Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development

Molecular oxygen is essential for the development, growth and survival of multicellular organisms. Hypoxic microenvironments and oxygen gradients are generated physiologically during embryogenesis and organogenesis. In the eye, oxygen plays a crucial role in both physiological vascular development and common blinding diseases. The retinal pigment epithelium (RPE) is a monolayer of cells essential for normal ocular development and in the mature retina provides support for overlying photoreceptors and their vascular supply. Hypoxia at the level of the RPE is closely implicated in pathogenesis of age-related macular degeneration. Adaptive tissue responses to hypoxia are orchestrated by sophisticated oxygen sensing mechanisms. In particular, the von Hippel-Lindau tumour suppressor protein (pVhl) controls hypoxia-inducible transcription factor (HIF)-mediated adaptation. However, the role of Vhl/Hif1a in the RPE in the development of the eye and its vasculature is unknown. In this study we explored the function of Vhl and Hif1a in the developing RPE using a tissue-specific conditional-knockout approach. We found that deletion of Vhl in the RPE results in RPE apoptosis, aniridia and microphthalmia. Increased levels of Hif1a, Hif2a, Epo and Vegf are associated with a highly disorganised retinal vasculature, chorioretinal anastomoses and the persistence of embryonic vascular structures into adulthood. Additional inactivation of Hif1a in the RPE rescues the RPE morphology, aniridia, microphthalmia and anterior vasoproliferation, but does not rescue retinal vasoproliferation. These data demonstrate that Vhl-dependent regulation of Hif1a in the RPE is essential for normal RPE and iris development, ocular growth and vascular development in the anterior chamber, whereas Vhl-dependent regulation of other downstream pathways is crucial for normal development and maintenance of the retinal vasculature

HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia.

BACKGROUND: Hypoxia plays a key role in ischaemic and neovascular disorders of the retina. Cellular responses to oxygen are mediated by hypoxia-inducible transcription factors (HIFs) that are stabilised in hypoxia and induce the expression of a diverse range of genes. The purpose of this study was to define the cellular specificities of HIF-1alpha and HIF-2alpha in retinal ischaemia, and to determine their correlation with the pattern of retinal hypoxia and the expression profiles of induced molecular mediators. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the tissue distribution of retinal hypoxia during oxygen-induced retinopathy (OIR) in mice using the bio-reductive drug pimonidazole. We measured the levels of HIF-1alpha and HIF-2alpha proteins by Western blotting and determined their cellular distribution by immunohistochemistry during the development of OIR. We measured the temporal expression profiles of two downstream mediators, vascular endothelial growth factor (VEGF) and erythropoietin (Epo) by ELISA. Pimonidazole labelling was evident specifically in the inner retina. Labelling peaked at 2 hours after the onset of hypoxia and gradually declined thereafter. Marked binding to Müller glia was evident during the early hypoxic stages of OIR. Both HIF-1alpha and HIF-2alpha protein levels were significantly increased during retinal hypoxia but were evident in distinct cellular distributions; HIF-1alpha stabilisation was evident in neuronal cells throughout the inner retinal layers whereas HIF-2alpha was restricted to Müller glia and astrocytes. Hypoxia and HIF-alpha stabilisation in the retina were closely followed by upregulated expression of the downstream mediators VEGF and EPO. CONCLUSIONS/SIGNIFICANCE: Both HIF-1alpha and HIF-2alpha are activated in close correlation with retinal hypoxia but have contrasting cell specificities, consistent with differential roles in retinal ischaemia. Our findings suggest that HIF-2alpha activation plays a key role in regulating the response of Müller glia to hypoxia

The JCMT Gould Belt Survey: A First Look at the Auriga–California Molecular Cloud with SCUBA-2

We present 850 and 450 μm observations of the dense regions within the Auriga–California molecular cloud using SCUBA-2 as part of the JCMT Gould Belt Legacy Survey to identify candidate protostellar objects, measure the masses of their circumstellar material (disk and envelope), and compare the star formation to that in the Orion A molecular cloud. We identify 59 candidate protostars based on the presence of compact submillimeter emission, complementing these observations with existing Herschel/SPIRE maps. Of our candidate protostars, 24 are associated with young stellar objects (YSOs) in the Spitzer and Herschel/PACS catalogs of 166 and 60 YSOs, respectively (177 unique), confirming their protostellar nature. The remaining 35 candidate protostars are in regions, particularly around LkHα 101, where the background cloud emission is too bright to verify or rule out the presence of the compact 70 μm emission that is expected for a protostellar source. We keep these candidate protostars in our sample but note that they may indeed be prestellar in nature. Our observations are sensitive to the high end of the mass distribution in Auriga–Cal. We find that the disparity between the richness of infrared star-forming objects in Orion A and the sparsity in Auriga–Cal extends to the submillimeter, suggesting that the relative star formation rates have not varied over the Class II lifetime and that Auriga–Cal will maintain a lower star formation efficiency

Strong Continuum-continuum Couplings In The Direct Ionization Of Ar And He Atoms By 6-MeV/u U38+ And Th38+ Projectiles

Doubly differential cross sections have been measured as a function of the electron energy and observation angle for electron emission following collisions of 6-MeV/u U38+ and Th38+ on He and Ar. The electron-emission data show an enhancement at forward angles and a decrease at backward angles with respect to scaled-cross-section results based on the Born approximation. Comparison with classical-trajectory Monte Carlo calculations suggests that the deviation from the Born approximation can be explained by continuum-continuum couplings. By comparing with previously published data, we found that the forward enhancement as well as the backward decrease follow a q/vp (q,vp are the projectile charge and velocity) scaling. © 1989 The American Physical Society

An evaluation of metal removal during wastewater treatment: The potential to achieve more stringent final effluent standards

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2011 Taylor & Francis.Metals are of particular importance in relation to water quality, and concern regarding the impact of these contaminants on biodiversity is being encapsulated within the latest water-related legislation such as the Water Framework Directive in Europe and criteria revisions to the Clean Water Act in the United States. This review undertakes an evaluation of the potential of 2-stage wastewater treatment consisting of primary sedimentation and biological treatment in the form of activated sludge processes, to meet more stringent discharge consents that are likely to be introduced as a consequence. The legislation, sources of metals, and mechanisms responsible for their removal are discussed, to elucidate possible pathways by which the performance of conventional processes may be optimized or enhanced. Improvements in effluent quality, achievable by reducing concentrations of suspended solids or biochemical oxygen demand, may also reduce metal concentrations although meeting possible requirements for the removal of copper my be challenging

A Gradualist Approach to Criminality: Early British Socialists, Utopia and Crime

The attitudes of early British socialists to criminality are a thoroughly under-researched area of historical scholarship. This paper draws on the utopian ideas of Robert Owen, William Morris, H. G. Wells, Robert Blatchford, Edward Carpenter and Ramsay MacDonald as a vehicle for investigating the attitudes of mainstream fin de siècle British socialists to crime, punishment and penal reform. Placing these figures and their utopias along a spectrum that sees radical ‘Arcadian’ socialists on the far left, ‘technological’ socialists on the far right, and moderate socialists occupying the middle ground, it presents two principal findings. First it demonstrates how crime was predicted by most of the left to decrease to a minimum level under socialism. ‘Arcadians’, ‘technological’ and moderate socialists invoked different methods in this pursuit, but each were in essence grappling with the same broader issue of the relationship of the individual to the state under socialism. Secondly, examining the multifaceted ideological heritage of the British left in relation to their approaches to crime, it is argued that, despite the left’s gradualist philosophy, their own attitudes to criminality actually closely reflected utopian conceptions. Examination of these issues offers an important opportunity to re-evaluate the evolution of British socialist thought

Legacy of COVID‐19 – the opportunity to enhance surgical services for patients with colorectal disease

Description to be added.Cannot be left empt

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC):a multicentre, double-blind, randomised controlled trial

SummaryBackgroundUp to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.MethodsWe did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).FindingsBetween June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28–0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04–0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42–1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group.InterpretationMercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.FundingMedical Research Council