Multistep IgE Mast Cell Desensitization Is a Dose- and Time-Dependent Process Partially Regulated by SHIP-1.

Multistep mast cell desensitization blocks the release of mediators following IgE crosslinking with increasing doses of Ag. Although its in vivo application has led to the safe reintroduction of drugs and foods in IgE-sensitized patients at risk for anaphylaxis, the mechanisms of the inhibitory process have remained elusive. We sought to investigate the kinetics, membrane, and cytoskeletal changes and to identify molecular targets. IgE-sensitized wild-type murine (WT) and FcεRIα humanized (h) bone marrow mast cells were activated and desensitized with DNP, nitrophenyl, dust mites, and peanut Ags. The movements of membrane receptors, FcεRI/IgE/Ag, actin, and tubulin and the phosphorylation of Syk, Lyn, P38-MAPK, and SHIP-1 were assessed. Silencing SHIP-1 protein was used to dissect the SHIP-1 role. Multistep IgE desensitization of WT and transgenic human bone marrow mast cells blocked the release of ß-hexosaminidase in an Ag-specific fashion and prevented actin and tubulin movements. Desensitization was regulated by the initial Ag dose, number of doses, and time between doses. FcεRI, IgE, Ags, and surface receptors were not internalized during desensitization. Phosphorylation of Syk, Lyn, p38 MAPK, and SHIP-1 increased in a dose-response manner during activation; in contrast, only SHIP-1 phosphorylation increased in early desensitization. SHIP-1 phosphatase function had no impact on desensitization, but silencing SHIP-1 increased ß-hexoxaminidase release, preventing desensitization. Multistep IgE mast cell desensitization is a dose- and time-regulated process that blocks ß-hexosaminidase, impacting membrane and cytoskeletal movements. Signal transduction is uncoupled, favoring early phosphorylation of SHIP-1. Silencing SHIP-1 impairs desensitization without implicating its phosphatase function.

Identifying the Gate-Opening Mechanism in the Flexible Metal-Organic Framework UTSA-300.

Atomic-level understanding of the gate-opening phenomenon in flexible porous materials is an important step toward learning how to control, design, and engineer them for applications such as the separation of gases from complex mixtures. Here, we report such mechanistic insight through an in-depth study of the pressure-induced gate-opening phenomenon in our earlier reported metal-organic framework (MOF) Zn(dps)2(SiF6) (dps = 4,4'-dipyridylsulfide), also called UTSA-300, using isotherm and calorimetry measurements, in situ infrared spectroscopy, and ab initio simulations. UTSA-300 is shown to selectively adsorb acetylene (C2H2) over ethylene (C2H4) and ethane (C2H6) and undergoes an abrupt gate-opening phenomenon, making this framework a highly selective gas separator of this complex mixture. The selective adsorption is confirmed by pressure-dependent in situ infrared spectroscopy, which, for the first time, shows the presence of multiple C2H2 species with varying strengths of bonding. A rare energetic feature at the gate-opening condition of the flexible MOF is observed in our differential heat energies, directly measured by calorimetry, showcasing the importance of this tool in adsorption property exploration of flexible frameworks and offering an energetic benchmark for further energy-based fundamental studies. Based on the agreement of this feature with ab initio-based adsorption energies of C2H2 in the closed-pore structure UTSA-300a ("a" refers to the activated form), this feature is assigned to the weakening of the H-bond C-H···F formed between C2H2 and fluorine of the MOF. Our analysis identifies the weakening of this H-bond, the expansion of the closed-pore MOF upon successive C2H2 coadsorption until its volume is close to that of the open-pore MOF, and the spontaneous gate opening to energetically favor C2H2 adsorption in the open-pore structure as crucial steps in the gate-opening mechanism in this system.

Role of Pairwise Reactions on the Synthesis of Li0.3La0.57TiO3 and the Resulting Structure-Property Correlations.

The performance of single-ion conductors is highly sensitive to the material's defect chemistry. Tuning these defects is limited for solid-state reactions as they occur at particle-particle interfaces, which provide a complex evolving energy landscape for atomic rearrangement and product formation. In this report, we investigate the (1) order of addition and (2) lithium precursor decomposition temperature and their effect on the synthesis and grain boundary conductivity of the perovskite lithium lanthanum titanium oxide (LLTO). We use an intimately mixed sol-gel, a solid-state reaction of Li precursor + La2O3 + TiO2, and Li precursor + amorphous La0.57TiOx as different chemical routes to change the way in which the elements are brought together. The results show that the perovskite can accommodate a wide range of Li deficiencies (upward of 50%) while maintaining the tetragonal LLTO structure, indicating that X-ray diffraction (XRD) is insufficient to fully characterize the chemical nature of the product (i.e., Li-deficient LLTO may behave differently than stoichiometric LLTO). Variations in the relative intensities of different reflections in XRD suggest variations in the La ordering within the crystal structure between synthesis methods. Furthermore, the choice of the precursor and the order of addition of the reactants lower the time required to form a pure phase. Density functional theory calculations of the formation energy of possible reaction intermediates support the hypothesis that a greater thermodynamic driving force to form LLTO leads to a greater LLTO yield. The retention of lithium is correlated with the thermal decomposition temperature of the Li precursor and the starting material mixing strategy. Taking the results together suggests that cations that share a site with Li should be mixed early to avoid ordering. Such cation ordering inhibits Li motion, leading to higher Li ion resistance.

Atomic-Scale Structure and Catalysis on Positively Charged Bimetallic Sites for Generation of H2.

Here, we report that a cationic bimetallic site consisting of one Pd and three Zn atoms (Pd1Zn3) supported on ZnO (Pd1Zn3/ZnO) exhibits an extraordinarily high catalytic activity for the generation of H2 through methanol partial oxidation (MPO) that is 2-3 orders of magnitude higher than that of a metallic Pd-Zn site on Pd-Zn nanoalloy (Pd-Zn/ZnO). Computational studies uncovered that the positively charged Pd atom of the subnanometer Pd1Zn3 bimetallic site largely decreases the activation barrier for dehydrogenation of methanol as compared to a metallic Pd atom of Pd-Zn alloy, thus switching the rate-determining step of MPO from methanol dehydrogenation over a Pd-Zn alloy with high barrier to the O2 dissociation step on a cationic Pd1Zn3 site with a low barrier, which is supported by our kinetics studies. The significantly higher catalytic activity and selectivity for H2 production over a cationic bimetallic site suggest a new approach to design bimetallic catalysts.

Splitting Mono- and Dibranched Alkane Isomers by a Robust Aluminum-Based Metal-Organic Framework Material with Optimal Pore Dimensions.

The separation of alkanes with different degrees of branching, particularly mono- and dibranched isomers, represents a challenging yet important industrial process for the production of premium gasoline blending components with high octane number. We report here the separation of linear/monobranched and dibranched alkanes through complete molecular sieving by a robust aluminum-based MOF material, Al-bttotb (H3bttotb = 4,4',4″-(benzene-1,3,5-triyltris(oxy))tribenzoicacid). Single- and multicomponent adsorption experiments reveal that the material adsorbs linear and monobranched alkanes, but fully excludes their dibranched isomers. Adsorption sites of alkanes within the MOF channels have been identified by single-crystal X-ray diffraction studies, and the adsorption mechanism was explored through computational calculations and modeling. The highly selective adsorption of the MOF should be attributed to its optimal pore dimensions.

Ultrafast Electron Correlations and Memory Effects at Work: Femtosecond Demagnetization in Ni.

Experimental observations of the ultrafast (less than 50 fs) demagnetization of Ni have so far defied theoretical explanations particularly since its spin-flipping time is much less than that resulting from spin-orbit and electron-lattice interactions. Through the application of an approach that benefits from spin-flip time-dependent density-functional theory and dynamical mean-field theory, we show that proper inclusion of electron correlations and memory (time dependence of electron-electron interaction) effects leads to demagnetization at the femtosecond scale, in good agreement with experimental observations. Furthermore, our calculations reveal that this ultrafast demagnetization results mainly from spin-flip transitions from occupied to unoccupied orbitals implying a dynamical reduction of exchange splitting. These conclusions are found to be valid for a wide range of laser pulse amplitudes. They also pave the way for ab initio investigations of ultrafast charge and spin dynamics in a variety of quantum materials in which electron correlations may play a definitive role.

Basophil Activation Test as a Biomarker for Taxanes Anaphylaxis.

Introduction: Taxanes are widely used chemotherapy agents, and their administration, despite premedication, is associated with hypersensitivity reactions (HR) in up to 9% of patients, 1% of which are severe. The mechanisms of these reactions are not fully understood. Finding biomarkers for early diagnosis and better understanding the underlying mechanisms of these reactions are key to defining the best treatment strategy for patients. Methods: The purpose of this study was to evaluate the effectiveness of the basophil activation test (BAT) to diagnose patients with anaphylactic reactions to taxanes. Patients with anaphylaxis to taxane compounds (n = 15) were assessed through clinical history, skin testing (when possible), and BAT. BAT was performed immediately before rapid drug desensitization or before skin testing using anti-CD123 conjugated (APC-Biolegend), anti-HLADR conjugated (FITC-Biolegend) to gate Basophils and anti-CD63 conjugated (PE-Biolegend), and anti-CD203c conjugated (BV-Biolegend) to assess CD203c and CD63 expression on basophils under taxane stimulation. BAT was also performed in eight healthy volunteers. Results: BAT was positive for CD203c in eight out of 15 patients and for CD63 in four out of 15 patients and in two out of eight controls. The sensitivity for CD203c was 53%, the specificity was 87%, and the area under the curve was 0.66 (p = 0.19%). For CD63, these rates were 33%, 87%, and 0.6 (p = 0.4). In a subgroup analysis of patients with positive skin tests (11 patients), CD203c was positive in six patients (sensitivity of 54.5% and specificity of 87.5%), and CD63 was positive in five patients (sensitivity of 45% and specificity of 75%). Conclusions: BAT as a diagnostic tool for immediate hypersensitivity reactions to taxanes may be relevant in patients with selected phenotypes and endotypes, especially those with severe reactions or when the diagnosis cannot be established by the skin test. Increased expression of CD203c was more frequent than of CD63 in patients with positive results, and the sensitivity of this biomarker was higher in patient sub-group with positive skin tests, i.e., patients with IgE-mediated endotypes.

Design of tough adhesive from commodity thermoplastics through dynamic crosslinking.

Tough adhesives provide resistance against high debonding forces, and these adhesives are difficult to design because of the simultaneous requirement of strength and ductility. Here, we report a design of tough reversible/recyclable adhesive materials enabled by incorporating dynamic covalent bonds of boronic ester into commodity triblock thermoplastic elastomers that reversibly bind with various fillers and substrates. The spectroscopic measurements and density functional theory calculations unveil versatile dynamic covalent binding of boronic ester with various hydroxy-terminated surfaces such as silica nanoparticles, aluminum, steel, and glass. The designed multiphase material exhibits exceptionally high adhesion strength and work of debonding with a rebonding capability, as well as outstanding mechanical, thermal, and chemical resistance properties. Bonding and debonding at the interfaces dictate hybrid material properties, and this revelation of tailored dynamic interactions with multiple interfaces will open up a new design of adhesives and hybrid materials.

Dominant contributions to the apparent activation energy in two-dimensional submonolayer growth: comparison between Cu/Ni(111) and Ni/Cu(111).

For surface-mediated processes in general, such as epitaxial growth and heterogeneous catalysis, a constant slope in the Arrhenius diagram of the rate of interest, R, against inverse temperature, log R vs 1/T, is traditionally interpreted as the existence of a bottleneck elementary reaction (or rate-determining step), whereby the constant slope (or apparent activation energy, [Formula: see text]) reflects the value of the energy barrier for that elementary reaction. In this study, we express [Formula: see text] as a weighted average, where every term contains the traditional energy barrier for the corresponding elementary reaction plus an additional configurational term, while identifying each weight as the probability of executing the corresponding elementary reaction. Accordingly, the change in the leading (most probable) elementary reaction with the experimental conditions (e.g. temperature) is automatically captured and it is shown that a constant value of [Formula: see text] is possible even if control shifts from one elementary reaction to another. To aid the presentation, we consider kinetic Monte Carlo simulations of submonolayer growth of Cu on Ni(111) and Ni on Cu(111) at constant deposition flux, including a large variety of single-atom, multi-atom and complete-island diffusion events. In addition to analysing the dominant contributions to the diffusion constant of the complete adparticle system (or tracer diffusivity) and its apparent activation energy as a function of both coverage and temperature for the two heteroepitaxial systems, their surface morphologies and island densities are also compared.