Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome

peer-reviewedBackground Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. Results Here, we apply an approach to gene set enrichment analysis that allows for detection of bi-directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p < 0.05), followed by muscle (601 genes) and adipose (16 genes). Results from modified GSEA showed that the high-CLA beef diet affected diverse biological processes across the three tissues, and that the majority of pathway changes reached significance only with the bi-directional test. Combining the liver tissue microarray results with plasma marker data revealed 110 CLA-sensitive genes showing strong canonical correlation with one or more plasma markers of metabolic health, and 9 significantly overrepresented pathways among this set; each of these pathways was also significantly changed by the high-CLA diet. Closer inspection of two of these pathways - selenoamino acid metabolism and steroid biosynthesis - illustrated clear diet-sensitive changes in constituent genes, as well as strong correlations between gene expression and plasma markers of metabolic syndrome independent of the dietary effect. Conclusion Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of analysis has the potential to generate novel transcriptome-based biomarkers of disease.Department of Agriculture and Food, Ireland - Food Institutional Research Measure (project no. 5254); IRCSET postgraduate scholarship scheme (MJM); Science Foundation Ireland Principal Investigator Programme (HMR) Programme

Beam Dynamics and First Operation of the Sub-Harmonic Bunching System in the CTF3 Injector

The CLIC Test Facility 3 (CTF3), built at CERN by an international collaboration, aims at demonstrating the feasibility of the CLIC scheme by 2010. The CTF3 drive beam generation scheme relies on the use of a fast phase switch of a sub-harmonic bunching system in order to phase-code the bunches. The amount of charge in unwanted satellite bunches is an important quantity, which must be minimized. Beam dynamic simulations have been used to study the problem, showing the limitation of the present CTF3 design and the gain of potential upgrades. In this paper the results are discussed and compared with beam measurements taken during the first operation of the system

Selective expansion of viral variants following experimental transmission of a reconstituted feline immunodeficiency virus quasispecies

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development

Visual neglect in posterior cortical atrophy

In posterior cortical atrophy (PCA), there is a progressive impairment of high-level visual functions and parietal damage, which might predict the occurrence of visual neglect. However, neglect may pass undetected if not assessed with specific tests, and might therefore be underestimated in PCA. In this prospective study, we aimed at establishing the side, the frequency and the severity of visual neglect, visual extinction, and primary visual field defects in an unselected sample of PCA patients

Clinical and genetic characterization of leukoencephalopathies in adults

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults

CTF3 Design Report: Preliminary Phase

The design of CLIC is based on a two-beam scheme, where the short pulses of high power 30 GHz RF are extracted from a drive beam running parallel to the main beam. The 3rd generation CLIC Test Facility (CTF3) will demonstrate the generation of the drive beam with the appropriate time structure, the extraction of 30 GHz RF power from this beam, as well as acceleration of a probe beam with 30 GHz RF cavities. The project makes maximum use of existing equipment and infrastructure of the LPI complex, which became available after the closure of LEP. In the first stage of the project, the "Preliminary Phase", the existing LIL linac and the EPA ring, both modified to suit the new requirements, are used to investigate the technique of frequency multiplication by means of interleaving bunches from subsequent trains. This report describes the design of this phase

Posterior cortical atrophy and Alzheimer’s disease : a meta-analytic review of neuropsychological and brain morphometry studies

This paper presents the first systematic review and meta-analysis of neuropsychological and brain morphometry studies comparing posterior cortical atrophy (PCA) to typical Alzheimer's disease (tAD). Literature searches were conducted for brain morphometry and neuropsychological studies including a PCA and a tAD group. Compared to healthy controls (HC), PCA patients exhibited significant decreases in temporal, occipital and parietal gray matter (GM) volumes, whereas tAD patients showed extensive left temporal atrophy. Compared to tAD patients, participants with PCA showed greater GM volume reduction in the right occipital gyrus extending to the posterior lobule. In addition, PCA patients showed less GM volume loss in the left parahippocampal gyrus and left hippocampus than tAD patients. PCA patients exhibit significantly greater impairment in Immediate Visuospatial Memory as well as Visuoperceptual and Visuospatial Abilities than patients with tAD. However, tAD patients showed greater impairment in Delayed Auditory/Verbal Memory than patients with PCA. PCA is characterized by significant atrophy of the occipital and parietal regions and severe impairments in visuospatial functioning.JA is funded by a doctoral grant from the Foundation for Science and Technology, FCT (SFRH/BD/64457/2009, co-funded by FSE/POPH). JA and AS are funded by project PIC/IC/83290/2007, which is supported by FEDER (POFC-COMPETE) and FCT. JMS is supported by a fellowship of the project SwitchBox-FP7-HEALTH-2010-grant 259772-2. These organizations had no role in the study design, data collection, analysis, interpretation, or in the decision to submit the paper for publication

A primary electron beam facility at CERN -- eSPS Conceptual design report

The design of a primary electron beam facility at CERN is described. The study has been carried out within the framework of the wider Physics Beyond Colliders study. It re-enables the Super Proton Synchrotron (SPS) as an electron accelerator, and leverages the development invested in Compact Linear Collider (CLIC) technology for its injector and as an accelerator research and development infrastructure. The facility would be relevant for several of the key priorities in the 2020 update of the European Strategy for Particle Physics, such as an electron-positron Higgs factory, accelerator R\&D, dark sector physics, and neutrino physics. In addition, it could serve experiments in nuclear physics. The electron beam delivered by this facility would provide access to light dark matter production significantly beyond the targets predicted by a thermal dark matter origin, and for natures of dark matter particles that are not accessible by direct detection experiments. It would also enable electro-nuclear measurements crucial for precise modelling the energy dependence of neutrino-nucleus interactions, which is needed to precisely measure neutrino oscillations as a function of energy. The implementation of the facility is the natural next step in the development of X-band high-gradient acceleration technology, a key technology for compact and cost-effective electron/positron linacs. It would also become the only facility with multi-GeV drive bunches and truly independent electron witness bunches for plasma wakefield acceleration. A second phase capable to deliver positron witness bunches would make it a complete facility for plasma wakefield collider studies. [...