Multi-Messenger Gravitational Wave Searches with Pulsar Timing Arrays: Application to 3C66B Using the NANOGrav 11-year Data Set

When galaxies merge, the supermassive black holes in their centers may form binaries and, during the process of merger, emit low-frequency gravitational radiation in the process. In this paper we consider the galaxy 3C66B, which was used as the target of the first multi-messenger search for gravitational waves. Due to the observed periodicities present in the photometric and astrometric data of the source of the source, it has been theorized to contain a supermassive black hole binary. Its apparent 1.05-year orbital period would place the gravitational wave emission directly in the pulsar timing band. Since the first pulsar timing array study of 3C66B, revised models of the source have been published, and timing array sensitivities and techniques have improved dramatically. With these advances, we further constrain the chirp mass of the potential supermassive black hole binary in 3C66B to less than $(1.65\pm0.02) \times 10^9~{M_\odot}$ using data from the NANOGrav 11-year data set. This upper limit provides a factor of 1.6 improvement over previous limits, and a factor of 4.3 over the first search done. Nevertheless, the most recent orbital model for the source is still consistent with our limit from pulsar timing array data. In addition, we are able to quantify the improvement made by the inclusion of source properties gleaned from electromagnetic data to `blind' pulsar timing array searches. With these methods, it is apparent that it is not necessary to obtain exact a priori knowledge of the period of a binary to gain meaningful astrophysical inferences.Comment: 14 pages, 6 figures. Accepted by Ap

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Greed Is Good: Exploration and Exploitation Trade-offs in Bayesian Optimisation

The performance of acquisition functions for Bayesian optimisation to locate the global optimum of continuous functions is investigated in terms of the Pareto front between exploration and exploitation. We show that Expected Improvement (EI) and the Upper Confidence Bound (UCB) always select solutions to be expensively evaluated on the Pareto front, but Probability of Improvement is not guaranteed to do so and Weighted Expected Improvement does so only for a restricted range of weights. We introduce two novel ϵ-greedy acquisition functions. Extensive empirical evaluation of these together with random search, purely exploratory, and purely exploitative search on 10 benchmark problems in 1 to 10 dimensions shows that ϵ-greedy algorithms are generally at least as effective as conventional acquisition functions (e.g. EI and UCB), particularly with a limited budget. In higher dimensions ϵ-greedy approaches are shown to have improved performance over conventional approaches. These results are borne out on a real world computational fluid dynamics optimisation problem and a robotics active learning problem. Our analysis and experiments suggest that the most effective strategy, particularly in higher dimensions, is to be mostly greedy, occasionally selecting a random exploratory solution

Evaluation of fluoropyruvate as nucleophile in reactions catalysed by N-acetyl neuraminic acid lyase variants: Scope, limitations and stereoselectivity

The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90:10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30:70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied. Using fluoropyruvate and (2R,3S)- or (2S,3R)-2,3-dihydroxy-4-oxo-N,N-dipropylbutanamide as substrates, it was possible to obtain three of the four possible diastereomeric products; for each product, the ratio of anomeric and pyranose/furanose forms was determined. The crystal structure of S. aureus NAL in complex with fluoropyruvate was determined, assisting rationalisation of the stereochemical outcome of C-C bond formation

MRI directed multidisciplinary team preoperative treatment strategy: the way to eliminate positive circumferential margins?

Histopathological audit of positive circumferential resection margins (CRMs) can be used as a surrogate measure of the success of rectal cancer treatment. We audited CRM involvement in rectal cancer patients and the impact of the multidisciplinary team (MDT) on implementing a magnetic resonance imaging (MRI)-based preoperative treatment strategy. Data were collected on all newly diagnosed rectal cancer patients treated in our network between January 1999 and December 2002. Data were analysed for MRI prediction and histopathological assessment of CRM together with the MDT meeting treatment decisions. The CRM+ve rate of those discussed at MDT vs those not discussed were compared. We re-audited the CRM+ve rates 1 year after introducing a policy of mandatory preoperative MRI-based MDT discussion. Of the 298 patients diagnosed with rectal cancer, 39 (13%) were deemed palliative, 178 underwent surgery alone and 81 underwent neoadjuvant therapy. Of these, 62 out of 178 patients underwent surgery alone without MRI-based MDT discussion resulting in positive CRM in 16 cases (26%) as compared to 1 out of 116 (1%) in those patients with MDT discussion of MRI. Overall CRM+ve rate in all nonpalliative patients with or without MDT discussion was 12.5% (32 out of 256), significantly lower than the <20% rate (P<0.001) quoted in national guidelines. Re-audit in 98 consecutive patients following a change of policy produced a lower CRM+ve rate of 3% (1 out of 37) for all surgery alone patients and an overall CRM+ve rate of 7% (5 out of 70). In conclusion, MDT discussion of MRI and implementation of a preoperative treatment strategy results in significantly reduced positive CRM in rectal cancer patients

The NANOGrav 11-year Data Set: High-precision Timing of 45 Millisecond Pulsars

We present high-precision timing data over time spans of up to 11 years for 45 millisecond pulsars observed as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project, aimed at detecting and characterizing low-frequency gravitational waves. The pulsars were observed with the Arecibo Observatory and/or the Green Bank Telescope at frequencies ranging from 327 MHz to 2.3 GHz. Most pulsars were observed with approximately monthly cadence, and six high-timing-precision pulsars were observed weekly. All were observed at widely separated frequencies at each observing epoch in order to fit for time-variable dispersion delays. We describe our methods for data processing, time-of-arrival (TOA) calculation, and the implementation of a new, automated method for removing outlier TOAs. We fit a timing model for each pulsar that includes spin, astrometric, and (for binary pulsars) orbital parameters; time-variable dispersion delays; and parameters that quantify pulse-profile evolution with frequency. The timing solutions provide three new parallax measurements, two new Shapiro delay measurements, and two new measurements of significant orbital-period variations. We fit models that characterize sources of noise for each pulsar. We find that 11 pulsars show significant red noise, with generally smaller spectral indices than typically measured for non-recycled pulsars, possibly suggesting a different origin. A companion paper uses these data to constrain the strength of the gravitational-wave background

Generation of Human CEACAM1 Transgenic Mice and Binding of Neisseria Opa Protein to Their Neutrophils

Human CEACAM1 is a cell-cell adhesion molecule with multiple functions including insulin clearance in the liver, vasculogenesis in endothelial cells, lumen formation in the mammary gland, and binding of certain human pathogens.Three genomic BAC clones containing the human CEACAM1 gene were microinjected into pronuclei of fertilized FVB mouse oocytes. The embryos were implanted in the oviducts of pseudopregnant females and allowed to develop to term. DNA from newborn mice was evaluated by PCR for the presence of the human CEACAM1 gene. Feces of the PCR positive offspring screened for expression of human CEACAM1. Using this assay, one out of five PCR positive lines was positive for human CEACAM1 expression and showed stable transmission to the F1 generation with the expected transmission frequency (0.5) for heterozygotes. Liver, lung, intestine, kidney, mammary gland, and prostate were strongly positive for the dual expression of both murine and human CEACAM1 and mimic that seen in human tissue. Peripheral blood and bone marrow granulocytes stained strongly for human CEACAM1 and bound Neisseria Opa proteins similar to that in human neutrophils.These transgenic animals may serve as a model for the binding of human pathogens to human CEACAM1