Zeitschriftenartikel: „Nuclear disruption“

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Riccardo, V., und JET EFDA contributors. „Disruptions and disruption mitigation“. Plasma Physics and Controlled Fusion 45, Nr. 12A (17.11.2003): A269—A284. http://dx.doi.org/10.1088/0741-3335/45/12a/018.

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Aymerich, E., G. Sias, F. Pisano, B. Cannas, S. Carcangiu, C. Sozzi, C. Stuart, P. J. Carvalho, A. Fanni und JET Contributors. „Disruption prediction at JET through deep convolutional neural networks using spatiotemporal information from plasma profiles“. Nuclear Fusion 62, Nr. 6 (04.04.2022): 066005. http://dx.doi.org/10.1088/1741-4326/ac525e.

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Abstract In view of the future high power nuclear fusion experiments, the early identification of disruptions is a mandatory requirement, and presently the main goal is moving from the disruption mitigation to disruption avoidance and control. In this work, a deep-convolutional neural network (CNN) is proposed to provide early detection of disruptive events at JET. The CNN ability to learn relevant features, avoiding hand-engineered feature extraction, has been exploited to extract the spatiotemporal information from 1D plasma profiles. The model is trained with regularly terminated discharges and automatically selected disruptive phase of disruptions, coming from the recent ITER-like-wall experiments. The prediction performance is evaluated using a set of discharges representative of different operating scenarios, and an in-depth analysis is made to evaluate the performance evolution with respect to the considered experimental conditions. Finally, as real-time triggers and termination schemes are being developed at JET, the proposed model has been tested on a set of recent experiments dedicated to plasma termination for disruption avoidance and mitigation. The CNN model demonstrates very high performance, and the exploitation of 1D plasma profiles as model input allows us to understand the underlying physical phenomena behind the predictor decision.

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Thornton, J. W. „Nonmammalian nuclear receptors: Evolution and endocrine disruption“. Pure and Applied Chemistry 75, Nr. 11-12 (01.01.2003): 1827–39. http://dx.doi.org/10.1351/pac200375111827.

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Most research to identify endocrine-disrupting chemicals and their impacts has relied on mammalian models or in vitro systems derived from them. But nuclear receptors (NRs), the proteins that transduce hydrophobic hormonal signals and are major mediators of endocrine disruption, emerged early in animal evolution and now play biologically essential roles throughout the Metazoa. Nonmammalian vertebrates and invertebrates, many of which are of considerable ecological, economic, and cultural importance, are therefore potentially subject to endocrine disruption by synthetic environmental pollutants. Are methods that rely solely on mammalian models adequate to predict or detect all chemicals that may disrupt NR signaling? Regulation of NRs by small hydrophobic molecules is ancient and evolutionarily labile. Within and across genomes, the NR superfamily is very diverse, due to many lineage-specific gene and genome duplications followed by independent divergence. Receptors in nonmammalian species have in many cases evolved unique molecular and organismal functions that cannot be predicted from those of their mammalian orthologs. Endocrine disruption is therefore likely to occur throughout the metazoan kingdom, and a significant number of the thousands of synthetic chemicals now in production may disrupt NR signaling in one or more nonmammalian taxa. Many of these endocrine disruptors will not be detected by current regulatory/scientific protocols, which should be reformulated to take account of the diversity and complexity of the NR gene family.

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Yang, Zongyu, Fan Xia, Xianming Song, Zhe Gao, Shuo Wang und Yunbo Dong. „In-depth research on the interpretable disruption predictor in HL-2A“. Nuclear Fusion 61, Nr. 12 (12.11.2021): 126042. http://dx.doi.org/10.1088/1741-4326/ac31d8.

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Abstract In-depth research is implemented on the disruption predictor in HL-2A to improve the accuracy and interpretability of the model. For higher accuracy, four adjustments are tried to solve four corresponding problems in a baseline model. Reductive comparison experiments are designed to evaluate their contribution to performance. The result shows that these adjustments together can improve the AUC (area under receiver operating characteristic curve) of the baseline model by 0.039. For interpretability of model, an interpretation method is proposed to evaluate the real-time importance of each input signal. The result of single shot interpretation shows good coherence with the causes of disruptions. To further validate the reasonability of this interpretation method, disruption causes of shot nos. 20000–36000 are analysed to make a disruption cause dataset. Statistical analysis of the output of the interpretation algorithm on this dataset also shows a good coherence with the disruption causes. Then a Bayes classifier is developed to recognize the cause of disruption based on the interpretation algorithm’s output. This classifier has an accuracy of 71.2% on the labelled dataset, which contains 605 disruptive shots categorized into five disruption causes.

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Fyfe, Ian. „TDP pathology leads to nuclear disruption“. Nature Reviews Neurology 14, Nr. 3 (19.01.2018): 127. http://dx.doi.org/10.1038/nrneurol.2018.2.

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6

Wie, B. „Hypervelocity nuclear interceptors for asteroid disruption“. Acta Astronautica 90, Nr. 1 (September 2013): 146–55. http://dx.doi.org/10.1016/j.actaastro.2012.04.028.

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Furukawa, Manabu, Yanping Zhang, Joseph McCarville, Tomohiko Ohta und Yue Xiong. „The CUL1 C-Terminal Sequence and ROC1 Are Required for Efficient Nuclear Accumulation, NEDD8 Modification, and Ubiquitin Ligase Activity of CUL1“. Molecular and Cellular Biology 20, Nr. 21 (01.11.2000): 8185–97. http://dx.doi.org/10.1128/mcb.20.21.8185-8197.2000.

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ABSTRACT Members of the cullin and RING finger ROC protein families form heterodimeric complexes to constitute a potentially large number of distinct E3 ubiquitin ligases. We report here that the highly conserved C-terminal sequence in CUL1 is dually required, both for nuclear localization and for modification by NEDD8. Disruption of ROC1 binding impaired nuclear accumulation of CUL1 and decreased NEDD8 modification in vivo but had no effect on NEDD8 modification of CUL1 in vitro, suggesting that ROC1 promotes CUL1 nuclear accumulation to facilitate its NEDD8 modification. Disruption of NEDD8 binding had no effect on ROC1 binding, nor did it affect nuclear localization of CUL1, suggesting that nuclear localization and NEDD8 modification of CUL1 are two separable steps, with nuclear import preceding and required for NEDD8 modification. Disrupting NEDD8 modification diminishes the IκBα ubiquitin ligase activity of CUL1. These results identify a pathway for regulation of CUL1 activity—ROC1 and the CUL1 C-terminal sequence collaboratively mediate nuclear accumulation and NEDD8 modification, facilitating assembly of active CUL1 ubiquitin ligase. This pathway may be commonly utilized for the assembly of other cullin ligases.

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Clark-Walker, G. D., und X. J. Chen. „Dual Mutations Reveal Interactions Between Components of Oxidative Phosphorylation in Kluyveromyces lactis“. Genetics 159, Nr. 3 (01.11.2001): 929–38. http://dx.doi.org/10.1093/genetics/159.3.929.

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Abstract Loss of mtDNA or mitochondrial protein synthesis cannot be tolerated by wild-type Kluyveromyces lactis. The mitochondrial function responsible for ρ0-lethality has been identified by disruption of nuclear genes encoding electron transport and F0-ATP synthase components of oxidative phosphorylation. Sporulation of diploid strains heterozygous for disruptions in genes for the two components of oxidative phosphorylation results in the formation of nonviable spores inferred to contain both disruptions. Lethality of spores is thought to result from absence of a transmembrane potential, ΔΨ, across the mitochondrial inner membrane due to lack of proton pumping by the electron transport chain or reversal of F1F0-ATP synthase. Synergistic lethality, caused by disruption of nuclear genes, or ρ0-lethality can be suppressed by the atp2.1 mutation in the β-subunit of F1-ATPase. Suppression is viewed as occurring by an increased hydrolysis of ATP by mutant F1, allowing sufficient electrogenic exchange by the translocase of ADP in the matrix for ATP in the cytosol to maintain ΔΨ. In addition, lethality of haploid strains with a disruption of AAC encoding the ADP/ATP translocase can be suppressed by atp2.1. In this case suppression is considered to occur by mutant F1 acting in the forward direction to partially uncouple ATP production, thereby stimulating respiration and relieving detrimental hyperpolarization of the inner membrane. Participation of the ADP/ATP translocase in suppression of ρ0-lethality is supported by the observation that disruption of AAC abolishes suppressor activity of atp2.1.

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Ohkawa, Taro, und Matthew D. Welch. „Baculovirus Actin-Based Motility Drives Nuclear Envelope Disruption and Nuclear Egress“. Current Biology 28, Nr. 13 (Juli 2018): 2153–59. http://dx.doi.org/10.1016/j.cub.2018.05.027.

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Spann, Timothy P., Anne E. Goldman, Chen Wang, Sui Huang und Robert D. Goldman. „Alteration of nuclear lamin organization inhibits RNA polymerase II–dependent transcription“. Journal of Cell Biology 156, Nr. 4 (18.02.2002): 603–8. http://dx.doi.org/10.1083/jcb.200112047.

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RTegulation of gene activity is mediated by alterations in chromatin organization. In addition, chromatin organization may be governed in part by interactions with structural components of the nucleus. The nuclear lamins comprise the lamina and a variety of nucleoplasmic assemblies that together are major structural components of the nucleus. Furthermore, lamins and lamin-associated proteins have been reported to bind chromatin. These observations suggest that the nuclear lamins may be involved in the regulation of gene activity. In this report, we test this possibility by disrupting the normal organization of nuclear lamins with a dominant negative lamin mutant lacking the NH2-terminal domain. We find that this disruption inhibits RNA polymerase II activity in both mammalian cells and transcriptionally active embryonic nuclei from Xenopus laevis. The inhibition appears to be specific for polymerase II as disruption of lamin organization does not detectably inhibit RNA polymerases I and III. Furthermore, immunofluorescence observations indicate that this selective inhibition of polymerase II–dependent transcription involves the TATA binding protein, a component of the basal transcription factor TFIID.

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Mockler, Brenna, Angela A. Twum, Katie Auchettl, Sierra Dodd, K. D. French, Jamie A. P. Law-Smith und Enrico Ramirez-Ruiz. „Evidence for the Preferential Disruption of Moderately Massive Stars by Supermassive Black Holes“. Astrophysical Journal 924, Nr. 2 (01.01.2022): 70. http://dx.doi.org/10.3847/1538-4357/ac35d5.

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Abstract Tidal disruption events (TDEs) provide a unique opportunity to probe the stellar populations around supermassive black holes (SMBHs). By combining light-curve modeling with spectral line information and knowledge about the stellar populations in the host galaxies, we are able to constrain the properties of the disrupted star for three TDEs. The TDEs in our sample have UV spectra, and measurements of the UV N iii to C iii line ratios enabled estimates of the nitrogen-to-carbon abundance ratios for these events. We show that the measured nitrogen line widths are consistent with originating from the disrupted stellar material dispersed by the central SMBH. We find that these nitrogen-to-carbon abundance ratios necessitate the disruption of moderately massive stars (≳1–2 M ⊙). We determine that these moderately massive disruptions are overrepresented by a factor of ≳102 when compared to the overall stellar population of the post-starburst galaxy hosts. This implies that SMBHs are preferentially disrupting higher mass stars, possibly due to ongoing top-heavy star formation in nuclear star clusters or to dynamical mechanisms that preferentially transport higher mass stars to their tidal radii.

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Liang, Jiali, Marc Ernoult, Xavier Doligez, Sylvain David, Léa Tillard und Nicolas Thiollière. „Robustness Study of Electro-Nuclear Scenario under Disruption“. Journal of Nuclear Engineering 2, Nr. 1 (28.01.2021): 1–8. http://dx.doi.org/10.3390/jne2010001.

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As the future of nuclear power is uncertain, only choosing one development objective for the coming decades can be risky; while trying to achieve several possible objectives at the same time may lead to a deadlock due to contradiction among them. In this work, we study a simple scenario to illustrate the newly developed method of robustness study, which considers possible change of objectives. Starting from the current French fleet, two objectives are considered regarding the possible political choices for the future of nuclear power: A. Complete substitution of Pressurized Water Reactors by Sodium-cooled Fast Reactors in 2180; B. Minimization of all potential nuclear wastes without SFR deployment in 2180. To study the robustness of strategies, the disruption of objective is considered: the objective to be pursued is possibly changed abruptly from A into B at unknown time. To minimize the consequence of such uncertainty, the first option is to identify a robust static strategy, which shows the best performance for both objectives A and B in the predisruption situation. The second option is to adapt a trajectory which pursues initially objective A, for objective B in case of the disruption. To identify and to analyze the adaptively robust strategies, outcomes of possible adaptations upon a given trajectory are compared with the robust static optimum. The temporality of adaptive robustness is analyzed by investigating different adaptation times.

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Melo, Sonia A., und Manel Esteller. „Disruption of microRNA nuclear transport in human cancer“. Seminars in Cancer Biology 27 (August 2014): 46–51. http://dx.doi.org/10.1016/j.semcancer.2014.02.012.

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Razafsky, David, Shulun Zang und Didier Hodzic. „UnLINCing the nuclear envelope: towards an understanding of the physiological significance of nuclear positioning“. Biochemical Society Transactions 39, Nr. 6 (21.11.2011): 1790–94. http://dx.doi.org/10.1042/bst20110660.

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Appropriate tissue morphogenesis strictly requires the developmental regulation of different types of nuclear movements. LINC (linker of nucleoskeleton and cytoskeleton) complexes are macromolecular scaffolds that span the nuclear envelope and physically connect the nuclear interior to different cytoskeletal elements and molecular motors, thereby playing essential roles in nucleokinesis. Recent studies dedicated to the in vivo disruption of LINC complexes not only confirmed their widespread role in nuclear dynamics, but also led to a vigorous regain of interest in the physiological relevance of nuclear positioning within cells and syncitia. In the present paper, we review the results of LINC complex disruption in vivo across different organisms and the potential implications of observed phenotypes in human diseases.

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Mattila, S., M. J. Graham, E. Kankare, E. Kool, T. Moriya, M. Perez-Torres und Ł. Wyrzykowski. „Nuclear Transients“. Proceedings of the International Astronomical Union 14, S339 (November 2017): 263–68. http://dx.doi.org/10.1017/s1743921318002727.

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AbstractWorkshop 11 covered the substantial recent progress in studies of supernovæ (SNe), tidal disruption events (TDEs), and other types of luminous transients occurring within the nuclear regions of galaxies. In the past, such transients have largely been missed owing to the substantial extinction of those regions, and to the problems of contrast against the bright (and often complex) nuclear background – or mistaken for normal active galactic nucleus (AGN) variability.

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Lane, Cynthia M., Ian Cushman und Mary Shannon Moore. „Selective Disruption of Nuclear Import by a Functional Mutant Nuclear Transport Carrier“. Journal of Cell Biology 151, Nr. 2 (16.10.2000): 321–32. http://dx.doi.org/10.1083/jcb.151.2.321.

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p10/NTF2 is a nuclear transport carrier that mediates the uptake of cytoplasmic RanGDP into the nucleus. We constructed a point mutant of p10, D23A, that exhibited unexpected behavior both in digitonin-permeabilized and microinjected mammalian cells. D23A p10 was markedly more efficient than wild-type (wt) p10 at supporting Ran import, but simultaneously acted as a dominant-negative inhibitor of classical nuclear localization sequence (cNLS)-mediated nuclear import supported by karyopherins (Kaps) α and β1. Binding studies indicated that these two nuclear transport carriers of different classes, p10 and Kap-β1, compete for identical and/or overlapping binding sites at the nuclear pore complex (NPC) and that D23A p10 has an increased affinity relative to wt p10 and Kap-β1 for these shared binding sites. Because of this increased affinity, D23A p10 is able to import its own cargo (RanGDP) more efficiently than wt p10, but Kap-β1 can no longer compete efficiently for shared NPC docking sites, thus the import of cNLS cargo is inhibited. The competition of different nuclear carriers for shared NPC docking sites observed here predicts a dynamic equilibrium between multiple nuclear transport pathways inside the cell that could be easily shifted by a transient modification of one of the carriers.

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Shahin, Victor. „Strategic disruption of nuclear pores structure, integrity and barrier for nuclear apoptosis“. Seminars in Cell & Developmental Biology 68 (August 2017): 85–90. http://dx.doi.org/10.1016/j.semcdb.2017.07.002.

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Ma, Hong, Alan J. Siegel und Ronald Berezney. „Association of Chromosome Territories with the Nuclear Matrix“. Journal of Cell Biology 146, Nr. 3 (09.08.1999): 531–42. http://dx.doi.org/10.1083/jcb.146.3.531.

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To study the possible role of the nuclear matrix in chromosome territory organization, normal human fibroblast cells are treated in situ via classic isolation procedures for nuclear matrix in the absence of nuclease (e.g., DNase I) digestion, followed by chromosome painting. We report for the first time that chromosome territories are maintained intact on the nuclear matrix. In contrast, complete extraction of the internal nuclear matrix components with RNase treatment followed by 2 M NaCl results in the disruption of higher order chromosome territory architecture. Correlative with territorial disruption is the formation of a faint DNA halo surrounding the nuclear lamina and a dispersive effect on the characteristically discrete DNA replication sites in the nuclear interior. Identical results were obtained using eight different human chromosome paints. Based on these findings, we developed a fractionation strategy to release the bulk of nuclear matrix proteins under conditions where the chromosome territories are maintained intact. A second treatment results in disruption of the chromosome territories in conjunction with the release of a small subset of acidic proteins. These proteins are distinct from the major nuclear matrix proteins and may be involved in mediating chromosome territory organization.

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Zhou, Zheng, Jaclyn M. Goodrich und Rita S. Strakovsky. „Mitochondrial Epigenetics and Environmental Health: Making a Case for Endocrine Disrupting Chemicals“. Toxicological Sciences 178, Nr. 1 (10.08.2020): 16–25. http://dx.doi.org/10.1093/toxsci/kfaa129.

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Abstract Recent studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases, which may be partially due to modifications in mitochondrial DNA (mtDNA). There is also mounting evidence that epigenetic modifications to mtDNA may be an additional layer of regulation that controls mitochondrial biogenesis and function. Several environmental factors (eg, smoking, air pollution) have been associated with altered mtDNA methylation in a handful of mechanistic studies and in observational human studies. However, little is understood about other environmental contaminants that induce mtDNA epigenetic changes. Numerous environmental toxicants are classified as endocrine disrupting chemicals (EDCs). Beyond their actions on hormonal pathways, EDC exposure is associated with elevated oxidative stress, which may occur through or result in mitochondrial dysfunction. Although only a few studies have assessed the impacts of EDCs on mtDNA methylation, the current review provides reasons to consider mtDNA epigenetic disruption as a mechanism of action of EDCs and reviews potential limitations related to currently available evidence. First, there is sufficient evidence that EDCs (including bisphenols and phthalates) directly target mitochondrial function, and more direct evidence is needed to connect this to mtDNA methylation. Second, these and other EDCs are potent modulators of nuclear DNA epigenetics, including DNA methylation and histone modifications. Finally, EDCs have been shown to disrupt several modulators of mtDNA methylation, including DNA methyltransferases and the mitochondrial transcription factor A/nuclear respiratory factor 1 pathway. Taken together, these studies highlight the need for future research evaluating mtDNA epigenetic disruption by EDCs and to detail specific mechanisms responsible for such disruptions.

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Boyer, M. D., C. Rea und M. Clement. „Toward active disruption avoidance via real-time estimation of the safe operating region and disruption proximity in tokamaks“. Nuclear Fusion 62, Nr. 2 (16.12.2021): 026005. http://dx.doi.org/10.1088/1741-4326/ac359e.

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Abstract This paper describes a real-time capable algorithm for identifying the safe operating region around a tokamak operating point. The region is defined by a convex set of linear constraints, from which the distance of a point from a disruptive boundary can be calculated. The disruptivity of points is calculated from an empirical machine learning predictor that generates the likelihood of disruption. While the likelihood generated by such empirical models can be compared to a threshold to trigger a disruption mitigation system, the safe operating region calculation enables active optimization of the operating point to maintain a safe margin from disruptive boundaries. The proposed algorithm is tested using a random forest disruption predictor fit on data from DIII-D. The safe operating region identification algorithm is applied to historical data from DIII-D showing the evolution of disruptive boundaries and the potential impact of optimization of the operating point. Real-time relevant execution times are made possible by parallelizing many of the calculation steps and implementing the algorithm on a graphics processing unit. A real-time capable algorithm for optimizing the target operating point within the identified constraints is also proposed and simulated.

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I. Simunic, David, Neil D. Broom und Peter A. Robertson. „Biomechanical Factors Influencing Nuclear Disruption of the Intervertebral Disc“. Spine 26, Nr. 11 (Juni 2001): 1223–30. http://dx.doi.org/10.1097/00007632-200106010-00010.

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Dube, Thembalami, Christina A. Rabeler und Dawn Carone. „In vivo disruption of nuclear HSATII RNA biomolecular condensates“. Biophysical Journal 122, Nr. 3 (Februar 2023): 486a—487a. http://dx.doi.org/10.1016/j.bpj.2022.11.2601.

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Clarke, Teagan A., Lani Chastain, Paul D. Lasky und Eric Thrane. „Nuclear Physics with Gravitational Waves from Neutron Stars Disrupted by Black Holes“. Astrophysical Journal Letters 949, Nr. 1 (01.05.2023): L6. http://dx.doi.org/10.3847/2041-8213/acd33b.

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Abstract Gravitational waves from neutron star–black hole (NSBH) mergers that undergo tidal disruption provide a potential avenue to study the equation of state of neutron stars and hence the behavior of matter at its most extreme densities. We present a phenomenological model for the gravitational-wave signature of tidal disruption, which allows us to measure the disruption time. We carry out a study with mock data, assuming an optimistically nearby NSBH event with parameters tuned for measuring the tidal disruption. We show that a two-detector network of 40 km Cosmic Explorer instruments can measure the time of disruption with a precision of ≈0.5 ms, which corresponds to a constraint on the neutron star radius of ≈0.7 km (90% credibility). This radius constraint is wider than the constraint obtained by measuring the tidal deformability of the neutron star of the same system during the inspiral. Moreover, the neutron star radius is likely to be more tightly constrained using binary neutron star mergers. While NSBH mergers are important for the information they provide about stellar and binary astrophysics, they are unlikely to provide insights into nuclear physics beyond what we will already know from binary neutron star mergers.

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Swedenborg, Elin, Joëlle Rüegg, Sari Mäkelä und Ingemar Pongratz. „Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders“. Journal of Molecular Endocrinology 43, Nr. 1 (11.02.2009): 1–10. http://dx.doi.org/10.1677/jme-08-0132.

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Endocrine disruption refers to the ability of chemicals to interfere with hormonal systems, and has raised considerable concern in recent years. Endocrine disruptive chemicals (EDCs) pose a documented risk to wildlife and have the potential to negatively influence human health. This review focuses on the molecular mechanisms of endocrine disruption and the possible involvement of EDCs in metabolic disorders. The first part describes the role of aryl hydrocarbon receptor (AhR) and nuclear receptors (NRs) in mediating effects of EDCs, in particular, how cross-talk between AhR and NR pathways can lead to endocrine disruption. The second part deals with how these receptors are involved in metabolic functions and how their targeting by EDCs can lead to disturbances in glucose and fat metabolism. The article illustrates that, although there is accumulating data on molecular mechanisms of EDC action as well as on EDC involvement in metabolic disorders, there is still a great demand for data that can unite the mechanistic and the toxicological/epidemiological observations.

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Moravcsik, Eva, Melanie Joannides, Edwige Voisset, Eva Wessel Stratford, Bernd B. Zeisig, Jo Morris, Ruth Densham et al. „Disruption Of PML Nuclear Bodies Cooperates In The Pathogenesis Of Acute Promyelocytic Leukemia“. Blood 122, Nr. 21 (15.11.2013): 3721. http://dx.doi.org/10.1182/blood.v122.21.3721.3721.

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Abstract Acute promyelocytic leukemia (APL) is characterised by the t(15;17)(q22;q21) leading to fusion of PML to the gene encoding the myeloid transcription factor Retinoic Acid Receptor α (RARα). Chromosomal translocations such as the t(15;17) are considered to be initiating events in leukemogenesis; however, sequencing of APL genomes has provided further evidence that the PML-RARα fusion is insufficient to induce leukemia, which depends upon the acquisition of cooperating mutations. The PML-RARα oncoprotein exerts a profound effect on nuclear architecture, disrupting multiprotein structures known as PML nuclear bodies (NBs). The function of these structures remains an enigma; however, their disruption in PML-RARα+ APL and acute lymphoblastic leukemia with the t(9;15)(p13;q24)/PAX5-PML fusion is associated with delocalisation of a number of component proteins including PML, which have been implicated in growth control and neoplastic transformation. It is now established that the PML moiety contributes to APL pathogenesis by conferring via the translocation a novel dimerisation capacity to RARα, but it has been unclear whether deregulation of PML and other NB components cooperates in leukemic transformation or impacts the response to differentiating agents. To address these questions, we generated a knock-in mouse model with targeted NB disruption achieved through mutation of key zinc-binding cysteine residues in the amino-terminal RING domain of Pml. Homozygous Pml RING mutant mice are viable, with no overt developmental defect; however, analysis of the bone marrow revealed significant expansion of the Lin(-)Sca-1(+)c-Kit(+) (LSK) population compared to wild type (WT) controls (p<0.01), accompanied by increased LSK cell proliferation (p<0.0001) as evaluated by in vivo labelling through incorporation of 5-ethynyl-2'-deoxyuridine (EdU). In addition, hematopoietic cells derived from homozygous Pml RING mutant mice exhibited markedly elevated levels of DNA damage compared to WT cells from age-matched controls, as evidenced by increased numbers of γH2AX foci (p=0.009). This was associated with significantly delayed DNA damage repair responses in Pml RING mutant cells following γ-irradiation (p=0.005). Accordingly, expression of PML-RARα in human hematopoietic cells, which led to disruption of NBs, also induced a significant increase in γH2AX foci (p=0.0023). While no leukemias arose in homozygous Pml RING mutant mice, they developed an excess of T- and B-cell lymphomas (p=0.03), consistent with the proposed tumour suppressor function of PML and the NBs. Since a key property conferred by the PML moiety required for leukemogenicity of the PML-RARα oncoprotein is the capacity to dimerise, we evaluated whether Pml NB disruption could cooperate with forced RARα homodimerisation (mediated artificially by linking RARα to the p50 dimerisation motif of NFκB). While Pml NB disruption or p50-RARA expressed under the control of the MRP8 promoter in murine hematopoietic stem/progenitor cells conferred limited replating capacity, in combination they exhibited marked cooperativity, with a significant increase in third round colonies (p=0.03). Moreover, NB disruption was found to cooperate with forced RARα homodimerisation in vivo with a doubling in the rate of leukemia development in p50-RARα mice with mutated Pml (p<0.0001), leading to a penetrance comparable to that observed in previously published PML-RARα transgenic models. Moreover, the latency to onset of leukemia was significantly shorter in p50-RARα mice with the Pml RING mutation, occurring from 213 days of age vs 310 days with WT Pml (p=0.008). While Pml NB disruption did not affect engraftment of p50-RARα leukemias in serial transplantation, the in vitro differentiation response of p50-RARα leukemias to All transretinoic acid (ATRA) as determined by nitroblue tetrazolium assay was significantly impaired in the context of NB disruption (p<0.05). Moreover, prolongation of survival following ATRA treatment in mice transplanted with p50-RARα leukemic blasts was dependent upon Pml NB integrity (p=0.03). Overall, these data suggest that the NB disruption mediated by the PML-RARα oncoprotein plays a key role in APL pathogenesis contributing to expansion of the LSK population and defective DNA repair predisposing to the acquisition of cooperating mutations, but also implicate NBs in the response to differentiating agents. Disclosures: No relevant conflicts of interest to declare.

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Ryu, Taeho, Rosalba Perna und Matteo Cantiello. „Tidal Disruption Encores“. Astrophysical Journal Letters 965, Nr. 2 (01.04.2024): L25. http://dx.doi.org/10.3847/2041-8213/ad3946.

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Abstract Nuclear star clusters (NSCs), made up of a dense concentration of stars and the compact objects they leave behind, are ubiquitous in the central regions of galaxies surrounding the central supermassive black hole (SMBH). Close interactions between stars and stellar-mass black holes (sBHs) lead to tidal disruption events (TDEs). We uncover an interesting new phenomenon: for a subset of these, the unbound debris (to the sBH) remains bound to the SMBH, accreting at a later time, thus giving rise to a second flare. We compute the rate of such events and find them ranging within 10−6–10−3 yr−1 gal−1 for SMBH mass ≃106–109 M ⊙. Time delays between the two flares spread over a wide range, from less than a year to hundreds of years. The temporal evolution of the light curves of the second flare can vary between the standard t −5/3 power law to much steeper decays, providing a natural explanation for observed light curves in tension with the classical TDE model. Our predictions have implications for learning about NSC properties and calibrating its sBH population. Some double flares may be electromagnetic counterparts to LISA extreme-mass-ratio inspiral sources. Another important implication is the possible existence of TDE-like events in very massive SMBHs, where TDEs are not expected. Such flares can affect spin measurements relying on TDEs in the upper SMBH range.

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Morrissette, Naomi S., und L. David Sibley. „Disruption of microtubules uncouples budding and nuclear division inToxoplasma gondii“. Journal of Cell Science 115, Nr. 5 (01.03.2002): 1017–25. http://dx.doi.org/10.1242/jcs.115.5.1017.

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The tachyzoite stage of the protozoan parasite Toxoplasma gondiihas two populations of microtubules: spindle microtubules and subpellicular microtubules. To determine how these two microtubule populations are regulated, we investigated microtubule behavior during the cell cycle following treatment with microtubule-disrupting drugs. Previous work had established that the microtubule populations are individually nucleated by two distinct microtubule-organizing centers (MTOCs): the apical polar ring for the subpellicular microtubules and spindle pole plaques/centrioles for the spindle microtubules. When replicating tachyzoites were treated with 0.5 μM oryzalin or 1.0 mM colchicine they retained the capacity to form a spindle and undergo nuclear division. Although these parasites could complete budding,they lost the bulk of their subpellicular microtubules and the ability to reinvade host cells. Both nascent spindle and subpellicular microtubules were disrupted in 2.5 μM oryzalin or 5.0 mM colchicine. Under these conditions,parasites grew in size and replicated their genome but were incapable of nuclear division. After removal from 0.5 μM oryzalin, Toxoplasmatachyzoites were able to restore normal subpellicular microtubules and a fully invasive phenotype. When oryzalin was removed from Toxoplasmatachyzoites treated with 2.5 μM drug, the parasites attempted to bud as crescent-shaped tachyzoites. Because the polyploid nuclear mass could not be correctly segregated, many daughter parasites lacked nuclei altogether although budding and scission from the maternal mass was able to be completed. Multiple MTOCs permit Toxoplasma tachyzoites to control nuclear division independently from cell polarity and cytokinesis. This unusual situation grants greater cell cycle flexibility to these parasites but abolishes the checks for coregulation of nuclear division and cytokinesis found in other eukaryotes.

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Gezari, Suvi. „Tidal Disruption Events“. Annual Review of Astronomy and Astrophysics 59, Nr. 1 (08.09.2021): 21–58. http://dx.doi.org/10.1146/annurev-astro-111720-030029.

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The concept of stars being tidally ripped apart and consumed by a massive black hole (MBH) lurking in the center of a galaxy first captivated theorists in the late 1970s. The observational evidence for these rare but illuminating phenomena for probing otherwise dormant MBHs first emerged in archival searches of the soft X-ray ROSAT All-Sky Survey in the 1990s, but has recently accelerated with the increasing survey power in the optical time domain, with tidal disruption events (TDEs) now regarded as a class of optical nuclear transients with distinct spectroscopic features. Multiwavelength observations of TDEs have revealed panchromatic emission, probing a wide range of scales, from the innermost regions of the accretion flow to the surrounding circumnuclear medium. I review the current census of 56 TDEs reported in the literature, and their observed properties can be summarized as follows: ▪ The optical light curves follow a power-law decline from peak that scales with the inferred central black hole mass as expected for the fallback rate of the stellar debris, but the rise time does not. ▪ The UV-optical and soft X-ray thermal emission come from different spatial scales, and their intensity ratio has a large dynamic range and is highly variable, providing important clues as to what is powering the two components. ▪ They can be grouped into three spectral classes, and those with Bowen fluorescence line emission show a preference for a hotter and more compact line-emitting region, whereas those with only Heii emission lines are the rarest class.

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Zhong, Shiyan, Shuo Li, Peter Berczik und Rainer Spurzem. „Revisit the Rate of Tidal Disruption Events: The Role of the Partial Tidal Disruption Event“. Astrophysical Journal 933, Nr. 1 (01.07.2022): 96. http://dx.doi.org/10.3847/1538-4357/ac71ad.

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Abstract Tidal disruption of stars in dense nuclear star clusters containing supermassive central black holes (SMBH) is modeled by high-accuracy direct N-body simulation. Stars getting too close to the SMBH are tidally disrupted, and a tidal disruption event (TDE) happens. The TDEs probe the properties of SMBHs, their accretion disks, and the surrounding nuclear stellar cluster. In this paper, we compare the rates of full tidal disruption events (FTDEs) with partial tidal disruption events (PTDEs). Since a PTDE does not destroy the star, a leftover object emerges; we use the term “leftover star” for it. Two novel effects occur in the simulation: (1) variation of the leftover star’s mass and radius and (2) variation of the leftover star’s orbital energy. After switching on these two effects in our simulation, the number of FTDEs is reduced by roughly 28%, and the reduction is mostly due to the ejection of the leftover stars from PTDEs originally coming from a relatively large distance. The number of PTDEs is about 75% higher than the simple estimation given by Stone et al., and the enhancement is mainly due to the multiple PTDEs produced by the leftover stars residing in the diffusive regime. We compute the peak mass fallback rate for the PTDEs and FTDEs recorded in the simulation and find that 58% of the PTDEs have a peak mass fallback rate exceeding the Eddington limit, and the number of super-Eddington PTDEs is 2.3 times the number of super-Eddington FTDEs.

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Li, Su-Ting T., und Alexander B. Baxter. „Traumatic Ossicular Disruption“. American Journal of Roentgenology 174, Nr. 5 (Mai 2000): 1296. http://dx.doi.org/10.2214/ajr.174.5.1741296.

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Leach, Natalie, Susan L. Bjerke, Desire K. Christensen, Jacques M. Bouchard, Fan Mou, Richard Park, Joel Baines, Tokuko Haraguchi und Richard J. Roller. „Emerin Is Hyperphosphorylated and Redistributed in Herpes Simplex Virus Type 1-Infected Cells in a Manner Dependent on both UL34 and US3“. Journal of Virology 81, Nr. 19 (25.07.2007): 10792–803. http://dx.doi.org/10.1128/jvi.00196-07.

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ABSTRACT Cells infected with wild-type herpes simplex virus type 1 (HSV-1) show disruption of the organization of the nuclear lamina that underlies the nuclear envelope. This disruption is reflected in changes in the localization and phosphorylation of lamin proteins. Here, we show that HSV-1 infection causes relocalization of the LEM domain protein emerin. In cells infected with wild-type virus, emerin becomes more mobile in the nuclear membrane, and in cells infected with viruses that fail to express UL34 protein (pUL34) and US3 protein (pUS3), emerin no longer colocalizes with lamins, suggesting that infection causes a loss of connection between emerin and the lamina. Infection causes hyperphosphorylation of emerin in a manner dependent upon both pUL34 and pUS3. Some emerin hyperphosphorylation can be inhibited by the protein kinase Cδ (PKCδ) inhibitor rottlerin. Emerin and pUL34 interact physically, as shown by pull-down and coimmunoprecipitation assays. Emerin expression is not, however, necessary for infection, since virus growth is not impaired in cells derived from emerin-null transgenic mice. The results suggest a model in which pUS3 and PKCδ that has been recruited by pUL34 hyperphosphorylate emerin, leading to disruption of its connections with lamin proteins and contributing to the disruption of the nuclear lamina. Changes in emerin localization, nuclear shape, and lamin organization characteristic of cells infected with wild-type HSV-1 also occur in cells infected with recombinant virus that does not make viral capsids, suggesting that these changes occur independently of capsid envelopment.

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KUSTERMANS, Gaelle, Jamel EL BENNA, Jacques PIETTE und Sylvie LEGRAND-POELS. „Perturbation of actin dynamics induces NF-κB activation in myelomonocytic cells through an NADPH oxidase-dependent pathway“. Biochemical Journal 387, Nr. 2 (05.04.2005): 531–40. http://dx.doi.org/10.1042/bj20041318.

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Although several reports showed the effect of compounds disrupting microtubules on NF-κB (nuclear factor κB) activation, nothing is known about agents perturbing actin dynamics. In the present study, we have shown that actin cytoskeleton disruption induced by actin-depolymerizing agents such as cytochalasin D and latrunculin B and actin-polymerizing compounds such as jasplakinolide induced NF-κB activation in myelomonocytic cells. The transduction pathway involved the IκB (inhibitory κB) kinase complex and a degradation of IκBα. We have shown that NF-κB activation in response to the perturbation of actin dynamics required reactive oxygen species, as demonstrated by the effect of antioxidants. Actin cytoskeleton disruption by cytochalasin D induced O2− release from human monocytes, through the activation of the NADPH oxidase, as confirmed by the phosphorylation and by the membrane translocation of p47phox. NF-κB activation after actin cytoskeleton disruption could be physiologically relevant during monocyte activation and/or recruitment into injured tissues, where cellular attachment, migration and phagocytosis result in cyclic shifts in cytoskeletal organization and disorganization.

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Hamilton, Bruce A., Wayne N. Frankel, Anne W. Kerrebrock, Trevor L. Hawkins, William FitzHugh, Kenro Kusumi, Liane B. Russell et al. „Disruption of the nuclear hormone receptor RORα in staggerer mice“. Nature 379, Nr. 6567 (22.02.1996): 736–39. http://dx.doi.org/10.1038/379736a0.

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Grün, Felix, und Bruce Blumberg. „Environmental Obesogens: Organotins and Endocrine Disruption via Nuclear Receptor Signaling“. Endocrinology 147, Nr. 6 (01.06.2006): s50—s55. http://dx.doi.org/10.1210/en.2005-1129.

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Abella, Neus, Sonia Brun, Maria Calvo, Olga Tapia, Jason D. Weber, Maria T. Berciano, Miguel Lafarga, Oriol Bachs und Neus Agell. „Nucleolar Disruption Ensures Nuclear Accumulation of p21 upon DNA Damage“. Traffic 11, Nr. 6 (19.03.2010): 743–55. http://dx.doi.org/10.1111/j.1600-0854.2010.01063.x.

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Balaguer, Patrick, Vanessa Delfosse und William Bourguet. „Mechanisms of endocrine disruption through nuclear receptors and related pathways“. Current Opinion in Endocrine and Metabolic Research 7 (August 2019): 1–8. http://dx.doi.org/10.1016/j.coemr.2019.04.008.

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Kelly, C., R. Van Driel und G. W. G. Wilkinson. „Disruption of PML-associated nuclear bodies during human cytomegalovirus infection“. Journal of General Virology 76, Nr. 11 (01.11.1995): 2887–93. http://dx.doi.org/10.1099/0022-1317-76-11-2887.

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Jachmich, S., U. Kruezi, M. Lehnen, M. Baruzzo, L. R. Baylor, D. Carnevale, D. Craven et al. „Shattered pellet injection experiments at JET in support of the ITER disruption mitigation system design“. Nuclear Fusion 62, Nr. 2 (21.12.2021): 026012. http://dx.doi.org/10.1088/1741-4326/ac3c86.

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Abstract A series of experiments have been executed at JET to assess the efficacy of the newly installed shattered pellet injection (SPI) system in mitigating the effects of disruptions. Issues, important for the ITER disruption mitigation system, such as thermal load mitigation, avoidance of runaway electron (RE) formation, radiation asymmetries during thermal quench mitigation, electromagnetic load control and RE energy dissipation have been addressed over a large parameter range. The efficiency of the mitigation has been examined for the various SPI injection strategies. The paper summarises the results from these JET SPI experiments and discusses their implications for the ITER disruption mitigation scheme.

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Wu, Li-Ying, Chia-Lin Han, Hsi-Hui Lin und Ming-Jer Tang. „Ha-RasV12-Induced Multilayer Cellular Aggregates Is Mediated by Rac1 Activation Rather Than YAP Activation“. Biomedicines 10, Nr. 5 (23.04.2022): 977. http://dx.doi.org/10.3390/biomedicines10050977.

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We demonstrate that Ha-RasV12 overexpression induces the nuclear translocation of Hippo effector Yes-associated protein (YAP) in MDCK cells via the hippo-independent pathway at the confluent stage. Ha-RasV12 overexpression leads to the downregulation of Caveolin-1 (Cav1) and the disruption of junction integrity. It has been shown that the disruption of actin belt integrity causes YAP nuclear translocation in epithelial cells at high density. Therefore, we hypothesized that Ha-RasV12-decreased Cav1 leads to the disruption of cell junction integrity, which subsequently facilitates YAP nuclear retention. We revealed that Ha-RasV12 downregulated Cav1 through the ERK pathway. Furthermore, the distribution and expression of Cav1 mediated the cell junction integrity and YAP nuclear localization. This suggests that the downregulation of Cav1 induced by Ha-RasV12 disrupted the cell junction integrity and promoted YAP nuclear translocation. We further indicated the consequence of Ha-RasV12-induced YAP activation. Surprisingly, the activation of YAP is not required for Ha-RasV12-induced multilayer cellular aggregates. Instead, Ha-RasV12 triggered the ERK-Rac pathway to promote cellular aggregate formation. Moreover, the overexpression of constitutively active Rac is sufficient to trigger cellular aggregation in MDCK cells at the confluent stage. This highlights that Rac activity is essential for cellular aggregates.

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Anantharaju, Abhinandana, Ahmad Cheema, David H. Van Thiel und Jack Leya. „Complete esophagogastric anastomotic disruption“. Gastrointestinal Endoscopy 57, Nr. 7 (Juni 2003): 921. http://dx.doi.org/10.1016/s0016-5107(03)70034-0.

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Moir, Robert D., Timothy P. Spann, Harald Herrmann und Robert D. Goldman. „Disruption of Nuclear Lamin Organization Blocks the Elongation Phase of DNA Replication“. Journal of Cell Biology 149, Nr. 6 (12.06.2000): 1179–92. http://dx.doi.org/10.1083/jcb.149.6.1179.

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The role of nuclear lamins in DNA replication is unclear. To address this, nuclei were assembled in Xenopus extracts containing AraC, a reversible inhibitor that blocks near the onset of the elongation phase of replication. Dominant-negative lamin mutants lacking their NH2-terminal domains were added to assembled nuclei to disrupt lamin organization. This prevented the resumption of DNA replication after the release of the AraC block. This inhibition of replication was not due to gross disruption of nuclear envelope structure and function. The organization of initiation factors was not altered by lamin disruption, and nuclei resumed replication when transferred to extracts treated with CIP, an inhibitor of the cyclin-dependent kinase (cdk) 2–dependent step of initiation. This suggests that alteration of lamin organization does not affect the initiation phase of DNA replication. Instead, we find that disruption of lamin organization inhibited chain elongation in a dose-dependent fashion. Furthermore, the established organization of two elongation factors, proliferating cell nuclear antigen, and replication factor complex, was disrupted by ΔNLA. These findings demonstrate that lamin organization must be maintained in nuclei for the elongation phase of DNA replication to proceed.

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Kankare, E., R. Kotak, S. Mattila und P. Lundqvist. „A New Population of Highly Energetic Nuclear Transients“. Proceedings of the International Astronomical Union 14, S339 (November 2017): 131–34. http://dx.doi.org/10.1017/s1743921318002387.

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AbstractWe have identified a new population of luminous, optical, narrow-lined transients (FWHM ∼1000 km s−1) coincident with the nuclear region of Seyfert galaxies. According to extensive spectrophotometric follow-ups of the main event (PS1-10adi), we could exclude both normal active galactic nucleus activity and changing-look quasars as the origin. The integrated energy output and spectral evolution over a time-scale of several years point to two possible paths of origin: a tidal disruption of a star by a supermassive black hole, or an extremely energetic supernova occurring within the Seyfert galaxy’s narrow-line (or broad-line) region. The former model would require invoking a specific variant of a tidal disruption, while the latter would require an extremely efficient conversion of kinetic energy via shock interaction between the supernova ejecta and the dense ambient medium.

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Voisset, Edwige, Eva Moravcsik, Eva W. Stratford, Amie Jaye, Christopher J. Palgrave, Robert K. Hills, Paolo Salomoni, Scott C. Kogan, Ellen Solomon und David Grimwade. „Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice“. Blood 131, Nr. 6 (08.02.2018): 636–48. http://dx.doi.org/10.1182/blood-2017-07-794784.

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Key Points A novel mouse model elucidates the impact of Pml NB disruption on APL pathogenesis and response to targeted therapy. The mode of action of this disruption appears to be via the perturbation of the NHEJ and HR pathways.

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Woyke, Tanja, Robert W. Roberson, George R. Pettit, Günther Winkelmann und Robin K. Pettit. „Effect of Auristatin PHE on Microtubule Integrity and Nuclear Localization in Cryptococcus neoformans“. Antimicrobial Agents and Chemotherapy 46, Nr. 12 (Dezember 2002): 3802–8. http://dx.doi.org/10.1128/aac.46.12.3802-3808.2002.

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ABSTRACT The mechanism of action of the fungicidal peptide auristatin PHE was investigated in Cryptococcus neoformans. Since auristatin PHE causes budding arrest in C. neoformans (T. Woyke, G. R. Pettit, G. Winkelmann, and R. K. Pettit, Antimicrob. Agents Chemother. 45:3580-3584, 2001), microtubule integrity and nuclear localization in auristatin PHE-treated cells were examined. Iterative deconvolution in conjunction with an optimized C. neoformans microtubule immunolabeling procedure enabled detailed visualization of the microtubule cytoskeleton in auristatin PHE-treated C. neoformans. The effect of auristatin PHE on C. neoformans microtubule organization was compared with that of the tubulin-binding agent nocodazole. Both drugs produced complete disruption first of cytoplasmic and then of spindle microtubules in a time- and concentration-dependent manner. Sub-MICs of auristatin PHE caused complete microtubule disruption within 4.5 h, while 1.5 times the nocodazole MIC was required for the same effect. For both drugs, disruption of microtubules was accompanied by blockage of nuclear migration and of nuclear and cellular division, resulting in cells arrested in a uninucleate, large-budded stage. Nocodazole and the linear peptide auristatin PHE are remarkably different in structure and spectrum of activity, yet on the cellular level, they have similar effects.

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Sivachandran, Nirojini, Feroz Sarkari und Lori Frappier. „Epstein-Barr Nuclear Antigen 1 Contributes to Nasopharyngeal Carcinoma through Disruption of PML Nuclear Bodies“. PLoS Pathogens 4, Nr. 10 (03.10.2008): e1000170. http://dx.doi.org/10.1371/journal.ppat.1000170.

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Shani, Vered, Hazem Safory, Raymonde Szargel, Ninghan Wang, Tsipora Cohen, Fatimah Abd Elghani, Haya Hamza et al. „Physiological and pathological roles of LRRK2 in the nuclear envelope integrity“. Human Molecular Genetics 28, Nr. 23 (19.10.2019): 3982–96. http://dx.doi.org/10.1093/hmg/ddz245.

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Abstract Mutations in LRRK2 cause autosomal dominant and sporadic Parkinson’s disease, but the mechanisms involved in LRRK2 toxicity in PD are yet to be fully understood. We found that LRRK2 translocates to the nucleus by binding to seven in absentia homolog (SIAH-1), and in the nucleus it directly interacts with lamin A/C, independent of its kinase activity. LRRK2 knockdown caused nuclear lamina abnormalities and nuclear disruption. LRRK2 disease mutations mostly abolish the interaction with lamin A/C and, similar to LRRK2 knockdown, cause disorganization of lamin A/C and leakage of nuclear proteins. Dopaminergic neurons of LRRK2 G2019S transgenic and LRRK2 −/− mice display decreased circularity of the nuclear lamina and leakage of the nuclear protein 53BP1 to the cytosol. Dopaminergic nigral and cortical neurons of both LRRK2 G2019S and idiopathic PD patients exhibit abnormalities of the nuclear lamina. Our data indicate that LRRK2 plays an essential role in maintaining nuclear envelope integrity. Disruption of this function by disease mutations suggests a novel phosphorylation-independent loss-of-function mechanism that may synergize with other neurotoxic effects caused by LRRK2 mutations.

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Park, Ji-Hwan, Sung Jin Ryu, Byung Ju Kim, Hyun-Ji Cho, Chi Hyun Park, Hyo Jei Claudia Choi, Eun-Jin Jang et al. „Disruption of nucleocytoplasmic trafficking as a cellular senescence driver“. Experimental & Molecular Medicine 53, Nr. 6 (Juni 2021): 1092–108. http://dx.doi.org/10.1038/s12276-021-00643-6.

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AbstractSenescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This diminished reaction may be explained by the disrupted transmission of nuclear signals. However, this hypothesis requires more evidence before it can be accepted as a mechanism of cellular senescence. A proteomic analysis of the cytoplasmic and nuclear fractions obtained from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced the acquisition of an RS-like senescence phenotype, named nuclear barrier-induced senescence (NBIS). A transcriptome analysis revealed that, among various types of cellular senescence, NBIS exhibited a gene expression pattern most similar to that of RS. Core proteomic and transcriptomic patterns common to both RS and NBIS included upregulation of the endocytosis-lysosome network and downregulation of NCT in senescent cells, patterns also observed in an aging yeast model. These results imply coordinated aging-dependent reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was critical for the downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that may represent the nature of physiological aging in eukaryotes.

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Beck, Samuel, und Junyeong Lee. „DISRUPTION OF CPG ISLAND-MEDIATED CHROMATIN ARCHITECTURE AND TRANSCRIPTIONAL HOMEOSTASIS DURING AGING“. Innovation in Aging 3, Supplement_1 (November 2019): S208. http://dx.doi.org/10.1093/geroni/igz038.756.

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Abstract Aging causes the global disorganization of nuclear chromatin architecture. In a normal young nucleus, silent heterochromatin is associated with the nuclear lamina layer underlying nuclear envelope, thus spatially separated from euchromatin at the nuclear center. Notably, aging causes the disruption of nuclear lamina and the decondensation of associated heterochromatin. However, it is not clearly understood how these changes of chromatin architectures contribute to age-related diseases. Through large-scale computational analyses, we present that CpG islands (CGIs) give important clues to answering this question. CGIs are DNA elements with high Cytosine-phosphate-Guanine dinucleotide frequencies. In human, about 60% of total genes contain CGIs at their promoters (CGI+ genes) and are broadly expressed throughout the body. The other 40% of genes that do not have CGIs (CGI- genes) exhibit tissue-restricted expression patterns. Our results demonstrate that, in normal young nuclei, only CGI- genes can reside within lamina-associated heterochromatin when transcriptionally inactive, while CGI+ genes associate with nuclear central euchromatin even when they are repressed. In parallel, we show that age-associated heterochromatin decondensation can specifically de-repress tissue-specific CGI- genes leading to their uncontrolled expressions. Our results further demonstrate that global misregulation of CGI- genes increases the noise in gene transcription that, in turn, causes the loss of cellular identities during aging. Taken together, our study establishes critical implication of CGI-mediated chromatin architecture in age-associated degenerative changes and loss of tissue homeostasis.

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Di Micco, Antonia, Gianluca Frera, Jérôme Lugrin, Yvan Jamilloux, Erh-Ting Hsu, Aubry Tardivel, Aude De Gassart et al. „AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity“. Proceedings of the National Academy of Sciences 113, Nr. 32 (26.07.2016): E4671—E4680. http://dx.doi.org/10.1073/pnas.1602419113.

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Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R–dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity.

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Fiocchetti, Marco, Giovanna Bastari, Manuela Cipolletti, Stefano Leone, Filippo Acconcia und Maria Marino. „The Peculiar Estrogenicity of Diethyl Phthalate: Modulation of Estrogen Receptor α Activities in the Proliferation of Breast Cancer Cells“. Toxics 9, Nr. 10 (25.09.2021): 237. http://dx.doi.org/10.3390/toxics9100237.

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Phthalates comprise a group of synthetic chemicals present in the environment because of their wide use as plasticizers and as additives in products for personal care. Among others, diethyl phthalate (DEP) is largely used in products for infants, children, and adults, in which its exposure has been correlated with an increased risk of breast cancer. The adverse health outcomes deriving from phthalate exposure have been associated with their activity as endocrine disruptors (EDCs) of the steroid and thyroid hormone signaling by affecting developmental and reproductive health, and even carcinogenicity. However, the estrogen disruptor activities of DEP are still controversial, and the mechanism at the root of the estrogenic-disrupting action of DEP remains to be clarified. Here, we evaluated the DEP mechanism of action on the activation status of estrogen receptor α (ERα) by analyzing the receptor’s phosphorylation as well as both nuclear and extra-nuclear pathways triggered by the receptor to modulate the proliferation of breast cancer cells. Although DEP does not bind to ERα, our results suggest that this phthalate ester exerts multiple parallel interactions with ERα signaling and emphasize the importance to determine an appropriate battery of in vitro methods that will include specific molecular mechanisms involved in the endocrine disruption.

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Zeitschriftenartikel zum Thema „Nuclear disruption“

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