A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase

l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL

Fragment properties of fragmenting heavy nuclei produced in central and semi-peripheral collisions

Fragment properties of hot fragmenting sources of similar sizes produced in central and semi-peripheral collisions are compared in the excitation energy range 5-10 AMeV. For semi-peripheral collisions a method for selecting compact quasi-projectiles sources in velocity space similar to those of fused systems (central collisions) is proposed. The two major results are related to collective energy. The weak radial collective energy observed for quasi-projectile sources is shown to originate from thermal pressure only. The larger fragment multiplicity observed for fused systems and their more symmetric fragmentation are related to the extra radial collective energy due to expansion following a compression phase during central collisions. A first attempt to locate where the different sources break in the phase diagram is proposed.Comment: 23 pages submitted to NP

Bimodality: a possible experimental signature of the liquid-gas phase transition of nuclear matter

We have observed a bimodal behaviour of the distribution of the asymmetry between the charges of the two heaviest products resulting from the decay of the quasi-projectile released in binary Xe+Sn and Au+Au collisions from 60 to 100 MeV/u. Event sorting has been achieved through the transverse energy of light charged particles emitted on the quasi-target side, thus avoiding artificial correlations between the bimodality signal and the sorting variable. Bimodality is observed for intermediate impact parameters for which the quasi-projectile is identified. A simulation shows that the deexcitation step rather than the geometry of the collision appears responsible for the bimodal behaviour. The influence of mid-rapidity emission has been verified. The two bumps of the bimodal distribution correspond to different excitation energies and similar temperatures. It is also shown that it is possible to correlate the bimodality signal with a change in the distribution of the heaviest fragment charge and a peak in potential energy fluctuations. All together, this set of data is coherent with what would be expected in a finite system if the corresponding system in the thermodynamic limit exhibits a first order phase transition.Comment: 30 pages, 31 figure

Effect of the intermediate velocity emissions on the quasi-projectile properties for the Ar+Ni system at 95 A.MeV

The quasi-projectile (QP) properties are investigated in the Ar+Ni collisions at 95 A.MeV taking into account the intermediate velocity emission. Indeed, in this reaction, between 52 and 95 A.MeV bombarding energies, the number of particles emitted in the intermediate velocity region is related to the overlap volume between projectile and target. Mean transverse energies of these particles are found particularly high. In this context, the mass of the QP decreases linearly with the impact parameter from peripheral to central collisions whereas its excitation energy increases up to 8 A.MeV. These results are compared to previous analyses assuming a pure binary scenario

Study of intermediate velocity products in the Ar+Ni collisions between 52 and 95 A.MeV

Intermediate velocity products in Ar+Ni collisions from 52 to 95 A.MeV are studied in an experiment performed at the GANIL facility with the 4$\pi$ multidetector INDRA. It is shown that these emissions cannot be explained by statistical decays of the quasi-projectile and the quasi-target in complete equilibrium. Three methods are used to isolate and characterize intermediate velocity products. The total mass of these products increases with the violence of the collision and reaches a large fraction of the system mass in mid-central collisions. This mass is found independent of the incident energy, but strongly dependent on the geometry of the collision. Finally it is shown that the kinematical characteristics of intermediate velocity products are weakly dependent on the experimental impact parameter, but strongly dependent on the incident energy. The observed trends are consistent with a participant-spectator like scenario or with neck emissions and/or break-up.Comment: 37 pages, 13 figure

Measurements of sideward flow around the balance energy

Sideward flow values have been determined with the INDRA multidetector for Ar+Ni, Ni+Ni and Xe+Sn systems studied at GANIL in the 30 to 100 A.MeV incident energy range. The balance energies found for Ar+Ni and Ni+Ni systems are in agreement with previous experimental results and theoretical calculations. Negative sideward flow values have been measured. The possible origins of such negative values are discussed. They could result from a more important contribution of evaporated particles with respect to the contribution of promptly emitted particles at mid-rapidity. But effects induced by the methods used to reconstruct the reaction plane cannot be totally excluded. Complete tests of these methods are presented and the origins of the ``auto-correlation'' effect have been traced back. For heavy fragments, the observed negative flow values seem to be mainly due to the reaction plane reconstruction methods. For light charged particles, these negative values could result from the dynamics of the collisions and from the reaction plane reconstruction methods as well. These effects have to be taken into account when comparisons with theoretical calculations are done.Comment: 27 pages, 15 figure

SYMBA: An end-to-end VLBI synthetic data generation pipeline: Simulating Event Horizon Telescope observations of M 87

Context. Realistic synthetic observations of theoretical source models are essential for our understanding of real observational data. In using synthetic data, one can verify the extent to which source parameters can be recovered and evaluate how various data corruption effects can be calibrated. These studies are the most important when proposing observations of new sources, in the characterization of the capabilities of new or upgraded instruments, and when verifying model-based theoretical predictions in a direct comparison with observational data. Aims. We present the SYnthetic Measurement creator for long Baseline Arrays (SYMBA), a novel synthetic data generation pipeline for Very Long Baseline Interferometry (VLBI) observations. SYMBA takes into account several realistic atmospheric, instrumental, and calibration effects. Methods. We used SYMBA to create synthetic observations for the Event Horizon Telescope (EHT), a millimetre VLBI array, which has recently captured the first image of a black hole shadow. After testing SYMBA with simple source and corruption models, we study the importance of including all corruption and calibration effects, compared to the addition of thermal noise only. Using synthetic data based on two example general relativistic magnetohydrodynamics (GRMHD) model images of M 87, we performed case studies to assess the image quality that can be obtained with the current and future EHT array for different weather conditions. Results. Our synthetic observations show that the effects of atmospheric and instrumental corruptions on the measured visibilities are significant. Despite these effects, we demonstrate how the overall structure of our GRMHD source models can be recovered robustly with the EHT2017 array after performing calibration steps, which include fringe fitting, a priori amplitude and network calibration, and self-calibration. With the planned addition of new stations to the EHT array in the coming years, images could be reconstructed with higher angular resolution and dynamic range. In our case study, these improvements allowed for a distinction between a thermal and a non-thermal GRMHD model based on salient features in reconstructed images

THEMIS: A Parameter Estimation Framework for the Event Horizon Telescope

The Event Horizon Telescope (EHT) provides the unprecedented ability to directly resolve the structure and dynamics of black hole emission regions on scales smaller than their horizons. This has the potential to critically probe the mechanisms by which black holes accrete and launch outflows, and the structure of supermassive black hole spacetimes. However, accessing this information is a formidable analysis challenge for two reasons. First, the EHT natively produces a variety of data types that encode information about the image structure in nontrivial ways; these are subject to a variety of systematic effects associated with very long baseline interferometry and are supplemented by a wide variety of auxiliary data on the primary EHT targets from decades of other observations. Second, models of the emission regions and their interaction with the black hole are complex, highly uncertain, and computationally expensive to construct. As a result, the scientific utilization of EHT observations requires a flexible, extensible, and powerful analysis framework. We present such a framework, Themis, which defines a set of interfaces between models, data, and sampling algorithms that facilitates future development. We describe the design and currently existing components of Themis, how Themis has been validated thus far, and present additional analyses made possible by Themis that illustrate its capabilities. Importantly, we demonstrate that Themis is able to reproduce prior EHT analyses, extend these, and do so in a computationally efficient manner that can efficiently exploit modern high-performance computing facilities. Themis has already been used extensively in the scientific analysis and interpretation of the first EHT observations of M87

Monitoring the Morphology of M87* in 2009–2017 with the Event Horizon Telescope

The Event Horizon Telescope (EHT) has recently delivered the first resolved images of M87*, the supermassive black hole in the center of the M87 galaxy. These images were produced using 230 GHz observations performed in 2017 April. Additional observations are required to investigate the persistence of the primary image feature—a ring with azimuthal brightness asymmetry—and to quantify the image variability on event horizon scales. To address this need, we analyze M87* data collected with prototype EHT arrays in 2009, 2011, 2012, and 2013. While these observations do not contain enough information to produce images, they are sufficient to constrain simple geometric models. We develop a modeling approach based on the framework utilized for the 2017 EHT data analysis and validate our procedures using synthetic data. Applying the same approach to the observational data sets, we find the M87* morphology in 2009–2017 to be consistent with a persistent asymmetric ring of ~40 μas diameter. The position angle of the peak intensity varies in time. In particular, we find a significant difference between the position angle measured in 2013 and 2017. These variations are in broad agreement with predictions of a subset of general relativistic magnetohydrodynamic simulations. We show that quantifying the variability across multiple observational epochs has the potential to constrain the physical properties of the source, such as the accretion state or the black hole spin