Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging

Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diameter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (p < 0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 μm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p < 0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint.     

Dietary fat and breast cancer mortality: A systematic review and meta-analysis

Background: The influence of dietary fat upon breast cancer mortality remains largely understudied despite extensive investigation into its influence upon breast cancer risk. Objective: To conduct meta-analyses of studies to clarify the association between dietary fat and breast cancer mortality. Design: MEDLINE and EMBASE were searched for relevant articles published up to March 2012. Risk of all-cause or breast-cancer-specific death was evaluated by combining multivariable adjusted estimates comparing highest versus lowest categories of intake; and per 20 g increase in intake of total and/or saturated fat (g/day) using random-effects meta-analyses. Results: Fifteen prospective cohort studies investigating total fat and/or saturated fat intake (g/day) and breast cancer mortality were included. There was no difference in risk of breast-cancer-specific death (n = 6; HR = 1.14; 95% CI: 0.86, 1.52; p = 0.34) or all-cause death (n = 4; HR = 1.73; 95% CI: 0.82, 3.66; p = 0.15) for women in the highest versus lowest category of total fat intake. Breast-cancer-specific death (n = 4; HR = 1.51; 95% CI: 1.09, 2.09; p < 0.01) was higher for women in the highest versus lowest category of saturated fat intake. Conclusions: These meta-analyses have shown that saturated fat intake negatively impacts upon breast cancer survival.     

Antimicrobial peptides and pregnancy

Antimicrobial peptides (AMPs) are small proteins produced by epithelial surfaces and inflammatory cells, which have broad-spectrum antimicrobial and immunomodulatory activities. They are known to be important in a number of infectious and inflammatory conditions and have been shown to be present in a number of sites throughout the female reproductive tract. Inflammation and infection are associated with a number of complications of pregnancy including preterm labor, and AMPs may play a key role in maintaining and protecting pregnancy. The aim of this review is to describe the expression and function of AMPs in the pregnant female reproductive tract and their relation to preterm labor.     

Interior-architectured ZnO nanostructure for enhanced electrical conductivity via stepwise fabrication process

Fabrication of ZnO nanostructure via direct patterning based on sol-gel process has advantages of low-cost, vacuum-free, and rapid process and producibility on flexible or non-uniform substrates. Recently, it has been applied in light-emitting devices and advanced nanopatterning. However, application as an electrically conducting layer processed at low temperature has been limited by its high resistivity due to interior structure. In this paper, we report interior-architecturing of sol-gel-based ZnO nanostructure for the enhanced electrical conductivity. Stepwise fabrication process combining the nanoimprint lithography (NIL) process with an additional growth process was newly applied. Changes in morphology, interior structure, and electrical characteristics of the fabricated ZnO nanolines were analyzed. It was shown that filling structural voids in ZnO nanolines with nanocrystalline ZnO contributed to reducing electrical resistivity. Both rigid and flexible substrates were adopted for the device implementation, and the robustness of ZnO nanostructure on flexible substrate was verified. Interior-architecturing of ZnO nanostructure lends itself well to the tunability of morphological, electrical, and optical characteristics of nanopatterned inorganic materials with the large-area, low-cost, and low-temperature producibility.     

Mycotoxin Biomarkers of Exposure: A Comprehensive Review

To date, the use of biomarkers has become generally accepted. Biomarker‐driven research has been proposed as a successful method to assess the exposure to xenobiotics by using concentrations of the parent compounds and/or metabolites in biological matrices such as urine or blood. However, the identification and validation of biomarkers of exposure remain a challenge. Recent advances in high‐resolution mass spectrometry along with new analytical (post‐acquisition data‐mining) techniques will improve the quality and output of the biomarker identification process. Chronic or even acute exposure to mycotoxins remains a daily fact, and therefore it is crucial that the mycotoxins’ metabolism is unravelled so more knowledge on biomarkers in humans and animals is acquired. This review aims to provide the scientific community with a comprehensive overview of reported in vitro and in vivo mycotoxin metabolism studies in relation to biomarkers of exposure for deoxynivalenol, nivalenol, fusarenon‐X, T‐2 toxin, diacetoxyscirpenol, ochratoxin A, citrinin, fumonisins, zearalenone, aflatoxins, and sterigmatocystin.     

Quinone emissions from gasoline and diesel motor vehicles

Gas- and particle-phase emissions from gasoline and diesel vehicles operated on chassis dynamometers were collected using annular denuders, quartz filters, and PUF substrates. Quinone species were measured using O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine derivatization in conjunction with gas chromatography-mass spectrometry and high-performance liquid chromatography-mass spectrometry. Nine quinones were observed, ranging from C6 to C16. New species identified in motor vehicle exhaust include methyl-1,4-benzoquinone, 2-methyl-1,4-naphthoquinone (MNQN), and aceanthrenequinone. Gas-phase motor vehicle emissions of quinones are also reported for the first time. Six gas-phase quinones were quantified with emission rates of 2-28 000 microg L(-1) fuel consumed. The most abundant gas-phase quinones were 1,4-benzoquinone (BON) and MNQN. The gas-phase fraction was > or = 69% of quinone mass for light-duty gasoline emissions, and > or = 84% for heavy-duty diesel emissions. Eight particle-phase quinones were observed between 2 and 1600 microg L(-1), with BQN the most abundant species followed by 9,10-phenanthrenequinone and 1,2-naphthoquinone. Current particle-phase quinone measurements agree well with the few available previous results. Further research is needed concerning the gas-particle partitioning behavior of quinones in ambient and combustion source conditions.     

Dietary induced alterations in the fatty acids of rat bone marrow

Weanling rats were fed fat free diets supplemented with 10% added fatty acids so that dietary effects on bone marrow fatty acids could be determined. The addition or deletion of linoleic acid from the fatty acid supplement resulted in alterations of the fatty acid patterns of bone marrow lipids but to a lesser degree than in erythrocyte lipids. With myristic acid supplementation, increased amounts of stearic acid were found in the lipid fractions, the difference between the bone marrow and erythrocyte lipids being less marked than when linoleic acid was fed. The activities of the bone marrow lipases varied with the dietary treatment. When linoleic acid was fed, higher rates of hydrolysis were observed with saturated fatty acid substrates. The reverse occurred when saturated fatty acids were fed.     

Dietary Supplementation of Calcium may Counteract Obesity in Mice Mediated by Changes in Plasma Fatty Acids

The scope of this study was to assess the impact of calcium and conjugated linoleic acid (CLA) supplementation on plasma fatty acid profiles and to evaluate potential synergistic effects of both compounds against dietary obesity. Mice separated into five experimental groups were followed: control (C), high-fat diet (HF), HF with calcium (Ca), HF plus CLA and HF with both Ca and CLA. Plasma metabolites and fatty acids were determined by commercial kits and gas chromatography, respectively. Both dietary calcium and CLA supplementation contributed to lower body fat gain under a HF diet. Maximum efficacy was seen with calcium; no additional effect was associated with the combined treatment with CLA. Plasma leptin, adiponectin and HOMA index were in accordance with an altered glucose/insulin homeostasis in the HF and HF + CLA groups, whereas control levels were attained under Ca-enriched diets. Plasma fatty acids showed minor changes associated to CLA treatment, but a high impact on PUFA was observed under Ca-enriched diets. Our results show that the mechanism underlying the anti-obesity effects of calcium supplementation is mediated mainly by changes in PUFA plasma profile. In addition, the lack of synergy on body weight reduction in combination with associated lipid profiles of calcium and CLA suggests that calcium may interfere with absorption and/or bioactivity of CLA, which can be of relevance when using CLA-fortified dairy products against human obesity.     

Discovery of a Short‐Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid

Plant monoterpene indole alkaloids, a large class of natural products, derive from the biosynthetic intermediate strictosidine aglycone. Strictosidine aglycone, which can exist as a variety of isomers, can be reduced to form numerous different structures. We have discovered a short‐chain alcohol dehydrogenase (SDR) from plant producers of monoterpene indole alkaloids (Catharanthus roseus and Rauvolfia serpentina) that reduce strictosidine aglycone and produce an alkaloid that does not correspond to any previously reported compound. Here we report the structural characterization of this product, which we have named vitrosamine, as well as the crystal structure of the SDR. This discovery highlights the structural versatility of the strictosidine aglycone biosynthetic intermediate and expands the range of enzymatic reactions that SDRs can catalyse. This discovery further highlights how a sequence‐based gene mining discovery approach in plants can reveal cryptic chemistry that would not be uncovered by classical natural product chemistry approaches.