Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery into the Posterior Segment of the Eyeball

Topical instillation is the most widely preferred noninvasive route of drug administration to treat diseases affecting the anterior segment of the eye. Nonetheless, the ocular bioavailability for deeper ocular tissues is very low. Different routes of administration, such as intravitreal injections, periocular injections, and systemic administration, have been used to deliver drugs into the posterior segment ocular tissues. However, the presence of blood-retinal barriers (BRBs) makes systemic administration an impractical approach, whereas the drug delivery with the periocular administration route is compromised by ocular static and dynamic barriers. On the other hand, intravitreal injection, the most common and widely recommended route for drug administration to treat posterior ocular diseases, is related to several side effects such as endophthalmitis, hemorrhage, retinal detachment, and poor patient tolerance. Diverse strategies to overcome ocular barriers have been explored for topical drop formulations in order to deliver drugs into the posterior segment ocular tissues. In this chapter, we will review the promising topical nanocarriers for drug delivery into the posterior segment of the eye, emphasizing the use of liposomes for topical ophthalmic formulations targeting the vitreous cavity and the retina

New considerations for PM, black carbon and particle number concentration for air quality monitoring across different European cities

In many large cities of Europe standard air quality limit values of particulate matter (PM) are exceeded. Emissions from road traffic and biomass burning are frequently reported to be the major causes. As a consequence of these exceedances a large number of air quality plans, most of them focusing on traffic emissions reductions, have been implemented in the last decade. In spite of this implementation, a number of cities did not record a decrease of PM levels. Thus, is the efficiency of air quality plans overestimated? Do the road traffic emissions contribute less than expected to ambient air PM levels in urban areas? Or do we need a more specific metric to evaluate the impact of the above emissions on the levels of urban aerosols? This study shows the results of the interpretation of the variability of levels of PM, Black Carbon (BC), aerosol number concentration (N) and a number of gaseous pollutants in seven selected urban areas covering road traffic, urban background, urban-industrial, and urban-shipping environments from southern, central and northern Europe. The results showed that variations of PM and N levels do not always reflect the variation of the impact of road traffic emissions on urban aerosols. However, BC levels vary proportionally with those of traffic related gaseous pollutants, such as CO, NO₂ and NO. Due to this high correlation, one may suppose that monitoring the levels of these gaseous pollutants would be enough to extrapolate exposure to traffic-derived BC levels. However, the BC/CO, BC/NO₂ and BC/NO ratios vary widely among the cities studied, as a function of distance to traffic emissions, vehicle fleet composition and the influence of other emission sources such as biomass burning. Thus, levels of BC should be measured at air quality monitoring sites. During morning traffic rush hours, a narrow variation in the N/BC ratio was evidenced, but a wide variation of this ratio was determined for the noon period. Although in central and northern Europe N and BC levels tend to vary simultaneously, not only during the traffic rush hours but also during the whole day, in urban background stations in southern Europe maximum N levels coinciding with minimum BC levels are recorded at midday in all seasons. These N maxima recorded in southern European urban background environments are attributed to midday nucleation episodes occurring when gaseous pollutants are diluted and maximum insolation and O₃ levels occur. The occurrence of SO₂ peaks may also contribute to the occurrence of midday nucleation bursts in specific industrial or shipping-influenced areas, although at several central European sites similar levels of SO₂ are recorded without yielding nucleation episodes. Accordingly, it is clearly evidenced that N variability in different European urban environments is not equally influenced by the same emission sources and atmospheric processes. We conclude that N variability does not always reflect the impact of road traffic on air quality, whereas BC is a more consistent tracer of such an influence. However, N should be measured since ultrafine particles (<100 nm) may have large impacts on human health. The combination of PM₁₀ and BC monitoring in urban areas potentially constitutes a useful approach for air quality monitoring. BC is mostly governed by vehicle exhaust emissions, while PM₁₀ concentrations at these sites are also governed by non-exhaust particulate emissions resuspended by traffic, by midday atmospheric dilution and by other nontraffic emissions

New considerations for PM, Black Carbon and particle number concentration for air quality monitoring across different European cities

In many large cities of Europe standard air quality limit values of particulate matter (PM) are exceeded. Emissions from road traffic and biomass burning are frequently reported to be the major causes. As a consequence of these exceedances a large number of air quality plans, most of them focusing on traffic emissions reductions, have been implemented in the last decade. In spite of this implementation, a number of cities did not record a decrease of PM levels. Thus, is the efficiency of air quality plans overestimated? Do the road traffic emissions contribute less than expected to ambient air PM levels in urban areas? Or do we need a more specific metric to evaluate the impact of the above emissions on the levels of urban aerosols? This study shows the results of the interpretation of the 2009 variability of levels of PM, Black Carbon (BC), aerosol number concentration (N) and a number of gaseous pollutants in seven selected urban areas covering road traffic, urban background, urban-industrial, and urban-shipping environments from southern, central and northern Europe. The results showed that variations of PM and N levels do not always reflect the variation of the impact of road traffic emissions on urban aerosols. However, BC levels vary proportionally with those of traffic related gaseous pollutants, such as CO, NO2 and NO. Due to this high correlation, one may suppose that monitoring the levels of these gaseous pollutants would be enough to extrapolate exposure to traffic-derived BC levels. However, the BC/CO, BC/NO2 and BC/NO ratios vary widely among the cities studied, as a function of distance to traffic emissions, vehicle fleet composition and the influence of other emission sources such as biomass burning. Thus, levels of BC should be measured at air quality monitoring sites. During morning traffic rush hours, a narrow variation in the N/BC ratio was evidenced, but a wide variation of this ratio was determined for the noon period. Although in central and northern Europe N and BC levels tend to vary simultaneously, not only during the traffic rush hours but also during the whole day, in urban background stations in southern Europe maximum N levels coinciding with minimum BC levels are recorded at midday in all seasons. These N maxima recorded in southern European urban background environments are attributed to midday nucleation episodes occurring when gaseous pollutants are diluted and maximum insolation and O3 levels occur. The occurrence of SO2 peaks may also contribute to the occurrence of midday nucleation bursts in specific industrial or shipping-influenced areas, although at several central European sites similar levels of SO2 are recorded without yielding nucleation episodes. Accordingly, it is clearly evidenced that N variability in different European urban environments is not equally influenced by the same emission sources and atmospheric processes. We conclude that N variability does not always reflect the impact of road traffic on air quality, whereas BC is a more consistent tracer of such an influence. However, N should be measured since ultrafine particles (<100 nm) may have large impacts on human health. The combination of PM10 and BC monitoring in urban areas potentially constitutes a useful approach for air quality monitoring. BC is mostly governed by vehicle exhaust emissions, while PM10 concentrations at these sites are also governed by non-exhaust particulate emissions resuspended by traffic, by midday atmospheric dilution and by other non-traffic emissions

Very high energy particle acceleration powered by the jets of the microquasar SS 433

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star). Two jets of ionized matter with a bulk velocity of $\sim0.26c$ extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets. SS 433 differs from other microquasars in that the accretion is believed to be super-Eddington, and the luminosity of the system is $\sim10^{40}$ erg s$^{-1}$. The lobes of W50 in which the jets terminate, about 40 pc from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed. At higher energies (>100 GeV), the particle fluxes of $\gamma$ rays from X-ray hotspots around SS 433 have been reported as flux upper limits. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons interacting with the ambient gas. Here we report TeV $\gamma$-ray observations of the SS 433/W50 system where the lobes are spatially resolved. The TeV emission is localized to structures in the lobes, far from the center of the system where the jets are formed. We have measured photon energies of at least 25 TeV, and these are certainly not Doppler boosted, because of the viewing geometry. We conclude that the emission from radio to TeV energies is consistent with a single population of electrons with energies extending to at least hundreds of TeV in a magnetic field of $\sim16$~micro-Gauss.Comment: Preprint version of Nature paper. Contacts: S. BenZvi, B. Dingus, K. Fang, C.D. Rho , H. Zhang, H. Zho

All-particle cosmic ray energy spectrum measured by the HAWC experiment from 10 to 500 TeV

We report on the measurement of the all-particle cosmic ray energy spectrum with the High Altitude Water Cherenkov (HAWC) Observatory in the energy range 10 to 500 TeV. HAWC is a ground based air-shower array deployed on the slopes of Volcan Sierra Negra in the state of Puebla, Mexico, and is sensitive to gamma rays and cosmic rays at TeV energies. The data used in this work were taken from 234 days between June 2016 to February 2017. The primary cosmic-ray energy is determined with a maximum likelihood approach using the particle density as a function of distance to the shower core. Introducing quality cuts to isolate events with shower cores landing on the array, the reconstructed energy distribution is unfolded iteratively. The measured all-particle spectrum is consistent with a broken power law with an index of $-2.49\pm0.01$ prior to a break at $(45.7\pm0.1$) TeV, followed by an index of $-2.71\pm0.01$. The spectrum also respresents a single measurement that spans the energy range between direct detection and ground based experiments. As a verification of the detector response, the energy scale and angular resolution are validated by observation of the cosmic ray Moon shadow's dependence on energy.Comment: 16 pages, 11 figures, 4 tables, submission to Physical Review

Constraining the pˉ/p\bar{p}/p Ratio in TeV Cosmic Rays with Observations of the Moon Shadow by HAWC

An indirect measurement of the antiproton flux in cosmic rays is possible as the particles undergo deflection by the geomagnetic field. This effect can be measured by studying the deficit in the flux, or shadow, created by the Moon as it absorbs cosmic rays that are headed towards the Earth. The shadow is displaced from the actual position of the Moon due to geomagnetic deflection, which is a function of the energy and charge of the cosmic rays. The displacement provides a natural tool for momentum/charge discrimination that can be used to study the composition of cosmic rays. Using 33 months of data comprising more than 80 billion cosmic rays measured by the High Altitude Water Cherenkov (HAWC) observatory, we have analyzed the Moon shadow to search for TeV antiprotons in cosmic rays. We present our first upper limits on the $\bar{p}/p$ fraction, which in the absence of any direct measurements, provide the tightest available constraints of $\sim1\%$ on the antiproton fraction for energies between 1 and 10 TeV.Comment: 10 pages, 5 figures. Accepted by Physical Review

Search for very-high-energy emission from Gamma-ray Bursts using the first 18 months of data from the HAWC Gamma-ray Observatory

The High Altitude Water Cherenkov (HAWC) Gamma-ray Observatory is an extensive air shower detector operating in central Mexico, which has recently completed its first two years of full operations. If for a burst like GRB 130427A at a redshift of 0.34 and a high-energy component following a power law with index -1.66, the high-energy component is extended to higher energies with no cut-off other than from extragalactic background light attenuation, HAWC would observe gamma rays with a peak energy of $\sim$300 GeV. This paper reports the results of HAWC observations of 64 gamma-ray bursts (GRBs) detected by $\mathit{Swift}$ and $\mathit{Fermi}$, including three GRBs that were also detected by the Large Area Telescope ($\mathit{Fermi}$-LAT). An ON/OFF analysis method is employed, searching on the time scale given by the observed light curve at keV-MeV energies and also on extended time scales. For all GRBs and time scales, no statistically significant excess of counts is found and upper limits on the number of gamma rays and the gamma-ray flux are calculated. GRB 170206A, the third brightest short GRB detected by the Gamma-ray Burst Monitor on board the $\mathit{Fermi}$ satellite ($\mathit{Fermi}$-GBM) and also detected by the LAT, occurred very close to zenith. The LAT measurements can neither exclude the presence of a synchrotron self-Compton (SSC) component nor constrain its spectrum. Instead, the HAWC upper limits constrain the expected cut-off in an additional high-energy component to be less than $100~\rm{GeV}$ for reasonable assumptions about the energetics and redshift of the burst.Comment: 19 pages, 6 figures, published in Ap