Dual enzyme-triggered controlled release on capped nanometric silica mesoporous supports

We thank the Spanish Government (project MAT2009-14564-C04 and CTQ2007-64735-AR07) the Generalitat Valencia (project PROMETEO/2009/016) for support. A.A. and L.M. thank the Generalitat Valenciana for their Santiago Grisolia Fellowship and VALI+D postdoctoral contract, respectively. We thank the confocal microscopy service from CIPF for technical support.Agostini, A.; Mondragón Martínez, L.; Coll Merino, MC.; Aznar Gimeno, E.; Marcos Martínez, MD.; Martínez Mañez, R.; Sancenón Galarza, F.... (2012). Dual enzyme-triggered controlled release on capped nanometric silica mesoporous supports. ChemistryOpen. 1:17-20. https://doi.org/10.1002/open.201200003S17201Saha, S., Leung, K. C.-F., Nguyen, T. D., Stoddart, J. F., & Zink, J. I. (2007). Nanovalves. Advanced Functional Materials, 17(5), 685-693. doi:10.1002/adfm.200600989Trewyn, B. G., Slowing, I. I., Giri, S., Chen, H.-T., & Lin, V. S.-Y. (2007). 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Measurement of time-dependent CP violation parameters in B0 → KS0 KS0 KS0 decays at Belle

We measure the time-dependent CP violation parameters in B0→KS0KS0KS0 decays using 772×106BB¯ pairs collected at the ϒ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider. The obtained mixing-induced and direct CP asymmetries are -0.71±0.23 (stat)±0.05 (syst) and 0.12±0.16 (stat)±0.05 (syst), respectively. These values are consistent with the Standard Model predictions. The significance of CP violation differs from zero by 2.5 standard deviations. © 2021 authors. Published by the American Physical Society

Safety and Efficacy of Dacomitinib in Korean Patients with KRAS Wild-Type Advanced Non–Small-Cell Lung Cancer Refractory to Chemotherapy and Erlotinib or Gefitinib: A Phase I/II Trial

IntroductionDacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib).MethodsThe phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS4m).ResultsTwelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms “cough” and “pain” showed improvement within 3 weeks of initiating treatment.ConclusionsDacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor

On Aharonov-Casher bound states

In this work bound states for the Aharonov-Casher problem are considered. According to Hagen's work on the exact equivalence between spin-1/2 Aharonov-Bohm and Aharonov-Casher effects, is known that the $\boldsymbol{\nabla}\cdot\mathbf{E}$ term cannot be neglected in the Hamiltonian if the spin of particle is considered. This term leads to the existence of a singular potential at the origin. By modeling the problem by boundary conditions at the origin which arises by the self-adjoint extension of the Hamiltonian, we derive for the first time an expression for the bound state energy of the Aharonov-Casher problem. As an application, we consider the Aharonov-Casher plus a two-dimensional harmonic oscillator. We derive the expression for the harmonic oscillator energies and compare it with the expression obtained in the case without singularity. At the end, an approach for determination of the self-adjoint extension parameter is given. In our approach, the parameter is obtained essentially in terms of physics of the problem.Comment: 11 pages, matches published versio

Molecular recognition of poly(A) by small ligands: an alternative method of analysis reveals nanomolar, cooperative and shape-selective binding

A few drug-like molecules have recently been found to bind poly(A) and induce a stable secondary structure (Tm ≈ 60°C), even though this RNA homopolymer is single-stranded in the absence of a ligand. Here, we report results from experiments specifically designed to explore the association of small molecules with poly(A). We demonstrate that coralyne, the first small molecule discovered to bind poly(dA), binds with unexpectedly high affinity (Ka >107 M−1), and that the crescent shape of coralyne appears necessary for poly(A) binding. We also show that the binding of similar ligands to poly(A) can be highly cooperative. For one particular ligand, at least six ligand molecules are required to stabilize the poly(A) self-structure at room temperature. This highly cooperative binding produces very sharp transitions between unstructured and structured poly(A) as a function of ligand concentration. Given the fact that junctions between Watson–Crick and A·A duplexes are tolerated, we propose that poly(A) sequence elements and appropriate ligands could be used to reversibly drive transitions in DNA and RNA-based molecular structures by simply diluting/concentrating a sample about the poly(A)-ligand ‘critical concentration’. The ligands described here may also find biological or medicinal applications, owing to the 3′-polyadenylation of mRNA in living cells

Corrigendum: Therapeutic Effect of Intestinal Autochthonous Lactobacillus reuteri P16 Against Waterborne Lead Toxicity in Cyprinus carpio

Harmful effects of heavy metals are myriad. Lead (Pb) from soil and atmosphere contaminates water bodies and affects the aquatic animals. Our previous study confirmed the in vitro probiotic potential of Lactobacillus reuteri against Pb toxicity, but further investigation is necessary for gaining insights into the related protection mode. Therefore, in this study, we investigated the protective effects of the potential probiotic L. reuteri P16 against waterborne Pb exposure-induced toxicity in the freshwater fish Cyprinus carpio. Fish (average weight: 23.16 ± 0.73 g) were allocated to four groups (control, Pb only, Pb + L. reuteri P16, and L. reuteri P16 only) and Pb groups were exposed to waterborne Pb (1 mg L−1) for 6 weeks. L. reuteri P16 (108 CFU g−1) supplemented diet was provided twice daily. Growth performances, hemato-biochemical parameters, innate immune responses, intestinal microbiota, and Pb accumulation in tissues were measured at the end of the trial. When the fish were exposed to Pb, dietary supplementation of L. reuteri P16 effectively decreased mortality and accumulation of Pb in tissues, and improved the growth performance. Co-treatment with Pb and L. reuteri P16 alleviated Pb exposure-induced oxidative stress, reversed alterations in hemato-biochemical parameters, improved innate immune parameters, and restored intestinal enzymatic activities. Moreover, L. reuteri P16 supplementation reversed the changes in intestinal microbiota in Pb-exposed fish. Furthermore, Pb exposure decreased the expressions of pro-inflammatory cytokines (TNF-α, IL-1β). However, the expression of heat shock proteins (HSP70 and HSP90) increased, which might have increased the cellular stress. Interestingly, the Pb-induced alterations of gene expressions were reversed by L. reuteri P16 supplementation. Thus, dietary administration of the potential probiotic L. reuteri P16 had several beneficial effects on growth performance and immune responses, decreased Pb accumulation in tissues, and reversed alterations in hematological responses of C. carpio. Furthermore, it offered direct protection against Pb-induced oxidative stress. Therefore, L. reuteri P16 may be a novel dietary supplement for enhancing growth performance and preventing Pb-exposure-induced toxicity in fish in aquaculture and aquatic products

B --> Phi K_S and Supersymmetry

The rare decay B --> Phi K_S is a well-known probe of physics beyond the Standard Model because it arises only through loop effects yet has the same time-dependent CP asymmetry as B --> Psi K_S. Motivated by recent data suggesting new physics in B --> Phi K_S, we look to supersymmetry for possible explanations, including contributions mediated by gluino loops and by Higgs bosons. Chirality-preserving LL and RR gluino contributions are generically small, unless gluinos and squarks masses are close to the current lower bounds. Higgs contributions are also too small to explain a large asymmetry if we impose the current upper limit on B(B_s --> mu mu). On the other hand, chirality-flipping LR and RL gluino contributions can provide sizable effects and while remaining consistent with related results in B --> Psi K_S, Delta M_s, B --> X_s gamma and other processes. We discuss how the LR and RL insertions can be distinguished using other observables, and we provide a string-based model and other estimates to show that the needed sizes of mass insertions are reasonable.Comment: 33 pages, 32 figures, Updated version for PRD. Includes discussions of other recent works on this topic. Added discussions & plots for gluino mass dependence and effects of theoretical uncertaintie

Scope and Mechanistic Study of the Coupling Reaction of α,β-Unsaturated Carbonyl Compounds with Alkenes: Uncovering Electronic Effects on Alkene Insertion vs Oxidative Coupling Pathways

The cationic ruthenium-hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4– (1) was found to be a highly effective catalyst for the intermolecular conjugate addition of simple alkenes to α,β-unsaturated carbonyl compounds to give (Z)-selective tetrasubstituted olefin products. The analogous coupling reaction of cinnamides with electron-deficient olefins led to the oxidative coupling of two olefinic C–H bonds in forming (E)-selective diene products. The intramolecular version of the coupling reaction efficiently produced indene and bicyclic fulvene derivatives. The empirical rate law for the coupling reaction of ethyl cinnamate with propene was determined as follows: rate = k[1]1[propene]0[cinnamate]−1. A negligible deuterium kinetic isotope effect (kH/kD = 1.1 ± 0.1) was measured from both (E)-C6H5CH═C(CH3)CONHCH3 and (E)-C6H5CD═C(CH3)CONHCH3 with styrene. In contrast, a significant normal isotope effect (kH/kD = 1.7 ± 0.1) was observed from the reaction of (E)-C6H5CH═C(CH3)CONHCH3 with styrene and styrene-d8. A pronounced carbon isotope effect was measured from the coupling reaction of (E)-C6H5CH═CHCO2Et with propene (13C(recovered)/13C(virgin) at Cβ = 1.019(6)), while a negligible carbon isotope effect (13C(recovered)/13C(virgin) at Cβ = 0.999(4)) was obtained from the reaction of (E)-C6H5CH═C(CH3)CONHCH3 with styrene. Hammett plots from the correlation of para-substituted p-X-C6H4CH═CHCO2Et (X = OCH3, CH3, H, F, Cl, CO2Me, CF3) with propene and from the treatment of (E)-C6H5CH═CHCO2Et with a series of para-substituted styrenes p-Y-C6H4CH═CH2 (Y = OCH3, CH3, H, F, Cl, CF3) gave the positive slopes for both cases (ρ = +1.1 ± 0.1 and +1.5 ± 0.1, respectively). Eyring analysis of the coupling reaction led to the thermodynamic parameters, ΔH⧧ = 20 ± 2 kcal mol–1 and ΔS⧧ = −42 ± 5 eu. Two separate mechanistic pathways for the coupling reaction have been proposed on the basis of these kinetic and spectroscopic studies