Targeting Neutrophilic Inflammation using Polymersome-Mediated Cellular Delivery

Neutrophils are key effector cells in inflammation and play an important role in neutralizing invading pathogens. During inflammation resolution, neutrophils undergo apoptosis before they are removed by macrophages, but if apoptosis is delayed, neutrophils can cause extensive tissue damage and chronic disease. Promotion of neutrophil apoptosis is a potential therapeutic approach for treating persistent inflammation, yet neutrophils have proven difficult cells to manipulate experimentally. In this study, we deliver therapeutic compounds to neutrophils using biocompatible, nanometer-sized synthetic vesicles, or polymersomes, which are internalized by binding to scavenger receptors and subsequently escape the early endosome through a pH-triggered disassembly mechanism. This allows polymersomes to deliver molecules into the cell cytosol of neutrophils without causing cellular activation. After optimizing polymersome size, we show that polymersomes can deliver the cyclin-dependent kinase inhibitor (R)-roscovitine into human neutrophils to promote apoptosis in vitro. Finally, using a transgenic zebrafish model, we show that encapsulated (R)-roscovitine can speed up inflammation resolution in vivo more efficiently than the free drug. These results show that polymersomes are effective intracellular carriers for drug delivery into neutrophils. This has important consequences for the study of neutrophil biology and the development of neutrophil-targeted therapeutics

Efficacy of increased resistant starch consumption in human type 2 diabetes

Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1

Chan–Lam amination of secondary and tertiary benzylic boronic esters

We report a Chan–Lam coupling reaction of benzylic and allylic boronic esters with primary and secondary anilines to form valuable alkyl amine products. Both secondary and tertiary boronic esters can be used as coupling partners, with mono-alkylation of the aniline occurring selectively. This is a rare example of a transition-metal-mediated transformation of a tertiary alkylboron reagent. Initial investigation into the reaction mechanism suggests that transmetalation from B to Cu occurs through a single-electron, rather than a two-electron process

The hydration state of HO−^-(aq)

The HO$^-$(aq) ion participates in myriad aqueous phase chemical processes of biological and chemical interest. A molecularly valid description of its hydration state, currently poorly understood, is a natural prerequisite to modeling chemical transformations involving HO$^-$(aq). Here it is shown that the statistical mechanical quasi-chemical theory of solutions predicts that $\mathrm{HO\cdot[H_2O]_3{}^-}$ is the dominant inner shell coordination structure for HO$^-$(aq) under standard conditions. Experimental observations and other theoretical calculations are adduced to support this conclusion. Hydration free energies of neutral combinations of simple cations with HO$^-$(aq) are evaluated and agree well with experimental values.Comment: 10 pages, 1 figur

Water wave propagation and scattering over topographical bottoms

Here I present a general formulation of water wave propagation and scattering over topographical bottoms. A simple equation is found and is compared with existing theories. As an application, the theory is extended to the case of water waves in a column with many cylindrical steps

Sputter deposition and characterization of lithium cobalt oxide thin films and their applications in thin-film rechargeable lithium batteries

Li Co oxide thin films were deposited by rf magnetron sputtering of a LiCoO{sub 2} target in a 3:1 Ar/O{sub 2} mixture gas. From proton-induced gamma-ray emission analysis and Rutherford backscattering spectrometry, the average composition of these films was determined to be Li{sub 1.15}CoO{sub 2.16}. X-ray powder diffraction patterns of films annealed in air at 500-700 C were consistent with regular rhombohedral structure of crystalline LiCoO{sub 2}. Discharge curves of thin film lithium cells with amoprohous LiCoO{sub 2} showed no obvious structural transition between 4.2 and 1.5 V. Shape of discharge curves of cells with polycrystalline cathodes were consistent with a two-phase voltage plateau at {similar_to}3.9 V with a relatively large capacity and two additional smaller plateaus at higher voltages. Cells with the 700 C annealed cathodes showed a capacity loss of {similar_to} after 1000 cycles between 4.2 and 3.0 V

A Derivation of Three-Dimensional Inertial Transformations

The derivation of the transformations between inertial frames made by Mansouri and Sexl is generalised to three dimensions for an arbitrary direction of the velocity. Assuming lenght contraction and time dilation to have their relativistic values, a set of transformations kinematically equivalent to special relativity is obtained. The ``clock hypothesis'' allows the derivation to be extended to accelerated systems. A theory of inertial transformations maintaining an absolute simultaneity is shown to be the only one logically consistent with accelerated movements. Algebraic properties of these transformations are discussed. Keywords: special relativity, synchronization, one-way velocity of light, ether, clock hypothesis.Comment: 16 pages (A5), Latex, one figure, to be published in Found. Phys. Lett. (1997

Ionic Conductivities of Lithium Phosphorus Oxynitride Glasses, Polycrystals and Thin Films

Various lithium phosphorus oxynitrides have been prepared in the form of glasses, polycrystals, and thin films. The structures of these compounds were investigated by X-ray and neutron diffraction, X-ray photoelectron spectroscopy (XPS), and high-performance liquid chromatography (HPLC). The ac impedance measurements indicate a significant improvement of ionic conductivity as the result of incorporation of nitrogen into the structure. In the case of polycrystalline Li{sub 2.88}PO{sub 3.73}N{sub 0.14} with the {gamma}-Li{sub 3}PO{sub 4} structure, the conductivity increased by several orders of magnitude on small addition of nitrogen. The highest conductivities in the bulk glasses and thin films were found to be 3.0 {times} 10{sup -7} and 8.9 {times} 10{sup -7} S{center_dot}cm{sup -1} at 25{degrees}C, respectively