Dithiolane quartets: thiol-mediated uptake enables cytosolic delivery in deep tissue

The cytosolic delivery of various substrates in 3D multicellular spheroids by thiol-mediated uptake is reported. This is important because most orthodox systems, including polycationic cell-penetrating peptides, fail to deliver efficiently into deep tissue. The grand principles of supramolecular chemistry, that is the pH dependence of dynamic covalent disulfide exchange with known thiols on the transferrin receptor, are proposed to account for transcytosis into deep tissue, while the known but elusive exchange cascades along the same or other partners assure cytosolic delivery in kinetic competition. For quantitative detection in the cytosol, the 2D chloroalkane penetration assay (CAPA) is translated to 3D deep tissue. The targeted delivery of quantum dots, otherwise already troublesome in 2D culture, and the controlled release of mechanophores are realized to exemplify the power of thiol-mediated uptake into spheroids. As transporters, dithiolane quartets on streptavidin templates are introduced as modular motifs. Built from two amino acids only, the varied stereochemistry and peptide sequence are shown to cover maximal functional space with minimal structural change, i.e., constitutional isomers. Reviving a classic in peptide chemistry, this templated assembly of β quartets promises to expand streptavidin biotechnology in new directions, while the discovery of general cytosolic delivery in deep tissue as an intrinsic advantage further enhances the significance and usefulness of thiol-mediated uptake.

Cytosolic delivery in multicellular 3D spheroids is shown to be an intrinsic advantage of thiol-mediated uptake, which is compatible with proteins and QDs, achieving targeting and controlled release.     

Cationic Polymerization of Hexamethylcyclotrisiloxane in Excess Water

Ring-opening ionic polymerization of cyclosiloxanes in dispersed media has long been discovered, and is nowadays both fundamentally studied and practically used. In this short communication, we show some preliminary results on the cationic ring-opening polymerization of hexamethylcyclotrisiloxane (D₃), a crystalline strained cycle, in water. Depending on the catalyst or/and surfactants used, polymers of various molar masses are prepared in a straightforward way. Emphasis is given here on experiments conducted with tris(pentafluorophenyl)borane (BCF), where high-molar polymers were generated at room temperature. In surfactant-free conditions, µm-sized droplets are stabilized by silanol end-groups of thus generated amphiphilic polymers, the latter of which precipitate in the course of reaction through chain extension. Introducing various surfactants in the recipe allows generating smaller emulsions in size with close polymerization ability, but better final colloidal stability, at the expense of low small cycles’ content. A tentative mechanism is finally proposed.     

Mapping Dicorynia guianensis Amsh. wood constituents by submicron resolution cluster‐TOF‐SIMS imaging

The preparation of tropical wood surface sections for time‐of‐flight secondary ion mass spectrometry imaging is described, and the use of delayed extraction of secondary ions and its interest for the analysis of vegetal surface are shown. The method has been applied to the study by time‐of‐flight secondary ion mass spectrometry imaging with a resolution of less than one micron of a tropical wood species, Dicorynia guianensis, which is one of the most exploited wood in French Guiana for its durable heartwood. The heartwood of this species exhibits an economical importance, but its production is not controlled in forestry. Results show an increase of tryptamine from the transition zone and a concomitant decrease of inorganic ions and starch fragment ions. These experiments lead to a better understanding of the heartwood formation and the origin of the natural durability of D. guianensis. Copyright © 2016 John Wiley & Sons, Ltd.     

Relative contributions of porosity and mineralized matrix properties to the bulk axial ultrasonic wave velocity in human cortical bone

Velocity of ultrasound waves has proved to be a useful indicator of bone biomechanical competence. A detailed understanding of the dependence of ultrasound parameters such as velocity on bone characteristics is a key to the development of bone quantitative ultrasound (QUS). The objective of this study is to investigate the relative contributions of porosity and mineralized matrix properties to the bulk compressional wave velocity (BCV) along the long bone axis. Cross-sectional slabs from the diaphysis of four human femurs were included in the study. Seven regions of interest (ROIs) were selected in each slab. BCV was measured in through-transmission at 5 MHz. Impedance of the mineralized matrix (Z_m) and porosity (Por) were obtained from 50 MHz scanning acoustic microscopy. Por and Z_m had comparable effects on BCV along the bone axis (R = −0.57 and R = 0.72, respectively).     

Thermal characteristics of bitumen pyrolysis

The pyrolysis behavior of bitumen was investigated using a thermogravimetric analyzer–mass spectrometer system (TG–MS) and a differential scanning calorimeter (DSC) as well as a pyrolysis-gas chromatograph/mass spectrometer system (Py-GC/MS). TG results showed that there were three stages of weight loss during pyrolysis—less than 110, 110–380, and 380–600 °C. Using distributed activation energy model, the average activation energy of the thermal decomposition of bitumen was calculated at 79 kJ mol⁻¹. The evolved gas from the pyrolysis showed that organic species, such as alkane and alkene fragments had a peak maximum temperature of 130 and 480 °C, respectively. Benzene, toluene, and styrene released at 100 and 420 °C. Most of the inorganic compounds, such as H₂, H₂S, COS, and SO₂, released at about 380 °C while the CO₂ had the maximum temperature peaks at 400 and 540 °C, respectively. FTIR spectra were taken of the residues of the different stages, and the results showed that the C–H bond intensity decreased dramatically at 380 °C. Py-GC/MS confirmed the composition of the evolved gas. The DSC revealed the endothermic nature of the bitumen pyrolysis.     

Strict L<Subscript>∞</Subscript> Isotonic Regression

Given a function f and weights w on the vertices of a directed acyclic graph G, an isotonic regression of (f,w) is an order-preserving real-valued function that minimizes the weighted distance to f among all order-preserving functions. When the distance is given via the supremum norm there may be many isotonic regressions. One of special interest is the strict isotonic regression, which is the limit of p-norm isotonic regression as p approaches infinity. Algorithms for determining it are given. We also examine previous isotonic regression algorithms in terms of their behavior as mappings from weighted functions over G to isotonic functions over G, showing that the fastest algorithms are not monotonic mappings. In contrast, the strict isotonic regression is monotonic.     

Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases

Voltage-gated Na⁺ (Na_V) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel Na_V channel ligands. With the objective of discovering new blockers of Na_V channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of Na_V channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC₅₀. These five alkaloids were then assayed using the Na⁺ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNa_V1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na⁺ currents elicited by the hNa_V1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na⁺ currents elicited by the hNav1.2 and hNav1.6 channels, with IC₅₀ values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block Na_V channels, with promising therapeutical applications.     

T3P-promoted synthesis of a series of novel 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones

A series of 11 novel 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-aryl-C-phenyl imines with thiosalicylic acid. This provides simple and ready access to N-aryl compounds in this family, which have been generally difficult to prepare.     

The Taming of Redox-Labile Phosphidotitanocene Cations

Tame d⁰ phosphidotitanocene cations stabilized with a pendant tertiary phosphane arm are reported. These compounds were obtained by one-electron oxidation of d¹ precursors with [Cp₂Fe][BPh₄]. The electronic structure of these compounds was studied experimentally (EPR, UV/Vis, and NMR spectroscopy, X-ray diffraction analysis) and through DFT calculations. The theoretical analysis of the bonding situation by using the electron localization function (ELF) shows the presence of π-interactions between the phosphido ligand and Ti in the d⁰ complexes, whereas dπ–pπ repulsion prevents such interactions in the d¹ complexes. In addition, CH–π interactions were observed in several complexes, both in solution and in the solid state, between the phosphido ligand and the phosphane arm. The d⁰ complexes were found to be light sensitive, and decompose through Ti−P bond homolysis to give Ti^III species. A naked d⁰ phosphidotitanocene cation has been trapped by reaction with diphenylacetylene, yielding a Ti/P frustrated Lewis pair (FLP), which was found to be less reactive than a previously reported Zr analog.