BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein

Patients with chronic myeloid leukemia in whom tyrosine kinase inhibitors (TKIs) fail often present mutations in the BCR-ABL catalytic domain. We noticed a lack of substitutions involving 4 amino acids (E286, M318, I360, and D381) that form hydrogen bonds with ponatinib. We therefore introduced mutations in each of these residues, either preserving or altering their physicochemical properties. We found that E286, M318, I360, and D381 are dispensable for ABL and BCR-ABL protein stability but are critical for preserving catalytic activity. Indeed, only a "conservative" I360T substitution retained kinase proficiency and transforming potential. Molecular dynamics simulations of BCR-ABLI360T revealed differences in both helix αC dynamics and protein-correlated motions, consistent with a modified ATP-binding pocket. Nevertheless, this mutant remained sensitive to ponatinib, imatinib, and dasatinib. These results suggest that changes in the 4 BCR-ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Notably, amino acids equivalent to those identified in BCR-ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.This work was supported by an investigator grant to P.V. from Associazione Italiana per la Ricerca sul Cancro (AIRC) and by funding from the Biotechnology and Biological Sciences Research Council (BB/I023291/1 and BB/H018409/1 to AP and FF). P.B. is the recipient of an AIRC - Marie Curie fellowship

Influência do tamanho da semente na qualidade fisiológica e na produtividade da cultura da soja.

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Phosphonate additives do not always inhibit crystallization

This paper investigates crystal growth modifiers based on 1,3,5-substituted benzene derivatives. The results show that as expected, the phosphonated derivative inhibits calcite precipitation to a much greater degree than the analogous sulfonate. However, on barium sulfate, both molecules show some crystallization promotion behaviour, with the phosphonate being the more potent promoter overall. Thus, the functional group alone does not determine the impact the organic molecule will have on crystallization. This opens the way for additives that have dual purposes (inhibiting the crystallization of one phase while not impacting or promoting the crystallization of other phases)

Ionised outflows in z ∼\sim 2.4 quasar host galaxies

AGN-driven outflows are invoked by galaxy evolutionary models to quench star formation and to explain the origin of the relations observed locally between super massive black holes and their host galaxies. This work aims to detect the presence of extended ionised outflows in luminous quasars where we expect the maximum activity both in star formation and in black hole accretion. Currently, there are only a few studies based on spatially resolved observations of outflows at high redshift, $z>2$. We analyse a sample of six luminous (${\rm L>10^{47} \ erg/s}$) quasars at $z\sim2.4$, observed in H-band using the near-IR integral field spectrometer SINFONI at VLT. We perform a kinematic analysis of the [OIII] emission line at $\lambda = 5007\AA$. [OIII] has a complex gas kinematic, with blue-shifted velocities of a few hundreds of km/s and line widths up to 1500 km/s. Using the spectroastrometric method we infer size of the ionised outflows of up to $\sim$2 kpc. The properties of the ionised outflows, mass outflow rate, momentum rate and kinetic power, are correlated with the AGN luminosity. The increase in outflow rate with increasing AGN luminosity is consistent with the idea that a luminous AGN pushes away the surrounding gas through fast outflows driven by radiation pressure, which depends on the emitted luminosity. We derive mass outflow rates of about 6-700 M$_{\odot}$/yr for our sample, which are lower than those observed in molecular outflows. Indeed physical properties of ionised outflows show dependences on AGN luminosity which are similar to those of molecular outflows but indicating that the mass of ionised gas is smaller than that of the molecular one. Alternatively, this discrepancy between ionised and molecular outflows could be explained with different acceleration mechanisms.Comment: 13 pages, 11 figures; accepted for publication in A&

Quasars as Cosmological Probes: The Ionizing Continuum, Gas Metallicity and the EW-L Relation

Using a realistic model for line emission from the broad emission line regions of quasars, we are able to reproduce the previously observed correlations of emission-line ratios with the shape of the spectral energy distribution (SED). In agreement with previous studies, we find that the primary driving force behind the Baldwin Effect (EW ~ L^beta, beta < 0) is a global change in the SED with quasar luminosity, in that more luminous quasars must have characteristically softer ionizing continua. This is completely consistent with observations that show correlations between L_uv, alpha_ox, alpha_uvx, line ratios and EWs. However, to explain the complete lack of a correlation in the EW(NV)--L_uv diagram we propose that the more luminous quasars have characteristically larger gas metallicities (Z). As a secondary element, nitrogen's rapidly increasing abundance with increasing Z compensates for the losses in EW(NV) emitted by gas illuminated by softer continua in higher luminosity quasars. A characteristic relationship between Z and L has an impact on the EW--L_uv relations for other lines as well. For a fixed SED, an increasing gas metallicity reduces the EW of the stronger metal lines (the gas cools) and that of Ly_alpha and especially HeII (because of the increasing metal opacity), while the weaker lines (e.g., CIII] 1909) generally respond positively. The interplay between the effects of a changing SED and Z with L results in the observed luminosity dependent spectral variations. All of the resulting dependences on L_uv are within the range of the observed slopes.Comment: 11 pages, 3 figures, AASTeX aas2pp4.sty, accepted for publication in Ap

A Case-by-Case Evolutionary Analysis of Four Imprinted Retrogenes

Retroposition is a widespread phenomenon resulting in the generation of new genes that are initially related to a parent gene via very high coding sequence similarity. We examine the evolutionary fate of four retrogenes generated by such an event; mouse Inpp5f_v2, Mcts2, Nap1l5, and U2af1-rs1. These genes are all subject to the epigenetic phenomenon of parental imprinting. We first provide new data on the age of these retrogene insertions. Using codon-based models of sequence evolution, we show these retrogenes have diverse evolutionary trajectories, including divergence from the parent coding sequence under positive selection pressure, purifying selection pressure maintaining parent-retrogene similarity, and neutral evolution. Examination of the expression pattern of retrogenes shows an atypical, broad pattern across multiple tissues. Protein 3D structure modeling reveals that a positively selected residue in U2af1-rs1, not shared by its parent, may influence protein conformation. Our case-by-case analysis of the evolution of four imprinted retrogenes reveals that this interesting class of imprinted genes, while similar in regulation and sequence characteristics, follow very varied evolutionary paths