Thyroxine differentially modulates the peripheral clock: lessons from the human hair follicle

The human hair follicle (HF) exhibits peripheral clock activity, with knock-down of clock genes (BMAL1 and PER1) prolonging active hair growth (anagen) and increasing pigmentation. Similarly, thyroid hormones prolong anagen and stimulate pigmentation in cultured human HFs. In addition they are recognized as key regulators of the central clock that controls circadian rhythmicity. Therefore, we asked whether thyroxine (T4) also influences peripheral clock activity in the human HF. Over 24 hours we found a significant reduction in protein levels of BMAL1 and PER1, with their transcript levels also decreasing significantly. Furthermore, while all clock genes maintained their rhythmicity in both the control and T4 treated HFs, there was a significant reduction in the amplitude of BMAL1 and PER1 in T4 (100 nM) treated HFs. Accompanying this, cell-cycle progression marker Cyclin D1 was also assessed appearing to show an induced circadian rhythmicity by T4 however, this was not significant. Contrary to short term cultures, after 6 days, transcript and/or protein levels of all core clock genes (BMAL1, PER1, clock, CRY1, CRY2) were up-regulated in T4 treated HFs. BMAL1 and PER1 mRNA was also up-regulated in the HF bulge, the location of HF epithelial stem cells. Together this provides the first direct evidence that T4 modulates the expression of the peripheral molecular clock. Thus, patients with thyroid dysfunction may also show a disordered peripheral clock, which raises the possibility that short term, pulsatile treatment with T4 might permit one to modulate circadian activity in peripheral tissues as a target to treat clock-related disease

Global 21cm signal experiments: a designer's guide

[Abridged] The spatially averaged global spectrum of the redshifted 21cm line has generated much experimental interest, for it is potentially a direct probe of the Epoch of Reionization and the Dark Ages. Since the cosmological signal here has a purely spectral signature, most proposed experiments have little angular sensitivity. This is worrisome because with only spectra, the global 21cm signal can be difficult to distinguish from foregrounds such as Galactic synchrotron radiation, as both are spectrally smooth and the latter is orders of magnitude brighter. We establish a mathematical framework for global signal data analysis in a way that removes foregrounds optimally, complementing spectra with angular information. We explore various experimental design trade-offs, and find that 1) with spectral-only methods, it is impossible to mitigate errors that arise from uncertainties in foreground modeling; 2) foreground contamination can be significantly reduced for experiments with fine angular resolution; 3) most of the statistical significance in a positive detection during the Dark Ages comes from a characteristic high-redshift trough in the 21cm brightness temperature; and 4) Measurement errors decrease more rapidly with integration time for instruments with fine angular resolution. We show that if observations and algorithms are optimized based on these findings, an instrument with a 5 degree beam can achieve highly significant detections (greater than 5-sigma) of even extended (high Delta-z) reionization scenarios after integrating for 500 hrs. This is in contrast to instruments without angular resolution, which cannot detect gradual reionization. Abrupt ionization histories can be detected at the level of 10-100's of sigma. The expected errors are also low during the Dark Ages, with a 25-sigma detection of the expected cosmological signal after only 100 hrs of integration.Comment: 34 pages, 30 figures. Replaced (v2) to match accepted PRD version (minor pedagogical additions to text; methods, results, and conclusions unchanged). Fixed two typos (v3); text, results, conclusions etc. completely unchange

Geophysical-geotechnical sensor networks for landslide monitoring

Landslides are often the result of complex, multi-phase processes where gradual deterioration of shear strength within the sub-surface precedes the appearance of surface features and slope failure. Moisture content increases and the build-up of associated pore water pressures are invariably associated with a loss of strength, and thus are a precursor to failure. Consequently, hydraulic processes typically play a major role in the development of landslides. Geoelectrical techniques, such as resistivity and self-potential are being increasingly applied to study landslide structure and the hydraulics of landslide processes. The great strengths of these techniques are that they provide spatial or volumetric information at the site scale, which, when calibrated with appropriate geotechnical and hydrogeological data, can be used to characterise lithological variability and monitor hydraulic changes in the subsurface. In this study we describe the development of an automated time-lapse electrical resistivity tomography (ALERT) and geotechnical monitoring system on an active inland landslide near Malton, North Yorkshire, UK. The overarching objective of the research is to develop a 4D landslide monitoring system that can characterise the subsurface structure of the landslide, and reveal the hydraulic precursors to movement. The site is a particularly import research facility as it is representative of many lowland UK situations in which weak mudrocks have failed on valley sides. Significant research efforts have already been expended at the site, and a number of baseline data sets have been collected, including ground and airborne LIDAR, geomorphologic and geological maps, and geophysical models. The monitoring network comprises an ALERT monitoring station connected to a 3D monitoring electrode array installed across an area of 5,500 m2, extending from above the back scarp to beyond the toe of the landslide. The ALERT instrument uses wireless telemetry (in this case GPRS) to communicate with an office based server, which runs control software and a database management system. The control software is used to schedule data acquisition, whilst the database management system stores, processes and inverts the remotely streamed ERT data. Once installed and configured, the system operates autonomously without manual intervention. Modifications to the ALERT system at this site have included the addition of environmental and geotechnical sensors to monitor rainfall, ground movement, ground and air temperature, and pore pressure changes within the landslide. The system is housed in a weatherproof enclosure and is powered by batteries charged by a wind turbine & solar panels. 3D ERT images generated from the landslide have been calibrated against resistivity information derived from laboratory testing of borehole core recovered from the landslide. The calibrated images revealed key aspects of the 3D landslide structure, including the lateral extent of slipped material and zones of depletion and accumulation; the surface of separation and the thickness of individual earth flow lobes; and the dipping in situ geological boundary between the bedrock formations. Time-lapse analysis of resistivity signatures has revealed artefacts within the images that are diagnostic of electrode movement. Analytical models have been developed to simulate the observed artefacts, from which predictions of electrode movement have been derived. This information has been used to correct the ERT data sets, and has provided a means of using ERT to monitor landslide movement across the entire ALERT imaging area. Initial assessment of seasonal changes in the resistivity signature has indicated that the system is sensitive to moisture content changes in the body of the landslide, thereby providing a basis for further development of the system with the aim of monitoring hydraulic precursors to failure

Academic leadership: changing conceptions, identities and experiences in UK Higher Education

© Leadership Foundation for Higher EducationThis report presents the findings from a research project on academic leadership in UK higher education. The overall aim of this project was to explore and understand ‘academic leadership’ that relates directly to the core academic functions of teaching, research and service (including academic administration and outreach), as distinct from managerial aspects of leading higher education institutions (HEIs) such as financial and strategic planning, marketing and human resource management (HRM).Leadership Foundation for Higher Educatio

Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis

Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington's disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development.</p

Hearts and Minds: Public archaeology and the Queensland school curriculum

The school education system is an important public sphere where popular notions of archaeology and the archaeological past are produced and reproduced. Within the framework of an interpretive public archaeology, schools represent a significant social context in which archaeologists might seek meaningful engagement with the wider community. Analysis of the Queensland Education Studies of Society and Environment (SOSE) syllabus reveals that there are many opportunities for the inclusion of Australian archaeology examples in the curricula of both primary and secondary schools. In this paper we develop a public outreach strategy for engaging the Queensland school curriculum and report on two case studies from southeast Queensland where this strategy was implemented

The Global Trachoma Mapping Project: Methodology of a 34-Country Population-Based Study.

PURPOSE: To complete the baseline trachoma map worldwide by conducting population-based surveys in an estimated 1238 suspected endemic districts of 34 countries. METHODS: A series of national and sub-national projects owned, managed and staffed by ministries of health, conduct house-to-house cluster random sample surveys in evaluation units, which generally correspond to "health district" size: populations of 100,000-250,000 people. In each evaluation unit, we invite all residents aged 1 year and older from h households in each of c clusters to be examined for clinical signs of trachoma, where h is the number of households that can be seen by 1 team in 1 day, and the product h × c is calculated to facilitate recruitment of 1019 children aged 1-9 years. In addition to individual-level demographic and clinical data, household-level water, sanitation and hygiene data are entered into the purpose-built LINKS application on Android smartphones, transmitted to the Cloud, and cleaned, analyzed and ministry-of-health-approved via a secure web-based portal. The main outcome measures are the evaluation unit-level prevalence of follicular trachoma in children aged 1-9 years, prevalence of trachomatous trichiasis in adults aged 15 + years, percentage of households using safe methods for disposal of human feces, and percentage of households with proximate access to water for personal hygiene purposes. RESULTS: In the first year of fieldwork, 347 field teams commenced work in 21 projects in 7 countries. CONCLUSION: With an approach that is innovative in design and scale, we aim to complete baseline mapping of trachoma throughout the world in 2015

Functional Characterization of the Arabidopsis β-Ketoacyl-Coenzyme A Reductase Candidates of the Fatty Acid Elongase

In plants, very-long-chain fatty acids (VLCFAs; \u3e18 carbon) are precursors of sphingolipids, triacylglycerols, cuticular waxes, and suberin. VLCFAs are synthesized by a multiprotein membrane-bound fatty acid elongation system that catalyzes four successive enzymatic reactions: condensation, reduction, dehydration, and a second reduction. A bioinformatics survey of the Arabidopsis (Arabidopsis thaliana) genome has revealed two sequences homologous to YBR159w encoding a Saccharomyces cerevisiae β-ketoacyl reductase (KCR), which catalyzes the first reduction during VLCFA elongation. Expression analyses showed that both AtKCR1 and AtKCR2 genes were transcribed in siliques, flowers, inflorescence stems, leaves, as well as developing embryos, but only AtKCR1 transcript was detected in roots. Fluorescent protein-tagged AtKCR1 and AtKCR2 were localized to the endoplasmic reticulum, the site of fatty acid elongation. Complementation of the yeast ybr159Δ mutant demonstrated that the two KCR proteins are divergent and that only AtKCR1 can restore heterologous elongase activity similar to the native yeast KCR gene. Analyses of insertional mutants in AtKCR1 and AtKCR2 revealed that loss of AtKCR1 function results in embryo lethality, which cannot be rescued by AtKCR2 expression using the AtKCR1 promoter. In contrast, a disruption of the AtKCR2 gene had no obvious phenotypic effect. Taken together, these results indicate that only AtKCR1 is a functional KCR isoform involved in microsomal fatty acid elongation. To investigate the roles of AtKCR1 in postembryonic development, transgenic lines expressing RNA interference and overexpression constructs targeted against AtKCR1 were generated. Morphological and biochemical characterization of these lines confirmed that suppressed KCR activity results in a reduction of cuticular wax load and affects VLCFA composition of sphingolipids, seed triacylglycerols, and root glycerolipids, demonstrating in planta that KCR is involved in elongation reactions supplying VLCFA for all these diverse classes of lipids

Cumulative Environmental Vulnerability and Environmental Justice in California’s San Joaquin Valley

The identification of “environmental justice (EJ) communities” is an increasingly common element in environmental planning, policy, and regulation. As a result, the choice of methods to define and identify these communities is a critical and often contentious process. This contentiousness is, in turn, a factor of the lack of a commonly accepted method, the concern among many EJ advocates and some regulators that existing frameworks are inadequate, and ultimately, the significant consequences of such designations for both public policy and community residents. With the aim of assisting regulators and advocates to more strategically focus their efforts, the authors developed a Cumulative Environmental Vulnerability Assessment (CEVA). This CEVA is composed of a Cumulative Environmental Hazard Index and a Social Vulnerability Index, with a Health Index as a reference. Applying CEVA produces spatial analysis that identifies the places that are subject to both the highest concentrations of cumulative environmental hazards and the fewest social, economic and political resources to prevent, mitigate, or adapt to these conditions. We recommended that these areas receive special consideration in permitting, monitoring, and enforcement actions, as well as investments in public participation, capacity building, and community economic development