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  • 1
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    Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa (2014)
    Oxford University Press
    Details
    Publication Date: 2014-06-10
    Description: In humans, the Crumbs homolog-1 ( CRB1 ) gene is mutated in autosomal recessive Leber congenital amaurosis and early-onset retinitis pigmentosa. In mammals, the Crumbs family is composed of: CRB1, CRB2, CRB3A and CRB3B. Recently, we showed that removal of mouse Crb2 from retinal progenitor cells, and consequent removal from Müller glial and photoreceptor cells, results in severe and progressive retinal degeneration with concomitant loss of retinal function that mimics retinitis pigmentosa due to mutations in the CRB1 gene. Here, we studied the effects of cell-type-specific loss of CRB2 from the developing mouse retina using targeted conditional deletion of Crb2 in photoreceptors or Müller cells. We analyzed the consequences of targeted loss of CRB2 in the adult mouse retina using adeno-associated viral vectors encoding Cre recombinase and short hairpin RNA against Crb2. In vivo retinal imaging by means of optical coherence tomography on retinas lacking CRB2 in photoreceptors showed progressive thinning of the photoreceptor layer and cellular mislocalization. Electroretinogram recordings under scotopic conditions showed severe attenuation of the a-wave, confirming the degeneration of photoreceptors. Retinas lacking CRB2 in developing photoreceptors showed early onset of abnormal lamination, whereas retinas lacking CRB2 in developing Müller cells showed late onset retinal disorganization. Our data suggest that in the developing retina, CRB2 has redundant functions in Müller glial cells, while CRB2 has essential functions in photoreceptors. Our data suggest that short-term loss of CRB2 in adult mouse photoreceptors, but not in Müller glial cells, causes sporadic loss of adhesion between photoreceptors and Müller cells.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Gene therapy restores vision and delays degeneration in the CNGB1-/- mouse model of retinitis pigmentosa (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-28
    Description: Retinitis pigmentosa (RP) is a group of genetically heterogeneous, severe retinal diseases commonly leading to legal blindness. Mutations in the CNGB1a subunit of the rod cyclic nucleotide-gated (CNG) channel have been found to cause RP in patients. Here, we demonstrate the efficacy of gene therapy as a potential treatment for RP by means of recombinant adeno-associated viral (AAV) vectors in the CNGB1 knockout (CNGB1 –/– ) mouse model. To enable efficient packaging and rod-specific expression of the relatively large CNGB1a cDNA (~4 kb), we used an AAV expression cassette with a short rod-specific promoter and short regulatory elements. After injection of therapeutic AAVs into the subretinal space of 2-week-old CNGB1 –/– mice, we assessed the restoration of the visual system by analyzing (i) CNG channel expression and localization, (ii) retinal function and morphology and (iii) vision-guided behavior. We found that the treatment not only led to expression of full-length CNGB1a, but also restored normal levels of the previously degraded CNGA1 subunit of the rod CNG channel. Both proteins co-localized in rod outer segments and formed regular CNG channel complexes within the treated area of the CNGB1 –/– retina, leading to significant morphological preservation and a delay of retinal degeneration. In the electroretinographic analysis, we also observed restoration of rod-driven light responses. Finally, treated CNGB1 –/– mice performed significantly better than untreated mice in a rod-dependent vision-guided behavior test. In summary, this work provides a proof-of-concept for the treatment of rod channelopathy-associated RP by AAV-mediated gene replacement.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    The equipartition magnetic field formula in starburst galaxies: accounting for pionic secondaries and strong energy losses (2013)
    Oxford University Press
    Details
    Publication Date: 2013-03-23
    Description: Equipartition arguments provide an easy way to find a characteristic scale for the magnetic field from radio emission by assuming that the energy densities in cosmic rays and magnetic fields are the same. Yet most of the cosmic ray content in star-forming galaxies is in protons, which are invisible in radio emission. Therefore, the argument needs assumptions about the proton spectrum, typically that of a constant proton/electron ratio. In some environments, particularly starburst galaxies, the reasoning behind these assumptions does not necessarily hold: secondary pionic positrons and electrons may be responsible for most of the radio emission, and strong energy losses can alter the proton/electron ratio. We derive an equipartition expression that should work in a hadronic loss-dominated environment like starburst galaxies. Surprisingly, despite the radically different assumptions from the classical equipartition formula, numerically the results for starburst magnetic fields are similar. We explain this fortuitous coincidence using the energetics of secondary production and energy loss times. We show that these processes cause the proton/electron ratio to be ~100 for GHz-emitting electrons in starbursts.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 4
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    In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death (2012)
    Oxford University Press
    Details
    Publication Date: 2012-12-01
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
    Electronic Resource
    Electronic Resource
    Fluid-escape features as a precursor of a large sublacustrine sediment slide in Lake Le Bourget, NW Alps, France (2004)
    Oxford, UK : Blackwell Science Ltd
    Terra nova 16 (2004), S. 0 
    Details
    ISSN: 1365-3121
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Geosciences
    Notes: The north-western corner of Lake Le Bourget is situated along an active fault zone and accommodated a large sediment supply from the Rhone River until the end of the Late Glacial period. On the delta slope, the Holocene sheet drape that covers the largest buried mass wasting deposit (the HDU) shows undulations, small fractures and discontinuities that are attributed to downslope creep. Evidence for episodes of vigorous fluid expulsion is found in association with these discontinuities. All these features are rooted at the top of the HDU and occur along two specific isobaths. These observations indicate a close link between fractures and focused fluid flow. We suggest that focused fluid flow triggered by earthquakes facilitates the formation of small-scale faults that accommodate part of the downslope movement and eventually link up to form a head-scarp of a large slide (c. 107 m3).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3121.2004.00566.x
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    Paper (German National Licenses)
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  • 6
    Electronic Resource
    Electronic Resource
    Flood and earthquake disturbance of 210Pb geochronology (Lake Anterne, NW Alps) (2002)
    Oxford UK : Blackwell Science Ltd
    Terra nova 14 (2002), S. 0 
    Details
    ISSN: 1365-3121
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Geosciences
    Notes: Dating recent lake sediment records yielding disturbed 210Pb profiles has been a problem of wide interest in palaeoclimatic and palaeoseismic studies over the last few centuries. When applied to an alpine lake sedimentary record, a high-resolution sedimentological study reveals that the 210Pb profile is disturbed by the occurrence of single-event deposits triggered by two different mechanisms: flood events deposits and gravity reworking. Removing disturbed layers from the 210Pb profile yields a logarithmic depth–activity relationship. Using a simple 210Pb decay model (CFCS) provides an assessment of mean accumulation rate of `continuous sedimentation', as opposed to `event-linked sedimentation'. The correlation of the thickest four gravity-reworked deposits with historically known earthquakes permits both validation and refinement of the age–depth relationship. This refinement highlights variations in accumulation rate consistent with post-Little Ice Age climatic variations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-3121.2002.00413.x
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  • 7
    Electronic Resource
    Electronic Resource
    1822 earthquake-triggered homogenite in Lake Le Bourget (NW Alps) (1999)
    Oxford, UK : Blackwell Science Ltd
    Terra nova 11 (1999), S. 0 
    Details
    ISSN: 1365-3121
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Geosciences
    Notes: High-resolution textural signatures of an earthquake-induced historical ‘homogenite’ layer are presented, as well as its 3D distribution. This homogeneous deposit is correlated with the AD 1822 event (VII–VIII MSK intensity), the main historical earthquake of the French outer Alps, using 210Pb dating and historical chronicles. During this earthquake a violent lake water oscillation was reported (seiche effect). In the present study we discuss the influence of lake water oscillations during earthquake-induced subaqueous slide, through a pluridisciplinary analysis of subbottom sediments including high-resolution seismic, sidescan sonar and short gravity coring.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-3121.1999.00230.x
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  • 8
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    Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3 (2015)
    Oxford University Press
    Details
    Publication Date: 2015-06-23
    Description: Alu repetitive elements are known to be major contributors to genome instability by generating Alu -mediated copy-number variants (CNVs). Most of the reported Alu -mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu – Alu -mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30% of total sequence annotated in the human reference genome, compared with the 10% genome-wide and 18% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with ~150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu – Alu -mediated rearrangements were identified in 80% of the interstitial deletions, 46% of the tandem duplications and 50% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu -mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 9
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    PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways (2014)
    Oxford University Press
    Details
    Publication Date: 2014-05-20
    Description: The repair of toxic double-strand breaks (DSB) is critical for the maintenance of genome integrity. The major mechanisms that cope with DSB are: homologous recombination (HR) and classical or alternative nonhomologous end joining (C-NHEJ versus A-EJ). Because these pathways compete for the repair of DSB, the choice of the appropriate repair pathway is pivotal. Among the mechanisms that influence this choice, deoxyribonucleic acid (DNA) end resection plays a critical role by driving cells to HR, while accurate C-NHEJ is suppressed. Furthermore, end resection promotes error-prone A-EJ. Increasing evidence define Poly(ADP-ribose) polymerase 3 (PARP3, also known as ARTD3) as an important player in cellular response to DSB. In this work, we reveal a specific feature of PARP3 that together with Ku80 limits DNA end resection and thereby helps in making the choice between HR and NHEJ pathways. PARP3 interacts with and PARylates Ku70/Ku80. The depletion of PARP3 impairs the recruitment of YFP-Ku80 to laser-induced DNA damage sites and induces an imbalance between BRCA1 and 53BP1. Both events result in compromised accurate C-NHEJ and a concomitant increase in DNA end resection. Nevertheless, HR is significantly reduced upon PARP3 silencing while the enhanced end resection causes mutagenic deletions during A-EJ. As a result, the absence of PARP3 confers hypersensitivity to anti-tumoral drugs generating DSB.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    Curcumin facilitates a transitory cellular stress response in Trembler-J mice (2013)
    Oxford University Press
    Details
    Publication Date: 2013-11-08
    Description: We have previously shown that oral administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and partially mitigates the severe neuropathy phenotype of the Trembler-J ( Tr-J ) mouse model in a dose-dependent manner. Here we compared the gene expression in sciatic nerves of 2-week-old pups and adult Tr-J with the same age groups of wild-type mice and found a significant increase in gene expression for hypoxia, inflammatory response and heat-shock proteins, the latter specifically the Hsp70 family, in Tr-J mice. We also detected an activation of different branches of unfolded protein responses (UPRs) in Tr-J mice . Administering curcumin results in lower expression of UPR markers suggesting it relieves endoplasmic reticulum (ER) cell stress sensors in sciatic nerves of Tr-J mice while the level of heat-shock proteins stays comparable to untreated Tr-J mice. We further tested if Hsp70 levels could influence the severity of the Tr-J neuropathy. Notably, reduced dosage of the Hsp70 strongly potentiates the severity of the Tr-J neuropathy, though the absence of Hsp70 had little effect in wild-type mice. In aggregate, these data provide further insights into the pathological disease mechanisms caused by myelin gene mutations and further support the exploration of curcumin as a therapeutic approach for selected forms of inherited neuropathy and potentially for other genetic diseases due to ER-retained mutants.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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