Climatic impacts of stratospheric geoengineering with sulfate, black carbon and titania injection

In this paper, we examine the potential climatic effects of geoengineering by sulfate, black carbon and titania injection against a baseline RCP8.5 scenario. We use the HadGEM2-CCS model to simulate scenarios in which the top-of-the-atmosphere radiative imbalance due to rising greenhouse gas concentrations is offset by sufficient aerosol injection throughout the 2020–2100 period. We find that the global-mean temperature is effectively maintained at historical levels for the entirety of the period for all 3 aerosol-injection scenarios, though there are a wide range of side-effects which are discussed in detail. The most prominent conclusion is that although the BC injection rate necessary to produce an equivalent global mean temperature-response is much lower, the severity of stratospheric temperature changes (> +70 °C) and precipitation impacts effectively exclude BC from being a viable option for geoengineering. Additionally, while it has been suggested that titania would be an effective particle because of its high scattering efficiency, it also efficiently absorbs solar ultraviolet radiation producing a significant stratospheric warming (> +20 °C). As injection rates for titania are close to those for sulfate, there appears little benefit of using titania when compared to injection of sulfur dioxide, which has the added benefit of being well modelled through extensive research that has been carried out on naturally occurring explosive volcanic eruptions.The authors would like to thank Valentina Aquila for supplying AVHRR and SAGE data, and to Peter Cox, Angus Ferraro, David Keith and Alan Robock for helpful discussions. A. C. Jones was supported by a Met Office/NERC CASE (ref. 580 009 183) PhD studentship; J. M. Haywood and A. Jones were supported by the Joint UK DECC/Defra Met Office Hadley Centre Climate Programme (GA01101)

Ferritin and Iron Studies in Anaemia and Chronic Disease

Anaemia is a condition in which the number of red cells necessary to meet the body's physiological requirements is insufficient. Iron deficiency anaemia (IDA) and the anaemia of chronic disease (ACD) are the two most common causes of anaemia worldwide; iron homeostasis plays a pivotal role in the pathogenesis of both diseases. An understanding of how iron studies can be used to distinguish between these diseases is therefore essential, not only for diagnosis but also in guiding management. This review will primarily focus on IDA and ACD; however iron overload in anaemia will also be briefly discussed

Googling DNA sequences on the World Wide Web

Background: New web-based technologies provide an excellent opportunity for sharing and accessing information and using web as a platform for interaction and collaboration. Although several specialized tools are available for analyzing DNA sequence information, conventional webbased tools have not been utilized for bioinformatics applications. We have developed a novel algorithm and implemented it for searching species-specific genomic sequences, DNA barcodes, by using popular web-based methods such as Google. Results: We developed an alignment independent character based algorithm based on dividing a sequence library (DNA barcodes) and query sequence to words. The actual search is conducted by conventional search tools such as freely available Google Desktop Search. We implemented our algorithm in two exemplar packages. We developed pre and post-processing software to provide customized input and output services, respectively. Our analysis of all publicly available DNA barcode sequences shows a high accuracy as well as rapid results. Conclusion: Our method makes use of conventional web-based technologies for specialized genetic data. It provides a robust and efficient solution for sequence search on the web. The integration of our search method for large-scale sequence libraries such as DNA barcodes provides an excellent web-based tool for accessing this information and linking it to other available categories of information on the web

Identification of a variant in NDP associated with X-linked retinal dysplasia in the English cocker spaniel dog.

PURPOSE: Three related male English Cocker Spaniels (ECS) were reported to be congenitally blind. Examination of one of these revealed complete retinal detachment. A presumptive diagnosis of retinal dysplasia (RD) was provided and pedigree analysis was suggestive of an X-linked mode of inheritance. We sought to investigate the genetic basis of RD in this family of ECS. METHODS: Following whole genome sequencing (WGS) of the one remaining male RD-affected ECS, two distinct investigative approaches were employed: a candidate gene approach and a whole genome approach. In the candidate gene approach, COL9A2, COL9A3, NHEJ1, RS1 and NDP genes were investigated based on their known associations with RD and retinal detachment in dogs and humans. In the whole genome approach, affected WGS was compared with 814 unaffected canids to identify candidate variants, which were filtered based on appropriate segregation and predicted pathogenic effects followed by subsequent investigation of gene function. Candidate variants were tested for appropriate segregation in the ECS family and association with disease was assessed using samples from a total of 180 ECS. RESULTS: The same variant in NDP (c.653_654insC, p.Met114Hisfs*16) that was predicted to result in 15 aberrant amino acids before a premature stop in norrin protein, was identified independently by both approaches and was shown to segregate appropriately within the ECS family. Association of this variant with X-linked RD was significant (P = 0.0056). CONCLUSIONS: For the first time, we report a variant associated with canine X-linked RD. NDP variants are already known to cause X-linked RD, along with other abnormalities, in human Norrie disease. Thus, the dog may serve as a useful large animal model for research

The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach

The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271–294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.</jats:p

Microalbuminuria could improve risk stratification in patients with TIA and minor stroke.

Published onlineJournal ArticleThis is the final version of the article. Available from Wiley Open Access via the DOI in this record.OBJECTIVE: Transient ischemic attacks (TIA) and minor strokes are important risk factors for recurrent strokes. Current stroke risk prediction scores such as ABCD2, although widely used, lack optimal sensitivity and specificity. Elevated urinary albumin excretion predicts cardiovascular disease, stroke, and mortality. We explored the role of microalbuminuria (using albumin creatinine ratio (ACR)) in predicting recurrence risk in patients with TIA and minor stroke. METHODS: Urinary ACR was measured on a spot sample in 150 patients attending a daily stroke clinic with TIA or minor stroke. Patients were followed up at day 7, 30, and 90 to determine recurrent stroke, cardiovascular events, or death. Eligible patients had a carotid ultrasound Doppler investigation. High-risk patients were defined as those who had an event within 90 days or had >50% internal carotid artery (ICA) stenosis. RESULTS: Fourteen (9.8%) recurrent events were reported by day 90 including two deaths. Fifteen patients had severe ICA stenosis. In total, 26 patients were identified as high risk. These patients had a higher frequency of previous stroke or hypercholesterolemia compared to low-risk patients (P = 0.04). ACR was higher in high-risk patients (3.4 [95% CI 2.2-5.2] vs. 1.7 [1.5-2.1] mg/mmol, P = 0.004), independent of age, sex, blood pressure, diabetes, and previous stroke. An ACR greater than 1.5 mg/mmol predicted high-risk patients (Cox proportional hazard ratio 3.5 (95% CI 1.3-9.5, P = 0.01). INTERPRETATION: After TIA or minor stroke, a higher ACR predicted recurrent events and significant ICA stenosis. Incorporation of urinary ACR from a spot sample in the acute setting could improve risk stratification in patients with TIA and minor stroke.This article presents independent research supported by the NIHR Exeter Clinical Research Facility and the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR Exeter Clinical Research Facility, the NHS, the NIHR or the Department of Health in England. We also acknowledge and thank the South West Stroke Research Network for their help with patient recruitment and follow-up, and Mrs. Audrey Peters and Mr. Frank Summers for performing the carotid Doppler scans

Joint modelling rationale for chained equations.

BACKGROUND: Chained equations imputation is widely used in medical research. It uses a set of conditional models, so is more flexible than joint modelling imputation for the imputation of different types of variables (e.g. binary, ordinal or unordered categorical). However, chained equations imputation does not correspond to drawing from a joint distribution when the conditional models are incompatible. Concurrently with our work, other authors have shown the equivalence of the two imputation methods in finite samples. METHODS: Taking a different approach, we prove, in finite samples, sufficient conditions for chained equations and joint modelling to yield imputations from the same predictive distribution. Further, we apply this proof in four specific cases and conduct a simulation study which explores the consequences when the conditional models are compatible but the conditions otherwise are not satisfied. RESULTS: We provide an additional "non-informative margins" condition which, together with compatibility, is sufficient. We show that the non-informative margins condition is not satisfied, despite compatible conditional models, in a situation as simple as two continuous variables and one binary variable. Our simulation study demonstrates that as a consequence of this violation order effects can occur; that is, systematic differences depending upon the ordering of the variables in the chained equations algorithm. However, the order effects appear to be small, especially when associations between variables are weak. CONCLUSIONS: Since chained equations is typically used in medical research for datasets with different types of variables, researchers must be aware that order effects are likely to be ubiquitous, but our results suggest they may be small enough to be negligible

Oxygen-dependent histone lysine demethylase 4 restricts hepatitis B virus replication

Mammalian cells have evolved strategies to regulate gene expression when oxygen is limited. Hypoxia-inducible factors (HIF) are the major transcriptional regulators of host gene expression. We previously reported that HIFs bind and activate hepatitis B virus (HBV) DNA transcription under low oxygen conditions; however, the global cellular response to low oxygen is mediated by a family of oxygenases that work in concert with HIFs. Recent studies have identified a role for chromatin modifiers in sensing cellular oxygen and orchestrating transcriptional responses, but their role in the HBV life cycle is as yet undefined. We demonstrated that histone lysine demethylase 4 (KDM4) can restrict HBV, and pharmacological or oxygen-mediated inhibition of the demethylase increases viral RNAs derived from both episomal and integrated copies of the viral genome. Sequencing studies demonstrated that KDM4 is a major regulator of the hepatic transcriptome, which defines hepatocellular permissivity to HBV infection. We propose a model where HBV exploits cellular oxygen sensors to replicate and persist in the liver. Understanding oxygen-dependent pathways that regulate HBV infection will facilitate the development of physiologically relevant cell-based models that support efficient HBV replication