thiagarajan, James S. Hale, et al. "CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors." Journal of Experimental Medicine 214, no. 9 (August 24, 2017): 2715–32. http://dx.doi.org/10.1084/jem.20170438.
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Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors.
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Magdalena, Juana, Thomas H. Millard, Sandrine Etienne-Manneville, Sophie Launay, Helen K. Warwick, and Laura M. Machesky. "Involvement of the Arp2/3 Complex and Scar2 in Golgi Polarity in Scratch Wound Models." Molecular Biology of the Cell 14, no. 2 (February 2003): 670–84. http://dx.doi.org/10.1091/mbc.e02-06-0345.
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Cell motility and cell polarity are essential for morphogenesis, immune system function, and tissue repair. Many animal cells move by crawling, and one main driving force for movement is derived from the coordinated assembly and disassembly of actin filaments. As tissue culture cells migrate to close a scratch wound, this directional extension is accompanied by Golgi apparatus reorientation, to face the leading wound edge, giving the motile cell inherent polarity aligned relative to the wound edge and to the direction of cell migration. Cellular proteins essential for actin polymerization downstream of Rho family GTPases include the Arp2/3 complex as an actin nucleator and members of the Wiskott–Aldrich Syndrome protein (WASP) family as activators of the Arp2/3 complex. We therefore analyzed the involvement of the Arp2/3 complex and WASP-family proteins in in vitro wound healing assays using NIH 3T3 fibroblasts and astrocytes. In NIH 3T3 cells, we found that actin and Arp2/3 complex contributed to cell polarity establishment. Moreover, overexpression of N-terminal fragments of Scar2 (but not N-WASP or Scar1 or Scar3) interfere with NIH 3T3 Golgi polarization but not with cell migration. In contrast, actin, Arp2/3, and WASP-family proteins did not appear to be involved in Golgi polarization in astrocytes. Our results thus indicate that the requirement for Golgi polarity establishment is cell-type specific. Furthermore, in NIH 3T3 cells, Scar2 and the Arp2/3 complex appear to be involved in the establishment and maintenance of Golgi polarity during directed migration.
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Henzi, Anna, Assunta Senatore, Asvin K. K. Lakkaraju, Claudia Scheckel, Jonas Mühle, Regina Reimann, Silvia Sorce, Gebhard Schertler, Klaus V. Toyka, and Adriano Aguzzi. "Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice." PLOS ONE 15, no. 11 (November 12, 2020): e0242137. http://dx.doi.org/10.1371/journal.pone.0242137.
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The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the early molecular signs demyelination was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.
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Burrow, Michael P. N., Jin Shi, Mohamed Wehbi, and Gurmel S. Ghataora. "Assessing the Damaging Effects of Railway Dynamic Wheel Loads on Railway Foundations." Transportation Research Record: Journal of the Transportation Research Board 2607, no. 1 (January 2017): 62–73. http://dx.doi.org/10.3141/2607-09.
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Dynamic train wheel loads, which can be significantly greater than static loads, occur because of a variety of factors and unless they are properly considered in track structural design, significant unplanned maintenance and premature track failure may result. This is particularly so for traditional ballasted railways built on soft foundations, because although ballast lends itself to maintenance, it is often problematic and costly to repair damaged foundations. A novel rigorous analytical–numerical approach is described to predict and characterize, for the first time, the damage to which railway foundations can be subjected as a result of dynamic loads. The approach marries a sophisticated three-dimensional dynamic model of the train–track system incorporating vertical track quality, foundation soil distress models, statistical analysis methods, and results of field investigation. The resulting analyses demonstrate that the magnitudes and distributions of dynamic loads are a function of train speed and track quality, and that specific locations experience significantly higher amounts of damage, which can lead to a variety of track faults. The approach is illustrated via a study of a heavy haul railway line in China where the wheel loads and tonnage carried are set to increase significantly. Findings from the study suggest that the thickness of the ballasted layer would need to increase by over 20% to prevent premature foundation failure provided that the track is maintained in good condition, and by significantly more should the track condition be allowed to deteriorate.
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VAZHYNSKYI, A., and S. ZHUKOV. "Methods and tools of ensuring the operational reliability of complex industrial facilities." Journal of Electrical and power engineering 14, no. 1 (February 27, 2020): 34–42. http://dx.doi.org/10.31474/2074-2630-2020-1-34-42.
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Approaches and algorithms for processing experimental data and data obtained as a result of using modern means of measuring equipment, selecting diagnostic parameters, pattern recognition, which constitute the methodological basis for developing methods and designing tools for creating a service system for complex industrial facilities based on predicting their performance and residual life are described in submitted article. Along with classical methods, methods based on using the full potential of the modern elemental base of microprocessor technology and the use of artificial neural networks, machine learning, and "big data" are discovered. The given examples can serve as the basis for constructing a methodology for the application of the considered approaches for organizing predictive maintenance of complex industrial equipment. An analytical review of a number of scientific publications showed that the creation of new automated diagnostic systems that can increase fault tolerance and extend the life of sophisticated modern power equipment is extremely relevant. For this, various approaches are applied, based on mathematical models, expert systems, artificial neural networks and other algorithms. Summarizing the results of scientific publications, it can be argued that the implementation of a systematic approach to the organization of repair service at the enterprise requires a comprehensive solution to the following urgent problems: • monitoring is formulated as the task of interrogating sensors and collecting information necessary for further analysis; • diagnostics, it is solved as tasks of identifying informative signs with further detection and classification of failures and anomalies in data sets; • improving the accuracy of algorithms aimed at pattern recognition; • condition forecasting is the task of assessing the current and accumulated readings of monitoring systems for making decisions regarding either a specific element of the complex or the facilities. Thus, modern technology make it possible to arrange arbitrarily complex algorithms. However, to use the full potential that artificial neural networks, expert systems, and classical methods for identifying and diagnosing equipment it is necessary to have a conceptual development of the foundations of building systems for organizing maintenance and repair of complex energy equipment
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Yang, Xifeng, Shihao Chen, Jiaxin Chen, Yunqi Liu, Ying Bai, Shengli Yin, and Daping Quan. "The Different Effect of Decellularized Myocardial Matrix Hydrogel and Decellularized Small Intestinal Submucosa Matrix Hydrogel on Cardiomyocytes and Ischemic Heart." Applied Sciences 11, no. 17 (August 24, 2021): 7768. http://dx.doi.org/10.3390/app11177768.
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Injectable decellularized matrix hydrogels derived from either myocardium or small intestinal submucosa (pDMYO-gel, pDSIS-gel) have been successfully used for myocardial injury repair. However, the relationship between tissue-specific biological functions and protein composition in these two materials is not clear yet. In this study, the protein composition, mechanical properties, and morphology of these two hydrogels and their effects on the behavior of neonatal rat cardiomyocytes (NRCMs) and human umbilical vein endothelial cells (HUVECs), are investigated. The results show that pDMYO-gel is more conducive to growth, adhesion, spreading, and maintenance of normal NRCM beating, due to its higher proportion of extracellular matrix (ECM) glycoproteins (49.55%) and some unique functional proteins such as annexin-6 (ANXA6), agrin (AGRN), cathepsin D (CTSD) and galectin-1 (LGALS1), whereas pDSIS-gel is more conducive to the proliferation of HUVECs. Animal study shows that pDMYO-gel has a better effect on improving cardiac function, inhibiting myocardial fibrosis and maintaining ventricular wall thickness in acute myocardial infarction models in vivo. Therefore, it is proposed that injectable pDMYO-gel hydrogel may be more suitable for functional recovery of myocardial injuries.
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Moll, Solange, Andrea Angeletti, Leonardo Scapozza, Andrea Cavalli, Gian Marco Ghiggeri, and Marco Prunotto. "Glomerular Macrophages in Human Auto- and Allo-Immune Nephritis." Cells 10, no. 3 (March 9, 2021): 603. http://dx.doi.org/10.3390/cells10030603.
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Macrophages are involved in tissue homeostasis. They participate in inflammatory episodes and are involved in tissue repair. Macrophages are characterized by a phenotypic heterogeneity and a profound cell plasticity. In the kidney, and more particularly within glomeruli, macrophages are thought to play a maintenance role that is potentially critical for preserving a normal glomerular structure. Literature on the glomerular macrophage role in human crescentic glomerulonephritis and renal transplantation rejection with glomerulitis, is sparse. Evidence from preclinical models indicates that macrophages profoundly modulate disease progression, both in terms of number—where depletion has resulted in a reduced glomerular lesion—and sub-phenotype—M1 being more profoundly detrimental than M2. This evidence is corroborated by better outcomes in patients with a lower number of glomerular macrophages. However, due to the very limited biopsy sample size, the type and role of macrophage subpopulations involved in human proliferative lesions is more difficult to precisely define and synthesize. Therefore, specific biomarkers of macrophage activation may enhance our ability to assess their role, potentially enabling improved monitoring of drug activity and ultimately allowing the development of novel therapeutic strategies to target these elusive cellular players.
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Liu, Xiaosong, and Zelieann R. Craig. "Environmentally relevant exposure to dibutyl phthalate disrupts DNA damage repair gene expression in the mouse ovary†." Biology of Reproduction 101, no. 4 (July 18, 2019): 854–67. http://dx.doi.org/10.1093/biolre/ioz122.
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Abstract Phthalates have a history of reproductive toxicity in animal models and associations with adverse reproductive outcomes in women. Human exposure to dibutyl phthalate (DBP) occurs via consumer products (7–10 μg/kg/day) and medications (1–233 μg/kg/day). Most DBP toxicity studies have focused on high supraphysiological exposure levels; thus, very little is known about exposures occurring at environmentally relevant levels. CD-1 female mice (80 days old) were treated with tocopherol-stripped corn oil (vehicle control) or DBP dissolved in oil at environmentally relevant (10 and 100 μg/kg/day) or higher (1000 μg/kg/day) levels for 30 days to evaluate effects on DNA damage response (DDR) pathway genes and folliculogenesis. DBP exposure caused dose-dependent effects on folliculogenesis and gene expression. Specifically, animals exposed to the high dose of DBP had more atretic follicles in their ovaries, while in those treated with environmentally relevant doses, follicle numbers were no different from vehicle-treated controls. DBP exposure significantly reduced the expression of DDR genes including those involved in homologous recombination (Atm, Brca1, Mre11a, Rad50), mismatch repair (Msh3, Msh6), and nucleotide excision repair (Xpc, Pcna) in a dose-specific manner. Interestingly, staining for the DNA damage marker, γH2AX, was similar between treatments. DBP exposure did not result in differential DNA methylation in the Brca1 promoter but significantly reduced transcript levels for the maintenance DNA methyltransferase, Dnmt1, in the ovary. Collectively, these findings show that oral exposure to environmentally relevant levels of DBP for 30 days does not significantly impact folliculogenesis in adult mice but leads to aberrant ovarian expression of DDR genes.
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Hameed, Abdul, Syed Asif Raza, Qadeer Ahmed, Faisal Khan, and Salim Ahmed. "A decision support tool for bi-objective risk-based maintenance scheduling of an LNG gas sweetening unit." Journal of Quality in Maintenance Engineering 25, no. 1 (March 11, 2019): 65–89. http://dx.doi.org/10.1108/jqme-04-2017-0027.
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Purpose The purpose of this paper is to develop a decision support tool for risk-based maintenance scheduling for a large heavily equipped gas sweetening unit in a Liquefied Natural Gas (LNG) plant. Two conflicting objectives, i.e., total maintenance cost and the reliability, are considered in the tool. The tool is tested with the real plant data and suggests several Pareto-optimal schedules for a decision maker to choose from. The financial impacts are assessed. Design/methodology/approach A bi-objective scheduling optimization model is developed for maintenance scheduling using a risk-based framework. The model is developed integrating genetic algorithm and simulation-based optimization to find Pareto-optimal schedules. The model delivered true Pareto front optimal solutions for given plant-specific data. The two conflicting objectives: the minimization of total expenditures incurred on maintenance-related activities and improving the total reliability are considered. Findings For large and complex processing facilities such as LNG plant, a shutdown of facility generates a significant financial impact, resulting in millions of dollars in production loss. The developed risk-based equipment selection strategy helps to minimize such an event of production loss by generating a thorough maintenance strategy for inspection, repair, overhaul or replacement schedule of the unit without initiating the shutdown. The proposed model has been successfully applied to obtain an optimize maintenance schedule for a gas sweetening unit. Research limitations/implications A future work may consider the state-dependent models for various failure modes that will result in obtaining a better representation of the model. The proposed scheduling can further be extended to multi-criteria scheduling including availability, resource limitation and inflationary condition. A comparative analysis with other meta-heuristic techniques such as harmony search algorithm, tabu search, and simulated annealing will further help in confirming the schedule obtained from this application. Practical implications Maintenance scheduling using a conventional approach for special equipment generally does not consider the conflicting objectives. This research addresses this aspect using a bi-objective model. The usefulness of risk-based method is to assist in minimizing the financial and safety risk exposure to the operating companies, but some variation in results is expected due to varying risk matrix for different organizations. Social implications Managing two objectives, i.e., minimizing the cost of maintenance-related activities, while at the same time maximizing the overall reliability dramatically, helps in mitigating adverse safety and financial risk due to fires, explosions, fatality and excessive maintenance cost. Originality/value Research develops a decision support tool for managing conflicting objectives for an LNG process. This research highlights the impact of utilizing the simulation-based approach coupled with risk-based equipment selection for complex processing unit or plant maintenance scheduling optimization.
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Lund-Ricard, Yasmine, Patrick Cormier, Julia Morales, and Agnès Boutet. "mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases." International Journal of Molecular Sciences 21, no. 8 (April 14, 2020): 2718. http://dx.doi.org/10.3390/ijms21082718.
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A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.
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Apryshkin, A. S., and G. S. Khazanovich. "Determination of capacity and comfort indicators of a passenger elevator." SAFETY OF TECHNOGENIC AND NATURAL SYSTEMS, no. 1 (2021): 38–50. http://dx.doi.org/10.23947/2541-9129-2021-1-38-50.
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Introduction. Elevators are mass weight-handling units used by millions of residents of multi-storey buildings. Safety of elevator units and comfort of their use are determined not only by the correct choice of their design and parameters, but first of all, by the organization of the maintenance system. Each elevator is an individual unit that serves a residential building with a specific number of passengers, number of floors and other features. However, regulatory documents recommend standard maintenance plans. There is the need to establish the relationship between the loading modes of the main components and the optimal scheme of technical and repair works. The present work is devoted to the solution of this problem, along with the study of transport comfort. Problem Statement. The operation of the elevator in a residential building with a number of floors N occurs in separate cycles. Standing, lift call, and destination floors are random variables for which probabilistic characteristics must be reliably established. In general, the elevator operation mode includes three stages: calling to the passenger boarding level, moving with passengers to the destination level, and waiting for the next cycle. There are stops inside the movement stages. The specific problem of mathematical description of the random process of implementing the operating characteristics of the main drive of the elevator is reduced to two directions: 1) the development of mathematical models for the formation of the main indicators of the main elevator drive load during the cycle (net machine time τmi and the number of switches n)i; 2) the study of the relationship between passenger traffic, building residential density and cycle duration. Theoretical Part. To meet these objectives the authors have performed the studies of the following main processes characterizing the functioning of the lift, the level of capacity of the transport drive and comfort: the development of mathematical models of formation of indicators of the elevator drive load; the establishment of the relationship of traffic flow, residential density and the duration of the cycle; development of methodology for calculation of the number of flights went by the elevator in different modes; development of methods of calculating the transport comfort indicator; justification of the structure of the algorithm for modeling the operating modes of the elevator. Conclusion. The paper provides the results, which complement the theoretical provisions for determining the capacity and transport comfort of elevators.
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Patnaik, Srinivas, Sudeep P. George, Eric Pham, Swati Roy, Kanchan Singh, John M. Mariadason, and Seema Khurana. "By moonlighting in the nucleus, villin regulates epithelial plasticity." Molecular Biology of the Cell 27, no. 3 (February 2016): 535–48. http://dx.doi.org/10.1091/mbc.e15-06-0453.
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Villin is a tissue-specific, actin-binding protein involved in the assembly and maintenance of microvilli in polarized epithelial cells. Conversely, villin is also linked with the loss of epithelial polarity and gain of the mesenchymal phenotype in migrating, invasive cells. In this study, we describe for the first time how villin can switch between these disparate functions to change tissue architecture by moonlighting in the nucleus. Our study reveals that the moonlighting function of villin in the nucleus may play an important role in tissue homeostasis and disease. Villin accumulates in the nucleus during wound repair, and altering the cellular microenvironment by inducing hypoxia increases the nuclear accumulation of villin. Nuclear villin is also associated with mouse models of tumorigenesis, and a systematic analysis of a large cohort of colorectal cancer specimens confirmed the nuclear distribution of villin in a subset of tumors. Our study demonstrates that nuclear villin regulates epithelial–mesenchymal transition (EMT). Altering the nuclear localization of villin affects the expression and activity of Slug, a key transcriptional regulator of EMT. In addition, we find that villin directly interacts with a transcriptional corepressor and ligand of the Slug promoter, ZBRK1. The outcome of this study underscores the role of nuclear villin and its binding partner ZBRK1 in the regulation of EMT and as potential new therapeutic targets to inhibit tumorigenesis.
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Sadridinov, A. B. "Analysis of energy performance of heading sets of equipment at a coal mine." Gornye nauki i tekhnologii = Mining Science and Technology (Russia) 5, no. 4 (January 6, 2021): 367–75. http://dx.doi.org/10.17073/2500-0632-2020-4-367-375.
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The growth of volume of tunneling, power supplied per job, and consumption of fuel and energy resources makes it necessary to increase energy performance of production processes with reducing energy losses. Tunneling conditions are determined by a combination of mutually influencing factors (geological, technological and organizational), and assessing their impact on tunneling energy performance requires a deep detailed study. For criterion assessment of tunneling performance, indicators of energy consumption, performance, and quality of tunneling performed by shift crews, allowing to objectively assess their work, were proposed. Indicators of process and specific power consumption in the process of tunneling vary over a wide range, therefore, to ensure smooth equipment operation, shift crews must adhere to the recommended indicators that determine the optimum rates of tunneling and enables adherence to permissible operation modes. Statistical models of energy performance indicators of heading sets of equipment operation were investigated using the example of the Severnaya coal mine. Indicators of energy consumption, energy performance, and tunneling (on shift basis) were proposed. Distribution laws have been determined for the main indicators characterizing tunneling energy performance. Recommendations have been developed to ensure sustainable operation of heading sets of equipment throughout the entire period of tunneling. Tunneling requires permanent monitoring its parameters and rates of advance, the quality of face preparation, timely maintenance and repair of machinery and equipment, control of the process through ensuring optimal operating modes of the heading sets of equipment.
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Strømland, Øyvind, Marc Niere, Andrey A. Nikiforov, Magali R. VanLinden, Ines Heiland, and Mathias Ziegler. "Keeping the balance in NAD metabolism." Biochemical Society Transactions 47, no. 1 (January 9, 2019): 119–30. http://dx.doi.org/10.1042/bst20180417.
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Abstract Research over the last few decades has extended our understanding of nicotinamide adenine dinucleotide (NAD) from a vital redox carrier to an important signalling molecule that is involved in the regulation of a multitude of fundamental cellular processes. This includes DNA repair, cell cycle regulation, gene expression and calcium signalling, in which NAD is a substrate for several families of regulatory proteins, such as sirtuins and ADP-ribosyltransferases. At the molecular level, NAD-dependent signalling events differ from hydride transfer by cleavage of the dinucleotide into an ADP-ribosyl moiety and nicotinamide. Therefore, non-redox functions of NAD require continuous biosynthesis of the dinucleotide. Maintenance of cellular NAD levels is mainly achieved by nicotinamide salvage, yet a variety of other precursors can be used to sustain cellular NAD levels via different biosynthetic routes. Biosynthesis and consumption of NAD are compartmentalised at the subcellular level, and currently little is known about the generation and role of some of these subcellular NAD pools. Impaired biosynthesis or increased NAD consumption is deleterious and associated with ageing and several pathologies. Insults to neurons lead to depletion of axonal NAD and rapid degeneration, partial rescue can be achieved pharmacologically by administration of specific NAD precursors. Restoring NAD levels by stimulating biosynthesis or through supplementation with precursors also produces beneficial therapeutic effects in several disease models. In this review, we will briefly discuss the most recent achievements and the challenges ahead in this diverse research field.
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Sadridinov, A. B. "Analysis of energy performance of heading sets of equipment at a coal mine." Gornye nauki i tekhnologii = Mining Science and Technology (Russia) 5, no. 4 (January 6, 2021): 367–75. http://dx.doi.org/10.17073/2500-0632-2020-4-367-375.
Full textAbstract:
The growth of volume of tunneling, power supplied per job, and consumption of fuel and energy resources makes it necessary to increase energy performance of production processes with reducing energy losses. Tunneling conditions are determined by a combination of mutually influencing factors (geological, technological and organizational), and assessing their impact on tunneling energy performance requires a deep detailed study. For criterion assessment of tunneling performance, indicators of energy consumption, performance, and quality of tunneling performed by shift crews, allowing to objectively assess their work, were proposed. Indicators of process and specific power consumption in the process of tunneling vary over a wide range, therefore, to ensure smooth equipment operation, shift crews must adhere to the recommended indicators that determine the optimum rates of tunneling and enables adherence to permissible operation modes. Statistical models of energy performance indicators of heading sets of equipment operation were investigated using the example of the Severnaya coal mine. Indicators of energy consumption, energy performance, and tunneling (on shift basis) were proposed. Distribution laws have been determined for the main indicators characterizing tunneling energy performance. Recommendations have been developed to ensure sustainable operation of heading sets of equipment throughout the entire period of tunneling. Tunneling requires permanent monitoring its parameters and rates of advance, the quality of face preparation, timely maintenance and repair of machinery and equipment, control of the process through ensuring optimal operating modes of the heading sets of equipment.
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Aulin, Viktor, Andrey Grinkiv, and Artem Holovatyi. "Cyberphysical Approach to the Creation, Operation and Improvement of Transport and Production Systems." Central Ukrainian Scientific Bulletin. Technical Sciences, no. 3(34) (October 2020): 331–43. http://dx.doi.org/10.32515/2664-262x.2020.3(34).331-343.
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The content of the cyberphysical approach to the creation, functioning and improvement of transport and production systems is analyzed. It was found out how, on the basis of the approach, cyberphysical transport and production systems are created as the integration of special technologies of the Internet of Things; embedded systems; ubiquitous and cloud computing. It was revealed that cyberphysical transport and production systems have a trinitarian concept and are defined by three entities: communication, computation and control, which unites information. It is determined that the main functions of cyberphysical transport and production systems are: information processing, intelligent communications, performance and process control. A component model of such a system has been built, which includes two groups of components - evolutionary and technological. The evolutionary group of components includes subsystems: digital; integrated; robotic, intelligent distributed. These components are a kind of basis for the presence of prerequisites for the creation of transport and production systems. It is noted that the technology group of components is the basis for concrete implementations of the Internet of Things, embedded systems and ubiquitous and cloud computing. A cyberphysical system of technical service is proposed as a specific implementation of cyberphysical transport and production systems. It was determined that the modes of the proposed functional cyber system are: high adaptability; an appropriate level of efficiency; intelligence of management; high level of reliability; the use of a new on-net online simulation type; using a new type of self-verifying models; internal online optimization, etc. It is shown that the presence of intelligent models in the cyberphysical model of technical service makes the system resistant to cyberattacks and increases the degree of safety when ensuring traffic in transport and the development of an occupational safety system during maintenance and repair operations.
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Young, In-Chi, Sung-Ting Chuang, Amit Gefen, Wei-Ting Kuo, Chun-Ting Yang, Chia-Hsien Hsu, and Feng-Huei Lin. "A novel compressive stress-based osteoarthritis-like chondrocyte system." Experimental Biology and Medicine 242, no. 10 (March 22, 2017): 1062–71. http://dx.doi.org/10.1177/1535370217699534.
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Mechanical stress damage and insufficient self-repair can contribute to osteoarthritis (OA) in the affected joint. As the effects of stress on chondrocyte metabolism can regulate cartilage homeostasis, the specific stress–response condition is therefore a key to the generation of an OA disease model. We aimed to produce a specific stress- and cell-based OA model after evaluating the metabolic responses of chondrocytes in response to a series of static and cyclic compression stressors. A static load exceeding 40 psi initiated extracellular matrix (ECM) degradation through a decrease in the sulphated-glycosaminoglycan (GAG) content, upregulation of catabolic matrix metalloproteinase (MMP)-13 encoding gene expression, and downregulation of the ECM-related aggrecan and type II collagen encoding genes within 24 h. Indicators of pro-inflammatory events and oxidative stress were found to correlate with increased IL-6 expression and reactive oxygen species (ROS) production, respectively. However, chondrocytes stimulated by moderate cyclic loading (30–40 psi) exhibited increased ECM-related gene expression without significant changes in catabolic and pro-inflammatory gene expression. BMP-7 expression increased at cyclic loading levels above 30–60 psi. These results demonstrated that static compression exceeding 60 psi is sufficient to produce OA-like chondrocytes that exhibit signs of ECM degradation and inflammation. These OA-like chondrocytes could therefore be used as a novel cell-based drug screening system. Impact statement The lack of an effective treatment for osteoarthritis (OA) reflects the great need for alternative therapies and drug discovery. Disease models can be used for early-stage compound screening and disease studies. Chondrocytes are solely responsible for the maintenance of the articular cartilage extracellular matrix. Our strategy involved the generation of a cell-based model of OA, a more readily studied disease. Instead of using animal cartilage explants, we incorporated isolated porcine chondrocytes with hydrogel to form three-dimensional assemblies. We could identify the specific magnitude-dependent metabolic responses of chondrocytes by applying a series of static and cyclic compression, and therefore successfully generated a novel OA-like cell-based model for drug screening.
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Li, Haijun, and Moshe Shaked. "Imperfect repair models with preventive maintenance." Journal of Applied Probability 40, no. 04 (December 2003): 1043–59. http://dx.doi.org/10.1017/s0021900200020283.
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Brown and Proschan (1983) introduced the imperfect repair model, in which an item, upon failure, is replaced with a new one with probability α, and is minimally repaired with probability 1 − α. In this paper we equip the imperfect repair model with preventive maintenance, and we obtain stochastic maintenance comparisons for the numbers of failures under different policies via a point-process approach. We also obtain some results involving stochastic monotonicity properties of these models with respect to the unplanned complete repair probability α.
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Li, Haijun, and Moshe Shaked. "Imperfect repair models with preventive maintenance." Journal of Applied Probability 40, no. 4 (September 2003): 1043–59. http://dx.doi.org/10.1239/jap/1067436099.
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Brown and Proschan (1983) introduced the imperfect repair model, in which an item, upon failure, is replaced with a new one with probability α, and is minimally repaired with probability 1 − α. In this paper we equip the imperfect repair model with preventive maintenance, and we obtain stochastic maintenance comparisons for the numbers of failures under different policies via a point-process approach. We also obtain some results involving stochastic monotonicity properties of these models with respect to the unplanned complete repair probability α.
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Gorenstein, Ariel, Meir Kalech, Daniela Fuchs Hanusch, and Sharon Hassid. "Pipe Fault Prediction for Water Transmission Mains." Water 12, no. 10 (October 14, 2020): 2861. http://dx.doi.org/10.3390/w12102861.
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Every network of supply waterlines experiences thousands of yearly bursts, breaks, leakages, and other failures. These failures waste a great amount of resources, as not only the waterlines need to be repaired, but also water is wasted and the distribution service is interrupted. For that reason, many water facilities employ proactive maintenance strategies in their networks, where they replace likely-to-fail pipes in advance to prevent the failures. In this paper, we aim to establish a reliable prediction model that can accurately predict faults in waterlines prior to their occurrence. We propose a specific segmentation method for long transmission mains, as well as three data-driven models and one rule-based prediction model. We evaluate a real world waterline network used in Israel, operated by Mekorot company, using three common metrics. The results show that the data-driven algorithms outperform the rule-based model by at least 5% in each of the metrics. Additionally, their prediction becomes more accurate as they are trained with more data, but enhancing these data with geographically related features does not improve the accuracy further.
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Kahle, Waltraud. "Optimal maintenance policies in incomplete repair models." Reliability Engineering & System Safety 92, no. 5 (May 2007): 563–65. http://dx.doi.org/10.1016/j.ress.2006.05.004.
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WANG, HONGZHOU, and HOANG PHAM. "OPTIMAL AGE-DEPENDENT PREVENTIVE MAINTENANCE POLICIES WITH IMPERFECT MAINTENANCE." International Journal of Reliability, Quality and Safety Engineering 03, no. 02 (June 1996): 119–35. http://dx.doi.org/10.1142/s0218539396000090.
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This paper proposes three age-dependent preventive maintenance models with imperfect repair and/or imperfect preventive maintenance (pm). In these models imperfect repair is treated in a way that after repair the lifetime of a unit will decrease to a fraction of its immediately previous one and its repair time will increase to a multiple of immediately previous one. In this paper, the expected maintenance cost rate and asymptotic average availability are derived with a consideration that the maintenance and repair times are not negligible. The optimum maintenance policies are then determined for the three imperfect maintenance models respectively. A class of related optimization problems is also discussed. Finally, a numerical example is presented to illustrate the results.
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Boretti, Alberto. "Cost of dispatchable electricity from concentrated solar power, solar tower plants, with 10 hours’ molten salt thermal energy storage." E3S Web of Conferences 173 (2020): 02003. http://dx.doi.org/10.1051/e3sconf/202017302003.
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While there is a consensus that concentrated solar power solar tower plants with thermal energy storage 10 hours may permit the production of dispatchable electricity at 6 c/kWh, without a single plant utility size produced and operated featuring this technology at this cost, the recent experience of Crescent Dunes has clearly shown that this is not the case. Crescent Dunes started operation in October 2015 demonstrating since the very beginning the lack of maturity of this specific technology, with lack of production or no production at all, every single month since then. As the 110 MW plant of cost about 1 billion $ US has been shut down after less than 4 years of operation, and a total production of only 418, 849 MWh, that is less than the 500, 000 MWh expected every year for 25 years, this translate in a total cost, excluding repairs and maintenance costs incurred in the 4 years, of 2.38 $ per kWh of unpredictable electricity. This experience suggests that every estimation of costs and performances should be based on data of plants built and operated, and to avoid the use of models not yet validated to predict performances of novel plants. There is a mature solar thermal technology, and this is the parabolic trough.
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Chlon, Timothy M., Elizabeth E. Hoskins, Sonya Ruiz-Torres, Christopher N. Mayhew, Kathryn A. Wikenheiser-Brokamp, Stella M. Davies, Parinda A. Mehta, Kasiani C. Myers, James M. Wells, and Susanne I. Wells. "Inducible Loss of the Fanconi Anemia Pathway in iPSC Causes Rapid Cell Cycle Arrest and Apoptosis through ATM/ATR and p53 Signaling." Blood 124, no. 21 (December 6, 2014): 3528. http://dx.doi.org/10.1182/blood.v124.21.3528.3528.
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Abstract As the source of all cells in the developing embryo proper, embryonic stem cells (ESC) bear the unique responsibility to prevent mutations from being propagated throughout the entire organism and the germ line. It is likely for this reason that ESC and induced pluripotent stem cells (iPSC) maintain a dramatically lower mutation frequency than cultured somatic cells. Multiple mechanisms for this enhanced genomic surveillance have been proposed, including hypersensitivity of DNA damage response signaling pathways and increased activity of error-free DNA repair pathways, such as homologous recombination. However, the effect of loss of function of DNA repair pathways in these cells remains poorly understood. The Fanconi Anemia (FA) pathway is a DNA repair pathway that is required for the repair of DNA interstrand crosslink damage and also promotes repair of DNA double-strand breaks by homologous recombination . Genetic defects in this pathway cause a disease characterized by bone marrow failure and extreme cancer incidence. Several recent studies have revealed that the FA pathway is required for efficient somatic cell reprogramming to iPSC and suggest that FA cells undergo cell death during this process. Another recent study found that the growth of FA patient-specific iPSC was attenuated with a G2/M arrest when compared to control iPSC, suggesting that these cells arrest upon failed DNA repair. In this study, we sought to determine the effects of acute loss of function of the FA pathway in iPSC through the generation of FA patient-derived iPSC with inducible complementation of the defective FA gene. Fibroblasts were cultured from skin biopsies of multiple FA patients and transduced with a lentiviral vector expressing the complementing FA gene product under DOX-inducible control. Cells were then reprogrammed to iPSC using episomal transfection. These cells formed iPSC colonies only when reprogramming was carried out in the presence of DOX, confirming that the FA pathway is required for efficient reprogramming. Once cell lines were obtained, DOX-dependent FA functionality was verified based on FANCD2 monoubiquitination and nuclear focus formation after treatment with DNA damaging agents. We then cultured the iPSC for extended periods of time in the presence and absence of DOX. Interestingly, the cultures underwent profound cell death and cell cycle arrest within 7 days of DOX-withdrawal and completely failed to expand after one passage. EdU cell cycle analysis confirmed cell cycle arrest in the G2/M phase. Furthermore, cleaved caspase 3 staining confirmed that the number of apoptotic cells increased by 3-fold in the -DOX culture. Despite these effects, cells cultured in both the presence and absence of DOX formed teratomas in nude mice, thus indicating the maintenance of full differentiation capacity in the absence of the FA pathway. In order to determine the mechanisms underlying G2/M arrest and cell death, expression of p53 and its target genes was detected by both western blot analysis and qRT-PCR. Only a slight increase in p53 activation was observed by 7 days post DOX-withdrawal. Furthermore, knockdown of p53 resulted in rescue from apoptosis to normal levels but not rescue from cell cycle arrest. Increased ATM and ATR DNA damage sensor kinase activities were also detected in –DOX cells, concominant with increased phosphorylation of the ATM-target Chk2 and reduced abundance of the G2/M checkpoint protein CDC25A. These results reveal hyperactive DNA damage responses upon FA loss which may underlie the attenuated cell cycle progression of FA-iPSC independent of p53. Remarkably, effects in this FA model system appear equivalent to those responsible for the depletion of HSC in the bone marrow of FA patients. Thus, iPSC models may be useful for future studies of the mechanisms underlying FA stem cell arrest and for the development of therapeutics that alleviate these phenotypes. Disclosures No relevant conflicts of interest to declare.
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Stewart, Rainey A. "Endosymbiont bacteria Holospora undulata confers oxidative tolerance in host Paramecium caudatum." IU Journal of Undergraduate Research 2, no. 1 (May 31, 2016): 41. http://dx.doi.org/10.14434/iujur.v2i1.20912.
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Paramecium is a genus of ciliated protozoan that, while unicellular, has a complex intracellular structure, comparable to Metazoan cells, which has made them excellent models for the study of genetics and cellular functions. Holospora undulata is a bacterial endosymbiont specific to the species Paramecium caudatum; they are unable to grow outside of P. caudatum. The presence of this endosymbiont has proven to have an effect on the subsequent gene expression and cellular maintenance of its host cells. Recent studies have demonstrated that infection by H. obtusa increases the expression of host heat-shock genes and leads to both resistance at normally-lethal high temperatures and heat resistance in ciliary movement (Fujishima, Kawai, & Yamamoto, 2005; Hori & Fujishima, 2003). Heat-shock resistance occurs because bacterial DNA triggers the upregulation of its P. caudatum host’s heat-shock genes (i.e., hsp60 and hsp70), although the mechanisms are not known (Hori & Fujishima, 2003). These studies demonstrate that infection of P. caudatum by H. undulata (a closely-related species to H. obtusa) induces heat-shock resistance, but fail to address whether H. undulata protects against other common environmental stressors such as oxidative damage. To determine if infection by H. undulata has the ability to induce additional tolerances, we examined differences in oxidative tolerance, based on percent survival, between P. caudatum with and without H. undulata infection. Samples of both lines were treated with increasing concentrations of hydrogen peroxide, the number of surviving cells were counted, and the percent survivability of each sample was calculated. There was an approximate 20% increase in survival when P. caudautum was infected with H. undulata—thus H. undulata infections confer oxidative tolerance. Further studies will be conducted to determine if an increase in survivability occurs in response to other damaging mechanisms. Future work will also investigate if the genes responsible for oxidative damage repair are upregulated, in addition to the already characterized heat-shock genes.
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Ovsiannikov, V. E., and V. I. Vasiliev. "Development of model for human factor influence assessment on construction and road machines operation efficiency." Russian Automobile and Highway Industry Journal 17, no. 4 (August 28, 2020): 476–86. http://dx.doi.org/10.26518/2071-7296-2020-17-4-476-486.
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Introduction. The human factor and the characteristics of construction and road machine operators, such as experience, work experience, professional skills, skill, etc., have a significant impact on the efficiency of equipment operation. The human factor, on average, is the cause of about a third of the failures of construction and road machines. One of the most effective ways out of this situation is to improve the machines from the point of view of ensuring the compatibility of the elements of the human-machine system. The article considers the issues of the engineering and psychological component of compatibility.Materials and methods. The method of analysis of hierarchies is used, when solving the problem of identifying the causes of operators’ errors and fuzzy logic, to build a model for assessing the impact of the human factor on the efficiency of construction and road machines.Results. As a result of a comprehensive assessment of the causes of errors, it was found that the largest combination of criteria is a group of errors associated with the peculiarities of the task being performed, as well as the properties of the information processed by a person. The developed model for assessing the influence of the human factor on the efficiency of machine operation uses risk as an output variable, and input variables a generalized indicator of the complexity of the algorithm and the level of qualification of the machine operator.Discussion and conclusions. The resulting model allows you to make a primary assessment of the impact of the human factor and maintenance and repair planning, as well as be used in personnel management processes, for example, in terms of sending personnel for training. Further improvement is seen in the development of neurofuzzy anfys models which provide a knowledge base for more effective risk assessment by specific precedents. The structure of the model in terms of input variables for a more correct risk assessment is also possible to be changed.
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WANG, HONGZHOU, and HOANG PHAM. "Optimal maintenance policies for several imperfect repair models." International Journal of Systems Science 27, no. 6 (June 1996): 543–49. http://dx.doi.org/10.1080/00207729608929248.
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Milovanović, Zdravko, Valentina Janičić-Milovanović, and Dejan Branković. "Application of the Markov process to evaluate the reliability of a complex thermal power system." Tehnika 76, no. 4 (2021): 447–56. http://dx.doi.org/10.5937/tehnika2104477m.
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Determining the reliability of a thermal power plant as a whole or in its individual components often requires long and very expensive tests under special operating modes on a very large number of samples or gathering the required exploitation data, which is even more difficult because of the choice of a general mathematical method (different forms of curves which quantitatively define reliability with different failure density functions and the high dependence of such curves on changes in the operating modes of components and environmental conditions). The introduction of approximate calculations, in order to overcome these problems, gives an insight into the basic reliability characteristics of the observed system as a whole, but also insufficiently exact final parameters, due to a whole series of larger or smaller approximations, as well as the inability to take into account all existing influences (development of new technologies, specifics newly developed disorders, etc.). Calculating the reliability of a complex system is only the first initial phase of verifying quantitative characteristics, that is, the hypothesis itself that we have more or less confidence in. Their final acceptance or rejection is a verification of reliability through the control of certain quantitative system indicators for the given technical conditions of operation. For these reasons, alternative terms are often used to verify reliability in the literature, such as reliability control or hypothesis testing. Designing a reliability model, through the application of simulation methods, to select the best parameters for the functioning of components and systems as a whole, in technological terms, should be supported by appropriate experimental methods (using collected data and stored data from the past). This paper provides an analysis of the application of the Markov process to assess the reliability of a complex thermal power system, with the aim of scheduling appropriate decisions on maintenance actions based on the required level of reliability. The optimum timing of replacement / repair of parts of a complex thermal power system is defined before its failure or the need to act correctively. Also, these models serve to provide a level of reliability by carrying out adequate maintenance actions on complex units within the thermal power plant.
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Stadje, Wolfgang, and Dror Zuckerman. "Optimal repair policies with general degree of repair in two maintenance models." Operations Research Letters 11, no. 2 (March 1992): 77–80. http://dx.doi.org/10.1016/0167-6377(92)90036-3.
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Block, Henry W., Naftali A. Langberg, and Thomas H. Savits. "Maintenance comparisons: block policies." Journal of Applied Probability 27, no. 3 (September 1990): 649–57. http://dx.doi.org/10.2307/3214548.
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Complete repair and minimal repair models with a block maintenance policy are considered. Each of these models gives rise to a counting process, and these processes are compared stochastically. This contrasts with most previous work on maintenance policies where only univariate marginal comparisons were made. Also a more general block schedule is considered than is customary.
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Block, Henry W., Naftali A. Langberg, and Thomas H. Savits. "Maintenance comparisons: block policies." Journal of Applied Probability 27, no. 03 (September 1990): 649–57. http://dx.doi.org/10.1017/s0021900200039188.
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Complete repair and minimal repair models with a block maintenance policy are considered. Each of these models gives rise to a counting process, and these processes are compared stochastically. This contrasts with most previous work on maintenance policies where only univariate marginal comparisons were made. Also a more general block schedule is considered than is customary.
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Wang, Hongzhou. "Warranty cost models considering imperfect repair and preventive maintenance." Bell Labs Technical Journal 11, no. 3 (November 8, 2006): 147–59. http://dx.doi.org/10.1002/bltj.20185.
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Guitart, Francis, Moonjung Jung, Stefan Cordes, Shiqin Yu, Jizhong Zou, So Gun Hong, Vinh Dang, et al. "Single Cell Transcriptome Analysis of GATA2 Deficiency in Hematopoiesis Modeled with Induced Pluripotent Stem Cells." Blood 132, Supplement 1 (November 29, 2018): 5087. http://dx.doi.org/10.1182/blood-2018-99-118410.
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Abstract GATA2 deficiency is a rare, inherited or sporadic genetic disorder characterized by variable onset of a pleomorphic constellation of immune, hematologic and lymphatic abnormalities linked to heterozygous mutations in the Gata2 gene. Patients develop monocyte, B cell, NK cell and dendritic cell deficiencies resulting in vulnerabilities to unusual infections. Patients with GATA2 deficiency also frequently progress to bone marrow failure, myelodysplastic syndrome and/or acute myelogenous leukemia. GATA proteins are transcription factors with central roles in early embryonic development and lineage specification. GATA2 is a master regulator of hematopoiesis, implicated in the initial generation and maintenance of hematopoietic stem cells (HSC). Murine models recapitulate the human phenotype incompletely: GATA2 heterozygous knockout mice do not manifest loss of monocyte, B cells or NK cells; however, serial repopulation assays show decreased engraftment potential. Direct studies of primary HSC from patients with GATA2 deficiency are challenging due to the generally hypocellular marrow. We hypothesized that human pluripotent stem cells, particularly patient-specific iPSC, could be used to study potential developmental defects in GATA2 deficiency, overcoming a lack of primary HSC. In order to gain insights into the impact of human GATA2 deficiency on hematopoietic differentiation, we compared the single cell transcriptomes of HSPC differentiated from (i) iPSCs from a patient with GATA2 deficiency due to a mutation p.R337X (c.1009C>T) (ii) isogenic iPSCs created via homology-directed repair of Gata2 p.R337X, (iii) iPSCs from a healthy control and (iv) isogenic Gata2 heterozygous mutant iPSCs with monoallelic frameshift mutations in the second zinc finger domain. Mesodermal and hematopoietic differentiation was performed under feeder-free, defined media conditions. At day 0, iPSCs were plated in mesodermal induction media containing VEGF, SCF, Activin A and Y27632 in STEMdiff APEL media. Mesodermal induction was continued until day 4, when embryoid bodies were cultured in hematopoietic specification media with SCF, FLT3L, IL3, IL6, G-CSF and BMP4 until day 16, when CD34+CD45+ iPSC-derived hematopoietic stem and progenitor cells (iHSC) were enumerated and sorted by fluorescence-activated cell sorting. Single cell RNA-seq was performed using the 10XGenomics Chromium platform and primary analysis via CellRanger. Scater was used to filter outlier cells. Seurat as used to compute multiple manifold alignment and differential gene expression. Cell classification, pseudotemporal ordering and branch point analysis were performed with monocle. URD was used to calculate confirmatory diffusion maps and pseudotemporal ordering. We analyzed 7,855 iHSPC (2952 from GATA2-deficient patient, 241 isogenic iHSPCs after repair of Gata2 mutation, 2,605 from a healthy volunteer and 2,057 from isogenic heterozygous Gata2 knockout iHSPCs) after filtering of outliers. We computed multiple manifold alignment to mitigate batch effects. Differential gene expression across Gata2 mutation status found that 42 out of 102 (42%) target genes of GATA2 (c.f. TRANSFAC database of curated transcription factor targets) were differentially expressed with adjusted p-values less than 0.05. Semi-supervised classification of cell-types and pseudotemporal ordering via monocle revealed two branch points, consistent with developmental branchings at the level of CLP and CMP multipotent progenitors. The numbers of cells along each branch was found to be statistically different (χ2=30.07, p-value = 3e-7) with the biggest differences noted in the lymphoid branch (state 4). Differential gene expression in this branch revealed a differential up-regulation of Notch1, CD69 and FKBPs and differential down-regulation of CD14. In conclusion, iPSC/iHSPC differentiation models combined with single cell transcriptome analysis may be a valuable tool to identify pathways responsible for impaired hematopoietic/lymphatic development in GATA2 deficiency. Figure. Figure. Disclosures Dunbar: National Institute of Health: Research Funding. Winkler:National Institute of Health: Research Funding.
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Reik, Andreas, Kai-Hsin Chang, Sandra Stehling-Sun, Yuanyue Zhou, Gary K. Lee, Lynn Truong, Travis Wood, et al. "Targeted Gene Modification In Hematopoietic Stem Cells: A Potential Treatment For Thalassemia and Sickle Cell Anemia." Blood 122, no. 21 (November 15, 2013): 434. http://dx.doi.org/10.1182/blood.v122.21.434.434.
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Abstract Beta-thalassemia (β-thal) and sickle cell disease (SCD) are monogenic diseases caused by mutations in the adult β-globin gene. A bone marrow transplant (BMT) is the only curative treatment, but its application is limited since (i) HLA-matched donors can be found for <20% of cases, and (ii) the allogeneic nature of the transplant involves the significant risk of graft vs host disease (GvHD). Elevated levels of fetal γ-globin proteins observed in a subset of individuals carrying β-thal and SCD mutations ameliorate the clinical picture or prevent the development of disease complications. Thus, strategies for the selective and persistent upregulation of γ-globin represent an attractive therapeutic approach. Recent insights into the regulation of γ-globin transcription by a network of transcription factors and regulatory elements both inside and outside the β-globin locus have revealed a set of new molecular targets, the modulation of which is expected to elevate γ-globin levels for potential therapeutic intervention. To this end, we and others have established that designed zinc finger nucleases (ZFNs) transiently introduced into stem cells ex vivo provide a safe and efficient way to permanently ablate the expression of a specific target gene in hematopoietic stem cells (HSC) by introduction of mutations following target site cleavage and error-prone DNA repair. Here we report the development and comparison of different ZFNs that target various regulators of γ-globin gene transcription in human HSCs: Bcl11a, Klf1, and specific positions in the γ-globin promoters that result in hereditary persistence of fetal hemoglobin (HPFH). In all cases these target sites / transcription factors have previously been identified as crucial repressors of γ-globin expression in humans, as well as by in vitro and in vivo experiments using human erythroid cells and mouse models. ZFN pairs with very high genome editing activity in CD34+ HSCs were identified for all targeted sites (>75% of alleles modified). In vitro differentiation of these ZFN-treated CD34+ HSCs into erythroid cells resulted in potent elevation of γ-globin mRNA and protein levels without significant effects on erythroid development. Importantly, a similar and specific elevation of γ-globin levels was observed with RBC progeny of genome-edited CD34+ cells obtained from SCD and β-thal patients. Notably, in the latter case a normalization of the β-like to α-globin ratio to ∼1.0 was observed in RBCs obtained from genome-edited CD34s from two individuals with β-thalassemia major. To deploy this strategy in a clinical setting, we developed protocols that yielded comparably high levels of target gene editing in mobilized adult CD34+ cells at large scale (>108 cells) using a clinical-grade electroporation device to deliver mRNA encoding the ZFN pair. Analysis of modification at the most likely off-target sites based on ZFN binding properties, combined with the maintenance of target genome editing observed throughout erythroid differentiation (and in isolated erythroid colonies) demonstrated that the ZFNs were both highly specific and well-tolerated when deployed at clinical scale. Finally, to assess the stemness of the genome-edited CD34+ HSCs we performed transplantation experiments in immunodeficient mice which revealed long term engraftment of the modified cells (>16 weeks, ∼25% human chimerism in mouse bone marrow) with maintenance of differentiation in vivo. Moreover, ex vivo erythroid differentiation of human precursor cells isolated from the bone marrow of transplanted animals confirmed the expected elevation of γ-globin. Taken together, these data suggest that a therapeutic level of γ-globin elevation can be obtained by the selective disruption, at the genome level, of specific regulators of the fetal to adult globin developmental switch. The ability to perform this modification at scale, with full retention of HSC engraftment and differentiation in vivo, provides a foundation for advancing this approach to a clinical trial for the hemoglobinopathies. Disclosures: Reik: Sangamo BioSciences: Employment. Zhou:Sangamo BioSciences: Employment. Lee:Sangamo BioSciences: Employment. Truong:Sangamo BioSciences: Employment. Wood:Sangamo BioSciences: Employment. Zhang:Sangamo BioSciences: Employment. Luong:Sangamo BioSciences: Employment. Chan:Sangamo BioSciences: Employment. Liu:Sangamo BioSciences: Employment. Miller:Sangamo BioSciences: Employment. Paschon:Sangamo BioSciences: Employment. Guschin:Sangamo BioSciences: Employment. Zhang:Sangamo BioSciences: Employment. Giedlin:Sangamo BioSciences: Employment. Rebar:Sangamo BioSciences: Employment. Gregory:Sangamo BioSciences: Employment. Urnov:Sangamo BioSciences: Employment.
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Ottoman, Gregory R., W. Brent Nixon, and Steven T. Lofgren. "Budgeting for Facility Maintenance and Repair. I: Methods and Models." Journal of Management in Engineering 15, no. 4 (July 1999): 71–83. http://dx.doi.org/10.1061/(asce)0742-597x(1999)15:4(71).
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