Prologue to Power: Selecting Supreme Court Justices

Review of God Save This Honorable Court: How the Choice of Supreme Court Justices Shapes Our History, by Laurence A. Tribe (Random House, 1985)

A community approach to road safety education using practical training methods : the Drumchapel project

Research shows that practical training methods, in which children receive guided experience of solving traffic problems in realistic traffic situations, are amongst the most effective in improving children's pedestrian competence. However, practical training is both time consuming and labour intensive, making it difficult to capitalise on the strengths of the method. The report describes a solution to this problem by adopting a community participation approach in which local volunteers carried out all roadside training, working in co-operation with schools and project staff. The project took place in an area of Glasgow known for its exceptionally high child pedestrian accident rate

The influence of MRI scan position on patients with oropharyngeal cancer undergoing radical radiotherapy

<p>Background: The purpose of this study was to demonstrate how magnetic resonance imaging (MRI) patient position protocols influence registration quality in patients with oropharyngeal cancer undergoing radical radiotherapy and the consequences for gross tumour volume (GTV) definition and radiotherapy planning.</p> <p>Methods and materials: Twenty-two oropharyngeal patients underwent a computed tomography (CT), a diagnostic MRI (MRID) and an MRI in the radiotherapy position within an immobilization mask (MRIRT). Clinicians delineated the GTV on the CT viewing the MRID separately (GTVC); on the CT registered to MRID (GTVD) and on the CT registered to MRIRT (GTVRT). Planning target volumes (PTVs) were denoted similarly. Registration quality was assessed by measuring disparity between structures in the three set-ups. Volumetric modulated arc therapy (VMAT) radiotherapy planning was performed for PTVC, PTVD and PTVRT. To determine the dose received by the reference PTVRT, we optimized for PTVC and PTVD while calculating the dose to PTVRT. Statistical significance was determined using the two-tailed Mann–Whitney or two-tailed paired student t-tests.</p> <p>Results: A significant improvement in registration accuracy was found between CT and MRIRT versus the MRID measuring distances from the centre of structures (geometric mean error of 2.2 mm versus 6.6 mm). The mean GTVC (44.1 cm3) was significantly larger than GTVD (33.7 cm3, p value = 0.027) or GTVRT (30.5 cm3, p value = 0.014). When optimizing the VMAT plans for PTVC and investigating the mean dose to PTVRT neither the dose to 99% (58.8%) nor 95% of the PTV (84.7%) were found to meet the required clinical dose constraints of 90% and 95% respectively. Similarly, when optimizing for PTVD the mean dose to PTVRT did not meet clinical dose constraints for 99% (14.9%) nor 95% of the PTV (66.2%). Only by optimizing for PTVRT were all clinical dose constraints achieved.</p> <p>Conclusions: When oropharyngeal patients MRI scans are performed in the radiotherapy position there are significant improvements in CT-MR image registration, target definition and PTV dose coverage.</p&gt

Study of diffusion weighted MRI as a predictive biomarker of response during radiotherapy for high and intermediate risk squamous cell cancer of the oropharynx: The MeRInO study

Introduction and background: A significant proportion of patients with intermediate and high risk squamous cell cancer of the oropharynx (OPSCC) continue to relapse locally despite radical chemoradiotherapy (CRT). The toxicity of the current combination of intensified dose per fraction radiotherapy and platinum based chemotherapy limits further uniform intensification. If a predictive biomarker for outcomes from CRT can be identified during treatment then individualised and adaptive treatment strategies may be employed. Methods/design: The MeRInO study is a prospective observational imaging study of patients with intermediate and high risk, locally advanced OPSCC receiving radical RT or concurrent CRT Patients undergo diffusion weighted MRI prior to treatment (MRI_1) and during the third week of RT (MRI_2). Apparent diffusion coefficient (ADC) measurements will be made on each scan for previously specified target lesions (primary and lymph nodes) and change in ADC calculated. Patients will be followed up and disease status for each target lesion noted. The primary aim of the MeRInO study is to determine the threshold change in ADC from baseline to week 3 of RT that may identify the sub-group of non-responders during treatment. Discussion: The use of DW-MRI as a predictive biomarker during RT for SCC H&N is in its infancy but studies to date have found that response to treatment may indeed be predicted by comparison of DW-MRI carried out before and during treatment. However, previous studies have included all sub-sites and biological sub-types. Establishing ADC thresholds that predict for local failure is an essential step towards using DW-MRI to improve the therapeutic ratio in treating SCC H&N. This would be done most robustly in a specific H&N sub-site and in sub-types with similar biological behaviour. The MeRInO study will help establish these thresholds in OPSCC

DNA methylation affects nuclear organization, histone modifications, and linker histone binding but not chromatin compaction

DNA methylation has been implicated in chromatin condensation and nuclear organization, especially at sites of constitutive heterochromatin. How this is mediated has not been clear. In this study, using mutant mouse embryonic stem cells completely lacking in DNA methylation, we show that DNA methylation affects nuclear organization and nucleosome structure but not chromatin compaction. In the absence of DNA methylation, there is increased nuclear clustering of pericentric heterochromatin and extensive changes in primary chromatin structure. Global levels of histone H3 methylation and acetylation are altered, and there is a decrease in the mobility of linker histones. However, the compaction of both bulk chromatin and heterochromatin, as assayed by nuclease digestion and sucrose gradient sedimentation, is unaltered by the loss of DNA methylation. This study shows how the complete loss of a major epigenetic mark can have an impact on unexpected levels of chromatin structure and nuclear organization and provides evidence for a novel link between DNA methylation and linker histones in the regulation of chromatin structure

A global climatological model of extreme geomagnetic field fluctuations

This paper presents a multi-parameter global statistical model of extreme horizontal geomagnetic field fluctuations (dBH/dt), which are a useful input to models assessing the risk of geomagnetically induced currents in ground infrastructure. Generalised Pareto (GP) distributions were fitted to 1-min measurements of |dBH/dt| from 125 magnetometers (with an average of 28 years of data per site) and return levels (RL) predicted for return periods (RP) between 5 and 500 years. Analytical functions characterise the profiles of maximum-likelihood GP model parameters and the derived RLs as a function of corrected geomagnetic latitude, λ. A sharp peak in both the GP shape parameter and the RLs is observed at |λ| = 53° in both hemispheres, indicating a sharp equatorward limit of the auroral electrojet region. RLs also increase strongly in the dayside region poleward of the polar cusp (|λ| > 75°) for RPs > 100 years. We describe how the GP model may be further refined by modelling the probability of occurrences of |dBH/dt| exceeding the 99.97th percentile as a function of month, magnetic local time, and the direction of the field fluctuation, dBH, and demonstrate that these patterns of occurrence align closely to known patterns of auroral substorm onsets, ULF Pc5 wave activity, and (storm) sudden commencement impacts. Changes in the occurrence probability profiles with the interplanetary magnetic field (IMF) orientation reveal further details of the nature of the ionospheric currents driving extreme |dBH/dt| fluctuations, such as the changing location of the polar cusp and seasonal variations explained by the Russell-McPherron effect

TF-Cluster: A pipeline for identifying functionally coordinated transcription factors via network decomposition of the shared coexpression connectivity matrix (SCCM)

<p>Abstract</p> <p>Background</p> <p>Identifying the key transcription factors (TFs) controlling a biological process is the first step toward a better understanding of underpinning regulatory mechanisms. However, due to the involvement of a large number of genes and complex interactions in gene regulatory networks, identifying TFs involved in a biological process remains particularly difficult. The challenges include: (1) Most eukaryotic genomes encode thousands of TFs, which are organized in gene families of various sizes and in many cases with poor sequence conservation, making it difficult to recognize TFs for a biological process; (2) Transcription usually involves several hundred genes that generate a combination of intrinsic noise from upstream signaling networks and lead to fluctuations in transcription; (3) A TF can function in different cell types or developmental stages. Currently, the methods available for identifying TFs involved in biological processes are still very scarce, and the development of novel, more powerful methods is desperately needed.</p> <p>Results</p> <p>We developed a computational pipeline called TF-Cluster for identifying functionally coordinated TFs in two steps: (1) Construction of a shared coexpression connectivity matrix (SCCM), in which each entry represents the number of shared coexpressed genes between two TFs. This sparse and symmetric matrix embodies a new concept of coexpression networks in which genes are associated in the context of other shared coexpressed genes; (2) Decomposition of the SCCM using a novel heuristic algorithm termed "Triple-Link", which searches the highest connectivity in the SCCM, and then uses two connected TF as a primer for growing a TF cluster with a number of linking criteria. We applied TF-Cluster to microarray data from human stem cells and <it>Arabidopsis </it>roots, and then demonstrated that many of the resulting TF clusters contain functionally coordinated TFs that, based on existing literature, accurately represent a biological process of interest.</p> <p>Conclusions</p> <p>TF-Cluster can be used to identify a set of TFs controlling a biological process of interest from gene expression data. Its high accuracy in recognizing true positive TFs involved in a biological process makes it extremely valuable in building core GRNs controlling a biological process. The pipeline implemented in Perl can be installed in various platforms.</p

Tectonic and climatic drivers of Asian monsoon evolution.

Asian Monsoon rainfall supports the livelihood of billions of people, yet the relative importance of different drivers remains an issue of great debate. Here, we present 30 million-year model-based reconstructions of Indian summer monsoon and South East Asian monsoon rainfall at millennial resolution. We show that precession is the dominant direct driver of orbital variability, although variability on obliquity timescales is driven through the ice sheets. Orographic development dominated the evolution of the South East Asian monsoon, but Indian summer monsoon evolution involved a complex mix of contributions from orography (39%), precession (25%), atmospheric CO2 (21%), ice-sheet state (5%) and ocean gateways (5%). Prior to 15 Ma, the Indian summer monsoon was broadly stable, albeit with substantial orbital variability. From 15 Ma to 5 Ma, strengthening was driven by a combination of orography and glaciation, while closure of the Panama gateway provided the prerequisite for the modern Indian summer monsoon state through a strengthened Atlantic meridional overturning circulation