ALBERT

Description: We use GNSS observations in northeastern Venezuela to constrain the El Pilar Fault (EPF) kinematics and to explore the effects of the variable elastic properties of the surrounding medium and of the fault geometry on inferred slip rates and locking depth. The velocity field exhibits an asymmetric velocity gradient on either side of the EPF. We use five different approaches to explore possible models to explain this asymmetry. First, we infer a 1.6-km locking depth using a classic elastic half-space dislocation model. Second, we infer a 1.5-km locking depth and a 0.33 asymmetry coefficient using a heterogeneous asymmetric model, including contrasting material properties on either side of a vertical fault, suggesting that the igneous-metamorphic terranes on the northern side are ~2 times more rigid than the sedimentary southern side. Third, we use a three-dimensional elasto-static model to evaluate the presence of a compliant zone (CZ), suggesting a 30% reduction of rigidity in the upper 3 km at the depth of a 1- to 5-km wide fault zone. Fourth, we evaluate the distribution of fault slip, revealing a widespread partial-creep pattern in the eastern upper segment, while the upper western segment exhibits a partially locked area, which coincides with the rupture surface of the 1797 and 1929 earthquakes. To supplement these models, we upgrade the previously published displacement simulation method using non-vertical dislocations with data acquired between 2003 and 2013. The localized aseismic displacement pattern associated with creeping or partially creeping fault segments could explain the low level of historic seismicity.

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.

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.

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.

Description: [1]  We have measured the bidirectional reflectance of analogs of dry, wet and frozen Martian soils over a wide range of phase angles in the visible spectral range. All samples were produced from two geologic samples: the standard JSC Mars-1 soil simulant and Hawaiian basaltic sand. In a first step, experiments were conducted with the dry samples to investigate the effects of surface texture. Comparisons with results independently obtained by different teams with similar samples showed a satisfying reproducibility of the photometric measurements as well as a noticeable influence of surface textures resulting from different sample preparation procedures. In a second step, water was introduced to produce wet and frozen samples and their photometry investigated. Optical microscope images of the samples provided information about their micro-texture. Liquid water, even in relatively low amount, resulted in the disappearance of the backscattering peak and the appearance of a forward scattering peak whose intensity increases with the amount of water. Specular reflections only appeared when water was present in an amount large enough to allow water to form a film at the surface of the sample. Icy samples showed a wide variability of photometric properties depending on the physical properties of the water ice. We discuss the implications of these measurements in terms of the expected photometric behavior of the Martian surface, from equatorial to circum-polar regions. In particular, we propose some simple photometric criteria to improve the identification of wet and/or icy soils from multiple observations under different geometries.

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.

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.

Description: [1]  The causes of renewed growth in the atmospheric CH 4 burden since 2007 are still poorly understood and the subject of intensive scientific discussion. Here, we present a reanalysis of global CH 4 emissions during the 2000s, based on the TM5-4DVAR inverse modeling system. We use high-accuracy surface observations from the NOAA Earth System Research Laboratory global cooperative air sampling network for 2000–2010, together with retrievals of column-averaged CH 4 mole fractions from the Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) instrument onboard ENVISAT from 2003 onwards. [2]  Using climatological OH fields, derived global total emissions for 2007–2010 are 16–20 Tg CH 4 /yr higher than for 2003–2005. Most of the inferred increase was located in the tropics (9–14 Tg CH 4 /yr) and mid-latitudes of the northern hemisphere (6–8 Tg CH 4 /yr), while no significant trend was derived for Arctic latitudes. The atmospheric increase can be attributed mainly to an increase of anthropogenic emissions. However, the derived trend in anthropogenic emissions is significantly smaller than the one estimated in the EDGARv4.2 emission inventory. Superimposed on the increasing trend in anthropogenic CH 4 emissions are significant inter-annual variations (IAV) of CH 4 emissions from wetlands (up to ±10 Tg CH 4 /yr), and biomass burning (up to ±7 Tg CH 4 /yr). [3]  Various sensitivity experiments have been performed to investigate the impact of the SCIAMACHY observations (compared to inversions using only surface observations), of the OH fields used, and of a priori emission inventories on the derived CH 4 emission trends and their inter-annual variability. Despite significant differences among these sensitivity experiments in their latitudinal attribution of IAV of CH 4 emissions, they show a reasonably consistent picture regarding the IAV aggregated on larger latitude bands. Furthermore, all sensitivity experiments show very similar performance against a comprehensive independent dataset of observations used for validation, including NOAA ship and aircraft profile samples, HIPPO aircraft transects, and CARIBIC aircraft data. Comparison of model simulations with BARCA aircraft measurements, however, show significantly better agreement in the free troposphere over the Amazon for the inversions using the SCIAMACHY and NOAA surface observations compared to inversions using only the surface observations, demonstrating the usefulness of the satellite measurements to better constrain tropical CH 4 emissions.

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.