p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21.Methodsp21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay.ResultsWe show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis.ConclusionThe novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy

Application of the Priestley–Taylor Approach in a Two-Source Surface Energy Balance Model

The Priestley–Taylor (PT) approximation for computing evapotranspiration was initially developed for conditions of a horizontally uniform saturated surface sufficiently extended to obviate any significant advection of energy. Nevertheless, the PT approach has been effectively implemented within the framework of a thermal-based two-source model (TSM) of the surface energy balance, yielding reasonable latent heat flux estimates over a range in vegetative cover and climate conditions. In the TSM, however, the PT approach is applied only to the canopy component of the latent heat flux, which may behave more conservatively than the bulk (soil + canopy) system. The objective of this research is to investigate the response of the canopy and bulk PT parameters to varying leaf area index (LAI) and vapor pressure deficit (VPD) in both natural and agricultural vegetated systems, to better understand the utility and limitations of this approximation within the context of the TSM. Micrometeorological flux measurements collected at multiple sites under a wide range of atmospheric conditions were used to implement an optimization scheme, assessing the value of the PT parameter for best performance of the TSM. Overall, the findings suggest that within the context of the TSM, the optimal canopy PT coefficient for agricultural crops appears to have a fairly conservative value of ~1.2 except when under very high vapor pressure deficit (VPD) conditions, when its value increases. For natural vegetation (primarily grasslands), the optimal canopy PT coefficient assumed lower values on average (~0.9) and dropped even further at high values of VPD. This analysis provides some insight as to why the PT approach, initially developed for regional estimates of potential evapotranspiration, can be used successfully in the TSM scheme to yield reliable heat flux estimates over a variety of land cover types

TWO-SOURCE ENERGY BALANCE MODEL TO CALCULATE E, T, AND ET: COMPARISON OF PRIESTLEY-TAYLOR AND PENMAN-MONTEITH FORMULATIONS AND TWO TIME SCALING METHODS

The two-source energy balance (TSEB) model calculates the energy balance of the soil-canopy-atmosphere continuum, where transpiration is initially determined by the Priestley-Taylor equation. The TSEB was revised recently using the Penman-Monteith equation to replace the Priestley-Taylor formulation, thus better accounting for the impact of large and varying vapor pressure deficits (VPD) typical of advective, semiarid climates. This study is a comparison of the Priestley- Taylor and Penman-Monteith versions of the TSEB (termed TSEB-PT and TSEB-PM, respectively). Evaporation (E), transpiration (T), and evapotranspiration (ET) calculated by the TSEB-PT and TSEB-PM versions were compared to measurements obtained with microlysimeters, sap flow gauges, and weighing lysimeters, respectively, for fully irrigated cotton (Gossypium hirsutum L.) at Bushland, Texas. Radiometric surface temperature (TR) was used to calculate E, T, and ET in both TSEB versions in 15 min intervals and summed to intervals coinciding with times of measurements. In addition, a one-time-of-day TR measurement was used (9:45, 11:15, 12:45, 14:15, or 15:45 CST), and E, T, and ET were calculated for the appropriate measurement interval (i.e., daytime, nighttime, and 24 h) using the time scaling methods based on reference ET (TSCET) and reference temperature (TSCTEMP). Measured average values of E, T, and ET during the study period were 0.94 mm (24 h), 6.9 mm (7:00 to 22:00 CST), and 7.2 mm (24 h), respectively. The TSEB-PT consistently overestimated E and underestimated T, with RMSE/MBE of up to 2.8/1.8 mm and 4.1/-3.9 mm, respectively. In comparison, the TSEB-PM greatly reduced discrepancies between calculations and measurements, with respective RMSE/MBE for E and T of only up to 1.5/0.79 mm and 1.3/±0.76 mm, respectively. For 24 h ET, the TSEB-PT resulted in maximum RMSE/MBE of 3.2/-1.9 mm, and the TSEB-PM had maximum RMSE/MBE of 1.7/0.95 mm. Daytime ET model agreement was very similar for both model versions (RMSE/MBE usually \u3c1.1/ET or TSCTEMP methods, and results did not greatly differ for TSCET or TSCTEMP. Both time scaling methods were not very sensitive to the TR measurement time used, although morning (9:45 CST) TR measurement times did not perform as well as the other times

Mapping daily evapotranspiration at Landsat spatial scales during the BEAREX’08 field campaign

Robust spatial information about environmental water use at field scales and daily to seasonal timesteps will benefit many applications in agriculture and water resource management. This information is particularly critical in arid climates where freshwater resources are limited or expensive, and groundwater supplies are being depleted at unsustainable rates to support irrigated agriculture as well as municipal and industrial uses. Gridded evapotranspiration (ET) information at field scales can be obtained periodically using land–surface temperature-based surface energy balance algorithms applied to moderate resolution satellite data from systems like Landsat, which collects thermal-band imagery every 16 days at a resolution of approximately 100 m. The challenge is in finding methods for interpolating between ET snapshots developed at the time of a clear-sky Landsat overpass to provide complete daily time-series over a growing season. This study examines the efficacy of a simple gap-filling algorithm designed for applications in data-sparse regions, which does not require local ground measurements of weather or rainfall, or estimates of soil texture. The algorithm relies on general conservation of the ratio between actual ET and a reference ET, generated from satellite insolation data and standard meteorological fields from a mesoscale model. The algorithm was tested with ET retrievals from the Atmosphere–Land Exchange Inverse (ALEXI) surface energy balance model and associated DisALEXI flux disaggregation technique, which uses Landsat-scale thermal imagery to reduce regional ALEXI maps to a finer spatial resolution. Daily ET at the Landsat scale was compared with lysimeter and eddy covariance flux measurements collected during the Bushland Evapotranspiration and Agricultural Remote sensing EXperiment of 2008 (BEAREX08), conducted in an irrigated agricultural area in the Texas Panhandle under highly advective conditions. The simple gap-filling algorithm performed reasonably at most sites, reproducing observed cumulative ET to within 5–10% over the growing period from emergence to peak biomass in both rainfed and irrigated fields

Multicolour correlative imaging using phosphor probes

Correlative light and electron microscopy exploits the advantages of optical methods, such as multicolour probes and their use in hydrated live biological samples, to locate functional units, which are then correlated with structural details that can be revealed by the superior resolution of electron microscopes. One difficulty is locating the area imaged by the electron beam in the much larger optical field of view. Multifunctional probes that can be imaged in both modalities and thus register the two images are required. Phosphor materials give cathodoluminescence (CL) optical emissions under electron excitation. Lanthanum phosphate containing thulium or terbium or europium emits narrow bands in the blue, green and red regions of the CL spectrum; they may be synthesised with very uniform-sized crystals in the 10- to 50-nm range. Such crystals can be imaged by CL in the electron microscope, at resolutions limited by the particle size, and with colour discrimination to identify different probes. These materials also give emissions in the optical microscope, by multiphoton excitation. They have been deposited on the surface of glioblastoma cells and imaged by CL. Gadolinium oxysulphide doped with terbium emits green photons by either ultraviolet or electron excitation. Sixty-nanometre crystals of this phosphor have been imaged in the atmospheric scanning electron microscope (JEOL ClairScope). This probe and microscope combination allow correlative imaging in hydrated samples. Phosphor probes should prove to be very useful in correlative light and electron microscopy, as fiducial markers to assist in image registration, and in high/super resolution imaging studies

Axonal Injury Partially Mediates Associations Between Increased Left Ventricular Mass Index and White Matter Damage

BACKGROUND AND PURPOSE: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. METHODS: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE-ε4 positive, LV mass index 51.4±8.1 g/m2, NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE-ε4. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. RESULTS: Among all participants, LV mass index was unrelated to CSF biomarkers (P>0.33). LV mass index interacted with MCI (P=0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE-ε4 carriers (P=0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. CONCLUSIONS: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE-ɛ4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage

Understanding innovators' experiences of barriers and facilitators in implementation and diffusion of healthcare service innovations: A qualitative study

This article is made available through the Brunel Open Access Publishing Fund - Copyright @ 2011 Barnett et al.Background: Healthcare service innovations are considered to play a pivotal role in improving organisational efficiency and responding effectively to healthcare needs. Nevertheless, healthcare organisations encounter major difficulties in sustaining and diffusing innovations, especially those which concern the organisation and delivery of healthcare services. The purpose of the present study was to explore how healthcare innovators of process-based initiatives perceived and made sense of factors that either facilitated or obstructed the innovation implementation and diffusion. Methods: A qualitative study was designed. Fifteen primary and secondary healthcare organisations in the UK, which had received health service awards for successfully generating and implementing service innovations, were studied. In-depth, semi structured interviews were conducted with the organisational representatives who conceived and led the development process. The data were recorded, transcribed and thematically analysed. Results: Four main themes were identified in the analysis of the data: the role of evidence, the function of inter-organisational partnerships, the influence of human-based resources, and the impact of contextual factors. "Hard" evidence operated as a proof of effectiveness, a means of dissemination and a pre-requisite for the initiation of innovation. Inter-organisational partnerships and people-based resources, such as champions, were considered an integral part of the process of developing, establishing and diffusing the innovations. Finally, contextual influences, both intra-organisational and extra-organisational were seen as critical in either impeding or facilitating innovators' efforts. Conclusions: A range of factors of different combinations and co-occurrence were pointed out by the innovators as they were reflecting on their experiences of implementing, stabilising and diffusing novel service initiatives. Even though the innovations studied were of various contents and originated from diverse organisational contexts, innovators' accounts converged to the significant role of the evidential base of success, the inter-personal and inter-organisational networks, and the inner and outer context. The innovators, operating themselves as important champions and being often willing to lead constructive efforts of implementation to different contexts, can contribute to the promulgation and spread of the novelties significantly.This research was supported financially by the Multidisciplinary Assessment of Technology Centre for Healthcare (MATCH)