LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2

High cholesterol and diabetes are major risk factors for atherosclerosis. Regression of atherosclerosis is mediated in part by the Liver X Receptor (LXR) through the induction of genes involved in cholesterol transport and efflux. In the context of diabetes, regression of atherosclerosis is impaired. We proposed that changes in glucose levels modulate LXR-dependent gene expression. Using a mouse macrophage cell line (RAW 264.7) and primary bone marrow derived macrophages (BMDMs) cultured in normal or diabetes relevant high glucose conditions we found that high glucose inhibits the LXR-dependent expression of ATP-binding cassette transporter A1 (ABCA1), but not ABCG1. To probe for this mechanism, we surveyed the expression of a host of chromatin-modifying enzymes and found that Protein Arginine Methyltransferase 2 (PRMT2) was reduced in high compared to normal glucose conditions. Importantly, ABCA1 expression and ABCA1-mediated cholesterol efflux were reduced in Prmt2 ^-/- compared to wild type BMDMs. Monocytes from diabetic mice also showed decreased expression of Prmt2 compared to non-diabetic counterparts. Thus, PRMT2 represents a glucose-sensitive factor that plays a role in LXR-mediated ABCA1-dependent cholesterol efflux and lends insight to the presence of increased atherosclerosis in diabetic patients.     

The Sampled Red List Index for Plants,phase II: ground-truthing specimen-based conservation assessments

The IUCN Sampled Red List Index (SRLI) is a policy response by biodiversity scientists to the need to estimate trends in extinction risk of the world''s diminishing biological diversity. Assessments of plant species for the SRLI project rely predominantly on herbarium specimen data from natural history collections, in the overwhelming absence of accurate population data or detailed distribution maps for the vast majority of plant species. This creates difficulties in re-assessing these species so as to measure genuine changes in conservation status, which must be observed under the same Red List criteria in order to be distinguished from an increase in the knowledge available for that species, and thus re-calculate the SRLI. However, the same specimen data identify precise localities where threatened species have previously been collected and can be used to model species ranges and to target fieldwork in order to test specimen-based range estimates and collect population data for SRLI plant species. Here, we outline a strategy for prioritizing fieldwork efforts in order to apply a wider range of IUCN Red List criteria to assessments of plant species, or any taxa with detailed locality or natural history specimen data, to produce a more robust estimation of the SRLI.     

Does application of methyl jasmonate to birch mimic herbivory and attract insectivorous birds in nature?

Earlier studies have suggested that insectivorous birds, similar to invertebrate predators and parasitoids, may be guided by herbivore-induced plant volatiles (HIPVs) to damaged, herbivore-rich trees. Recent studies have also shown that birds use olfaction more than previously thought, underlying the potential for HIPVs to be sensed by insectivorous birds and utilised during foraging for prey. The HIPV production in plants is mediated, at least partly, by the jasmonic acid signalling pathway, and similar HIPVs to those induced by herbivores can often be induced by exposing plants to methyl jasmonate (MeJa). We studied the effects of MeJa on volatile emission and bird attraction using mature mountain birches (Betula pubescens ssp. czerepanovii) under natural conditions in northern Finland. Experimental trees were assigned to four treatment groups: herbivore-damaged [autumnal moth (Epirrita autumnata)], higher dose of MeJa (30 mM), lower dose of MeJa (15 mM) and control. All trees had three branches covered with mesh bags, but there were larvae inside the bags only of the herbivore-damage treatment. Bird predation rate was monitored with artificial plasticine larvae which were checked daily for peck marks. Birds most often pecked the larvae in the herbivore-damaged trees, but the attractiveness of MeJa-treated trees did not differ from the control. High within-treatment variation in systemic HIPV emissions probably masked MeJa treatment effects. The bird predation rate was high in birches that emitted large amounts of α-pinene. Thus, α-pinene may be one cue used by birds to find herbivore-rich birches.     

Pharmacogenomics of Cisplatin Sensitivity in Non-small Cell Lung Cancer

Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer （NSCLC） as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomark- ers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensitivity biomarkers in NSCLC. We focused on several key pathways, including nucleotide excision repair, drug transport and metabolism. Both expression and germline DNA variation were evaluated in these key pathways. Current evidence suggests that cisplatin-based treatment could be improved by the use of these biomarkers.     

Supplementation with vitamin E but not with vitamin C lowers lipid peroxidation in vivo in mildly hypercholesterolemic men

Although the use of vitamin E supplements has been associated with a reduction in coronary events, assumed to be due to lowered lipid peroxidation, there are no previous long-term clinical trials into the effects of vitamin C or E supplementation on lipid peroxidation in vivo. Here, we have studied the long-term effects of vitamins C and E on plasma F₂-isoprostanes, a widely used marker of lipid peroxidation in vivo. As a study cohort, a subset of the “Antioxidant Supplementation in Atherosclerosis Prevention” (ASAP) study was used. ASAP is a double-masked placebo-controlled randomized clinical trial to study the long-term effect of vitamin C (500 mg of slow release ascorbate daily), vitamin E (200 mg of d-α-tocopheryl acetate daily), both vitamins (CellaVie^®), or placebo on lipid peroxidation, atherosclerotic progression, blood pressure and myocardial infarction (n = 520 at baseline). Lipid peroxidation measurements were carried out in 100 consecutive men at entry and repeated at 12 months. The plasma F₂-isoprostane concentration was lowered by 17.3% (95% CI 3.9–30.8%) in the vitamin E group (p = 0.006 for the change, as compared with the placebo group). On the contrary, vitamin C had no significant effect on plasma F₂-isoprostanes as compared with the placebo group. There was also no interaction in the effect between these vitamins. In conclusion, long-term oral supplementation of clinically healthy, but hypercholesterolemic men, who have normal vitamin C and E levels with a reasonable dose of vitamin E lowers lipid peroxidation in vivo, but a relatively high dose of vitamin C does not. This observation may provide a mechanism for the observed ability of vitamin E supplements to prevent atherosclerosis.     

A systematic review of MRI studies of language development from birth to 2 years of age

Neurocognitive functions supporting language development start to develop well before first words are spoken during the first years of life. This process coincides with the initial growth spurt of the brain. While the core components of the language network are well characterized in adults and children, the initial neural correlates of language skills are still relatively unknown. We reviewed 10 studies identified via a systematic search that combined magnetic resonance imaging and language‐related measures in healthy infants from birth to 2 years of age. We aimed to describe the current knowledge as well as point out viable future directions for similar studies. Expectedly, the implicated cerebral areas included many established components of the language networks, including frontal and temporal regions. A volumetric leftward asymmetry of the brain was suggested as a determinant of language skills, yet with marked interindividual variation. Overall, temporal and frontal brain volumes associated positively with language skills. Positive associations were described between the maturation of language related white matter tracts and language skills. The language networks showed adult‐like structural similarities already in neonates, with weaker asymmetry compared to adults. In summary, we found some evidence that the language circuit described in older age groups is also associated to language skills during the first 2 years of life. However, across the reviewed studies there were no systematic neural correlates of language skills, which is partly explained by a modest number of studies, scattered representation of ages in measurements and the variance in the used methods.     

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children

Background

The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).

Methods and Findings

All studies identified to have data on the FTO rs9939609 variant (or any proxy [r ²>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (p _interaction  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents.

Conclusions

The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors'' Summary