Model-based asymptotically optimal dispersion measure correction for pulsar timing

In order to reach the sensitivity required to detect gravitational waves, pulsar timing array experiments need to mitigate as much noise as possible in timing data. A dominant amount of noise is likely due to variations in the dispersion measure. To correct for such variations, we develop a statistical method inspired by the maximum likelihood estimator and optimal filtering. Our method consists of two major steps. First, the spectral index and amplitude of dispersion measure variations are measured via a time-domain spectral analysis. Second, the linear optimal filter is constructed based on the model parameters found in the first step, and is used to extract the dispersion measure variation waveforms. Compared to current existing methods, this method has better time resolution for the study of short timescale dispersion variations, and generally produces smaller errors in waveform estimations. This method can process irregularly sampled data without any interpolation because of its time-domain nature. Furthermore, it offers the possibility to interpolate or extrapolate the waveform estimation to regions where no data is available. Examples using simulated data sets are included for demonstration.Comment: 15 pages, 15 figures, submitted 15th Sept. 2013, accepted 2nd April 2014 by MNRAS. MNRAS, 201

An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a

Many low-penetrance breast cancer susceptibility loci are found to be located in non-protein-coding regions, suggesting their involvement in gene expression regulation. We identified the human/rat-conserved breast cancer susceptibility locus MCS5A/Mcs5a. This locus has been shown to act in a non-mammary cell-autonomous fashion through the immune system. The resistant Mcs5a allele from the Wistar–Kyoto (WKy) rat strain consists of two non-protein-coding genetic elements that must be located on the same chromosome to elicit the phenotype. In this study, we show the presence of a conserved higher order chromatin structure in MCS5A/Mcs5a located in between the synthetically interacting genetic elements. The looped elements are shown to be bound by CTCF and cohesin. We identify the downregulation of Fbxo10 expression in T cells as a strong candidate mechanism through which the interacting genetic elements of the resistant Mcs5a allele modulate mammary carcinoma susceptibility. Finally, we show that the human MCS5A polymorphisms associated with breast cancer risk are located at both sides of the looped structure and functionally interact to downregulate transcriptional activity, similar to rat Mcs5a. We propose a mechanistic model for MCS5a/Mcs5a in which a CTCF-mediated insulator loop encompassing the TOMM5/Tomm5 gene, resides in between and brings into closer physical proximity the synthetically and functionally interacting resistant genetic variants

A VLT VIMOS integral field spectroscopic study of perturbed blue compact galaxies: UM 420 and UM 462

We report on optical integral field spectroscopy of two unrelated blue compact galaxies mapped with the 13 x 13 arcsec^2 VIMOS integral field unit at a resolution of 0.33 x 0.33 arcsec^2. Continuum and background subtracted emission line maps in the light of [O III] 5007, H-alpha, and [N II] 6584 are presented. Both galaxies display signs of ongoing perturbation and/or interaction. UM 420 is resolved for the first time to be a merging system composed of two starbursting components with an 'arm-like' structure associated with the largest component. UM 462 which is a disrupted system of irregular morphology is resolved into at least four starbursting regions. Maps of the H-alpha radial velocity and FWHM are discussed. No underlying broad line region was detected from either galaxy as the emission lines are well-fitted with single Gaussian profiles only. Electron temperatures and densities as well as the abundances of helium, oxygen, nitrogen, and sulphur were computed from spectra integrated over the whole galaxies and for each area of recent star formation. Maps of the O/H ratio are presented: these galaxies show oxygen abundances that are ~20 per cent solar. No evidence of substantial abundance variations across the galaxies that would point to significant nitrogen or oxygen self-enrichment is found (<0.2 dex limit). Contrary to previous observations, this analysis does not support the classification of these BCGs as Wolf-Rayet galaxies as the characteristic broad emission line features have not been detected in our spectra. Baldwin-Phillips-Terlevich emission line ratio diagrams which were constructed on a pixel by pixel basis indicate that the optical spectra of these systems are predominantly excited by stellar photoionization.Comment: 19 pages, 14 figure

Elevated Levels of the Polo Kinase Cdc5 Override the Mec1/ATR Checkpoint in Budding Yeast by Acting at Different Steps of the Signaling Pathway

Checkpoints are surveillance mechanisms that constitute a barrier to oncogenesis by preserving genome integrity. Loss of checkpoint function is an early event in tumorigenesis. Polo kinases (Plks) are fundamental regulators of cell cycle progression in all eukaryotes and are frequently overexpressed in tumors. Through their polo box domain, Plks target multiple substrates previously phosphorylated by CDKs and MAPKs. In response to DNA damage, Plks are temporally inhibited in order to maintain the checkpoint-dependent cell cycle block while their activity is required to silence the checkpoint response and resume cell cycle progression. Here, we report that, in budding yeast, overproduction of the Cdc5 polo kinase overrides the checkpoint signaling induced by double strand DNA breaks (DSBs), preventing the phosphorylation of several Mec1/ATR targets, including Ddc2/ATRIP, the checkpoint mediator Rad9, and the transducer kinase Rad53/CHK2. We also show that high levels of Cdc5 slow down DSB processing in a Rad9-dependent manner, but do not prevent the binding of checkpoint factors to a single DSB. Finally, we provide evidence that Sae2, the functional ortholog of human CtIP, which regulates DSB processing and inhibits checkpoint signaling, is regulated by Cdc5. We propose that Cdc5 interferes with the checkpoint response to DSBs acting at multiple levels in the signal transduction pathway and at an early step required to resect DSB ends

The Lyman break analogue Haro 11: spatially resolved chemodynamics with VLT FLAMES

Using VLT/Fibre Large Array Multi Element Spectrograph (FLAMES) optical integral field unit observations, we present the first spatially resolved spectroscopic study of the well-known blue compact galaxy Haro 11, thought to be a local analogue to high-redshift Lyman break galaxies. Haro 11 displays complex emission line profiles, consisting of narrow (full width at half-maximum, FWHM ≲ 200 km s-1) and broad (FWHM ∼ 200–300 km s-1) components. We identify three distinct emission knots kinematically connected to one another. A chemodynamical analysis is presented, revealing that spatially resolved ionic and elemental abundances do not agree with those derived from integrated spectra across the galaxy. We conclude that this is almost certainly due to the surface brightness weighting of electron temperature in integrated spectra, leading to higher derived abundances. We find that the eastern knot has a low gas density, but a higher temperature (by ∼4000 K) and consequently an oxygen abundance ∼0.4 dex lower than the neighbouring regions. A region of enhanced N/O is found specifically in Knot C, confirming previous studies that found anomalously high N/O ratios in this system. Maps of the Wolf–Rayet (WR) feature at 4686 Å reveal large WR populations (∼900–1500 stars) in Knots A and B. The lack of WR stars in Knot C combined with an age of ∼7.4 Myr suggests that a recently completed WR phase may be responsible for the observed N/O excess. Conversely, the absence of N-enriched gas and strong WR emission in Knots A and B suggests that we are observing these regions at an epoch where stellar ejecta has yet to cool and mix with the interstellar medium

A Key Role for E-cadherin in Intestinal Homeostasis and Paneth Cell Maturation

E-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn's disease. To genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen. These results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

Pacing and Decision Making in Sport and Exercise: The Roles of Perception and Action in the Regulation of Exercise Intensity

In pursuit of optimal performance, athletes and physical exercisers alike have to make decisions about how and when to invest their energy. The process of pacing has been associated with the goal-directed regulation of exercise intensity across an exercise bout. The current review explores divergent views on understanding underlying mechanisms of decision making in pacing. Current pacing literature provides a wide range of aspects that might be involved in the determination of an athlete's pacing strategy, but lacks in explaining how perception and action are coupled in establishing behaviour. In contrast, decision-making literature rooted in the understanding that perception and action are coupled provides refreshing perspectives on explaining the mechanisms that underlie natural interactive behaviour. Contrary to the assumption of behaviour that is managed by a higher-order governor that passively constructs internal representations of the world, an ecological approach is considered. According to this approach, knowledge is rooted in the direct experience of meaningful environmental objects and events in individual environmental processes. To assist a neuropsychological explanation of decision making in exercise regulation, the relevance of the affordance competition hypothesis is explored. By considering pacing as a behavioural expression of continuous decision making, new insights on underlying mechanisms in pacing and optimal performance can be developed. © 2014 Springer International Publishing Switzerland

Federated learning enables big data for rare cancer boundary detection.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing