Investigating regulatory relationships in plant nitrogen and phosphorus nutrition

Modern crop varieties rely heavily on artificial fertiliser application, which is both unsustainable and detrimental to the environment. Understanding regulatory relationships underlying plant nutrition is therefore important to improve the nutrient use efficiency of modern crop varieties. This thesis identifies new regulators of Arabidopsis phosphorus and nitrogen nutrition using a combination of genetic and physiological approaches, achieved by investigating how nutrient metabolism is perturbed in Arabidopsis lines containing mutations in genes encoding proteins of interest. This study identifies the Arabidopsis constitutive triple response 1 (ctr1) mutant, which displays constitutive ethylene signalling, as having compromised nitrogen metabolism. ctr1 is shown to have increased resistance to chlorate, a chemical analogue of nitrate, and utilises enzymatic assays to determine this is likely due to reduced nitrate reductase activity. A genetic screen identifies several mutagenized ctr1 lines which uncouple the dwarfed and chlorate resistant phenotypes of the ctr1 mutant, providing material that may uncover new regulators of ethylene-mediated nitrogen assimilation. This thesis also explores the interaction between the regulation of nitrate and phosphate metabolism, identifying that reduced phosphate availability alters Arabidopsis nitrogen metabolism, and that this is likely due to known genetic regulators of phosphate metabolism rather than shoot phosphate levels themselves. In particular, this study implicates known components of phosphate signalling, specifically PHOSPHATE STARVATION RESPONSE 1 (PHR1) and PHOSPHATE 2 (PHO2), as having additional roles in regulating nitrate assimilation. Finally, this thesis provides further evidence that the transcription factor HY5 modulates some, but not all, aspects of Arabidopsis phosphate metabolism. The hy5 mutant is found to be partially deficient in phosphate uptake, as well as in a subset of phosphate-starvation responses. By utilising differing light regimes HY5 is identified as regulating Arabidopsis phosphate assimilation in response to shoot illumination. Together, these findings further our understanding of regulatory relationships governing Arabidopsis nitrate and phosphate metabolism. Ultimately this research hopes to offer potential new targets to alter plant nutrient use efficiency in modern crops, reducing dependence on fertiliser application and furthering efforts to improve food security

Just Emotions? The need for emotionally-intelligent justice policy

What are the Obstacles to a Rational Criminal Justice Policy? It is often wondered why we do not have a more rational, evidence-based system of criminal justice. All the evidence points towards a more targeted use of imprisonment, a joined up system of criminal and social justice and improved resourcing for community penalties and community services. Yet a key reason which prevents justice policy from proceeding rationally is the fear of looking ‘soft’ in the eyes of the public. People feel let down and angry about a system which seems uninterested in showing justice to be done, publicly recognising the wrong, encouraging the wrong-doer to to face up to the wrong, and make amends. Is there any way out of this policy quandary? Here we propose that a key public frustration, which drives cynicism and penal populism, lies in the failure of criminal justice to engage, and be seen to engage, in emotionally-intelligent communication. Too often the process appears sterile, lacking emotional meaning and participation. Mention of ‘emotion’ in law sometimes rings alarm bells. Our argument, however, is that emotionally-intelligent communication is not opposed to, but essential to, rational and progressive policy

Narratives of crime and punishment : a study of Scottish judicial culture

This thesis explores recent Scottish penal culture through the biographical narrative accounts of retired judges. Insights from the sociology of punishment are used to develop a more fully cultural approach to the judiciary and to sentencing practice. This entails a view of the judiciary as a complex institution whose practices reflect tension and compromise, and which recognises judges as bearers of penal culture through their sentencing practices. The aims of the research are twofold: to provide insight into the changing conditions of judging in Scotland and into the judicial role in criminal justice. Narrative research methods were used to interview retired judges and gain contextual accounts of judicial life and practice. This approach focuses on subjectivity and on individual responses to experiences and constraints. Reflecting the judicial role in punishment, an interpretive position based on the hermeneutics of faith and suspicion is used to evaluate and interpret these narrative accounts. This conceptual and methodological framework is used to explore aspects of judicial occupational culture including training and early experiences, the status of criminal work, judicial conduct, collegiality, the influence of criminological research on sentencing practice, and the relevance of the ‘master narrative’ - judicial independence - to sentencing. It is also used to explore the frameworks of meaning and vocabularies of motive which judges bring to penal practice. What emerges from these judicial narratives is firstly the entanglement of individual life histories and organisational imperatives. Secondly, a picture emerges of a judicial habitus that includes complex motivations, some openness to new approaches, and capacity for reflecting on the conditions which structure and constrain criminal justice practice. This suggests the reflexive judge may be an important vector of penal change and there are implications for judicial training, penal reform and for the dissemination of criminological and criminal justice research

ECR collective response:the future of criminology and the unsustainability of the status quo for ECRs

We were delighted to be asked to respond to Richard Spark’s paper. We are encouraged by the themes and issues highlighted, and feel passionately about many of the areas of future research identified in the piece. Indeed, many of the areas of scholarship (such as research with the Global South, practices and experiences of crime and punishment, violence in all its forms, crime and technology, socio-legal research, and political discourses around crime) are areas with which we – as a collective group of early career researchers (ECRs) – are currently engaged, often in collaboration with other ECRs within and outwith the United Kingdom. We commend both Prof. Sparks and the Economic and Social Research Council (ESRC) for this important and timely reflection on the direction and possible futures of criminology

An ancient river landscape preserved beneath the East Antarctic Ice Sheet

The East Antarctic Ice Sheet (EAIS) has its origins ca. 34 million years ago. Since then, the impact of climate change and past fluctuations in the EAIS margin has been reflected in periods of extensive vs. restricted ice cover and the modification of much of the Antarctic landscape. Resolving processes of landscape evolution is therefore critical for establishing ice sheet history, but it is rare to find unmodified landscapes that record past ice conditions. Here, we discover an extensive relic pre-glacial landscape preserved beneath the central EAIS despite millions of years of ice cover. The landscape was formed by rivers prior to ice sheet build-up but later modified by local glaciation before being dissected by outlet glaciers at the margin of a restricted ice sheet. Preservation of the relic surfaces indicates an absence of significant warm-based ice throughout their history, suggesting any transitions between restricted and expanded ice were rapid

Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.

BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m(2) on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m(2) on days 1 and 8 and intravenous docetaxel 75 mg/m(2) on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7-29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5-54·6] vs 46·4% [37·5-54·8]); median progression-free survival (23·3 weeks [95% CI 19·6-30·4] vs 23·7 weeks [18·1-20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99-1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

BACKGROUND: Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)-guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. OBJECTIVES: The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]-), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G-LVH+) and structural phenotype. METHODS: This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH-, 104 LVH+ (51 G+/53 G-), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH- from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. RESULTS: Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G-LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). CONCLUSIONS: In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status

Consensus Statement on Public Involvement and Engagement with Data-Intensive Health Research.

This consensus statement reflects the deliberations of an international group of stakeholders with a range of expertise in public involvement and engagement (PI&E) relating to data-intensive health research. It sets out eight key principles to establish a secure role for PI&E in and with the research community internationally and ensure best practice in its execution. Our aim is to promote culture change and societal benefits through ensuring a socially responsible trajectory for innovations in this field.Peer reviewe

Publisher Correction: Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Electrophysiological characterization of subclinical and overt hypertrophic cardiomyopathy by magnetic resonance imaging-guided electrocardiography

Background: Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. Objectives: The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. Methods: This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. Results: Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P &lt; 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P &lt; 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). Conclusions: In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status