Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis

Chemical tools to monitor drug-target engagement of endogenously expressed protein kinases are highly desirable for preclinical target validation in drug discovery. Here, we describe a chemical genetics strategy to selectively study target engagement of endogenous kinases. By substituting a serine residue into cysteine at the DFG-1 position in the ATP-binding pocket, we sensitize the non-receptor tyrosine kinase FES towards covalent labeling by a complementary fluorescent chemical probe. This mutation is introduced in the endogenous FES gene of HL-60 cells using CRISPR/Cas9 gene editing. Leveraging the temporal and acute control offered by our strategy, we show that FES activity is dispensable for differentiation of HL-60 cells towards macrophages. Instead, FES plays a key role in neutrophil phagocytosis via SYK kinase activation. This chemical genetics strategy holds promise as a target validation method for kinases.Medicinal Chemistr

Collective properties of neutron-deficient Nd isotopes: Lifetime measurements of the yrast states in 136^{136}Nd

International audienceLifetimes of the low-energy levels in Nd136, populated in the reaction Te124(O16,4n), were measured with the ROSPHERE array at the Horia Hulubei National Institute for Physics and Nuclear Engineering (IFIN-HH), Bucharest-Magurele. The data were analyzed using the recoil distance Doppler shift method, and, in the cases where lifetimes were τ⩽1 ps, Doppler attenuation effects were taken into account. The deduced electromagnetic transition probabilities are discussed in the framework of the five-dimensional collective Hamiltonian (5DCH) theoretical model implemented with the D1S Gogny force, and detailed systematics of several observables in the even-even Nd isotopic chain are presented that highlight the transitional character of the neutron-deficient Nd isotopes. The 5DCH predictions are in overall good agreement with the present experimental results

Lifetime measurements in 138^{138}Nd

International audienceLifetimes of several short-lived excited states in Nd138 were measured with the ROSPHERE array at IFIN-HH, Bucharest, using the recoil-distance Doppler shift technique following the Sb123(F19,4n) reaction. The resulting electromagnetic transition probabilities are compared to large-scale shell model calculations and to constrained Hartree-Fock-Bogoliubov calculations with the Gogny D1S interaction, configuration mixing, and a five-dimensional collective Hamiltonian formalism. The onset of collectivity in Nd isotopes below the N=82 shell closure and the deformation induced by the alignment of protons and neutron holes in the h11/2 orbitals are discussed

New evidence for alpha clustering structure in the ground state band of ²¹²Po

Half-lives of the low-lying yrast states of 212Po have been measured using the delayed coincidence fast-timing method. We report on the first measurement of the 41+ half-life, as well as a new measurement of the 61+ half-life with improved accuracy compared to previous studies. The extracted lifetime of the 41+ and 61+ state have been determined to be 100(14) ps and 1.66(28) ns respectively. With these measurements, precise values are now available for the reduced transition strengths B(E2) of all ground state band levels in 212Po up to the first 8+ state, in particular B(E2; 41+→21+) = 9.4(13) W.u. and B(E2;61+→41+) = 8.7(15) W.u. Comparison of the new available data with an α-clustering model calculation provides evidence that the inclusion of the α-cluster degree of freedom significantly improves agreement with experimental data compared to earlier shell model calculations

Lifetime measurements in 138Nd

Lifetimes of several short-lived excited states in 138Nd were measured with the ROSPHERE array at IFIN-HH, Bucharest, using the recoil-distance Doppler shift technique following the 123Sb(19F,4n) reaction. The resulting electromagnetic transition probabilities are compared to large-scale shell model calculations and to constrained Hartree-Fock-Bogoliubov calculations with the Gogny D1S interaction, configuration mixing, and a five-dimensional collective Hamiltonian formalism. The onset of collectivity in Nd isotopes below the N = 82 shell closure and the deformation induced by the alignment of protons and neutron holes in the h11/2 orbitals are discussed