scholarly journals Nuclear Plasticity Increases Susceptibility to Damage During Confined Migration

2020 ◽  
Author(s):  
Abhishek Mukherjee ◽  
Amlan Barai ◽  
Ramesh K Singh ◽  
Wenyi Yan ◽  
Shamik Sen
Keyword(s):  
Dna Damage ◽  
Plastic Deformation ◽  
Nuclear Membrane ◽  
Element Model ◽  
Membrane Rupture ◽  
Confined Spaces ◽  
Model Predictions ◽  
A Cell ◽  
Static Plane ◽  
Nuclear Damage

AbstractLarge nuclear deformations during migration through confined spaces have been associated with nuclear membrane rupture and DNA damage. However, the stresses associated with nuclear damage remain unclear. Here, using a quasi-static plane strain finite element model, we map evolution of nuclear shape and stresses during confined migration of a cell through a deformable matrix. Plastic deformation of the nucleus observed for a cell with stiff nucleus transiting through a stiffer matrix lowered nuclear stresses, but also led to kinking of the nuclear membrane. In line with model predictions, transwell migration experiments with fibrosarcoma cells showed that while nuclear softening increased invasiveness, nuclear stiffening led to plastic deformation and higher levels of DNA damage. In addition to highlighting the advantage of nuclear softening during confined migration, our results suggest that plastic deformations of the nucleus during transit through stiff tissues may lead to bending-induced nuclear membrane disruption and subsequent DNA damage.

Structure and Hardness of Cryorolled and Heat-Treated 2xxx Aluminum Alloy

2010 ◽  
Vol 667-669 ◽  
pp. 925-930
Author(s):  
S.V. Krymskiy ◽  
Elena Avtokratova ◽  
M.V. Markushev ◽  
Maxim Yu. Murashkin ◽  
O.S. Sitdikov
Keyword(s):  
Heat Treatment ◽  
Solid Solution ◽  
Plastic Deformation ◽  
Aluminum Alloy ◽  
Severe Plastic Deformation ◽  
Coarse Grained ◽  
Aging Response ◽  
Heat Treated ◽  
Aluminum Solid Solution ◽  
A Cell

The effects of severe plastic deformation (SPD) by isothermal rolling at the temperature of liquid nitrogen combined with prior- and post-SPD heat treatment, on microstructure and hardness of Al-4.4%Cu-1.4%Mg-0.7%Mn (D16) alloy were investigated. It was found no nanostructuring even after straining to 75%. Сryodeformation leads to microshear banding and processing the high-density dislocation substructures with a cell size of ~ 100-200 nm. Such a structure remains almost stable under 1 hr annealing up to 200oC and with further temperature increase initially transforms to bimodal with a small fraction of nanograins and then to uniform coarse grained one. It is found the change in the alloy post–SPD aging response leading to more active decomposition of the preliminary supersaturated aluminum solid solution, and to the alloy extra hardening under aging with shorter times and at lower temperatures compared to T6 temper.

Effect of Interfacial Properties on the Mechanical Behavior of Bone-Like Materials: A Numerical Study

2017 ◽  
Vol 09 (01) ◽  
pp. 1750014 ◽  
Author(s):  
Xingguo Li ◽  
Bingbing An ◽  
Dongsheng Zhang
Keyword(s):  
Mechanical Properties ◽  
Plastic Deformation ◽  
Numerical Study ◽  
Element Model ◽  
Interfacial Behavior ◽  
Yield Behavior ◽  
Bonding Property ◽  
The Matrix ◽  
Bonding Properties ◽  
Superior Mechanical Properties

Interfacial behavior in the microstructure and the plastic deformation in the protein matrix influence the overall mechanical properties of biological hard tissues. A cohesive finite element model has been developed to investigate the inelastic mechanical properties of bone-like biocomposites consisting of hard mineral crystals embedded in soft biopolymer matrix. In this study, the complex interaction between plastic dissipation in the matrix and bonding properties of the interface between minerals and matrix is revealed, and the effect of such interaction on the toughening of bone-like biocomposites is identified. For the case of strong and intermediate interfaces, the toughness of biocomposites is controlled by the post yield behavior of biopolymer; the matrix with low strain hardening can undergo significant plastic deformation, thereby promoting enhanced fracture toughness of biocomposites. For the case of weak interfaces, the toughness of biocomposites is governed by the bonding property of the interface, and the post-yield behavior of biopolymer shows negligible effect on the toughness. The findings of this study help to direct the path for designing bioinspired materials with superior mechanical properties.

Rigid-Plastic Impact of Single Angular Particles

2021 ◽  
Author(s):  
Sandeep Dhar
Keyword(s):  
Finite Element ◽  
Finite Element Model ◽  
Element Model ◽  
Orientation Dependence ◽  
Particle Orientation ◽  
Rigid Plastic ◽  
Plastic Model ◽  
Model Predictions ◽  
Good Agreement ◽  
Angular Particles

The trajectory of an angular particle as it cuts a ductile target is, in general, complicated because of its dependence not only on particle shape, but also on particle orientation at the initial instant of impact. This orientation dependence has also made experimental measurement of impact parameters of single angular particles very difficult, resulting in a relatively small amount of available experimental data in the literature. The current work is focused on obtaining measurements of particle kinematics for comparison to rigid plastic model developed by Papini and Spelt. Fundamental mechanisms of material removal are identified, and measurements of rebound parameters and corresponding crater dimensions of single hardened steel particles launched against flat aluminium alloy targets are presented. Also a 2-D finite element model is developed and a dynamic analysis is performed to predict the erosion mechanism. Overall, a good agreement was found among the experimental results, rigid-plastic model predictions and finite element model predictions.

scholarly journals Unrestrained ESCRT-III drives chromosome fragmentation and micronuclear catastrophe

2019 ◽  
Author(s):  
Marina Vietri ◽  
Sebastian W. Schultz ◽  
Aurélie Bellanger ◽  
Carl M. Jones ◽  
Camilla Raiborg ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Genome Stability ◽  
Membrane Deformation ◽  
Chromosome Fragmentation ◽  
Inner Nuclear Membrane ◽  
Membrane Rupture ◽  
Membrane Fission ◽  
Stable Association ◽  
Inner Nuclear Membrane Protein

AbstractThe ESCRT-III membrane fission machinery1,2 restores nuclear envelope integrity during mitotic exit3,4 and interphase5,6. Whereas primary nuclei resealing takes minutes, micronuclear envelope ruptures appear irreversible and result in catastrophic collapse associated with chromosome fragmentation and rearrangements (chromothripsis), thought to be a major driving force in cancer development7-10. Despite its importance11-13, the mechanistic underpinnings of nuclear envelope sealing in primary nuclei and the defects observed in micronuclei remain largely unknown. Here we show that CHMP7, the nucleator of ESCRT-III filaments at the nuclear envelope3,14, and the inner nuclear membrane protein LEMD215 act as a compartmentalization sensor detecting the loss of nuclear integrity. In cells with intact nuclear envelope, CHMP7 is actively excluded from the nucleus to preclude its binding to LEMD2. Nuclear influx of CHMP7 results in stable association with LEMD2 at the inner nuclear membrane that licenses local polymerization of ESCRT-III. Tight control of nuclear CHMP7 levels is critical, as induction of nuclear CHMP7 mutants is sufficient to induce unrestrained growth of ESCRT-III foci at the nuclear envelope, causing dramatic membrane deformation, local DNA torsional stress, single-stranded DNA formation and fragmentation of the underlying chromosomes. At micronuclei, membrane rupture is not associated with repair despite timely recruitment of ESCRT-III. Instead, micronuclei inherently lack the capacity to restrict accumulation of CHMP7 and LEMD2. This drives unrestrained ESCRT-III recruitment, membrane deformation and DNA defects that strikingly resemble those at primary nuclei upon induction of nuclear CHMP7 mutants. Preventing ESCRT-III recruitment suppresses membrane deformation and DNA damage, without restoring nucleocytoplasmic compartmentalization. We propose that the ESCRT-III nuclear integrity surveillance machinery is a double-edged sword, as its exquisite sensitivity ensures rapid repair at primary nuclei while causing unrestrained polymerization at micronuclei, with catastrophic consequences for genome stability16-18.

scholarly journals KCTD19 and its associated protein ZFP541 are independently essential for meiosis in male mice

PLoS Genetics ◽  
2021 ◽  
Vol 17 (5) ◽  
pp. e1009412
Author(s):  
Seiya Oura ◽  
Takayuki Koyano ◽  
Chisato Kodera ◽  
Yuki Horisawa-Takada ◽  
Makoto Matsuyama ◽  
...  
Keyword(s):  
Dna Damage ◽  
Reproductive Tract ◽  
Zinc Finger Protein ◽  
Male Mice ◽  
Late Pachytene ◽  
Histone Deacetylase 1 ◽  
Tetramerization Domain ◽  
Evolutionarily Conserved ◽  
Division Process ◽  
A Cell

Meiosis is a cell division process with complex chromosome events where various molecules must work in tandem. To find meiosis-related genes, we screened evolutionarily conserved and reproductive tract-enriched genes using the CRISPR/Cas9 system and identified potassium channel tetramerization domain containing 19 (Kctd19) as an essential factor for meiosis. In prophase I, Kctd19 deficiency did not affect synapsis or the DNA damage response, and chiasma structures were also observed in metaphase I spermatocytes of Kctd19 KO mice. However, spermatocytes underwent apoptotic elimination during the metaphase-anaphase transition. We were able to rescue the Kctd19 KO phenotype with an epitope-tagged Kctd19 transgene. By immunoprecipitation-mass spectrometry, we confirmed the association of KCTD19 with zinc finger protein 541 (ZFP541) and histone deacetylase 1 (HDAC1). Phenotyping of Zfp541 KO spermatocytes demonstrated XY chromosome asynapsis and recurrent DNA damage in the late pachytene stage, leading to apoptosis. In summary, our study reveals that KCTD19 associates with ZFP541 and HDAC1, and that both KCTD19 and ZFP541 are essential for meiosis in male mice.

scholarly journals In silico stress fibre content affects peak strain in cytoplasm and nucleus but not in membrane for uniaxial substrate stretch

2019 ◽  
Author(s):  
Tamer Abdalrahman ◽  
Neil H. Davies ◽  
Thomas Franz
Keyword(s):  
Elastic Modulus ◽  
In Silico ◽  
Focal Adhesions ◽  
Element Model ◽  
Homogenization Method ◽  
Fibre Volume ◽  
Fibre Content ◽  
Peak Strain ◽  
Stress Fibre ◽  
A Cell

AbstractExisting in silico models for single cell mechanics feature limited representations of cytoskeletal structures that contribute substantially to the mechanics of a cell. We propose a micromechanical hierarchical approach to capture the mechanical contribution of actin stress fibres. For a cell-specific fibroblast geometry with membrane, cytoplasm and nucleus, the Mori-Tanaka homogenization method was employed to describe cytoplasmic inhomogeneities and constitutive contribution of actin stress fibres. The homogenization was implemented in a finite element model of the fibroblast attached to a substrate through focal adhesions. Strain in cell membrane, cytoplasm and nucleus due to uniaxial substrate stretch was assessed for different stress fibre volume fractions and different elastic modulus of the substrate. A considerable decrease of the peak strain with increasing stress fibre content was observed in cytoplasm and nucleus but not the membrane, whereas the peak strain in cytoplasm, nucleus and membrane increased for increasing elastic modulus of the substrate.

scholarly journals DNA double-strand break repair: a theoretical framework and its application

2016 ◽  
Vol 13 (114) ◽  
pp. 20150679 ◽  
Author(s):  
Philip J. Murray ◽  
Bart Cornelissen ◽  
Katherine A. Vallis ◽  
S. Jon Chapman
Keyword(s):  
Dna Damage ◽  
Auger Electron ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Histone H2ax ◽  
Dna Double Strand Break ◽  
A Cell

DNA double-strand breaks (DSBs) are formed as a result of genotoxic insults, such as exogenous ionizing radiation, and are among the most serious types of DNA damage. One of the earliest molecular responses following DSB formation is the phosphorylation of the histone H2AX, giving rise to γ H2AX. Many copies of γ H2AX are generated at DSBs and can be detected in vitro as foci using well-established immuno-histochemical methods. It has previously been shown that anti- γ H2AX antibodies, modified by the addition of the cell-penetrating peptide TAT and a fluorescent or radionuclide label, can be used to visualize and quantify DSBs in vivo . Moreover, when labelled with a high amount of the short-range, Auger electron-emitting radioisotope, 111 In, the amount of DNA damage within a cell can be increased, leading to cell death. In this report, we develop a mathematical model that describes how molecular processes at individual sites of DNA damage give rise to quantifiable foci. Equations that describe stochastic mean behaviours at individual DSB sites are derived and parametrized using population-scale, time-series measurements from two different cancer cell lines. The model is used to examine two case studies in which the introduction of an antibody (anti- γ H2AX-TAT) that targets a key component in the DSB repair pathway influences system behaviour. We investigate: (i) how the interaction between anti- γ H2AX-TAT and γ H2AX effects the kinetics of H2AX phosphorylation and DSB repair and (ii) model behaviour when the anti- γ H2AX antibody is labelled with Auger electron-emitting 111 In and can thus instigate additional DNA damage. This work supports the conclusion that DSB kinetics are largely unaffected by the introduction of the anti- γ H2AX antibody, a result that has been validated experimentally, and hence the hypothesis that the use of anti- γ H2AX antibody to quantify DSBs does not violate the image tracer principle. Moreover, it provides a novel model of DNA damage accumulation in the presence of Auger electron-emitting 111 In that is supported qualitatively by the available experimental data.

scholarly journals Hypersensitivity to DNA damage leads to increased apoptosis during early mouse development

2000 ◽  
Vol 14 (16) ◽  
pp. 2072-2084
Author(s):  
Babette S. Heyer ◽  
Alasdair MacAuley ◽  
Ole Behrendtsen ◽  
Zena Werb
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Genotoxic Stress ◽  
Embryonic Cells ◽  
Mouse Development ◽  
Potential Cost ◽  
Proliferation And Differentiation ◽  
A Cell ◽  
Early Mouse ◽  
Surveillance Mechanism

Gastrulation in mice is associated with the start of extreme proliferation and differentiation. The potential cost to the embryo of a very rapid proliferation rate is a high production of damaged cells. We demonstrate a novel surveillance mechanism for the elimination of cells damaged by ionizing radiation during mouse gastrulation. During this restricted developmental window, the embryo becomes hypersensitive to DNA damage induced by low dose irradiation (<0.5 Gy) and undergoes apoptosis without cell cycle arrest. Intriguingly, embryonic cells, including germ cell progenitors, but not extraembryonic cells, become hypersensitive to genotoxic stress and undergo Atm- and p53-dependent apoptosis. Thus, hypersensitivity to apoptosis in the early mouse embryo is a cell fate-dependent mechanism to ensure genomic integrity during a period of extreme proliferation and differentiation.

scholarly journals γH2AX in the S Phase after UV Irradiation Corresponds to DNA Replication and Does Not Report on the Extent of DNA Damage

2020 ◽  
Vol 40 (20) ◽  
Author(s):  
Shivnarayan Dhuppar ◽  
Sitara Roy ◽  
Aprotim Mazumder
Keyword(s):  
Dna Damage ◽  
Uv Irradiation ◽  
S Phase ◽  
Dna Double Strand Breaks ◽  
Cyclobutane Pyrimidine Dimers ◽  
Environmental Mutagen ◽  
Strand Breaks ◽  
Pyrimidine Dimers ◽  
Replication Sites ◽  
A Cell

ABSTRACT Ultraviolet (UV) radiation is a major environmental mutagen. Exposure to UV leads to a sharp peak of γH2AX, the phosphorylated form of the histone variant H2AX, in the S phase within an asynchronous population of cells. γH2AX is often considered a definitive marker of DNA damage inside a cell. In this report, we show that γH2AX in the S-phase cells after UV irradiation reports neither on the extent of primary DNA damage in the form of cyclobutane pyrimidine dimers nor on the extent of its secondary manifestations in the form of DNA double-strand breaks or in the inhibition of global transcription. Instead, γH2AX in the S phase corresponds to the sites of active replication at the time of UV irradiation. This accumulation of γH2AX at replication sites slows down the replication. However, the cells do complete the replication of their genomes and arrest within the G2 phase. Our study suggests that it is not DNA damage, but the response elicited, which peaks in the S phase upon UV irradiation.

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