Whole-transcriptome, high-throughput RNA sequence analysis of the bovine macrophage response to Mycobacterium bovis infection in vitro

BACKGROUND: Mycobacterium bovis, the causative agent of bovine tuberculosis, is an intracellular pathogen that can persist inside host macrophages during infection via a diverse range of mechanisms that subvert the host immune response. In the current study, we have analysed and compared the transcriptomes of M. bovis-infected monocyte-derived macrophages (MDM) purified from six Holstein-Friesian females with the transcriptomes of non-infected control MDM from the same animals over a 24 h period using strand-specific RNA sequencing (RNA-seq). In addition, we compare gene expression profiles generated using RNA-seq with those previously generated by us using the high-density Affymetrix® GeneChip® Bovine Genome Array platform from the same MDM-extracted RNA. RESULTS: A mean of 7.2 million reads from each MDM sample mapped uniquely and unambiguously to single Bos taurus reference genome locations. Analysis of these mapped reads showed 2,584 genes (1,392 upregulated; 1,192 downregulated) and 757 putative natural antisense transcripts (558 upregulated; 119 downregulated) that were differentially expressed based on sense and antisense strand data, respectively (adjusted P-value ≤ 0.05). Of the differentially expressed genes, 694 were common to both the sense and antisense data sets, with the direction of expression (i.e. up- or downregulation) positively correlated for 693 genes and negatively correlated for the remaining gene. Gene ontology analysis of the differentially expressed genes revealed an enrichment of immune, apoptotic and cell signalling genes. Notably, the number of differentially expressed genes identified from RNA-seq sense strand analysis was greater than the number of differentially expressed genes detected from microarray analysis (2,584 genes versus 2,015 genes). Furthermore, our data reveal a greater dynamic range in the detection and quantification of gene transcripts for RNA-seq compared to microarray technology. CONCLUSIONS: This study highlights the value of RNA-seq in identifying novel immunomodulatory mechanisms that underlie host-mycobacterial pathogen interactions during infection, including possible complex post-transcriptional regulation of host gene expression involving antisense RNA

See-Saw Masses for Quarks and Leptons in SU(5)

We build on a recent paper by Grinstein, Redi and Villadoro, where a see-saw like mechanism for quark masses was derived in the context of spontaneously broken gauged flavour symmetries. The see-saw mechanism is induced by heavy Dirac fermions which are added to the Standard Model spectrum in order to render the flavour symmetries anomaly-free. In this letter we report on the embedding of these fermions into multiplets of an SU(5) grand unified theory and discuss a number of interesting consequences.Comment: 15 pages, 4 figures (v3: outline restructured, modified mechanism to cancel anomalies

Timing of retinal neuronal and axonal loss in MS: a longitudinal OCT study

The objective of the study was to investigate the timing of central nervous system tissue atrophy in MS by evaluating longitudinal retinal volume changes in a broadly representative cohort with disease duration across the entire arc of disease. In this longitudinal study, 135 patients with MS and 16 healthy reference subjects underwent spectral-domain optical coherence tomography (OCT) at baseline and 2 years later. Following OCT quality control, automated segmentation of the peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell–inner plexiform layer (mGCIPL) and macular inner nuclear layer (mINL) was performed. Generalized estimation equations were used to analyze longitudinal changes and associations with disease duration and clinical measures. Participants had a median disease duration at baseline of 16.4 years (range 0.1–45.4). Nearly half (44 %) of the MS patients had previously experienced MS-related optic neuritis (MSON) more than 6 months prior. The MS patients demonstrated a significant decrease over 2 years of the pRNFL (−1.1 µm, 95 % CI 1.4–0.7, p < 0.001) and mGCIPL (−1.1 µm, 95 % CI −1.4 to −0.8, p < 0.001). This thinning was most pronounced early in the course of disease. These findings were irrespective of previous episodes of MSON. No consistent pattern of change was observed for the mINL (−0.03 µm, 95 % CI −0.2 to 0.2, p = 0.795). This longitudinal study demonstrated that injury of the innermost retinal layers is found in MS and that this damage occurs most rapidly during the early stages of disease. The attenuation of atrophy with longer disease duration is suggestive of a plateau effect. These findings emphasize the importance of early intervention to prevent such injury

A Comparative Study of Contributions to ϵK\epsilon_K in the RS Model

We contrast the impact of Higgs mediated flavor changing neutral currents on epsilon_K in the framework of a warped extra dimension that was recently calculated by Azatov et al. with the older results for Kaluza-Klein gluon induced corrections to that observable. We find that the most stringent constraint on the KK scale for a Higgs field localized on the infrared brane for reasonable additional assumptions comes from KK gluon exchange. In the case of a bulk Higgs field we show that for certain scenarios the Higgs contribution can in fact exceed the KK gluon contribution. In the course of this analysis we also describe in detail the different renormalization procedures that have to be employed in the KK gluon and Higgs cases to relate the new physics at high energies to low energy observables.Comment: 13 pages, 5 figures. Extended discussion, references added, typos correcte

Effective Feedback to Improve Primary Care Prescribing Safety (EFIPPS) a pragmatic three-arm cluster randomised trial:designing the intervention (ClinicalTrials.gov registration NCT01602705)

Peer reviewedPublisher PD

The Impact of Flavour Changing Neutral Gauge Bosons on B->X_s gamma

The branching ratio of the rare decay B->X_s gamma provides potentially strong constraints on models beyond the Standard Model. Considering a general scenario with new heavy neutral gauge bosons, present in particular in Z' and gauge flavour models, we point out two new contributions to the B->X_s gamma decay. The first one originates from one-loop diagrams mediated by gauge bosons and heavy exotic quarks with electric charge -1/3. The second contribution stems from the QCD mixing of neutral current-current operators generated by heavy neutral gauge bosons and the dipole operators responsible for the B->X_s gamma decay. The latter mixing is calculated here for the first time. We discuss general sum rules which have to be satisfied in any model of this type. We emphasise that the neutral gauge bosons in question could also significantly affect other fermion radiative decays as well as non-leptonic two-body B decays, epsilon'/epsilon, anomalous (g-2)_mu and electric dipole moments.Comment: 31 pages, 5 figures; version published on JHEP; added magic QCD numbers for flavour-violating Z gauge boson contribution to B -> X_s gamm

Meaning behind measurement : self-comparisons affect responses to health related quality of life questionnaires

Purpose The subjective nature of quality of life is particularly pertinent to the domain of health-related quality of life (HRQOL) research. The extent to which participants’ responses are affected by subjective information and personal reference frames is unknown. This study investigated how an elderly population living with a chronic metabolic bone disorder evaluated self-reported quality of life. Methods Participants (n = 1,331) in a multi-centre randomised controlled trial for the treatment of Paget’s disease completed annual HRQOL questionnaires, including the SF-36, EQ-5D and HAQ. Supplementary questions were added to reveal implicit reference frames used when making HRQOL evaluations. Twenty-one participants (11 male, 10 female, aged 59–91 years) were interviewed retrospectively about their responses to the supplementary questions, using cognitive interviewing techniques and semi-structured topic guides. Results The interviews revealed that participants used complex and interconnected reference frames to promote response shift when making quality of life evaluations. The choice of reference frame often reflected external factors unrelated to individual health. Many participants also stated that they were unclear whether to report general or disease-related HRQOL. Conclusions It is important, especially in clinical trials, to provide instructions clarifying whether ‘quality of life’ refers to disease-related HRQOL. Information on selfcomparison reference frames is necessary for the interpretation of responses to questions about HRQOL.The Chief Scientist Office of the Scottish Government Health Directorates, The PRISM funding bodies (the Arthritis Research Campaign, the National Association for the Relief of Paget’s disease and the Alliance for Better Bone Health)Peer reviewedAuthor final versio

Gauged flavour symmetry for the light generations

We study the phenomenology of a model where an SU(2)^3 flavour symmetry acting on the first two generation quarks is gauged and Yukawa couplings for the light generations are generated by a see-saw mechanism involving heavy fermions needed to cancel flavour-gauge anomalies. We find that, in constrast to the SU(3)^3 case studied in the literature, most of the constraints related to the third generation, like electroweak precision bounds or B physics observables, can be evaded, while characteristic collider signatures are predicted.Comment: 16 pages, 3 figure

Inflation on the Brane with Vanishing Gravity

Many existing models of brane inflation suffer from a steep irreducible gravitational potential between the branes that causes inflation to end too early. Inspired by the fact that point masses in 2+1 D exert no gravitational force, we propose a novel unwarped and non-supersymmetric setup for inflation, consisting of 3-branes in two extra dimensions compactified on a sphere. The size of the sphere is stabilized by a combination of a bulk cosmological constant and a magnetic flux. Computing the 4D effective potential between probe branes in this background, we find a non-zero contribution only from exchange of level-1 KK modes of the graviton and radion. Identifying antipodal points on the 2-sphere projects out these modes, eliminating entirely the troublesome gravitational contribution to the inflationary potential.Comment: 19 pages, 11 figures, JHEP forma