880 research outputs found
Predicting Cell Death and Mutation Frequency for a Wide Spectrum of LET by Assuming DNA Break Clustering Inside Repair Domains
Cosmic radiation, which is composed of high charged and energy (HZE) particles, is responsible for cell death and mutation, which may be involved in cancer induction. Mutations are consequences of mis-repaired DNA breaks especially double-strand breaks (DSBs) that induce inter- and intra-chromosomal rearrangements (translocations, deletions, inversion). In this study, a computer simulation model is used to investigate the clustering of DSBs in repair domains, previously evidenced by our group in human breast cells [1]. This model is calibrated with experimental data measuring persistent 53BP1 radiation-induced foci (RIF) and is used to explain the high relative biological effectiveness (RBE) of HZE for both cell death and DNA mutation frequencies. We first validate our DSB cluster model using a new track structure model deployed on a simple geometrical configuration for repair domains in the nucleus; then we extend the scope from cell death to mutation induction. This work suggests that mechanism based on DSB repair process can explain several biological effects induced by HZE particles on different type of living cell
Preparation and characterization of electrolytic alumina deposit on austenitic stainless steel
Conversion coating modified by alumina has been studied as a way for improving the resistance to thermal oxidation of an austenitic stainless steel. Conversion coating, characterized by a particular morphology and strong interfacial adhesion with the substrate, facilitate the electrochemical deposition of ceramic layers and enhance their adhesion to the substrate. The influence of the current density and treatment time on alumina deposit was studied using statistical experimental designs like Doehlert uniform shell design. After heating, coatings present a continuous composition gradient with refractory compounds at the surface. The behavior at high temperature (1000 8C) of the alumina coating was investigated. The presence of alumina increases the oxidation resistance of an austenitic stainless steel at 1000 8C. The morphology and the chemical composition of the deposit are analyzed. Results on the thermal stability of coating on austenitic stainless steel are presented
Whole slide image registration for the study of tumor heterogeneity
Consecutive thin sections of tissue samples make it possible to study local
variation in e.g. protein expression and tumor heterogeneity by staining for a
new protein in each section. In order to compare and correlate patterns of
different proteins, the images have to be registered with high accuracy. The
problem we want to solve is registration of gigapixel whole slide images (WSI).
This presents 3 challenges: (i) Images are very large; (ii) Thin sections
result in artifacts that make global affine registration prone to very large
local errors; (iii) Local affine registration is required to preserve correct
tissue morphology (local size, shape and texture). In our approach we compare
WSI registration based on automatic and manual feature selection on either the
full image or natural sub-regions (as opposed to square tiles). Working with
natural sub-regions, in an interactive tool makes it possible to exclude
regions containing scientifically irrelevant information. We also present a new
way to visualize local registration quality by a Registration Confidence Map
(RCM). With this method, intra-tumor heterogeneity and charateristics of the
tumor microenvironment can be observed and quantified.Comment: MICCAI2018 - Computational Pathology and Ophthalmic Medical Image
Analysis - COMPA
Impaired exercise training-induced muscle fiber hypertrophy and Akt/mTOR pathway activation in hypoxemic patients with COPD
Exercise training (ExTr) is largely used to improve functional capacity of chronic obstructive pulmonary disease (COPD) patients. However, ExTr partially restores muscle function in COPD patients, suggesting that confounding factors may limit the efficiency of ExTr. In the present study, we hypothesized that skeletal muscle adaptations triggered by ExTr could be compromised in hypoxemic COPD patients. Vastus lateralis muscle biopsies were obtained from normoxemic (n = 15; resting arterial PO2 = 68.5 +/- 1.5 mm Hg) and hypoxemic (n = 8; resting arterial PO2 = 57.0 +/- 1.0 mm Hg) COPD patients before and after a 2 month-ExTr program. ExTr induced a significant increase in exercise capacity both in normoxemic and hypoxemic COPD patients. However, ExTr increased citrate synthase and lactate dehydrogenase enzyme activities only in skeletal muscle of normoxemic patients. Similarly, muscle fiber cross-sectional area and capillary-to-fiber ratio were only increased in normoxemic patients. Expression of atrogenes (MuRF1, MAFbx/Atrogin-1) and autophagy-related genes (Beclin, LC3, Bnip, Gabarapl) remained unchanged in both groups. The phosphorylation level of Akt (Ser473), GSK-3beta (Ser9) and p70S6k (Thr389), which was non-significantly increased in normoxemic patients in response to ExTr, was significantly decreased in hypoxemic patients. We further showed on C2C12 myotubes that hypoxia completely prevented IGF-1-induced phosphorylation of Akt, GSK-3beta and p70S6K. Together, our observations suggest a role for hypoxemia in the adaptive response of skeletal muscle of COPD patients to ExTr
Chromosome Model reveals Dynamic Redistribution of DNA Damage into Nuclear Sub-domains
Several proteins involved in the response to DNA double strand breaks (DSB) form microscopically visible nuclear domains, or foci, after exposure to ionizing radiation. Radiation-induced foci (RIF) are believed to be located where DNA damage is induced. To test this assumption, we analyzed the spatial distribution of 53BP1, phosphorylated ATM and gammaH2AX RIF in cells irradiated with high linear energy transfer (LET) radiation. Since energy is randomly deposited along high-LET particle paths, RIF along these paths should also be randomly distributed. The probability to induce DSB can be derived from DNA fragment data measured experimentally by pulsed-field gel electrophoresis. We used this probability in Monte Carlo simulations to predict DSB locations in synthetic nuclei geometrically described by a complete set of human chromosomes, taking into account microscope optics from real experiments. As expected, simulations produced DNA-weighted random (Poisson) distributions. In contrast, the distributions of RIF obtained as early as 5 min after exposure to high LET (1 GeV/amu Fe) were non-random. This deviation from the expected DNA-weighted random pattern can be further characterized by relative DNA image measurements. This novel imaging approach shows that RIF were located preferentially at the interface between high and low DNA density regions, and were more frequent in regions with lower density DNA than predicted. This deviation from random behavior was more pronounced within the first 5 min following irradiation for phosphorylated ATM RIF, while gammaH2AX and 53BP1 RIF showed very pronounced deviation up to 30 min after exposure. These data suggest the existence of repair centers in mammalian epithelial cells. These centers would be nuclear sub-domains where DNA lesions would be collected for more efficient repair
Image-Based Modeling Reveals Dynamic Redistribution of DNA Damage into Nuclear Sub-Domains
Several proteins involved in the response to DNA double strand breaks (DSB) form microscopically visible nuclear domains, or foci, after exposure to ionizing radiation. Radiation-induced foci (RIF) are believed to be located where DNA damage occurs. To test this assumption, we analyzed the spatial distribution of 53BP1, phosphorylated ATM, and γH2AX RIF in cells irradiated with high linear energy transfer (LET) radiation and low LET. Since energy is randomly deposited along high-LET particle paths, RIF along these paths should also be randomly distributed. The probability to induce DSB can be derived from DNA fragment data measured experimentally by pulsed-field gel electrophoresis. We used this probability in Monte Carlo simulations to predict DSB locations in synthetic nuclei geometrically described by a complete set of human chromosomes, taking into account microscope optics from real experiments. As expected, simulations produced DNA-weighted random (Poisson) distributions. In contrast, the distributions of RIF obtained as early as 5 min after exposure to high LET (1 GeV/amu Fe) were non-random. This deviation from the expected DNA-weighted random pattern can be further characterized by “relative DNA image measurements.” This novel imaging approach shows that RIF were located preferentially at the interface between high and low DNA density regions, and were more frequent than predicted in regions with lower DNA density. The same preferential nuclear location was also measured for RIF induced by 1 Gy of low-LET radiation. This deviation from random behavior was evident only 5 min after irradiation for phosphorylated ATM RIF, while γH2AX and 53BP1 RIF showed pronounced deviations up to 30 min after exposure. These data suggest that DNA damage–induced foci are restricted to certain regions of the nucleus of human epithelial cells. It is possible that DNA lesions are collected in these nuclear sub-domains for more efficient repair
DNA Repair Domain Modeling Can Predict Cell Death and Mutation Frequency for Wide Range Spectrum of Radiation
Exploration missions to Mars and other destinations raise many questions about the health of astronauts. The continuous exposure of astronauts to galactic cosmic rays is one of the main concerns for long-term missions. Cosmic ionizing radiations are composed of different ions of various charges and energies notably, highly charged energy (HZE) particles. The HZE particles have been shown to be more carcinogenic than low-LET radiation, suggesting the severity of chromosomal aberrations induced by HZE particles is one possible explanation. However, most mathematical models predicting cell death and mutation frequency are based on directly fitting various HZE dose response and are in essence empirical approaches. In this work, we assume a simple biological mechanism to model DNA repair and use it to simultaneously explain the low- and high-LET response using the exact same fitting parameters. Our work shows that the geometrical position of DNA repair along tracks of heavy ions are sufficient to explain why high-LET particles can induce more death and mutations. Our model is based on assuming DNA double strand breaks (DSBs) are repaired within repair domain, and that any DSBs located within the same repair domain cluster into one repair unit, facilitating chromosomal rearrangements and increasing the probability of cell death. We introduced this model in 2014 using simplified microdosimetry profiles to predict cell death. In this work, we collaborated with NASA Johnson Space Center to generate more accurate microdosimetry profiles derived by Monte Carlo techniques, taking into account track structure of HZE particles and simulating DSBs in realistic cell geometry. We simulated 224 data points (D, A, Z, E) with the BDSTRACKS model, leading to a large coverage of LET from ~10 to 2,400 keV/m. This model was used to generate theoretical RBE for various particles and energies for both cell death and mutation frequencies. The RBE LET dependence is in agreement with experimental data known in human and murine cells. It suggests that cell shape and its orientation with respect to the HZE particle beam can modify the biological response to radiation. Such discovery will be tested experimentally and, if proven accurate, will be another strong supporting evidence for DNA repair domains and their critical role in interpreting cosmic radiation sensitivity
Magnetic and thermal properties of 4f-3d ladder-type molecular compounds
We report on the low-temperature magnetic susceptibilities and specific heats
of the isostructural spin-ladder molecular complexes L[M(opba)]_{3\cdot
xDMSOHO, hereafter abbreviated with LM (where L =
La, Gd, Tb, Dy, Ho and M = Cu, Zn). The results show that the Cu containing
complexes (with the exception of LaCu) undergo long range magnetic
order at temperatures below 2 K, and that for GdCu this ordering is
ferromagnetic, whereas for TbCu and DyCu it is probably
antiferromagnetic. The susceptibilities and specific heats of TbCu
and DyCu above have been explained by means of a model
taking into account nearest as well as next-nearest neighbor magnetic
interactions. We show that the intraladder L--Cu interaction is the predominant
one and that it is ferromagnetic for L = Gd, Tb and Dy. For the cases of Tb, Dy
and Ho containing complexes, strong crystal field effects on the magnetic and
thermal properties have to be taken into account. The magnetic coupling between
the (ferromagnetic) ladders is found to be very weak and is probably of dipolar
origin.Comment: 13 pages, 15 figures, submitted to Phys. Rev.
Time Correlation Functions of Three Classical Heisenberg Spins on an Isosceles Triangle and on a Chain: Strong Effects of Broken Symmetry
At arbitrary temperature , we solve for the dynamics of single molecule
magnets composed of three classical Heisenberg spins either on a chain with two
equal exchange constants , or on an isosceles triangle with a third,
different exchange constant . As T\rightrarrow\infty, the Fourier
transforms and long-time asymptotic behaviors of the two-spin time correlation
functions are evaluated exactly. The lack of translational symmetry on a chain
or an isosceles triangle yields time correlation functions that differ
strikingly from those on an equilateral trinagle with . At low ,
the Fourier transforms of the two autocorrelation functions with
show one and four modes, respectively. For a semi-infinite range, one
mode is a central peak. At the origin of this range, this mode has a novel
scaling form.Comment: 9 pages, 14 figures, accepted for publication in Phys. Rev.
Proteasomal degradation of the histone acetyl transferase p300 contributes to beta-cell injury in a diabetes environment
In type 2 diabetes, amyloid oligomers, chronic hyperglycemia, lipotoxicity, and pro-inflammatory cytokines are detrimental to beta-cells, causing apoptosis and impaired insulin secretion. The histone acetyl transferase p300, involved in remodeling of chromatin structure by epigenetic mechanisms, is a key ubiquitous activator of the transcriptional machinery. In this study, we report that loss of p300 acetyl transferase activity and expression leads to beta-cell apoptosis, and most importantly, that stress situations known to be associated with diabetes alter p300 levels and functional integrity. We found that proteasomal degradation is the mechanism subserving p300 loss in beta-cells exposed to hyperglycemia or pro-inflammatory cytokines. We also report that melatonin, a hormone produced in the pineal gland and known to play key roles in beta-cell health, preserves p300 levels altered by these toxic conditions. Collectively, these data imply an important role for p300 in the pathophysiology of diabetes
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