104 research outputs found
Alterations to nuclear architecture and genome behavior in senescent cells.
The organization of the genome within interphase nuclei, and how it interacts with nuclear structures is important for the regulation of nuclear functions. Many of the studies researching the importance of genome organization and nuclear structure are performed in young, proliferating, and often transformed cells. These studies do not reveal anything about the nucleus or genome in nonproliferating cells, which may be relevant for the regulation of both proliferation and replicative senescence. Here, we provide an overview of what is known about the genome and nuclear structure in senescent cells. We review the evidence that nuclear structures, such as the nuclear lamina, nucleoli, the nuclear matrix, nuclear bodies (such as promyelocytic leukemia bodies), and nuclear morphology all become altered within growth-arrested or senescent cells. Specific alterations to the genome in senescent cells, as compared to young proliferating cells, are described, including aneuploidy, chromatin modifications, chromosome positioning, relocation of heterochromatin, and changes to telomeres
The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals
Flow shop rescheduling under different types of disruption
This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Production Research on 2013, available online:http://www.tandfonline.com/10.1080/00207543.2012.666856Almost all manufacturing facilities need to use production planning and scheduling systems to increase productivity and to reduce production costs. Real-life production operations are subject to a large number of unexpected disruptions that may invalidate the original schedules. In these cases, rescheduling is essential to minimise the impact on the performance of the system. In this work we consider flow shop layouts that have seldom been studied in the rescheduling literature. We generate and employ three types of disruption that interrupt the original schedules simultaneously. We develop rescheduling algorithms to finally accomplish the twofold objective of establishing a standard framework on the one hand, and proposing rescheduling methods that seek a good trade-off between schedule quality and stability on the other.The authors would like to thank the anonymous referees for their careful and detailed comments that helped to improve the paper considerably. This work is partially financed by the Small and Medium Industry of the Generalitat Valenciana (IMPIVA) and by the European Union through the European Regional Development Fund (FEDER) inside the R + D program "Ayudas dirigidas a Institutos tecnologicos de la Red IMPIVA" during the year 2011, with project number IMDEEA/2011/142.Katragjini Prifti, K.; Vallada Regalado, E.; Ruiz García, R. (2013). Flow shop rescheduling under different types of disruption. International Journal of Production Research. 51(3):780-797. https://doi.org/10.1080/00207543.2012.666856S780797513Abumaizar, R. J., & Svestka, J. A. (1997). Rescheduling job shops under random disruptions. International Journal of Production Research, 35(7), 2065-2082. doi:10.1080/002075497195074Adiri, I., Frostig, E., & Kan, A. H. G. R. (1991). Scheduling on a single machine with a single breakdown to minimize stochastically the number of tardy jobs. Naval Research Logistics, 38(2), 261-271. doi:10.1002/1520-6750(199104)38:23.0.co;2-iAkturk, M. S., & Gorgulu, E. (1999). Match-up scheduling under a machine breakdown. European Journal of Operational Research, 112(1), 81-97. doi:10.1016/s0377-2217(97)00396-2Allahverdi, A. (1996). Two-machine proportionate flowshop scheduling with breakdowns to minimize maximum lateness. Computers & Operations Research, 23(10), 909-916. doi:10.1016/0305-0548(96)00012-3Arnaout, J. P., & Rabadi, G. (2008). Rescheduling of unrelated parallel machines under machine breakdowns. International Journal of Applied Management Science, 1(1), 75. doi:10.1504/ijams.2008.020040Artigues, C., Billaut, J.-C., & Esswein, C. (2005). Maximization of solution flexibility for robust shop scheduling. European Journal of Operational Research, 165(2), 314-328. doi:10.1016/j.ejor.2004.04.004Azizoglu, M., & Alagöz, O. (2005). Parallel-machine rescheduling with machine disruptions. IIE Transactions, 37(12), 1113-1118. doi:10.1080/07408170500288133Bean, J. C., Birge, J. R., Mittenthal, J., & Noon, C. E. (1991). Matchup Scheduling with Multiple Resources, Release Dates and Disruptions. Operations Research, 39(3), 470-483. doi:10.1287/opre.39.3.470Caricato, P., & Grieco, A. (2008). An online approach to dynamic rescheduling for production planning applications. International Journal of Production Research, 46(16), 4597-4617. doi:10.1080/00207540601136225CHURCH, L. K., & UZSOY, R. (1992). Analysis of periodic and event-driven rescheduling policies in dynamic shops. International Journal of Computer Integrated Manufacturing, 5(3), 153-163. doi:10.1080/09511929208944524Cowling, P., & Johansson, M. (2002). Using real time information for effective dynamic scheduling. European Journal of Operational Research, 139(2), 230-244. doi:10.1016/s0377-2217(01)00355-1Curry, J., & Peters *, B. (2005). Rescheduling parallel machines with stepwise increasing tardiness and machine assignment stability objectives. International Journal of Production Research, 43(15), 3231-3246. doi:10.1080/00207540500103953DUTTA, A. (1990). Reacting to Scheduling Exceptions in FMS Environments. IIE Transactions, 22(4), 300-314. doi:10.1080/07408179008964185Ghezail, F., Pierreval, H., & Hajri-Gabouj, S. (2010). Analysis of robustness in proactive scheduling: A graphical approach. Computers & Industrial Engineering, 58(2), 193-198. doi:10.1016/j.cie.2009.03.004Goren, S., & Sabuncuoglu, I. (2008). Robustness and stability measures for scheduling: single-machine environment. IIE Transactions, 40(1), 66-83. doi:10.1080/07408170701283198Hall, N. G., & Potts, C. N. (2004). Rescheduling for New Orders. Operations Research, 52(3), 440-453. doi:10.1287/opre.1030.0101Herrmann, J. W., Lee, C.-Y., & Snowdon, J. L. (1993). A Classification of Static Scheduling Problems. Complexity in Numerical Optimization, 203-253. doi:10.1142/9789814354363_0011Herroelen, W., & Leus, R. (2005). Project scheduling under uncertainty: Survey and research potentials. European Journal of Operational Research, 165(2), 289-306. doi:10.1016/j.ejor.2004.04.002Hozak, K., & Hill, J. A. (2009). Issues and opportunities regarding replanning and rescheduling frequencies. International Journal of Production Research, 47(18), 4955-4970. doi:10.1080/00207540802047106Huaccho Huatuco, L., Efstathiou, J., Calinescu, A., Sivadasan, S., & Kariuki, S. (2009). Comparing the impact of different rescheduling strategies on the entropic-related complexity of manufacturing systems. International Journal of Production Research, 47(15), 4305-4325. doi:10.1080/00207540701871036Jensen, M. T. (2003). Generating robust and flexible job shop schedules using genetic algorithms. IEEE Transactions on Evolutionary Computation, 7(3), 275-288. doi:10.1109/tevc.2003.810067King, J. R. (1976). The theory-practice gap in job-shop scheduling. Production Engineer, 55(3), 137. doi:10.1049/tpe.1976.0044Kopanos, G. M., Capón-García, E., Espuña,, A., & Puigjaner, L. (2008). Costs for Rescheduling Actions: A Critical Issue for Reducing the Gap between Scheduling Theory and Practice. Industrial & Engineering Chemistry Research, 47(22), 8785-8795. doi:10.1021/ie8005676Lee, C.-Y., Leung, J. Y.-T., & Yu, G. (2006). Two Machine Scheduling under Disruptions with Transportation Considerations. Journal of Scheduling, 9(1), 35-48. doi:10.1007/s10951-006-5592-7Li, Z., & Ierapetritou, M. (2008). Process scheduling under uncertainty: Review and challenges. Computers & Chemical Engineering, 32(4-5), 715-727. doi:10.1016/j.compchemeng.2007.03.001Liao, C. J., & Chen, W. J. (2004). Scheduling under machine breakdown in a continuous process industry. Computers & Operations Research, 31(3), 415-428. doi:10.1016/s0305-0548(02)00224-1Mehta, S. V. (1999). Predictable scheduling of a single machine subject to breakdowns. International Journal of Computer Integrated Manufacturing, 12(1), 15-38. doi:10.1080/095119299130443MUHLEMANN, A. P., LOCKETT, A. G., & FARN, C.-K. (1982). Job shop scheduling heuristics and frequency of scheduling. International Journal of Production Research, 20(2), 227-241. doi:10.1080/00207548208947763Nawaz, M., Enscore, E. E., & Ham, I. (1983). A heuristic algorithm for the m-machine, n-job flow-shop sequencing problem. Omega, 11(1), 91-95. doi:10.1016/0305-0483(83)90088-9O’Donovan, R., Uzsoy, R., & McKay, K. N. (1999). Predictable scheduling of a single machine with breakdowns and sensitive jobs. International Journal of Production Research, 37(18), 4217-4233. doi:10.1080/002075499189745Özlen, M., & Azizoğlu, M. (2009). Generating all efficient solutions of a rescheduling problem on unrelated parallel machines. International Journal of Production Research, 47(19), 5245-5270. doi:10.1080/00207540802043998Pfeiffer, A., Kádár, B., & Monostori, L. (2007). Stability-oriented evaluation of rescheduling strategies, by using simulation. Computers in Industry, 58(7), 630-643. doi:10.1016/j.compind.2007.05.009Pierreval, H., & Durieux-Paris, S. (2007). Robust simulation with a base environmental scenario. European Journal of Operational Research, 182(2), 783-793. doi:10.1016/j.ejor.2006.07.045Damodaran, P., Hirani, N. S., & Gallego, M. C. V. (2009). Scheduling identical parallel batch processing machines to minimise makespan using genetic algorithms. European J. of Industrial Engineering, 3(2), 187. doi:10.1504/ejie.2009.023605Qi, X., Bard, J. F., & Yu, G. (2006). Disruption management for machine scheduling: The case of SPT schedules. International Journal of Production Economics, 103(1), 166-184. doi:10.1016/j.ijpe.2005.05.021Rangsaritratsamee, R., Ferrell, W. G., & Kurz, M. B. (2004). Dynamic rescheduling that simultaneously considers efficiency and stability. Computers & Industrial Engineering, 46(1), 1-15. doi:10.1016/j.cie.2003.09.007Ruiz, R., & Stützle, T. (2007). A simple and effective iterated greedy algorithm for the permutation flowshop scheduling problem. European Journal of Operational Research, 177(3), 2033-2049. doi:10.1016/j.ejor.2005.12.009Sabuncuoglu, I., & Goren, S. (2009). Hedging production schedules against uncertainty in manufacturing environment with a review of robustness and stability research. International Journal of Computer Integrated Manufacturing, 22(2), 138-157. doi:10.1080/09511920802209033Sabuncuoglu, I., & Kizilisik, O. B. (2003). Reactive scheduling in a dynamic and stochastic FMS environment. International Journal of Production Research, 41(17), 4211-4231. doi:10.1080/0020754031000149202Salveson, M. E. (1952). On a Quantitative Method in Production Planning and Scheduling. Econometrica, 20(4), 554. doi:10.2307/1907643Samarghandi, H., & ElMekkawy, T. Y. (2011). An efficient hybrid algorithm for the two-machine no-wait flow shop problem with separable setup times and single server. European J. of Industrial Engineering, 5(2), 111. doi:10.1504/ejie.2011.039869Subramaniam *, V., Raheja, A. S., & Rama Bhupal Reddy, K. (2005). Reactive repair tool for job shop schedules. International Journal of Production Research, 43(1), 1-23. doi:10.1080/0020754042000270412Taillard, E. (1990). Some efficient heuristic methods for the flow shop sequencing problem. European Journal of Operational Research, 47(1), 65-74. doi:10.1016/0377-2217(90)90090-xTaillard, E. (1993). Benchmarks for basic scheduling problems. European Journal of Operational Research, 64(2), 278-285. doi:10.1016/0377-2217(93)90182-mValente, J. M. S., & Schaller, J. E. (2010). Improved heuristics for the single machine scheduling problem with linear early and quadratic tardy penalties. European J. of Industrial Engineering, 4(1), 99. doi:10.1504/ejie.2010.029572Vallada, E., & Ruiz, R. (2010). Genetic algorithms with path relinking for the minimum tardiness permutation flowshop problem☆. Omega, 38(1-2), 57-67. doi:10.1016/j.omega.2009.04.002Vieira, G. E., Herrmann, J. W., & Lin, E. (2000). Predicting the performance of rescheduling strategies for parallel machine systems. Journal of Manufacturing Systems, 19(4), 256-266. doi:10.1016/s0278-6125(01)80005-4Vieira, G. E., Herrmann, J. W., & Lin, E. (2003). Journal of Scheduling, 6(1), 39-62. doi:10.1023/a:1022235519958Yang, J., & Yu, G. (2002). Journal of Combinatorial Optimization, 6(1), 17-33. doi:10.1023/a:1013333232691Zandieh, M., & Gholami, M. (2009). An immune algorithm for scheduling a hybrid flow shop with sequence-dependent setup times and machines with random breakdowns. International Journal of Production Research, 47(24), 6999-7027. doi:10.1080/0020754080240063
Functional KV10.1 Channels Localize to the Inner Nuclear Membrane
Ectopically expressed human KV10.1 channels are relevant players in tumor biology. However, their function as ion channels at the plasma membrane does not totally explain their crucial role in tumors. Both in native and heterologous systems, it has been observed that a majority of KV10.1 channels remain at intracellular locations. In this study we investigated the localization and possible roles of perinuclear KV10.1. We show that KV10.1 is expressed at the inner nuclear membrane in both human and rat models; it co-purifies with established inner nuclear membrane markers, shows resistance to detergent extraction and restricted mobility, all of them typical features of proteins at the inner nuclear membrane. KV10.1 channels at the inner nuclear membrane are not all transported directly from the ER but rather have been exposed to the extracellular milieu. Patch clamp experiments on nuclei devoid of external nuclear membrane reveal the existence of channel activity compatible with KV10.1. We hypothesize that KV10.1 channels at the nuclear envelope might participate in the homeostasis of nuclear K+, or indirectly interact with heterochromatin, both factors known to affect gene expression
Transcription factories in the context of the nuclear and genome organization
In the eukaryotic nucleus, genes are transcribed in transcription factories. In the present review, we re-evaluate the models of transcription factories in the light of recent and older data. Based on this analysis, we propose that transcription factories result from the aggregation of RNA polymerase II-containing pre-initiation complexes assembled next to each other in the nuclear space. Such an aggregation can be triggered by the phosphorylation of the C-terminal domain of RNA polymerase II molecules and their interaction with various transcription factors. Individual transcription factories would thus incorporate tissue-specific, co-regulated as well as housekeeping genes based only on their initial proximity to each other in the nuclear space. Targeting genes to be transcribed to protein-dense factories that contain all factors necessary for transcription initiation and elongation through chromatin templates clearly favors a more economical utilization and better recycling of the transcription machinery
Nucleolus: the fascinating nuclear body
Nucleoli are the prominent contrasted structures of the cell nucleus. In the nucleolus, ribosomal RNAs are synthesized, processed and assembled with ribosomal proteins. RNA polymerase I synthesizes the ribosomal RNAs and this activity is cell cycle regulated. The nucleolus reveals the functional organization of the nucleus in which the compartmentation of the different steps of ribosome biogenesis is observed whereas the nucleolar machineries are in permanent exchange with the nucleoplasm and other nuclear bodies. After mitosis, nucleolar assembly is a time and space regulated process controlled by the cell cycle. In addition, by generating a large volume in the nucleus with apparently no RNA polymerase II activity, the nucleolus creates a domain of retention/sequestration of molecules normally active outside the nucleolus. Viruses interact with the nucleolus and recruit nucleolar proteins to facilitate virus replication. The nucleolus is also a sensor of stress due to the redistribution of the ribosomal proteins in the nucleoplasm by nucleolus disruption. The nucleolus plays several crucial functions in the nucleus: in addition to its function as ribosome factory of the cells it is a multifunctional nuclear domain, and nucleolar activity is linked with several pathologies. Perspectives on the evolution of this research area are proposed
Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial
Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council
Adult population ecology and egg laying strategy in the ‘cruciata’ ecotype of the endangered butterfly Maculinea alcon (Lepidoptera: Lycaenidae)
S-phase progression in mammalian cells: modelling the influence of nuclear organization
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