Single-nanoparticle phase transitions visualized by four-dimensional electron microscopy

The advancement of techniques that can probe the behaviour of individual nanoscopic objects is of paramount importance in various disciplines, including photonics and electronics. As it provides images with a spatiotemporal resolution, four-dimensional electron microscopy, in principle, should enable the visualization of single-nanoparticle structural dynamics in real and reciprocal space. Here, we demonstrate the selectivity and sensitivity of the technique by visualizing the spin crossover dynamics of single, isolated metal–organic framework nanocrystals. By introducing a small aperture in the microscope, it was possible to follow the phase transition and the associated structural dynamics within a single particle. Its behaviour was observed to be distinct from that imaged by averaging over ensembles of heterogeneous nanoparticles. The approach reported here has potential applications in other nanosystems and those that undergo (bio)chemical transformations

Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT

International audienceBackground: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT. Methodology/Principal Findings: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200 ± 40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150 ± 80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant. Conclusions: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicit

Depression in Patients with Mastocytosis: Prevalence, Features and Effects of Masitinib Therapy

Depression in patients with mastocytosis is often reported but its prevalence and characteristics are not precisely described. In addition, the impact of therapies targeting mast cells proliferation, differentiation and degranulation on psychic symptoms of depression have never been investigated. Our objective was to determine the prevalence and to describe features of depression in a large cohort of mastocytosis patients (n = 288) and to investigate the therapeutic impact of the protein kinase inhibitor masitinib in depression symptoms. The description of depression was based on the analysis of a database with Hamilton scores using Principal Component Analysis (PCA). Efficacy of masitinib therapy was evaluated using non parametric Wilcoxon test for paired data within a three months period (n = 35). Our results show that patients with indolent mastocytosis present an elevated prevalence of depression (64%). Depression was moderate in 56% but severe in 8% of cases. Core symptoms (such as psychic anxiety, depressed mood, work and interests) characterized depression in mastocytosis patients. Masitinib therapy was associated with significant improvement (67% of the cases) of overall depression, with 75% of recovery cases. Global Quality of Life slightly improved after masitinib therapy and did not predicted depression improvement. In conclusion, depression is very frequent in mastocytosis patients and masitinib therapy is associated with the reduction its psychic experiences. We conclude that depression in mastocytosis may originate from processes related to mast cells activation. Masitinib could therefore be a useful treatment for mastocytosis patients with depression and anxiety symptoms

Time-resolved single-crystal X-ray crystallography

In this chapter the development of time-resolved crystallography is traced from its beginnings more than 30 years ago. The importance of being able to “watch” chemical processes as they occur rather than just being limited to three-dimensional pictures of the reactant and final product is emphasised, and time-resolved crystallography provides the opportunity to bring the dimension of time into the crystallographic experiment. The technique has evolved in time with developments in technology: synchrotron radiation, cryoscopic techniques, tuneable lasers, increased computing power and vastly improved X-ray detectors. The shorter the lifetime of the species being studied, the more complex is the experiment. The chapter focusses on the results of solid-state reactions that are activated by light, since this process does not require the addition of a reagent to the crystalline material and the single-crystalline nature of the solid may be preserved. Because of this photoactivation, time-resolved crystallography is often described as “photocrystallography”. The initial photocrystallographic studies were carried out on molecular complexes that either underwent irreversible photoactivated processes where the conversion took hours or days. Structural snapshots were taken during the process. Materials that achieved a metastable state under photoactivation and the excited (metastable) state had a long enough lifetime for the data from the crystal to be collected and the structure solved. For systems with shorter lifetimes, the first time-resolved results were obtained for macromolecular structures, where pulsed lasers were used to pump up the short lifetime excited state species and their structures were probed by using synchronised X-ray pulses from a high-intensity source. Developments in molecular crystallography soon followed, initially with monochromatic X-ray radiation, and pump-probe techniques were used to establish the structures of photoactivated molecules with lifetimes in the micro- to millisecond range. For molecules with even shorter lifetimes in the sub-microsecond range, Laue diffraction methods (rather than using monochromatic radiation) were employed to speed up the data collections and reduce crystal damage. Future developments in time-resolved crystallography are likely to involve the use of XFELs to complete “single-shot” time-resolved diffraction studies that are already proving successful in the macromolecular crystallographic field.</p

Picosecond observation of cation-stepwise delayed and cation-triggered photoinduced intramolecular charge transfer in fluorescent cation probes

International audienceTime-resolved transient absorption and gain spectra with subpicosecond laser excitation are reported for donor-donor and acceptor-donor stilbene-crowns (in each compound the electron donor group is the 15-aza-5-crown macrocycle, D1). The effect of the calcium cation on the photoinduced intramolecular charge transfer (ICT) rate constants are measured. When the cation is on the donor side of the molecular system (class 1: D1CS-Crown), the photoinduced ICT process is slowed down and goes through several intermediates characterized by a distancing of the cation, while a solvent molecule enters its coordination sphere. When the cation is on the acceptor side (class 2: D1DS-Crown,D1DB-Crown and D1DCS-Crown), the photoinduced ICT process becomes too fast to be measured, even on the picosecond scale

Cation-triggered photoinduced intramolecular charge transfer and fluorescence red-shift in fluorescence probes

We report the synthesis of two new nonpolar fluorescence cation probes (DDS-crown, 5 and DDB-crown, 6) designed from stilbene and 1,4-diphenyl 1,3-butadiene, respectively, by substitution at the two ends with two electron-donor groups (D) (dimethylamino and monoaza-15-crown-5), one of which is able to chelate a cation. The absorption and fluorescence spectra in several solvents of different polarity and the picosecond transient absorption spectra give an estimate of the Intramolecular Charge Transfer (ICT) strength in the excited state. When a cation (Ca2+) is chelated by the macrocycle, the ICT process is increased and the fluorescence is red-shifted. These spectroscopic effects of cation-chelation are enhanced in a third probe (DDCS-crown, 7) derived from DDS-crown by inserting an electron-acceptor (A) group (CN) at the ortho position of the macrocycle in order to increase the ICT

Cation-triggered photoinduced intramolecular charge transfer and fluorescence red-shift in fluorescence probes

We report the synthesis of two new nonpolar fluorescence cation probes (DDS-crown, 5 and DDB-crown, 6) designed from stilbene and 1,4-diphenyl 1,3-butadiene, respectively, by substitution at the two ends with two electron-donor groups (D) (dimethylamino and monoaza-15-crown-5), one of which is able to chelate a cation. The absorption and fluorescence spectra in several solvents of different polarity and the picosecond transient absorption spectra give an estimate of the Intramolecular Charge Transfer (ICT) strength in the excited state. When a cation (Ca2+) is chelated by the macrocycle, the ICT process is increased and the fluorescence is red-shifted. These spectroscopic effects of cation-chelation are enhanced in a third probe (DDCS-crown, 7) derived from DDS-crown by inserting an electron-acceptor (A) group (CN) at the ortho position of the macrocycle in order to increase the ICT

Design of new fluorinated bridged push-pull stilbenes and preparation of LB films for second harmonic generation in the blue domain

no abstrac

Design of new fluorinated bridged push-pull stilbenes and preparation of LB films for second harmonic generation in the blue domain

International audienceno abstrac