Germ-line and somatic EPHA2 coding variants in lens aging and cataract

Rare germ-line mutations in the coding regions of the human EPHA2 gene (EPHA2) have been associated with inherited forms of pediatric cataract, whereas, frequent, non-coding, single nucleotide variants (SNVs) have been associated with age-related cataract. Here we sought to determine if germ-line EPHA2 coding SNVs were associated with age-related cataract in a case-control DNA panel (> 50 years) and if somatic EPHA2 coding SNVs were associated with lens aging and/or cataract in a post-mortem lens DNA panel (> 48 years). Micro-fluidic PCR amplification followed by targeted amplicon (exon) next-generation (deep) sequencing of EPHA2 (17-exons) afforded high read-depth coverage (1000x) for > 82% of reads in the cataract case-control panel (161 cases, 64 controls) and > 70% of reads in the post-mortem lens panel (35 clear lens pairs, 22 cataract lens pairs). Novel and reference (known) missense SNVs in EPHA2 that were predicted in silico to be functionally damaging were found in both cases and controls from the age-related cataract panel at variant allele frequencies (VAFs) consistent with germ-line transmission (VAF > 20%). Similarly, both novel and reference missense SNVs in EPHA2 were found in the post-mortem lens panel at VAFs consistent with a somatic origin (VAF > 3%). The majority of SNVs found in the cataract case-control panel and post-mortem lens panel were transitions and many occurred at di-pyrimidine sites that are susceptible to ultraviolet (UV) radiation induced mutation. These data suggest that novel germ-line (blood) and somatic (lens) coding SNVs in EPHA2 that are predicted to be functionally deleterious occur in adults over 50 years of age. However, both types of EPHA2 coding variants were present at comparable levels in individuals with or without age-related cataract making simple genotype-phenotype correlations inconclusive

Cat-Map: putting cataract on the map

Lens opacities, or cataract(s), may be inherited as a classic Mendelian disorder usually with early-onset or, more commonly, acquired with age as a multi-factorial or complex trait. Many genetic forms of cataract have been described in mice and other animal models. Considerable progress has been made in mapping and identifying the genes and mutations responsible for inherited forms of cataract, and genetic determinants of age-related cataract are beginning to be discovered. To provide a convenient and accurate summary of current information focused on the increasing genetic complexity of Mendelian and age-related cataract we have created an online chromosome map and reference database for cataract in humans and mice (Cat-Map)

Predicting Students Progression Using Existing University Datasets: A Random Forest Application

This paper proposes the use of data available at Manchester Metropolitan University to assess the variables that can best predict student progression. We combine Virtual Learning Environment and MIS student records data sets and apply the Random Forest (RF) algorithm to ascertain which variables can best predict students’ progression (students satisfactorily completing one year and passing to the next or graduating). RF was deemed useful in this case because of the large amount of data available for analysis. The paper reports on the initial findings for data available in the period 2007-08. Results seem to indicate that variables such as students’ time of day usage, the last time students access the VLE and the number of document hits by staff, are the best predictors of student progression. The paper contributes to VLE evaluation and highlights the usefulness of a technique initially developed in the field of biology in an educational environment

Review of the Role of EBUS-TBNA for the Pulmonologist, Including Lung Cancer Staging

This review focuses on the role of endobronchial ultrasound-guided transbronchial needle aspiration in day-to-day pulmonology practice. Case examples are given of the common indications for endobronchial ultrasound-guided transbronchial needle aspiration which are: (i) lung cancer staging; (ii) confirming a diagnosis of malignancy in thoracic lymph nodes; (iii) diagnosing central pulmonary masses; (iv) sarcoidosis; and (v) inflammatory/benign thoracic lymph nodes. The technique is widely used, and after appropriate training by experienced bronchoscopists can be easily integrated into a bronchoscopy service

Scenario-Led Habitat Modelling of Land Use Change Impacts on Key Species

Accurate predictions of the impacts of future land use change on species of conservation concern can help to inform policy-makers and improve conservation measures. If predictions are spatially explicit, predicted consequences of likely land use changes could be accessible to land managers at a scale relevant to their working landscape. We introduce a method, based on open source software, which integrates habitat suitability modelling with scenario-building, and illustrate its use by investigating the effects of alternative land use change scenarios on landscape suitability for black grouse Tetrao tetrix. Expert opinion was used to construct five near-future (twenty years) scenarios for the 800 km2 study site in upland Scotland. For each scenario, the cover of different land use types was altered by 5–30% from 20 random starting locations and changes in habitat suitability assessed by projecting a MaxEnt suitability model onto each simulated landscape. A scenario converting grazed land to moorland and open forestry was the most beneficial for black grouse, and ‘increased grazing’ (the opposite conversion) the most detrimental. Positioning of new landscape blocks was shown to be important in some situations. Increasing the area of open-canopy forestry caused a proportional decrease in suitability, but suitability gains for the ‘reduced grazing’ scenario were nonlinear. ‘Scenario-led’ landscape simulation models can be applied in assessments of the impacts of land use change both on individual species and also on diversity and community measures, or ecosystem services. A next step would be to include landscape configuration more explicitly in the simulation models, both to make them more realistic, and to examine the effects of habitat placement more thoroughly. In this example, the recommended policy would be incentives on grazing reduction to benefit black grouse.This study was part of a PhD studentship funded through the World Pheasant Association (from the Henry Angest Foundation, Howman Charitable Foundation, Mactaggart Third Charitable Trust, PF Charitable Trust and AF Wallace Charity Trust) and the Dalton Research Institute

Noncoding variation of the gene for ferritin light chain in hereditary and age-related cataract

PURPOSE: Cataract is a clinically and genetically heterogeneous disorder of the ocular lens and an important cause of visual impairment. The aim of this study was to map and identify the gene underlying autosomal dominant cataract segregating in a four-generation family, determine the lens expression profile of the identified gene, and test for its association with age-related cataract in a case-control cohort. METHODS: Genomic DNA was prepared from blood leukocytes, and genotyping was performed by means of single-nucleotide polymorphism markers and microsatellite markers. Linkage analyses were performed using the GeneHunter and MLINK programs, and mutation detection was achieved by dideoxy cycle sequencing. Lens expression studies were performed using reverse-transcription polymerase chain reaction (RT–PCR) and in situ hybridization. RESULTS: Genome-wide linkage analysis with single nucleotide polymorphism markers in the family identified a likely disease-haplotype interval on chromosome 19q (rs888861-[~17Mb]-rs8111640) that encompassed the microsatellite marker D19S879 (logarithm of the odds score [Z]=2.03, recombination distance [θ]=0). Mutation profiling of positional-candidate genes detected a heterozygous, noncoding G-to-T transversion (c.-168G>T) located in the iron response element (IRE) of the gene coding for ferritin light chain (FTL) that cosegregated with cataract in the family. Serum ferritin levels were found to be abnormally elevated (~fourfold), without evidence of iron overload, in an affected family member; this was consistent with a diagnosis of hereditary hyperferritinemia-cataract syndrome. No sequence variations located within the IRE were detected in a cohort of 197 cases with age-related cataract and 102 controls with clear lenses. Expression studies of human FTL, and its mouse counterpart FTL1, in the lens detected RT–PCR amplicons containing full-length protein-coding regions, and strong in situ localization of FTL1 transcripts to the lens equatorial epithelium and peripheral cortex. CONCLUSIONS: The data are consistent with robust transcription of FTL in the lens, and suggest that whereas variations clustered in the IRE of the FTL gene are directly associated with hereditary hyperferritinemia-cataract syndrome, such IRE variations are unlikely to play a significant role in the genetic etiology of age-related cataract

A new Holocene record of geomagnetic secular variation from Windermere, UK

Paleomagnetic secular variation (PSV) records serve as valuable independent stratigraphic correlation and dating tools for marine and terrestrial sediment sequences, and enhance knowledge of geomagnetic field dynamics. We present a new radiocarbon-dated record (WINPSV-12K) of Holocene geomagnetic secular variation from Windermere, updating the existing 1981 UK master PSV curve. Our analyses used continuous U-channel samples taken from the center of four sediment cores retrieved from Windermere in 2012. The natural remanent magnetization (NRM) of each U-channel was measured before and after stepwise alternating field (AF) demagnetization on a superconducting rock magnetometer at intervals of 0.5-cm or 1-cm. The NRM data reveal a stable and well-defined primary magnetization. Component declinations and inclinations estimated using Principal Component Analysis (PCA) of NRM data from the four Windermere cores correlate well on their independent radiocarbon age models. The four records were stacked using a sliding window bootstrap method, resulting in a composite Holocene PSV record (WINPSV-12K). On millennial timescales WINPSV-12K correlates well with other records from Western Europe and the northern North Atlantic to a resolution of ∼ 1 kyr, given age uncertainties and spatial variability between records. WINPSV-12K also compares well to the CALS10k.2 and pfm9k.1a model predictions for Windermere. Key regionally-significant PSV inclination features of WINPSV-12K which correlate with other North Atlantic records include peaks at 5–6, 8.5, and 10 cal ka BP, and a trough at 7calkaBP. Key PSV declination features include the eastward swing from 5.5–2.3 cal ka BP followed by a major westward excursion at 2.3 cal ka BP, peaks at 1.1 and 7calkaBP, and troughs at 5.4 and 8.2 cal ka BP, with the caveat that an estimated magnetic lock-in delay of at least 100–200 yr is present. PSV variations on 1–3 kyr timescales are interpreted to represent strengthening and weakening of the North American versus the Siberian and European–Mediterranean high-latitude flux lobes, based on the close similarities between the North Atlantic regional records and the antiphase existing in the East Asian Stack record and the North East Pacific inclination stack. WINPSV-12K provides a regionally-important new PSV reference curve whose prominent features may serve as stratigraphic markers for North Atlantic paleo-records