oxBS-450K: A method for analysing hydroxymethylation using 450K BeadChips

DNA methylation analysis has become an integral part of biomedical research. For high-throughput applications such as epigenome-wide association studies, the Infinium HumanMethylation450 (450K) BeadChip is currently the platform of choice. However, BeadChip processing relies on traditional bisulfite (BS) based protocols which cannot discriminate between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Here, we report the adaptation of the recently developed oxidative bisulfite (oxBS) chemistry to specifically detect both 5mC and 5hmC in a single workflow using 450K BeadChips, termed oxBS-450K. Supported by validation using mass spectrometry and pyrosequencing, we demonstrate reproducible (R(2)>0.99) detection of 5hmC in human brain tissue using the optimised oxBS-450K protocol described here

Holographic Fermi and Non-Fermi Liquids with Transitions in Dilaton Gravity

We study the two-point function for fermionic operators in a class of strongly coupled systems using the gauge-gravity correspondence. The gravity description includes a gauge field and a dilaton which determines the gauge coupling and the potential energy. Extremal black brane solutions in this system typically have vanishing entropy. By analyzing a charged fermion in these extremal black brane backgrounds we calculate the two-point function of the corresponding boundary fermionic operator. We find that in some region of parameter space it is of Fermi liquid type. Outside this region no well-defined quasi-particles exist, with the excitations acquiring a non-vanishing width at zero frequency. At the transition, the two-point function can exhibit non-Fermi liquid behaviour.Comment: 52 pages, 6 figures. v3: Appendix F added showing numerical interpolation between the near-horizon region and AdS4. Additional minor comments also adde

Diffractive Higgs Production by AdS Pomeron Fusion

The double diffractive Higgs production at central rapidity is formulated in terms of the fusion of two AdS gravitons/Pomerons first introduced by Brower, Polchinski, Strassler and Tan in elastic scattering. Here we propose a simple self-consistent holographic framework capable of providing phenomenologically compelling estimates of diffractive cross sections at the LHC. As in the traditional weak coupling approach, we anticipate that several phenomenological parameters must be tested and calibrated through factorization for a self-consistent description of other diffractive process such as total cross sections, deep inelastic scattering and heavy quark production in the central region.Comment: 53 pages, 8 figure

String Theory on Warped AdS_3 and Virasoro Resonances

We investigate aspects of holographic duals to time-like warped AdS_3 space-times--which include G\"odel's universe--in string theory. Using worldsheet techniques similar to those that have been applied to AdS_3 backgrounds, we are able to identify space-time symmetry algebras that act on the dual boundary theory. In particular, we always find at least one Virasoro algebra with computable central charge. Interestingly, there exists a dense set of points in the moduli space of these models in which there is actually a second commuting Virasoro algebra, typically with different central charge than the first. We analyze the supersymmetry of the backgrounds, finding related enhancements, and comment on possible interpretations of these results. We also perform an asymptotic symmetry analysis at the level of supergravity, providing additional support for the worldsheet analysis.Comment: 24 pages + appendice

Modulated Instability in Five-Dimensional U(1) Charged AdS Black Hole with R**2-term

We study the effect of R**2 term to the modulated instability in the U(1) charged black hole in five-dimensional Anti-de Sitter space-time. We consider the first-order corrections of R**2 term to the background and the linear order perturbations in the equations of motion. From the analysis, we clarify the effect of R**2 term in the modulated instability, and conclude that fluctuations are stable in the whole bulk in the range of values the coefficient of R**2 term can take.Comment: 19 pages, 1 figures; (v4) Published version in JHE

Non-classical ProIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent

Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1

The role of the RACK1 ortholog Cpc2p in modulating pheromone-induced cell cycle arrest in fission yeast

The detection and amplification of extracellular signals requires the involvement of multiple protein components. In mammalian cells the receptor of activated C kinase (RACK1) is an important scaffolding protein for signal transduction networks. Further, it also performs a critical function in regulating the cell cycle by modulating the G1/S transition. Many eukaryotic cells express RACK1 orthologs, with one example being Cpc2p in the fission yeast Schizosaccharomyces pombe. In contrast to RACK1, Cpc2p has been described to positively regulate, at the ribosomal level, cells entry into M phase. In addition, Cpc2p controls the stress response pathways through an interaction with Msa2p, and sexual development by modulating Ran1p/Pat1p. Here we describe investigations into the role, which Cpc2p performs in controlling the G protein-mediated mating response pathway. Despite structural similarity to Gβ-like subunits, Cpc2p appears not to function at the G protein level. However, upon pheromone stimulation, cells overexpressing Cpc2p display substantial cell morphology defects, disorientation of septum formation and a significantly protracted G1 arrest. Cpc2p has the potential to function at multiple positions within the pheromone response pathway. We provide a mechanistic interpretation of this novel data by linking Cpc2p function, during the mating response, with its previous described interactions with Ran1p/Pat1p. We suggest that overexpressing Cpc2p prolongs the stimulated state of pheromone-induced cells by increasing ste11 gene expression. These data indicate that Cpc2p regulates the pheromone-induced cell cycle arrest in fission yeast by delaying cells entry into S phase

DWSB in heterotic flux compactifications

We address the construction of non-supersymmetric vacua in heterotic compactifications with intrinsic torsion and background fluxes. In particular, we implement the approach of domain-wall supersymmetry breaking (DWSB) previously developed in the context of type II flux compactifications. This approach is based on considering backgrounds where probe NS5-branes wrapping internal three-cycles and showing up as four-dimensional domain-walls do not develop a BPS bound, while all the other BPS bounds characterizing the N=1 supersymmetric compactifications are preserved at tree-level. Via a scalar potential analysis we provide the conditions for these backgrounds to solve the ten-dimensional equations of motion including order \alpha' corrections. We also consider backgrounds where some of the NS5-domain-walls develop a BPS bound, show their relation to no-scale SUSY-breaking vacua and construct explicit examples via elliptic fibrations. Finally, we consider backgrounds with a non-trivial gaugino condensate and discuss their relation to supersymmetric and non-supersymmetric vacua in the present context.Comment: 56 pages, 1 figur

Soft branes in supersymmetry-breaking backgrounds

We revisit the analysis of effective field theories resulting from non-supersymmetric perturbations to supersymmetric flux compactifications of the type-IIB superstring with an eye towards those resulting from the backreaction of a small number of anti-D3-branes. Independently of the background, we show that the low-energy Lagrangian describing the fluctuations of a stack of probe D3-branes exhibits soft supersymmetry breaking, despite perturbations to marginal operators that were not fully considered in some previous treatments. We take this as an indication that the breaking of supersymmetry by anti-D3-branes or other sources may be spontaneous rather than explicit. In support of this, we consider the action of an anti-D3-brane probing an otherwise supersymmetric configuration and identify a candidate for the corresponding goldstino.Comment: 36+5 pages. References added, minor typos correcte

Pulmonary tuberculosis among women with cough attending clinics for family planning and maternal and child health in Dar Es Salaam, Tanzania

Tuberculosis (TB) case detection in women has remained low in developing world. This study was conducted to determine the proportion of smear positive TB among women with cough regardless of the duration attending family Planning (FP) and Maternal and child health (MCH) clinics in Dar es Salaam. We conducted a cross sectional study in all three municipal hospitals of Dar es Salaam, between October 2007 and June 2008. All women with cough attending FP and MCH clinics were screened for TB by smear microscopy. Pearson chi-square was used to compare group difference for categorical variables. Risk factors for smear positive were estimated by logistics regression with 95% confidence intervals (CI) given for odds ratios indicating statistically significant relationship if the CI did not include one. We enrolled a total of 749 TB suspects. Five hundred and twenty nine patients (70.6%) were from MCH clinics. Mean (SD) age was 27.6 (5.2) years. A total of 616 (82.2%) patients were coughing for less than two weeks as compared to 133 (17.8%), who coughed for two or more weeks. Among 616 TB suspects, 14 (2.3%) were smear positive TB patients, and of the 133 who had coughed for two or more weeks, 13 (9.8%) were smear positive TB patients. Risk factors associated with smear positive results were having attended more than one visit to any facility prior to diagnosis (OR = 6.8; 95%CI 2.57-18.0) and having HIV/AIDS (OR = 4.4; 95%CI 1.65-11.96). Long duration of cough was not a risk factor for being smear positive (OR = 1.6; 95%CI 0.59-4.49). The proportion of smear positive TB patients among women with cough attending MCH and FP was 3.8%. Visits to any health facility prior to Diagnosis and HIV infection were risk for having a smear positive TB