Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria

Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells' immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury. Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance. Methods: We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury. Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria. Conclusions: In E. coli-injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.

Nile blue-based nano-sized pH sensors for simultaneous far-red and near-infrared live bioimaging

Diblock copolymer vesicles are tagged with pH-responsive Nile Blue-based labels and used as a new type of pH-responsive colorimetric/fluorescent biosensor for far-red and near-infrared imaging of live cells. The diblock copolymer vesicles described herein are based on poly(2-(methacryloyloxy)ethyl phosphorylcholine-block-2-(diisopropylamino)ethyl methacrylate) [PMPC-PDPA]: the biomimetic PMPC block is known to facilitate rapid cell uptake for a wide range of cell lines, while the PDPA block constitutes the pH-responsive component that enables facile vesicle self-assembly in aqueous solution. These biocompatible vesicles can be utilized to detect interstitial hypoxic/acidic regions in a tumor model via a pH-dependent colorimetric shift. In addition, they are also useful for selective intracellular staining of lysosomes and early endosomes via subtle changes in fluorescence emission. Such nanoparticles combine efficient cellular uptake with a pH-responsive Nile Blue dye label to produce a highly versatile dual capability probe. This is in marked contrast to small molecule dyes, which are usually poorly uptaken by cells, frequently exhibit cytotoxicity, and are characterized by intracellular distributions invariably dictated by their hydrophilic/hydrophobic balance.

Sea-level changes in Iceland and the influence of the North Atlantic Oscillation during the last half millennium

We present a new, diatom-based sea-level reconstruction for Iceland spanning the last -500 years, and investigate the possible mechanisms driving the sea-level changes. A sea-level reconstruction from near the Icelandic low pressure system is important as it can improve understanding of ocean-atmosphere forcing on North Atlantic sea-level variability over multi-decadal to centennial timescales. Our reconstruction is from Viarhólmi salt marsh in Snæfellsnes in western Iceland, a site from where we previously obtained a 2000-yr record based upon less precise sea-level indicators (salt-marsh foraminifera). The 20th century part of our record is corroborated by tide-gauge data from Reykjavik. Overall, the new reconstruction shows ca0.6m rise of relative sea level during the last four centuries, of which ca0.2m occurred during the 20th century. Low-amplitude and high-frequency sea-level variability is super-imposed on the pre-industrial long-term rising trend of 0.65m per 1000 years. Most of the relative sea-level rise occurred in three distinct periods: AD 1620-1650, AD 1780-1850 and AD 1950-2000, with maximum rates of ~3±2mm/yr during the latter two of these periods. Maximum rates were achieved at the end of large shifts (from negative to positive) of the winter North Atlantic Oscillation (NAO) Index as reconstructed from proxy data. Instrumental data demonstrate that a strong and sustained positive NAO (a deep Icelandic Low) generates setup on the west coast of Iceland resulting in rising sea levels. There is no strong evidence that the periods of rapid sea-level rise were caused by ocean mass changes, glacial isostatic adjustment or regional steric change. We suggest that wind forcing plays an important role in causing regional-scale coastal sea-level variability in the North Atlantic, not only on (multi-)annual timescales, but also on multi-decadal to centennial timescales.

Dipping Wings:for flute (alto fl), clarinet (bass cot), tpt, vla, vcl, perc and live electronics

commissioned by Ballet Rambert for 60th Anniversary season, choreographer Mary Evelyn, designer Liz Emmanuel. World premiere: Theatre Royal York 03/06/86

Liminal Lines:work for euphonium and live electronics

This is the first in series of works that explores the edges of musical styles, in particular the musical language associated with the brass band traditions and the relationship between this performance genre and the work of experimental electronic composition.

Superimposition: A composition for harp, saxophone and live electronics

Superimposition is built on a live-scoring system. Computer animated graphics combined with computer generated algorithms produce the score in real time based on preferences input by the composer. Notably, this system introduces a methodology for eliciting complex and coordinated rhythms from instrumentalists through notation generated in real time. This work also incorporates a system for live electronics and live sampling and processing.

Dielectronic recombination of W20 + (4d104f8): Addressing the half-open f shell

A recent measurement of the dielectronic recombination (DR) of W20+ [Schippers et al., Phys.Rev.A 83, 012711 (2011)] found an exceptionally large contribution from near-threshold resonances (1 eV). This still affected the Maxwellian rate coefficient at much higher temperatures. The experimental result was found to be higher by a factor of 4 or more than that currently in use in the 100- to 300-eV range, which is of relevance for modeling magnetic fusion plasmas. We have carried out DR calculations with AUTOSTRUCTURE which include all significant single-electron promotions. Our intermediate-coupling (IC) results are more than a factor of 4 larger than our LS-coupling ones at 1 eV but still lie a factor of 3 below experiment here. If we assume complete (chaotic)mixing of near-threshold autoionizing states, then our results come into agreement (to within 20%)with experiment below 2 eV. Our total IC Maxwellian rate coefficients are 50%–30% smaller than those based on experiment over 100–300 eV.