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The ENVISAT validation programme for the atmospheric instruments MIPAS, SCIAMACHY and GOMOS is based on a number of balloon-borne, aircraft, satellite and ground-based correlative measurements. In particular the activities of validation scientists were coordinated by ESA within the ENVISAT Stratospheric Aircraft and Balloon Campaign or ESABC. As part of a series of similar papers on other species [this issue] and in parallel to the contribution of the individual validation teams, the present paper provides a synthesis of comparisons performed between MIPAS CH4 and N2O profiles produced by the current ESA operational software (Instrument Processing Facility version 4.61 or IPF v4.61, full resolution MIPAS data covering the period 9 July 2002 to 26 March 2004) and correlative measurements obtained from balloon and aircraft experiments as well as from satellite sensors or from ground-based instruments. In the middle stratosphere, no significant bias is observed between MIPAS and correlative measurements, and MIPAS is providing a very consistent and global picture of the distribution of CH4 and N2O in this region. In average, the MIPAS CH4 values show a small positive bias in the lower stratosphere of about 5%. A similar situation is observed for N2O with a positive bias of 4%. In the lower stratosphere/upper troposphere (UT/LS) the individual used MIPAS data version 4.61 still exhibits some unphysical oscillations in individual CH4 and N2O profiles caused by the processing algorithm (with almost no regularization). Taking these problems into account, the MIPAS CH4 and N2O profiles are behaving as expected from the internal error estimation of IPF v4.61 and the estimated errors of the correlative measurements.
Estimates of the recovery time of stratospheric ozone heavily rely on the exact knowledge of the processes that lead to the decomposition of the relevant halogenated source gases. Crucial parameters in this context are fractional release factors (FRFs) as well as stratospheric lifetimes and ozone depletion potentials (ODPs). We here present data from the analysis of air samples collected between 2009 and 2011 on board research aircraft flying in the mid- and high-latitude stratosphere and infer the above-mentioned parameters for ten major source gases: CFCl3 (CFC-11), CF2Cl2 (CFC-12), CF2ClCFCl2 (CFC-113), CCl4 (carbon tetrachloride), CH3CCl3 (methyl chloroform), CHF2Cl (HCFC-22), CH3CFCl2 (HCFC-141b), CH3CF2Cl (HCFC-142b), CF2ClBr (H-1211), and CF3Br (H-1301). The inferred correlations of their FRFs with mean ages of air reveal less decomposition as compared to previous studies for most compounds. When using the calculated set of FRFs to infer equivalent stratospheric chlorine, we find a reduction of more than 20% as compared to the values inferred in the most recent Scientific Assessment of Ozone Depletion by the World Meteorological Organisation (WMO, 2011). We also note that FRFs and their correlations with mean age are not generally time-independent as often assumed. The stratospheric lifetimes were calculated relative to that of CFC-11. Within our uncertainties the ratios between stratospheric lifetimes inferred here agree with the values in recent WMO reports except for CFC-11, CFC-12 and CH3CCl3. Finally, we calculate lower ODPs than recommended by WMO for six out of ten compounds, with changes most pronounced for the three HCFCs. Collectively these newly calculated values may have important implications for the severity and recovery time of stratospheric ozone loss.
The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.
The Match method for the quantification of polar chemical ozone loss is investigated mainly with respect to the impact of the transport of air masses across the vortex edge. For the winter 2002/03, we show that significant transport across the vortex edge occurred and was simulated by the Chemical Lagrangian Model of the Stratosphere. In-situ observations of inert tracers and ozone from HAGAR on the Geophysica aircraft and balloon-borne sondes, and remote observations from MIPAS on the ENVISAT satellite were reproduced well by CLaMS. The model even reproduced a small vortex remnant that remained a distinct feature until June 2003 and was also observed in-situ by a balloon-borne whole air sampler. We use this CLaMS simulation to quantify the impact of transport across the vortex edge on ozone loss estimates from the Match method. We show that a time integration of the determined vortex average ozone loss rates, as performed in Match, results in a larger ozone loss than the polar vortex average ozone loss in CLaMS. The determination of the Match ozone loss rates is also influenced by the transport of air across the vortex edge. We use the model to investigate how the sampling of the ozone sondes on which Match is based represents the vortex average ozone loss rate. Both the time integration of ozone loss and the determination of ozone loss rates for Match are evaluated using the winter 2002/2003 CLaMS simulation. These impacts can explain the majority of the differences between CLaMS and Match column ozone loss. While the investigated effects somewhat reduce the apparent discrepancy in January ozone loss rates reported earlier, a distinct discrepancy between simulations and Match remains. However, its contribution to the accumulated ozone loss over the winter is not large.
The Match method for quantification of polar chemical ozone loss is investigated mainly with respect to the impact of mixing across the vortex edge onto this estimate. We show for the winter 2002/03 that significant mixing across the vortex edge occurred and was accurately modeled by the Chemical Lagrangian Model of the Stratosphere. Observations of inert tracers and ozone in-situ from HAGAR on the Geophysica aircraft and sondes and also remote from MIPAS on ENVISAT were reproduced well. The model even reproduced a small vortex remnant that was isolated until June 2003 and was observed in-situ by a balloon-borne whole air sampler. We use this CLaMS simulation to quantify the impact of cross vortex edge mixing on the results of the Match method. It is shown that a time integration of the determined vortex average ozone loss rates as performed in Match results in larger ozone loss than the polar vortex average ozone loss in CLaMS. Also, the determination of the Match ozone loss rates can be influenced by mixing. This is especially important below 430 K, where ozone outside the vortex is lower than inside and the vortex boundary is not a strong transport barrier. This effect and further sampling effects cause an offset between vortex average ozone loss rates derived from Match and deduced from CLaMS with an even sampling for the entire vortex. Both, the time-integration of ozone loss and the determination of ozone loss rates for Match are evaluated using the winter 2002/03 CLaMS simulation. These impacts can explain the differences between CLaMS and Match column ozone loss. While the investigated effects somewhat reduce the apparent discrepancy in January ozone loss rates, a discrepancy between simulations and Match remains. However, its contribution to the accumulated ozone loss over the winter is not large.
So far clinical human immunodeficiency virus (HIV) therapy is limited to non-curative treatments. However, as recently shown, alternative approaches such as HIV gene therapy have the potential to functionally cure the disease (e.g. the hematopoietic stem cell (HSC)-transplantation with a CCR5Δ32 homozygous transplant) (1). In contrast to the highly personalized medical treatment applied in the ‘Berlin case’, more broadly applicable approaches are currently under intensive investigation.
One example is the adeno-associated-virus (AAV)-mediated delivery of in vivo secreted antiviral entry inhibitors (iSAVE), the concept of which is based on the direct in vivo administration of a broadly applicable highly potent antiviral gene (here: a C46-derived entry inhibitory peptide interfering with HIV-1 membrane fusion). The AAV-based gene delivery is believed to overcome several limitations of gene therapeutic treatments based on ex vivo lentiviral trials in the past. It is (i) targeting differentiated HIV target cells (i.e. liver and differentiated lymphatic cells) reducing the risk of genotoxicity compared to stem cell-based trials, (ii) overcoming the limitation of a low number of genetically modifiable cells as in lentivirally based ex vivo transduction strategies (i.e. limited modifiable cell number due to culture conditions and lower vector titers) and (iii) using the safe AAV vector system, which has not been associated with major genotoxicity in men. (iv) Most importantly, the concept of secretable entry inhibitors does not require transduction of large amounts of cells due to the protective bystander effect. Thus, iSAVE might be a treatment principle for HIV infection that might be able to cure patients irrespective of their viral isolates or adherence.
Accordingly, the iSAVE concept could aim at two different sites in the patient for the production of antiviral transgenes, either the systemic production via suitable producer cells (e.g. hepatocytes) or the local production in the lymphatic system.
In a first approach, we are able to efficiently target hepatocytes using the natural AAV serotype 8 to express high plasma levels of secretable antiviral entry inhibitors in order to systemically suppress viral replication. In this setting we could show that iSAVE peptides are highly expressed in hepatocytes. However, plasma levels of iSAVE were insufficient when using a secretable peptide as sole antiviral transgene.
As a second treatment strategy, the iSAVE project aimed to deliver antiviral genes directly to the site of viral replication, the lymphatic system. Here, (i) a panel of naturally occurring AAV serotypes as well as (ii) AAV retargeting approaches were employed to design a highly efficient and selective AAV vector variant for gene delivery into the lymphatic system after intravenous vector administration.
In detail, (i) screening of the natural occurring serotypes revealed that the AAV serotype 1 (AAV-1) was best in targeting splenic tissue in two humanized mouse models, however at a very low level. After systemic AAV-1 vector administration neither transduction of human lymphocytes did occur nor was iSAVE expressed in the lymphatic system in a humanized mouse model.
(ii) In a second approach, we modified the well-characterized AAV-2 serotype in a tropism-defining region of its capsid gene by insertion of human peripheral blood lymphocytes (hPBL)-tropic peptide ligands. These in turn were selected by M13 in vivo phage display and by in vivo AAV peptide display. Selected variants were cloned and tested for hPBL transduction in vitro. Although the selected variants did not show increased expression efficacies compared to AAV-2 WT, it still might be possible that the selected variant are more specific for hPBLs as these conditions have not been tested.
As these selection processes required a humanized mouse model that comprises a functional lymphatic system, we established the previously described Trimera mouse model in our lab (2). We found that this mouse model could be further improved to allow engraftment of a lower number of gene-modified (gm) human T cells as in the classical Trimera model. These modified Trimera mice (mT3 mice) were conditioned by inclusion of cyclophosphamide (CTX) to the irradiation-conditioning scheme of the classical Trimera model.
Comparison of mT3 mice with established NSG and DKO mice in an adoptive gm T cell transplantation setting revealed that NSG mice were the most robust model providing high reproducibility in human T cell engraftment. MT3 mice allowed a substantial, yet more variable engraftment of gm T cells. Besides comparing engraftment kinetics, the graft quality (i.e. clonality and cytokine milieu) was analyzed. Again, NSG mice showed the most balanced homeostatic repopulation three weeks after transplantation, while mT3 mice were prone to Th1-type, oligloclonal repopulation, indicating an early onset of xenograft-versus-host disease. Finally, the lymphatic infiltration was analyzed. As expected, mT3 mice provided the most intact lymphatic structures, although the normal lymphatic morphology was not restored.
In conclusion, it was demonstrated in this work that AAV-mediated iSAVE gene therapy faces specific limitations depending on the respective targeting approach
In the systemic approach, iSAVE peptides have to be further optimized in terms of transgene design itself, as high-level accumulation in murine plasma was not feasible for the short iSAVE precursor. In the local, lymphatic targeting approach, AAV-mediated expression faces its limits in targeting specificity but foremost expression efficacy. Thus, the AAV vector itself needs further optimization for sufficient local iSAVE expression levels. Independently from the AAV-related approaches, a novel humanized mouse model was established in this work. Despite drawbacks regarding repopulation variability and set-up complexity, the novel mT3 mouse model comprised improved secondary lymphatic structures for adoptive T cell transfer, which might be an interesting platform for studies in lymphoma or leukemia therapy.
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
Subvisible cirrus clouds (SVCs) may contribute to dehydration close to the tropical tropopause. The higher and colder SVCs and the larger their ice crystals, the more likely they represent the last efficient point of contact of the gas phase with the ice phase and, hence, the last dehydrating step, before the air enters the stratosphere. The first simultaneous in situ and remote sensing measurements of SVCs were taken during the APE-THESEO campaign in the western Indian ocean in February/March 1999. The observed clouds, termed Ultrathin Tropical Tropopause Clouds (UTTCs), belong to the geometrically and optically thinnest large-scale clouds in the Earth´s atmosphere. Individual UTTCs may exist for many hours as an only 200--300 m thick cloud layer just a few hundred meters below the tropical cold point tropopause, covering up to 105 km2. With temperatures as low as 181 K these clouds are prime representatives for defining the water mixing ratio of air entering the lower stratosphere.
Mechanisms by which subvisible cirrus clouds (SVCs) might contribute to dehydration close to the tropical tropopause are not well understood. Recently Ultrathin Tropical Tropopause Clouds (UTTCs) with optical depths around 10-4 have been detected in the western Indian ocean. These clouds cover thousands of square kilometers as 200-300 m thick distinct and homogeneous layer just below the tropical tropopause. In their condensed phase UTTCs contain only 1-5% of the total water, and essentially no nitric acid. A new cloud stabilization mechanism is required to explain this small fraction of the condensed water content in the clouds and their small vertical thickness. This work suggests a mechanism, which forces the particles into a thin layer, based on upwelling of the air of some mm/s to balance the ice particles, supersaturation with respect to ice above and subsaturation below the UTTC. In situ measurements suggest that these requirements are fulfilled. The basic physical properties of this mechanism are explored by means of a single particle model. Comprehensive 1-D cloud simulations demonstrate this stabilization mechanism to be robust against rapid temperature fluctuations of +/- 0.5 K. However, rapid warming (Delta T > 2 K) leads to evaporation of the UTTC, while rapid cooling (Delta T < -2 K) leads to destabilization of the particles with the potential for significant dehydration below the cloud