Small extracellular vesicles secreted from human amniotic fluid mesenchymal stromal cells possess cardioprotective and promigratory potential

Mesenchymal stromal cells (MSCs) exhibit antiapoptotic and proangiogenic functions in models of myocardial infarction which may be mediated by secreted small extracellular vesicles (sEVs). However, MSCs have frequently been harvested from aged or diseased patients, while the isolated sEVs often contain high levels of impurities. Here, we studied the cardioprotective and proangiogenic activities of size-exclusion chromatography-purified sEVs secreted from human foetal amniotic fluid stem cells (SS-hAFSCs), possessing superior functional potential to that of adult MSCs. We demonstrated for the first time that highly pure (up to 1.7 × 1010 particles/µg protein) and thoroughly characterised SS-hAFSC sEVs protect rat hearts from ischaemia–reperfusion injury in vivo when administered intravenously prior to reperfusion (38 ± 9% infarct size reduction, p < 0.05). SS-hAFSC sEVs did not protect isolated primary cardiomyocytes in models of simulated ischaemia–reperfusion injury in vitro, indicative of indirect cardioprotective effects. SS-hAFSC sEVs were not proangiogenic in vitro, although they markedly stimulated endothelial cell migration. Additionally, sEVs were entirely responsible for the promigratory effects of the medium conditioned by SS-hAFSC. Mechanistically, sEV-induced chemotaxis involved phosphatidylinositol 3-kinase (PI3K) signalling, as its pharmacological inhibition in treated endothelial cells reduced migration by 54 ± 7% (p < 0.001). Together, these data indicate that SS-hAFSC sEVs have multifactorial beneficial effects in a myocardial infarction setting

Organisational response to the 2007 Ruapehu Crater Lake breakout lahar in New Zealand: Use of communication in creating an effective response

When Mt. Ruapehu erupted in 1995-1996 in New Zealand, a tephra barrier was created alongside Crater Lake on the top of Mt. Ruapehu. This barrier acted as a dam, with Crater Lake rising behind it over time. In 2007 the lake breached the dam and a lahar occurred down the Whangaehu Valley and across the volcano’s broad alluvial ring-plain. Given the lahar history from Ruapehu, the risk from the 2007 event was identified beforehand and steps taken to reduce the risks to life and infrastructure. An early warning system was set up to notify when the dam had broken and the lahar had occurred. Physical works to mitigate the risk were put in place. A planning group was also formed and emergency management plans were put in place to respond to the risk. To assess the effectiveness of planning for and responding to the lahar, semi-structured interviews were undertaken with personnel from key organisations both before and after the lahar event. This chapter discusses the findings from the interviews in the context of communications, and highlights how good communications contributed to an effective emergency management response. As the potential for a lahar was identifiable, approximately 10 years of lead-up time was available to install warning system hardware, implement physical mitigation measures, create emergency management plans, and practice exercises for the lahar. The planning and exercising developed effective internal communications, engendered relationships, and moved individuals towards a shared mental model of how a respond to the event. Consequently, the response played out largely as planned with only minor communication issues occurring on the day of the lahar. The minor communication issues were due to strong personal connections leading to at least one case of the plan being bypassed. Communication levels during the lahar event itself were also different from that experienced in exercises, and in some instances communications were seen to increase almost three-fold. This increase in level of communication, led to some difficulty in getting through to the main Incident Control Point. A final thought regarding public communications prior to the event was that more effort could have been given to developing and integrating public information about the lahar, to allow for ease of understanding about the event and integration of information across agencies.falseSubmitte

Synthesis and interaction of terminal unsaturated chemical probes with Mycobacterium tuberculosis CYP124A1

A series of C15–C20 isoprenyl derivatives bearing terminal alkenyl and alkynyl groups were synthesized as possible substrates of the methyl-branched lipid ω-hydroxylase CYP124A1 from Mycobacterium tuberculosis. The interactions of each compound with the enzyme active site were characterized using UV–vis spectroscopy. We found that C10 and C15 analogs bind with similar affinity to the corresponding parent C10 and C15 substrates geraniol and farnesol, respectively. Three analogs (C10-ω-ene, C10-ω-yne, C15-ω-yne) interact with the proximal side of the heme iron by coordinating to the oxygen atom of the ferric heme, as judged by the appearance of typical Type-IA binding spectra. On the other hand, the C15-ω-ene analog interacts with the ferric heme by displacing the bound water that generates a typical Type I binding spectrum. We were unable to detect P450-mediated oxidation of these probes following extended incubations with CYP124A1 in our reconstituted assay system, whereas a control reaction containing farnesol was converted to ω-hydroxy farnesol under the same conditions. To understand the lack of detectable oxidation, we explored the possibility that the analogs were acting as mechanism-based inhibitors, but we were unable to detect time-dependent loss of enzymatic activity. In order to gain insight into the lack of detectable turnover or time-dependent inhibition, we examined the interaction of each compound with the CYP124A1 active site using molecular docking simulations. The docking studies revealed a binding mode where the terminal unsaturated functional groups were sequestered within the methyl-binding pocket, rather than positioned close to the heme iron for oxidation. These results aid in the design of specific inhibitors of Mtb-CYP124A1, an interesting enzyme that is implicated in the oxidation of methyl-branched lipids, including cholesterol, within a deadly human pathogen

Personhood, consciousness, and god : how to be a proper pantheist

© Springer Nature B.V. 2018In this paper I develop a theory of personhood which leaves open the possibility of construing the universe as a person. If successful, it removes one bar to endorsing pantheism. I do this by examining a rising school of thought on personhood, on which persons, or selves, are understood as identical to episodes of consciousness. Through a critique of this experiential approach to personhood, I develop a theory of self as constituted of qualitative mental contents, but where these contents are also capable of unconscious existence. On this theory, though we can be conscious of our selves, consciousness turns out to be inessential to personhood. This move, I then argue, provides resources for responding to the pantheist’s problem of God’s person.Peer reviewedFinal Accepted Versio

The mass discrepancy in intermediate- and high-mass eclipsing binaries: The need for higher convective core masses

Context. Eclipsing, spectroscopic double-lined binary star systems are excellent laboratories for calibrating theories of stellar interior structure and evolution. Their precise and accurate masses and radii measured from binary dynamics offer model-independent constraints and challenge current theories of stellar evolution. Aims. We aim to investigate the mass discrepancy in binary stars. This is the significant difference between stellar components’ masses measured from binary dynamics and those inferred from models of stellar evolution via positions of the components in the Teff − log g Kiel diagram. We study the effect of near-core mixing on the mass of the convective core of the stars and interpret the results in the context of the mass discrepancy. Methods. We fitted stellar isochrones computed from a grid of MESA stellar evolution models to a homogeneous sample of eleven high-mass binary systems. Two scenarios are considered where individual stellar components of a binary system are treated independent of each other and where they are forced to have the same age and initial chemical composition. We also study the effect of the microturbulent velocity and turbulent pressure on the atmosphere model structure and stellar spectral lines, and its link with the mass discrepancy. Results. We find that the mass discrepancy is present in our sample and that it is anti-correlated with the surface gravity of the star. No correlations are found with other fundamental and atmospheric parameters, including the stellar mass. The mass discrepancy can be partially accounted for by increasing the amount of near-core mixing in stellar evolution models. We also find that ignoring the microturbulent velocity and turbulent pressure in stellar atmosphere models of hot evolved stars results in the overestimation of their effective temperature by up to 8%. Together with enhanced near-core mixing, this can almost entirely account for the ∼30% mass discrepancy found for the evolved primary component of V380 Cyg. Conclusions. We find a strong link between the mass discrepancy and the convective core mass. The mass discrepancy can be solved by considering the combined effect of extra near-core boundary mixing and the consistent treatment in the spectrum analysis of hot evolved stars. Our binary modelling results in convective core masses between 17 and 35% of the stellar mass, which is in excellent agreement with the results from gravity-mode asteroseismology of single stars. This implies larger helium core masses near the end of the main sequence than have been anticipated so far

Scallop swimming kinematics and muscle performance: modelling the effects of "within-animal" variation in temperature sensitivity

Escape behaviour was investigated in Queen scallops (Aequipecten opercularis) acclimated to 5, 10 or 15 degrees C and tested at their acclimation temperature. Scallops are active molluscs, able to escape from predators by jet-propelled swimming using a striated muscle working in opposition to an elastic hinge ligament. The first cycle of the escape response was recorded using high-speed video ( 250 Hz) and whole-animal velocity and acceleration determined. Muscle shortening velocity, force and power output were calculated using measurements of valve movement and jet area, and a simple biomechanical model. The average shortening speed of the adductor muscle had a Q(10) of 2.04, significantly reducing the duration of the jetting phase of the cycle with increased temperature. Muscle lengthening velocity and the overall duration of the clap cycle were changed little over the range 5 - 15 degrees C, as these parameters were controlled by the relatively temperature-insensitive, hinge ligament. Improvements in the average power output of the adductor muscle over the first clap cycle ( 222 vs. 139 W kg(-1) wet mass at 15 and 5 degrees C respectively) were not translated into proportional increases in overall swimming velocity, which was only 32% higher at 15 degrees C ( 0.37m s(-1)) than 5 degrees C (0.28 m s(-1))

Forming spectroscopic massive proto-binaries by disk fragmentation

The surroundings of massive protostars constitute an accretion disc which has numerically been shown to be subject to fragmentation and responsible for luminous accretion-driven outbursts. Moreover, it is suspected to produce close binary companions which will later strongly influence the star's future evolution in the Hertzsprung–Russel diagram. We present three-dimensional gravitation-radiation-hydrodynamic numerical simulations of 100 M⊙ pre-stellar cores. We find that accretion discs of young massive stars violently fragment without preventing the (highly variable) accretion of gaseous clumps on to the protostars. While acquiring the characteristics of a nascent low-mass companion, some disc fragments migrate on to the central massive protostar with dynamical properties showing that its final Keplerian orbit is close enough to constitute a close massive protobinary system, having a young high- and a low-mass components. We conclude on the viability of the disc fragmentation channel for the formation of such short-period binaries, and that both processes – close massive binary formation and accretion bursts – may happen at the same time. FU-Orionis-type bursts, such as observed in the young high-mass star S255IR−NIRS3, may not only indicate ongoing disc fragmentation, but also be considered as a tracer for the formation of close massive binaries – progenitors of the subsequent massive spectroscopic binaries – once the high-mass component of the system will enter the main-sequence phase of its evolution. Finally, we investigate the Atacama Large (sub-)Millimeter Array observability of the disc fragments

Assessing the Health of Richibucto Estuary with the Latent Health Factor Index

The ability to quantitatively assess the health of an ecosystem is often of great interest to those tasked with monitoring and conserving ecosystems. For decades, research in this area has relied upon multimetric indices of various forms. Although indices may be numbers, many are constructed based on procedures that are highly qualitative in nature, thus limiting the quantitative rigour of the practical interpretations made from these indices. The statistical modelling approach to construct the latent health factor index (LHFI) was recently developed to express ecological data, collected to construct conventional multimetric health indices, in a rigorous quantitative model that integrates qualitative features of ecosystem health and preconceived ecological relationships among such features. This hierarchical modelling approach allows (a) statistical inference of health for observed sites and (b) prediction of health for unobserved sites, all accompanied by formal uncertainty statements. Thus far, the LHFI approach has been demonstrated and validated on freshwater ecosystems. The goal of this paper is to adapt this approach to modelling estuarine ecosystem health, particularly that of the previously unassessed system in Richibucto in New Brunswick, Canada. Field data correspond to biotic health metrics that constitute the AZTI marine biotic index (AMBI) and abiotic predictors preconceived to influence biota. We also briefly discuss related LHFI research involving additional metrics that form the infaunal trophic index (ITI). Our paper is the first to construct a scientifically sensible model to rigorously identify the collective explanatory capacity of salinity, distance downstream, channel depth, and silt-clay content --- all regarded a priori as qualitatively important abiotic drivers --- towards site health in the Richibucto ecosystem.Comment: On 2013-05-01, a revised version of this article was accepted for publication in PLoS One. See Journal reference and DOI belo

The feasibility of using pedometers and brief advice to increase activity in sedentary older women:a pilot study

Background: People over the age of 70 carry the greatest burden of chronic disease, disability and health care use. Participation in physical activity is crucial for health, and walking accounts for much of the physical activity undertaken by sedentary individuals. Pedometers are a useful motivational tool to encourage increased walking and they are cheap and easy to use. The aim of this pilot study was to evaluate the feasibility of the use of pedometers plus a theory-based intervention to assist sedentary older women to accumulate increasing amounts of physical activity, mainly through walking. Methods: Female participants over the age of 70 were recruited from primary care and randomised to receive either pedometer plus a theory-based intervention or a theory-based intervention alone. The theory-based intervention consisted of motivational techniques, goal-setting, barrier identification and self-monitoring with pedometers and daily diaries. The pedometer group were further randomised to one of three target groups: a 10%, 15% or 20% monthly increase in step count to assess the achievability and acceptability of a range of targets. The primary outcome was change in daily activity levels measured by accelerometry. Secondary outcome measures were lower limb function, health related quality of life, anxiety and depression. Results: 54 participants were recruited into the study, with an average age of 76. There were 9 drop outs, 45 completing the study. All participants in the pedometer group found the pedometers easy to use and there was good compliance with diary keeping (96% in the pedometer group and 83% in the theory-based intervention alone group). There was a strong correlation (0.78) between accelerometry and pedometer step counts i.e. indicating that walking was the main physical activity amongst participants. There was a greater increase in activity (accelerometry) amongst those in the 20% target pedometer group compared to the other groups, although not reaching statistical significance (p = 0.192). Conclusion: We have demonstrated that it is feasible to use pedometers and provide theory-based advice to community dwelling sedentary older women to increase physical activity levels and a larger study is planned to investigate this further.Publisher PDFPeer reviewe