Oxygen consumption and ammonia excretion in the detritivore caddisfly Limnephillus sp. exposed to low pH & aluminum

Respiration and excretion were measured relative to pH and aluminum in three nymphal weight groups of a detritivore caddisfly. Although a reduction in respiration rates was consistently observed within all stages exposed to a pH of 4 and 0.3 mg 1⁻¹ of aluminum, the differencewas not statistically significant among treatments. Excretion rates, on the other hand, were significantly increased throughout the low pH treatment, but not when exposed to low pH and aluminum combined. The derived O:N ratios indicate low pH causes a shift to a protein-oriented metabolism which was most pronounced in the smallest size group. Aluminum mitigates this effect.     

Testing the Effectiveness of 3D Film for Laboratory-Based Studies of Emotion

Research in psychology and affective neuroscience often relies on film as a standardized and reliable method for evoking emotion. However, clip validation is not undertaken regularly. This presents a challenge for research with adolescent and young adult samples who are exposed routinely to high-definition (HD) three-dimensional (3D) stimuli and may not respond to older, validated film clips. Studies with young people inform understanding of emotional development, dysregulated affect, and psychopathology, making it critical to assess whether technological advances improve the study of emotion. In the present study, we examine whether 3D film is more evocative than 2D using a tightly controlled within-subjects design. Participants (n  =  408) viewed clips during a concurrent psychophysiological assessment. Results indicate that both 2D and 3D technology are highly effective tools for emotion elicitation. However, 3D does not add incremental benefit over 2D, even when individual differences in anxiety, emotion dysregulation, and novelty seeking are considered.     

Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib

Although orphan drug applications required by the EMEA must include assessments of similarity to pre-existing products, these can be difficult to quantify. Here we illustrate a paradigm in comparing nilotinib to the prototype kinase inhibitor imatinib, and equate the degree of structural similarity to differences in properties. Nilotinib was discovered following re-engineering of imatinib, employing structural biology and medicinal chemistry strategies to optimise cellular potency and selectivity towards BCR-ABL1. Through evolving only to conserve these properties, this resulted in significant structural differences between nilotinib and imatinib, quantified by a Daylight-fingerprint—Tanimoto similarity coefficient of 0.6, with the meaning of this absolute measure being supported by an analysis of similarity distributions of similar drug-like molecules. This dissimilarity is reflected in the drugs having substantially different preclinical pharmacology and a lack of cross-intolerance in CML patients, which translates into nilotinib being an efficacious treatment for CML, with a favourable side-effect profile.     

1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists

A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRβ binding IC₅₀ values <10 nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.     

Air Pollution and the microvasculature: a cross-sectional assessment of in vivo retinal images in the population-based multi-ethnic study of atherosclerosis (MESA)

Background

Long- and short-term exposures to air pollution, especially fine particulate matter (PM_2.5), have been linked to cardiovascular morbidity and mortality. One hypothesized mechanism for these associations involves microvascular effects. Retinal photography provides a novel, in vivo approach to examine the association of air pollution with changes in the human microvasculature.

Methods and Findings

Chronic and acute associations between residential air pollution concentrations and retinal vessel diameters, expressed as central retinal arteriolar equivalents (CRAE) and central retinal venular equivalents (CRVE), were examined using digital retinal images taken in Multi-Ethnic Study of Atherosclerosis (MESA) participants between 2002 and 2003. Study participants (46 to 87 years of age) were without clinical cardiovascular disease at the baseline examination (2000–2002). Long-term outdoor concentrations of PM_2.5 were estimated at each participant''s home for the 2 years preceding the clinical exam using a spatio-temporal model. Short-term concentrations were assigned using outdoor measurements on the day preceding the clinical exam. Residential proximity to roadways was also used as an indicator of long-term traffic exposures. All associations were examined using linear regression models adjusted for subject-specific age, sex, race/ethnicity, education, income, smoking status, alcohol use, physical activity, body mass index, family history of cardiovascular disease, diabetes status, serum cholesterol, glucose, blood pressure, emphysema, C-reactive protein, medication use, and fellow vessel diameter. Short-term associations were further controlled for weather and seasonality. Among the 4,607 participants with complete data, CRAE were found to be narrower among persons residing in regions with increased long- and short-term levels of PM_2.5. These relationships were observed in a joint exposure model with −0.8 µm (95% confidence interval [CI] −1.1 to −0.5) and −0.4 µm (95% CI −0.8 to 0.1) decreases in CRAE per interquartile increases in long- (3 µg/m³) and short-term (9 µg/m³) PM_2.5 levels, respectively. These reductions in CRAE are equivalent to 7- and 3-year increases in age in the same cohort. Similarly, living near a major road was also associated with a −0.7 µm decrease (95% CI −1.4 to 0.1) in CRAE. Although the chronic association with CRAE was largely influenced by differences in exposure between cities, this relationship was generally robust to control for city-level covariates and no significant differences were observed between cities. Wider CRVE were associated with living in areas of higher PM_2.5 concentrations, but these findings were less robust and not supported by the presence of consistent acute associations with PM_2.5.

Conclusions

Residing in regions with higher air pollution concentrations and experiencing daily increases in air pollution were each associated with narrower retinal arteriolar diameters in older individuals. These findings support the hypothesis that important vascular phenomena are associated with small increases in short-term or long-term air pollution exposures, even at current exposure levels, and further corroborate reported associations between air pollution and the development and exacerbation of clinical cardiovascular disease. Please see later in the article for the Editors'' Summary     

Transgenic tools for members of the genus Drosophila with sequenced genomes

The sequencing of the genomes of 12 Drosophila species has created an opportunity for much in the way of comparative molecular analyses amongst these species. To aid that endeavor, we have made several transformation vectors based on the piggyBac transposon with 3xP3-EGFP and -ECFP transgenic markers that should be useful for mutagenesis and establishing the GAL4/UAS system in these species. We have tested the ability of mini-white to be used as a marker for insertional mutagenesis, and have observed mini-white derived pigmentation of the testes sheath in a subset of lines from D. pseudoobscura and D. virilis. We have incorporated a source of piggyBac transposase into nine Drosophila species, and have demonstrated the functionality of these transposase lines for mobilization of marked inserts in vivo. Additionally, we tested the ability of a D. melanogaster nanos enhancer element to drive expression of GAL4 in D. melanogaster, D. simulans, D. erecta, D. yakuba, D. pseudoobscura, and D. virilis. The efficacy of the nos-Gal4 transgene was determined by measuring the response of UAS-EGFPtub in all six species. Our results show that D. melanogaster nos-Gal4 drives expression in other species, to varying degrees, in similar spatiotemporal domains in the ovaries, testes, and embryos as seen in D. melanogaster. However, expression levels are variable, demonstrating the possible need to use species-specific promoters in some cases. In summary, we hope to provide a set of guidelines and basic tools, based upon this work, for both insertional mutagenesis and GAL4/UAS system-based experiments in multiple species of Drosophila.