Increasing doxorubicin activity against breast cancer cells using PPARγ-ligands and by exploiting circadian rhythms

Doxorubicin is effective against breast cancer, but its major side effect is cardiotoxicity. The aim of this study was to determine whether the efficacy of doxorubicin on cancer cells could be increased in combination with PPARγ agonists or chrono-optimization by exploiting the diurnal cycle. We determined cell toxicity using MCF-7 cancer cells, neonatal rat cardiac myocytes and fibroblasts in this study. Doxorubicin damages the contractile filaments of cardiac myocytes and affects cardiac fibroblasts by significantly inhibiting collagen production and proliferation at the level of the cell cycle. Cyclin D1 protein levels decreased significantly following doxorubicin treatment indicative of a G1 /S arrest. PPARγ agonists with doxorubicin increased the toxicity to MCF-7 cancer cells without affecting cardiac cells. Rosiglitazone and ciglitazone both enhanced anti-cancer activity when combined with doxorubicin (e.g. 50% cell death for doxorubicin at 0.1 μM compared to 80% cell death when combined with rosiglitazone). Thus, the therapeutic dose of doxorubicin could be reduced by 20-fold through combination with the PPARγ agonists, thereby reducing adverse effects on the heart. The presence of melatonin also significantly increased doxorubicin toxicity, in cardiac fibroblasts (1 μM melatonin) but not in MCF-7 cells. Our data show, for the first time, that circadian rhythms play an important role in doxorubicin toxicity in the myocardium; doxorubicin should be administered mid-morning, when circulating levels of melatonin are low, and in combination with rosiglitazone to increase therapeutic efficacy in cancer cells while reducing the toxic effects on the heart.

Diurnal warm-layer events in the western Mediterranean and European shelf seas

We characterize near-surface ocean diurnal warm-layer events, using satellite observations and fields from numerical weather forecasting. The study covers April to September, 2006, over the area 11°W to 17°E and 35°N to 57°N, with 0.1° cells. We use hourly satellite SSTs from which peak amplitudes of diurnal cycles in SST (dSSTs) can be estimated with error ∼0.3 K. The diurnal excursions of SST observed are spatially and temporally coherent. The largest dSSTs exceed 6 K, affect 0.01% of the surface, and are seen in the Mediterranean, North and Irish Seas. There is an anti-correlation between the magnitude and the horizontal length scale of dSST events. Events wherein dSST exceeds 4 K have length scales of ≤40 km. From the frequency distribution of different measures of wind-speed minima, we infer that extreme dSST maxima arise where conditions of low wind speed are sustained from early morning to mid afternoon.

Analysis and modeling of active occupancy of the residential sector in Spain: an indicator of residential electricity consumption

The growing energy consumption in the residential sector represents about 30% of global demand. This calls for Demand Side Management solutions propelling change in behaviors of end consumers, with the aim to reduce overall consumption as well as shift it to periods in which demand is lower and where the cost of generating energy is lower. Demand Side Management solutions require detailed knowledge about the patterns of energy consumption. The profile of electricity demand in the residential sector is highly correlated with the time of active occupancy of the dwellings; therefore in this study the occupancy patterns in Spanish properties was determined using the 2009–2010 Time Use Survey (TUS), conducted by the National Statistical Institute of Spain. The survey identifies three peaks in active occupancy, which coincide with morning, noon and evening. This information has been used to input into a stochastic model which generates active occupancy profiles of dwellings, with the aim to simulate domestic electricity consumption. TUS data were also used to identify which appliance-related activities could be considered for Demand Side Management solutions during the three peaks of occupancy.

An optimal inverse method using Doppler lidar measurements to estimate the surface sensible heat flux

Inverse methods are widely used in various fields of atmospheric science. However, such methods are not commonly used within the boundary-layer community, where robust observations of surface fluxes are a particular concern. We present a new technique for deriving surface sensible heat fluxes from boundary-layer turbulence observations using an inverse method. Doppler lidar observations of vertical velocity variance are combined with two well-known mixed-layer scaling forward models for a convective boundary layer (CBL). The inverse method is validated using large-eddy simulations of a CBL with increasing wind speed. The majority of the estimated heat fluxes agree within error with the proscribed heat flux, across all wind speeds tested. The method is then applied to Doppler lidar data from the Chilbolton Observatory, UK. Heat fluxes are compared with those from a mast-mounted sonic anemometer. Errors in estimated heat fluxes are on average 18 %, an improvement on previous techniques. However, a significant negative bias is observed (on average −63%) that is more pronounced in the morning. Results are improved for the fully-developed CBL later in the day, which suggests that the bias is largely related to the choice of forward model, which is kept deliberately simple for this study. Overall, the inverse method provided reasonable flux estimates for the simple case of a CBL. Results shown here demonstrate that this method has promise in utilizing ground-based remote sensing to derive surface fluxes. Extension of the method is relatively straight-forward, and could include more complex forward models, or other measurements.

Events of enhanced convection and related dayside auroral activity

In this paper we study the high-latitude plasma flow variations associated with a periodic (∼8 min) sequence of auroral forms moving along the polar cap boundary, which appear to be the most regularly occuring dayside auroral phenomenon under conditions of southward directed interplanetary magnetic field. Satellite data on auroral particle precipitation and ionospheric plasma drifts from DMSP F10 and F11 are combined with ground-based optical and ion flow measurements for January 7, 1992. Ionospheric flow measurements of 10-s resolution over the range of invariant latitudes from 71° to 76° were obtained by operating both the European incoherent scatter (EISCAT) UHF and VHF radars simultaneously. The optical site (Ny Ålesund, Svalbard) and the EISCAT radar field of view were located in the postnoon sector during the actual observations. The West Greenland magnetometers provided information about temporal variations of high-latitude convection in the prenoon sector. Satellite observations of polar cap convection in the northern and southern hemispheres show a standard two-cell pattern consistent with a prevailing negative By component of the interplanetary magnetic field. The 630.0 nm auroral forms located poleward of the persistent cleft aurora and the flow reversal boundary in the ∼1440–1540 MLT sector were observed to coincide with magnetosheath-like particle precipitation and a secondary population of higher energy ions, and they propagated eastward/tailward at speeds comparable with the convection velocity. It is shown that these optical events were accompanied by bursts of sunward (return) flow at lower latitudes in both the morning and the afternoon sectors, consistent with a modulation of Dungey cell convection. The background level of convection was low in this case (Kp =2+). The variability of the high-latitude convection may be explained as resulting from time-varying reconnection at the magnetopause. In that case this study indicates that time variations of the reconnection rate effectively modulates ionospheric convection.

Ionospheric convection response to slow, strong variations in a northward interplanetary magnetic field: A case study for January 14, 1988

We analyze ionospheric convection patterns over the polar regions during the passage of an interplanetary magnetic cloud on January 14, 1988, when the interplanetary magnetic field (IMF) rotated slowly in direction and had a large amplitude. Using the assimilative mapping of ionospheric electrodynamics (AMIE) procedure, we combine simultaneous observations of ionospheric drifts and magnetic perturbations from many different instruments into consistent patterns of high-latitude electrodynamics, focusing on the period of northward IMF. By combining satellite data with ground-based observations, we have generated one of the most comprehensive data sets yet assembled and used it to produce convection maps for both hemispheres. We present evidence that a lobe convection cell was embedded within normal merging convection during a period when the IMF By and Bz components were large and positive. As the IMF became predominantly northward, a strong reversed convection pattern (afternoon-to-morning potential drop of around 100 kV) appeared in the southern (summer) polar cap, while convection in the northern (winter) hemisphere became weak and disordered with a dawn-to-dusk potential drop of the order of 30 kV. These patterns persisted for about 3 hours, until the IMF rotated significantly toward the west. We interpret this behavior in terms of a recently proposed merging model for northward IMF under solstice conditions, for which lobe field lines from the hemisphere tilted toward the Sun (summer hemisphere) drape over the dayside magnetosphere, producing reverse convection in the summer hemisphere and impeding direct contact between the solar wind and field lines connected to the winter polar cap. The positive IMF Bx component present at this time could have contributed to the observed hemispheric asymmetry. Reverse convection in the summer hemisphere broke down rapidly after the ratio |By/Bz| exceeded unity, while convection in the winter hemisphere strengthened. A dominant dawn-to-dusk potential drop was established in both hemispheres when the magnitude of By exceeded that of Bz, with potential drops of the order of 100 kV, even while Bz remained northward. The later transition to southward Bz produced a gradual intensification of the convection, but a greater qualitative change occurred at the transition through |By/Bz| = 1 than at the transition through Bz = 0. The various convection patterns we derive under northward IMF conditions illustrate all possibilities previously discussed in the literature: nearly single-cell and multicell, distorted and symmetric, ordered and unordered, and sunward and antisunward.

Response time of the high-latitude dayside ionosphere to sudden changes in the north-south component of the IMF

The time scale of the response of the high-latitude dayside ionospheric flow to changes in the North-South component of the interplanetary magnetic field (IMF) has been investigated by examining the time delays between corresponding sudden changes. Approximately 40 h of simultaneous IMF and ionospheric flow data have been examined, obtained by the AMPTE-UKS and -IRM spacecraft and the EISCAT “Polar” experiment, respectively, in which 20 corresponding sudden changes have been identified. Ten of these changes were associated with southward turnings of the IMF, and 10 with northward turnings. It has been found that the corresponding flow changes occurred simultaneously over the whole of the “Polar” field-of-view, extending more than 2° in invariant latitude, and that the ionospheric response delay following northward turnings is the same as that following southward turnings, though the form of the response is different in the two cases. The shortest response time, 5.5 ± 3.2 min, is found in the early- to mid-afternoon sector, increasing to 9.5 ± 3.0 min in the mid-morning sector, and to 9.5 ± 3.1 min near to dusk. These times represent the delays in the appearance of perturbed flows in the “Polar” field-of-view following the arrival of IMF changes at the subsolar magnetopause. Overall, the results agree very well with those derived by Etemadi et al. (1988, Planet. Space Sci.36, 471) from a general cross-correlation analysis of the IMF Bz and “Polar” beam-swinging vector flow data.

The dependence of high-latitude dayside ionospheric flows on the North-South component of the IMF: A high time resolution correlation analysis using EISCAT “Polar” and AMPTE UKS and IRM data

In 1984 and 1985 a series of experiments was undertaken in which dayside ionospheric flows were measured by the EISCAT “Polar” experiment, while observations of the solar wind and interplanetary magnetic field (IMF) were made by the AMPTE UKS and IRM spacecraft upstream from the Earth's bow shock. As a result, 40 h of simultaneous data were acquired, which are analysed in this paper to investigate the relationship between the ionospheric flow and the North-South (Bz) component of the IMF. The ionospheric flow data have 2.5 min resolution, and cover the dayside local time sector from ∼ 09:30 to ∼ 18:30 M.L.T. and the latitude range from 70.8° to 74.3°. Using cross-correlation analysis it is shown that clear relationships do exist between the ionospheric flow and IMF Bz, but that the form of the relations depends strongly on latitude and local time. These dependencies are readily interpreted in terms of a twinvortex flow pattern in which the magnitude and latitudinal extent of the flows become successively larger as Bz becomes successively more negative. Detailed maps of the flow are derived for a range of Bz values (between ± 4 nT) which clearly demonstrate the presence of these effects in the data. The data also suggest that the morning reversal in the East-West component of flow moves to earlier local times as Bz, declines in value and becomes negative. The correlation analysis also provides information on the ionospheric response time to changes in IMF Bz, it being found that the response is very rapid indeed. The most rapid response occurs in the noon to mid-afternoon sector, where the westward flows of the dusk cell respond with a delay of 3.9 ± 2.2 min to changes in the North-South field at the subsolar magnetopause. The flows appear to evolve in form over the subsequent ~ 5 min interval, however, as indicated by the longer response times found for the northward component of flow in this sector (6.7 ±2.2 min), and in data from earlier and later local times. No evidence is found for a latitudinal gradient in response time; changes in flow take place coherently in time across the entire radar field-of-view.

Flow in the high latitude ionosphere: measurements at 15s resolution made using the EISCAT ‘Polar’ experiment

We present a first overview of flows in the high latitude ionosphere observed at 15 s resolution using the U.K.-Polar EISCAT experiment. Data are described from experiments conducted on two days, 27 October 1984 and 29 August 1985, which together span the local times between about 0200 and 2130MLT and cover five different regions of ionospheric flow. With increasing local time, these are: the dawn auroral zone flow cell, the dayside region of low background flows equatorward of the flow cells, the dusk auroral zone flow cell, the boundary region between the dusk auroral zone and the polar cap, and the evening polar cap. Flows in both the equatorward and poleward portions of the auroral zone cells appear to be relatively smooth, while in the central region of high speed flow considerable variations are generally present. These have the form of irregular fluctuations on a wide range of time scales in the early morning dawn cell, and impulsive wave-like variations with periods of a few minutes in the afternoon dusk cell. In the dayside region between the flow cells, the ionosphere is often essentially stagnant for long intervals, but low amplitude ULF waves with a period of about 5 min can also occur and persist for many cycles. These conditions are punctuated at one to two hour intervals by sudden ‘flow burst’ events with impulsively generated damped wave trains. Initial burst flows are generally directed poleward and can peak at line-of-sight speeds in excess of 1 km s^{−1} after perhaps 45 s. Flows in the polar cap are reasonably smooth on time scales of a few minutes and show no evidence for the presence of ULF waves. Under most, but not all, of the above conditions, the beam-swinging algorithm used to determine background vector flows should produce meaningful results. Comparison of these flow data with simultaneous plasma and magnetic field measurements in the solar wind, made by the AMPTE IRM and UKS spacecraft, emphasizes the strong control exerted on high latitude flows by the north-south component of the IMF.

The modelled occurrence of non-thermal plasma in the ionospheric F-region and the possible consequences for ion outflows into the magnetosphere

A global, time-dependent, three-dimensional, coupled ionosphere-thermosphere model is used to predict the spatial distribution of non-thermal plasma in the F-layer. It is shown that, even for steady-state conditions with Kp as low as 3, the difference between the ion and neutral velocities often exceeds the neutral thermal speed by a factor, D', which can be as large as 4. Theoretically, highly non-Maxwellian, and probably toroidal, ion velocity distributions are expected when D' exceeds about 1.5. The lack of response of the neutral winds to sunward ion drifts in the dawn sector of the auroral oval cause this to be the region most likely to contain toroidal distributions. The maximum in D' is found in the throat region of the convection pattern, where the strong neutral winds of the afternoon sector meet the eastward ion flows of the morning sector. These predictions are of interest, not only to radar scientists searching for non-thermal ionospheric plasma, but also as one possible explanation of the initial heating and upward flows of ions in the cleft ion fountain and nightside auroral oval, both of which are a major source of plasma for the magnetosphere.

Peak residential electricity demand and social practices: Deriving flexibility and greenhouse gas intensities from time use and locational data

Peak residential electricity demand takes place when people conduct simultaneous activities at specific times of the day. Social practices generate patterns of demand and can help understand why, where, with whom and when energy services are used at peak time. The aim of this work is to make use of recent UK time use and locational data to better understand: (i) how a set of component indices on synchronisation, variation, sharing and mobility indicate flexibility to shift demand; and (ii) the links between people’s activities and peaks in greenhouse gases’ intensities. The analysis is based on a recent UK time use dataset, providing 1 minute interval data from GPS devices and 10 minute data from diaries and questionnaires for 175 data days comprising 153 respondents. Findings show how greenhouse gases’ intensities and flexibility to shift activities vary throughout the day. Morning peaks are characterised by high levels of synchronisation, shared activities and occupancy, with low variation of activities. Evening peaks feature low synchronisation, and high spatial mobility variation of activities. From a network operator perspective, the results indicate that periods with lower flexibility may be prone to more significant local network loads due to the synchronization of electricity-demanding activities.

Quantifying particle size and turbulent scale dependence of dust uplift in the Sahara using aircraft measurements

The first size-resolved airborne measurements of dust fluxes and the first dust flux measurements from the central Sahara are presented and compared with a parameterization by Kok (2011a). High-frequency measurements of dust size distribution were obtained from 0.16 to 300 µm diameter, and eddy covariance fluxes were derived. This is more than an order of magnitude larger size range than previous flux estimates. Links to surface emission are provided by analysis of particle drift velocities. Number flux is described by a −2 power law between 1 and 144 µm diameter, significantly larger than the 12 µm upper limit suggested by Kok (2011a). For small particles, the deviation from a power law varies with terrain type and the large size cutoff is correlated with atmospheric vertical turbulent kinetic energy, suggesting control by vertical transport rather than emission processes. The measured mass flux mode is in the range 30–100 µm. The turbulent scales important for dust flux are from 0.1 km to 1–10 km. The upper scale increases during the morning as boundary layer depth and eddy size increase. All locations where large dust fluxes were measured had large topographical variations. These features are often linked with highly erodible surface features, such as wadis or dunes. We also hypothesize that upslope flow and flow separation over such features enhance the dust flux by transporting large particles out of the saltation layer. The tendency to locate surface flux measurements in open, flat terrain means these favored dust sources have been neglected in previous studies.

A critical evaluation of the ability of the Spinning Enhanced Visible and Infrared Imager (SEVIRI) thermal infrared red-green-blue rendering to identify dust events: theoretical analysis

Using a combination of idealized radiative transfer simulations and a case study from the first field campaign of the Saharan Mineral Dust Experiment (SAMUM) in southern Morocco, this paper provides a systematic assessment of the limitations of the widely used Spinning Enhanced Visible and Infrared Imager (SEVIRI) red-green-blue (RGB) thermal infrared dust product. Both analyses indicate that the ability of the product to identify dust, via its characteristic pink coloring, is strongly dependent on the column water vapor, the lower tropospheric lapse rate, and dust altitude. In particular, when column water vapor exceeds ∼20–25 mm, dust presence, even for visible optical depths of the order 0.8, is effectively masked. Variability in dust optical properties also has a marked impact on the imagery, primarily as a result of variability in dust composition. There is a moderate sensitivity to the satellite viewing geometry, particularly in moist conditions. The underlying surface can act to confound the signal seen through variations in spectral emissivity, which are predominantly manifested in the 8.7μm SEVIRI channel. In addition, if a temperature inversion is present, typical of early morning conditions over the Sahara and Sahel, an increased dust loading can actually reduce the pink coloring of the RGB image compared to pristine conditions. Attempts to match specific SEVIRI observations to simulations using SAMUM measurements are challenging because of high uncertainties in surface skin temperature and emissivity. Recommendations concerning the use and interpretation of the SEVIRI RGB imagery are provided on the basis of these findings.

Sea-breeze dynamics and convection initiation: the influence of convective parameterization in weather and climate model biases

There are some long-established biases in atmospheric models that originate from the representation of tropical convection. Previously, it has been difficult to separate cause and effect because errors are often the result of a number of interacting biases. Recently, researchers have gained the ability to run multiyear global climate model simulations with grid spacings small enough to switch the convective parameterization off, which permits the convection to develop explicitly. There are clear improvements to the initiation of convective storms and the diurnal cycle of rainfall in the convection-permitting simulations, which enables a new process-study approach to model bias identification. In this study, multiyear global atmosphere-only climate simulations with and without convective parameterization are undertaken with the Met Office Unified Model and are analyzed over the Maritime Continent region, where convergence from sea-breeze circulations is key for convection initiation. The analysis shows that, although the simulation with parameterized convection is able to reproduce the key rain-forming sea-breeze circulation, the parameterization is not able to respond realistically to the circulation. A feedback of errors also occurs: the convective parameterization causes rain to fall in the early morning, which cools and wets the boundary layer, reducing the land–sea temperature contrast and weakening the sea breeze. This is, however, an effect of the convective bias, rather than a cause of it. Improvements to how and when convection schemes trigger convection will improve both the timing and location of tropical rainfall and representation of sea-breeze circulations.

Kerb and urban increment of highly time-resolved trace elements in PM10, PM2.5 and PM1.0 winter aerosol in London during ClearfLo 2012

Ambient concentrations of trace elements with 2 h time resolution were measured in PM10–2.5, PM2.5–1.0 and PM1.0–0.3 size ranges at kerbside, urban background and rural sites in London during winter 2012. Samples were collected using rotating drum impactors (RDIs) and subsequently analysed with synchrotron radiation-induced X-ray fluorescence spectrometry (SR-XRF). Quantification of kerb and urban increments (defined as kerb-to-urban and urban-to-rural concentration ratios, respectively), and assessment of diurnal and weekly variability provided insight into sources governing urban air quality and the effects of urban micro-environments on human exposure. Traffic-related elements yielded the highest kerb increments, with values in the range of 10.4 to 16.6 for SW winds (3.3–6.9 for NE) observed for elements influenced by brake wear (e.g. Cu, Sb, Ba) and 5.7 to 8.2 for SW (2.6–3.0 for NE) for other traffic-related processes (e.g. Cr, Fe, Zn). Kerb increments for these elements were highest in the PM10–2.5 mass fraction, roughly twice that of the PM1.0–0.3 fraction. These elements also showed the highest urban increments (~ 3.0), although no difference was observed between brake wear and other traffic-related elements. All elements influenced by traffic exhibited higher concentrations during morning and evening rush hours, and on weekdays compared to weekends, with the strongest trends observed at the kerbside site, and additionally enhanced by winds coming directly from the road, consistent with street canyon effects. Elements related to mineral dust (e.g. Al, Si, Ca, Sr) showed significant influences from traffic-induced resuspension, as evidenced by moderate kerb (3.4–5.4 for SW, 1.7–2.3 for NE) and urban (~ 2) increments and increased concentrations during peak traffic flow. Elements related to regional transport showed no significant enhancement at kerb or urban sites, with the exception of PM10–2.5 sea salt (factor of up to 2), which may be influenced by traffic-induced resuspension of sea and/or road salt. Heavy-duty vehicles appeared to have a larger effect than passenger vehicles on the concentrations of all elements influenced by resuspension (including sea salt) and wearing processes. Trace element concentrations in London were influenced by both local and regional sources, with coarse and intermediate fractions dominated by traffic-induced resuspension and wearing processes and fine particles influenced by regional transport.