Speciation in the baboon and its relation to gamma-chain heterogeneity and to the response to induction of HbF by 5-azacytidine

In the baboon (Papio species), the two nonallelic gamma-genes produce gamma-chains that differ at a minimum at residue 75, where isoleucine (I gamma-chain) or valine (V gamma) may be present. This situation obtains in baboons that are sometimes designated as Papio anubis, Papio hamadryas, and Papio papio. However, in Papio cynocephalus, although the I gamma-chains are identical with those in the above mentioned types, the V gamma-chains have the substitutions ala----gly at residue 9 and ala----val at residue 23. The V gamma-chains of P. cynocephalus are called V gamma C to distinguish them from the V gamma A-chains of P. anubis, etc. A single cynocephalus animal has been found to have only normal I gamma-chains and I gamma C-chains (that is, glycine in residue 9, valine in 23, and isoleucine in 75). When HbF is produced in response to stress with 5-azacytidine, P. anubis baboons respond with greater production than do P. cynocephalus, and hybrids fall between. Minimal data on P. hamadryas and P. papio suggest an even lower response than P. cynocephalus. As HbF increases under stress, the ratio of I gamma to V gamma-chains changes from the value in the adult or juvenile baboon toward the ratio in the newborn baboon. However, it does not attain the newborn value. The V gamma A and V gamma C-genes respond differently to stress. In hybrids, the production of V gamma A- chains exceeds that of V gamma C-chains. A controlling factor in cis apparently is present and may be responsible for the species-related extent of total HbF production. It may be concluded that the more primitive the cell in the erythroid maturation series that has been subjected to 5-azacytidine, the more active is the I gamma-gene

Shear thickening in densely packed suspensions of spheres and rods confined to few layers

We investigate confined shear thickening suspensions for which the sample thickness is comparable to the particle dimensions. Rheometry measurements are presented for densely packed suspensions of spheres and rods with aspect ratios 6 and 9. By varying the suspension thickness in the direction of the shear gradient at constant shear rate, we find pronounced oscillations in the stress. These oscillations become stronger as the gap size is decreased, and the stress is minimized when the sample thickness becomes commensurate with an integer number of particle layers. Despite this confinement-induced effect, viscosity curves show shear thickening that retains bulk behavior down to samples as thin as two particle diameters for spheres, below which the suspension is jammed. Rods exhibit similar behavior commensurate with the particle width, but they show additional effects when the thickness is reduced below about a particle length as they are forced to align; the stress increases for decreasing gap size at fixed shear rate while the shear thickening regime gradually transitions to a Newtonian scaling regime. This weakening of shear thickening as an ordered configuration is approached contrasts with the strengthening of shear thickening when the packing fraction is increased in the disordered bulk limit, despite the fact that both types of confinement eventually lead to jamming.Comment: 21 pages, 14 figures. submitted to the Journal of Rheolog

Developments in CO2 research

CO2 can be a good solvent for many compounds when used in its compressed liq- uid or supercritical fluid state. Above its critical temperature and critical pressure (Tc = 31 °C, Pc = 73.8 bar), CO2 has liquid-like densities and gas-like viscosities, which allows for safe commercial and laboratory operating conditions. Many small molecules are readily soluble in CO2, whereas most macromolecules are not. This has prompted development of several classes of small molecule and polymeric surfactants that enable emulsion and dispersion polymerizations as well as other technological processes

Top-Down Particle Fabrication: Control of Size and Shape for Diagnostic Imaging and Drug Delivery

This review discusses rational design of particles for use as therapeutic vectors and diagnostic imaging agent carriers. The emerging importance of both particle size and shape is considered, and the adaptation and modification of soft lithography methods to produce nanoparticles is highlighted. To this end, studies utilizing particles made via a process called Particle Replication In Non-wetting Templates (PRINT™) are discussed. In addition, insights gained into therapeutic cargo and imaging agent delivery from related types of polymer-based carriers are considered

Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells

AbstractEngineered nanoparticles have the potential to expand the breadth of pulmonary therapeutics, especially as respiratory vaccines. Notably, cationic nanoparticles have been demonstrated to produce superior local immune responses following pulmonary delivery; however, the cellular mechanisms of this increased response remain unknown. To this end, we investigated the cellular response of lung APCs following pulmonary instillation of anionic and cationic charged nanoparticles. While nanoparticles of both surface charges were capable of trafficking to the draining lymph node and were readily internalized by alveolar macrophages, both CD11b and CD103 lung dendritic cell (DC) subtypes preferentially associated with cationic nanoparticles. Instillation of cationic nanoparticles resulted in the upregulation of Ccl2 and Cxc10, which likely contributes to the recruitment of CD11b DCs to the lung. In total, these cellular mechanisms explain the increased efficacy of cationic formulations as a pulmonary vaccine carrier and provide critical benchmarks in the design of pulmonary vaccine nanoparticles.From the Clinical EditorAdvance in nanotechnology has allowed the production of precise nanoparticles as vaccines. In this regard, pulmonary delivery has the most potential. In this article, the authors investigated the interaction of nanoparticles with various types of lung antigen presenting cells in an attempt to understand the cellular mechanisms. The findings would further help the future design of much improved vaccines for clinical use

The Complex Role of Multivalency in Nanoparticles Targeting the Transferrin Receptor for Cancer Therapies

Transferrin receptor (TfR, CD71) has long been therapeutic target due to its over-expression on many malignant tissues. In this study, PRINT® nanoparticles were conjugated with TfR ligands for targeted drug delivery. Cylindrical poly(ethylene glycol)-based PRINT nanoparticles (diameter [d] = 200 nm, height [h] = 200 nm) labeled with transferrin receptor antibody (NP-OKT9) or human transferrin (NP-hTf), showed highly specific TfR-mediated uptake by all human tumor cell lines tested, relative to negative controls (IgG1 for OKT9 or bovine transferrin (bTf) for hTf). The targeting efficiency was dependent on particle concentration, ligand density, dosing time and cell surface receptor expression level. Interestingly, NP-OKT9 or NP-hTf showed little cytotoxicity on all solid tumor cell lines tested but were very toxic to Ramos B-cell lymphoma, whereas free OKT9 or hTf was not toxic. There was a strong correlation between TfR ligand density on particle surface and cell viability and particle uptake. NP-OKT9 and NP-hTf were internalized into acidic intracellular compartments but were not localized in EEA1 enriched early endosomes or lysosomes. Elevated caspase 3/7 activity indicates activation of apoptosis pathways upon particle treatment. Supplementation of iron suppressed the toxicity of NP-OKT9 but not NP-hTf, suggesting different mechanisms by which NP-hTf and NP-OKT9 exerts cytotoxicity on Ramos cells. Based on such an observation, the complex role of multivalency in nanoparticles is discussed. In addition, our data clearly reveal that one must be careful in making claims of “lack of toxicity” when a targeting molecule is used on nanoparticles and also raise concerns for unanticipated off-target effects when one is designing targeted chemotherapy nano-delivery agents

Microfabricated Particles for Engineered Drug Therapies: Elucidation into the Mechanisms of Cellular Internalization of PRINT Particles

To investigate the cellular internalization pathways of shape- and size-specific particles as a function of zeta potential in different cell types

Shear thickening and jamming in densely packed suspensions of different particle shapes

We investigated the effects of particle shape on shear thickening in densely packed suspensions. Rods of different aspect ratios and non-convex hooked rods were fabricated. Viscosity curves and normal stresses were measured using a rheometer for a wide range of packing fractions for each shape. Suspensions of each shape exhibit qualitatively similar Discontinuous Shear Thickening. The logarithmic slope of the stress/shear-rate relation increases dramatically with packing fraction and diverges at a critical packing fraction phi_c which depends on particle shape. The packing fraction dependence of the viscosity curves for different convex shapes can be collapsed when the packing fraction is normalized by phi_c. Intriguingly, viscosity curves for non-convex particles do not collapse on the same set as convex particles, showing strong shear thickening over a wider range of packing fraction. The value of phi_c is found to coincide with the onset of a yield stress at the jamming transition, suggesting the jamming transition also controls shear thickening. The yield stress is found to correspond with trapped air in the suspensions, and the scale of the stress can be attributed to interfacial tension forces which dramatically increase above phi_c due to the geometric constraints of jamming. The relationship between shear and normal stresses is found to be linear in both the shear thickening and jammed regimes, indicating that the shear stresses come from friction. In the limit of zero shear rate, normal stresses pull the rheometer plates together due to the surface tension of the liquid below phi_c, but push the rheometer plates apart due to jamming above phi_c.Comment: 13 pages, 13 figures. published in Physical Review

Solvent-Resistant Photocurable “Liquid Teflon” for Microfluidic Device Fabrication

We report the first fabrication of a solvent-compatible microfluidic device based on photocurable “Liquid Teflon” materials. The materials are highly fluorinated functionalized perfluoropolyethers (PFPEs) that have liquidlike viscosities that can be cured into tough, highly durable elastomers that exhibit the remarkable chemical resistance of fluoropolymers such as Teflon. Poly(dimethylsiloxane) (PDMS) elastomers have rapidly become the material of choice for many recent microfluidic device applications. Despite the advantages of PDMS in relation to microfluidics technology, the material suffers from a serious drawback in that it swells in most organic solvents. The swelling of PDMS-based devices in organic solvents greatly disrupts the micrometer-sized features and makes it impossible for fluids to flow inside the channels. Our approach to this problem has been to replace PDMS with photocurable perfluoropolyethers. Device fabrication and valve actuation were accomplished using established procedures for PDMS devices. The additional advantage of photocuring allows fabrication time to be decreased from several hours to a matter of minutes. The PFPE-based device exhibited mechanical properties similar to those of Sylgard 184 before and after curing as well as remarkable resistance to organic solvents. This work has the potential to expand the field of microfluidics to many novel applications

Generality of shear thickening in suspensions

Suspensions are of wide interest and form the basis for many smart fluids. For most suspensions, the viscosity decreases with increasing shear rate, i.e. they shear thin. Few are reported to do the opposite, i.e. shear thicken, despite the longstanding expectation that shear thickening is a generic type of suspension behavior. Here we resolve this apparent contradiction. We demonstrate that shear thickening can be masked by a yield stress and can be recovered when the yield stress is decreased below a threshold. We show the generality of this argument and quantify the threshold in rheology experiments where we control yield stresses arising from a variety of sources, such as attractions from particle surface interactions, induced dipoles from applied electric and magnetic fields, as well as confinement of hard particles at high packing fractions. These findings open up possibilities for the design of smart suspensions that combine shear thickening with electro- or magnetorheological response.Comment: 11 pages, 9 figures, accepted for publication in Nature Material