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.

What drives city branding?

The article revises the role of architecture and iconic buildings in the branding of urban spaces.

What drives ICT clustering in European Cities?

ICT clusters have attracted much attention because of their rapid growth and their value for other economic activities. Using a nested multi-level model, we examine how conditions at the country level and at the city level affect ICT clustering activity in 227 cities across 22 European countries. We test for the influence of three country regulations (starting a business, registering property, enforcing contracts) and two city conditions (proximity to university, network density) on ICT clustering. We consider heterogeneity within the sector and study two types of ICT activities: ICT product firms and ICT content firms. Our results indicate that country conditions and city conditions each have idiosyncratic implications for ICT clustering, and further, that these can vary by activities in ICT products or ICT content manufacturing.

Science drives horticulture's progress and profit

Horticultural science linked with basic studies in biology, chemistry, physics and engineering has laid the foundation for advances in applied knowledge which are at the heart of commercial, environmental and social horticulture. In few disciplines is science more rapidly translated into applicable technologies than in the huge range of man’s activities embraced within horticulture which are discussed in this Trilogy. This chapter surveys the origins of horticultural science developing as an integral part of the 16th century “Scientific Revolution”. It identifies early discoveries during the latter part of the 19th and early 20th centuries which rationalized the control of plant growth, flowering and fruiting and the media in which crops could be cultivated. The products of these discoveries formed the basis on which huge current industries of worldwide significance are founded in fruit, vegetable and ornamental production. More recent examples of the application of horticultural science are used in an explanation of how the integration of plant breeding, crop selection and astute marketing highlighted by the New Zealand industry have retained and expanded the viability of production which supplies huge volumes of fruit into the world’s markets. This is followed by an examination of science applied to tissue and cell culture as an example of technologies which have already produced massive industrial applications but hold the prospect for generating even greater advances in the future. Finally, examples are given of nascent scientific discoveries which hold the prospect for generating horticultural industries with considerable future impact. These include systems modeling and biology, nanotechnology, robotics, automation and electronics, genetics and plant breeding, and more efficient and effective use of resources and the employment of benign microbes. In conclusion there is an estimation of the value of horticultural science to society.

Solar influences on dynamical coupling between the stratosphere and troposphere

We use a simplified atmospheric general circulation model (AGCM) to investigate the response of the lower atmosphere to thermal perturbations in the lower stratosphere. The results show that generic heating of the lower stratosphere tends to weaken the sub-tropical jets and the tropospheric mean meridional circulations. The positions of the jets, and the extent of the Hadley cells, respond to the distribution of the stratospheric heating, with low latitude heating displacing them poleward, and uniform heating displacing them equatorward. The patterns of response to the low latitude heating are similar to those found to be associated with solar variability in previous observational data analysis, and to the effects of varying solar UV radiation in sophisticated AGCMs. In order to investigate the chain of causality involved in converting the stratospheric thermal forcing to a tropospheric climate signal we conduct an experiment which uses an ensemble of model spin-ups to analyse the time development of the response to an applied stratospheric perturbation. We find that the initial effect of the change in static stability at the tropopause is to reduce the eddy momentum flux convergence in this region. This is followed by a vertical transfer of the momentum forcing anomaly by an anomalous mean circulation to the surface, where it is partly balanced by surface stress anomalies. The unbalanced part drives the evolution of the vertically integrated zonal flow. We conclude that solar heating of the stratosphere may produce changes in the circulation of the troposphere even without any direct forcing below the tropopause. We suggest that the impact of the stratospheric changes on wave propagation is key to the mechanisms involved.

NG2 cells differentiate into astrocytes in cerebellar slices

NG2-glia are an abundant population of glial cells that have been considered by many to be oligodendrocyte progenitor cells (OPCs). However, growing evidence suggests that NG2-glia may also be capable of differentiating into astrocytes and neurons under certain conditions. Here, we have examined NG2-glia in cerebellar slices, using transgenic mice in which the astroglial marker glial specific protein (GFAP) drives expression of the reporter gene enhanced green fluorescent protein (EGFP). Immunolabelling for NG2 shows that NG2-glia and GFAP-EGFP astroglia are separate populations in most areas of the brain, although a substantial population of NG2-glia in the pons also express the GFAP-EGFP reporter. In the cerebellum, NG2-glia did not express EGFP, either at postnatal day (P)12 or P29-30. We developed an organotypic culture of P12 cerebellar slices that maintain cytoarchitectural integrity of Purkinje neurons and Bergmann glia. In these cultures, BrdU labelling indicates that the majority of NG2-glia enter the cell cycle within 2 days in vitro (DIV), suggesting that NG2-glia undergo a [`]reactive' response in cerebellar cultures. After 2 DIV NG2-glia began to express the astroglial reporter EGFP and in some cases the respective GFAP protein. However, NG2-glia did not acquire phenotypic markers of neural stem cells or neurons. The results suggest that NG2-glia are not lineage restricted OPCs and are a potential source of astrocytes in the cerebellum.

Spatial calibration of an optical see-through head-mounted display

We present here a method for calibrating an optical see-through Head Mounted Display (HMD) using techniques usually applied to camera calibration (photogrammetry). Using a camera placed inside the HMD to take pictures simultaneously of a tracked object and features in the HMD display, we could exploit established camera calibration techniques to recover both the intrinsic and extrinsic properties of the~HMD (width, height, focal length, optic centre and principal ray of the display). Our method gives low re-projection errors and, unlike existing methods, involves no time-consuming and error-prone human measurements, nor any prior estimates about the HMD geometry.

The effects of difficulty and gain versus loss on vocal physiology and acoustics

To examine the basis of emotional changes to the voice, physiological and electroglottal measures were combined with acoustic speech analysis of 30 men performing a computer task in which they lost or gained points under two levels of difficulty. Predictions of the main effects of difficulty and reward on the voice were not borne out by the data. Instead, vocal changes depended largely on interactions between gain versus loss and difficulty. The rate at which the vocal folds open and close (fundamental frequency; f0) was higher for loss than for gain when difficulty was high, but not when difficulty was low. Electroglottal measures revealed that f0 changes corresponded to shorter glottal open times for the loss conditions. Longer closed and shorter open phases were consistent with raised laryngeal tension in difficult loss conditions. Similarly, skin conductance indicated higher sympathetic arousal in loss than gain conditions, particularly when difficulty was high. The results provide evidence of the physiological basis of affective vocal responses, confirming the utility of measuring physiology and voice in the study of emotion.

Estimating surface net solar radiation by use of Landsat-5 TM and digital elevation models

The ground surface net solar radiation is the energy that drives physical and chemical processes at the ground surface. In this paper, multi-spectral data from the Landsat-5 TM, topographic data from a gridded digital elevation model, field measurements, and the atmosphere model LOWTRAN 7 are used to estimate surface net solar radiation over the FIFE site. Firstly an improved method is presented and used for calculating total surface incoming radiation. Then, surface albedo is integrated from surface reflectance factors derived from remotely sensed data from Landsat-5 TM. Finally, surface net solar radiation is calculated by subtracting surface upwelling radiation from the total surface incoming radiation.

Influence of the seasonal cycle on the termination of El Nino events in a coupled general circulation model

In this study, the mechanisms leading to the El Nino peak and demise are explored through a coupled general circulation model ensemble approach evaluated against observations. The results here suggest that the timing of the peak and demise for intense El Nino events is highly predictable as the evolution of the coupled system is strongly driven by a southward shift of the intense equatorial Pacific westerly anomalies during boreal winter. In fact, this systematic late-year shift drives an intense eastern Pacific thermocline shallowing, constraining a rapid El Nino demise in the following months. This wind shift results from a southward displacement in winter of the central Pacific warmest SSTs in response to the seasonal evolution of solar insolation. In contrast, the intensity of this seasonal feedback mechanism and its impact on the coupled system are significantly weaker in moderate El Nino events, resulting in a less pronounced thermocline shallowing. This shallowing transfers the coupled system into an unstable state in spring but is not sufficient to systematically constrain the equatorial Pacific evolution toward a rapid El Nino termination. However, for some moderate events, the occurrence of intense easterly wind anomalies in the eastern Pacific during that period initiate a rapid surge of cold SSTs leading to La Nina conditions. In other cases, weaker trade winds combined with a slightly deeper thermocline allow the coupled system to maintain a broad warm phase evolving through the entire spring and summer and a delayed El Nino demise, an evolution that is similar to the prolonged 1986/87 El Nino event. La Nina events also show a similar tendency to peak in boreal winter, with characteristics and mechanisms mainly symmetric to those described for moderate El Nino cases.

Fast and frugal framing effects?

Three experiments examine whether simple pair-wise comparison judgments, involving the “recognition heuristic” (Goldstein & Gigerenzer, 2002), are sensitive to implicit cues to the nature of the comparison required. Experiments 1 & 2 show that participants frequently choose the recognized option of a pair if asked to make “larger” judgments but are significantly less likely to choose the unrecognized option when asked to make “smaller” judgments. Experiment 3 demonstrates that, overall, participants consider recognition to be a more reliable guide to judgments of a magnitude criterion than lack of recognition and that this intuition drives the framing effect. These results support the idea that, when making pair-wise comparison judgments, inferring that the recognized item is large is simpler than inferring that the unrecognized item is small.

Optimal inverter design for an induction machine using resonant frequency matching

The frequency responses of two 50 Hz and one 400 Hz induction machines have been measured experimentally over a frequency range of 1 kHz to 400 kHz. This study has shown that the stator impedances of the machines behave in a similar manner to a parallel resonant circuit, and hence have a resonant point at which the Input impedance of the machine is at a maximum. This maximum impedance point was found experimentally to be as low as 33 kHz, which is well within the switching frequency ranges of modern inverter drives. This paper investigates the possibility of exploiting the maximum impedance point of the machine, by taking it into consideration when designing an inverter, in order to minimize ripple currents due to the switching frequency. Minimization of the ripple currents would reduce torque pulsation and losses, increasing overall performance. A modified machine model was developed to take into account the resonant point, and this model was then simulated with an inverter to demonstrate the possible advantages of matching the inverter switching frequency to the resonant point. Finally, in order to experimentally verify the simulated results, a real inverter with a variable switching frequency was used to drive an induction machine. Experimental results are presented.

Species divergence and trait convergence in experimental plant community assembly

Despite decades of research, it remains controversial whether ecological communities converge towards a common structure determined by environmental conditions irrespective of assembly history. Here, we show experimentally that the answer depends on the level of community organization considered. In a 9-year grassland experiment, we manipulated initial plant composition on abandoned arable land and subsequently allowed natural colonization. Initial compositional variation caused plant communities to remain divergent in species identities, even though these same communities converged strongly in species traits. This contrast between species divergence and trait convergence could not be explained by dispersal limitation or community neutrality alone. Our results show that the simultaneous operation of trait-based assembly rules and species-level priority effects drives community assembly, making it both deterministic and historically contingent, but at different levels of community organization.

Resolving the energy paradox of chaperone/usher-mediated fibre assembly

Periplasmic chaperone/usher machineries are used for assembly of filamentous adhesion organelles of Gram-negative pathogens in a process that has been suggested to be driven by folding energy. Structures of mutant chaperone-subunit complexes revealed a final folding transition (condensation of the subunit hydrophobic core) on the release of organelle subunit from the chaperone-subunit pre-assembly complex and incorporation into the final fibre structure. However, in view of the large interface between chaperone and subunit in the pre-assembly complex and the reported stability of this complex, it is difficult to understand how final folding could release sufficient energy to drive assembly. In the present paper, we show the X-ray structure for a native chaperone-fibre complex that, together with thermodynamic data, shows that the final folding step is indeed an essential component of the assembly process. We show that completion of the hydrophobic core and incorporation into the fibre results in an exceptionally stable module, whereas the chaperone-subunit preassembly complex is greatly destabilized by the high-energy conformation of the bound subunit. This difference in stabilities creates a free energy potential that drives fibre formation.

Effect of PEG crystallization on the self-assembly of PEG/peptide copolymers containing amyloid peptide fragments

The effect of poly(ethylene glycol) PEG crystallization on P-sheet fibril formation is studied for a series of three peptide/PEG conjugates containing fragments modified from the amyloid P peptide, specifically KLVFF, FFKLVFF, and AAKLVFF. These are conjugated to PEG with M-n = 3300 g mol(-1). It is found, via small-angle X-ray scattering,X-ray diffraction, atomic force microscopy, and polarized optical microscopy, that PEG crystallinity in dried samples can disturb fibrillization, in particular cross-P amyloid structure formation, for the conjugate containing the weak fibrillizer KLVFF, whereas this is retained for the conjugates containing the stronger fibrillizers AAKLVFF and FFKLVFF. For these two samples, the alignment of peptide fibrils also drives the orientation of the attached PEG chains. Our results highlight the importance of the antagonistic effects of PEG crystallization and peptide fibril formation in PEG/peptide conjugates.