Hypoxia modulates platelet purinergic signalling pathways.

BACKGROUND:  Hypoxia resulting from ascent to high-altitude or pathological states at sea level is known to increase platelet reactivity. Previous work from our group has suggested that this may be adenosine diphosphate (ADP)-specific. Given the clinical importance of drugs targeting ADP pathways, research into the impact of hypoxia on platelet ADP pathways is highly important. METHODS:  Optimul aggregometry was performed on plasma from 29 lowland residents ascending to 4,700 m, allowing systematic assessment of platelet reactivity in response to several platelet agonists. Aggregometry was also performed in response to ADP in the presence of inhibitors of the two main ADP receptors, P2Y1 and P2Y12 (MRS2500 and cangrelor, respectively). Phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a key determinant of platelet aggregation, was analysed using the VASPFix assay. RESULTS:  Hypobaric hypoxia significantly reduced the ability of a fixed concentration of cangrelor to inhibit ADP-induced aggregation and increased basal VASP phosphorylation. However, in the absence of P2Y receptor inhibitors, we did not find evidence of increased platelet sensitivity to any of the agonists tested and found reduced sensitivity to thrombin receptor-activating peptide-6 amide. CONCLUSION:  Our results provide evidence of increased P2Y1 receptor activity at high altitude and suggest down-regulation of the P2Y12 pathway through increased VASP phosphorylation. These changes in ADP pathway activity are of potential therapeutic significance to high-altitude sojourners and hypoxic sea level patients prescribed platelet inhibitors and warrant further investigation

Observation of Crossover from Ballistic to Diffusion Regime for Excimer Molecules in Superfluid 4^4He

We have measured the temperature dependence of the time of flight of helium excimer molecules He2* in superfluid 4He and find that the molecules behave ballistically below 100mK and exhibit Brownian motion above 200 mK. In the intermediate temperature range the transport cannot be described by either of the models.Comment: 8 pages, 6 figures, submitted to the Proceedings of the International Conference on Quantum Fluids and Solids 201

Particles-vortex interactions and flow visualization in He4

Recent experiments have demonstrated a remarkable progress in implementing and use of the Particle Image Velocimetry (PIV) and particle tracking techniques for the study of turbulence in He4. However, an interpretation of the experimental data in the superfluid phase requires understanding how the motion of tracer particles is affected by the two components, the viscous normal fluid and the inviscid superfluid. Of a particular importance is the problem of particle interactions with quantized vortex lines which may not only strongly affect the particle motion, but, under certain conditions, may even trap particles on quantized vortex cores. The article reviews recent theoretical, numerical, and experimental results in this rapidly developing area of research, putting critically together recent results, and solving apparent inconsistencies. Also discussed is a closely related technique of detection of quantized vortices negative ion bubbles in He4.Comment: To appear in the J Low Temperature Physic

Novel solar sail mission concepts for high-latitude earth and lunar observation

This paper proposes the use of solar sail periodic orbits in the Earth-Moon system for observation of the high-latitudes of the Earth and Moon. At the Earth, the high-latitudes will be crucial in answering questions concerning global climate change, monitoring space weather events and ensuring sustainable development of these fragile regions. The polar regions of the Moon, especially the South Pole, are of great scientific interest as well as a potential destination for a future permanent lunar base. The existence of families of solar sail periodic orbits in the Earth-Moon system has previously been demonstrated by the authors and is expanded in this paper by introducing additional orbit families. The paper focuses in particular on orbits that are achievable with near-term solar sail technology and that originate by maintaining the solar sail at a constant attitude with respect to the Sun such that mission operations are greatly simplified. The results provide a set of constellations for continuous observation of the high-latitudes. For example, a constellation of two solar sail L2-displaced vertical Lyapunov orbits can achieve continuous observation of both the lunar South Pole and the centre of the Aitken Basin at a minimum elevation of 15 deg, while at the Earth, a set of two, so-called 'clover-shaped' orbits can provide continuous coverage of one of the Earth's Poles at 20 deg minimum elevation. Transferring these orbits to a higher-fidelity model, taking among others the eccentricity of the Moon into account, shows that these orbits still exist without any significant impact on their performance for high-latitude observation of the Earth and Moon

Localized hepatic lobular regeneration by central-vein-associated lineage-restricted progenitors.

The regeneration of organ morphology and function following tissue loss is critical to restore normal physiology, yet few cases are documented in mammalian postnatal life. Partial hepatectomy of the adult mammalian liver activates compensatory hepatocyte hypertrophy and cell division across remaining lobes, resulting in restitution of organ mass but with permanent alteration of architecture. Here, we identify a time window in early postnatal life wherein partial amputation culminates in a localized regeneration instead of global hypertrophy and proliferation. Quantifications of liver mass, enzymatic activity, and immunohistochemistry demonstrate that damaged lobes underwent multilineage regeneration, reforming a lobe often indistinguishable from undamaged ones. Clonal analysis during regeneration reveals local clonal expansions of hepatocyte stem/progenitors at injured sites that are lineage but not fate restricted. Tetrachimeric mice show clonal selection occurs during development with further selections following injury. Surviving progenitors associate mainly with central veins, in a pattern of selection different from that of normal development. These results illuminate a previously unknown program of liver regeneration after acute injury and allow for exploration of latent regenerative programs with potential applications to adult liver regeneration

Identification and isolation of a dermal lineage with intrinsic fibrogenic potential

Dermal fibroblasts represent a heterogeneous population of cells with diverse features that remain largely undefined. We reveal the presence of at least two fibroblast lineages in murine dorsal skin. Lineage tracing and transplantation assays demonstrate that a single fibroblast lineage is responsible for the bulk of connective tissue deposition during embryonic development, cutaneous wound healing, radiation fibrosis, and cancer stroma formation. Lineage-specific cell ablation leads to diminished connective tissue deposition in wounds and reduces melanoma growth. Using flow cytometry, we identify CD26/DPP4 as a surface marker that allows isolation of this lineage. Small molecule-based inhibition of CD26/DPP4 enzymatic activity during wound healing results in diminished cutaneous scarring. Identification and isolation of these lineages hold promise for translational medicine aimed at in vivo modulation of fibrogenic behavior.FWN – Publicaties zonder aanstelling Universiteit Leide