Inefficient Double-Strand Break Repair in Murine Rod Photoreceptors with Inverted Heterochromatin Organization

Frohns, Antonia; Frohns, Florian; Naumann, Steffen C.; Layer, Paul G.; Löbrich, Markus

doi:10.1016/j.cub.2014.03.061

Cited by 34 publications

(58 citation statements)

References 58 publications

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“…We used mouse tissue as a model system and quantified DSBs by counting γH2AX foci, which arise linearly with radiation dose (18,19,31). To further enhance the sensitivity of this biodosimetric approach, we investigated the mouse retina with its densely packed and uniformly arranged photoreceptors (32). Lamin B staining showed that mouse photoreceptors contained a low amount of cytoplasm and little intercellular space (Fig.…”

Section: Resultsmentioning

confidence: 99%

Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue

Mirsch

Tommasino

Frohns

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Charged particles are increasingly used in cancer radiotherapy and contribute significantly to the natural radiation risk. The difference in the biological effects of high-energy charged particles compared with X-rays or γ-rays is determined largely by the spatial distribution of their energy deposition events. Part of the energy is deposited in a densely ionizing manner in the inner part of the track, with the remainder spread out more sparsely over the outer track region. Our knowledge about the dose distribution is derived solely from modeling approaches and physical measurements in inorganic material. Here we exploited the exceptional sensitivity of γH2AX foci technology and quantified the spatial distribution of DNA lesions induced by charged particles in a mouse model tissue. We observed that charged particles damage tissue nonhomogenously, with single cells receiving high doses and many other cells exposed to isolated damage resulting from high-energy secondary electrons. Using calibration experiments, we transformed the 3D lesion distribution into a dose distribution and compared it with predictions from modeling approaches. We obtained a radial dose distribution with sub-micrometer resolution that decreased with increasing distance to the particle path following a 1/r 2 dependency. The analysis further revealed the existence of a background dose at larger distances from the particle path arising from overlapping dose deposition events from independent particles. Our study provides, to our knowledge, the first quantification of the spatial dose distribution of charged particles in biologically relevant material, and will serve as a benchmark for biophysical models that predict the biological effects of these particles.C harged particles, including protons, α-particles, and heavy ions, are increasingly used in cancer radiotherapy and represent a significant component of the natural background irradiation on earth and in space (1-3). Their biological effect is often very different from that of photons (X-or γ-rays), largely because charged particles deposit their energy along a track, whereas photons produce a fairly homogeneous dose distribution. Linear energy transfer (LET; typically given in units of keV/μm) has been introduced as a parameter to describe the amount of energy that charged particles deposit along their track. Particles with high LET are densely ionizing and typically biologically more effective than photons or low-LET particles. Energy deposition along a particle track is not restricted to the path itself (the so-called "track core"), but extends laterally into an area known as the penumbra of the particle, which can reach considerable distances for high-energy particles. Energy deposition in the penumbra arises from energetic secondary electrons, so-called δ-electrons, which are generated by ionization events of the charged particles and carry energy away from the immediate path into the penumbra. According to classical track structure theory, ∼50% of the total energy is deposited in the...

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Section: Resultsmentioning

confidence: 99%

Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue

Mirsch

Tommasino

Frohns

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The eyes of adult or postnatal (10 days old, P10) C57BL/6 mice were removed after decapitation; the retinae with the vitreous bodies were isolated by using a binocular microscope and cultured with 500 µl medium per well [DMEM complemented with 10% FCS, 1% L-glutamine, 1% nonessential amino acids, 100 U/mL penicillin, and 0.1 mg/mL streptomycin] in a 24-well plate (TPP, Trasadingen, Switzerland) at 37 °C and 5% CO 2 for 30 min as previously described (29). Subsequently, well plates were placed into a circulating water bath at 37 °C or 40 °C inside of an incubator (37 °C) for another 30 min with (+wIRA) and without (Ctrl) wIRA/VIS treatment (BTE 595) at 1000 W/m 2 .…”

Section: Preparation Temperature Exposure and Irradiation Of Mouse Rmentioning

confidence: 99%

Water-filtered infrared A reduces chlamydial infectivity in vitro without causing ex vivo eye damage in pig and mouse models

Rahn

Marti

Frohns

et al. 2016

Journal of Photochemistry and Photobiology B: Biology

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Originally published at: Rahn, Carolin. Water-filtered infrared A reduces chlamydial infectivity in vitro without causing ex vivo eye damage in pig and mouse models. 2016, University of Zurich, Vetsuisse Faculty. We demonstrated a significant wIRA-dependent reduction of chlamydial infectivity in HCjE cells.Moreover, we observed that wIRA treatment of HCjE prior to infection was sufficient to inhibit chlamydial infectivity and that visible light enhances the effect of wIRA. Irradiation did not reduce cell

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“…In contrast, rod nuclei of nocturnal mammals (including mouse and rat) have an inverted chromatin pattern that maximizes photon acquisition (Solovei et al, 2009). The relevance of this diurnal-nocturnal rod dimorphism was recently shown to go beyond photon capture in a study comparing the ability of adult mouse retinal cells to repair double-strand nuclear DNA breaks induced by X-irradiation (Frohns et al, 2014). Of the cell types examined, mouse rods were only half as efficient at repairing DNA as the other cell types – including mouse cones.…”

Section: Ground Squirrel Visual Systemmentioning

confidence: 99%

Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina

Merriman

Sajdak

et al. 2016

Experimental Eye Research

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With a photoreceptor mosaic containing ~85% cones, the ground squirrel is one of the richest known mammalian sources of these important retinal cells. It also has a visual ecology much like the human’s. While the ground squirrel retina is understandably prominent in the cone biochemistry, physiology, and circuitry literature, far less is known about the remodeling potential of its retinal pigment epithelium, neurons, macroglia, or microglia. This review aims to summarize the data from ground squirrel retina to this point in time, and to relate them to data from other brain areas where appropriate. We begin with a survey of the ground squirrel visual system, making comparisons with traditional rodent models and with human. Because this animal’s status as a hibernator often goes unnoticed in the vision literature, we then present a brief primer on hibernation biology. Next we review what is known about ground squirrel retinal remodeling concurrent with deep torpor and with rapid recovery upon re-warming. Notable here is rapidly-reversible, temperature-dependent structural plasticity of cone ribbon synapses, as well as pre- and post-synaptic plasticity throughout diverse brain regions. It is not yet clear if retinal cell types other than cones engage in torpor-associated synaptic remodeling. We end with the small but intriguing literature on the ground squirrel retina’s remodeling responses to insult by retinal detachment. Notable for widespread loss of (cone) photoreceptors, there is surprisingly little remodeling of the RPE or Müller cells. Microglial activation appears minimal, and remodeling of surviving second- and third-order neurons seems absent, but both require further study. In contrast, traumatic brain injury in the ground squirrel elicits typical macroglial and microglial responses. Overall, the data to date strongly suggest a heretofore unrecognized, natural checkpoint between retinal deafferentiation and RPE and Müller cell remodeling events. As we continue to discover them, the unique ways by which ground squirrel retina responds to hibernation or injury may be adaptable to therapeutic use.

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Inefficient Double-Strand Break Repair in Murine Rod Photoreceptors with Inverted Heterochromatin Organization

Cited by 34 publications

References 58 publications

Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue

Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue

Water-filtered infrared A reduces chlamydial infectivity in vitro without causing ex vivo eye damage in pig and mouse models

Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina

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