Novel insulated gamma and lentis retroviral vectors towards safer genetic modification of stem cells

In otherwise successful gene therapy trials insertional mutagenesis has resulted in leukemia. The identification of new short synthetic genetic insulator elements (GIE) which would both prevent such activation effects and shield the transgene from silencing, is a main challenge. Previous attempts with e.g. b-globin HS4, have met with poor efficacy and genetic instability. We have investigated potential improvement with two new candidate synthetic GIEs in SIN-gamma and lentiviral vectors. With each constructs two internal promoters have been tested: either the strong Fr- MuLV-U3 or the housekeeping hPGK.We could identify a specific combination of insulator 2 repeats which translates into best functional activity, high titers and boundary effect in both gammaretro and lentivectors. In target cells a dramatic shift of expression is observed with an homogenous profile the level of which strictly depends on the promoter strength. These data remain stable in both HeLa cells over three months and cord blood HSCs for two months, irrespective of the multiplicity of infection (MOI). In comparison, control native and SIN vectors expression levels show heterogeneous, depend on the MOI and prove unstable. We have undertaken genotoxicity assessment in comparing integration patterns ingenuity in human target cells sampled over three months using high-throughput pyro-sequencing. Data will be presented. Further genotoxicity assessment will include in vivo studies. We have established insulated vectors which harbour both boundary and enhancer-blocking effect and show stable in prolonged in vitro culture conditions. Work performed with support of EC-DG research FP6-NoE, CLINIGENE: LSHB-CT-2006-018933

Robust Estimators of the Generalized Log-Gamma Distribution

We propose robust estimators of the generalized log-gamma distribution and, more generally, of location-shape-scale families of distributions. A (weighted) Q tau estimator minimizes a tau scale of the differences between empirical and theoretical quantiles. It is n(1/2) consistent; unfortunately, it is not asymptotically normal and, therefore, inconvenient for inference. However, it is a convenient starting point for a one-step weighted likelihood estimator, where the weights are based on a disparity measure between the model density and a kernel density estimate. The one-step weighted likelihood estimator is asymptotically normal and fully efficient under the model. It is also highly robust under outlier contamination. Supplementary materials are available online.

Planificació del procés de producció en sèrie d'un silenciós d'escapament per a un turisme de gamma mitjana

A partir d'un disseny d'un silenciós, s'estudien tots els processos i la maquinària necessària per a implantar la fabricació en sèrie del producte, i d'aquesta manera es poden donar unes pautes generals per la fàbrica que haurà d'acollir aquest procés.

A computationally efficient shear deformable beam element for large deformation multibody applications

In this paper, a new two-dimensional shear deformable beam element based on the absolute nodal coordinate formulation is proposed. The nonlinear elastic forces of the beam element are obtained using a continuum mechanics approach without employing a local element coordinate system. In this study, linear polynomials are used to interpolate both the transverse and longitudinal components of the displacement. This is different from other absolute nodal-coordinate-based beam elements where cubic polynomials are used in the longitudinal direction. The accompanying defects of the phenomenon known as shear locking are avoided through the adoption of selective integration within the numerical integration method. The proposed element is verified using several numerical examples, and the results are compared to analytical solutions and the results for an existing shear deformable beam element. It is shown that by using the proposed element, accurate linear and nonlinear static deformations, as well as realistic dynamic behavior, can be achieved with a smaller computational effort than by using existing shear deformable two-dimensional beam elements.

Experimental insights into deformation dynamics and intermittency in rapid granular shear flows

This work concerns the experimental study of rapid granular shear flows in annular Couette geometry. The flow is induced by continuous driving of the horizontal plate at the top of the granular bed in an annulus. The compressive pressure, driving torque, instantaneous bed height and rotational speed of the shearing plate are measured. Moreover, local stress fluctuations are measured in a medium made of steel spheres 2 and 3 mm in diameter. Both monodisperse packing and bidisperse packing are investigated to reveal the influence of size diversity in intermittent features of granular materials. Experiments are conducted in an annulus that can contain up to 15 kg of spherical steel balls. The shearing granular medium takes place via the rotation of the upper plate which compresses the material loaded inside the annulus. Fluctuations of compressive force are locally measured at the bottom of the annulus using a piezoelectric sensor. Rapid shear flow experiments are pursued at different compressive forces and shear rates and the sensitivity of fluctuations are then investigated by different means through monodisperse and bidisperse packings. Another important feature of rapid granular shear flows is the formation of ordered structures upon shearing. It requires a certain range for the amount of granular material (uniform size distribution) loaded in the system in order to obtain stable flows. This is studied more deeply in this thesis. The results of the current work bring some new insights into deformation dynamics and intermittency in rapid granular shear flows. The experimental apparatus is modified in comparison to earlier investigations. The measurements produce data for various quantities continuously sampled from the start of shearing to the end. Static failure and dynamic shearing ofa granular medium is investigated. The results of this work revealed some important features of failure dynamics and structure formation in the system. Furthermore, some computer simulations are performed in a 2D annulus to examine the nature of kinetic energy dissipation. It is found that turbulent flow models can statistically represent rapid granular flows with high accuracy. In addition to academic outcomes and scientific publications our results have a number of technological applications associated with grinding, mining and massive grain storages.

Modern Gamma Knife radiosurgery of vestibular schwannomas: treatment concept, volumetric tumor response, and functional results.

The objective of the present study was longitudinal evaluation of the volumetric tumor response and functional results after Gamma Knife radiosurgery of vestibular schwannomas, performed according to the modern standards of treatment. From October 2003 to September 2007, 133 consecutive patients with vestibular schwannomas were treated according to the concept of robotic Gamma Knife microradiosurgery, which is based on precise irradiation of the lesion, sparing adjacent structures, and delivery of the high radiation energy to the target. Multiple small-sized isocenters located within the border of the neoplasm were applied. The mean marginal dose was 11.5 Gy (range, 11-12 Gy). In total, 126 cases with a minimum posttreatment follow-up of 2 years (range, 2-7 years; median, 4 years) were analyzed. Temporary enlargement was noted in 25 % of tumors at 6 months after radiosurgery. At 3 years of follow-up, tumor shrinkage, stabilization, and increase in volume were marked in 73 %, 23 %, and 4 % of cases, respectively. All progressing lesions spontaneously stabilized later on and did not require additional management. In 3 % of patients, transitory impairment of the facial nerve function was marked; however, neither its permanent dysfunction nor trigeminal neuropathy attributed to radiosurgery was noted. Impairment of hearing compared to its pretreatment level was revealed in 4 %, 12 %, 13 %, and 16 % of patients at 6 months, 1 year, 2 years, and 3 years after radiosurgery, respectively, and this trend was statistically significant (P = 0.0042). Overall, 77 % of patients with serviceable hearing before treatment preserved it 3 years thereafter. In conclusion, modern Gamma Knife radiosurgery provides effective and safe management of vestibular schwannomas. Nevertheless, possible temporary tumor enlargement, delay of its growth arrest, transient dysfunction of the cranial nerves, and gradual deterioration of hearing after irradiation should be always taken into consideration.

The star forming region Monoceros R2 as a gamma-ray source

After the release of the gamma-ray source catalog produced by the Fermi satellite during its first two years of operation, a significant fraction of sources still remain unassociated at lower energies. In addition to well-known high-energy emitters (pulsars, blazars, supernova remnants, etc.), theoretical expectations predict new classes of gamma-ray sources. In particular, gamma-ray emission could be associated with some of the early phases of stellar evolution, but this interesting possibility is still poorly understood. Aims: The aim of this paper is to assess the possibility of the Fermi gamma-ray source 2FGL J0607.5-0618c being associated with the massive star forming region Monoceros R2. Methods: A multi-wavelength analysis of the Monoceros R2 region is carried out using archival data at radio, infrared, X-ray, and gamma-ray wavelengths. The resulting observational properties are used to estimate the physical parameters needed to test the different physical scenarios. Results: We confirm the 2FGL J0607.5-0618c detection with improved confidence over the Fermi two-year catalog. We find that a combined effect of the multiple young stellar objects in Monoceros R2 is a viable picture for the nature of the source.

Very-High-Energy gamma rays from a Distant Quasar: How Transparent Is the Universe?

The atmospheric Cherenkov gamma-ray telescope MAGIC, designed for a low-energy threshold, has detected very-high-energy gamma rays from a giant flare of the distant Quasi-Stellar Radio Source (in short: radio quasar) 3C 279, at a distance of more than 5 billion light-years (a redshift of 0.536). No quasar has been observed previously in very-high-energy gamma radiation, and this is also the most distant object detected emitting gamma rays above 50 gigaelectron volts. Because high-energy gamma rays may be stopped by interacting with the diffuse background light in the universe, the observations by MAGIC imply a low amount for such light, consistent with that known from galaxy counts.

The changing milliarcsecond radio morphology of the gamma-ray binary LS 5039

LS 5039 is one of the few TeV emitting X-ray binaries detected so far. The powering source of its multiwavelength emission can be accretion in a microquasar scenario or wind interaction in a young nonaccreting pulsar scenario. Aims.To present new high-resolution radio images and compare them with the expected behavior in the different scenarios. Methods.We analyze Very Long Baseline Array (VLBA) radio observations that provide morphological and astrometric information at milliarcsecond scales. Results.We detect a changing morphology between two images obtained five days apart. In both runs there is a core component with a constant flux density, and an elongated emission with a position angle (PA) that changes by 12 $\pm$ $3\degr$ between both runs. The source is nearly symmetric in the first run and asymmetric in the second one. The astrometric results are not conclusive. Conclusions.A simple and shockless microquasar scenario cannot easily explain the observed changes in morphology. An interpretation within the young nonaccreting pulsar scenario requires the inclination of the binary system to be very close to the upper limit imposed by the absence of X-ray eclipses.

Biphasic response of a tecto-mesencephalic pilocytic astrocytoma after Gamma Knife surgery - A case report.

Biphasic response (shrinkage-regrowth-shrinkage) of tumors has never previously been reported in the postoperative course, neither after microsurgery, nor after Gamma Knife surgery (GKS). We present the case of an adult with dorsal midbrain syndrome resulting from a pilocytic astrocytoma centered on the mesencephalic tectum. The tumor extended to the third ventricle and the thalamus. Initially, due to tumor growth, a biopsy was performed and histology established. Later, a ventriculocisternostomy for obstructive hydrocephalus was performed. Finally, GKS was performed, as the tumor continued to grow. After GKS, the lesion exhibited a biphasic response, with a major shrinkage at 3 months, regrowth within the target volume at 6 and 9 months and a second phase of important shrinkage at 12 months, which persisted for the next two years. The possible mechanisms for this particular response pattern are discussed.

Spectral energy distribution of the gamma-ray microquasar LS 5039

The microquasar LS 5039 has recently been detected as a source of very high energy (VHE) $\gamma$-rays. This detection, that confirms the previously proposed association of LS 5039 with the EGRET source 3EG~J1824$-$1514, makes of LS 5039 a special system with observational data covering nearly all the electromagnetic spectrum. In order to reproduce the observed spectrum of LS 5039, from radio to VHE $\gamma$-rays, we have applied a cold matter dominated jet model that takes into account accretion variability, the jet magnetic field, particle acceleration, adiabatic and radiative losses, microscopic energy conservation in the jet, and pair creation and absorption due to the external photon fields, as well as the emission from the first generation of secondaries. The radiative processes taken into account are synchrotron, relativistic Bremsstrahlung and inverse Compton (IC). The model is based on a scenario that has been characterized with recent observational results, concerning the orbital parameters, the orbital variability at X-rays and the nature of the compact object. The computed spectral energy distribution (SED) shows a good agreement with the available observational data.