Investigation of eight candidate genes on chromosome 1p36 for autosomal dominant total congenital cataract

Purpose: To identify the causative gene for autosomal dominant total congenital cataract in a six-generation Australian family displaying linkage to chromosome 1p36. Methods: Eight candidate genes (HSPB7, FBXO42, EFHD2, ZBTB17, CAPZB, FBLIM1, ALDH4A1, and MFAP2) from within the previously defined linkage interval were selected based on expression in lens and their known or putative function. The coding exons were sequenced in multiple affected family members and compared to the reference sequence. Results: No segregating mutations were identified in any of the eight genes. Thirty-one polymorphisms were detected, 20 of which were in the exons and 11 in the flanking introns. Conclusions: Coding mutations in HSPB7, FBXO42, EFHD2, ZBTB17, CAPZB, FBLIM1, ALDH4A1, and MFAP2 do not account for congenital cataract in this family

Resourcing Scholar-Activism: Collaboration, Transformation, and the Production of Knowledge

In this article we offer a set of resources for scholar-activists to reflect on and guide their practice. We begin by suggesting that research questions should be triangulated to consider not only their scholarly merit but the intellectual and political projects the findings will advance and the research questions of interest to community and social movement collaborators

Thresholds and prediction models to support the sustainable management of herbivorous insects in wheat. A review

AbstractWheat is one of the most important arable crops grown worldwide, providing a significant proportion of the daily calorific intake for countries across the globe. Wheat crops are attacked by a diverse range of herbivorous invertebrates, pests, that cause significant yield loss. It is anticipated that yield loss caused by pests will increase in response to a changing climate. Currently, these pests are primarily controlled using pesticides; however, there is an increased need for more sustainable pest management solutions. Economic thresholds represent one avenue that can support the sustainable management of pests. Briefly, thresholds are the number of pests above which there is sufficient risk of yield loss. Here, we review the economic thresholds and prediction methods available for sustainable pest management in wheat. We focus on five economically damaging pests affecting wheat crops in the UK and Europe. For each, we highlight the key period of crop risk to pest attack, identify economic thresholds, and provide an overview of current decision support models that can help estimate crop risk and advise sustainable pest management; we end by proposing areas for future improvement for each pest. Furthermore, we take a novel approach by discussing economic thresholds and their applications to sustainable pest management within the context of crop physiology and the capacity for crops to tolerate pest damage, a consideration that is often overlooked when developing pest management strategies. We use the stem-boring pest, the gout fly, as a case study and use the economic injury level equation to conduct a theoretical assessment of the appropriateness of the current gout fly threshold. This theoretical assessment indicates that wheat crops can tolerate greater gout fly damage than currently considered, and shows that by incorporating crop physiology into sustainable pest tolerance schemes we can work towards developing more appropriate physiological-based pest thresholds.</jats:p

Manual / Issue 5 / Unfinished

Manual, a journal about art and its making. Unfinished.The fifth issue. Loose threads unknotted. Ideas unrealized. Outlines left bare. Function unperformed. Patterns uncut. Luster removed with time and wear. We rarely examine unfinished things. The unfinished is easily overlooked in favor of the fully rendered and complete, but consider those sketchy lines, those fraying ends: the unfinished has potency. The unfinished offers evidence of process, reveals traces of technique, trembles with latent possibility. The essays, images, and projects presented in the fifth issue of Manual attend to the fluid potential of objects that are in some way incomplete. Softcover, 68 pages. Published 2015 by the RISD Museum. Manual 5 (Unfinished) contributors include Jen Bervin, Jean Blackburn, Gina Borromeo, Laurie Brewer, A. Will Brown, Bolaji Campbell, Dennis Congdon, Jeremy Deller, Jan Howard, Kate Irvin, Maureen C. O’Brien, Emily J. Peters, Siebren Versteeg, Elizabeth A. Williams, and C. D. Wright.https://digitalcommons.risd.edu/risdmuseum_journals/1004/thumbnail.jp

A novel syndrome of paediatric cataract, dysmorphism, ectodermal features, and developmental delay in Australian Aboriginal family maps to 1p35.3-p36.32

Background: A novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family.Methods: Genome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes (ZBTB17, EPHA2 and EPHB2) were sequenced to screen for segregating mutations. Results: Under a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17. The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy. Conclusions: The gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region (EPHA2) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.Kathryn Hattersley, Kate J Laurie, Jan E Liebelt, Jozef Gecz, Shane R Durkin, Jamie E Craig and Kathryn P Burdo

The Transmembrane Domain of CEACAM1-4S Is a Determinant of Anchorage Independent Growth and Tumorigenicity

CEACAM1 is a multifunctional Ig-like cell adhesion molecule expressed by epithelial cells in many organs. CEACAM1-4L and CEACAM1-4S, two isoforms produced by differential splicing, are predominant in rat liver. Previous work has shown that downregulation of both isoforms occurs in rat hepatocellular carcinomas. Here, we have isolated an anchorage dependent clone, designated 253T-NT that does not express detectable levels of CEACAM1. Stable transfection of 253-NT cells with a wild type CEACAM1-4S expression vector induced an anchorage independent growth in vitro and a tumorigenic phenotype in vivo. These phenotypes were used as quantifiable end points to examine the functionality of the CEACAM1-4S transmembrane domain. Examination of the CEACAM1 transmembrane domain showed N-terminal GXXXG dimerization sequences and C-terminal tyrosine residues shown in related studies to stabilize transmembrane domain helix-helix interactions. To examine the effects of transmembrane domain mutations, 253-NT cells were transfected with transmembrane domain mutants carrying glycine to leucine or tyrosine to valine substitutions. Results showed that mutation of transmembrane tyrosine residues greatly enhanced growth in vitro and in vivo. Mutation of transmembrane dimerization motifs, in contrast, significantly reduced anchorage independent growth and tumorigenicity. 253-NT cells expressing CEACAM1-4S with both glycine to leucine and tyrosine to valine mutations displayed the growth-enhanced phenotype of tyrosine mutants. The dramatic effect of transmembrane domain mutations constitutes strong evidence that the transmembrane domain is an important determinant of CEACAM1-4S functionality and most likely by other proteins with transmembrane domains containing dimerization sequences and/or C-terminal tyrosine residues

AVURT: aspirin versus placebo for the treatment of venous leg ulcers a Phase II pilot randomised controlled trial

Background Venous leg ulcers (VLUs) are the most common cause of leg ulceration, affecting 1 in 100 adults. VLUs may take many months to heal (25% fail to heal). Estimated prevalence is between 1% and 3% of the elderly population. Compression is the mainstay of treatment and few additional therapies exist to improve healing. Two previous trials have indicated that low-dose aspirin, as an adjunct to standard care, may improve healing time, but these trials were insufficiently robust. Aspirin is an inexpensive, widely used medication but its safety and efficacy in the treatment of VLUs remains to be established. Objectives Primary objective – to assess the effects of 300 mg of aspirin (daily) versus placebo on the time to healing of the reference VLU. Secondary objectives – to assess the feasibility of leading into a larger pragmatic Phase III trial and the safety of aspirin in this population. Design A multicentred, pilot, Phase II randomised double-blind, parallel-group, placebo-controlled efficacy trial. Setting Community leg ulcer clinics or services, hospital outpatient clinics, leg ulcer clinics, tissue viability clinics and wound clinics in England, Wales and Scotland. Participants Patients aged ≥ 18 years with a chronic VLU (i.e. the VLU is > 6 weeks in duration or the patient has a history of VLU) and who are not regularly taking aspirin. Interventions 300 mg of daily oral aspirin versus placebo. All patients were offered care in accordance with Scottish Intercollegiate Guidelines Network (SIGN) guidance with multicomponent compression therapy aiming to deliver 40 mmHg at the ankle when possible. Randomisation Participants were allocated in a 1 : 1 (aspirin : placebo) ratio by the Research Pharmacy, St George’s University Hospitals NHS Foundation Trust, using a randomisation schedule generated in advance by the investigational medicinal product manufacturer. Randomisation was stratified according to ulcer size (≤ 5cm2 or > 5cm2). Main outcome measure The primary outcome was time to healing of the largest eligible ulcer (reference ulcer). Feasibility results – recruitment 27 patients were recruited from eight sites over a period of 8 months. The target of 100 patients was not achieved and two sites did not recruit. Barriers to recruitment included a short recruitment window and a large proportion of participants failing to meet the eligibility criteria. Results The average age of the 27 randomised participants (placebo, n = 13; aspirin, n = 14) was 62 years (standard deviation 13 years), and two-thirds were male (n = 18). Participants had their reference ulcer for a median of 15 months, and the median size of ulcer was 17.1 cm2. There was no evidence of a difference in time to healing of the reference ulcer between groups in an adjusted analysis for log-ulcer area and duration (hazard ratio 0.58, 95% confidence interval 0.18 to 1.85; p = 0.357). One expected, related serious adverse event was recorded for a participant in the aspirin group. Limitations The trial under-recruited because many patients did not meet the eligibility criteria. Conclusions There was no evidence that aspirin was efficacious in hastening the healing of chronic VLUs. It can be concluded that a larger Phase III (effectiveness) trial would not be feasible. Trial registration Clinical Trials.gov NCT02333123; European Clinical Trials Database (EudraCT) 2014-003979-39. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 55. See the NIHR Journals Library website for further project information

Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher’s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition