The relationship between oxidised LDL, endothelial progenitor cells and coronary endothelial function in patients with CHD

Objective The balance between coronary endothelial dysfunction and repair is influenced by many protective and deleterious factors circulating in the blood. We studied the relationship between oxidised low-density lipoprotein (oxLDL), circulating endothelial progenitor cells (EPCs) and coronary endothelial function in patients with stable coronary heart disease (CHD). Methods 33 patients with stable CHD were studied. Plasma oxLDL was measured using ELISA, coronary endothelial function was assessed using intracoronary acetylcholine infusion and EPCs were quantified using flow cytometry for CD34+/KDR+ cells. Results Plasma oxLDL correlated positively with the number of EPCs in the blood (r=0.46, p=0.02). There was a positive correlation between the number of circulating EPCs and coronary endothelial function (r=0.42, p=0.04). There was no significant correlation between oxLDL and coronary endothelial function. Conclusions Plasma levels of oxLDL are associated with increased circulating EPCs in the blood of patients with CHD, which may reflect a host-repair response to endothelial injury. Patients with stable CHD had a high prevalence of coronary endothelial dysfunction, which was associated with lower numbers of circulating EPCs, suggesting a mechanistic link between endothelial dysfunction and the pathogenesis of atherosclerosis

Noninvasive PET Imaging and Tracking of Engineered Human Muscle Precursor Cells for Skeletal Muscle Tissue Engineering

Transplantation of human muscle precursor cells (hMPCs) is envisioned for the treatment of various muscle diseases. However, a feasible noninvasive tool to monitor cell survival, migration, and integration into the host tissue is still missing. METHODS: In this study, we designed an adenoviral delivery system to genetically modify hMPCs to express a signaling-deficient form of human dopamine D2 receptor (hD2R). The gene expression levels of the receptor were evaluated by reverse transcriptase polymerase chain reaction, and infection efficiency was evaluated by fluorescent microscopy. The viability, proliferation, and differentiation capacity of the transduced cells, as well as their myogenic phenotype, were determined by flow cytometry analysis and fluorescent microscopy. (18)F-fallypride and (18)F-fluoromisonidazole, two well-established PET radioligands, were assessed for their potential to image engineered hMPCs in a mouse model and their uptakes were evaluated at different time points after cell inoculation in vivo. Biodistribution studies, autoradiography, and PET experiments were performed to determine the extent of signal specificity. To address feasibility for tracking hMPCs in an in vivo model, the safety of the adenoviral gene delivery was evaluated. Finally, the harvested tissues were histologically examined to determine whether survival of the transplanted cells was sustained at different time points. RESULTS: Adenoviral gene delivery was shown to be safe, with no detrimental effects on the primary human cells. The viability, proliferation, and differentiation capacity of the transduced cells were confirmed, and flow cytometry analysis and fluorescent microscopy showed that their myogenic phenotype was sustained. (18)F-fallypride and (18)F-fluoromisonidazole were successfully synthesized. Specific binding of (18)F-fallypride to hD2R hMPCs was demonstrated in vitro and in vivo. Furthermore, the (18)F-fluoromisonidazole signal was high at the early stages. Finally, sustained survival of the transplanted cells at different time points was confirmed histologically, with formation of muscle tissue at the site of injection. CONCLUSION: Our proposed use of a signaling-deficient hD2R as a potent reporter for in vivo hMPC PET tracking by (18)F-fallypride is a significant step toward potential noninvasive tracking of hD2R hMPCs and bioengineered muscle tissues in the clinic

Towards quantum superpositions of a mirror

We propose a scheme for creating quantum superposition states involving of order $10^{14}$ atoms via the interaction of a single photon with a tiny mirror. This mirror, mounted on a high-quality mechanical oscillator, is part of a high-finesse optical cavity which forms one arm of a Michelson interferometer. By observing the interference of the photon only, one can study the creation and decoherence of superpositions involving the mirror. All experimental requirements appear to be within reach of current technology.Comment: 5 pages, 2 figures, submitted to Phys. Rev. Let

Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation.

Activation of the NLRP3 inflammasome by microbial ligands or tissue damage requires intracellular generation of reactive oxygen species (ROS). We present evidence that macrophage secretion of IL1β upon stimulation with ATP, crystals or LPS is mediated by a rapid increase in the activity of xanthine oxidase (XO), the oxidized form of xanthine dehydrogenase, resulting in the formation of uric acid as well as ROS. We show that XO-derived ROS, but not uric acid, is the trigger for IL1β release and that XO blockade results in impaired IL1β and caspase1 secretion. XO is localized to both cytoplasmic and mitochondrial compartments and acts upstream to the PI3K-AKT signalling pathway that results in mitochondrial ROS generation. This pathway represents a mechanism for regulating NLRP3 inflammasome activation that may have therapeutic implications in inflammatory diseases

The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies

A Deep Search for Prompt Radio Emission from Thermonuclear Supernovae with the Very Large Array

Searches for circumstellar material around Type Ia supernovae (SNe Ia) are one of the most powerful tests of the nature of SN Ia progenitors, and radio observations provide a particularly sensitive probe of this material. Here we report radio observations for SNe Ia and their lower-luminosity thermonuclear cousins. We present the largest, most sensitive, and spectroscopically diverse study of prompt (delta t <~ 1 yr) radio observations of 85 thermonuclear SNe, including 25 obtained by our team with the unprecedented depth of the Karl G. Jansky Very Large Array. With these observations, SN 2012cg joins SN 2011fe and SN 2014J as a SN Ia with remarkably deep radio limits and excellent temporal coverage (six epochs, spanning 5--216 days after explosion, yielding Mdot/v_w <~ 5 x 10^-9 M_sun/yr / (100 km/s), assuming epsilon_B = 0.1 and epsilon_e = 0.1). All observations yield non-detections, placing strong constraints on the presence of circumstellar material. We present analytical models for the temporal and spectral evolution of prompt radio emission from thermonuclear SNe as expected from interaction with either wind-stratified or uniform density media. These models allow us to constrain the progenitor mass loss rates, with limits ranging from Mdot <~ 10^-9--10^-4 M_sun/yr, assuming a wind velocity v_w=100 km/s. We compare our radio constraints with measurements of Galactic symbiotic binaries to conclude that <~10% of thermonuclear SNe have red giant companions.Comment: Submitted to Ap

A human factors approach to defining requirements for low-speed autonomous vehicles to enable intelligent platooning

This paper presents results from a series of focus groups, aimed at enhancing technical engineering system requirements, for a public transport system, encompassing a fleet of platooning low-speed autonomous vehicles (LSAV; aka pods) in urban areas. A critical review of the pods was conducted, as part of a series of technical workshops, to examine the key areas of the system that could affect users and other stakeholders, such as businesses and the public. These initial findings were used to inform a series of focus groups, aimed at identifying the public's views of multiple autonomous vehicles being deployed in a pedestrianised area that can join and form platoons. Analysis of findings from the focus groups suggests that while people view platooning public transport vehicles favourably as a passenger, they have some concerns from a pedestrian perspective. Thematic analysis was applied to these findings and a systematic approach was used to identify where subjective outputs could be formalised to inform requirements. Finally, a step-by-step requirements elicitation process is presented that illustrates the method used to convert qualitative user data to objective engineering requirements

The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member–encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β–activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging