Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis

Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which - once applied to human neutrophils - attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2 biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor-deficient mice termed ALX/fpr2/3-/- . These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA

The LONI QC System: A Semi-Automated, Web-Based and Freely-Available Environment for the Comprehensive Quality Control of Neuroimaging Data.

Quantifying, controlling, and monitoring image quality is an essential prerequisite for ensuring the validity and reproducibility of many types of neuroimaging data analyses. Implementation of quality control (QC) procedures is the key to ensuring that neuroimaging data are of high-quality and their validity in the subsequent analyses. We introduce the QC system of the Laboratory of Neuro Imaging (LONI): a web-based system featuring a workflow for the assessment of various modality and contrast brain imaging data. The design allows users to anonymously upload imaging data to the LONI-QC system. It then computes an exhaustive set of QC metrics which aids users to perform a standardized QC by generating a range of scalar and vector statistics. These procedures are performed in parallel using a large compute cluster. Finally, the system offers an automated QC procedure for structural MRI, which can flag each QC metric as being 'good' or 'bad.' Validation using various sets of data acquired from a single scanner and from multiple sites demonstrated the reproducibility of our QC metrics, and the sensitivity and specificity of the proposed Auto QC to 'bad' quality images in comparison to visual inspection. To the best of our knowledge, LONI-QC is the first online QC system that uniquely supports the variety of functionality where we compute numerous QC metrics and perform visual/automated image QC of multi-contrast and multi-modal brain imaging data. The LONI-QC system has been used to assess the quality of large neuroimaging datasets acquired as part of various multi-site studies such as the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study and the Alzheimer's Disease Neuroimaging Initiative (ADNI). LONI-QC's functionality is freely available to users worldwide and its adoption by imaging researchers is likely to contribute substantially to upholding high standards of brain image data quality and to implementing these standards across the neuroimaging community

Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in two zebrafish models

RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the contribution of rbfox1 to behaviour, we used rbfox1sa15940, a zebrafish mutant line with TL background. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 mutant line with a different genetic background (TU), rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that mutations in rbfox1 lead to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study, thus, highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders

PrevenBox: Evaluation of concomitant use of preventive medications with OnabotulinumtoxinA in migraine

P114 Background: OnabotulinumtoxinA is an effective, tolerable and safepreventive treatment for chronic migraine (CM). Other than a reduc-tion in headache frequency or disability, in CM the withdrawal ofconcomitant preventive medication indicates treatment effectivenessand quality of life improvement. Objective: To characterize the change in the use of oral preventivemedication after treatment with OnabotulinumtoxinA in patientswith migraine. Methods: This is a multicentre study. We consecutively included pa-tients with migraine (ICHD-3) that were on preventive treatment withOnabotulinumtoxinA. We retrospectively collected demographic data, diagnosis of migraine, frequency and intensity changes, number ofcycle and OnabotulinumtoxinA dose. In addition, we listed the initialand current preventive treatment (number of drugs and group) andthe number and cycle of medications withdrawn. We performed aunivariate and logistic regression analysis. Results: We included 542 patients: 87.6% women, mean age 47.6 ±11.7 years. A 89.3% had chronic migraine and 10.8% had high fre-quency episodic migraine. The mean reduction in frequency aftertreatment was 13.4±8.2 headache days/month. At baseline, a 91.3%took other preventives and during treatment with Onabotulinumtox-inA a 58.6% withdrew at least one drug, 25.8% stopped completelyall oral preventive drugs. Factors associated with withdrawal were:being male, having >50% response in frequency and intensity, thenumber of infiltrations and a shorter chronification period until thefirst OnabotulinumtoxinA administration (p <0.05). The multivariateanalysis showed that a better response in intensity (OR:1.8 [1.4-2.2], p<0.001), a greater number of infiltrations (OR:1.1 [1.0-1.2], p<0.001)and a shorter chronification period (OR:0.994 [0.992-0.997], p<0.001)were predictors of withdrawal. The ROC curve, showed that 6 Onabo-tulinumtoxinA cycles was the cut-off point that better predicted oralpreventive medication withdrawal (p <0.001). Conclusions: Treatment with OnabotulinumtoxinA reduces the use ofother preventive medications for migraine. The highest probability ofwithdrawal occurs after 6 cycles of treatment

Experimental admixture among geographically disjunct populations of an invasive plant yields a global mosaic of reproductive incompatibility and heterosis

1. Invasive species have the ability to rapidly adapt in the new regions where they are introduced. Classic evolutionary theory predicts that the accumulation of genetic differences over time in allopatric isolation may lead to reproductive incompatibilities resulting in decreases in reproductive success and, eventually, to speciation. However, experimental evidence for this theoretical prediction in the context of invasive species is lacking. We aimed to test for the potential of allopatry to determine reproductive success of invasive plants, by experimentally admixing genotypes from six different native and non‐native regions of Centaurea solstitialis, an invasive forb for which preliminary studies have detected some degree of reproductive isolation between one native and non‐native region. 2. We grew plants under common garden conditions and outcrossed individuals originating from different source populations in the native and introduced range to evaluate reproductive success in terms of seed to ovule ratio produced. We also assessed geographical and genetic isolation among C. solstitialis regions as a potential driving factor of reproductive success. 3. Experimental admixture generated mixed fitness effects, including significant increases, decreases and no differences in reproductive success as compared to crosses within population (control). Centaurea solstitialis invasive populations in the Americas generated preponderantly negative fitness interactions, regardless of the pollen source, suggesting selection against immigrants and reinforcement. Other non‐native populations (Australia) as well as individuals from the native range of Spain demonstrated an increase in fitness for between‐region crosses, indicating inbreeding. These differences show an asymmetrical response to inter‐regional gene flow, but no evidence of isolation by distance. 4. Synthesis. The speed of adaptation and the accumulation of reproductive incompatibilities among allopatric populations of invasive species might be more rapid than previously assumed. Our data show a global mosaic of reproductive outputs, showcasing an array of evolutionary processes unfolding during colonization at large biogeographical scales

Enhancement of the non-invasive electroenterogram to identify intestinal pacemaker activity

Surface recording of electroenterogram (EEnG) is a non-invasive method for monitoring intestinal myoelectrical activity. However, surface EEnG is seriously affected by a variety of interferences: cardiac activity, respiration, very low frequency components and movement artefacts. The aim of this study is to eliminate respiratory interference and very low frequency components from external EEnG recording by means of empirical mode decomposition (EMD), so as to obtain more robust indicators of intestinal pacemaker activity from external EEnG signal. For this purpose, 11 recording sessions were performed in an animal model under fasting conditions and in each individual session the myoelectrical signal was recorded simultaneously in the intestinal serosa and the external abdominal surface in physiological states. Various parameters have been proposed for evaluating the efficacy of the method in reducing interferences: the signal-to-interference ratio (S/I ratio), attenuation of the target and interference signals, the normal slow wave percentage and the stability of the dominant frequency (DF) of the signal. The results show that the S/I ratio of the processed signals is significantly greater than the original values (9.66±4.44 dB vs. 1.23±5.13 dB), while the target signal was barely attenuated (-0.63±1.02 dB). The application of the EMD method also increased the percentage of the normal slow wave to 100% in each individual session and enabled the stability of the DF of the external signal to be increased considerably. Furthermore, the variation coefficient of the DF derived from the external processed signals is comparable to the coefficient obtained using internal recordings. Therefore the EMD method could be a very useful tool to improve the quality of external EEnG recording in the low frequency range, and therefore to obtain more robust indicators of the intestinal pacemaker activity from non invasive EEnG recordingsThe authors would like to thank D Alvarez-Martinez, Dr C Vila and the Veterinary Unit of the Research Centre of 'La Fe' University Hospital (Valencia, Spain), where the surgical interventions and recording sessions were carried out, and the R+D+I Linguistic Assistance Office at the UPV for their help in revising this paper. This research study was sponsored by the Ministerio de Ciencia y Tecnologia de Espana (TEC2007-64278) and by the Universidad Politecnica de Valencia, as part of a UPV research and development Grant Programme.Ye Lin, Y.; Garcia Casado, FJ.; Prats Boluda, G.; Ponce, JL.; Martínez De Juan, JL. (2009). Enhancement of the non-invasive electroenterogram to identify intestinal pacemaker activity. 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Evolutionary Convergence on Highly-Conserved 3′ Intron Structures in Intron-Poor Eukaryotes and Insights into the Ancestral Eukaryotic Genome

The presence of spliceosomal introns in eukaryotes raises a range of questions about genomic evolution. Along with the fundamental mysteries of introns' initial proliferation and persistence, the evolutionary forces acting on intron sequences remain largely mysterious. Intron number varies across species from a few introns per genome to several introns per gene, and the elements of intron sequences directly implicated in splicing vary from degenerate to strict consensus motifs. We report a 50-species comparative genomic study of intron sequences across most eukaryotic groups. We find two broad and striking patterns. First, we find that some highly intron-poor lineages have undergone evolutionary convergence to strong 3′ consensus intron structures. This finding holds for both branch point sequence and distance between the branch point and the 3′ splice site. Interestingly, this difference appears to exist within the genomes of green alga of the genus Ostreococcus, which exhibit highly constrained intron sequences through most of the intron-poor genome, but not in one much more intron-dense genomic region. Second, we find evidence that ancestral genomes contained highly variable branch point sequences, similar to more complex modern intron-rich eukaryotic lineages. In addition, ancestral structures are likely to have included polyT tails similar to those in metazoans and plants, which we found in a variety of protist lineages. Intriguingly, intron structure evolution appears to be quite different across lineages experiencing different types of genome reduction: whereas lineages with very few introns tend towards highly regular intronic sequences, lineages with very short introns tend towards highly degenerate sequences. Together, these results attest to the complex nature of ancestral eukaryotic splicing, the qualitatively different evolutionary forces acting on intron structures across modern lineages, and the impressive evolutionary malleability of eukaryotic gene structures

Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study

Background: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. Methods: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDGPET/CT focusing on several territories’ vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. Results: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. Conclusions: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory

Plasmon oscillations in ellipsoid nanoparticles: beyond dipole approximation

The plasmon oscillations of a metallic triaxial ellipsoid nanoparticle have been studied within the framework of the quasistatic approximation. A general method has been proposed for finding the analytical expressions describing the potential and frequencies of the plasmon oscillations of an arbitrary multipolarity order. The analytical expressions have been derived for an electric potential and plasmon oscillation frequencies of the first 24 modes. Other higher orders plasmon modes are investigated numerically.Comment: 33 pages, 12 figure