Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing

Age-related decline in the integrity of mitochondria is an important contributor to the human ageing process. In a number of ageing stem cell populations, this decline in mitochondrial function is due to clonal expansion of individual mitochondrial DNA (mtDNA) point mutations within single cells. However the dynamics of this process and when these mtDNA mutations occur initially are poorly understood. Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques (Random Mutation Capture, Next Generation Sequencing and mitochondrial enzyme histochemistry), and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (<20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.

Study of picosecond processes of an intercalated dipyridophenazine Cr(iii) complex bound to defined sequence DNAs using transient absorption and time-resolved infrared methods

Picosecond transient absorption (TA) and time-resolved infrared (TRIR) measurements of rac-[Cr(phen)2(dppz)]3+ (1) intercalated into double-stranded guanine-containing DNA reveal that the excited state is very rapidly quenched. As no evidence was found for the transient electron transfer products, it is proposed that the back electron transfer reaction must be even faster (<3 ps).

Infrared optical coatings for the EarthCARE Multispectral Imager

The Earth Cloud, Aerosol and Radiation Explorer mission (EarthCARE) Multispectral Imager (MSI) is a radiometric instrument designed to provide the imaging of the atmospheric cloud cover and the cloud top surface temperature from a sun-synchronous low Earth orbit. The MSI forms part of a suite of four instruments destined to support the European Space Agency Living Planet mission on-board the EarthCARE satellite payload to be launched in 2016, whose synergy will be used to construct three-dimensional scenes, textures and temperatures of atmospheric clouds and aerosols. The MSI instrument contains seven channels: four solar channels to measure visible and short-wave infrared wavelengths, and three channels to measure infrared thermal emission. In this paper, we describe the optical layout of the infrared instrument channels, thin-film multilayer designs, the coating deposition method and the spectral system throughput for the bandpass interference filters, dichroic beam splitters, lenses and mirror coatings to discriminate wavelengths at 8.8, 10.8, & 12.0 µm. The rationale for the selection of thin-film materials, spectral measurement technique, and environmental testing performance are also presented.

Thermal remote sensing of sea surface temperature

Sea surface temperature has been an important application of remote sensing from space for three decades. This chapter first describes well-established methods that have delivered valuable routine observations of sea surface temperature for meteorology and oceanography. Increasingly demanding requirements, often related to climate science, have highlighted some limitations of these ap-proaches. Practitioners have had to revisit techniques of estimation, of characterising uncertainty, and of validating observations—and even to reconsider the meaning(s) of “sea surface temperature”. The current understanding of these issues is reviewed, drawing attention to ongoing questions. Lastly, the prospect for thermal remote sens-ing of sea surface temperature over coming years is discussed.

Effects of a mid-latitude solar eclipse on the thermosphere and ionosphere: a modelling study

A modelling study is presented which investigates in-situ generated changes of the thermosphere and ionosphere during a solar eclipse. Neutral temperatures are expected to drop by up to 40 degrees K at 240 km height in the totality footprint, with neutral winds of up to 26 m/s responding to the change of pressure. Both temperatures and winds are found to respond with a time lag of 30 min after the passing of the Moon's shadow. A gravity wave is generated in the neutral atmosphere and propagates into the opposite hemisphere at around 300 m/s. The combined effects of thermal cooling and downwelling lead to an overall increase in [O], while [N(2)] initially rises and then for several hours after the eclipse is below the "steady state" level. An enhancement of [NmF2] is found and explained by the atmosphere's contraction during, and the reduced [O]/[N(2)] ratio after the eclipse.

Field-aligned plasma flow in the quiet, mid-latitude ionosphere deduced from topside soundings

A method for quantifying diffusive flows of O+ ions in the topside ionosphere from satellite soundings is described. A departure from diffusive equilibrium alters the shape of the plasma scale-height profile near the F2-peak where ion-neutral frictional drag is large. The effect enables the evaluation of , the field-aligned flux of O+ ions relative to the neutral oxygen atom gas, using MSIS model values for the neutral thermospheric densities and temperature. Upward flow values are accurate to within about 10%, the largest sources of error being the MSIS prediction for the concentration of oxygen atoms and the plasma temperature gradient deduced from the sounding. Downward flux values are only determined to within 20%. From 60,000 topside soundings, taken at the minimum and rising phase of the solar cycle, a total of 1098 mean scale-height profiles are identified for which no storm sudden commencement had occurred in the previous 12 days and for which Kp was less than 2o, each mean profile being an average of about six soundings. A statistical study ofdeduced from these profiles shows the diurnal cycle of O+ flow in the quiet, topside ionosphere at mid-latitudes and its seasonal variations. The differences betweenand ion flux observations from incoherent scatter radars are considered using the meridional thermospheric winds predicted by a global, three-dimensional model. The mean interhemispheric flow from summer to winter is compared with predictions by a numerical model of the protonospheric coupling of conjugate ionospheres for up to 6 days following a geomagnetic storm. The observed mean (of order 3 × 1016 ions day−1 along a flux tube of area 1 m2 at 1000 km) is larger than predicted for day 6 and the suggested explanation is a decrease in upward flows from the winter, daytime ionosphere between the sixth and twelfth days.

A simple model of the effects of the mid-latitude total ion trough in the bottomsideFlayer on HF radiowave propagation

Observations of the amplitudes and Doppler shifts of received HF radio waves are compared with model predictions made using a two-dimensional ray-tracing program. The signals are propagated over a sub-auroral path, which is shown to lie along the latitudes of the mid-latitude trough at times of low geomagnetic activity. Generalizing the predictions to include a simple model of the trough in the density and height of the F2 peak enables the explanation of the anomalous observed diurnal variations. The behavior of received amplitude, Doppler shift, and signal-to-noise ratio as a function of the Kp index value, the time of day, and the season (in 17 months of continuous recording) is found to agree closely with that predicted using the statistical position of the trough as deduced from 8 years of Alouette satellite soundings. The variation in the times of the observation of large signal amplitudes with the Kp value and the complete absence of such amplitudes when it exceeds 2.75 are two features that implicate the trough in these effects.

The bottomside mid-latitude ionospheric trough

The measured power losses and Doppler shifts of h.f. radio waves propagated over a long, west-east, sub-auroral path are found to exhibit features which cannot be explained by simple predictions and models. Both theory and the limited available data indicate that a bottomside F2-layer depletion should be present below the topside mid-latitude trough. Introducing this into the models (using the mean statistical positions of the trough deduced from Alouette I and II soundings) is shown to explain many of these features. From the Doppler shifts and a simple ray-tracing model the height of the depleted F2-peak inside the trough is deduced to be greater than its value outside the trough by an amount of the order of only 30–80 km.

Friction in mid-latitude cyclones: an Ekman-PV mechanism

The mechanism by which the atmospheric boundary layer reduces the intensity of mid-latitude cyclones is investigated. It is demonstrated that two alternative theories, Ekman pumping and the baroclinic potential vorticity (PV) mechanism, in fact act in union to maximize the spin-down. Ekman pumping aids the ventilation of PV from the boundary layer, and shapes the resulting PV anomaly into one of increased static stability. PV inversion techniques are used to demonstrate how this anomaly reduces the coupling between the upper- and lower-levels within the cyclone, reducing the growth rate.

Culture, compassion and clinical neglect: probity in the NHS after Mid Staffordshire

Speaking of the public response to the deaths of children at the Bristol Royal Infirmary before 2001, the BMJ commented that the NHS would be 'all changed, changed utterly'. Today, two inquiries into the Mid Staffordshire Foundation Trust suggest nothing changed at all. Many patients died as a result of their care and the stories of indifference and neglect there are harrowing. Yet Bristol and Mid Staffordshire are not isolated reports. In 2011, the Health Services Ombudsman reported on the care of elderly and frail patients in the NHS and found a failure to recognise their humanity and individuality and to respond to them with sensitivity, compassion and professionalism. Likewise, the Care Quality Commission and Healthcare Commission received complaints from patients and relatives about the quality of nursing care. These included patients not being fed, patients left in soiled bedding, poor hygiene practices, and general disregard for privacy and dignity. Why is there such tolerance of poor clinical standards? We need a better understanding of the circumstances that can lead to these outcomes and how best to respond to them. We discuss the findings of these and other reports and consider whether attention should be devoted to managing individual behaviour, or focus on the systemic influences which predispose hospital staff to behave in this way. Lastly, we consider whether we should look further afield to cognitive psychology to better understand how clinicians and managers make decisions?

Infrared and millimetre-wave scintillometry in the suburban environment – Part 1: Structure parameters

Scintillometry, a form of ground-based remote sensing, provides the capability to estimate surface heat fluxes over scales of a few hundred metres to kilometres. Measurements are spatial averages, making this technique particularly valuable over areas with moderate heterogeneity such as mixed agricultural or urban environments. In this study, we present the structure parameters of temperature and humidity, which can be related to the sensible and latent heat fluxes through similarity theory, for a suburban area in the UK. The fluxes are provided in the second paper of this two-part series. A millimetre-wave scintillometer was combined with an infrared scintillometer along a 5.5 km path over northern Swindon. The pairing of these two wavelengths offers sensitivity to both temperature and humidity fluctuations, and the correlation between wavelengths is also used to retrieve the path-averaged temperature–humidity correlation. Comparison is made with structure parameters calculated from an eddy covariance station located close to the centre of the scintillometer path. The performance of the measurement techniques under different conditions is discussed. Similar behaviour is seen between the two data sets at sub-daily timescales. For the two summer-to-winter periods presented here, similar evolution is displayed across the seasons. A higher vegetation fraction within the scintillometer source area is consistent with the lower Bowen ratio observed (midday Bowen ratio < 1) compared with more built-up areas around the eddy covariance station. The energy partitioning is further explored in the companion paper.

Infrared and millimetre-wave scintillometry in the suburban environment – Part 2: Large-area sensible and latent heat fluxes

A millimetre-wave scintillometer was paired with an infrared scintillometer, enabling estimation of large-area evapotranspiration across northern Swindon, a suburban area in the UK. Both sensible and latent heat fluxes can be obtained using this "two-wavelength" technique, as it is able to provide both temperature and humidity structure parameters, offering a major advantage over conventional single-wavelength scintillometry. The first paper of this two-part series presented the measurement theory and structure parameters. In this second paper, heat fluxes are obtained and analysed. These fluxes, estimated using two-wavelength scintillometry over an urban area, are the first of their kind. Source area modelling suggests the scintillometric fluxes are representative of 5–10 km2. For comparison, local-scale (0.05–0.5 km2) fluxes were measured by an eddy covariance station. Similar responses to seasonal changes are evident at the different scales but the energy partitioning varies between source areas. The response to moisture availability is explored using data from 2 consecutive years with contrasting rainfall patterns (2011–2012). This extensive data set offers insight into urban surface-atmosphere interactions and demonstrates the potential for two-wavelength scintillometry to deliver fluxes over mixed land cover, typically representative of an area 1–2 orders of magnitude greater than for eddy covariance measurements. Fluxes at this scale are extremely valuable for hydro-meteorological model evaluation and assessment of satellite data products

Evaluation of modern and mid-Holocene seasonal precipitation of the Mediterranean and northern Africa in the CMIP5 simulations

We analyse the spatial expression of seasonal climates of the Mediterranean and northern Africa in pre-industrial (piControl) and mid-Holocene (midHolocene, 6 yr BP) simulations from the fifth phase of the Coupled Model Intercomparison Project (CMIP5). Modern observations show four distinct precipitation regimes characterized by differences in the seasonal distribution and total amount of precipitation: an equatorial band characterized by a double peak in rainfall, the monsoon zone characterized by summer rainfall, the desert characterized by low seasonality and total precipitation, and the Mediterranean zone characterized by summer drought. Most models correctly simulate the position of the Mediterranean and the equatorial climates in the piControl simulations, but overestimate the extent of monsoon influence and underestimate the extent of desert. However, most models fail to reproduce the amount of precipitation in each zone. Model biases in the simulated magnitude of precipitation are unrelated to whether the models reproduce the correct spatial patterns of each regime. In the midHolocene, the models simulate a reduction in winter rainfall in the equatorial zone, and a northward expansion of the monsoon with a significant increase in summer and autumn rainfall. Precipitation is slightly increased in the desert, mainly in summer and autumn, with northward expansion of the monsoon. Changes in the Mediterranean are small, although there is an increase in spring precipitation consistent with palaeo-observations of increased growing-season rainfall. Comparison with reconstructions shows most models underestimate the mid-Holocene changes in annual precipitation, except in the equatorial zone. Biases in the piControl have only a limited influence on midHolocene anomalies in ocean–atmosphere models; carbon-cycle models show no relationship between piControl bias and midHolocene anomalies. Biases in the prediction of the midHolocene monsoon expansion are unrelated to how well the models simulate changes in Mediterranean climate.