Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms

Universal switching of plasmonic signals using optical resonator modes

We propose and investigate, both experimentally and theoretically, a novel mechanism for switching and modulating plasmonic signals based on a Fano interference process, which arises from the coupling between a narrow-band optical Fabry–Pérot cavity and a surface plasmon polariton (SPP) source. The SPP wave emitted from the cavity is actively modulated in the vicinity of the cavity resonances by altering the cavity Q-factor and/or resonant frequencies. We experimentally demonstrate dynamic SPP modulation both by mechanical control of the cavity length and all-optically by harnessing the ultrafast nonlinearity of the Au mirrors that form the cavity. An electro-optical modulation scheme is also proposed and numerically illustrated. Dynamic operation of the switch via mechanical means yields a modulation in the SPP coupling efficiency of ~ 80%, while the all-optical control provides an ultrafast modulation with an efficiency of 30% at a rate of ~ 0.6 THz. The experimental observations are supported by both analytical and numerical calculations of the mechanical, all-optical and electro-optical modulation methods

A principal factor analysis to characterize agricultural exposures among Nebraska veterans

Agricultural workers are at an increased risk of developing chronic respiratory disorders. Accurate estimation of long-term agricultural exposures based on questionnaires has been used to improve the validity of epidemiologic investigations and subsequent evaluation of the association between agricultural exposures and chronic diseases. Our aim was to use principal factor analysis (PFA) to distill exposure data into essential variables characterizing long-term agricultural exposures. This is a crosssectional study of veterans between the ages of 40 and 80 years and who worked on a farm for ≥ 2 years. Participant characteristics were: 98.1% were white males with a mean age 65 ± 8 (SD) years and 39.8% had chronic obstructive pulmonary disease. The final model included four factors and explained 16.6% of the variance in the exposure data. Factor 1 was a heterogeneous factor; however, Factor 2 was exclusively composed of exposure to livestock such as hogs, dairy and poultry. Factor 3 included exposures from jobs on or off the farm such as wood dust, mineral dust, asbestos and spray paint. Crop exposure loaded exclusively in Factor 4 and included lifetime hours of exposure and maximum number of acres farmed in the participants’ lifetime. The factors in the final model were interpretable and consistent with farming practices

Recording behaviour of indoor-housed farm animals automatically using machine vision technology: a systematic review

Large-scale phenotyping of animal behaviour traits is time consuming and has led to increased demand for technologies that can automate these procedures. Automated tracking of animals has been successful in controlled laboratory settings, but recording from animals in large groups in highly variable farm settings presents challenges. The aim of this review is to provide a systematic overview of the advances that have occurred in automated, high throughput image detection of farm animal behavioural traits with welfare and production implications. Peer-reviewed publications written in English were reviewed systematically following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After identification, screening, and assessment for eligibility, 108 publications met these specifications and were included for qualitative synthesis. Data collected from the papers included camera specifications, housing conditions, group size, algorithm details, procedures, and results. Most studies utilized standard digital colour video cameras for data collection, with increasing use of 3D cameras in papers published after 2013. Papers including pigs (across production stages) were the most common (n = 63). The most common behaviours recorded included activity level, area occupancy, aggression, gait scores, resource use, and posture. Our review revealed many overlaps in methods applied to analysing behaviour, and most studies started from scratch instead of building upon previous work. Training and validation sample sizes were generally small (mean±s.d. groups = 3.8±5.8) and in data collection and testing took place in relatively controlled environments. To advance our ability to automatically phenotype behaviour, future research should build upon existing knowledge and validate technology under commercial settings and publications should explicitly describe recording conditions in detail to allow studies to be reproduced

The reference frame for encoding and retention of motion depends on stimulus set size

YesThe goal of this study was to investigate the reference frames used in perceptual encoding and storage of visual motion information. In our experiments, observers viewed multiple moving objects and reported the direction of motion of a randomly selected item. Using a vector-decomposition technique, we computed performance during smooth pursuit with respect to a spatiotopic (nonretinotopic) and to a retinotopic component and compared them with performance during fixation, which served as the baseline. For the stimulus encoding stage, which precedes memory, we found that the reference frame depends on the stimulus set size. For a single moving target, the spatiotopic reference frame had the most significant contribution with some additional contribution from the retinotopic reference frame. When the number of items increased (Set Sizes 3 to 7), the spatiotopic reference frame was able to account for the performance. Finally, when the number of items became larger than 7, the distinction between reference frames vanished. We interpret this finding as a switch to a more abstract nonmetric encoding of motion direction. We found that the retinotopic reference frame was not used in memory. Taken together with other studies, our results suggest that, whereas a retinotopic reference frame may be employed for controlling eye movements, perception and memory use primarily nonretinotopic reference frames. Furthermore, the use of nonretinotopic reference frames appears to be capacity limited. In the case of complex stimuli, the visual system may use perceptual grouping in order to simplify the complexity of stimuli or resort to a nonmetric abstract coding of motion information

P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy

open access articleDuchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP–P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target