Association of drusen deposition with choroidal intercapillary pillars in the aging human eye

PURPOSE. To determine the pattern of drusen accumulation with age and to investigate the initial sites of deposition and their relationship to choroidal capillaries in human donor eyes from the eye bank of Moorfields Eye Hospital.METHODS. Wholemounted, hydrated preparations of the choriocapillaris and Bruch's membrane from donor eyes ranging from 42 to 95 years, with or without retinal pigment epithelium (RPE), were examined by conventional and confocal microscopy. Drusen were visualized by their autofluorescence.RESULTS. In all age groups studied autofluorescent drusen were present at the equator but were not found centrally where the vascular architecture is different, being tubular rather than a honeycomb pattern. Autofluorescing drusen were strongly associated with the lateral walls of the choriocapillaris (an area commonly known as the intercapillary pillars of the choriocapillaris (P = 0.028; Wilcoxon signed ranks test). Nonfluorescing drusen were occasionally seen centrally, but were not easily identified, and because of their large size, their localization with respect to capillary walls was not possible.CONCLUSIONS. These results strongly support the notion that autofluorescent drusen are not randomly distributed and have a specific spatial relationship to choroidal vessel walls. That equatorial drusen fluoresce, whereas central drusen do not, suggests that they may have different chemical compositions at the two sites and possibly different significance in age-related macular disease

Can HRCT be used as a marker of airway remodelling in children with difficult asthma?

BACKGROUND: Whole airway wall thickening on high resolution computed tomography (HRCT) is reported to parallel thickening of the bronchial epithelial reticular basement membrane (RBM) in adult asthmatics. A similar relationship in children with difficult asthma (DA), in whom RBM thickening is a known feature, may allow the use of HRCT as a non-invasive marker of airway remodelling. We evaluated this relationship in children with DA. METHODS: 27 children (median age 10.5 [range 4.1-16.7] years) with DA, underwent endobronchial biopsy from the right lower lobe and HRCT less than 4 months apart. HRCTs were assessed for bronchial wall thickening (BWT) of the right lower lobe using semi-quantitative and quantitative scoring techniques. The semi-quantitative score (grade 0-4) was an overall assessment of BWT of all clearly identifiable airways in HRCT scans. The quantitative score (BWT %; defined as [airway outer diameter - airway lumen diameter]/airway outer diameter x100) was the average score of all airways visible and calculated using electronic endpoint callipers. RBM thickness in endobronchial biopsies was measured using image analysis. 23/27 subjects performed spirometry and the relationships between RBM thickness and BWT with airflow obstruction evaluated. RESULTS: Median RBM thickness in endobronchial biopsies was 6.7(range 4.6-10.0) microm. Median qualitative score for BWT of the right lower lobe was 1(range 0-1.5) and quantitative score was 54.3 (range 48.2-65.6)%. There was no relationship between RBM thickness and BWT in the right lower lobe using either scoring technique. No relationship was found between FEV1 and BWT or RBM thickness. CONCLUSION: Although a relationship between RBM thickness and BWT on HRCT has been found in adults with asthma, this relationship does not appear to hold true in children with D

Fault-tolerance techniques for hybrid CMOS/nanoarchitecture

The authors propose two fault-tolerance techniques for hybrid CMOS/nanoarchitecture implementing logic functions as look-up tables. The authors compare the efficiency of the proposed techniques with recently reported methods that use single coding schemes in tolerating high fault rates in nanoscale fabrics. Both proposed techniques are based on error correcting codes to tackle different fault rates. In the first technique, the authors implement a combined two-dimensional coding scheme using Hamming and Bose-Chaudhuri-Hocquenghem (BCH) codes to address fault rates greater than 5. In the second technique, Hamming coding is complemented with bad line exclusion technique to tolerate fault rates higher than the first proposed technique (up to 20). The authors have also estimated the improvement that can be achieved in the circuit reliability in the presence of Don-t Care Conditions. The area, latency and energy costs of the proposed techniques were also estimated in the CMOS domain

UVSSA, UBP12, and RDO2/TFIIS Contribute to Arabidopsis UV Tolerance

Plant DNA is damaged by exposure to solar radiation, which includes ultraviolet (UV) rays. UV damaged DNA is repaired either by photolyases, using visible light energy, or by nucleotide excision repair (NER), also known as dark repair. NER consists of two subpathways: global genomic repair (GGR), which repairs untranscribed DNA throughout the genome, and transcription-coupled repair (TCR), which repairs transcribed DNA. In mammals, CSA, CSB, UVSSA, USP7, and TFIIS have been implicated in TCR. Arabidopsis homologs of CSA (AtCSA-1/2) and CSB (CHR8) have previously been shown to contribute to UV tolerance. Here we examine the role of Arabidopsis homologs of UVSSA, USP7 (UBP12/13), and TFIIS (RDO2) in UV tolerance. We find that loss of function alleles of UVSSA, UBP12, and RDO2 exhibit increased UV sensitivity in both seedlings and adults. UV sensitivity in atcsa-1, uvssa, and ubp12 mutants is specific to dark conditions, consistent with a role in NER. Interestingly, chr8 mutants exhibit UV sensitivity in both light and dark conditions, suggesting that the Arabidopsis CSB homolog may play a role in both NER and light repair. Overall our results indicate a conserved role for UVSSA, USP7 (UBP12), and TFIIS (RDO2) in TCR

Species-specific kinetics and zonation of hepatic DNA synthesis induced by ligands of PPAR?

PPAR? ligands evoke a profound mitogenic response in rodent liver, and the aim of this studywas to characterise the kinetics of induction of DNA synthesis. The CAR ligand, 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene, caused induction of hepatocyte DNA synthesis within 48 hours in129S4/SvJae mice, but the potent PPAR? ligand, ciprofibrate, induced hepatocyte DNA synthesisonly after 3 or 4 days dosing; higher or lower doses did not hasten the DNA synthesisresponse. This contrasted with the rapid induction (24 hours) reported by Styles et al. (Carcinogenesis9:1647-1655). C57BL/6 and DBA/2J mice showed significant induction of DNA synthesisafter 4, but not 2, days ciprofibrate treatment. Alderley Park and 129S4/SvJae mice dosedwith methylclofenapate induced hepatocyte DNA synthesis at 4, but not 2, days after dosing,and proved that inconsistency with prior work was not due to a difference in mouse strain orPPAR? ligand. Ciprofibrate-induced liver DNA synthesis and growth was absent in PPAR?-null mice, and are PPAR?-dependent. In the Fisher344 rat, hepatocyte DNA synthesis was inducedat 24 hours after dosing, with a second peak at 48 hours. Lobular localisation of hepatocyteDNA synthesis showed preferential periportal induction of DNA synthesis in rat, butpanlobular zonation of hepatocyte DNA synthesis in mouse. These results characterise a markedlylater hepatic induction of panlobular DNA synthesis by PPAR? ligands in mouse, comparedto rapid induction of periportal DNA synthesis in rat

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry

IMPORTANCE Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. OBJECTIVE To identify genetic variants associated with AD risk using a nonstatistical approach. DESIGN, SETTING, AND PARTICIPANTS Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer’s Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. MAIN OUTCOMES AND MEASURES Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer’s Disease Neuroimaging Initiative. RESULTS Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). CONCLUSIONS AND RELEVANCE Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets

A qualitative study of independent fast food vendors near secondary schools in disadvantaged Scottish neighbourhoods

Background: Preventing and reducing childhood and adolescent obesity is a growing priority in many countries. Recent UK data suggest that children in more deprived areas have higher rates of obesity and poorer diet quality than those in less deprived areas. As adolescents spend a large proportion of time in school, interventions to improve the food environment in and around schools are being considered. Nutrient standards for school meals are mandatory in the UK, but many secondary pupils purchase foods outside schools at break or lunchtime that may not meet these standards. Methods: Qualitative interviews were conducted with fast food shop managers to explore barriers to offering healthier menu options. Recruitment targeted independently-owned shops near secondary schools (pupils aged c.12-17) in low-income areas of three Scottish cities. Ten interviews were completed, recorded, and transcribed for analysis. An inductive qualitative approach was used to analyse the data in NVivo 10. Results: Five themes emerged from the data: pride in what is sold; individual autonomy and responsibility; customer demand; profit margin; and neighbourhood context. Interviewees consistently expressed pride in the foods they sold, most of which were homemade. They felt that healthy eating and general wellbeing are the responsibility of the individual and that offering what customers want to eat, not necessarily what they should eat, was the only way to stay in business. Most vendors felt they were struggling to maintain a profit, and that many aspects of the low-income neighbourhood context would make change difficult or impossible. Conclusions: Independent food shops in low-income areas face barriers to offering healthy food choices, and interventions and policies that target the food environment around schools should take the neighbourhood context into consideration

Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Little is known about airway remodelling in bronchial biopsies (BB) in smokers and chronic obstructive pulmonary disease (COPD). We conducted an initial pilot study comparing BB from COPD patients with nonsmoking controls. This pilot study suggested the presence of reticular basement membrane (Rbm) fragmentation and altered vessel distribution in COPD.</p> <p>Methods</p> <p>To determine whether Rbm fragmentation and altered vessel distribution in BB were specific for COPD we designed a cross-sectional study and stained BB from 19 current smokers and 14 ex-smokers with mild to moderate COPD and compared these to 15 current smokers with normal lung function and 17 healthy and nonsmoking subjects.</p> <p>Results</p> <p>Thickness of the Rbm was not significantly different between groups; although in COPD this parameter was quite variable. The Rbm showed fragmentation and splitting in both current smoking groups and ex-smoker COPD compared with healthy nonsmokers (p < 0.02); smoking and COPD seemed to have additive effects. Rbm fragmentation correlated with smoking history in COPD but not with age. There were more vessels in the Rbm and fewer vessels in the lamina propria in current smokers compared to healthy nonsmokers (p < 0.05). The number of vessels staining for vascular endothelial growth factor (VEGF) in the Rbm was higher in both current smoker groups and ex-smoker COPD compared to healthy nonsmokers (p < 0.004). In current smoker COPD VEGF vessel staining correlated with FEV1% predicted (r = 0.61, p < 0.02).</p> <p>Conclusions</p> <p>Airway remodelling in smokers and mild to moderate COPD is associated with fragmentation of the Rbm and altered distribution of vessels in the airway wall. Rbm fragmentation was also present to as great an extent in ex-smokers with COPD. These characteristics may have potential physiological consequences.</p

Insights from Amphioxus into the Evolution of Vertebrate Cartilage

Central to the story of vertebrate evolution is the origin of the vertebrate head, a problem difficult to approach using paleontology and comparative morphology due to a lack of unambiguous intermediate forms. Embryologically, much of the vertebrate head is derived from two ectodermal tissues, the neural crest and cranial placodes. Recent work in protochordates suggests the first chordates possessed migratory neural tube cells with some features of neural crest cells. However, it is unclear how and when these cells acquired the ability to form cellular cartilage, a cell type unique to vertebrates. It has been variously proposed that the neural crest acquired chondrogenic ability by recruiting proto-chondrogenic gene programs deployed in the neural tube, pharynx, and notochord. To test these hypotheses we examined the expression of 11 amphioxus orthologs of genes involved in neural crest chondrogenesis. Consistent with cellular cartilage as a vertebrate novelty, we find that no single amphioxus tissue co-expresses all or most of these genes. However, most are variously co-expressed in mesodermal derivatives. Our results suggest that neural crest-derived cartilage evolved by serial cooption of genes which functioned primitively in mesoderm