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

Measurement of throughput variation across a large format volume-phase holographic grating

In this paper, we report measurements of diffraction efficiency and angular dispersion for a large format (~ 25 cm diameter) Volume-Phase Holographic (VPH) grating optimized for near-infrared wavelengths (0.9 ~ 1.8 μm). The aim of this experiment is to see whether optical characteristics vary significantly across the grating. We sampled three positions in the grating aperture with a separation of 5 cm between each. A 2 cm diameter beam is used to illuminate the grating. At each position, throughput and diffraction angle were measured at several wavelengths. It is found that whilst the relationship between diffraction angle and wavelength is nearly he same at the three positions, the throughputs vary by up to ~ 10% from position to position. We explore the origin of the throughput variation by comparing the data with predictions from coupled-wave analysis. We find that it can be explained by a combination of small variations over the grating aperture in gelatin depth and/or refractive index modulation amplitude, and amount of energy loss by internal absorption and/or surface reflection

Growth and persistence of 17 annual medic (Medicago spp.) accessions on clay soils in central Queensland

Seventeen accessions of annual medics were evaluated on clay soil sites at Emerald, Theodore, Biloela and Mundubbera, central Queensland. Successful medics could have a role in both permanent and ley pastures. However, these are marginal areas for medics with winter (June-August) rainfalls of 80-100 mm. The accessions were selected on the basis of results in southern Queensland, a more favoured area for medics. There were 9 accessions of Medicago truncatula (barrel medic), 4 of M. scutellata (snail medic), 2 of M. polymorpha (burr medic) and 1 each of M. aculeata (keg medic) and M. orbicularis (button medic). Lucerne (M. sativa) cv. Trifecta was sown at 3 sites. All sites except Theodore were irrigated in the year of establishment (1993). The medic seedlings at Theodore died in 1993 and the trial was resown in 1994. Measurements were made of seed set in the first year and whenever it occurred in later years, seedling density in most years and yield when there was adequate growth. Selected measurements were made of soil seed reserves. Measurements ceased in 1998

Evaluating Sensitivities of Economic Factors through Coupled Economics-ALMANAC Model System

Using crop models to simulate crop growth and productivity at a regional scale is a complex process designed to represent the observed impact of individual farmer decision-making on the agricultural landscape. Typically, during agricultural simulation efforts, the planting acreages have largely been based on a set of predetermined, static scenarios. In this study, we developed a system to dynamically enhance the Agricultural Land Management Alternative with Numerical Assessment Criteria (ALMANAC) crop simulation model through a two-way linkage with an economics land-use model. This coupled model approach integrated farmers’ land-use choices based on relative economic returns and produced dynamic land-use probabilities for ALMANAC simulations through a feedback loop. The coupled model approach was intercompared with static crop modeling through a historic acreage approach, and comparable accuracies were found from both modeling efforts for the 2014 growing season. Furthermore, as a proof-of-concept effort, the method was applied to evaluate the impact of two scenarios on crop simulations: major crops (maize, soybean, and wheat) intensification through price increases (e.g., market change) and incentivized grassland conservation (e.g., policy change). The results of this sensitivity study suggest that the coupled system has the capability to integrate economic factors into traditional crop simulation, allowing for insight into the impacts of changes in markets and policies on agricultural landscapes and crop yields

Improved Satellite Robustness Through Application of Erosion Resistance and High Emissivity Coatings

Spacecraft can experience charging throughout operation due to high flux of incident electrons (ex. during geomagnetic substorm). As a result, different materials/components may experience a range of potentials which may lead to plasma-induced arcs, damaging spacecraft components. 54% of spacecraft failures are due to enhancement of radiation belt particles and magnetospheric plasma that cause charging/discharing Current space charge mitigation technologies: Metallic coatings System chassis ground leads to as many surfaces as possible Not effective in severe sub-storm conditions and do not enable local application of coatin

Metric trees of generalized roundness one

Every finite metric tree has generalized roundness strictly greater than one. On the other hand, some countable metric trees have generalized roundness precisely one. The purpose of this paper is to identify some large classes of countable metric trees that have generalized roundness precisely one. At the outset we consider spherically symmetric trees endowed with the usual combinatorial metric (SSTs). Using a simple geometric argument we show how to determine decent upper bounds on the generalized roundness of finite SSTs that depend only on the downward degree sequence of the tree in question. By considering limits it follows that if the downward degree sequence $(d_{0}, d_{1}, d_{2}...)$ of a SST $(T,\rho)$ satisfies $|\{j \, | \, d_{j} > 1 \}| = \aleph_{0}$, then $(T,\rho)$ has generalized roundness one. Included among the trees that satisfy this condition are all complete $n$-ary trees of depth $\infty$ ($n \geq 2$), all $k$-regular trees ($k \geq 3$) and inductive limits of Cantor trees. The remainder of the paper deals with two classes of countable metric trees of generalized roundness one whose members are not, in general, spherically symmetric. The first such class of trees are merely required to spread out at a sufficient rate (with a restriction on the number of leaves) and the second such class of trees resemble infinite combs.Comment: 14 pages, 2 figures, 2 table

Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease

We examined how HLA types A1-B8-DR3 and B27 were related to progression of clinical disease and rate of loss of CD4 lymphocytes in the Edinburgh City Hospital cohort of HIV-positive patients, mainly injection drug users. Patients (n = 692) were prospectively followed from 1985 through March 1994. Accurately estimated seroconversion times were determined retrospectively for a subgroup of 313 (45%). Of 262 patients (39%) who were fully or partially HLA typed, 155 (50%) had known seroconversions. Of 34 patients typed positive for A1-B8-DR3, 29 progressed to CDC stage IV, 22 to AIDS and 20 died. Twelve patients were typed positive for B27; six of these progressed to CDC stage IV, one to AIDS and none died. In a proportional hazards analysis of the 313 patients with known seroconversions, A1-B8-DR3 was significantly associated with covariate-adjusted relative risks of 3.7 (95% CI 1.9-7.2), 3.1 (1.6-6.0) and 1.9 (1.1-3.2) for progression from seroconversion to death, AIDS and CDC stage IV, respectively. Events for B27 were too rare to include B27 in analyses to death and AIDS, but B27 was significantly associated with slower progression to CDC stage IV (0.3, CI 0.1-0.9). Random effects growth curve models were used to estimate individual rates of loss of square root CD4 count and loss of CD4 percentage, for 603 and 617 patients, respectively. A1-B8-DR3 was associated with rapid loss of both markers (p=0.02 and p = 0.01, respectively); B27 was associated with slow loss of both markers (p=0.04 and p<0.005

The molecular epidemiology of human immunodeficiency virus type 1 in six cities in Britain and Ireland

The authors sequenced the p17 coding regions of the gag gene from 211 patients infected either through injecting drug use (IDU) or by sexual intercourse between men from six cities in Scotland, N. England, N. Ireland, and the Republic of Ireland. All sequences were of subtype 5. Phylogenetic analysis revealed substantial heterogeneity in the sequences from homosexual men. In contrast, sequence from over 80% of IDUs formed a relatively tight cluster, distinct both from those of published isolates and of the gay men. There was no large-scale clustering of sequences by city in either risk group, although a number of close associations between pairs of individuals were observed. From the known date of the HIV-1 epidemic among IDUs in Edinburgh, the rate of sequence divergence at synonymous sites is estimated to be about 0.8%. On this basis it has been estimated that the date of divergence of the sequences among homosexual men to be about 1975, which may correspond to the origin of the B subtype epidemic

Nonperturbative Renormalization and the QCD Vacuum

We present a self consistent approach to Coulomb gauge Hamiltonian QCD which allows one to relate single gluon spectral properties to the long range behavior of the confining interaction. Nonperturbative renormalization is discussed. The numerical results are in good agreement with phenomenological and lattice forms of the static potential.Comment: 23 pages in RevTex, 4 postscript figure