New Coordinates for the Amplitude Parameter Space of Continuous Gravitational Waves

The parameter space for continuous gravitational waves (GWs) can be divided into amplitude parameters (signal amplitude, inclination and polarization angles describing the orientation of the source, and an initial phase) and phase-evolution parameters. The division is useful in part because the Jaranowski-Krolak-Schutz (JKS) coordinates on the four-dimensional amplitude parameter space allow the GW signal to be written as a linear combination of four template waveforms with the JKS coordinates as coefficients. We define a new set of coordinates on the amplitude parameter space, with the same properties, which is more closely connected to the physical amplitude parameters. These naturally divide into two pairs of Cartesian-like coordinates on two-dimensional subspaces, one corresponding to left- and the other to right-circular polarization. We thus refer to these as CPF (circular polarization factored) coordinates. The corresponding two sets of polar coordinates (known as CPF-polar) can be related in a simple way to the physical parameters. We illustrate some simplifying applications for these various coordinate systems, such as: a calculation of Jacobians between various coordinate systems; an illustration of the signal coordinate singularities associated with left- and right-circular polarization, which correspond to the origins of the two two-dimensional subspaces; and an elucidation of the form of the log-likelihood ratio between hypotheses of Gaussian noise with and without a continuous GW signal. These are used to illustrate some of the prospects for approximate evaluation of a Bayesian detection statistic defined by marginalization over the physical parameter space. Additionally, in the presence of simplifying assumptions about the observing geometry, we are able to explicitly evaluate the integral for the Bayesian detection statistic, and compare it to the approximate results.Comment: REVTeX, 18 pages, 8 image files included in 7 figure

Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants

We recently mapped a genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes (T1D) diagnosed below the age of 7 years between the PTPRK and thymocyte-selection-associated (THEMIS) genes. As the thymus plays a central role in shaping the T cell repertoire, we aimed to identify the most likely causal genetic factors behind this association using thymocyte genomic data. In four thymocyte populations, we identified 253 DNA sequence motifs underlying histone modifications. The G insertion allele of rs138300818, associated with protection from diabetes, created thymocyte motifs for multiple histone modifications and thymocyte types. In a parallel approach to identifying variants that alter transcription factor binding motifs, the same variant disrupted a predicted motif for Rfx7, which is abundantly expressed in the thymus. Chromatin state and RNA sequencing data suggested strong transcription overlapping rs138300818 in fetal thymus, while expression quantitative trait locus and chromatin conformation data associate the insertion with lower THEMIS expression. Extending the analysis to other T1D loci further highlighted rs66733041 affecting the GATA3 transcription factor binding in the AFF3 locus. Taken together, our results support a role for thymic THEMIS gene expression and the rs138300818 variant in promoting the development of early-onset T1D.Peer reviewe

Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients.

Context:In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown.Objective:The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement.Design and Setting:This was a prospective observational study in the setting of US clinical practices.Patients and Outcome Measures:AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates.Results:After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects.Conclusions:In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement

The Mock LISA Data Challenges: from Challenge 3 to Challenge 4

The Mock LISA Data Challenges are a program to demonstrate LISA data-analysis capabilities and to encourage their development. Each round of challenges consists of one or more datasets containing simulated instrument noise and gravitational waves from sources of undisclosed parameters. Participants analyze the datasets and report best-fit solutions for the source parameters. Here we present the results of the third challenge, issued in Apr 2008, which demonstrated the positive recovery of signals from chirping Galactic binaries, from spinning supermassive--black-hole binaries (with optimal SNRs between ~ 10 and 2000), from simultaneous extreme-mass-ratio inspirals (SNRs of 10-50), from cosmic-string-cusp bursts (SNRs of 10-100), and from a relatively loud isotropic background with Omega_gw(f) ~ 10^-11, slightly below the LISA instrument noise.Comment: 12 pages, 2 figures, proceedings of the 8th Edoardo Amaldi Conference on Gravitational Waves, New York, June 21-26, 200

The Samurai Project: verifying the consistency of black-hole-binary waveforms for gravitational-wave detection

We quantify the consistency of numerical-relativity black-hole-binary waveforms for use in gravitational-wave (GW) searches with current and planned ground-based detectors. We compare previously published results for the $(\ell=2,| m | =2)$ mode of the gravitational waves from an equal-mass nonspinning binary, calculated by five numerical codes. We focus on the 1000M (about six orbits, or 12 GW cycles) before the peak of the GW amplitude and the subsequent ringdown. We find that the phase and amplitude agree within each code's uncertainty estimates. The mismatch between the $(\ell=2,| m| =2)$ modes is better than $10^{-3}$ for binary masses above $60 M_{\odot}$ with respect to the Enhanced LIGO detector noise curve, and for masses above $180 M_{\odot}$ with respect to Advanced LIGO, Virgo and Advanced Virgo. Between the waveforms with the best agreement, the mismatch is below $2 \times 10^{-4}$. We find that the waveforms would be indistinguishable in all ground-based detectors (and for the masses we consider) if detected with a signal-to-noise ratio of less than $\approx14$, or less than $\approx25$ in the best cases.Comment: 17 pages, 9 figures. Version accepted by PR

Observational Limit on Gravitational Waves from Binary Neutron Stars in the Galaxy

Using optimal matched filtering, we search 25 hours of data from the LIGO 40-meter prototype laser interferometric gravitational-wave detector for gravitational-wave chirps emitted by coalescing binary systems within our Galaxy. This is the first test of this filtering technique on real interferometric data. An upper limit on the rate R of neutron star binary inspirals in our Galaxy is obtained: with 90% confidence, R< 0.5/hour. Similar experiments with LIGO interferometers will provide constraints on the population of tight binary neutron star systems in the Universe.Comment: RevTeX, minor revisions, exactly as published in PRL 83 (1999) p1498, 4 pages, 2 figures include

Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome

Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy.This work was supported by the JDRF UK Centre for Diabetes Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003), the Wellcome Trust (WT061858/091157) and the NIHR Cambridge Biomedical Research Centre (CBRC). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140).This is the author accepted manuscript. The final version is available from the American Diabetes Association via http://dx.doi.org/10.2337/db15-051

IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients.

AIMS/HYPOTHESIS: Type 1 diabetes results from the autoimmune destruction of insulin-secreting pancreatic beta cells by T cells. Despite the established role of T cells in the pathogenesis of the disease, to date, with the exception of the identification of islet-specific T effector (Teff) cells, studies have mostly failed to identify reproducible alterations in the frequency or function of T cell subsets in peripheral blood from patients with type 1 diabetes. METHODS: We assessed the production of the proinflammatory cytokines IL-21, IFN-γ and IL-17 in peripheral blood mononuclear cells from 69 patients with type 1 diabetes and 61 healthy donors. In an additional cohort of 30 patients with type 1 diabetes and 32 healthy donors, we assessed the frequency of circulating T follicular helper (Tfh) cells in whole blood. IL-21 and IL-17 production was also measured in peripheral blood mononuclear cells (PBMCs) from a subset of 46 of the 62 donors immunophenotyped for Tfh. RESULTS: We found a 21.9% (95% CI 5.8, 40.2; p = 3.9 × 10(-3)) higher frequency of IL-21(+) CD45RA(-) memory CD4(+) Teffs in patients with type 1 diabetes (geometric mean 5.92% [95% CI 5.44, 6.44]) compared with healthy donors (geometric mean 4.88% [95% CI 4.33, 5.50]). Consistent with this finding, we found a 14.9% increase in circulating Tfh cells in the patients (95% CI 2.9, 26.9; p = 0.016). CONCLUSIONS/INTERPRETATION: These results indicate that increased IL-21 production is likely to be an aetiological factor in the pathogenesis of type 1 diabetes that could be considered as a potential therapeutic target.This work was supported by the JDRF UK Centre for Diabetes - Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003) in collaboration with M. Peakman and T. Tree at King’s College London, the JDRF, the Wellcome Trust (WT; WT061858/091157 and 083650/Z/07/Z) and the National Institute for Health Research Cambridge Biomedical Research Centre (CBRC). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). RCF is funded by a JDRF post-doctoral fellowship (3-2011-374). CW is funded by the Wellcome Trust (088998). The funding organisations had no involvement with the design and conduct of the study; collection,management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.This is the final published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00125-015-3509-8